ABSTRACT

The adrenal gland in conjunction with the pituitary gland is one of the major components of the endocrine system and regulates blood volume, blood pressure, serum electrolytes, and stress responses. Dysfunction of the adrenal glands may be related to diseases of the adrenal glands or pituitary gland. Adrenal disorders may present either due to structural or functional abnormalities. In the tropical countries, adrenal insufficiency is primarily due to adrenal infection by tuberculosis, adrenal mycosis infections, and adrenal hemorrhages. HIV (Human immunodeficiency virus) related adrenal problems are also common. Adrenal dysfunction due to pituitary disorders still occur frequently in tropical region and include Sheehan’s syndrome, vasculotoxic snake bite, and thalassemia. Adrenal hormone excess typically occurs secondary to exogenous glucocorticoid use. Adrenal disorders that occur in the developed world occur with similar frequencies in tropical regions.

INTRODUCTION  

PRIMARY ADRENAL INSUFFICIENCY  

The causes of primary adrenal insufficiency that are more frequent in tropical regions include infection of the adrenal glands by tuberculosis or mycotic infections. In addition, autoimmune Addison’s disease or adrenal failure as a component of polyglandular syndromes are equally prevalent in tropical regions as is in other parts of the world. 

Adrenal Gland Tuberculosis

Adrenal gland tuberculosis or Tuberculous adrenalitis is the result of infection of adrenal gland by mycobacterium tuberculosis. The infection causes a destructive lesion of the adrenal cortex with uncertain chances of recovery and remains one of the most important causes of Addison’s disease in the tropical countries (1). In fact, the adrenal glands are the most common endocrine organs to be involved in tuberculosis (2). Adrenal gland tuberculosis occurs almost always secondarily due to the hematogenous spread of the bacilli to the gland with the primary focus in lung. Adrenal failure or Addison’s disease clinically manifest when at least 90% of the gland has been destroyed (1,2,3). Though classically the adrenal cortex is involved, the medulla also may be involved in many cases of adrenal tuberculosis (3,4).

PATHOPHYSIOLOGY 

It is interesting to know why the adrenal glands are susceptible to infections. In fact, adrenal gland infections are common in response to a distant infection elsewhere in the body and in disseminated infection. Autopsy examination revealed that the prevalence of adrenal tuberculosis is about 6% in patients with active tuberculosis (4). However, subclinical adrenal dysfunction may be present in about 60-70% of patients with active tuberculosis (5). In any of these situations, there is an exaggerated response of the hypothalamo-pituitary-adrenal axis to produce excess cortisol in response to the stress of infection. This stress induced hypercortisolemia shifts the balance in the Th1/Th2 cell ratio towards a Th2 response (6). This T cell dysfunction (which is primarily responsible for cell mediated immunity) and low DHEA levels increases the host susceptibility to infection to mycobacterium tuberculosis and other organisms (6). Low DHEAS levels have been documented in tuberculosis (1,6). In addition, endotoxin released in response to the hyperactive HPA axis can cause pathological changes in the adrenal glands to increase the susceptibility to infection (7). The intrinsically rich vascularity of the adrenal glands promotes all of these pathophysiological events.

Histopathologically, four classic patterns have been described in adrenal tuberculosis (3). These are:  granuloma (caseating or non-caseating), enlargement of the gland with destruction by inflammatory granuloma, mass lesions due to cold abscesses, and adrenal atrophy due to fibrosis related to chronic infection. Caseating granuloma is the commonest one and this is identified in about 70% of cases (4). However, granuloma with typical presence of Langhan’s giant cell are less common and identified in less than 50% of cases (4), probably due to anti-inflammatory effects of local glucocorticoids. Calcification of the gland is a common but it is present in other chronic infections of the adrenal glands (3). In about 25 % cases the infection may be unilateral (1).

PRESENTATION

Typical symptoms of adrenal gland tuberculosis in a patient with diagnosed tuberculosis (whether or not on anti-tubercular chemotherapy) are mucocutaneous pigmentation in association with chronic ill health, vomiting, postural hypotension, and anorexia (3). The features are similar to Addison’s disease due to other conditions. As the features of progressively evolving adrenal hypofunction are mostly nonspecific, a high index of suspicion is necessary in subjects with diagnosed active tuberculosis especially when pigmentation is absent. However clinical manifestations may take months to years to become apparent.

The patient may also present rarely with frank adrenal crisis with hypotension, hyponatremia, hyperkalemia, and low serum cortisol levels. The crisis may even be precipitated after administration of rifampicin which increases the hepatic metabolism of cortisol in the background of subclinical adrenal dysfunction (8). 

Adrenal tuberculosis may also present as an adrenal incidentaloma. Nonspecific abdominal pain, weight loss, dizziness, and vomiting may lead to imaging of the abdomen which may reveal an incidental adrenal mass often with calcification. The differential diagnosis of Addison’s disease with adrenal enlargement includes (apart from tuberculosis) malignancy, fungal infections, hemorrhage, amyloidosis, sarcoidosis, etc. (3).

Subclinical adrenal dysfunction is also very common and should be actively sought in all cases of active tuberculosis (5).

INVESTIGATIONS

Laboratory Studies

Common laboratory findings include anemia, hyponatremia, and hyperkalemia. In the presence of a positive Mantoux test in association with typical clinical manifestations of adrenal hypofunction, adrenal tuberculosis must be ruled out. Adrenal insufficiency should be ruled out by using a standard protocol. Serum cortisol levels <5 µg/dL and a plasma ACTH more than 2-fold the upper limit of the reference range is suggestive of primary adrenal insufficiency (9). The serum cortisol may remain in the low-normal to mid-normal range in many cases.  However, a standard dose (250 µg) intravenous cosyntropin (Synacthen) stimulation test establishes the diagnosis of adrenal insufficiency when the peak level of cortisol remains below 18 µg/d (9). Random cortisol levels, though useful during an acute crisis, is not usually sufficient to rule out adrenal insufficiency (9). Documentation of subclinical adrenal dysfunction may reveal mineralocorticoid deficiency alone (as demonstrated by raised plasma rennin activity) when stimulated cortisol is within the normal range (8).

Imaging of Adrenal Glands

CT scan of the abdomen is the most important non-invasive investigation with a very good spatial resolution to diagnose adrenal tuberculosis. The findings are usually bilateral and vary with the duration of the disease before diagnosis (1, 3). The most common early findings during the initial 2 years include a mass lesion with smooth adrenal contour preserved. The glands may show central or patchy hypodensity corresponding to areas of caseous necrosis (3). On contrast administration there is peripheral rim enhancement. Calcification is not a common feature in early tuberculosis (3).

With chronic infection, the adrenal glands become small and shrunken, often with associated calcifications and the margins become irregular (3). Though prevalence and intensity of calcification increases with the duration of tuberculosis, this is not a specific finding and may be associated with other conditions.

Though MRI is also done in many cases, this imaging modality has limitations to assess calcification. However, T1 weighted image shows hypointense or isointense areas and T2 weighted image shows hyperintense areas because of necrosis (3).

Percutaneous FNA/ TB PCR 

 For confirmation of adrenal tuberculosis tissue diagnosis is required. CT scan guided fine needle aspiration from the adrenal gland is necessary to obtain adequate tissue specimens (3, 10). Pathological and microbiological confirmation is necessary, especially where there is isolated adrenal involvement. However, it should be remembered that PCR and culture of these specimens for tuberculosis bacilli are not consistently positive (3). Hence a combination of histopathology, PCR, and culture may be necessary to confirm the diagnosis (3). However, routine search for pulmonary tuberculosis with necessary investigations is mandatory.

TREATMENT

Treatment of adrenal insufficiency in tuberculosis requires administration of both glucocorticoids and mineralocorticoids. As the medulla is frequently involved, patients may require higher doses for maintenance of blood pressure. At the same time, rifampicin used in the anti-tubercular regimen is a potent hepatic enzyme inducer and accelerates cortisol metabolism. This also may necessitate a higher dose of glucocorticoids for adequate treatment. However, aldosterone is less likely to be involved. Adrenal crisis is also reported to occur following the administration of rifampicin (11).

Therapy is monitored with blood pressure, body weight, well-being, serum electrolytes and blood glucose. Patients should be also be monitored for over treatment with glucocorticoids with weight gain, blood pressure, decreasing bone mineral density, and other manifestations of Cushing’s syndrome. All subjects should carry a ‘steroid card’ and should be advised strictly on how to increase the dose of glucocorticoid in stressful situations such as fever, infection, vomiting, trauma, etc.

PROGNOSIS FOR ADRENAL FUNCTION RECOVERY

Chances of adrenal recovery with anti-tuberculosis therapy are uncertain and unpredictable. When the disease is diagnosed late, the glandular destruction is usually significant and the gland becomes atrophic, and anti-tuberculosis therapy does not lead to a recovery of adrenal function (12, 13). If therapy is started early before the gland is destroyed recovery may occur (14, 15). It is also suggested that if the gland size remains the same on subsequent follow up CT scans, it is prudent to follow up the patient for adrenal function recovery.

Adrenal Mycosis

HISTOPLASMOSIS 

Adrenal Histoplasmosis caused by the dimorphic fungus Histoplasma capsulatum, is a recognized cause of adrenal insufficiency. Though this opportunistic pathogen is known to affect immunocompromised individuals predominantly (16), it can rarely infect immunocompetent individuals (16, 17).  This is the most fungal infection of the adrenal glands (16, 18).

Involvement of the adrenals can occur during disseminated infection or many years after disease resolution (18). Adrenal involvement can vary from an asymptomatic milder form to a very severe form that presents with extensive bilateral granulomatous involvement of the entire adrenal gland with calcified lesions culminating in acute adrenal insufficiency (18, 19). Rarely the involvement can be unilateral (17). The common differential diagnosis includes tuberculosis, other fungal infections, adrenal metastasis, primary adrenal malignancy, and primary adrenal lymphoma (16). In immunocompetent individuals it commonly presents with a unilateral or bilateral adrenal mass with constitutional symptoms.

The hypothesis for why histoplasmosis involves the adrenal glands with increased frequency includes the local high levels of glucocorticoids in association with a relative paucity of reticulo-endothelial cells within the adrenal gland (6). The gland is destroyed by direct infection that leads to local ischemia and infarction due to perivasculitis, and caseation (6).

Diagnosis depends on imaging studies with pathological confirmation. CT scan of the adrenal glands typically reveals symmetric enlargement with central hypodensity and characteristic peripheral rim like enhancement (20). Frequently calcification is also present, particularly during the healing phase (20). Percutaneous ultrasound or CT guided fine-needle aspiration or biopsy is necessary for tissue diagnosis (18). The characteristic cytopathological findings are the presence of numerous small oval yeast like structures inside the cytoplasm of macrophages (16). On a necrotic background, this yeast like structures inside the macrophages is surrounded by a clear ring of space resembling a capsule. However, the gold standard for diagnosis is documentation of the organism in the culture of pathological specimen (16). Bhansali et al reported a high uptake in adrenal glands in FDG-PET scan in patients with adrenal histoplasmosis (17). 

Treatment for adrenal histoplasmosis depends on the severity of the infection and the condition of the patient. For severe infection in critically ill patient’s amphotericin B is used initially followed by long-term therapy with oral itraconazole (16). Parenteral liposomal amphotericin B is given 3mg/kg body weight for 2 weeks (17). The duration of therapy with itraconazole varies from six months to two years depending on the patient’s condition. For mild to-moderate histoplasmosis, the recommended treatment is itraconazole. The recommended dose is 200 mg twice daily given for 12 months (16). When itraconazole is used, liver enzymes should be monitored on a regular basis (18).  Treatment for adrenal insufficiency follows the same principles as described earlier.

Though the remission rate from adrenal histoplasmosis is high with long-term oral itraconazole, adrenal insufficiency rarely resolves and reversal of adrenal dysfunction can be seen only in some patients after prolonged antifungal therapy (21).  However, histoplasma in adrenals is reported to persist even 7 years after antifungal therapy (22). 

OTHER FUNGAL INFECTIONS

Paracoccidioidomycosis Brasiliensis

Paracoccidioidomycosis brasiliensis is a dimorphic fungus and can cause chronic, progressive, suppurative and granulomatous disease which can lead to adrenal insufficiency (3). The disease is endemic in Latin America. Humans are the accidental host for the organism and females are rarely affected (23). Smoking and alcohol increase the risk. The lungs are the usual portals of entry. Juvenile forms of the disease are also known (23). Apart from frank adrenal crisis, it can present as progressive constitutional symptoms, hyperpigmentation, and low blood pressure with postural drop and bilateral adrenal enlargement in imaging studies with frank adrenal calcification detected by CT scans (24, 25). Histopathology with GMS stain shows multiple budding yeast with steering wheels appearance which is consistent with Paracoccidioides brasiliensis (24). However, confirmation of the organism by culture material is the gold standard for diagnosis. Serology for antibody detection is also useful in the diagnosis. Diagnosis and treatment of adrenal insufficiency is not different than described above for histoplasmosis. P. brasiliensis primarily causes adrenal destruction by embolic infection of small vessels by large fungal cells and granuloma formation (3). Subjects who receive early antifungals with itraconazole over a 1–2-year period may have a full recovery of adrenal function by preventing fungal embolism in adrenal gland vasculature and reducing ischemic necrotic destruction of the gland (3). Hence an early diagnosis is crucial for preventing the progression of adrenal dysfunction. However, persistence of high antibody titer against paracoccidioidomycosis at the end of treatment or during follow-up is a frequent finding in subjects with paracoccidioidomycosis.

Blastomyces Dermatitidis

Blastomyces dermatitidis is also a dimorphic fungus, which has a strong affinity for the adrenal gland for reasons described earlier. Overt adrenal insufficiency is less common and adrenal Blastomyces dermatitidis typically presents as bilateral adrenal incidentaloma during radiological investigations for other reasons (3). The portal of entry is through the lungs and when there is lymphohematogenous dissemination the disease spreads to other organs (26). In situations when it presents as adrenal insufficiency, the presentation, investigations, and management are similar to those described above. Diagnosis is by fine-needle aspiration guided by ultrasound or CT scan followed by cytologic and histologic examinations. However, the gold standard is fungal culture showing thick-walled, broad-based budding yeast cells (27). Treatment is with long term oral itraconazole. In patients with severe manifestations initial treatment with liposomal amphotericin B for 2 weeks could be used.

Cryptocoocus Neoformans

Cryptocoocus neoformans is an encapsulated yeast-like fungus which infects primarily immunodeficient hosts, particularly subjects infected with HIV or lymphohematogenous malignancies (28). In immunocompromised hosts it usually affects the central nervous system and lungs.  However immune-competent individuals may also suffer adrenal cryptococcosis (29). Adrenal dysfunction is uncommon until almost the whole of adrenal gland is infiltrated with C. neoformans and caseating granulomas. Cryptococcosis is diagnosed by fine-needle aspiration biopsy of the adrenal mass. The serum cryptococcal antigen titer is highly elevated. Treatment is with antifungal therapy with fluconazole and amphotericin B. Adrenal enlargement by Cryptococcus may be completely reversible without any abnormality after antifungal treatment (30). Cases not responsive to anti-fungal therapy have been reported to improve after unilateral or bilateral adrenalectomy (28, 29).

Miscellaneous

Pneumocystis jirovecii (previously known P. carinii) occurs in individuals with advanced HIV due to defects in cell mediated immunity. Spread to other organs including the adrenal glands is also possible (3). Adrenal failure associated with coccidioidomycosis and rarely candidiasis has also been reported.

Adrenal Hemorrhage; the Waterhouse Friderichsen Syndrome

This is a condition in which patient presents with acute hypotension and shock due to adrenal insufficiency arising from acute adrenal hemorrhage. The syndrome is typically related to infection with Neisseria meningitides infection (3). However, this is also known to occur in septicemia due to infections with Staphylococcus aureus, Streptococcus spp, Haemophilus influenzae, Corynebacterium diphtheria, etc. (3). Hence this is more common in the tropical region.  The condition is hypothesized to be due to interplay between endotoxemia and elevated ACTH. The adrenal gland is anatomically prone to hemorrhage as it has three separate arterial supplies and does not have proportional venous drainage (3). In endotoxemia, elevated ACTH increases the blood supply several fold in this compromised anatomical setting. At the same time increased adrenaline secretion in relation to stress leads to constriction of adrenal veins, which further increases this imbalance between arterial supply and venous drainage. Management includes immediate fluid replacement and parenteral glucocorticoids apart from the management of the underlying infection.

SECONDARY ADRENAL INSUFFICIENCY 

Adrenal insufficiency secondary to disorders of pituitary gland is also very common in developing countries in tropical regions.  Secondary adrenal insufficiency caused by pituitary tumors and apoplexy, pituitary surgery, radiation therapy, hypophysitis, various genetic disorders, and withdrawal of exogenous steroids are equally common in tropical regions but certain other disorders like Sheehan’s syndrome, thalassemia, and vasculotoxic snake bite induced pituitary failure are more common in tropical regions.

Sheehan’s Syndrome 

Sheehan’s syndrome consists of various degrees of pituitary insufficiency, which develops as a result of ischemic pituitary necrosis due to severe postpartum hemorrhage. The important pathogenetic/predisposing factors include a small sella, increased pituitary volume, vasospasm induced by postpartum hemorrhage, thrombosis, and probable pituitary autoimmunity (31). In developed countries there has been a drastic reduction in the incidence of Sheehan’s syndrome. This is primarily due to the remarkable improvement in obstetric care and availability of rapid blood transfusion. However, this remains as a major cause of hypopituitarism in the other parts of the world.

CLINICAL FEATURES

Most commonly the disorder presents as a lactation failure in the post-partum state and non-resumption of menses following child birth, which was complicated by massive post-partum hemorrhage leading to hypotension and shock. However, it may very rarely occur without massive bleeding or after normal delivery. Patients may present in the emergency with altered sensorium, loss of consciousness, seizure, shock, intractable vomiting, or more commonly with chronic complaints like asthenia and weakness, dizziness, anorexia, weight loss, nausea, and vomiting with a typical history of failure to resume menses and lactation failure following child birth (31). Apart from anterior pituitary hormone deficiency, symptoms like anemia, pancytopenia, osteoporosis, cognitive impairment, and poor quality of life are also present in these patients (31,32).  Very rarely diabetes insipidus may occur. However, the mean age of the participants may be as late as 40 years or more and the mean interval between inciting event to diagnosis may be as high as 10 years or more (33).

Adrenal insufficiency due to ACTH deficiency is reported to occur in up to 100% of cases (in fact deficiency of all anterior pituitary hormones occur in a variable percentage of patients and may be up to 100%) (32). Weakness, fatigue, and postural drop are common manifestations. Hyponatremia is particularly common in Sheehan’s syndrome, which may be due to glucocorticoids deficiency coupled with increased AVP release as a consequence of reduced blood pressure and cardiac output resulting from glucocorticoid deficiency (32).

DIAGNOSIS

The basal pituitary hormonal levels and those after dynamic tests are beyond the purview of this chapter. However adrenal insufficiency is diagnosed with a morning cortisol level of 3 mcg/dl with low or inappropriately normal ACTH or a cosyntropin stimulated cortisol level <18 mcg/dl. Documentation of growth hormone deficiency does not require a dynamic test in presence of other pituitary hormone deficiencies. Only low age specific and assay specific IGF-1 assay may be sufficient to document adult growth hormone deficiency (AGHD) (34).

The preferred radiological imag­ing is an MRI of hypothalamic pituitary area.  CT scan may also be helpful. MRI findings in Sheehan’s syndrome usually vary with the stages of the disease. In earlier stages of the disease there may be an enlarged pituitary gland with central hypodensity (suggestive of infarction). However, an empty sella (complete or partial) is considered to be a characteristic of Sheehan’s syndrome in established cases (32).

TREATMENT

The acute adrenal crisis in Sheehan’s syndrome is treated with intravenous glucocorticoids. In other patients’ glucocorticoids should be started orally with hydrocortisone 15-25 mg daily in 2-3 divided doses with the higher dose in the morning and a lower dose in the evening (35). Mineralocorticoids are not necessary in general (35). Once daily prednisolone may also be used at a dose of 2.5-5 mg once daily in the early morning. As GH deficiency decreases cortisol clearance, it may necessary to increase the dose of glucocorticoid for those who receive GH treatment (35). Therapy is monitored with blood pressure, body weight, well-being, serum electrolytes, and blood glucose. Patients should be also be monitored for an overdose of glucocorticoids with weight gain, blood pressure, decreased bone mineral density, and other symptoms and signs of Cushing’s syndrome. All subjects with Sheehan’s syndrome should carry a ‘steroid card’ and should be advised strictly on how to increase the dose of glucocorticoid in stressful situation such as fever, infection, vomiting, trauma, etc.

Subjects with Sheehan’s syndrome should also be treated with levothyroxine, combined oral contraceptives according to guideline, calcium and vitamin D supplements, and growth hormone therapy (if possible) according to the protocol of adult growth hormone deficiency.

Viscerotropic Snake Bite

Snakebite is a major public health problem in tropical regions and is considered as one of the most neglected tropical diseases. The development of a Sheehan-like syndrome with chronic hypopituitarism following Russell viper envenomation is fairly common. Hypoadrenalism due to ACTH deficiency is the commonest abnormality (36). However acute hypopituitarism with predominant glucocorticoids deficiency has also been reported (37).

The venom of vipers is vasculotoxic in nature and the clinical features of viper venomation include local cellulitis and tissue necrosis, bleeding manifestations, disseminated intravascular coagulation, shock, and acute kidney injury (AKI) (38). Hypopituitarism is particularly common following vasculotoxic snake bite in subjects who develop AKI requiring hemodialysis. Hypopituitarism can develop as early as 7 days following snake bites and should be evaluated for particularly in younger subjects, especially those requiring increasing number of sessions of hemodialysis and in subjects with abnormal 20 min WBCT (whole blood clotting test) at presentation (36,39). On the other hand, the time of onset/presentation of hypopituitarism following snake bite may be as long as up to 24 years (40). Acute hypopituitarism is thought to occur due to acute damage to the pituitary gland at the time of the precipitating event, but a gradual/slower progression of pituitary damage may occur over years due to other unknown mechanisms (36).

Those who survive acute snake bite may later present with altered sensorium, loss of consciousness, seizure, shock, intractable vomiting, or more commonly with chronic complaints like asthenia and weakness, dizziness, anorexia, weight loss, nausea, vomiting and amenorrhea in females (36).

Variable degrees of hypopituitarism may be present. Cortisol deficiency is reported to be the commonest abnormality. Secondary adrenal insufficiency is diagnosed with a morning cortisol level of 3 mcg/dl with low or inappropriately normal ACTH or a co-syntropin stimulated cortisol level <18 mcg/dl (36). Documentation of growth hormone deficiency is done as mentioned in section of Sheehan’s Syndrome (34).

The preferred radiological imag­ing is the MRI of hypothalamic pituitary area which may show partial or complete empty sella or evidences of old hemorrhage. However, these changes are not present in all cases (41).

Treatment of secondary adrenal insufficiency and other hormone deficiencies are similar to described above. All subjects with hypopituitarism on glucocorticoids supplements should carry a ‘steroid card’ and should be advised on how to increase the dose of glucocorticoid in stressful situation such as fever, infection, vomiting, trauma, etc.

Thalassemia Major

Thalassemia’s are inherited autosomal recessive disorders of hemoglobin synthesis. Thalassemia major is the most severe form of beta thalassemia which involves the beta chain of hemoglobin. Organ dysfunction in thalassemia is principally attributed to excessive iron overload and suboptimal chelation. The precise underlying mechanism of iron overload induced organ dysfunction is not very unclear. The current management of thalassemia includes regular transfusion programs and chelation therapy. Pre-marital counselling and assessment with HPLC to assess the asymptomatic carrier has reduced its prevalence significantly in the developed world. However, this is still a major problem in many parts of the world.  Prevalence of adrenal insufficiency is variable and depends on the severity of iron overload. This secondary hemochromatosis can disrupt adrenal function by affecting the hypothalamic-pituitary-adrenal axis at the hypothalamic or pituitary level (42). In more severe cases primary adrenal failure may supervene due to iron deposition in the adrenal glands (42). Additionally, an extramedullary hematopoietic tumor has been reported in HbE thalassemia and beta thalassemia as non-hormone secretory unilateral or bilateral adrenal enlargement resembling adrenal myelolipoma (43). 

Biochemical adrenal insufficiency is reported to occur from   0% to 45% of subjects with thalassemia major (42), but adrenal crisis or clinical adrenal insufficiency is extremely uncommon and mostly they are asymptomatic. However, subclinical cortisol deficiency is not uncommon. In this context it should be remembered that mild symptoms of adrenal insufficiency like asthenia, weight loss, or postural drops are frequently overlooked as these features are common in thalassemia subjects with low levels of hemoglobin (42).                           

The unique finding in subjects with thalassemia is the dissociation between adrenal androgen levels with cortisol and aldosterone levels. This paradox is reflected by frequent documentation of low serum DHEA, DHEA-sulfate, androstenedione, and testosterone levels in the presence of normal serum cortisol and aldosterone levels (44). Absence of adrenarche occurring in most adolescents with thalassemia major is probably explained by this phenomenon (45). 

Diagnosis of adrenal dysfunction in thalassemia is similar to other causes of secondary adrenal insufficiency. If the morning cortisol is not unequivocally low, synacthen stimulation test should be done with either the low dose (1 µg) or the standard high dose (250 µg). A peak cortisol level of >18 µg/dL after 30-60 min of intravenous synacthen excludes adrenal insufficiency. Alternately an insulin tolerance test with a similar cut-off may also be done.

Treatment of clinical adrenal insufficiency is similar to that described above. Subjects with subclinical adrenal insufficiency require only steroid coverage during periods of stress.

HIV AND ADRENAL DYSFUNCTION

Endocrine manifestations of HIV infection may include adrenal dysfunction, hypothyroidism, hypogonadism, insulin resistance and diabetes etc. Changes in the HPA (hypothalamic-pituitary-adrenal) axis are the most frequent abnormality (46). Adrenal dysfunction in HIV infection may be a consequence of concomitant systemic illness, opportunistic infections, and neoplasm (47).

Probably the most frequent adrenal abnormality is a stress induced elevation in serum cortisol and ACTH (46). This may be due to activation of the HPA axis due to HIV infection itself or pro-inflammatory cytokines (e.g., IL-1β, IL-6 and TNF-α) (46). Alternately a peripheral increase in the conversion of cortisone to cortisol due to activation of 11-β HSD type 1 in adipose tissue or decrease in cortisol metabolism may be responsible for increased cortisol with subnormal ACTH (46). Tissue hypersensitivity to glucocorticoids is also reported in subjects with HIV-1 infection, which may result in hippocampal atrophy, altered secretion of cytokine/interleukins, etc. (48).

On the other hand, subclinical or clinical adrenal dysfunction can happen in about 10-20% of subjects with advanced disease and multiple co-morbidities when about 80-90% of the gland is destroyed (46). The involvement and destruction by HIV, opportunistic infections, or malignancies in the adrenal glands or the hypothalamus and/or pituitary area can result in either primary or secondary adrenal sufficiency (47).

The opportunistic infections include cytomegalovirus (CMV), Mycobacterium avium-intracellular and M. tuberculosis, fungal infections (such as Histoplasma, Cryptococcus, and Pneumocystis jirovecii), and Toxoplasma gondii (47). Of these opportunistic infections, CMV infection is known to be the commonest etiology with earlier literature reporting Cytomegalovirus adrenalitis in nearly 80 % of cases of HIV infection (46). However, due to improvements in active management of HIV by HAART (highly active anti- retroviral therapy), the prevalence of adrenal insufficiency has decreased over the last two decades.

Medications used for the treatment of HIV infection and its complication may also result in adrenal dysfunction. For example:  Rifampicin used for mycobacterial infection is a known hepatic Cytochrome P 450 (CYP) enzyme inducer and can lower serum cortisol levels by enhanced cortisol metabolism. Ketoconazole used to treat severe mycotic infections inhibits adrenal steroid synthesis and can lead to glucocorticoid deficiency or even adrenal crisis in patients with impaired adrenal reserve (49). Interestingly, ART-related lipodystrophy (dorsocervical fat pad enlargement and visceral adiposity) may mimic Cushing’s syndrome but it is typically not associated with hypercortisolism (49). On the contrary, some protease inhibitors (e.g., ritonavir) used in ART are reported to decrease metabolism of endogenous and exogenously co-administered glucocorticoids, resulting in an iatrogenic Cushing's syndrome.

Tumors of the adrenal gland in HIV infected patients include Kaposi’s sarcoma and high-grade non-Hodgkin’s lymphoma. Kaposi’s sarcoma is secondary to co-infection with the oncogenic human herpes virus type 8 (HHV8) and non-Hodgkin’s lymphoma could be secondary to Epstein-Barr virus (EBV).

Assessment for symptoms of adrenal involvement requires a high degree of suspicion as constitutional symptoms of HIV may mask the features of adrenal insufficiency.  Morning serum cortisol should be done in all cases suspected for adrenal dysfunction. Stress induced hypercortisolemia does not require any further testing and low serum cortisol <5 μg/dl with an elevated ACTH level requires treatment with glucocorticoids and mineralocorticoids. In other cases, synthacthen stimulated cortisol is used to determine the course of treatment. Stimulated cortisol <18 μg/dl, especially if associated with elevated plasma ACTH, should be treated as adrenal insufficiency. Asymptomatic subjects with stimulated serum cortisol <18 μg/dl should be advised to take stress doses of glucocorticoids only as mentioned before.

Diagnosis and management of adrenal disorders in a patient with HIV infection does not differ from that in immunocompetent persons in general.

ADRENAL HORMONE EXCESS SYNDROMES

Glucocorticoid Excess Syndromes 

The primary cause of Cushing’s syndrome, more common in tropical regions, is exogenous glucocorticoids. The background etiology for exogenous steroid usage includes: nephrotic syndrome, rheumatoid arthritis and other collagen vascular disease, bronchial asthma, Graves’ orbitopathy, etc.  Glucocorticoids used as inhalational agent for bronchial asthma, in creams and ointments for eczematous skin lesions may also be responsible. Endogenous steroid excess (Cushing’s disease, ectopic ACTH syndromes, adrenal tumors) are equally common in tropical regions as in other areas of the world.

Often it is a challenge to suspect exogenous glucocorticoid use based on the patient’s history, especially in situations when glucocorticoids were not being used for a therapeutic purpose. Subjects presenting with features suggestive of Cushing’s syndrome should therefore mandatorily undergo testing for basal morning cortisol (with paired ACTH if possible) to rule out exogenous glucocorticoid use. A suppressed morning cortisol and plasma ACTH strongly suggests the diagnosis (50). One important caveat is that prednisolone may cross react with some cortisol assays giving false positive results in some chemiluminescent assay (51). Additionally, if the patient is receiving hydrocortisone, the result will also be fallacious to interpret. It is not uncommon in tropical regions that some form of glucocorticoids is being used in disguise as an alternative medicine for joint pain, respiratory problems, fever, or even as a weight gain therapy for young lean subjects. Hence a more detailed evaluation of the history with leading questions and scrutiny of all past records of medicine, including that of the alternative medicines, may sometimes reveal the offending agent. 

The clinical features that suggest exogenous Cushing’s syndrome are lack of pigmentation and the absence of hypertension and hirsutism (as exogenous Cushing’s syndrome does not contain mineralocorticoids and androgens as opposed to endogenous Cushing’s syndrome). Patients with exogenous Cushing’s syndrome are prone to develop glaucoma, osteoporosis, psychiatric disturbances, etc. (50).

Once diagnosed, these subjects should be advised to withdraw the offending agents and should be given hydrocortisone in the lowest possible dose for preventing adrenal crisis. The withdrawal of hydrocortisone subsequently after 3 months depends on the morning cortisol, after stopping the previous evening dose and subjecting the patient to short synacthen test to assess the recovery of HPA axis. Those with morning cortisol between 5 -18 µ/dl should be advised stress coverage only. For bone protection, all subjects with exogenous Cushing’s syndrome should receive bisphosphonate therapy unless contraindicated (52). Adequate calcium supplements with cholecalciferol should also be used.

For subjects receiving glucocorticoids for therapeutic purpose, it is essential to maintain bone protection, check for secondary diabetes and hypertension, and prevent gastric ulceration. Withdrawal (if at all possible) should be performed very slowly. When the therapeutic steroid reaches the lowest possible dose to prevent crisis, it is converted to equivalent dose of hydrocortisone and the same principle is used as described before.

Licorice Induced Syndrome Of Apparent Mineralocorticoid Excess 

Licorice root extracts are used as a herbal medicine for several conditions like cough, peptic ulceration, etc. Licorice is also used as a sweetener and mouth freshener particularly in tropical regions (53). Licorice possesses some glucocorticoid activity, antiandrogen effect, estrogenic activity, and mineralocorticoid like activity. Subjects consuming excessive licorice may develop hypertension and hypokalemia (53). Sometimes this is severe enough to cause a cardiac arrhythmia. While screening for primary aldosteronism for subjects presenting with hypertension and hypokalemia, plasma aldosterone and plasma rennin activity are found to be suppressed in patients using licorice (53). 

                                                                                                                                                                           The active ingredient of liquorice is glycyrrhizic acid, which is hydrolyzed into glycyrrhetinic acid in vivo. Glycyrrhetinic acid has a very low affinity for the mineralocorticoid receptor but is a potent competitive inhibitor of the enzyme 11β-HSD type 2 which is preferentially expressed in kidney (54). Hence it may cause acquired 11β-HSD type 2 deficiency. The physiological role of the enzyme 11β-HSD type 2 is to inactivate cortisol to cortisone and thereby preventing access of cortisol to mineralocorticoid receptor. Cortisol and aldosterone have equipotent stimulating activity on mineralocorticoid receptor (54). Hence any situation associated with suppressed 11β-HSD type 2 activities may lead to overstimulation of mineralocorticoid receptors by cortisol, leading to hypertension with hypokalemia and metabolic alkalosis. After correction of hypokalemia, the screening test reveals suppressed aldosterone and plasma rennin activity (54). The hypertension is primarily due to sodium and water retention. A careful history for licorice ingestion clinches the diagnosis.

Treatment consists of avoidance of licorice products. In the interim period patients should be treated with oral potassium and spironolactone after the completion of screening of aldosterone rennin ratio (ARR). Withdrawal of licorice, even after prolonged use or ingestion of large amounts, leads to a complete resolution of the symptoms of acquired apparent mineralocorticoid excess (55).

REFERENCES

1. Upadhyay J, Sudhindra P, Abraham G, Trivedi N. Tuberculosis of the adrenal gland: a case report and review of the literature of infections of the adrenal gland. Int J Endocrinol. 2014;2014:876037. doi: 10.1155/2014/876037. Epub 2014 Aug 6. PMID: 25165474; PMCID: PMC4138934.
2. Kelestimur F. The endocrinology of adrenal tuberculosis: the effects of tuberculosis on the hypothalamo-pituitary-adrenal axis and adrenocortical function. J Endocrinol Invest. 2004 Apr;27(4):380-6. doi: 10.1007/BF03351067. PMID: 15233561.
3. Vinnard C, Blumberg EA. Endocrine and Metabolic Aspects of Tuberculosis. Microbiol Spectr. 2017 Jan;5(1):10.1128/microbiolspec.TNMI7-0035-2016. doi: 10.1128/microbiolspec.TNMI7-0035-2016. PMID: 28233510; PMCID: PMC5785104.
4. Lam KY, Lo CY. A critical examination of adrenal tuberculosis and a 28-year autopsy experience of active tuberculosis. Clin Endocrinol (Oxf). 2001 May;54(5):633-9. doi: 10.1046/j.1365-2265.2001.01266.x. PMID: 11380494.
5. Neogi S, Mukhopadhyay P, Sarkar N, Datta PK, Basu M, Ghosh S. Overt and Subclinical Adrenal Insufficiency in Pulmonary Tuberculosis. Endocr Pract. 2020 Dec 14:S1530-891X(20)48391-0. doi: 10.1016/j.eprac.2020.11.012. Epub ahead of print. PMID: 33645514.
6. Paolo WF Jr, Nosanchuk JD. Adrenal infections. Int J Infect Dis. 2006 Sep;10(5):343-53. doi: 10.1016/j.ijid.2005.08.001. Epub 2006 Feb 17. PMID: 16483815; PMCID: PMC7110804.
7. Beishuizen A, Thijs LG. Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis. J Endotoxin Res. 2003;9(1):3-24. doi: 10.1179/096805103125001298. PMID: 12691614.
8. Denny N, Raghunath S, Bhatia P, Abdelaziz M. Rifampicin-induced adrenal crisis in a patient with tuberculosis: a therapeutic challenge. BMJ Case Rep. 2016 Nov 29;2016:bcr2016216302. doi: 10.1136/bcr-2016-216302. PMID: 27899384; PMCID: PMC5175016.
9. Stefan R. Bornstein, Bruno Allolio, Wiebke Arlt, Andreas Barthel, Andrew Don-Wauchope, Gary D. Hammer, Eystein S. Husebye, Deborah P. Merke, M. Hassan Murad, Constantine A. Stratakis, David J. Torpy, Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 101, Issue 2, 1 February 2016, Pages 364–389, https://doi.org/10.1210/jc.2015-1710
10. Liatsikos EN, Kalogeropoulou CP, Papathanassiou Z, Tsota I, Athanasopoulos A, Perimenis P, Barbalias GA, Petsas T. Primary adrenal tuberculosis: role of computed tomography and CT-guided biopsy in diagnosis. Urol Int. 2006;76(3):285-7. doi: 10.1159/000091637. PMID: 16601397.
11. Kyriazopoulou V, Parparousi O, Vagenakis AG. Rifampicin-induced adrenal crisis in addisonian patients receiving corticosteroid replacement therapy. J Clin Endocrinol Metab. 1984 Dec; 59(6):1204-6. doi: 10.1210/jcem-59-6-1204. PMID: 6490796.
12. Bhatia E, Jain SK, Gupta RK, Pandey R. Tuberculous Addison's disease: lack of normalization of adrenocortical function after anti-tuberculous chemotherapy. Clin Endocrinol (Oxf). 1998 Mar;48(3):355-9. doi: 10.1046/j.1365-2265.1998.00409.x. PMID: 9578827.
13. Laway, B.A., Mir, S.A., Ganie, M.A. et al. Nonreversal of adrenal hypofunction after treatment of adrenal tuberculosis. Egypt J Intern Med 27, 42–44 (2015). https://doi.org/10.4103/1110-7782.155860
14. Penrice J, Nussey SS. Recovery of adrenocortical function following treatment of tuberculous Addison's disease. Postgrad Med J. 1992 Mar; 68(797):204-5. doi: 10.1136/pgmj.68.797.204. PMID: 1589379; PMCID: PMC2399240.
15. Kelestimur F. Recovery of adrenocortical function following treatment of tuberculous Addison's disease. Postgrad Med J (1993) 69, 832-34
16. Roxas MCA, Sandoval MAS, Salamat MS, Matias PJ, Cabal NP, Bartolo SS. Bilateral adrenal histoplasmosis presenting as adrenal insufficiency in an immunocompetent host in the Philippines. BMJ Case Rep. 2020 May 12;13(5):e234935. doi: 10.1136/bcr-2020-234935. PMID: 32404324; PMCID: PMC7228487.
17. Bhansali A, Das S, Dutta P, Walia R, Nahar U, Singh SK, Vellayutham P, Gopal S. Adrenal histoplasmosis: unusual presentations. J Assoc Physicians India. 2012 Oct;60:54-8. PMID: 23777028.
18. Jayathilake WAPP, Kumarihamy KWMPP, Ralapanawa DMPUK, Jayalath WATA, "A Rare Presentation of Possible Disseminated Histoplasmosis with Adrenal Insufficiency Leading to Adrenal Crisis in an Immunocompetent Adult: A Case Report", Case Reports in Medicine, vol. 2020, Article ID 8506746, 5 pages, 2020. https://doi.org/10.1155/2020/8506746
19. Vyas S, Kalra N, Das PJ, Lal A, Radhika S, Bhansali A, Khandelwal N. Adrenal histoplasmosis: An unusual cause of adrenomegaly. Indian J Nephrol. 2011 Oct;21(4):283-5. doi: 10.4103/0971-4065.78071. PMID: 22022092; PMCID: PMC3193675.
20. Mukherjee JJ, Villa ML, Tan L, Lee KO. Bilateral adrenal masses due to histoplasmosis. J Clin Endocrinol Metab. 2005 Dec; 90(12):6725-6. doi: 10.1210/jc.2005-1868. PMID: 16330806.
21. Robinson LJ, Lu M, Elsayed S, Joy TR. Bilateral adrenal histoplasmosis manifesting as primary adrenal insufficiency. CMAJ. 2019 Nov 4;191(44):E1217-E1221. doi: 10.1503/cmaj.190710. PMID: 31685665; PMCID: PMC6834444.
22. Kothari D, Chopra S, Bhardwaj M, Ajmani AK, Kulshreshtha B. Persistence of histoplasma in adrenals 7 years after antifungal therapy. Indian J Endocrinol Metab. 2013 May;17(3):529-31. doi: 10.4103/2230-8210.111679. PMID: 23869317; PMCID: PMC3712391.
23. de Oliveira FM, Fragoso MCBV, Meneses AF, Vilela LAP, Almeida MQ, Palhares RB, de Arruda Mattos TV, Scalissi NM, Viana Lima J. Adrenal insufficiency caused by Paracoccidioidomycosis: three case reports and review. AACE Clin Case Rep. 2019 Mar 13;5(4):e238-e243. doi: 10.4158/ACCR-2018-0632. PMID: 31967043; PMCID: PMC6873835.
24. Cataño J, Porras J. Adrenal Paracoccidioidomycosis. Am J Trop Med Hyg. 2020 Sep;103(3):935-936. doi: 10.4269/ajtmh.20-0083. PMID: 32896237; PMCID: PMC7470546.
25. Tobón AM, Agudelo CA, Restrepo CA, Villa CA, Quiceno W, Estrada S, Restrepo A. Adrenal function status in patients with paracoccidioidomycosis after prolonged post-therapy follow-up. Am J Trop Med Hyg. 2010 Jul; 83(1):111-4. doi: 10.4269/ajtmh.2010.09-0634. PMID: 20595488; PMCID: PMC2912586.
26. Kumar A, Sreehari S, Velayudhan K, Biswas L, Babu R, Ahmed S, Sharma N, Kurupath VP, Jojo A, Dinesh KR, Karim S, Biswas R. Autochthonous blastomycosis of the adrenal: first case report from Asia. Am J Trop Med Hyg. 2014 Apr;90(4):735-9. doi: 10.4269/ajtmh.13-0444. Epub 2014 Feb 3. PMID: 24493676; PMCID: PMC3973522.
27. Rimondi AP, Bianchini E, Barucchello G, Panzavolta R. Addison's disease caused by adrenal blastomycosis: a case report with fine needle aspiration (FNA) cytology. Cytopathology. 1995 Aug;6(4):277-9. doi: 10.1111/j.1365-2303.1995.tb00480.x. PMID: 8520008.
28. Matsuda Y, Kawate H, Okishige Y, Abe I, Adachi M, Ohnaka K, Satoh N, Inokuchi J, Tatsugami K, Naito S, Nomura M, Takayanagi R. Successful management of cryptococcosis of the bilateral adrenal glands and liver by unilateral adrenalectomy with antifungal agents: a case report. BMC Infect Dis. 2011 Dec 14; 11:340. doi: 10.1186/1471-2334-11-340. PMID: 22166121; PMCID: PMC3254187.
29. Ito M, Hinata T, Tamura K, Koga A, Ito T, Fujii H, Hirata F, Sakuta H. Disseminated Cryptococcosis with Adrenal Insufficiency and Meningitis in an Immunocompetent Individual. Intern Med. 2017; 56(10):1259-1264. doi: 10.2169/internalmedicine.56.7356. Epub 2017 May 15. PMID: 28502948; PMCID: PMC5491828.
30. Muraoka Y, Iwama S, Arima H. Normalization of Bilateral Adrenal Gland Enlargement after Treatment for Cryptococcosis. Case Rep Endocrinol. 2017; 2017:1543149. doi: 10.1155/2017/1543149. Epub 2017 Mar 26. PMID: 28458934; PMCID: PMC5385225.
31. Keleştimur F. Sheehan's syndrome. Pituitary. 2003;6(4):181-8. doi: 10.1023/b:pitu.0000023425.20854.8e. PMID: 15237929.
32. Karaca Z, Laway BA, Dokmetas HS, Atmaca H, Kelestimur F. Sheehan syndrome. Nat Rev Dis Primers. 2016 Dec 22; 2:16092. doi: 10.1038/nrdp.2016.92. PMID: 28004764.
33. Mandal S, Mukhopadhyay P, Banerjee M, Ghosh S. Clinical, endocrine, metabolic profile, and bone health in Sheehan’s syndrome. Indian J Endocr Metab 2020; 24:338-42.
34. Hartman ML, Crowe BJ, Biller BM, Ho KK, Clemmons DR, Chipman JJ; HyposCCS Advisory Board; U.S. HypoCCS Study Group. Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency? J Clin Endocrinol Metab. 2002 Feb; 87(2):477-85. doi: 10.1210/jcem.87.2.8216. PMID: 11836272.
35. Kilicli F, Dokmetas HS, Acibucu F. Sheehan's syndrome. Gynecol Endocrinol. 2013 Apr;29(4):292-5. doi: 10.3109/09513590.2012.752454. Epub 2012 Dec 18. PMID: 23245206.
36. Bhat S, Mukhopadhyay P, Raychaudhury A, Chowdhury S, Ghosh S. Predictors of hypopituitarism due to vasculotoxic snake bite with acute kidney injury. Pituitary. 2019 Dec; 22(6):594-600. doi: 10.1007/s11102-019-00990-8. PMID: 31556012
37. Rajagopala S, Thabah MM, Ariga KK, Gopalakrishnan M. Acute hypopituitarism complicating Russell's viper envenomation: case series and systematic review. QJM. 2015 Sep;108(9):719-28. doi: 10.1093/qjmed/hcv011. Epub 2015 Jan 27. PMID: 25630907.
38. Shivaprasad C, Aiswarya Y, Sridevi A, Anupam B, Amit G, Rakesh B, Annie PA, Anish K. Delayed hypopituitarism following Russell's viper envenomation: a case series and literature review. Pituitary. 2019 Feb; 22(1):4-12. doi: 10.1007/s11102-018-0915-1. PMID: 30317419.
39. Benjamin JM, Chippaux JP, Sambo BT, Massougbodji A. Delayed double reading of whole blood clotting test (WBCT) results at 20 and 30 minutes enhances diagnosis and treatment of viper envenomation. J Venom Anim Toxins Incl Trop Dis. 2018 May 16; 24:14. doi: 10.1186/s40409-018-0151-1. PMID: 29796013; PMCID: PMC5956810
40. Tun-Pe, Phillips RE, Warrell DA, Moore RA, Tin-Nu-Swe, Myint-Lwin, Burke CW. Acute and chronic pituitary failure resembling Sheehan's syndrome following bites by Russell's viper in Burma. Lancet. 1987 Oct 3;2(8562):763-7. doi: 10.1016/s0140-6736(87)92500-1. PMID: 2888987.
41. Naik BN, Bhalla A, Sharma N, Mokta J, Singh S, Gupta P, Rai A, Subbiah S, Bhansali A, Dutta P (2018) Pituitary dysfunction in survivors of Russell’s viper snake bite envenomation: A prospective study. Neurol India 66(5):1351
42. De Sanctis V, Soliman AT, Elsedfy H, Skordis N, Kattamis C, Angastiniotis M, Karimi M, Yassin MA, El Awwa A, Stoeva I, Raiola G, Galati MC, Bedair EM, Fiscina B, El Kholy M. Growth and endocrine disorders in thalassemia: The international network on endocrine complications in thalassemia (I-CET) position statement and guidelines. Indian J Endocrinol Metab. 2013 Jan;17(1):8-18. doi: 10.4103/2230-8210.107808. PMID: 23776848; PMCID: PMC3659911.
43. Saraogi RK, Chowdhury S, Mukherjee S, Roy S, Chatterjee P. Adrenal extramedullary haematopoietic tumor in HbE Thalassemia. BMJ 2002; 18(7). South Asia Edition.
44. Tiosano D, Hochberg Z. Endocrine complications of thalassemia. J Endocrinol Invest. 2001 Oct; 24(9):716-23. doi: 10.1007/BF03343916. PMID: 11716158.
45. De P, Mistry R, Wright C, Pancham S, Burbridge W, Gangopadhayay K, Pang T, Das D. A Review of Endocrine Disorders in Thalassaemia. OJEMD 2014; 4(2).
46. Bhatia E. Adrenal disorders in people with HIV: The highs and lows. Indian J Med Res. 2018 Feb; 147(2):125-127. doi: 10.4103/ijmr.IJMR_1087_17. PMID: 29806599; PMCID: PMC5991116.
47. Eledrisi MS, Verghese AC. Adrenal insufficiency in HIV infection: a review and recommendations. Am J Med Sci. 2001 Feb; 321(2):137-44. doi: 10.1097/00000441-200102000-00005. PMID: 11217816.
48. Bakari Adamu Girei, Sani-Bello Fatima. Endocrine Manifestations of HIV Infection.2013. http://dx.doi.org/10.5772/52684
49. Unachukwu CN, Uchenna DI, Young EE. Endocrine and metabolic disorders associated with human immune deficiency virus infection. West Afr J Med. 2009 Jan;28(1):3-9. doi: 10.4314/wajm.v28i1.48415. PMID: 19662737.
50. Hopkins RL, Leinung MC. Exogenous Cushing's syndrome and glucocorticoid withdrawal. Endocrinol Metab Clin North Am. 2005 Jun;34(2):371-84, ix. doi: 10.1016/j.ecl.2005.01.013. PMID: 15850848.
51. http://www.meditecno.pt/Upload/Product/Archive/lkco1.pdf . Last accessed on 14.4.2021
52. Patt H, Bandgar T, Lila A, Shah N. Management issues with exogenous steroid therapy. Indian J Endocrinol Metab. 2013 Dec; 17(Suppl 3):S612-7. doi: 10.4103/2230-8210.123548. PMID: 24910822; PMCID: PMC4046616.
53. Palermo M, Quinkler M, Stewart PM. Apparent mineralocorticoid excess syndrome: an overview. Arq Bras Endocrinol Metabol. 2004 Oct; 48(5):687-96. doi: 10.1590/s0004-27302004000500015. Epub 2005 Mar 7. PMID: 15761540.
54. Farese RV Jr, Biglieri EG, Shackleton CH, Irony I, Gomez-Fontes R. Licorice-induced hypermineralocorticoidism. N Engl J Med. 1991 Oct 24;325(17):1223-7. doi: 10.1056/NEJM199110243251706. PMID: 1922210.
55. Gallacher SD, Tsokolas G, Dimitropoulos I. Liquorice-induced apparent mineralocorticoid excess presenting in the emergency department. Clin Med (Lond). 2017 Feb; 17(1):43-45. doi: 10.7861/clinmedicine.17-1-43. PMID: 28148579; PMCID: PMC6297599.

ABSTRACT

The converging epidemics of non-communicable disease like DM (DM) and an infectious disease like tuberculosis (TB) is a double burden. DM is increasing in the same population that is at high risk for developing TB. There is a two-to-four-fold higher risk of active TB in individuals with DM and up to 30% of individuals with TB are likely to have DM. Immune deficiency either in absolute or relative quantities are sufficient for re-activation of latent TB. From a 10% risk of reactivation over the whole lifetime of an immunocompetent individual, the risk of reactivation increases to 10% every year in immune-deficient individuals. DM impairs cell mediated immunity and poor glycemic control affects cytokine response and alters the defenses in the alveolar macrophages. Fever, hemoptysis, extensive parenchymal lesions, and lung cavities are more common in those with DM particularly heavier and older males. DM increases the risk of treatment failure, death, and relapse. Evidence collected from meta-analysis conclude that DM can increase the odds of developing Multi Drug resistant TB (MDR-TB). The synergism between DM and TB necessitates bi-directional screening. Sputum examination for Ziehl-Neelsen staining is both a sensitive and specific screening test. Rapid molecular diagnostic tests like cartridge based nucleic acid amplification tests (CB-NAAT) are useful in cases where there is a high-index of suspicion and difficulty in arriving at a definitive diagnosis exists. Random plasma glucose and HbA1c (glycosylated Hemoglobin) measurements are convenient tests for DM screening that can be done in non-fasting individuals. Screening for DM more than once during the course of illness is sensible so that transient DM and new-onset DM can be identified. Anti-TB drugs affect glycemic control as they interact with anti-diabetic drugs by either stimulating or inhibiting the metabolizing enzymes. They may also aggravate metabolic, ocular, and neuropathic complications of DM. Insulin is the preferred drug in most instances. The presence of renal and hepatic dysfunction affects TB and hyperglycemic management.

INTRODUCTION

Tuberculosis (TB) and diabetes mellitus (DM) are two diverse conditions of immense public health importance existing for centuries. TB was traditionally identified with poverty while DM was considered as an entity associated with prosperity. TB is today one of the commonest and widespread communicable infectious diseases largely but not necessarily confined to low-economic groups. DM on the other hand spearheads the group of chronic non-communicable diseases affecting people across all socio-economic strata. Contrary to previous beliefs, a larger number of people with DM are living in middle- and low-income countries. Unfortunately, these are the countries where DM is expected to increase in the near future (1). Both DM and TB have been associated with significant morbidity and mortality from time immemorial. Advancements in modern medical science over the years has definitely improved the outcome in both these conditions. But the magnitude of these two diseases has not waned and both are collaborative in worsening each other. In fact, the increase in the population affected with DM is sustaining the TB epidemic.

TB is associated with the endocrine system in different ways. The effects of TB on the endocrine system are discussed in detail in another Endotext chapter (2).  The interaction of TB and DM is discussed in this chapter.

TUBERCULOSIS

TB is a global health threat, particularly to the poor and the susceptible. It is estimated that on average approximately 9 to 10 million people are affected by TB and around 1 to 2 million succumb to it annually (3). In 2019, 1.3 million people died due to TB. In developed countries, TB has slipped down in ranking among the global list of top 10 diseases causing mortality. However, in the underdeveloped regions it still remains among the top 10 diseases with high mortality (up to 30%). When in concurrence with retroviral infections, the risk of active TB is 12 to 20 times higher and the mortality is higher even in developed countries (4). Multi drug resistant TB is another rising problem which requires expensive second line drugs and a longer duration of treatment. A large proportion of the global population is at risk and the true prevalence and the annual incidence also depends on access to health care facilities and the laboratory-based testing capacity of the regions. Individuals who are in close contact with affected individuals, people living in crowded places, immigration to a country or area with a high prevalence of TB, and children less than 5 years of age are considered vulnerable to getting infected by the TB bacilli (Table 1). Bacillary load in the sputum of the infectious individual and close proximity to the infectious persons are two important external determinants for infection in any individual after exposure.

Latent Tuberculosis

In most of the exposed individuals the infection is quelled by the immune system and the bacilli are fenced inside a granuloma or tubercle, immunologically aborting an active disease. This is a subclinical disease (LTBI – Latent TB infection) which doesn’t have symptoms and can last for weeks or decades. This latent infection is seen in nearly one third of the world population. Even though non-infectious, they carry the risk (about 10%) of re-activation into active TB later (primary progressive TB) (5). Such re-activation occurs in immunocompromised as in HIV infection, those on immunosuppressive agents (such as post organ transplant, autoimmune diseases, and allergic diseases), conditions like DM, alcoholism, substance abuse, silicosis, malnutrition, steroid therapy, renal failure, malignancies, indoor air pollution, and smoking. The World Health Organization (WHO) has guidelines on the approach to latent TB especially in countries where the burden of TB is low (an incidence of < 100 / 1, 00,000 per year). It strongly recommends screening and treatment of latent TB in high-risk individuals in these countries (6).

TB is an airborne infectious disease which spreads by droplets. TB affects the lungs primarily (Pulmonary TB) and when it affects the pleura, bones/joints, abdominal organs, lymph nodes, and meninges it is called extra-pulmonary TB. Mycobacterium tuberculosis, the causative agent has a thick mycolic acid cell wall that enables its survival in the environment and in its host. External to its cell membrane it has a peptidoglycan polymer which makes it impermeable. Its cell wall also contains lipoarabinomannan which enables its phagocytosis by macrophages and facilitates its survival inside macrophages in airways especially alveoli (7). The ability of the host’s defense system then determines whether the outcome is a progressive primary pulmonary disease or a latent state.

DIABETES MELLITUS

The prevalence of DM is rapidly increasing to justify it to be termed as an epidemic disease. According to WHO, the global prevalence of DM has doubled from 4.7 % in 1980 to 8.5% in 2014 (8). From an estimated prevalence of 463 million in 2019, it is estimated to increase to 578 million in 2030, and 700 million in 2045. For every diagnosed individual with DM there is another undiagnosed person with DM (9). The differences in the prevalence of DM between high and middle-income countries and similarly between rural and urban population are decreasing.

According to WHO, non-communicable diseases constitute 7 out of the top 10 leading causes of death and DM is prominent among them. In 2019 the estimated number of deaths to have occurred due to DM globally is approximately 4 million (10). DM is associated with significant morbidity due to its microvascular and macrovascular complications and high cardiovascular mortality. DM is a major cause of cardiac ischemia, stroke, renal failure, blindness, and amputations.

THE DIABETES-TUBERCULOSIS EPIDEMIOLOGY: THE BIDIRECTIONAL LINK                          

The high prevalence of DM and TB being in epidemic proportions has rightly earned them the names ‘the converging epidemics’ and ‘double burden’ (11,12). Due to rapid changes in lifestyle, urbanization, and epidemiological changes, DM is increasingly seen in low- and medium-income groups, and in younger individuals more frequently than before. The prevalence of DM is increasing faster where TB is endemic already. Unfortunately, these are the regions in the world where health care facilities are less common. According to International Diabetes Federation, the 50-55% increase in the prevalence of DM over the next 2 decades will occur predominantly in the continent of Africa (10). A longitudinal, multi-national study involving low-income countries concluded that an odds ratio of 4.7 for prevalence and 8.1 for incidence of TB is highly likely in those counties where DM has increased over the last decade (13). The WHO states that younger age group individuals are three times more likely to get infected with TB (14). There is a two-to four-fold higher risk of active TB in individuals with DM compared to non-diabetic individuals (15). According to a meta-analysis by Wilkinson et al, around 4 % of people with type 2 DM develop TB (16). Since the number of individuals with undiagnosed DM in the world is expected to be more than 50%, the proportion of TB in DM also should be much higher. Analytical models that try to project the future burden of TB in DM predict that the increase in DM counteracts the decreasing incidence of TB by at least 3% over the next 15 years (17).

Increased chances of finding undetected and uncontrolled hyperglycemia in close household contacts of subjects with TB have been mentioned in studies from Asian counties. In fact, a systemic analysis of a group of heterogenous studies on bi-directional screening i.e., screening for TB in DM affected individuals and vice versa has shown some evidence to support active screening for both DM and TB in the affected individuals and family members (18). Up to 35% of TB patients may have DM and the quoted figures are variable in literature (19). Jean Jacques Noubiap et al in their systematic review and meta-analysis of data from 2.3 million people with TB world-wide estimated that the prevalence of DM in patients with TB is around 15 % and was twice that of the general population (20). These data clearly give epidemiological evidence for the co-existence of DM and TB as a syndemic. A potentially lethal combination of a communicable disease and a non-communicable disease having a synergistic effect is a challenge on the public health system.

Epidemiology of Diabetes Among Patients with Active Tuberculosis

The WHO collaborative framework recommends for a joint plan for DM and TB related activities which have to be reflected in the national plans on non-communicable diseases and TB respectively (21). As per the WHO approximately15% of TB cases in the world are associated with DM. Of these 15%, India accounts for more than 40% of the cases (19). Estimates of the burden of DM and TB co-existence has primarily come from studies looking at prevalence of DM and glucose intolerance among newly diagnosed patients with TB diagnosed in TB clinics. The community prevalence of these two disorders co-existing are not clear. Many of these studies have been done in hospitals where sicker patients with TB are treated which would probably account for a higher percentage of patients having glucose intolerance and DM. In a study from five randomly selected TB care clinics in the southern state of Tamil Nadu, around 25% of patients with TB had coexisting DM. Around 10% of these patients had newly diagnosed DM. Risk factors for having DM in this group of patients included older age, higher basal metabolic index (BMI), family history of DM among first degree relatives, and following a sedentary lifestyle (22). Close to Tamil Nadu in the southern state of Kerala, the prevalence of DM in patients with TB was nearly double that observed in the previous study. Among the patients with TB in Kerala, 44% had DM. Among them about half (21%) had newly diagnosed DM (23). The risk of DM was higher among those with sputum positive TB in both of these studies. In a study from Odisha on the Eastern part of India, 13.9% of tribal patients with TB had DM suggestive of a significant burden of disease even among poorer regions of the country (24). In a retrospective study, among 1000 patients with TB from the northern state of Punjab, 11.6% had DM and TB coexistence (25). In the same state the authors found 30% of patients with TB diagnosed in a tertiary referral hospital had DM (26).

To better understand the prevalence of DM among newly diagnosed patients with TB a large multicentric study involving five centers is in progress (GIANT Study - Glucose Intolerance Among New patients with TB - Clinical Trial Registry India - CTRI/2019/05/019396). This study incorporates simultaneous OGTT and HbA1c determinations at three different time points to ascertain if HbA1c can replace the standard oral glucose tolerance test (OGTT) in this population and avoid the inconvenience of performing an OGTT.

A recent systemic review and meta-analysis ascertained the worldwide prevalence of DM among active cases of TB. This meta-analysis involved over 200 studies that included a little under 2.3 million patients with active TB. The overall pooled prevalence was similar to the WHO estimate of 15% prevalence of DM in patients with active TB. However, this varied from 0.1% in Latvia to 45% in the Marshall Islands. The high prevalence areas as per the International Diabetes Federation included North America, Western Pacific (which includes Australia and China), South East Asia, North Africa, and Middle East Asia (27). Figure 1 summarizes the information on the prevalence of DM and active TB in 7 regions of the world.

Figure 1. Prevalence of DM among patients with active TB in the seven International Diabetes Federation (IDF) regions of the world. The areas in red have the high burden of DM co-existing with active TB. The low burden areas are marked in blue. (adapted from ref 27)

Chronic hyperglycemia impairs immunity (both innate and adaptive). DM impairs cell mediated immunity and poor glycemic control affects cytokine response and alters the defenses in the alveolar macrophages. Hyperglycemia disrupts the recruitment of neutrophils, chemotactic movement of monocytes, and phagocytic action of alveolar macrophages. Also, the antigen-specific interferon-gamma release is affected as the T-helper cell activation is ineffective. In addition, altered pulmonary microvasculature and micronutrient deficiency facilitate the invasion and establishment of TB as surveillance and nutrition is compromised. The chronic immunosuppression or ineffective immune response predisposes the individual for TB infection and with a higher bacilli load. This is summarized in Figure 2.

Figure 2. DM is associated with increase in active TB and relapse in TB which both may be a result of the direct effect of diabetes. There is increased death in DM and TB which may be secondary to TB or due to the inherent excess mortality of DM due to cardiovascular disease

CLINICAL PRESENTATION

 

The manifestations of tuberculous infection in patients with DM have been documented to be different from those without diabetes. Fever and hemoptysis in diabetic population is more common compared to the general population. Radiographic differences include higher than usual parenchymal lesions and lung cavities (30). There are reports of a higher incidence of lower lobe involvement in individuals with DM in contrast to the classical upper lobe involvement in the general population. Also, a higher rate of other atypical presentations like a reduced rate of sputum conversion (low quality evidence), higher probability of treatment failure and death (moderate quality evidences) is known to occur when DM occurs with TB. A higher rate of recurrence and reactivation of latent TB infection (OR=1.83) has been documented (31). Subjects affected with TB and DM are found to be heavier and older males compared to those without diabetes. More pulmonary than extra-pulmonary involvement is seen in TB with DM (32).

 

Outcome

 

Negative smear or culture on two separate occasions while on treatment and on completion of treatment defines a cured TB (Table 2). Apart from being a risk factor for increased incidence of active TB, co-existence of DM worsens the outcome even in treated patients. In the pre-insulin era, the commonest cause of death in DM apart from diabetic coma was the co-affection with TB (33). DM increases the risk of treatment failure, death and relapse. The risks are likely to be an underestimation as loss of follow-up or unreported death has been a major problem in data collection on outcome in TB management. In a systematic review and meta-analysis by Baker et al, the risk ratio for combined treatment failure and death was 1.69. The risk ratio for death was 1.89 when unadjusted and went up to 4.95 when adjusted for age and other confounding factors.

 

Table 2. Terminology and Definitions
Terminology	Definitions
Treatment completed	Bacteriologically confirmed TB patient who has completed treatment without evidence of failure, but not yet completed sputum test to prove negative result in the last month of treatment and on at least one previous occasion
Cured	Bacteriologically confirmed TB in whom smear- or culture-was negative in the last month of treatment and on at least one previous occasion
Treatment Success	The sum of cured and treatment completed
Treatment Failed	Sputum smear or culture positive at or beyond 5th month of treatment
Died	A proven patient who dies for any reason before or during the course of treatment
Lost to follow-up	A proven patient who did not start treatment or who has interrupted treatment for 2 or more consecutive months
Not Evaluated	A proven patient for whom no treatment outcome is assigned. Includes cases “transferred out” to another treatment unit as well as cases for which the treatment outcome is unknown to the reporting unit

Terminology and Definitions adopted from RNTCP, Revised National TB Control Programme, Training Course for Programme Manager (Modules 1-4), 2011.Training modules. Central TB Division. https://tbcindia.gov.in.

 

The risk ratio for relapse was 3.89 but no additional risk of TB relapse in those with multidrug resistant TB was demonstrated. In their analysis, Baker et al found that the effect of co-existing DM on sputum conversion 2 to 3 months after treatment was variable (0.79 to 3.25) and wide (34). Persistence of sputum positivity i.e., delay in sputum conversion has been shown in a few studies. The authors conclude that advancing age and underlying co-morbidity contribute to death and is not due to drug resistant TB or severity of hyperglycemia (35).

 

BI-DIRECTIONAL SCREENING FOR DIABETES AND TUBERCULOSIS

 

The synergism between DM and TB in terms of epidemiology and outcome necessitates bi-directional screening for the presence of either TB or DM in the presence of the other disorder. The Collaborative Framework for Care and Control of TB and DM proposed by the World Health Organization (WHO) along with the International Union against TB and Lung is an effort towards bi-directional screening and management of both these conditions (36). Studies implementing bi-directional screening point towards its feasibility and effectiveness (18).

 

Screening for Active TB Among Patients with Diabetes

 

The diagnosis and treatment of TB is affected by substantial delay which occurs at multiple levels a) between the onset of symptoms and clinical presentation b) clinical presentation and suspicion of TB c) Clinical suspicion of TB and its confirmation. This is due to variability in symptoms, host immunity, lack of knowledge, paucity of access to medical care, and lack of rapid and reliable diagnostic tools. The average delay even in resource- rich countries after presentation to heath care system is 3 weeks (37). According to WHO, patients with suspected TB should be promptly sent to TB diagnostic and treatment centers and evaluated accordingly.

 

The higher risk of TB in diabetic population compels intensive screening for detection of TB at the earliest time so as to reduce transmission, morbidity, and mortality. WHO recommends for TB surveillance among patients with DM in settings with medium to high TB burdens. The practical difficulties are the non-availability of TB screening tools in all DM clinics. Also, in areas of low TB burden, the cost-effectiveness is low. The number needed to screen to detect one case of active TB depends on the prevalence in that area. Screening of all patients with clinical history during their visit to diabetic clinic and additional testing in symptomatic and high-risk patients should be undertaken. Also screening for TB whenever there is unexplained worsening of metabolic control would help detect occult cases. Different modalities (clinical, radiological, sputum microbiology) alone or in combination are used for screening individuals with DM for the presence of active TB.

 

Clinical Assessment

 

It is inexpensive and requires minimum time. Fever, cough of more than 2 weeks duration, hemoptysis, weight loss, night sweats, and exposure to a case of active TB are the clinical clues to suspect pulmonary TB. Lymphadenopathy, fever with altered sensorium, neck stiffness, abdominal symptoms like ascites, intestinal obstruction etc. all favor the possibilities of extra-pulmonary TB. But clinical symptoms lack both sensitivity and specificity as it excludes asymptomatic patients and relies on the presence of symptoms.

 

Radiography of the Chest

 

It has good sensitivity to pick up asymptomatic pulmonary cases, but there can be false positive results. Inconsistent evidence exists on the presence of atypical findings of TB in the chest x-rays of individuals with diabetes. The presence of clinical symptoms of fever, cough, hemoptysis, and weight loss with an abnormal chest-x-ray helps in the presumptive diagnosis of TB. Figure 3, 4, and 5 show different radiological presentations of pulmonary TB.

Figure 3. Chest Radiographs suggesting fibrocavitatory lesions. Post primary infections and reactivation of pulmonary TB are more likely to cavitate. They are most common in the posterior segments of the upper lobes (85%) as seen in Picture A. Red arrow pointing to the cavity. The other common site is the superior segment of the lower lobe (Picture B) Yellow arrow pointing to the cavity (Picture courtesy- Prof Mary John, Christian Medical College and Hospital, Ludhiana)

Figure 4. Chest Radiographs suggesting lobar consolidation. (Picture courtesy- Prof Mary John& Dr Neeru Mittal, Christian Medical College and Hospital, Ludhiana)

Figure 5. Chest Radiographs suggesting miliary TB. It represents hematogenous dissemination of an uncontrolled tuberculous infection. Although implants are seen throughout the body, the lungs are usually the easiest location to image. Miliary deposits appear as 1-3 mm diameter nodules uniformly distributed in the lung parenchyma. (Picture courtesy- Prof Mary John & Dr Neeru Mittal, Christian Medical College and Hospital, Ludhiana)

Microscopic Examination 

 

Sputum collected for Ziehl-Neelsen staining and examination for acid -fast bacilli is both sensitive and specific. Even-though they are the commonly used confirmatory tests, most diabetes-oriented clinics are unlikely to have standard laboratory facilities for sputum tests even though having a radiography unit for screening TB appears feasible (32). Sputum tests have limitations in cases of scanty sputum or salivary contamination especially in children. If sputum availability is scanty then sputum is induced by saline nebulization, which if not helpful, can be followed by bronchoscopy assisted lavage or trans-bronchial pulmonary biopsy.

 

Sputum Culture

 

The gold standard test is sputum culture for TB bacilli but is both time consuming (turnaround time 8 weeks) and expensive. It cannot be used for all individuals attending the DM clinic and is reserved for those patients where the index of suspicion is high and in difficult cases when other available tests are not contributory for diagnosis. Sputum culture is also useful for assessing response in multi-drug resistant TB.

 

Rapid Molecular Diagnostic Tests

 

Tests like cartridge based nucleic acid amplification test (CB-NAAT) (Figure 6) or rapid automated molecular test Expert MTB/ RIF assay using polymerase chain reaction have a quick turnaround time of two hours and additional advantage of using a single sputum sample. They also detect the presence of rifampicin resistance. Being expensive it cannot be used for screening all patients with DM even though it has high sensitivity and specificity. But they are useful in cases with high-index of suspicion and difficulty in arriving at a definitive diagnosis.

Figure 6. All district hospitals in India have been provided with Cartridge Based-Nucleic Acid Amplification Testing equipment under the RNTPC program. Picture of the equipment at Civil Hospital, Ludhiana (Picture courtesy- Dr Ashish Chawla, Civil Hospital, Ludhiana)

Screening for Latent TB Among Patients with Diabetes

 

As mentioned earlier, Identification and treatment of latent TB infection to prevent its progression to active disease is necessary to prevent morbidity, mortality, and spread of TB. The WHO AND USPSTF (US preventive services task force) have issued strong guidelines for the screening and treatment of latent TB infection in high risk adults aged more than 18 years in countries with low incidence of TB (38,39).The high risk groups include persons hailing from countries with high TB prevalence, persons residing in homeless shelters and correctional facilities, immunocompromised individuals (HIV, those on immunosuppressants including post-organ transplant), silicosis, those receiving dialysis, those receiving anti-TNF-alfa inhibitor treatment, previously treated TB, and persons who come in contact with those active TB (household contacts and health care workers). The Mantoux tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) are the two screening tests used and they are moderately sensitive and highly specific (40,41). In the tuberculin test, purified protein derivative (PPD) is injected intradermally and assessed within 48 to 72 hours for the presence of induration which is a palpable hard swelling (a diameter of more than 10 mm is considered positive) over the injected area (42,43). In the IGRA a single venous blood sample is taken for the assay and the reports are available within a day. They are particularly useful in those who are unlikely to return for TST test reading and BCG vaccinees.

 

There is no consensus on the issue of screening for latent TB infection in DM as a high-risk group. The results of studies done previously have been inconsistent. Studies have shown a variable prevalence of latent TB infection and there are no randomized controlled trials demonstrating the benefits of screening. Similarly, there are no recommendations for chemoprophylaxis of latent TB infection in individuals with DM due to the lack of randomized controlled trials that show benefit. The small added risk of hepatotoxicity with chemoprophylactic drugs given for TB in latent TB infection has been the only concern arguing against such measures.

 

Screening for Diabetes in Tuberculosis

 

In geographical regions with a high prevalence of diabetes, screening for hyperglycemia in TB affected individuals is highly recommended (14). Detection and monitoring of hyperglycemia is an essential part of infection management in any patient with an infectious disease. Chronic infectious diseases like TB thrive in hyperglycemic individuals and the outcome is unfavorable in a hyperglycemic milieu. Recognition of hyperglycemia during the entire course of the illness in TB affected individuals implies either monitoring of pre-existing hyperglycemia or new onset of transient or permanent hyperglycemia. Transient hyperglycemia is a manifestation secondary to the insulin resistance induced by the inflammation of TB infection. There is evidence that hyperglycemic status improves during the course of anti-TB treatment. The optimal time to screen for DM in TB patients on anti-TB treatment is thus unresolved particularly when it is well known that transient hyperglycemia exists during the course of TB. Many groups have advocated for screening more than once during the course of illness i.e., once at the initiation of treatment and at least once again either during and at the time of completion of TB treatment.

 

In regions with high prevalence of diabetes, younger age of onset of DM is on the rise and this is an emerging problem. There is a three times higher risk for younger individuals to get TB and a two-to four-fold higher risk in diabetic individuals compared to non-diabetic individuals. Hence screening for DM in all individuals 18 years of age or older appears logical.

 

The type of tests for screening patients with TB for DM depends on the availability of the local health care facilities, cost of the tests, and the ability of patients to come back for additional or repeat tests. Symptom based screening for DM has a low sensitivity. Risk score-based screening also is marred by low sensitivity and specificity. Random plasma glucose test and HbA1c (glycosylated Hb) are convenient tests that can be done in non-fasting individuals as screening tests. Glycosylated Hb test which doesn’t require a fasting blood sample helps to differentiate stress induced hyperglycemia from spontaneous onset pre-existing diabetes. Oral glucose tolerance test (OGTT) with 75 gm helps in identifying impaired glucose tolerance (IGT) and frank DM. A FBG ≥126 mg/dL or random plasma glucose ≥200 mg/dl on two tests is diagnostic of diabetes; FBG 110to 125 mg/dL is considered as impaired fasting glucose and post glucose values between 141- to 199 mg/dl is taken as impaired glucose tolerance (43,44). In one study, the number of TB patients needed to screen (NNS) for detecting DM was on average 40. But in the same population it was lower among smear positive subjects (NNS = 23), in age less than 40 years (< 40 years vs. > 40 years NNS = 35 Vs 47), in males (male vs. female NNS = 31 vs. 116), smokers (smoker vs. non-smoker NNS = 27 vs. 68) and HIV positive (Positive vs. Negative 22 Vs 43) indicating that there are high risk individuals (46).

 

Currently, screening for DM in individuals with TB and screening for TB in patients with DM where the prevalence is > 100/1,00,000 population appears feasible. Once diagnosed as having diabetes, diet and drug therapy is initiated and the patients are followed up closely for assessing the glycemic response. Transient hyperglycemic situations improve either spontaneously or with minimal medical intervention. After completion of TB medications, regular follow-up with glycemic monitoring is recommended for all patients who had diabetes.

 

MANAGEMENT OF DIABETES AND TUBERCULOSIS 

 

Anti-Tuberculosis Therapy in Diabetes

 

Management of DM should be according to the existing global guidelines with adaptations according to the regional needs. The treatment of TB in DM is not different from the general population. DOTs (Directly Observed Treatment, short-course) is a patient-centered WHO strategy adopted to treat individuals with active TB. A trained health worker provides drugs and observes in-person the patient taking the drug. It guarantees compliance, completion of the treatment course and prevents transmission, treatment failure and development of drug resistance. For newly detected TB, 2 months of intensive phase with 4 drugs (INH, Rifampicin, Pyrazinamide and Ethambutol) and 4 months of continuation phase with 3 drugs (except pyrazinamide) is the standard regimen. For those with a relapse 3 months of intensive therapy with 5 drugs (streptomycin in addition) followed by 4 months of continuation phase with 3 drugs (except pyrazinamide and streptomycin) is administrated.

 

In Chronic Kidney Disease

 

All four first line drugs (RIF, INH, PZA and EMB) can be used in patients with CKD. Up to 50% dose reduction for EMB and PZA may be needed in patients with creatinine clearance <10 ml/min. Regular monitoring is advised to ensure optimal therapy.

 

Adverse Effects of Anti-TB Drugs

 

INH induced peripheral neuropathy may worsen the underlying diabetic neuropathy. Pyridoxine is supplemented to prevent this. INH is also associated with hepatitis. Ethambutol is known to produce optic nerve toxicity which may confound diabetic retinopathy. Also, ethambutol and rifampicin are known to affect the kidneys. Rifampicin can induce immune-allergic reactions. Pyrazinamide is rarely associated with liver injury but its more common side effect is hyperuricemia induced joint pain. Streptomycin is potentially associated with renal and cochleo-vestibular toxicity

 

Multi-Drug Resistant TB (MDR-TB)

 

Multi-drug resistant TB (MDR-TB) is an added medical and economical burden as it is much more difficult to treat, involves therapy with atypical anti-TB drugs for a longer duration of time, and requires referral to specialty centers. Infections caused by mycobacterial strains which are resistant to INH and rifampicin are called multi-drug resistant TB infections. If there is additional resistance to one fluroquinolone and one of the additional inject able drugs (Kanamycin, Capreomycin or Amikacin) then it is called extensive drug resistant TB (XDR-TB). It is associated with poor outcomes and risk of continued transmission (47). Treatment outcome always has been poor due to the complex drug regimen, non-availability of all the drugs, and the possible occurrence of XDR-TB. The reason for resistance is multi-factorial including patient’s non-compliance to therapy, incomplete or inadequate treatment of susceptible TB, decision error by the treating community, etc. Resistance to drugs arises from mutations which are spontaneous and restricted to specific gene loci making it detectable without much difficulty.

 

There is inconsistent data on the incidence of TB-drug resistance in diabetes. Tegegne et al in their meta-analysis concluded that DM can increase the odds of developing MDR-TB.  (47,48). Observational studies have shown delayed clearance of mycobacterium, failure of treatment, relapse and death in the presence of DM (49). The possible theoretical explanations pertaining to the influence of DM in developing resistance include lower drug concentrations, hyperglycemia induced acute and chronic effects of immune regulation, and the presence of more extensive disease in DM affected individuals (50).

 

Altered plasma concentrations of the anti-TB drug rifampicin has been demonstrated in the continuation phase (but not in the induction phase) of TB treatment in individuals with DM (51). The heavier body weight of insulin resistant individuals with DM is supposed to be one of the reasons because of the use of fixed-dose combination drugs. Giving an exact weight-based dose for a longer duration of time is suggested to overcome this hurdle (52). In addition, DM can influence the plasma concentrations of anti-TB drugs. The absorption, distribution, and metabolism of anti-TB drugs may be altered either due to local gastrointestinal causes (gastropathy, polypharmacy mediated interactions) or dysautonomia of DM predisposing to treatment failure.

 

After initiation of treatment all patients should be closely followed for evidence of resistance. Persistent sputum positivity at the end of 2-3 months of ATT therapy should prompt a look for evidence of drug resistance. CT chest features have been demonstrated to be different from non-DM subjects. Pulmonary segment consolidation and lobe consolidation seen as moth-eaten cavities without a wall and filled with fluid are the features mentioned in published data. They are accompanied by bronchial damage (53). Multiple moth-eaten cavities in chest CT while on ATT should prompt the suspicion of MDR-TB. Rapid molecular techniques like CB-NAAT or sputum culture for sensitivity should be used to look for drug resistance. All MDR-TB should be referred to specialized centers dealing with MDR-TB.

 

Drug Therapy in Multi-Drug Resistant Tuberculosis

 

The second line drugs are generally less efficacious and more toxic. In the presence of drug resistance second line agents are used in multiple combinations to address different pharmacological targets in the mycobacterium. In addition to one of the first line drugs to which there is retained susceptibility, an injectable agent, a fluroquinolone and class 4 and class 5 drugs are used in combination to combat MDR-TB (53). Bedaquiline and Delamanidare are new anti-TB drugs used in MDR-TB

 

Bedaquiline belongs to the diarylquinoline group. It inhibits mycobacterial ATP-synthase activity. A shorter time to sputum conversion compared to placebo has been demonstrated. The adverse effects include enzyme induction,electrolyte imbalance, QTc prolongation, and gastrointestinal toxicity (54).

 

Delamanid a dihydro-imidazooxazole that inhibits mycolic acid synthesis also has shown a shorter time period taken for sputum conversion while used in the regimen for MDR-TB. A dose dependent association with QT prolongation occurs (55).

 

Linezolid an oxazolidinone has demonstrated 87% sputum conversion but more than 80% of patients had adverse effects. Peripheral neuropathy, myelosuppression, optic neuropathy, and rhabdomyolysis have been documented in study subjects.

 

ANTI-DIABETES THERAPY IN TUBERCULOSIS    

 

The outcome of TB in DM is also dependent on good glycemic control. The management of hyperglycemia in TB depends on many factors like age, duration of diabetes, presence of complications of DM and co-morbidities, existing drugs, patient support and preferences, economic background and access to medical facilities.

 

Changes in the lifestyle pattern is once again reiterated when starting ATT. Adequate nutrition with high quality protein without affecting glycemic control is the corner stone of managing nutrition associated glycemic status in TB. In the presence of nephropathy or liver disease, the protein intake has to be modified appropriately and spurious use of protein is avoided. Vitamins particularly pyridoxine (B6), methylcobalamine (B12), vitamin A and Vitamin D should be adequately replaced. Tobacco use and alcohol consumptions have to be stopped. Moderate intensity exercise can help weight lose and improve glycemic control in overweight individuals.

 

Drug regimen, monitoring and follow-up should be individualized to maximize benefit with minimal discomfort and side effects like hypoglycemia, arrhythmias etc. Monitoring of capillary blood glucose at home, dose adjustment, monitoring of renal and liver functions are required during follow-up.

 

Anti-TB drugs can influence the metabolism of anti-diabetic medications (Table 3). Rifampicin, by cytochrome p450 enzyme induction, increases the metabolism of most oral anti-diabetic drugs, which may worsen the hyperglycemia. INH on the other hand inhibits cytochrome P450 enzymes and prolongs the effect of anti-diabetic drugs.

 

Table 3. Anti TB Drugs and Drug Metabolism (Ref 57-59)
Anti TB drug	Effect on Cytochrome P 450	Effect on anti- diabetic drugs
Rifampicin	Induces the cytochrome enzymes thereby accelerating the elimination of drugs like sulphonylureas, thiazolidinediones, and meglitinides	Reduced effect of sulphonylureas by one-third due to CYP2C-mediated accelerated metabolism leading to hyperglycemia   Reduced effect of thiazolidinedione by half due to CYP2C8-mediated accelerated metabolism leading to hyperglycemia
INH	Inhibits	Reduced elimination through action on CYP2C9; persistent effect and risk of hypoglycemia
Bedaquiline	Enzyme inducer	Can reduce the effect of anti- diabetic drugs

 

Aggressive therapy of DM is necessary for optimal response to TB therapy (Table 4). Insulin is the drug of choice in most illnesses including TB; insulin has the advantage of producing an anabolic effect, positive influence on appetite, and faster relief of hyperglycemic symptoms. It is the most suitable anti-hyperglycemic agent in cachexic and low BMI individuals. It is a mandatory therapeutic agent in Type 1 diabetes, pancreatic diabetes, severe DM and TB, coexisting renal or hepatic diseases, situations complicated by drug interactions and oral drug intolerance. Insulin is neutral in drug-to-drug interactions and achieves glycemic control faster than oral drugs. In the presence of fasting hyperglycemia of > 200 with ketonuria, Insulin is used to treat the hyperglycemia. It is also the preferred drug in renal impairment. The main disadvantage with insulin is that it has to be injected and more than twice a day in presence of infection/ stress. The indications for insulin use in patients with active TB and DM is summarized in Figure 7.

Figure 7. Indications of Insulin Use in patients with Type 2 DM and Active TB

Metformin has the advantage of not producing hypoglycemia when used alone. It can however reduce appetite and needs caution while being used in renal or hepatic dysfunction. It doesn’t interact much with ATT and doesn’t influence cytochrome enzyme induced metabolism. It can help to shorten the course of TB therapy. It modifies the immune response and inflammation. It acts on the mitochondrial respiratory chain and can reduce the intracellular growth by acting through AMPK pathway which has a negative impact on the inflammatory process.

 

Table 4. Anti-Diabetic Drug Use in Patients with Tuberculosis
Drug	Advantages	Disadvantages	Comment
Insulin	Increases appetite, weight; anabolic effect; No drug interactions with ATT	Injectable   Needs supervision for change in requirement	Preferred in lean diabetes, secondary diabetes, severe DM with ketosis or hyperosmolar state
Metformin	Oral; Cost-effective and easily available Not influenced by ATT; positive anti-TB adjuvant action	Gastrointestinal disturbances; Needs renal and hepatic function monitoring; Change in eGFR (< 35 ml/ min/l) or > 3 times raised liver enzymes necessitates stopping metformin; Not suitable in hypoperfusion states (risk of lactic acidosis)	Not potent in severe hyperglycemic situations. Can be used in mild forms of hyperglycemia.
Sulphonylureas	Quick restoration of euglycemia	Long-acting drugs can induce hypoglycemia in anorexic people	Shorter acting sulphonylureas such as gliclazide and glipizide
DPP4- inhibitors	Less hypoglycemic potential	? Risk of immune dysregulation – respiratory Infection	Selective use
Alpha glucosidase inhibitors	No hypoglycemia	GI intolerance	In mild post meal elevation
Thiazolidinediones	Against insulin resistance	Hepatic	Selective use
SGLT2 inhibitors	No hypoglycemia	Dehydration, DKA	Selective use

 

Metformin increases the host cell production of reactive oxygen species and acidification of mycobacterial phagosome (60). It has been found to downregulate oxidative phosphorylation, mammalian target of rapamycin (mTOR) signaling, and type I interferon response pathways (61).  Sulphonylureas can be used for quick glycemic control. The long acting sulphonylureas like glibenclamide and glimepride have a risk of prolonged hypoglycemia particularly seen in anorexic individuals. Their plasma concentration and their duration of action are modified by drugs acting on cytochrome P450 system and hence monitoring of glycemic status is essential while on these drugs. Thiazolidinediones (pioglitazone) do not produce GI symptoms and are non-hypoglycemic when used as monotherapy. Monitoring of hepatic enzymes is required particularly when TB drugs are co-administered. Alpha-glucosidase inhibitors may be helpful in mild postprandial hyperglycemias. SGLT-2 inhibitors have the risk of further weight loss, euglycemic ketoacidosis, worsening of dehydration in sick patients, and urinary tract infections. They should not be used for glycemic control in patients who are sick and cachexic. In individuals who have no contra-indications they can be continued selectively under close follow-up (62, 63).

 

CO-MORBIDITIES OF DIABETES

 

Cardiovascular Disease in Diabetes and Tuberculosis

 

The commonest cause of mortality in DM is cardiovascular disease due to atherosclerosis manifesting as coronary heart disease (myocardial infarction /cardiac failure), stroke and peripheral vascular disease. TB also has a possible role in chronic vascular inflammation, autoimmunity and inhabitation of TB bacilli atheromatous plaque (64). It also affects the myocardium (65). After successful initiation of TB treatment which is done on a priority basis, DM and cardiovascular status should be assessed. In addition to hyperglycemia management, lifestyle modification, antihypertensive treatment, lipid-lowering therapy, and anti-platelet therapy are the corner stones of management of cardiovascular disease in DM irrespective of the presence or absence of TB. In the presence of hemoptysis anti-platelet drugs are withdrawn or held back. Cessation of smoking and moderation of alcohol has to be counselled about. Anti-hypertensive therapy is initiated during review visits and titrated. Anti-lipid therapy using statins are added gradually and the liver enzymes should be monitored during the course of therapy while on ATT.

 

Renal Dysfunction in Diabetes and Tuberculosis

 

More than a third of individuals with DM develop renal complications due to diabetes. This complicates TB in many ways including increased susceptibility to TB and difficulty in the management of TB (66). In patients with chronic renal failure and on dialysis there is a 6.9‐ to 52.5‐fold risk of developing TB (67). Peritoneal TB is another risk for CKD patients on peritoneal dialysis. The altered immune function in chronic renal impairment increases susceptibility to TB (68). CKD adversely affects TB and its treatment. The anti-TB drugs (ethambutol and pyrazinamide) require dose reduction by up to 50%. Insulin is preferred in most instances for glycemic control. Short acting sulphonylureas or repaglinide can be used as an alternative.

 

Hepatic Dysfunction in Diabetes and Tuberculosis

 

DM liver pathology includes fatty liver disease, NASH, and cirrhosis. In TB, drug induced hepatitis is a concern. In such cases the drugs are withdrawn until resolution of hepatotoxicity. Pyrazinamide is withdrawn completely. Quinolones, ethambutol, and ofloxacin can be used instead of the first line agents. Anti-TB drugs are restarted when the liver enzymes are normalized. Insulin is the drug of choice in severe chronic liver disease with diabetes. Metformin is preferred in fatty liver but withdrawn in cirrhosis.

 

Tuberculosis and Diabetes in HIV – The Triangular Overlap

 

DM and HIV are two independent risk factors for developing TB. The wider prevalence of DM makes DM a more important risk factor for developing TB than retroviral diseases. A significantly higher preponderance of DM over HIV has been reported in cases of pulmonary TB while extra-pulmonary TB was predominant in HIV-TB patients (69). DM is increasing in areas where TB and HIV are rampant. Literature reports on the influence of HIV-co infection on DM with TB have been contradictory. Studies have reported reduced odds of developing DM in HIV infected TB patients (70).  A paradoxical protective effect of HIV on the development of TB was reported (71). However, they were cross-sectional single center studies of limited sample size and had used single random blood glucose tests for screening. But in a case-control study the association between DM and TB in HIV was found to be strong except when HbA1c was used for screening. This may be because of anemia of HIV compromising the true HbA1c value (72). HIV testing is mandatory in all presumptive TB and confirmatory assessment using Gene Xpert MTB/RIF assay for drug resistance.

 

PREVENTIVE METHODS

 

Aggressive DM screening among the population with TB and effective management of both TB and DM can improve outcome on an individual basis. The more effective approach to have an impact at the community level is to have a preventive strategy like vaccination against TB and aggressive prevention and management of DM (29).

 

SUMMARY

 

Epidemiological evidence for an uncharacteristic alliance between non-communicable disease like DM and a communicable disease like TB as a syndemic are overwhelming. A two-to four-fold higher risk of active TB in individuals with DM and twice the prevalence of DM in patients with TB explains the double burden. Ranked among the top ten mortal diseases, the geographical spread of both these diseases is unfortunately overlapping and the co-existence is progressive. They are increasing alarmingly in those regions where health care facilities are limited. DM impacts TB both from infection to disease stage and disease stage to progression stage. Chronic hyperglycemia compromises the alveolar defenses.

 

Latent TB infection is a dormant subclinical disease which lasts for weeks or decades. Immune deficiency either in absolute or relative quantities are sufficient for its re-activation. The clinical and radiological presentations of active TB have been reported to be pulmonary predominantly and atypical when DM co-exists with TB. DM increases the risk of treatment failure, death and relapse. The risk ratio for combined treatment failure and death was 1.69, unadjusted and adjusted risk ratios for death were 1.89 and 4.95 respectively and risk ratio for relapse was 3.89.

 

Bidirectional screening is recommended to improve the outcome in both diseases. Sputum microscopic examination, rapid molecular tests, random plasma glucose and glycosylated hemoglobin are the available among the screening tests with their own merits and limitations.

 

Anti-TB treatment has adverse impact on glycemic control and the complications of diabetes. The metabolism of some DM drugs is modified by ATT which affects glycemic control. Modifications of medications are required in co-morbid illnesses of DM like cardio-vascular diseases, renal, and hepatic dysfunction. Insulin is the drug of choice in lean diabetes, severe hyperglycemia, ketotic states, anorexic patients, and in drug intolerance. Metformin if tolerated has an advantage as a non-hypoglycemic agent with some favorable anti-TB activity.

 

Lifestyle modification, antihypertensive treatment, lipid-lowering therapy, and anti-platelet therapy are the cornerstones in the management of cardiovascular disease in DM and TB. Anti-platelet drugs are withdrawn in patients with hemoptysis. Chronic kidney diseases can predispose to TB and its management is complicated by drug toxicity and dose adjustment of ATT is required along with careful monitoring of response and renal functions. In case of ATT induced hepatotoxicity, ATT is withdrawn and second line agents are substituted. Once liver enzymes normalize the first line drugs are restarted cautiously.

 

Effective preventive strategies like vaccination against TB and aggressive prevention and management of DM will be the approach to be adopted till time throws new light on the means to fight these dual epidemics more effectively.

 

REFERENCES

 

1. Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract. 2011; 94(3):311-321.
2. Jacob JJ, Paul PAM. Infections in Endocrinology: Tuberculosis. In: Feingold KR, Anawalt B, Boyce A, et al., eds. Endotext. South Dartmouth (MA): MDText.com, Inc.; March 14, 2021.
3. Lönnroth K, Castro KG, Chakaya JM, et al. Tuberculosis control and elimination 2010-50: cure, care, and social development. Lancet. 2010; 375(9728):1814-1829. doi:10.1016/S0140-6736(10)60483-7
4. World Health Organization. Global Tuberculosis Report 2020. https://apps.who.int/iris/bitstream/handle/10665/336069/9789240013131-eng.pdf (Accessed 28 Nov 2020)
5. Narasimhan P, Wood J, Macintyre CR, Mathai D. Risk factors for tuberculosis. Pulm Med. 2013; 2013:828939. doi:10.1155/2013/828939
6. Getahun H, Matteelli A, Abubakar I, et al. Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries. Eur Respir J. 2015; 46(6):1563-1576. doi:10.1183/13993003.01245-2015
7. Lee RE, Li W, Chatterjee D, Lee RE. Rapid structural characterization of the arabinogalactan and lipoarabinomannan in live mycobacterial cells using 2D and 3D HR-MAS NMR: structural changes in the arabinan due to ethambutol treatment and gene mutation are observed. Glycobiology. 2005; 15(2):139-151. doi:10.1093/glycob/cwh150
8. Emerging Risk Factors Collaboration, Sarwar N, Gao P, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies [published correction appears in Lancet. 2010 Sep 18;376(9745):958. Hillage, H L [corrected to Hillege, H L]]. Lancet. 2010; 375(9733):2215-2222. Doi: 10.1016/S0140-6736(10)60484-9.
9. International Diabetes Federation. IDF Diabetes Atlas, 8th edn. Brussels, Belgium:International Diabetes Federation, 2019. https://diabetesatlas.org/en/resources/(Accessed 8 March 2021)
10. World Health Organization. Global tuberculosis report 2019: World Health Organization; 2019. https://www.who.int/tb/publications/global_report/en/ (Accessed 8 March 2021)
11. Dooley KE, Chaisson RE. Tuberculosis and diabetes mellitus: convergence of two epidemics. Lancet Infect Dis. 2009 Dec; 9(12):737-46. Doi: 10.1016/S1473-3099(09)70282-8. PMID: 19926034; PMCID: PMC2945809.
12. Viswanathan, V., Bajaj, S., Kalra, S. et al. RSSDI clinical practice recommendations for diagnosis, prevention, and control of the diabetes mellitus-tuberculosis double burden. Int J Diabetes Dev Ctries 2017; 37, 379–399
13. Goldhaber-Fiebert JD, Jeon CY, Cohen T, Murray MB. Diabetes mellitus and tuberculosis in countries with high tuberculosis burdens: individual risks and social determinants. Int J Epidemiology. 2011 Apr; 40(2):417-28. Doi: 10.1093/ije/dyq238. Epub 2011 Jan 20. PMID: 21252210; PMCID: PMC3621385.
14. World Health Organization/International Union Against Tuberculosis and Lung Disease. Provisional collaborative framework for care and control of tuberculosis and diabetes. WHO/HTM/TB/2011.15. Geneva, Switzerland: WHO, 2011.
15. Hayashi, S., &Chandramohan, D. (2018). Risk of active tuberculosis among people with diabetes mellitus: systematic review and meta-analysis. Tropical medicine & international health: TM & IH, 23(10), 1058–1070. https://doi.org/10.1111/tmi.13133
16. Workneh MH, Bjune GA, Yimer SA. Prevalence and associated factors of tuberculosis and diabetes mellitus co morbidity: A systematic review. PLoS One. 2017; 12(4):e0175925. Published 2017 Apr 21. doi:10.1371/journal.pone.0175925.
17. Odone A, Houben RM, White RG, Lönnroth K. The effect of diabetes and under nutrition trends on reaching 2035 global tuberculosis targets. Lancet Diabetes Endocrinol. 2014; 2(9):754-764. doi:10.1016/S2213-8587(14)70164-0
18. Jeon CY, Harries AD, Baker MA, et al. Bi-directional screening for tuberculosis and diabetes: a systematic review. Trop Med Int Health. 2010; 15(11):1300-1314. doi:10.1111/j.1365-3156.2010.02632.
19. Lönnroth K, Roglic G, Harries AD. Improving tuberculosis prevention and care through addressing the global diabetes epidemic: from evidence to policy and practice. Lancet Diabetes Endocrinol. 2014; 2(9):730-739. doi:10.1016/S2213-8587(14)70109-3
20. Noubiap JJ, Nansseu JR, Nyaga UF, et al. Global prevalence of diabetes in active tuberculosis: a systematic review and meta-analysis of data from 2·3 million patients with tuberculosis. Lancet Glob Health. 2019; 7(4):e448-e460. doi:10.1016/S2214-109X(18)30487
21. Collaborative framework for care and control of tuberculosis and diabetes. WHO/HTM/TB/2011.15
22. Viswanathan V, Kumpatla S, Aravindalochanan V, et al. Prevalence of diabetes and pre-diabetes and associated risk factors among tuberculosis patients in India. PLoS One. 2012;7(7):e41367.
23. Balakrishnan S, Vijayan S, Nair S, et al. High diabetes prevalence among tuberculosis cases in Kerala, India. PLoS One. 2012;7(10):e46502.
24. Manjareeka M, Palo SK, Swain S, Pati S, Pati S. Diabetes Mellitus among Newly Diagnosed Tuberculosis Patients in Tribal Odisha: An Exploratory Study. J Clin Diagn Res. 2016;10(10):LC06-LC08.
25. Singh SP, Singh SP, Kishan J, Kaur S, Ramana S. Association of tuberculosis and diabetes Mellitus: an analysis of 1000 consecutively admitted cases in a tertiary care hospital of North India. Pan Afr Med J. 2016;24:4
26. Kodiatte A, John M, Jacob JJ. Diabetes mellitus and prediabetes among patients with tuberculosis in a single north Indian tertiary care centre. J R Coll Physicians Edinb. 2020;50(3):242-246.
27. Noubiap JJ, Nansseu JR, Nyaga UF, Nkeck JR, Endomba FT, Kaze AD, Agbor VN, Bigna JJ. Global prevalence of diabetes in active tuberculosis: a systematic review and meta-analysis of data from 2·3 million patients with tuberculosis. Lancet Glob Health. 2019 Apr;7(4): e448-e460.
28. Alisjahbana B, Sahiratmadja E, Nelwan EJ, et al. The effect of type 2 diabetes mellitus on the presentation and treatment response of pulmonary tuberculosis. Clin Infect Dis. 2007; 45(4):428-435. doi:10.1086/519841
29. Crevel RV, Critchley JA. The Interaction of Diabetes and Tuberculosis: Translating Research to Policy and Practice. Trop Med Infect Dis. 2021; 6(1):8. Published 2021 Jan 8. doi:10.3390/tropicalmed6010008
30. Chiang CY, Lee JJ, Chien ST, et al. Glycemic control and radiographic manifestations of tuberculosis in diabetic patients. PLoS One. 2014; 9(4):e93397. Published 2014 Apr 3. doi:10.1371/journal.pone.0093397
31. Jiménez-Corona ME, Cruz-Hervert LP, García-García L, et al. Association of diabetes and tuberculosis: impact on treatment and post-treatment outcomes. Thorax. 2013; 68(3):214-220. Doi: 10.1136/thoraxjnl-2012-201756.
32. Riza AL, Pearson F, Ugarte-Gil C, et al. Clinical management of concurrent diabetes and tuberculosis and the implications for patient services. Lancet Diabetes Endocrinol. 2014; 2(9):740-753. doi:10.1016/S2213-8587(14)70110
33. Restrepo BI, Schlesinger LS. Impact of diabetes on the natural history of tuberculosis. Diabetes Res Clin Pract. 2014; 106(2):191-199. doi:10.1016/j.diabres.2014.06.011.
34. Baker MA Harries AD, Jeon CY, et al. The impact of diabetes on tuberculosis treatment outcomes: a systematic review. BMC Med. 2011; 9:81. Published 2011 Jul 1. doi:10.1186/1741-7015-9-81
35. Chang JT, Dou HY, Yen CL, et al. Effect of type 2 diabetes mellitus on the clinical severity and treatment outcome in patients with pulmonary tuberculosis: a potential role in the emergence of multidrug-resistance. J Formos Med Assoc. 2011; 110(6):372-381. doi:10.1016/S0929-6646(11)60055-7
36. Collaborative framework for care and control of tuberculosis and diabetes. WHO/HTM/TB/2011.15
37. Sreeramareddy CT, Panduru KV, Menten J, Van den Ende J. Time delays in diagnosis of pulmonary tuberculosis: a systematic review of literature. BMC Infect Dis. 2009; 9:91. Published 2009 Jun 11. doi:10.1186/1471-2334-9-91
38. Getahun H, Matteelli A, Abubakar I, et al. Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries. Eur Respir J. 2015; 46(6):1563-1576. doi:10.1183/13993003.01245-2015]
39. US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, et al. Screening for Latent Tuberculosis Infection in Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2016; 316(9):962-969. doi:10.1001/jama.2016.11046
40. Mansilla Bermejo MJ, Sanz Gil MJ, Moraleda Velasco P, Alvárez Prado A, Carbayo García JJ, Mata Guijarro F. Lectura de la prueba de la tuberculinaenpacientesdiabéticos de un centro de salud [Tuberculin test in diabetic patients in a health centre]. Aten Primaria. 1995; 16(3):154-157.
41. Vega Torres RA, Conde JG, Díaz M. Prevalence of tuberculin reactivity and risk factors for the development of active tuberculosis upon admission to a nursing home. P R Health Sci J. 1996; 15(4):275-277
42. Nwabudike LC, Ionescu-Tîrgovişte C. Intradermal reactions to purified protein derivative in patients with diabetes mellitus. Rom J Intern Med. 2005; 43(1-2):127-132.
43. Dabhi PA, Thangakunam B, Gupta R, et al. Screening for prevalence of current TB disease and latent TB infection in type 2 diabetes mellitus patients attending a diabetic clinic in an Indian tertiary care hospital. PLoS One. 2020; 15(6):e0233385. Published 2020 Jun 5. doi:10.1371/journal.pone.0233385
44. Kumpatla S, Aravindalochanan V, Rajan R, Viswanathan V, Kapur A. Evaluation of performance of A1C and FPG tests for screening newly diagnosed diabetes defined by an OGTT among tuberculosis patients-a study from India. Diabetes Res Clin Pract. 2013; 102(1):60-64. doi:10.1016/j.diabres.2013.08.007]
45. Sariko ML, Mpagama SG, Gratz J, Kisonga R, Saidi Q, Kibiki GS, Heysell SK. Glycated haemoglobin screening identifies patients admitted for retreatment of tuberculosis at risk for diabetes in Tanzania. J Infect Dev Ctries. 2016 Apr 28; 10(4):423-6. Doi: 10.3855/jidc.7324. PMID: 27131008; PMCID: PMC4869164.
46. Naik B, Kumar AM, Satyanarayana S, et al. Is screening for diabetes among tuberculosis patients feasible at the field level? Public Health Action. 2013; 3(Suppl 1):S34-S37. doi:10.5588/pha.13.0022
47. Tegegne BS, Habtewold TD, Mengesha MM, Burgerhof JG. Association between diabetes mellitus and multi-drug-resistant tuberculosis: a protocol for a systematic review and meta-analysis. Syst Rev. 2017; 6(1):6. Published 2017 Jan 14. Doi: 10.1186/s13643-017-0407-9.
48. Pérez-Navarro LM, Fuentes-Domínguez F, Morales-Romero J, Zenteno-Cuevas R. Factoresasociados a tuberculosis pulmonarenpacientes con diabetes mellitus de Veracruz, México [Factors associated to pulmonary tuberculosis in patients with diabetes mellitus from Veracruz, México]. Gac Med Mex. 2011; 147(3):219-225.
49. Kang YA, Kim SY, Jo KW, et al. Impact of diabetes on treatment outcomes and long-term survival in multidrug-resistant tuberculosis. Respiration. 2013; 86(6):472-478. doi:10.1159/000348374
50. Ruslami R, Aarnoutse RE, Alisjahbana B, van der Ven AJ, van Crevel R. Implications of the global increase of diabetes for tuberculosis control and patient care. Trop Med Int Health. 2010; 15(11):1289-1299. doi:10.1111/j.1365-3156.2010.02625.
51. Nijland HM, Ruslami R, Stalenhoef JE, et al. Exposure to rifampicin is strongly reduced in patients with tuberculosis and type 2 diabetes. Clin Infect Dis. 2006; 43(7):848-854. doi:10.1086/507543
52. Van Ingen J, Aarnoutse RE, Donald PR, et al. Why Do We Use 600 mg of Rifampicin in Tuberculosis Treatment? Clin Infect Dis. 2011; 52(9):e194-e199. doi:10.1093/cid/cir184.
53. Song Q, Zhang G, Jiang H, Ren Y, Lu X. Imaging Features of Pulmonary CT in Type 2 Diabetic Patients with Multidrug-Resistant Tuberculosis. PLoS One. 2016; 11(3):e0152507. Published 2016 Mar 29. doi:10.1371/journal.pone.0152507
54. Kurz SG, Furin JJ, Bark CM. Drug-Resistant Tuberculosis: Challenges and Progress. Infect Dis Clin North Am. 2016; 30(2):509-522. doi:10.1016/j.idc.2016.02.010
55. U.S. Food and Drug Administration. SIRTURO Prescribing Information.http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/204384s000lbl.
56. Shimokawa Y, Sasahara K, Yoda N, Mizuno K, Umehara K. Delamanid does not inhibit or induce cytochrome p450 enzymes in vitro. Biol Pharm Bull. 2014; 37(11):1727-1735. doi:10.1248/bpb.b14-00311 ]
57. Niemi M, Backman JT, Neuvonen M, Neuvonen PJ, Kivistö KT. Effects of rifampin on the pharmacokinetics and pharmacodynamics of glyburide and glipizide. Clin Pharmacol Ther. 2001;69(6):400-406. doi:10.1067/mcp.2001.115822
58. Niemi M, Backman JT, Neuvonen PJ. Effects of trimethoprim and rifampin on the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglitazone. Clin Pharmacol Ther. 2004;76(3):239-249. doi:10.1016/j.clpt.2004.05.001
59. Boglou P, Steiropoulos P, Papanas N, Bouros D. Hypoglycaemia due to interaction of glimepiride with isoniazid in a patient with type 2 diabetes mellitus. BMJ Case Rep. 2013;2013:bcr2012008528. Published 2013 Apr 16. doi:10.1136/bcr-2012-008528
60. Singhal A, Jie L, Kumar P, et al. Metformin as adjunct antituberculosis therapy. Sci Transl Med. 2014; 6(263):263ra159.doi:10.1126/scitranslmed.3009885.
61. Yu X, Li L, Xia L, et al. Impact of metformin on the risk and treatment outcomes of tuberculosis in diabetics: a systematic review. BMC Infect Dis. 2019; 19(1):859. Published 2019 Oct 17. doi:10.1186/s12879-019-4548-4
62. Niazi AK, Kalra S. Diabetes and tuberculosis: a review of the role of optimal glycemic control. J Diabetes MetabDisord. 2012; 11(1):28. Published 2012 Dec 20. doi:10.1186/2251-6581-11-28
63. Hsia DS, Grove O, Cefalu WT. An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus. CurrOpin Endocrinol Diabetes Obes. 2017; 24(1):73-79. doi:10.1097/MED.0000000000000311
64. Huaman MA, Henson D, Ticona E, Sterling TR, Garvy BA. Tuberculosis and Cardiovascular Disease: Linking the Epidemics. Trop Dis Travel Med Vaccines. 2015; 1:10. doi:10.1186/s40794-015-0014-5
65. Liu A, Hu Y, Coates A. Sudden cardiac death and tuberculosis - how much do we know? Tuberculosis (Edinb). 2012; 92(4):307-313. doi:10.1016/j.tube.2012.02.002
66. CKD TB : Ates G, Yildiz T, Danis R, et al. Incidence of tuberculosis disease and latent tuberculosis infection in patients with end stage renal disease in an endemic region. Ren Fail. 2010; 32(1):91-95. doi:10.3109/08860220903367528
67. Hussein MM, Mooij JM, Roujouleh H. Tuberculosis and chronic renal disease. Semin Dial. 2003; 16(1):38-44. doi:10.1046/j.1525-139x.2003.03010.x
68. Levey AS, Atkins R, Coresh J, et al. Chronic kidney disease as a global public health problem: approaches and initiatives - a position statement from Kidney Disease Improving Global Outcomes. Kidney Int. 2007; 72(3):247-259. doi:10.1038/sj.ki.5002343
69. Gupta S, Shenoy VP, Bairy I, Srinivasa H, Mukhopadhyay C. Diabetes mellitus and HIV as co-morbidities in tuberculosis patients of rural south India. J Infect Public Health. 2011;4(3):140-144. doi:10.1016/j.jiph.2011.03.005
70. Faurholt-Jepsen D, Range N, Praygod G, et al. Diabetes is a risk factor for pulmonary tuberculosis: a case-control study from Mwanza, Tanzania. PLoS One. 2011;6(8):e24215. doi:10.1371/journal.pone.0024215
71. Kibirige D, Ssekitoleko R, Mutebi E, Worodria W. Overt diabetes mellitus among newly diagnosed Ugandan tuberculosis patients: a cross sectional study. BMC Infect Dis. 2013; 13:122. Published 2013 Mar 5. doi:10.1186/1471-2334-13-122
72. Boillat-Blanco N, Ramaiya KL, Mganga M, et al. Transient Hyperglycemia in Patients With Tuberculosis in Tanzania: Implications for Diabetes Screening Algorithms. J Infect Dis. 2016;213(7):1163-1172. doi:10.1093/infdis/jiv568

 

ABSTRACT

Helminths are parasitic worms that can infect humans. They are broadly classified as flatworms (including Cestodes and Trematodes) and roundworms (nematodes). These worms infect organs such as intestines, liver, skin, as well as other tissues. These infections are more common in underdeveloped parts of the world affecting almost one-sixth of the world population. These infections can lead to a variety of endocrine manifestations. A decreased risk of developing type 2 diabetes mellitus has been observed in affected populations. Helminths modulate the host immunity towards a type 2 immune response which is anti-inflammatory in nature. An increase in T regulatory cells has also been seen which reduces T cell response to infections.  By virtue of these changes, chronic inflammation is suppressed in adipose tissues - this phenomenon may explain the protective effect in type 2 diabetes mellitus. A reduction in insulin resistance independent of BMI has been observed in animal as well as human studies. Hepatic lipid production can be reduced by the soluble egg antigen from certain schistosomes. The immunomodulatory effects of helminth infections can also protect against autoimmune endocrine conditions such as type 1 diabetes mellitus and Graves' disease. These observations may reflect the well-known "hygiene hypothesis". Thyroid nodules and hypothyroidism can occur in helminth infections. Insights into thyroid physiology, including thyroid hormone receptors and de-iodination pathways, have been obtained from studies in helminths. Certain helminth infections can impair osteoclast maturation suggesting potential implications for osteoporosis. Similarities between human and helminth bone morphogenetic protein pathways have been observed. Adrenal masses as well as adrenal insufficiency, have been observed in helminth infections. Infertility has frequently been reported with Schistosomiasis due to inflammation in the genital tracts. An estrogen like compound may be produced by schistosomes which can lead to hypogonadism in males. The helminth, Caenorhabditis elegans can serve as a model for studies on Kallman syndrome as the KAL-1 gene appears to be functionally conserved in this helminth.  A reduction in IGF-1 levels may be seen in adults infected with helminths. Apart from these manifestations, novel insights regarding endocrine disease mechanisms as well endocrine physiology can be derived from studies on helminths.

INTRODUCTION

The term helminth refers to parasitic worms which are broadly classified as flatworms (including Cestodes and Trematodes) and roundworms (nematodes) (1). These infections may be soil-transmitted and present as intestinal infections while others may invade different tissues such as blood vessels or other organs. These parasitic worms are endemic in several parts of the world, specifically in underdeveloped and parts of developing countries (1). It is estimated that approximately one-sixth of the world’s population is affected by helminth infections  (2). Helminths employ complex mechanisms to evade host immunity. They induce malnutrition in the host while simultaneously ensuring an adequate supply of nutrients for their own growth and reproduction.

These immunological and metabolic interactions between helminth and the host may modulate the pathophysiology of several endocrine disorders including diabetes, thyroid disorders, and gonadal disorders apart from others. A discussion of each of these groups of disorders is presented below.

DIABETES MELLITUS

Diabetes mellitus is among the most common endocrine disorders with its rapidly growing prevalence earning it the designation of a pandemic. While type 1 diabetes mellitus is an autoimmune disease, type 2 diabetes is mediated by insulin resistance which is of multifactorial origin with genetics, environmental factors, and inflammation all playing their part. Among these factors, it has been noticed that areas with a high prevalence of soil-transmitted helminth infections have a relatively lower prevalence of diabetes (3). Although several other factors may also be operational in such areas, there are several proposed mechanisms by which helminth infections may influence diabetes and its pathogenesis.

Type 2 Diabetes Mellitus

Type 2 diabetes mellitus has been described as a chronic inflammatory disorder. Chronic inflammation in adipose tissues has been shown to be among the factors underlying this disease. The inflammatory process in adipose tissue involves infiltration by inflammatory cells such as lymphocytes, macrophages, and neutrophils.  Eosinophils on the other hand appear to have an anti-inflammatory effect. Apart from infiltration, several phenotypic changes occur in these cells which tip the balance towards inflammation. These include the predominance of T helper type 1 (Th1) and T helper type 17 (Th17) instead of the T helper type 2 (Th2) and the regulatory T cells (Tregs). The Th1 and Th17 cells promote the macrophage activation into classically activated macrophages (CAM) which in turn secrete inflammatory markers such as tumor necrosis factor-alpha (TNF-α), interleukin 6 and 12(IL6, IL12). TNF-α has been shown to interfere with insulin signaling. On the other hand, Th2 and T reg cells secrete IL-3 and IL 4 which stimulate the formation of alternatively activated macrophages (AAM) which are anti-inflammatory and express IL-10. Adipokines such as leptin, lipocalin 2, retinol-binding protein (RBP4), resistin, angiopoietin-like protein 2 (ANGPTL2), IL-6, IL-1, CC-chemokine ligand 2 (CCL2), CXC-chemokine ligand 5 (CXCL5) are also pro-inflammatory while adiponectin may have anti-inflammatory actions.

Helminth infections are associated with induction of type 2 immune response which involves increased activation of Th2 cells, eosinophilia, and production of IgE. The Th2 response in turn manifests as increased secretion of IL-4, IL-5, IL-9, IL-10, IL-13 which are anti-inflammatory. This also promotes the induction of anti-inflammatory AAMs.  Similarly, helminth infections are associated with an increase in T reg cells which mediate a state of T cell hypo-responsiveness. These changes on one hand limit the damage to host tissues by uncontrolled inflammation in response to helminth antigens and on the other hand prevent the clearance of the helminth from the host. The T cell hypo-responsiveness to parasite antigens can spill over to other antigens as well and this phenomenon has been invoked to explain the reduced prevalence of certain allergic and autoimmune disorders in helminth infected populations. Therefore, it has been hypothesized that since the immunological changes associated with helminth infections are anti-inflammatory in nature, they can reduce chronic inflammation in adipose and other tissues, thereby mitigating insulin resistance and the resultant type 2 diabetes.

The above hypothesis is supported by epidemiological data. In a study from China, previous schistosome infection was associated with a lower prevalence of obesity and metabolic syndrome as compared to those without such infection (4). Another study, which used ultrasonography to document chronic liver disease caused by schistosomiasis, found that metabolic syndrome prevalence was reduced to half of that seen in those without evidence of schistosomiasis (5). Serological evidence of chronic Strongyloides stercoralis infection was associated with a 61% lower risk of developing type 2 diabetes as compared to those who did not have this infection, despite adjustment for parameters such as age, BMI, and hypertension (6). In Indonesia, higher insulin sensitivity was demonstrated in patients who had infections with soil-transmitted helminths as evidenced by lower BMI and HOMA-IR levels (7). A randomized controlled trial to demonstrate the effect of ongoing helminth infection on insulin sensitivity has been conducted (8). This trial randomized households in an area endemic for helminth infection to receive albendazole or placebo over a period of time. In this trial, treatment of helminth infected subjects with albendazole lead to an increase in insulin resistance along with a reduction in IgE and eosinophil counts. However, at the community level, insulin resistance remained unchanged (9).

While the mechanisms of the reduction in type 2 diabetes have not been concretely studied in humans, animal studies provide support for the role of immunomodulation. Infections with Schistosoma mansoni, Nippostrongylus brasiliensis, and Litomosoides sigmodontis have been shown to increase eosinophils and AAMs in mice with diet-induced obesity (10–12). These animals had improved insulin sensitivity and glucose tolerance - this effect was lost in eosinophil deficient mice. S. mansoni soluble egg antigen and egg-derived ὠ-1 antigens stimulate innate lymphoid type 2 cells which produce IL-5 and IL-13 cytokines necessary for sustaining eosinophils and AAMs (13). L. sigmodontis Ag-treated obese mice had greater numbers of CD4+Foxp3+ Tregs in white adipose tissues as compared to controls indicating the upregulation of these cells as a mechanism of reducing insulin resistance (12).

Apart from these immunomodulatory mechanisms, the effect on body weight and gut microbiota are also potential mechanisms. The soluble egg antigen of S. japonicum, has been shown to reduce hepatic expression of microRNA 802 (miR802) which suppresses hepatic lipid production by upregulating the AMPK pathway. This has been proposed to be a future therapeutic target in obesity (14). However, the effect of helminth infection on insulin sensitivity has been shown to be independent of BMI in mice (10). This echoes the study on Australian aboriginals where the findings persisted despite adjusting for BMI (6).

Similarly, data on gut microbiota changes is scanty and conflicting. A few studies show an increase in gut bacterial diversity after helminth infection (15,16). Other authors have not found any significant changes in gut microbiota (17). While the mechanisms require further elucidation in both animal as well as human studies, there seems to be sufficient evidence to support the role of helminth infections in modulating the pathophysiology of type 2 diabetes.

Type 1 Diabetes Mellitus

Regarding type 1 diabetes, the type 2 immune response and suppressive regulatory environment induced by helminths may induce a protective effect. The incidence of type 1 diabetes has been increasing rapidly in developed countries and these regions are relatively less affected by helminth infections (18). The hygiene hypothesis has been invoked to explain this phenomenon (19). There are very few human studies which directly look at helminth infection and amelioration of type 1 diabetes risk. Enterobiasis did not reduce risk of type 1 diabetes in a population based study (19). Several animal studies do support the protective role of helminth infection. Axenic Caenorhabditis elegans antigen can protect against type 1 diabetes in the non-obese diabetes (NOD) mouse model (20). Trehalose produced by some helminths can alter intestinal microbiota leading to induction of CD8+ T cells which protect against type 1 diabetes in mice models (21). The severity of type 1 diabetes in mice models is ameliorated by recombinant Schistosoma japonicum cystatin and fructose-1,6-bisphosphate aldolase (22). Interestingly, children with schistosomiasis appear to have islet cell antibodies and defects in insulin secretion when compared to non infected siblings of children with insulin-dependent diabetes mellitus (23). Future studies may further shed light on this interesting topic.

THYROID DISORDERS

There appears to be a bidirectional relationship between the thyroid gland and helminth infections. On one hand, helminths appear to possess several proteins which are analogous to those involved in human thyroid physiology while on the other hand helminths can play a role in several thyroid diseases.

Thyroid hormone receptors which were earlier thought to be found only in chordates have been found to be present in S. mansoni (24). Two homologues of mammalian thyroid receptor (TR) has been isolated and characterized in S. mansoni (25), The thyroid hormone receptor beta from S. japonicum has also been characterized and evaluated as a vaccine candidate for this infection (26). Similarly, a nuclear hormone receptor has been identified in S. stercoralis which has some resemblance with steroid/thyroid hormone receptor found in humans (27). A transthyretin like protein has also been identified in Schistosoma dublin and Caenorhabditis elegans, although its function is unclear (28). Thyroid hormones may be essential for helminth growth and multiplication. In mice infected with Schistosoma mansoni, thyroid hormone therapy led to parasite multiplication and an increase in size whereas iodine deficient or thyroid hormone receptor knockout mice had lesser parasite numbers and smaller sized worms (29).

Some novel insights into thyroid physiology have also come from studies in helminths. Studies on the nematode Caenorhabditis have helped elucidate the mechanisms behind toxic effects of excess iodine - the dual oxidase maturation factor (DOXA-1) being among the implicated factors (30). Similarly, helminth studies have shown that iodotyrosine deiodinase may also have a role in regulating potassium channels in muscles (31).

Hypothyroidism and Thyroid Nodules

With respect to thyroid disorders, hypothyroidism and thyroid nodules appear to have some associations with helminth infections. S. stercoralis has been associated with hypothyroidism in one case report (32). Fasciola gigantica infection in buffaloes has been shown to lead to lymphocytic thyroiditis and hypothyroidism (33).

Hydatid cyst disease can mimic thyroid nodules and is often diagnosed by fine needle aspiration cytology (34). Cysticerosis may also present as a thyroid nodule (35). Similarly, microfilaria have also been found in fine needle aspirations from the thyroid (36). Schistosomiasis may interfere with technetium pertechnetate uptake in various tissues including the thyroid as demonstrated in mice- this may have implications for thyroid scan performed in infected humans (37).

Hyperthyroidism

Graves' disease, which is the most common cause of hyperthyroidism, may be affected by helminth infections. Considering that helminths affect host immune response and Graves' disease is an autoimmune process, such an association is not unexpected. Graves' disease is characterized by autoantibodies to the TSH receptor which leads to gland enlargement, hyperthyroidism, as well as extrathyroidal manifestations such as orbitopathy and dermopathy.  Animal models of Graves' disease have been developed which involve introduction of TSH receptor complementary DNA. It has been shown in such a mouse model that prior infection with S. mansoni may lead to a sustained Th2 type immune response towards the parasite egg antigens. This Th2 type immune response prevented the development of Graves' disease when mice were immunized with non-replicative recombinant adenovirus expressing the human TSHR. However, if given after disease onset, the Schistosoma infection could not cure the disease. Graves’ disease was once thought to be a Th2-type immune response, but recent studies have described a Th1-type as well as a Th2-type response suggesting that reversal of an activated immune response to the TSH receptor is not possible (38).  Based on similar findings with other infections, a hygiene hypothesis for Graves disease has also been proposed (39). 

BONES AND CALCIUM METABOLISM

There is limited information regarding calcium metabolism and bone health in helminth infections. Hydatid cyst disease involving the vertebrae has been described recently  and pathological hip fracture has also been reported (40,41). However, this is likely to represent direct involvement of the bone rather than alterations in bone metabolism.

Inflammatory arthritis is associated with secondary osteoporosis. The Th2 type immune response seen with helminth infections may attenuate inflammatory arthritis. N. brasiliensis was able to inhibit arthritis and bone loss in two experimental models of inflammatory arthritis (42). In vitro osteoclast differentiation has been shown to be inhibited by excretory/ secretory products from Heligmosomoides polygyrus bakeri, a murine helminth (43).  C-terminal sequence of Fasciola helminth defense molecule-1 (C-FhHDM-1) has been shown to reduce RANKL secretion as well as prevents both the formation of osteoclasts and acidification of lysosomes in animal models [6]. These features may be beneficial in osteoporotic states. However, in a study on pregnant mice, Heligmosomoides bakeri infection in late pregnancy and lactation led to a decrease in maternal bone mineral density and was associated with an increase in levels of inflammatory cytokines (IL-1 beta and IL-6) (44).

There may be several similarities between human and helminth physiology with respect to certain metabolic pathways. Homologues of  osteonectin, also called SPARC [Secreted Protein Acidic and Rich in Cysteine]), have been found in C. elegans while S. mansoni has homologues of TGF-beta receptor (45,46). More recently, it has been found that bone morphogenetic protein signaling may be conserved between humans and helminths, especially C. elegans. Secreted Modular Calcium-binding protein-1 (SMOC-1) gene identified in Caenorhabditis elegans may promote BMP signaling leading to the growth of the helminth (47,48). While BMP pathway plays several roles in human physiology including bone growth, the implications of these discoveries in helminths are still unclear.

 ADRENALS

Helminth infections in the adrenal with presentation as an adrenal mass have been reported in the literature.  Paragonimus westermani has been reported in a patient who had a lung cavity and an adrenal mass (49). Echinococcus multilocularis can infrequently present as a right adrenal mass detected incidentally (50). Adrenal schistosomiasis has also been reported (51). F. gigantica can cause adrenal insufficiency in animals (33). Acute adrenal insufficiency accompanied by adrenal hemorrhage has also been reported with S. stercoralis (52).

Activation of the hypothalamic-pituitary-adrenal axis leading to immunosuppression has been shown in mouse studies with Angiostrongylus cantonensis (53). While chronic immunosuppressive  therapy can lead to hyperinfection with helminths like S. stercoralis (54,55), adrenalectomized mice appeared to have higher worm burden and worm fecundity rates when infected with S mansoni (56). Previous mouse studies have shown adrenal hypertrophy and higher cortisol levels in S. mansoni infection (57). In vitro treatment of S. mansoni with adrenal hormones suggests that DHEA has a toxic effect with cercariae being more susceptible than schistosomula and adults (58).

GONADS

The manifestations of helminth infections with respect to gonads include hypogonadism and infertility. 

Hypogonadism

1. mansoni infection has been associated with low normal testosterone and elevated estrogen levels in males although hepatic dysfunction may also play a role in these abnormalities (59). Patients infected with Loa loa and Mansonella perstans filariasis are more likely to have low testosterone and elevated gonadotropins as compared to control subjects (60). Further research in this area revealed that an estradiol-related compound was present in schistosome worm extracts (61). Later, the same authors confirmed the presence of this estradiol-related compound by mass spectrometry and also demonstrated that this compound has an antagonistic activity on the estrogen receptor and leads to a reduced expression of the estrogen receptor (62). Schistosome eggs can also convert estrogens to catechol-estrogens which in turn can be metabolized to active quinones. These quinones can cause DNA modifications and are implicated in the pathogenesis of malignancies related to schistosomiasis (63). These hormonal changes explain the pathogenesis of hypogonadism in schistosomiasis.

 Infertility

Schistosomiasis has been well recognized as a cause of infertility especially in females. Apart from hypogonadism caused by alterations in the estrogen axis, schistosomiasis can affect the genital tract leading to infertility. Genital involvement occurs in the form of granulomatous inflammation, fibrosis, and adhesion formation. The manifestations of this infection in females include tubal blockage, tubal pregnancy, tubal abortions, hemoperitoneum, preterm births, and miscarriages (64). Males can also have direct testicular inflammation along with, blockage of the genital ductal system and venous drainage leading to infarction. However, the involvement of male genital tract has been reported infrequently (65). Female infertility has also been reported with enterobiasis (66). Filarial involvement of male genitalia leading to hydrocele is well recognized (67). Male sterility can occur in such cases (68).

Some insights into genetic hypogonadism may come from helminth studies. The gene responsible for Kallman syndrome, KAL-1, appears to have a functionally conserved homologue in C. elegans. This gene plays a role in morphogenesis by influencing migration of epidermal cells in C. elegans. This discovery has established C. elegans as a model for study of Kallman syndrome for which a mouse model has proved to be elusive [33].

GROWTH

Children with helminth infections may have impaired growth- a phenomenon that can easily be attributed to malnutrition. However, helminth infections in adults are associated with significantly lower free IGF-1 which showed improvement after anti-helminth treatment(69). IGF-BP3 levels remain unchanged. Thus, direct effects on the GH-IGF-1 axis may occur in these infections.

CONCLUSION 

In conclusion, helminths appear to play an important role in several endocrine disorders in endemic areas. Apart from contributing to the pathogenesis of disease, they may have a protective effect in some metabolic disorders. Novel insights regarding endocrine disease mechanisms as well endocrine physiology can be derived from studies using helminths. This is an interesting area for research which should encourage both helminthologists as well as endocrinologists.

REFERENCES

1. Bethony J, Brooker S, Albonico M, Geiger S, Loukas A, D D, Pj H. Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm. Lancet 2006;367(9521):1521–32.
2. Pullan RL, Smith JL, Jasrasaria R, Brooker SJ. Global numbers of infection and disease burden of soil transmitted helminth infections in 2010. Parasit. Vectors 2014;7(1):37.
3. de Ruiter K, Tahapary DL, Sartono E, Soewondo P, Supali T, Smit JWA, Yazdanbakhsh M. Helminths, hygiene hypothesis and type 2 diabetes. Parasite Immunol. 2017;39(5):e12404.
4. Chen Y, Lu J, Huang Y, Wang T, Xu Y, Xu M, Li M, Wang W, Li D, Bi Y, Ning G. Association of Previous Schistosome Infection With Diabetes and Metabolic Syndrome: A Cross-Sectional Study in Rural China. J. Clin. Endocrinol. Metab. 2013;98(2):E283-7.
5. Shen S-W, Lu Y, Li F, Shen Z-H, Xu M, Yao W-F, Feng Y-B, Yun J-T, Wang Y-P, Ling W, Qi H-J, Tong D-X. The potential long-term effect of previous schistosome infection reduces the risk of metabolic syndrome among Chinese men. Parasite Immunol. 2015;37(7):333–339.
6. Hays R, Esterman A, Giacomin P, Loukas A, McDermott R. Does Strongyloides stercoralis infection protect against type 2 diabetes in humans? Evidence from Australian Aboriginal adults. Diabetes Res. Clin. Pract. 2015;107(3):355–361.
7. Wiria AE, Hamid F, Wammes LJ, Prasetyani MA, Dekkers OM, May L, Kaisar MMM, Verweij JJ, Guigas B, Partono F, Sartono E, Supali T, Yazdanbakhsh M, Smit JWA. Infection with Soil-Transmitted Helminths Is Associated with Increased Insulin Sensitivity. PloS One 2015;10(6):e0127746.
8. Tahapary DL, de Ruiter K, Martin I, van Lieshout L, Guigas B, Soewondo P, Djuardi Y, Wiria AE, Mayboroda OA, Houwing-Duistermaat JJ, Tasman H, Sartono E, Yazdanbakhsh M, Smit JWA, Supali T. Helminth infections and type 2 diabetes: a cluster-randomized placebo controlled SUGARSPIN trial in Nangapanda, Flores, Indonesia. BMC Infect. Dis. 2015;15(1):133.
9. Tahapary DL, de Ruiter K, Martin I, Brienen EAT, van Lieshout L, Cobbaert CM, Soewondo P, Djuardi Y, Wiria AE, Houwing-Duistermaat JJ, Sartono E, Smit JWA, Yazdanbakhsh M, Supali T. Effect of Anthelmintic Treatment on Insulin Resistance: A Cluster-Randomized, Placebo-Controlled Trial in Indonesia. Clin. Infect. Dis. 2017;65(5):764–771.
10. Hussaarts L, García-Tardón N, van Beek L, Heemskerk MM, Haeberlein S, van der Zon GC, Ozir-Fazalalikhan A, Berbée JFP, Willems van Dijk K, van Harmelen V, Yazdanbakhsh M, Guigas B. Chronic helminth infection and helminth-derived egg antigens promote adipose tissue M2 macrophages and improve insulin sensitivity in obese mice. FASEB J. 2015;29(7):3027–3039.
11. Yang Z, Grinchuk V, Smith A, Qin B, Bohl JA, Sun R, Notari L, Zhang Z, Sesaki H, Urban JF, Shea-Donohue T, Zhao A. Parasitic nematode-induced modulation of body weight and associated metabolic dysfunction in mouse models of obesity. Infect. Immun. 2013;81(6):1905–1914.
12. Berbudi A, Surendar J, Ajendra J, Gondorf F, Schmidt D, Neumann A-L, Wardani APF, Layland LE, Hoffmann LS, Pfeifer A, Hoerauf A, Hübner MP. Filarial Infection or Antigen Administration Improves Glucose Tolerance in Diet-Induced Obese Mice. J. Innate Immun. 2016;8(6):601–616.
13. Hams E, Bermingham R, Wurlod FA, Hogan AE, O’Shea D, Preston RJ, Rodewald H-R, McKenzie ANJ, Fallon PG. The helminth T2 RNase ω1 promotes metabolic homeostasis in an IL-33- and group 2 innate lymphoid cell-dependent mechanism. FASEB J. 2016;30(2):824–835.
14. Ni Y, Xu Z, Li C, Zhu Y, Liu R, Zhang F, Chang H, Li M, Sheng L, Li Z, Hou M, Chen L, You H, McManus DP, Hu W, Duan Y, Liu Y, Ji M. Therapeutic inhibition of miR-802 protects against obesity through AMPK-mediated regulation of hepatic lipid metabolism. Theranostics 2021;11(3):1079–1099.
15. Lee SC, Tang MS, Lim YAL, Choy SH, Kurtz ZD, Cox LM, Gundra UM, Cho I, Bonneau R, Blaser MJ, Chua KH, Loke P. Helminth Colonization Is Associated with Increased Diversity of the Gut Microbiota. PLoS Negl. Trop. Dis. 2014;8(5):e2880.
16. Kay G, Millard A, Sergeant M, Midzi N, R G, T M, A I, N N, F M, M P. Differences in the Faecal Microbiome in Schistosoma haematobium Infected Children vs. Uninfected Children. PLoS Negl. Trop. Dis. 2015;9(6):e0003861.
17. Cooper P, Walker AW, Reyes J, Chico M, Salter SJ, Vaca M, Parkhill J. Patent Human Infections with the Whipworm, Trichuris trichiura, Are Not Associated with Alterations in the Faecal Microbiota. PLOS ONE 2013;8(10):e76573.
18. Zaccone P, Hall SW. Helminth infection and type 1 diabetes. Rev. Diabet. Stud. RDS 2012;9(4):272–286.
19. Bager P, Vinkel Hansen A, Wohlfahrt J, Melbye M. Helminth infection does not reduce risk for chronic inflammatory disease in a population-based cohort study. Gastroenterology 2012;142(1):55–62.
20. Jackson-Thompson B, Torrero M, Mitre B, Long J, Packiam M, Mitre E. Axenic Caenorhabditis elegans antigen protects against development of type-1 diabetes in NOD mice. J. Transl. Autoimmun. 2020;3:100065.
21. Shimokawa C, Kato T, Takeuchi T, Ohshima N, Furuki T, Ohtsu Y, Suzue K, Imai T, Obi S, Olia A, Izumi T, Sakurai M, Arakawa H, Ohno H, Hisaeda H. CD8+ regulatory T cells are critical in prevention of autoimmune-mediated diabetes. Nat. Commun. 2020;11(1):1922.
22. Yan K, Wang B, Zhou H, Luo Q, Shen J, Xu Y, Zhong Z. Amelioration of type 1 diabetes by recombinant fructose-1,6-bisphosphate aldolase and cystatin derived from Schistosoma japonicum in a murine model. Parasitol. Res. 2020;119(1):203–14.
23. Soliman AT, El-Nawawy AA, El-Azzouni OF, Amer EA, Demian SR, El-Sayed MH. High prevalence of islet cell antibody and defective insulin release in children with schistosomiasis. J. Trop. Pediatr. 1996;42(1):46–49.
24. Wu W, Niles EG, LoVerde PT. Thyroid hormone receptor orthologues from invertebrate species with emphasis on Schistosoma mansoni. BMC Evol. Biol. 2007;7:150.
25. Wu W, LoVerde PT. Nuclear hormone receptors in parasitic Platyhelminths. Mol. Biochem. Parasitol. 2019;233:111218.
26. Qiu C, Liu S, Hong Y, Fu Z, Wei M, Ai D, Lin J. Molecular characterization of thyroid hormone receptor beta from Schistosoma japonicum and assessment of its potential as a vaccine candidate antigen against schistosomiasis in BALB/c mice. Parasit. Vectors 2012;5:172.
27. Siddiqui AA, Stanley CS, Skelly PJ, Berk SL. A cDNA encoding a nuclear hormone receptor of the steroid/thyroid hormone-receptor superfamily from the human parasitic nematode Strongyloides stercoralis. Parasitol. Res. 2000;86(1):24–29.
28. Richardson SJ, Hennebry SC, Smith BJ, Wright HM. Evolution of the thyroid hormone distributor protein transthyretin in microbes, C. elegans, and vertebrates. Ann. N. Y. Acad. Sci. 2005;1040:448–451.
29. Saule P, Adriaenssens E, Delacre M, Chassande O, Bossu M, Auriault C, Wolowczuk I. Early variations of host thyroxine and interleukin-7 favor Schistosoma mansoni development. J. Parasitol. 2002;88(5):849–855.
30. Zhaofa X, Jintao L, Yu L, Long M. The BLI-3/TSP-15/DOXA-1 dual oxidase complex is required for iodide toxicity in Caenorhabditis elegans. G3 Bethesda 2014;5(2):195–203.
31. de la Cruz IP, Ma L, Horvitz HR. The Caenorhabditis elegans Iodotyrosine Deiodinase Ortholog SUP-18 Functions through a Conserved Channel SC-Box to Regulate the Muscle Two-Pore Domain Potassium Channel SUP-9. PLoS Genet. 2014;10(2):e1004175.
32. Yue S, Min L. [Strongyloides stercoralis infection with hypothyroidism: one case report]. Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi 2017;29(3):393–394.
33. Ganga G, Varshney JP, Sharma RL, Varshney VP, Kalicharan null. Effect of Fasciola gigantica infection on adrenal and thyroid glands of riverine buffaloes. Res. Vet. Sci. 2007;82(1):61–67.
34. Dissanayake PI, Chennuri R, Tarjan G. Fine-needle aspiration diagnosis of primary hydatid disease of the thyroid; first reported case in the USA. Diagn. Cytopathol. 2016;44(4):334–337.
35. Gupta S, Sodhani P. Clinically unsuspected thyroid involvement in cysticercosis: a case report. Acta Cytol. 2010;54(5 Suppl):853–856.
36. Yenkeshwar PN, Kumbhalkar DT, Bobhate SK. Microfilariae in fine needle aspirates: a report of 22 cases. Indian J. Pathol. Microbiol. 2006;49(3):365–369.
37. Góes VC, Neves RH, Arnóbio A, Bernardo-Filho M, Machado-Silva JR. Streptozotocin (STZ) and schistosomiasis mansoni change the biodistribution of radiopharmaceutical sodium (99m)Tc-pertechnetate in mice. Nucl. Med. Biol. 2016;43(9):581–586.
38. Nagayama Y, Watanabe K, Niwa M, McLachlan SM, Rapoport B. Schistosoma mansoni and alpha-galactosylceramide: prophylactic effect of Th1 Immune suppression in a mouse model of Graves’ hyperthyroidism. J. Immunol. 2004;173(3):2167–2173.
39. Nagayama Y, McLachlan SM, Rapoport B, Oishi K. Graves’ hyperthyroidism and the hygiene hypothesis in a mouse model. Endocrinology 2004;145(11):5075–5079.
40. Meinel TR, Gottstein B, Geib V, Keel MJ, Biral R, Mohaupt M, Brügger J. Vertebral alveolar echinococcosis-a case report, systematic analysis, and review of the literature. Lancet Infect. Dis. 2018;18(3):e87–e98.
41. Salman F, Khan MI, Hussain I, Abdullah HMA. Pathological fracture of femoral neck in a middle-aged woman: a rare presentation of primary hydatid cyst disease in humans. BMJ Case Rep. 2018;2018:bcr-2017-222980.
42. Chen Z, Andreev D, Oeser K, Krljanac B, Hueber A, Kleyer A, Voehringer D, Schett G, Bozec A. Th2 and eosinophil responses suppress inflammatory arthritis. Nat. Commun. 2016;7:11596.
43. Sarter K, Kulagin M, Schett G, Harris NL, Zaiss MM. Inflammatory arthritis and systemic bone loss are attenuated by gastrointestinal helminth parasites. Autoimmunity 2017;50(3):151–157.
44. Odiere MR, Scott ME, Weiler HA, Koski KG. Protein deficiency and nematode infection during pregnancy and lactation reduce maternal bone mineralization and neonatal linear growth in mice. J. Nutr. 2010;140(9):1638–1645.
45. Schwarzbauer JE, Spencer CS. The Caenorhabditis elegans homologue of the extracellular calcium binding protein SPARC/osteonectin affects nematode body morphology and mobility. Mol. Biol. Cell 1993;4(9):941–952.
46. Beall MJ, Pearce EJ. Human transforming growth factor-beta activates a receptor serine/threonine kinase from the intravascular parasite Schistosoma mansoni. J. Biol. Chem. 2001;276(34):31613–31619.
47. DeGroot MS, Shi H, Eastman A, McKillop AN, Liu J. The Caenorhabditis elegans SMOC-1 Protein Acts Cell Nonautonomously To Promote Bone Morphogenetic Protein Signaling. Genetics 2019;211(2):683–702.
48. Schultz RD, Bennett EE, Ellis EA, Gumienny TL. Regulation of extracellular matrix organization by BMP signaling in Caenorhabditis elegans. PloS One 2014;9(7):e101929.
49. Kwon YS, Lee HW, Kim HJ. Paragonimus westermani infection manifesting as a pulmonary cavity and adrenal gland mass: A case report. J. Infect. Chemother. Off. J. Jpn. Soc. Chemother. 2019;25(3):200–203.
50. Spahn S, Helmchen B, Zingg U. Alveolar echinococcosis of the right adrenal gland: a case report and review of the literature. J. Med. Case Reports 2016;10(1):325.
51. Poderoso WLS, Santana WB de, Costa EF da, Cipolotti R, Fakhouri R. Ectopic schistosomiasis: description of five cases involving skin, one ovarian case and one adrenal case. Rev. Soc. Bras. Med. Trop. 2008;41(6):668–671.
52. Mutreja D, Sivasami K, Tewari V, Nandi B, Nair GL, Patil SD. A 36-year-old man with vomiting, pain abdomen, significant weight loss, hyponatremia, and hypoglycemia. Indian J. Pathol. Microbiol. 2015;58(4):500–505.
53. Chen A-L, Sun X, Wang W, Liu J-F, Zeng X, Qiu J-F, Liu X-J, Wang Y. Activation of the hypothalamic-pituitary-adrenal (HPA) axis contributes to the immunosuppression of mice infected with Angiostrongylus cantonensis. J. Neuroinflammation 2016;13(1):266.
54. Jones N, Cocchiarella A, Faris K, Heard SO. Pancreatitis associated with Strongyloides stercoralis infection in a patient chronically treated with corticosteroids. J. Intensive Care Med. 2010;25(3):172–174.
55. Darlong J. Strongyloides hyper infection in a steroid dependent leprosy patient. Lepr. Rev. 2016;87(4):536–542.
56. Morales-Montor J, Mohamed F, Damian RT. Schistosoma mansoni: the effect of adrenalectomy on the murine model. Microbes Infect. 2004;6(5):475–480.
57. Antonios SN, Ismail HI, el-Nouby KA, Khalifa EA. Morphometric and histochemical study of the adrenal cortex in experimental schistosomiasis mansoni. J. Egypt. Soc. Parasitol. 2001;31(1):13–20.
58. Morales-Montor J, Mohamed F, Ghaleb AM, Baig S, Hallal-Calleros C, Damian RT. In vitro effects of hypothalamic-pituitary-adrenal axis (HPA) hormones on Schistosoma mansoni. J. Parasitol. 2001;87(5):1132–1139.
59. Saad AH, Abdelbaky A, Osman AM, Abdallah KF, Salem D. Possible role of Schistosoma mansoni infection in male hypogonadism. J. Egypt. Soc. Parasitol. 1999;29(2):307–323.
60. Lansoud-Soukate J, Dupont A, De Reggi ML, Roelants GE, Capron A. Hypogonadism and ecdysteroid production in Loa loa and Mansonella perstans filariasis. Acta Trop. 1989;46(4):249–256.
61. Botelho MC, Crespo M, Almeida A, Vieira P, Delgado ML, Araujo L, Machado JC, Correia da Costa JM. Schistosoma haematobium and Schistosomiasis mansoni: production of an estradiol-related compound detected by ELISA. Exp. Parasitol. 2009;122(3):250–253.
62. Botelho MC, Soares R, Vale N, Ribeiro R, Camilo V, Almeida R, Medeiros R, Gomes P, Machado JC, Correia da Costa JM. Schistosoma haematobium: Identification of new estrogenic molecules with estradiol antagonistic activity and ability to inactivate estrogen receptor in mammalian cells. Exp. Parasitol. 2010;126(4):526–535.
63. Cardoso R, Lacerda PC, Costa PP, Machado A, Carvalho A, Bordalo A, Fernandes R, Soares R, Richter J, Alves H, Botelho MC. Estrogen Metabolism-Associated CYP2D6 and IL6-174G/C Polymorphisms in Schistosoma haematobium Infection. Int. J. Mol. Sci. 2017;18(12):2560.
64. Ribeiro AR, Luis C, Fernandes R, Botelho MC. Schistosomiasis and Infertility: What Do We Know? Trends Parasitol. 2019;35(12):964–971.
65. Kini S, Dayoub N, Raja A, Pickering S, Thong J. Schistosomiasis-induced male infertility. Case Rep. 2009;2009:bcr0120091481.
66. Dezsényi B, Sárközi L, Kaiser L, Tárkányi K, Nikolova R, Belics Z. Gynecological and obstetrical aspects of Enterobius vermicularis infection. Acta Microbiol. Immunol. Hung. 2018;65(4):459–465.
67. Mand S, Debrah AY, Klarmann U, Mante S, Kwarteng A, Batsa L, Marfo-Debrekyei Y, Adjei O, Hoerauf A. The role of ultrasonography in the differentiation of the various types of filaricele due to bancroftian filariasis. Acta Trop. 2011;120 Suppl 1:S23-32.
68. Panda DK, Mohapatra DP. Bancroftian filariasis associated with male sterility. BMJ Case Rep. 2018;2018:bcr-2017-223236.
69. Kurniawan F, Tahapary DL, de Ruiter K, Yunir E, Biermasz NR, Smit JWA, Supali T, Sartono E, Yazdanbakhsh M, Soewondo P. Effect of anthelmintic treatment on serum free IGF-1 and IGFBP-3: a cluster-randomized-controlled trial in Indonesia. Sci. Rep. 2020;10(1):19023.

ABSTRACT

Endocrine Disrupting Chemicals (EDCs) impact health and disease. Scientific research conducted over the last few decades has solidified our knowledge of the health impacts of these chemicals. Intrauterine exposure of EDCs can have transgenerational effects, thus laying the foundation for disease in later life, when exposure may not be documentable. The meticulously orchestrated endocrine system is often a target for these chemicals. As the endocrine system is central to the body’s physiological and biological functions, EDCs can lead to perturbations in the functioning of an individual. Exposure to EDCs can occur right from children’s products to personal care products, food containers to pesticides and herbicides. Moreover, there are many unsuspected chemicals which may be contributing to the disease burden in the society, which have never been studied. The dose response relationship may not always be predictable for the different EDCs as even low-level exposures that may occur in everyday life can have significant effects in a susceptible individual. Although individual compounds have been studied in detail, the effects of a combination of these chemicals are yet to be studied in order to understand the real-life situation, where human beings are exposed to a cocktail of these EDCs. This chapter aims to summarize the available literature regarding these EDCs and their effects on endocrine physiology.

INTRODUCTION

Endocrine Disrupting Chemicals (EDCs) are a ubiquitous problem. This is a global issue and health hazard not well addressed due to lack of evidence and testing. Only a few EDCs are known and the others are suspected or yet to be explored (1). EDCs represent a broad class of natural or synthetic chemicals which are widely dispersed in the environment. This can be ingested or consumed or inhaled and may be found in larger quantities or trace amounts in serum, placenta, fat, umbilical cord blood etc. Exposure to EDCs can occur as early as in gestational period or childhood and can impact later stages of life. EDCs can alter normal physiological mechanisms in our body leading to a myriad of endocrinological problems both in children and adults.

The Endocrine Society defined EDC as “an exogenous chemical, or mixture of chemicals, that interfere with any aspect of hormone action.” In other words, the chemical substances that can affect the endocrine system resulting in adverse effects are called Endocrine Disruptor Chemicals (EDCs) (2). These chemicals often bind to the endogenous receptors (e.g.: estrogen receptor, steroid receptor) and interfere with the normal function of brain, reproductive organs, development, immune system, and other organs (3).

The common EDCs are bisphenol A (BPA), perchlorate, dioxins, phthalates, phytoestrogens, polychlorinated biphenyls (PCB), polybrominated diphenyl ethers (PBDE), triclosan, perfluoroalkyl and polyfluoroalkyl substances (PFAS), pesticides like dichlorodiphenyldichloroethylene (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE), organophosphorus compounds, alkylphenols(surfactants), parabans, methoxychlor,  diethylstilbestrol (DES), fungicide vinclozolin, and natural hormones (2) (4) (5). Among these, BPA is the most commonly encountered EDC, which has both estrogenic and antiandrogenic properties. EDCs are  mostly lipophilic in nature and resistant to metabolism (6). EDCs are usually present in food, beverages, pesticides, or air. People who get exposed to any of these EDCs may have hormonal imbalance. Even a small amount of EDC consumed can result in hormonal imbalance especially in children (2). Sometimes they are stored in body fats, and transferred to the developing fetus via the placenta (6).

Studies on animal models and humans reveal that the mechanisms through which the EDCs act involve divergent pathways. The EDC`s can act like endogenous hormones and thereby increase or decrease the cellular response. Also, they can block the effects of hormones and stimulate or inhibit the production of hormones. They can thus interfere with synthesis, transport, action, and degradation of hormones (7). EDCs can act via nuclear receptors, nonsteroidal receptors, transcription coactivators, and certain enzymatic pathways (5).

HISTORY OF EDCs

The effect of EDCs was first noticed by pig farmers in USA. Farmers observed pigs fed on moldy grain did not reproduce. Later it was found that moldy grain contained mycoestrogens. Several other incidents with such EDCs were noticed by farmers in other parts of the world. In 1940, diethylstilbestestrol (DES), a synthetic estrogen, was prescribed to women in their first trimester of pregnancy to prevent threatened miscarriage. Later in 1971, a rare vaginal cancer in daughters born to mothers who had taken DES was noted. All these events inspired Rachel Carlson to write a book named ‘Silent Spring’. In this book the author warned about long- term consequences of the use of pesticides and herbicides. In another book ‘Our Stolen Future ‘by Theo Colbron, Dianne Dumankosi, and John Peterson Meyers additional evidence on EDC was described. The hypothesis and evidence generated by this book was used for future research on EDC. This booked paved the path for the US regulators to create the United States Environment Protect Agency.

ARE HORMONES AND EDCs THE SAME?

EDCs are not the same as hormones but they can mimic hormones, and produce ill effects in the body.

EDCs AND HUMAN HEALTH

EDCs can affect several systems in our body resulting in many ill health effects. There is evidence showing various diseases are linked to EDCs as shown in Table 2.

TBBPA- Tetrabromobisphenol A, CYP - cytochrome P450 enzymes, NMDA- N-methyl-D-aspartate, AhR - aryl hydrocarbon receptor

EFFECT OF EDCs ON ENDOCRINE SYSTEM

Neuro- Hypothalamic Effects

According to recent studies one in eight children 2-9 years of age suffer from neurodevelopmental disorders (NDDs) in India. NDDs include speech and language disorders, autism, cerebral palsy, epilepsy, vision impairment, ADHD, learning disorders, etc. EDCs are one among other risk factors associated with development of NDDs in children. NDD burden can be lessened by eliminating the causative factors or by preventing exposure to them. The major EDCs associated with NDDs are PCB and polybrominated diphenyl ethers (PBDEs).  Other EDCs that are linked to NDDs but lack firm evidence are brominated flame retardants, perfluorinated compounds, and pesticides. Animal studies reveal that EDCs can alter or affect neuronal development, synaptic organization, neurotransmitter synthesis and release, and structural development of the brain (11). Studies of pregnant women who lived near Lake Michigan, with high levels of exposure to PCBs, revealed that children of mothers with the highest exposure levels were much more likely to have lower average IQ levels and poorer performance on reading comprehension (12). BPA and phthalates have also been shown to be associated with behavioral problems in children, including anxiety and depression (13,14). Prenatal pesticide exposure has been linked to increased likelihood of children having autism spectrum disorder or developmental delay (15).

EDCs can cause perturbations of the neuroendocrine processes originating in the hypothalamus, and can also act on the steroid hormone receptors and other signaling pathways that occur widely throughout the brain. The critical period of exposure is important because even minor alterations in hormones can alter the neurobiological outcome during development. Our knowledge in this area is predominantly derived from animal studies as human studies (postmortem studies, accurate measurement of hypothalamic releasing hormones) are not feasible. Animal studies have shown the variable effects of BPA exposure on ER α and β protein and mRNA expression in different areas of the brain (16,17,18,19). Treatment of adult male and female rats for 4 days with low-dose BPA had significant effects on mRNAs for aromatase (increased in both sexes) and 5α-reductase 1 (decreased in females) in the prefrontal cortex (20). Although we know that developmental EDC exposure can alter the expression of genes and proteins for steroid hormone receptors, we cannot draw generalized conclusions from these animal models and future research should target especially this area of early EDC exposure.

EDC exposure can also have neuroendocrine effects. Animal studies have reported on the stimulatory as well as inhibitory actions of BPA on GnRH and kisspeptin systems (21,22). Studies on PCBs and phthalates have shown mixed results. Animal studies have shed some light on the effect of EDCs on the developing hypothalamic pituitary adrenal (HPA) axis. BPA exposure has been found to be associated with an increase in adrenal weight and an attenuated stress response (23). Basal corticosterone, as well as CRH- or ACTH-induced corticosterone release, has been found to be significantly suppressed in PCB exposed rats (24). These effects of EDCs on the HPA axis leading to aberrant stress response needs to be evaluated further in humans. Animal studies have opened up some new and interesting possibilities of EDC exposure with changes in AVP and oxytocin levels and social behavior (25,26).

Thyroid Function

EDCs can interfere with thyroid hormone synthesis, release, transport, metabolism and clearance.

PCB - Polychlorinated biphenyls, BPA - Bisphenol A, ADHD- Attention Deficit Hyperactivity Disorder, TBBPA - Tetrabromobisphenol A, T4 - tetraiodothyronine (thyroxine), T3 - triiodothyronine, TPO – Thyroperoxidase, TR – Thyroid Receptor, TH - Thyroid hormone, GH- Growth Hormone

Adipose Tissue and Metabolic Disorders

OBESITY

Obesity can result in the metabolic syndrome, reproductive problems, and cardiovascular risk factors. “Obesogens” are defined as “xenobiotic chemicals that can disrupt the normal developmental and homeostatic controls over adipogenesis and/or energy balance” (29). The “obesogen hypothesis” suggests that prenatal or early-life exposure to certain EDCs compounded by sedentary lifestyle and improper nutrition predisposes certain individuals to become obese later in life (30).  

In DES exposed mice an increase in body fat, leptin, adiponectin, interleukin (IL) - 6, triglyceride (TG) was observed. EDCs cause upregulation of gene expression involved in adipocyte differentiation and lipid metabolism resulting in fat accumulation (31). PPARg (peroxisome proliferator-activated receptors), a major regulator of adipogenesis, are expressed in adipocytes. It promotes adipocyte differentiation and the induction of lipogenic enzymes. During activation, PPARg along with retinoid X receptor (RXR), forms a heterodimer complex which then binds to PPAR response elements for regulation of fatty acids and repression of lipolysis. EDCs like tributyltin (TBT) and triphenyltin acts as PPARg and RXR agonists and increases adipose tissue mass.

Phytoestrogens mimic endogenous estrogens and exert various biological actions. They can bind to estrogen receptor (ER)a and estrogen receptor (ER)b and influence lipogenesis. One of the major sources of phytoestrogens is soy protein which contains genistein, a phytoestrogen. At low doses genistein inhibits lipogenesis whereas at high doses it can promote lipogenesis (27). EDCs like BPA, phthalates, dioxins perfluorinated compounds, and some pesticides are emerging as potential obeso­gens warranting further research.

DIABETES AND GLUCOSE HOMEOSTASIS

EDCs can disrupt glucose homeostasis in our body by affecting both insulin- and glucagon-secretory cells. Any toxic chemical that kills β cells or disrupts their function has been termed a “diabetogen”. The “diabetogen hypothesis” suggests that “every EDC circulating in plasma able to produce insulin resistance, independently of its obesogenic potential and its accumulation in adipocytes, may be considered a risk factor for metabolic syndrome and type 2 diabetes” (40). The obesogenic EDCs are risk factors for type 2 diabetes as well and lead to the dangerous combination of obesity and diabetes or “Diabesity”. However, certain EDCs may directly cause insulin resistance and defects in insulin production and secretion, without significantly affecting the weight of the individual. Studies have shown that acute treatment with BPA causes a temporary hyperinsulinemia, whereas longer-term exposure suppresses adiponectin release, and aggravates insulin resistance, obesity related syndromes, and development of diabetes mellitus. The hyperinsulinemia is attributed to the very rapid closure of ATP-sensitive K+ channels, potentiation of glucose-stimulated Ca2+ signals, and release of insulin via binding at extranuclear ER (41). Low doses of DES have been shown to impair the molecular signaling that regulates glucagon production through non genomic mechanism (27). POPs have been demonstrated to have direct effects on insulin signaling (42). They can lead to insulin resistance by causing adipose tissue inflammation. Heavy metals such as arsenic and mercury have also been considered as potential diabetogens. Intake of a high fat diet along with exposure to a cocktail of these EDCs (DEHP, BPA, PCB153, and TCDD) has been found to have sex specific alterations in the metabolic milieu in offspring. In males, there was alteration in the cholesterol metabolism whereas in females, there was pronounced effect on the glucose metabolism through a decrease in ER α expression and estrogen target genes (43).

The causal relationship between EDCs and type 1 diabetes is an area warranting research as animal studies have shown exposure to EDCs associated with insulitis (44).

Reproductive System

Over the past few decades there has been a surge in the incidence of reproductive system related disorders among both the males and females. EDCs can be attributed to this surge. Exposure to EDCs especially phytoestrogens have resulted in early menarche and polycystic ovarian diseases (PCODs) in adolescent girls. Infertility affects up to 15% of couples in the reproductive age group worldwide. The EDCs and their effect on reproductive system is summarized in Table 5.

DES – Diethylstilbestrol, DDT – dichlorodiphenyldichloroethylene, DDE - dichlorodiphenyldichloroethylen, DNA – Deoxyribonucleicacid, AR – Androgen Receptor, ER – Estrogen Receptor, AhR - aryl hydrocarbon receptor, ERK1/2 - extracellular signal-regulated kinase 2, mRNA – messenger RNA

EFFECTS ON THE FEMALE REPRODUCTIVE SYSTEM

In vivo animal studies and thereafter in vitro studies indicate that exposure to BPA (1–30M) impairs meiotic progression in human fetal oocytes, increased levels of recombination, and induces epigenetic changes that may contribute to chromosome congression failure (45,46). Studies in rats have shown that neonatal BPA exposure decreased the numbers of all follicle types and increased atretic follicles during adulthood (47). In vitro animal studies have demonstrated the toxic effect of phthalates on the follicle growth and inhibition of estradiol production (48). Similar toxic effects of pesticides and environmental pollutants on gene expression, follicle growth and oocyte quality have been confirmed in animal studies. BPA and phthalates have also been implicated in altered steroidogenesis in the gonads (49). Findings of alteration in uterine structure and function after exposure to EDCs is more concerning as it may lead to abnormalities in implantation and recurrent abortions (50). BPA exposure has been associated with increased risk of implantation failure and miscarriages (51). Animal studies have also pointed towards the transgenerational effect of prenatal BPA exposure on female fertility (52). Experimental studies have shown an association between phthalate exposure and reduced fertility (53). The findings of these studies need to be confirmed in the human ovary to fully understand the impact of these EDCs on fertility and reproductive health as well as the transgenerational impact. EDCs have also been found to have adverse effects on menstrual cyclicity in women. Fungicide exposure has been associated with a significant decrease in bleeding (54). BPA and pesticides may accelerate ovarian failure and may lead to premature menopause in women (55). In utero exposure to DES increases the lifetime risk of premature menopause (56). Propyl paraben, a preservative in personal care product, was associated with lower antral follicle counts as well as higher day-3 FSH levels indicating accelerated ovarian aging (57). It may not be exposure to just a single EDC and more often than not it may be a cocktail of these that could lead to early reproductive senescence. In animal studies, late gestational exposure to DES causes ovarian hyperandrogenism and menstrual abnormalities similar to those in women with PCOS (58). A few epidemiological studies have pointed towards an association between phthalate exposure and risk of endometriosis, possibly due to increased viability of cells (59). 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure may disrupt cannabinoid signaling in the human endometrium and lead to increased inflammation in the endometrium (60). TCCD exposure can cause a progesterone-resistant phenotype that may persist over multiple generations, suggesting that TCDD exposure has transgenerational effects on endometriosis (61). TCDD increases the expression of thymus-expressed chemokine and promotes the invasiveness of endometrial stromal cells by increasing the expression of matrix metalloproteinase-2 and -9(62). TCDD also reduces the expression of CD82 (a wide-spectrum tumor metastasis suppressor that inhibits the mobility and invasiveness of cells), and increases the expression of CCL2-CCR2, which recruits macrophages and further down-regulates CD82 (63). Pesticides like fenvalerate stimulate the growth of uterine fibroid cells by enhancing cell cycle progression and inhibiting apoptosis through an ER-independent pathway (64). DES exposure has been shown to increase the occurrence of early onset fibroids in the Sister Study and Nurses’ Health Study II (65,66). Given the multiplicity of effects of EDCs on the female reproductive system, there remains an urgent need for future studies to confirm the findings of experimental and animal studies and understand the underlying mechanisms.

EFFECTS ON THE MALE REPRODUCTIVE SYSTEM

EDCs, by virtue of their antiandrogenic and estrogenic effects can have a profound influence on the male reproductive physiology. Studies on the causative effect of EDCs on hypospadias have not given consistent results due to the small number of subjects studied. Levels of chlorinated pesticides have been found to be higher in breast milk of mothers with cryptorchid boys (77). Studies on the incidence of cryptorchidism with xenoestrogen exposure showed detectable levels of lindane and mirex in placenta with higher cryptorchidism risk (78). Higher dioxin levels in breast milk and dibutyltin concentrations in placenta were associated with cryptorchidism in Danish boys (79). Dioxins may have estrogenic effects through interaction of the dioxin-AhR nuclear translocator complex with estrogen receptor. High exposure to DDE and PCBs also has a higher risk of cryptorchidism (80). Environmental factors play an important role in the development of testicular cancers. Cryptorchidism and hypospadias are well-characterized risk factors of testicular germ cell cancers (TGCC). Although TGCC is probably a condition with fetal origins, it has been practically difficult to prove the association between pre and postnatal exposure of EDCs and TGCC, given the long lag time between exposure and effect. A positive association of TGCC with DDE (81) and chlordane exposure (cis-nonachlor and trans-nonachlor) has been found (82). Intra uterine exposure to EDCs that affect the spermatogonial stem cells or Sertoli cells, can cause irreversible changes that result in permanently low adult sperm number. PCB exposure may affect sperm DNA integrity and motility (83). DDE exposure has been inversely associated with sperm motility and total sperm count (84), and positively correlated with defects in sperm chromatin condensation and morphology (85). Fetal and perinatal exposure via breast-feeding to dioxin in the Seveso accident was associated with reductions in sperm concentration, number of motile sperm, and total sperm number (86). PBDEs used as flame retardants have been found to negatively affect sperm concentration, testicular size and sperm motility (87). The major impediment to establishing a causal role of these effects of EDCs is the long lag time between the critical exposure and the manifestation of the adverse outcomes.

EFFECTS ON PUBERTY  

There has been a decrease in the age of breast development but the age of menarche has not changed significantly. This finding alerted researchers about the possible interfering role of EDCs in pubertal mechanisms. Results of epidemiological studies have been equivocal on the effects of BPA and phthalates on pubertal onset (67,68). Studies have pointed towards higher kisspeptin levels in girls exposed to phthalates, which may promote precocious puberty (69). There have been inconsistencies between animal and human studies and hence, inconclusive data on the effects of other EDCs like pesticides and environmental contaminants on puberty. Apparently innocuous substances like lavender oil and tea tree oil present in lotions and creams can lead to prepubertal gynecomastia by their estrogenic effects (70). A very interesting hypothesis has been put forward to explain the role of EDCs in precocious puberty seen in immigrant girls from developing countries. Early and temporary exposure to weakly estrogenic dichlorodiphenyltrichloroethane (DDT) in developing countries, where the exposure is still high, could stimulate hypothalamic maturation while the pituitary gonadotrophins are inhibited via a negative feedback that prevents manifestation of central maturation. This negative feedback disappears after withdrawal from the exposure, as happens when the child migrates to a different environment. This could precipitate precocious puberty in these migrant children (71). High exposure to endosulfan has been shown to be associated with pubertal delay, due to its antisteroidogenic properties (72). Dioxins act through aryl hydrocarbon receptors and thereby interact with other nuclear receptors. Exposure in boys has been associated with delayed puberty and in girls with delayed thelarche due to its antiestrogenic effects (73,74). Lead exposure has been implicated in delayed puberty in both boys and girls (75,76). Endocrine disrupters may alter the levels of endogenous hormones and their ratios by influencing their production, secretion, binding to carriers, metabolism and excretion. When studying these compounds, one needs to keep in mind about their active metabolites and the multiplicity of effects on the complex endocrine milieu.  

Hormone Responsive Cancer

Most cancer occur due to genetic predisposition or exposure to environmental or occupational hazards. EDCs can alter the genes and result in uncontrolled proliferation of cells. Almost all the EDCs identified are known to cause cancer. People working in certain industries like coal, steel, rubber, textile, paper manufacturing, paint are at higher risk of developing cancers due to increased exposure to these EDCs. Studies have shown that early exposure to these EDCs BPA, PCBs, perflourinated compounds, phthalates, and some pesticides can increase cancer risk(1).Several EDCs that mimic endogenous estrogens are potential carcinogens. The estrogen-responsive cancers including breast, endometrial, ovarian, and prostate cancers are caused due to several chemical xenoestrogens and phytoestrogens (88). EDC exposure during the critical periods of mammary gland development like gestation, puberty, and pregnancy may predispose to carcinogenesis. Dioxin exposure, especially TCDD has been found to increase the incidence of breast cancer (89). Inconsistent results have been obtained with regards to pesticide exposure and breast cancer risk, possibly due to individual chemicals studied whereas in real life, humans are often exposed to a mixture of them. Breast cancer patients present more frequently with a combination of aldrin, DDE, and DDD, and this mixture has not been found in healthy women (90). Exposure to diethyl phthalate, the parent may be associated with a 2-fold increase in breast cancer risk (91). EDCs may influence other estrogen dependent cancers as well. In women previously exposed to chlorotriazine herbicides, there was a significant 2.7-fold increased risk for ovarian neoplasms (92). Higher PFOA levels are associated with ovarian cancer (93). In males, those EDCs that can interfere with androgen and estrogen signaling pathways can increase the risk of prostate cancer. A classic example of developmental exposure and onset of latent disease is the progeny of mothers exposed to DES during pregnancy. Although prostatic structural abnormalities have been documented in this cohort (94), the exact effect on prostate cancer is yet to be ascertained as the cohort is still being followed up. Pesticide exposure and carcinogenesis has garnered much interest after the Agricultural Health Study (AHS) in the United States. Specific organophosphate insecticides like fonofos, malathion, terbufos, and aldrin) have been associated with increased risk of aggressive prostate cancer (95). Certain organophosphates like coumaphos and organochlorine (aldrin) pesticides increase prostate cancer risk in men with a family history of the disease (96). Compounds like chlorpyrifos, coumaphos, fonofos, and phorate strongly inhibit the hepatic CYP1A2 and CYP3A4 enzymes that metabolize testosterone, estradiol, and estrone (97) and thereby act as EDCs apart from causing DNA damage by oxidative stress. TCDD, the most toxin dioxin in the Agent Orange herbicide spray has been found to have a strong positive association in the incidence and aggressiveness of prostate cancer in the Vietnam veterans (98). Trace elements like arsenic and cadmium, have been classified as EDCs due to their ability to act as a ligand and/or interact with members of the steroid receptor superfamily and have been implicated in prostate cancer although more conclusive studies are needed.

Effect on The Adrenals

The adrenal gland is probably one of the most ignored glands in toxicology, despite it being very sensitive to toxins. By virtue of its intense vascularity, its capacity for uptake and storage of lipophilic agents and high local concentrations of enzymes of CYP family with potential for bioactivation of toxins, the adrenals are very susceptible to the toxic effects of EDCs. The results of toxicological research on adrenals may not always be straightforward because of the dynamic nature of the HPA axis. Thus, even in the face of compromised adrenal steroidogenesis, it is not surprising to find relatively normal levels of circulating cortisol, albeit with an increased ACTH drive. Hence, scientists studying the toxic effect of EDCs on the adrenals, need to take into account the ACTH and cortisol levels as well as the adrenal weight. One of the earliest evidences for an adrenal disruptor was the use of the anesthetic, etomidate, which inhibits CYP11B1, leading to adrenal insufficiency. Another direct inhibitor of adrenal steroidogenic enzymes is a derivative of the pesticide DDD, mitotane (o,p’-DDD), which is used to treat Cushing’s syndrome. Polychlorinated biphenyl 126 (PCB126) causes an increase in aldosterone biosynthesis by increasing expression of CYP11B2, the enzyme which catalyzes the final step of aldosterone biosynthesis. High concentrations PCB126 has been shown to increase expression of the Angiotensin 1 (AT1) receptor, enhancing angiotensin II responsiveness of adrenal cells. Lead has also been reported to increase aldosterone synthesis by a mechanism consistent with upregulation of CYP11B2. It has also been reported that a class of herbicides (2-chloro-s-triazine herbicides) increase the expression of CYP19, which encodes aromatase, raising the possibility of increased adrenal estrogen secretion (99). The lack of a clear understanding of the adrenal toxicology can be overcome by the use of sophisticated endocrine studies, which take into account the dynamicity of the HPA axis.

EFFECT OF EDCs DURING PREGNANCY

Studies on animals have shown that EDCs can affect germ cell lines. In a cohort study of 47,540 women with history of exposure to diethylstilbestrol (DES) during pregnancy and ADHD diagnosis were followed up to three generations (F0, F1, F2) to know consequences of exposure to DES. This study revealed that the progeny of mothers who used DES in the 1^st trimester of pregnancy had higher risk of developing ADHD. BPA is another EDC which can lead to neuroendocrinal problems (100). This highlights the ill effects of EDCs in vertical transmission. EDCs like perfluorooctanoic acid have been implicated in pregnancy induced hypertension. There have been some pointers towards an association between BPA and preterm birth but it has not been conclusively proven in experimental animal studies (101).

Phthalate exposure during pregnancy may be associated with increased odds of prematurity (102). The possible mechanisms are interference with the placental function via effects on trophoblast differentiation and placental steroidogenesis which could increase the risk of preterm birth. Similar genetic effects of pesticides have also been shown to result in increased prematurity and preterm birth. This risk has been shown to be magnified in those with certain genetic mutations, highlighting the gene- environment interaction (103). Environmental contaminants like TCCD exert pro-inflammatory effects on the placenta, leading to infection-mediated preterm birth (104). EDCs have also been implicated in adverse birth outcomes. In the Generation R study in The Netherlands, prenatal BPA exposure was associated with reduced fetal weight and head circumference (105). The same study also showed that maternal phthalate exposure was associated with an increased time-to-pregnancy (106) and impaired fetal growth during pregnancy and decreased placental weight (107). In a similar Japanese study, maternal urinary MEHP levels were negatively associated with anogenital distance (AGD) in male offspring (108). Pesticide exposure during the second trimester of pregnancy have been negatively associated with birth weight, birth length, and head circumference as shown in the data from Center for Health Assessment of Mothers and Children of Salinas (CHAMACOS) (109). Increased incidence of infants being born as small for gestational age has also been reported in mothers who were exposed to pesticides (110). A sex dependent nature of these adverse birth outcomes has been demonstrated in a Chinese study with a decrease in gestational duration in girls but not boys (111). Similarly, in the Hokkaido Study on Environment and Children’s Health, an ongoing cohort study in Japan, PCDF and PCDD exposures were negatively associated with birth weight and infant development, with males being more susceptible than females (112). However, not all studies are shown these consistent adverse effects of EDCs. Hence future studies should confirm these preliminary findings and also study certain EDCs which have never been studied so far in experimental and epidemiological studies.

DETECTION OF EDCs

EDCs may be in complex forms or in trace amounts in biological fluids or environment which makes it difficult to identify or detect them. The methods used for the detection of these compounds should be highly sensitive and specific. These include liquid chromatography, gas chromatography and capillary electrophoresis. The bioassay techniques (Receptor binding assay, Receptor gene assay, DNA binding assay) are either qualitative or quantitative and can be helpful to know the biological effects of the complex samples. Due to the complexities and trace amount of the EDC, preconcentration is required (5). However, the limitations in sensitivity, reproductivity, difficulty in separation, and affordability still remain.

FUTURE TRENDS  

Newer methods are being explored to predict the effect of chemical disruptors using artificial intelligence (AI).  Combining artificial neural network (ANN) and chemical similarity approaches, a significant role of AI in chemical endocrine receptor disruption prediction has been demonstrated. For example, isoflavone genistein, a phytoestrogenfrom soy was found to be active or disruptive whereas isoflavone daidzein from the soy was predicted to be inactive or non-disruptive (113).  ANN can be used to predict chemical activity against estrogen and androgen receptors. Machine learning and ANN can more accurately and precisely predict EDCs in future.

Biosensors are newer devices which can detect chemicals up to femtomolar limit of detection.  Aptasensors, Nanotubes, Molecularly imprinted polymer (MIP)-based sensors are the emerging EDC detectors (114). Recently a device called ‘Tethys’ has been invented to detect presence of lead in water. Lead is known to affect the hormone signaling and central nervous system. This device works on the basis of nanocarbon tubes and could send water quality information via Bluetooth (115).

Among several computer aided approaches,  invitro and in silico predictions are now used to predict large number of chemical disruptors in the environment (116). Also the ligand-based models, like QSAR models which can predict biological activities of EDC and structure-based models can be combined with Artificial Intelligence technology for more accurate EDC predictions (117).

EDCs IN THE TROPICS

Pesticide use has increased over the years due to intensification of agricultural practices in the tropical countries. While the developed countries do have a well-established legal framework for pesticide environmental risk assessments, such requirements are either not available or inadequately implemented in tropical countries. Added to these woes are the fact that cheap compounds that are environmentally persistent and highly toxic, banned from agriculture use in developed countries, still remain popular in developing countries (118). These may lead to soil and water contamination with pesticide residues. The effect of these compounds on the applicators as well as the consumers are manyfold. In a multi-centric study to assess the pesticide residues in selected food commodities (Surveillance of Food Contaminants in India, 1993), DDT residues were found in about 82% of the 2205 samples of bovine milk. Data on 186 samples of 20 commercial brands of infants’ formulae showed the presence of residues of DDT and Hexachlorocyclohexane (HCH) isomers in about 70 and 94% of the samples with their maximum level of 4.3 and 5.7 mg/kg respectively (119). The average daily intake of HCH and DDT by Indians was reported to be 115 and 48 mg per person respectively, which were higher than those observed in most of the developed countries (120). Over these continuous levels of exposure through food, water and soil are the occasional spillovers and accidents that lead to greater exposure. Although these exposures have been documented well in literature, there are sparse studies from the tropical areas on the long-term effects, especially in relation to the endocrine system. Although there are compelling social and economic benefits for the rampant use of EDCs, the policymakers need to be made aware of the long term and sometimes transgenerational effects of these molecules.

CONCLUSION

EDCs are an emerging global health problem that requires urgent attention and action. The most common EDCs that we encounter in our day-to-day life are BPA, PCBs, paraben etc. This results in endocrinological problems in all the age groups. There is an urgent need of novel biomarkers, detectors or assays using novel technologies for the early detection of EDCs. The novel technologies like Artificial Intelligence, OMICS (Genomics, Epigenomics, Mitochondriomics) and Nano technology are the new-way forward in this regard. Food and Health authorities play a vital role in curbing this problem. Food and safety laws should be more stringent and higher throughput screening for EDCs should be done prior to approval of any products. BPA free, paraben free products should be encouraged. Industrialists and others manufacturers must make sure not to pollute the water with the industrial wastes. All these measures will help in eliminating EDCs related health problems.

REFERENCES

1. Gore AC, Crews D, Doan LL, Merrill ML, Patisaul H, Zota A. INTRODUCTION TO ENDOCRINE DISRUPTING CHEMICALS (EDCs). :76.
2. Endocrine Disruptors [Internet]. National Institute of Environmental Health Sciences. [cited 2021 Feb 7]. Available from: https://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm
3. Research NC for T. Endocrine Disruptor Knowledge Base [Internet]. FDA. FDA; 2019 [cited 2021 Feb 7]. Available from: https://www.fda.gov/science-research/bioinformatics-tools/endocrine-disruptor-knowledge-base
4. WHO | Global assessment of the state-of-the-science of endocrine disruptors [Internet]. WHO. World Health Organization; [cited 2021 Feb 8]. Available from: https://www.who.int/ipcs/publications/new_issues/endocrine_disruptors/en/
5. Jones L, Regan F. Endocrine Disrupting Chemicals. In: Reference Module in Chemistry, Molecular Sciences and Chemical Engineering [Internet]. Elsevier; 2018 [cited 2021 Feb 7]. p. B9780124095472144000. Available from: https://linkinghub.elsevier.com/retrieve/pii/B9780124095472145123
6. Elobeid MA, Allison DB. Putative environmental-endocrine disruptors and obesity: a review. Curr Opin Endocrinol Diabetes Obes. 2008 Oct;15(5):403–8.
7. Schneider M, Pons J-L, Labesse G, Bourguet W. In Silico Predictions of Endocrine Disruptors Properties. Endocrinology. 2019 Nov 1;160(11):2709–16.
8. Bergman Å, United Nations Environment Programme, World Health Organization. State of the science of endocrine disrupting chemicals - 2012 an assessment of the state of the science of endocrine disruptors [Internet]. Geneva: WHO : UNEP; 2013 [cited 2021 Feb 7]. Available from: http://www.who.int/ceh/publications/endocrine/en/index.html
9. Lucaccioni L, Trevisani V, Marrozzini L, Bertoncelli N, Predieri B, Lugli L, et al. Endocrine-Disrupting Chemicals and Their Effects during Female Puberty: A Review of Current Evidence. Int J Mol Sci. 2020 Mar 18;21(6):2078.
10. Bell MR. Endocrine-disrupting actions of PCBs on brain development and social and reproductive behaviors. Curr Opin Pharmacol. 2014 Dec;19:134–44.
11. Arora NK, Nair MKC, Gulati S, Deshmukh V, Mohapatra A, Mishra D, et al. Neurodevelopmental disorders in children aged 2–9 years: Population-based burden estimates across five regions in India. PLOS Med. 2018 Jul 24;15(7):e1002615.
12. Jacobson JL, Jacobson SW. Intellectual impairment in children exposed to polychlorinated biphenyls in utero. N Engl J Med. 1996;335:783–789.
13. Harley KG, Gunier RB, Kogut K, et al. Prenatal and early childhood bisphenol A concentrations and behavior in school-aged children. Environ Res. 2013;126:43–50.
14. Braun JM, Kalkbrenner AE, Calafat AM, et al. Impact of early-life bisphenol A exposure on behavior and executive function in children. Pediatrics. 2011;128:873–882.
15. Shelton JF, Geraghty EM, Tancredi DJ, et al. Neurodevelopmental disorders and prenatal residential proximity to agricultural pesticides: the CHARGE Study. Environ Health Perspect. 2014;122:1103–1109.
16. Chen F, Zhou L, Bai Y, Zhou R, Chen L. Sex differences in the adult HPA axis and affective behaviors are altered by perinatal exposure to a low dose of bisphenol A. Brain Res. 2014;1571:12–24.
17. Cao J, Rebuli ME, Rogers J, et al. Prenatal bisphenol A exposure alters sex-specific estrogen receptor expression in the neonatal rat hypothalamus and amygdala. Toxicol Sci. 2013;133:157–173.
18. Monje L, Varayoud J, Muñoz-de-Toro M, Luque EH, Ramos JG. Exposure of neonatal female rats to bisphenol A disrupts hypothalamic LHRH pre-mRNA processing and estrogen receptor expression in nuclei controlling estrous cyclicity. Reprod Toxicol. 2010;30:625–634.
19. Yu B, Chen QF, Liu ZP, et al. Estrogen receptor and expressions in hypothalamus-pituitary-ovary axis in rats exposed lactationally to soy isoflavones and bisphenol A. Biomed Environ Sci. 2010;23:357–362.
20. Castro B, Sánchez P, Torres JM, Preda O, del Moral RG, Ortega E. Bisphenol A exposure during adulthood alters expression of aromatase and 5 alpha-reductase isozymes in rat prostate. PLoS One. 2013;8:e55905.
21. Bai Y, Chang F, Zhou R, et al. Increase of anteroventral periventricular kisspeptin neurons and generation of E2- induced LH-surge system in male rats exposed perinatally to environmental dose of bisphenol-A. Endocrinology.2011;152:1562–1571.
22. Patisaul HB, Todd KL, Mickens JA, Adewale HB. Impact of neonatal exposure to the ER agonist CD-1, bisphenol- A or phytoestrogens on hypothalamic kisspeptin fiber density in male and female rats. Neurotoxicology.2009;30:350–357.
23. Panagiotidou E, Zerva S, Mitsiou DJ, AlexisMN,Kitraki E. Perinatal exposure to low-dose bisphenol A affects the neuroendocrine stress response in rats. J Endocrinol.2014;220:207–218.
24. Meserve LA, Murray BA, Landis JA. Influence of maternal ingestion of Aroclor 1254 (PCB) or FireMaster BP-6 (PBB) on unstimulated and stimulated corticosterone levels in young rats. Bull Environ Contam Toxicol. 1992;48:715–720.
25. Wolstenholme JT, Taylor JA, Shetty SR, Edwards M, Connelly JJ, Rissman EF. Gestational exposure to low dose bisphenol A alters social behavior in juvenile mice. PLoS One. 2011;6:e25448.
26. Sullivan AW, Beach EC, Stetzik LA, et al. A novel model for neuroendocrine toxicology: neurobehavioral effects of BPA exposure in a prosocial species, the prairie vole (Microtus ochrogaster). Endocrinology.2014;155:3867–3881.
27. Diamanti-Kandarakis E, Bourguignon J-P, Giudice LC, Hauser R, Prins GS, Soto AM, et al. Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement. Endocr Rev. 2009 Jun 1;30(4):293–342.
28. Lauretta R, Sansone A, Sansone M, Romanelli F, Appetecchia M. Endocrine Disrupting Chemicals: Effects on Endocrine Glands. Front Endocrinol. 2019 Mar 21;10:178.
29. Grün F, Blumberg B. Environmental obesogens: organotins and endocrine disruption via nuclear receptor signaling. Endocrinology. 2006;147:S50–S55.
30. Grün F, Watanabe H, Zamanian Z, et al. Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates. Mol Endocrinol. 2006;20:2141–2155.
31. Newbold RR, Padilla-Banks E, Snyder RJ, Phillips TM, Jefferson WN. Developmental exposure to endocrine disruptors and the obesity epidemic. Reprod Toxicol Elmsford N. 2007 May;23(3):290–6.
32. Kanayama T, Kobayashi N, Mamiya S, Nakanishi T, Nishikaw J. Organotin compounds promote adipocyte differentiation as agonists of the peroxisome proliferator activated receptor /retinoid X receptor pathway. Mol Pharmacol. 2005;67:766–774.
33. Masuno H, Iwanami J, Kidani T, Sakayama K, Honda K. Bisphenol A accelerates terminal differentiation of 3T3–L1 cells into adipocytes through the phosphatidylinositol 3-kinase pathway. Toxicol Sci. 2005;84:319–327.
34. Wang J, Sun B, Hou M, Pan X, Li X. The environmental obesogen bisphenol A promotes adipogenesis by increasing the amount of 11ẞ-hydroxysteroid dehydrogenase type 1 in the adipose tissue of children. Int J Obes (Lond).2013;37:999–1005.
35. Neel BA, Brady MJ, SargisRM.The endocrine disrupting chemical tolylfluanid alters adipocyte metabolism via glucocorticoid receptor activation. Mol Endocrinol. 2013;27:394–406.
36. Angle BM, Do RP, Ponzi D, et al. Metabolic disruption in male mice due to fetal exposure to low but not high doses of bisphenolA(BPA): evidence for effects on body weight,food intake, adipocytes, leptin, adiponectin, insulin and glucose regulation. Reprod Toxicol. 2013;42:256–268.
37. Batista TM, Alonso-Magdalena P, Vieira E, et al. Shortterm treatment with bisphenol-A leads to metabolic abnormalities in adult male mice. PLoS One. 2012;7:e33814.
38. Decherf S, Demeneix BA. The obesogen hypothesis: a shift of focus from the periphery to the hypothalamus. J Toxicol Environ Health B Crit Rev. 2011;14:423–448.
39. Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner MK. Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. PLoS One. 2013;8:e55387.
40. Alonso-Magdalena P, Quesada I, Nadal A. Endocrine disruptors in the etiology of type 2 diabetes mellitus. Nat Rev Endocrinol. 2011;7:346–353.
41. Soriano S, Alonso-Magdalena P, García-Arévalo M, et al.Rapid insulinotropic action of low doses of bisphenol-A on mouse and human islets of Langerhans: role of estrogen receptor . PLoS One. 2012;7:e31109.
42. Ruzzin J, Petersen R, Meugnier E, et al. Persistent organic pollutant exposure leads to insulin resistance syndrome. Environ Health Perspect. 2010;118:465–471.
43. Naville D, Pinteur C, Vega N, et al. Low-dose food contaminants trigger sex-specific, hepatic metabolic changes in the progeny of obese mice. FASEB J. 2013;27:3860–3870.
44. Bodin J, Bølling AK, Becher R, Kuper F, Løvik M, Nygaard UC. Transmaternal bisphenol A exposure accelerates diabetes type 1 development in NOD mice. Toxicol Sci. 2014;137:311–323.
45. Brieño-Enríquez MA, Reig-Viader R, Cabero L, et al. Gene expression is altered after bisphenol A exposure in human fetal oocytes in vitro. Mol Hum Reprod. 2012;18:171–183.
46. Trapphoff T, Heiligentag M, El Hajj N, Haaf T, Eichenlaub-Ritter U. Chronic exposure to a low concentration of bisphenolA during follicle culture affects the epigenetic status of germinal vesicles and metaphase II oocytes. Fertil Steril. 2013;100:1758–1767.
47. Li Y, Zhang W, Liu J, et al. Prepubertal bisphenol A exposure interferes with ovarian follicle development and its relevant gene expression. Reprod Toxicol. 2014;44:33– 40.
48. Craig ZR, Hannon PR, Wang W, Ziv-Gal A, Flaws JA. Di-n-butyl phthalate disrupts the expression of genes involved in cell cycle and apoptotic pathways in mouse ovarian antral follicles. Biol Reprod. 2013;88:23.
49. Peretz J, Gupta RK, Singh J, Hernández-Ochoa I, Flaws JA. Bisphenol A impairs follicle growth, inhibits steroidogenesis, and downregulates rate-limiting enzymes in the estradiol biosynthesis pathway. Toxicol Sci. 2011;119:209–217.
50. Chang CC, Hsieh YY, Hsu KH, Tsai HD, Lin WH, Lin CS. Deleterious effects of arsenic, benomyl and carbendazim on human endometrial cell proliferation in vitro. Taiwan J Obstet Gynecol. 2010;49:449–454.
51. Ehrlich S, Williams PL, Missmer SA, et al. Urinary bisphenol A concentrations and implantation failure among women undergoing in vitro fertilization. Environ Health Perspect. 2012;120:978–983.
52. Ziv-Gal A, Wang W, Zhou C, Flaws JA. The effects of in utero bisphenol A exposure on reproductive capacity in several generations of mice. Toxicol Appl Pharmacol.2015;284:354–362.
53. Schmidt JS, Schaedlich K, Fiandanese N, Pocar P, Fischer B. Effects of di(2-ethylhexyl) phthalate (DEHP) on female fertility and adipogenesis inC3H/N mice. Environ Health Perspect. 2012;120:1123–1129.
54. Buck Louis GM, Rios LI, McLain A, Cooney MA, Kostyniak PJ, Sundaram R. Persistent organochlorine pollutants and menstrual cycle characteristics. Chemosphere. 2011;85:1742–1748.
55. Grindler NM, Allsworth JE, Macones GA, Kannan K, Roehl KA, Cooper AR. Persistent organic pollutants and early menopause in U.S. women. PLoS One. 2015;10:e0116057.
56. Hoover RN, Hyer M, Pfeiffer RM, et al. Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med. 2011;365:1304–1314.
57. Smith KW, Souter I, Dimitriadis I, et al. Urinary paraben concentrations and ovarian aging among women from a fertility center. Environ Health Perspect. 2013;121:1299–1305.
58. Abbott DH, Nicol LE, Levine JE, Xu N, Goodarzi MO, Dumesic DA. Nonhuman primate models of polycystic ovary syndrome. Mol Cell Endocrinol. 2013;373:21–28.
59. Kim SH, Chun S, Jang JY, Chae HD, Kim CH, Kang BM. Increased plasma levels of phthalate esters in women with advanced-stage endometriosis: a prospective case-control study. Fertil Steril. 2011;95:357–359.
60. Resuehr D, Glore DR, Taylor HS, Bruner-Tran KL, Osteen KG. Progesterone-dependent regulation of endometrial cannabinoid receptor type 1 (CB1-R) expression is disrupted in women with endometriosis and in isolated stromal cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Fertil Steril. 2012;98:948–956.e1.
61. Bruner-Tran KL, Ding T, Osteen KG. Dioxin and endometrial progesterone resistance. Semin Reprod Med. 2010;28:59–68.
62. Wang Y, Yu J, Luo X, et al. Abnormal regulation of chemokine TECK and its receptor CCR9 in the endometriotic milieu is involved in pathogenesis of endometriosis by way of enhancing invasiveness of endometrial stromal cells. Cell Mol Immunol. 2010;7:51–60.
63. Li MQ, Hou XF, Lv SJ, et al. CD82 gene suppression in endometrial stromal cells leads to increase of the cell invasiveness in the endometriotic milieu. J Mol Endocrinol. 2011;47:195–208.
64. Gao X, Yu L, Castro L, et al. An endocrine-disrupting chemical, fenvalerate, induces cell cycle progression and collagen type I expression in human uterine leiomyoma and myometrial cells. Toxicol Lett. 2010;196:133–141.
65. D’Aloisio AA, Baird DD, DeRoo LA, Sandler DP. Association of intrauterine and early-life exposures with diagnosis of uterine leiomyomata by 35 years of age in the Sister Study. Environ Health Perspect. 2010;118:375–381.
66. Mahalingaiah S, Hart JE, Wise LA, Terry KL, Boynton-Jarrett R, Missmer SA. Prenatal diethylstilbestrol exposure and risk of uterine leiomyomata in the Nurses’ Health Study II. Am J Epidemiol. 2014;179:186–191.
67. Peretz J, Vrooman L, Ricke WA, et al. Bisphenol A and reproductive health: update of experimental and human evidence, 2007–2013. Environ Health Perspect. 2014;122:775–786.
68. Chakraborty TR, Alicea E, Chakraborty S. Relationships between urinary biomarkers of phytoestrogens, phthalates, phenols, and pubertal stages in girls. Adolesc Health Med Ther. 2012;3:17–26.
69. Chen CY, Chou YY, Wu YM, Lin CC, Lin SJ, Lee CC. Phthalates may promote female puberty by increasing kisspeptin activity. Hum Reprod. 2013;28:2765–2773.
70. Henley, D.V., Lipson, N., Korach, K.S., Bloch, C.A., 2007. Prepubertal gynecomastia linked to lavender and tea tree oils. N. Engl. J. Med. 356, 479–485.
71. Rasier, G., Toppari, J., Parent, A.-S., Bourguignon, J.-P., 2006. Female sexual maturation and reproduction after prepubertal exposure to estrogens and endocrine disrupting chemicals: a review of rodent and human data. Mol. Cell. Endo.254–255, 187–201.
72. Saiyed, H., Dewan, A., Bhatnagar, V., Shenoy, U., Shenoy, R., Rajmohan, H., Patel, K., Kashyap, R., Kulkarni, P., Rajan, B., Lakkad, B., 2003. Effect of endosulfan on male reproductive development. Environ. Health Perspect. 111, 1958–1962.
73. . Guo, Y.L., Lambert, G.H., Hsu, C.C., Hsu, M.M., 2004. Yucheng: health effects of prenatal exposure to polychlorinated biphenyls and dibenzofurans. Int. Arch. Occup. Environ. Health 77, 153–158.
74. Leijs,M.M., Koppe, J.G., Olie, K., van Aalderen,W.M.C., de Voogt, P., Vulsma, T.,Westra, M., ten Tusscher, G.W., 2008. Delayed initiation of breast development in girls with higher prenatal dioxin exposure; a longitudinal cohort study. Chemosphere 73, 999–1004.
75. Hauser, R., Sergeyev, O., Korrick, S., Lee,M.M., Revich, B., Gitin, E., Burns, J.S.,Williams, P.L., 2008. Association of blood lead levels with onset of puberty in Russian boys. Environ. Health Perspect. 116, 976–980.
76. Selevan, S.G., Rice, D.C., Hogan, K.A., Euling, S.Y., Pfahles-Hutchens, A., Bethel, J., 2003. Blood lead concentration and delayed puberty in girls. N. Engl. J. Med.348, 1527–1536.
77. Damgaard IN, Skakkebaek NE, Toppari J, et al. Persistent pesticides in human breast milk and cryptorchidism. Environ Health Perspect. 2006;114:1133–1138.
78. Fernandez MF, Olmos B, Granada A, et al. Human exposure to endocrine-disrupting chemicals and prenatal risk factors for cryptorchidism and hypospadias: a nested case-control study. Environ Health Perspect. 2007;115(suppl 1):8 –14.
79. Virtanen HE, Koskenniemi JJ, Sundqvist E, et al. Associations between congenital cryptorchidism in newborn boys and levels of dioxins and PCBs in placenta. Int J Androl. 2012;35:283–293.
80. Brucker-Davis F, Wagner-Mahler K, Delattre I, et al. Cryptorchidism at birth in Nice area (France) is associated with higher prenatal exposure to PCBs and DDE, as assessed by colostrum concentrations. Hum Reprod.2008;23:1708–1718.
81. Cook MB, Trabert B, McGlynn KA. Organochlorine compounds and testicular dysgenesis syndrome: human data. Int J Androl. 2011;34:e68–e84; discussion e84–e65.
82. Trabert B, Longnecker MP, Brock JW, Klebanoff MA, McGlynn KA. Maternal pregnancy levels of trans-nonachlor and oxychlordane and prevalence of cryptorchidism and hypospadias in boys. Environ Health Perspect.2012;120:478–482.
83. Vested A, Giwercman A, Bonde JP, Toft G. Persistent organic pollutants and male reproductive health. Asian J Androl. 2014;16:71–80.
84. Aneck-Hahn NH, Schulenburg GW, Bornman MS, Farias P, de Jager C. Impaired semen quality associated with environmental DDT exposure in young men living in a malaria area in the Limpopo Province, South Africa. J Androl. 2007;28:423–434.
85. De Jager C, Farias P, Barraza-Villarreal A, et al. Reduced seminal parameters associated with environmental DDT exposure and p,p’-DDE concentrations in men in Chiapas, Mexico: a cross-sectional study. J Androl. 2006;27:16–27.
86. Mocarelli P, Gerthoux PM, Needham LL, et al. Perinatal exposure to low doses of dioxin can permanently impair human semen quality. Environ Health Perspect. 2011;119:713–718.
87. Abdelouahab N, Ainmelk Y, Takser L. Polybrominated diphenyl ethers and sperm quality. Reprod Toxicol.2011;31:546–550.
88. Hwang K-A, Choi K-C. Endocrine-Disrupting Chemicals with Estrogenicity Posing the Risk of Cancer Progression in Estrogen-Responsive Organs. In: Advances in Molecular Toxicology [Internet]. Elsevier; 2015 [cited 2021 Feb 7]. p. 1–33. Available from: https://linkinghub.elsevier.com/retrieve/pii/B9780128022290000013.
89. Warner M, Eskenazi B, Mocarelli P, et al. Serum dioxin concentrations and breast cancer risk in the Seveso Women’s Health Study. Environ Health Perspect. 2002;110:625–628.
90. Boada LD,ZumbadoM,Henríquez-Hernández LA, et al. Complex organochlorine pesticide mixtures as determinant factor for breast cancer risk: a population-based case-control study in the Canary Islands (Spain). Environ Health. 2012;11:28.
91. López-Carrillo L, Hernández-Ramírez RU, Calafat AM, et al. Exposure to phthalates and breast cancer risk in northern Mexico. Environ Health Perspect. 2010;118:539–544.
92. Donna A, Crosignani P, Robutti F, et al. Triazine herbicides and ovarian epithelial neoplasms. Scand J Work Environ Health. 1989;15:47–53.
93. VieiraVM,HoffmanK, ShinHM,Weinberg JM, Webster TF, Fletcher T. Perfluorooctanoic acid exposure and cancer cancer outcomes in a contaminated community: a geographic analysis. Environ Health Perspect. 2013;121:318–323.
94. Driscoll SG, Taylor SH. Effects of prenatal maternal estrogen on the male urogenital system. Obstet Gynecol.1980;56:537–542.
95. Koutros S, Beane Freeman LE, Lubin JH, et al. Risk of total and aggressive prostate cancer and pesticide use in the Agricultural Health Study. Am J Epidemiol. 2013;177:59–74.
96. ChristensenCH,Platz EA, Andreotti G, et al. Coumaphos exposure and incident cancer among male participants in the Agricultural Health Study (AHS). Environ Health Perspect. 2010;118:92–96.
97. Usmani KA, ChoTM,Rose RL, Hodgson E. Inhibition of the human liver microsomal and human cytochrome P450 1A2 and 3A4 metabolism of estradiol by deployment-related and other chemicals. Drug Metab Dispos.2006;34:1606–1614.
98. Institute of Medicine. Veterans and Agent Orange: Update 2012. Washington DC: The National Academy of Sciences; 2014.
99. Hinson, J. P., & Raven, P. W. (2006). Effects of endocrine-disrupting chemicals on adrenal function. Best Practice & Research Clinical Endocrinology & Metabolism, 20(1), 111–120.
100. Kioumourtzoglou M-A, Coull BA, O’Reilly ÉJ, Ascherio A, Weisskopf MG. Association of Exposure to Diethylstilbestrol During Pregnancy With Multigenerational Neurodevelopmental Deficits. JAMA Pediatr. 2018 Jul 1;172(7):670–7.
101. Cantonwine D, Meeker JD, Hu H, et al. Bisphenol A exposure in Mexico City and risk of prematurity: a pilot nested case control study. Environ Health. 2010;9:62.
102. Ferguson KK, McElrath TF, Meeker JD. Environmental phthalate exposure and preterm birth. JAMA Pediatr.2014;168:61–67.
103. Mustafa MD, Banerjee BD, Ahmed RS, Tripathi AK, Guleria K. Gene-environment interaction in preterm delivery with special reference to organochlorine pesticides. Mol Hum Reprod. 2013;19:35–42.
104. Peltier MR, Arita Y, Klimova NG, et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) enhances placental inflammation. J Reprod Immunol. 2013;98:10–20.
105. Snijder CA, Heederik D, Pierik FH, et al. Fetal growth and prenatal exposure to bisphenol A: the generationRstudy. Environ Health Perspect. 2013;121:393–398.
106. Burdorf A, Brand T, Jaddoe VW, Hofman A, Mackenbach JP, Steegers EA. The effects of work-related maternal risk factors on time to pregnancy, preterm birth and birth weight: the Generation R Study. Occup Environ Med. 2011;68:197–204.
107. Snijder CA, te Velde E, Roeleveld N, Burdorf A. Occupational exposure to chemical substances and time to pregnancy: a systematic review. Hum Reprod Update. 2012;18:284–300.
108. Suzuki Y, Yoshinaga J, Mizumoto Y, Serizawa S, Shiraishi H. Foetal exposure to phthalate esters and anogenital distance in male newborns. Int J Androl. 2012;35:236–244.
109. Gemmill A, Gunier RB, Bradman A, Eskenazi B, Harley KG. Residential proximity to methyl bromide use and birth outcomes in an agricultural population in California. Environ Health Perspect. 2013;121:737–743.
110. Migeot V, Albouy-Llaty M, Carles C, et al. Drinking water exposure to a mixture of nitrate and low-dose atrazine metabolites and small-for-gestational age (SGA) babies: a historic cohort study. Environ Res. 2013;122:58–64.
111. Wang P, Tian Y, Wang XJ, et al. Organophosphate pesticide exposure and perinatal outcomes in Shanghai, China. Environ Int. 2012;42:100–104.
112. Kishi R, Sasaki S, Yoshioka E, Yuasa M, Sata F, Saijo Y, Kurahashi N, Tamaki J, Endo T, Sengoku K, Nonomura K, Minakami H; Hokkaido Study on Environment and Children's Health. Cohort profile: the Hokkaido study on environment and children's health in Japan. Int J Epidemiol. 2011 Jun;40(3):611-8.
113. Paulose R, Jegatheesan K, Balakrishnan GS. A big data approach with artificial neural network and molecular similarity for chemical data mining and endocrine disruption prediction. Indian J Pharmacol. 2018 Jul 1;50(4):169.
114. Jaffrezic-Renault N, Kou J, Tan D, Guo Z. New trends in the electrochemical detection of endocrine disruptors in complex media. Anal Bioanal Chem. 2020 Sep;412(24):5913–23.
115. Street ME, Audouze K, Legler J, Sone H, Palanza P. Endocrine Disrupting Chemicals: Current Understanding, New Testing Strategies and Future Research Needs. Int J Mol Sci. 2021 Jan 19;22(2):933.
116. Artificial Intelligence Facilitates Chemical Toxicity Evaluation: the Case of Bisphenol S [Internet]. Newsroom | Inserm. 2019 [cited 2021 Feb 8]. Available from: https://presse.inserm.fr/en/artificial-intelligence-facilitates-chemical-toxicity-evaluation-the-case-of-bisphenol-s/34525/
117. Porta N, ra Roncaglioni A, Marzo M, Benfenati E. QSAR Methods to Screen Endocrine Disruptors. Nucl Recept Res [Internet]. 2016 [cited 2021 Feb 17];3. Available from: http://www.kenzpub.com/journals/nurr/2016/101203/
118. Carvalho, F.P., 2006. Agriculture, pesticides, food security and food safety. Environ. Sci.Policy 9, 685–692.
119. Toteja G.S, Dasgupta J, Saxena B.N, Kalra R.L, editors. Report of an ICMR Task Force Study (Part 1). New Delhi: Indian Council of Medical Research; 1993. Surveillance of Food Contaminants in India.
120. Kannan K, Tanabe S, Ramesh A, Subramanian A, Tatsukawa R. Persistent organochlorine residues in food stuffs from India and their implications on human dietary exposure. J Agric Food Chem. 1992;40:518.

ABSTRACT

Viruses are one of the simplest pathogenic organisms infecting the human body. Association between viral infections and endocrine system is complex and has not been fully studied. Viral infections can induce several physiological changes in the human endocrine system, resulting in cytokine mediated activation of hypothalamo-pituitary-adrenal axis to increase cortisol production, thus modulating the immune response. Further, many viral infections impact different endocrine organs, either by direct viral invasion or by systemic or local inflammation resulting in transient or permanent endocrinopathies; both hyper and hypofunction of endocrine organs may ensue. Viruses can encode production of specific viral proteins that have structural and functional homology to human hormones. Since endocrine hormones have immunoregulatory functions, endocrinopathies may alter the susceptibility of human body for viral infections. Recently the pandemic causing SARS 2 CoV infection has been shown to affect multiple endocrine organs through a variety of mechanisms, highlighting the significance of viral infection related endocrinopathies in morbidity and mortality. With improving understanding of viruses and their role in the human endocrine system, further research on this field would be required to explore new targets for prevention and treatment of endocrinopathies.

INTRODUCTION

The endocrine system plays a vital role in homeostasis and immunity. Hormones modulate host defenses by strengthening or weakening the body’s immune system, being one of the key determinants of susceptibility of humans for infections. On the other hand, infective agents through different mechanisms may affect endocrine organs, causing endocrinopathies.

Viruses are the most abundant form of life on earth, estimate at 10 quintillion (10³¹) (1, 2). They are obligate parasites with single or double-stranded DNA or RNA, infecting a variety of hosts; bacteria, algae, fungi, plants, insects, and vertebrates. Viral infections are common among humans, resulting in diseases which may extend into epidemics. The literature is evolving on viral agents being important pathogens in endocrine disorders. Knowledge about the interplay between viruses and the human endocrine system would expand the understanding of acute and chronic effects of viral disease on the human body.

HUMANS VIROME

The role of viruses in the human body is diverse. Many viruses have been identified to play an essential part in the human microbiome, with an estimate of 380 trillion viral particles inhabiting the human body. This human virome consists of:

1. Human Endogenous Retroviruses (HERV): These viruses are integrated viral genomic material which consists of 8% of the total human genome (1, 3). As they are incorporated into the human genome, they are transmitted vertically to offspring. The function of the HERV in the human genome is not known. However, transcription of these genes may produce proteins, which may alter the function of regulatory genes and elicit an immune response (autoimmune diseases) or cell growth (cancers) in the host (4, 5).

2. Bacteriophages: These viruses inhabit their bacterial hosts, mainly in the human gut in addition to the skin and oral cavity (6, 7). Mostly they show a symbiotic relationship with their host. They may promote health or disease by phage-mediated lysis of pathogenic or commensal bacteria triggered by external factors, thereby controlling bacterial populations and promoting evolutionary advantages to host bacteria (e.g., antibiotic resistance through the transfer of genetic material)

3. Eukaryotic viruses: These viruses infect human cells often resulting in symptomatic diseases or may exist in an asymptomatic carrier state (8).

PATHOGENESIS OF VIRAL INFECTIONS IN HUMANS

Being an obligate parasite, viruses need to enter the human cell in order to replicate and complete its life cycle. The first step of viral entry into a host cell involves recognition and binding to host cell specific receptors by viral surface proteins (fusion proteins/ spikes). This specificity determines the host range for a particular virus (e.g. HIV viral surface protein, gp120 specifically interact only with CD4, CCR5, and CXCR4 molecules on T lymphocytes) (9). Subsequent events are conformational change of fusion proteins and subsequent entry into the cell through endocytosis (e.g. Adenovirus), cell membrane fusion (e.g. HIV) or direct cell to cell contact (virological synapses e.g. HTLV1) (10). Once the viral DNA or RNA material is inside the host cell, they are incorporated into the host genome and replication of the viral genome and/or transcription of specific proteins will occur. The replicated viral genome gets assembled with viral proteins to produce an increased number of viral particles (virions), which will be released from the infected cell by cell lysis or budding from the host cell. Some viruses undergo a lysogenic cycle where the viral genome is incorporated into a specific location in the host chromosome. This viral genome is known as provirus and mostly remain non-functional within host cells until being activated at some point when the provirus gives rise to active virus which would lead to the cellular death, necrosis, or apoptosis of the host cell (9).

Many changes occur in the infected cell and its surrounding tissues leading to immune modulations. Direct cellular damage could occur in the infected host cell by viral proliferation/replication. Proteins encoded by the viral genome can also modulate cellular functions and cause damage to the infected cell (11). Further, the virus itself and infected tissues trigger the innate immune system through cytokines (IL-1, IL-6, IL-8, IL-12, TNF-α, IFN-α/β, TGF-β), complements, and natural killer cells (12, 13). The resultant immune response can cause inflammation or subsequent damage to the infected cell which may further progress to inflammation and damage of nearby uninfected cells (11, 14). Virus induced tissue inflammation increases the production of systemic mediators of inflammation, which may induce a systemic inflammatory condition in the host, affecting many other organs ((11, 15). Subsequently adaptive immunity develops where the host develops cell mediated immunity (to control disease) and humoral immunity with antibodies (to prevent reinfection) against specific viruses (12).  

VIRUS INDUCED ALTERATIONS IN THE ENDOCRINE SYSTEM

Virus induced changes of endocrine cells and organs can occur in several ways (11).

1. Activation of the hypothalamo-pituitary-adrenal (HPA) axis indirectly as a result of systemic viral infection and inflammation.
2. Damage to specific endocrine cells by direct viral infection of the cell (through stages of the viral cell cycle).
3. Damage to specific endocrine cells by viral proteins produced within the cell as a result of viral replication within the cell.
4. Damage of virus infected endocrine organs by inflammation through activation of an immune reaction (innate and cell mediated).
5. Damage of uninfected endocrine organs through the systemic immune response as a result of the immune reaction to the viral infection.
6. Damage of uninfected endocrine organs through autoimmune mechanisms/cross reaction of antibodies.
7. Viral gene products may induce an alteration of hormonal activity/ production by endocrine cells.

Pituitary Gland

HPA AXIS RESPONSE TO VIRAL INFECTIONS

Any virus which causes systemic viremia and inflammation may stimulate the HPA axis to release cortisol through early innate proinflammatory cytokines (IL-1, IL-6 and TNF-α) and late acquired T cell cytokines (INF-ϒ and IL-2) during an acute viral infection (16). These mediators act on the CRH producing cells of the hypothalamus, corticotrophs in the anterior pituitary as well as on the adrenal cortex to increase glucocorticoids during the illness. Cytokines (IL-1, -2, -4, -7, -8, TNFα and INF-α) are responsible for the expression of glucocorticoid receptors on lymphocytes and neutrophils, enhancing the immune reaction (17). While the stress hormones norepinephrine and epinephrine mobilize immune cells into the blood stream, epinephrine and cortisol are responsible for enhancing differentiation of specific immune cells and directing the cells to the tissues where they are needed (18-20). On the other hand, elevations in glucocorticoids negatively regulate the immune system to reduce the further production of cytokines (e.g., HSV-1, MCMV, influenza,) and promote switching of cellular immunity to humoral immunity, thus protecting the body from an overactive immune response (16). The extent of viral induced glucocorticoid production is specific to the virus and the immune response stimulated by the virus; thus, in infections like LCMV clone E350 where no significant inflammation occurs, glucocorticoid production is minimal (21). However, mouse models with corneal inoculation of HSV-1 virus have shown that even without significant viremia, brainstem infection of HSV-1 can alter the HPA axis stress response through central mediated pathways (22).

ANTERIOR PITUITARY DYSFUNCTION

Hypothalamo-pituitary dysfunction due to infections remain underestimated (23). Isolated or multiple anterior pituitary hormone deficiencies had been identified during acute viral illnesses of the central nervous system, especially following viral meningo-encephalitis (24, 25). Pituitary dysfunction mainly involves corticotrophin deficiency and hyperprolactinemia and to a lesser extent gonadotrophin, growth hormone, or thyrotrophin deficiencies (24-27). The prevalence of individual deficiencies following viral infections vary among studies. Patterns of hormonal deficiencies following CNS infections depend on the type of causative agent, the localization of the infection, as well as with the severity of the disease (24). Partial or complete deficiency of specific hormones may occur depending on the degree of damage (28).

The main mechanisms involved in hypopituitarism with examples are shown in Table 1.

Hypophysitis can occur either early in the acute phase of the infection or at a later stage as a sequela of a CNS infection (24, 25). A proportion of patients who have deficiencies in anterior pituitary hormones during the acute phase of a viral infection recover hormonal function, typically within 1 year, indicating the transient nature of the damage in a subset of patients (25, 29). Delayed development of pituitary insufficiency can remain asymptomatic or present with vague symptoms. The deficiencies in such case will remain permanent, needing life-long hormonal replacement. If not for a high degree of suspicion, hypopituitarism can be misdiagnosed as the post-encephalic syndrome (23).

Acute viral infections can cause hyperprolactinemia in response to elevated cytokines IL-1, IL-2 and IL-6, which stimulate prolactin production (52). Further, certain viral infections (e.g., HIV) directly reduce the dopaminergic tone increasing prolactin levels (53). Macrophages, monocytes, lymphocytes, and natural killer cells possess prolactin receptors. Prolactin binding to these receptors activates downstream signaling pathways that will stimulate immune cell proliferation, differentiation, and survival (52). Prolactin also antagonizes the immunosuppressive effects of TNF-α and TGF-β (54). Therefore, elevated prolactin acts as an immunomodulator during acute infections.

Although rare, CNS viral infections may also present as an emergency with pituitary apoplexy, precipitating ischemia or bleeding in a normal pituitary gland or a pituitary tumor (33, 37, 38, 40). Some patients present with the empty sella syndrome following initial hemorrhagic insult to the pituitary, mostly with anterior pituitary hormonal deficiencies.

POSTERIOR PITUITARY DYSFUNCTION

SIADH is a well-known complication of infections, particularly CNS viral infections with HSV and tick-born infections(55, 56). The possible mechanism is cytokines released during inflammation, especially IL-6, causing non-osmotic release of vasopressin from the posterior pituitary (57). The presence and severity of hyponatremia depends on the infective agent, severity of the infection, and infected foci. Hyponatremia portends a worse prognosis (45).

Direct viral destruction of ADH and oxytocin producing neurons in the hypothalamus, pituitary stork, or posterior pituitary would result in central diabetes insipidus (49). It is usually associated with anterior pituitary hormone deficiency and is described mainly in immunocompromised patients with encephalitis (49, 58, 59). 

Thyroid Gland

Systemic viral infections may result in alterations of thyroid functions, giving rise to the “Sick Euthyroid syndrome”, “non-thyroidal illness syndrome”, or “Low T3 syndrome”(60). This is characterized by decreased levels of serum T3 and sometimes thyroxine (T4), without an increased secretion of TSH. Mechanisms involved are elevated circulating cytokines, cortisol, and free fatty acids influencing deactivation of deiodinase-1 enzyme (reduces T4 to T3 conversion), activation of deiodinase-3 enzyme (increased conversion of T3 to rT3), down regulation of hypothalamo-pituitary-thyroid axis resulting in normal or low TSH levels despite low T3 levels, and changes in thyroid binding proteins (61).

Direct viral invasion of the thyroid gland with subsequent cytotoxic T-cell mediated inflammation of the gland results in infiltration of thyroid follicles with disruption of the basement membrane leading to subacute thyroiditis and the release of thyroid hormones (62). Presence of viral material had been identified in diseased thyroid glands in certain patients (e.g., mumps) while others show viral IgG antibodies / rise in titers (Mumps, Coxsackie, adeno and influenza) (63, 64). However, elevated antibodies to common respiratory tract viruses may be an anamnestic response due to the inflammatory process (65). Epidemiological data has shown subacute thyroiditis during outbreaks of viral infections and seasonal clustering when viral infections are also commonly seen (66).

Viruses triggering the immune response leading to the development of autoimmune thyroid diseases like Hashimoto’s thyroiditis and Grave’s disease has been suggested (67, 68). Possible mechanism include (69);

• Molecular mimicry: recognizing an epitope on an external antigen
• TLR activation by virus and heat-shock protein effects
• Enhanced thyroid expression of human leukocyte antigen molecules

The above mechanisms could facilitate the development of antigen-specific adaptive immunity, causing autoimmune thyroiditis (68, 70). In Grave’s disease, significant homology had been identified in HIV-1 induced viral Nef-protein and the human TSH receptor, raising the possibility of T cell activation through a viral antigen acting as an autoantigen (71). Further, EBV infection results in over-expression of HLA antigens, predisposing to immune mediated mechanisms of Grave’s disease (72).

Elevated levels of TBG had been observed in patients with HIV in both stable and ill patients (36). The mechanism of this finding is unknown but care should be taken in interpreting total T4/T3 levels in patients with HIV.

Parathyroid Glands and Calcium Metabolism

Although rare, parathyroid dysfunction following viral infections has been documented in case reports. Acute hyperparathyroidism has been reported with acute Hepatitis B infection, where hypercalcemia resolved following resolution of the hepatitis. It was postulated that antibody mediated lowering of the calcium set point in the  parathyroid gland had resulted in hyperparathyroidism (75).

Hypoparathyroidism is documented with several viral infections including HIV and SARS-COVID 19 (76-78). Parathyroid cells express a protein recognized by antibodies against CD4, the HIV-1 receptor. Therefore, it is possible for the virus to directly infect the parathyroid cells and also circulating autoantibodies against CD4, may impaired PTH release though direct interaction (76).

Hypocalcemia is a well-recognized metabolic derangement in some viral infections (e.g., Dengue, measles, SARS-COVID-19), indicating severe disease and worse outcomes (79-81). This is usually transient during the active disease and could be secondary to vitamin D deficiency, hypoalbuminemia secondary to infection, calcium influx into damaged cells, or hypoxia induced cytokine release mediating impaired PTH secretion or tissue response to PTH (82).

Pancreas

TYPE 1 DIABETES

Different viral infections are linked as a potential trigger for the development of Type 1 diabetes. This happens through different mechanisms; direct pancreatic β-cell lysis or immune mediated progressive β-cell destruction though autoimmunity generated from molecular mimicry, bystander activation of autoreactive T cells, and loss of regulatory T cells (83). As a result, hyperglycemia / new-onset insulin dependent diabetes develops.

Direct β-cell damage can occur as a result of viral invasion resulting in beta-cell lysis (e.g. coxsackieviruses, Rubella, mumps, enterovirus, influenza, Hep C (84-87) or inflammation following pancreatitis secondary to viral infection (hepatotropic virus, coxsackie virus, CMV, HSV, mumps, varicella-zoster virus), systemic inflammation, or immunomodulation (88). Although the incidence of diabetes following acute pancreatitis is as high as 23% (89), the incidence following viral pancreatitis had not been studied.

Virus induced autoimmunity appears to be the main mechanism for viral induced type 1 diabetes. However, the role of viruses seems to be more complex. Certain virus infections induce upregulation of  MHC class I on β cells, thereby enhancing recognition of β cells by autoreactive CD8+ cytotoxic T lymphocytes, thus inducing autoimmunity (90). However, some virus strains (LCMV, CVB) reduce the incidence or delay the onset of type 1 diabetes, probably through a TLR mediated mechanism (90). Whether inductive or protective autoimmunity depends on several factors; level of infection (more severe infections enhance diabetes while low-replicating strains of the same infection seem protective), genetic predisposition, presence of other detrimental environmental triggering factors like viruses, and direct β-cell toxins (91). Adding to the complexity, research on the intestinal virome has shown that certain changes in the intestinal virome precede autoimmunity, especially in developing type 1 diabetes in genetically susceptible people (92).

To-date, literature support viral infection (e.g. enterovirus, influenza virus, cytomegalovirus, mumps, rubella, rotavirus, and coxsackie virus) mediated autoimmune destruction of beta-cells through molecular mimicry or activating cross-reactive T cells as one of the potential mechanisms for the pathogenesis of type 1 diabetes (93).

Adrenal Glands

Primary adrenal insufficiency is a well-known consequence of certain viral infections. Common pathological mechanisms are direct viral invasion causing adrenalitis, adrenal hypofunction due to immunological impact from systemic inflammatory response, and viral-induced autoimmune destruction of the adrenal gland (94). Although less frequent, adrenal glands can be infected in early HSV-1 and -2 infections irrespective of the immune status of the host, with the adrenal gland having the highest number of viral particles of any organ (95). SARS-COVID 19 virus also affects the adrenals by direct cytopathic effects by the virus or due to the systemic inflammatory response (96). Antibody mediated adrenal insufficiency is also seen in SARS viral infection by producing molecular mimics to ACTH. Antibodies to the viral peptides bind both viral protein and host ACTH, may destroy ACTH or reduce the functionality of the hormone, thus reducing the ability of ACTH to induce cortisol production (97).

More severe forms of adrenal disruption (usually bilateral) are seen in less common fulminant viral infections; H5N1 avian influenza causing multifocal necrosis of adrenal cells (98),  filoviruses (e.g. Ebola) giving rise to liquefaction of the adrenals (99). Further, immunosuppression has been identified as a predisposing factor for severe adrenal infections. Echoviruses serotypes 6 and 11 which cause lethal disseminated intravascular coagulation in children can affect the adrenals with hemorrhagic necrosis (100). CMV adrenalitis had been reported in more than half of the patients with AIDS, with or without evidence of CMV viremia (101, 102).

Adrenal glands are the most commonly affected endocrine organ by HIV infection (103, 104). Early stages of HIV result in a rise in cortisol secretion, as an adaptive response to a stressor. In some patients, this rise in cortisol levels may precipitate reactivation of EBV. During the latter stages, adrenal ‘burnout’, direct viral infection, co-infection by opportunistic microbes (viral – CMV, bacterial, fungal), anti-adrenal cell antibodies (unique to HIV infection), and increased peripheral cortisol resistance may lead to progression to overt adrenal failure (105-107). An autopsy series has shown the adrenal gland to be pathologically compromised in 99.2% of cases of patients with AIDS, highlighting the degree of damage in immunocompromised state (108).

Some adrenal neoplasms have a viral etiological relationship, particularly in HIV infected people; EBV associated lymphoma of the adrenal gland and AIDS-associated neoplasms (e.g. Kaposi sarcoma from HHV-8, non-Hodgkin's lymphoma) (109).

Gonads

TESTES

Viruses are well known to cause orchitis, both unilateral and bilateral, as a consequence of a systemic viral infection. Mumps virus is the commonest viral infection affecting the testes, being the most common complication of mumps in post-pubertal men (110). Virus attacks the testicular tissues, leading to an innate immune response, inflammation, and perivascular intestinal lymphocyte infiltration. Resultant swelling exert pressure on intratesticular tissues and leads to testicular atrophy (111, 112). In addition to having varying degrees of hypogonadism, viral infection leads to subfertility; transient changes in sperm count, mobility, and morphology of fertility in unilateral disease while 30 – 87% having infertility due to oligo-asthenospermia in bilateral disease (113). Other viruses have also been identified to cause direct testicular damage including coxsackievirus, varicella, echovirus, Hep E, Zika virus, and cytomegalovirus, leading to varying degree of testicular damage but to a lesser extent than mumps virus (114-116). Certain viruses have also been detected in semen (e.g., Zika, Ebola, HIV, Hep B, Herpes and SARS-COV) and within spermatozoa (e.g., HIV, Hep B and Zika) of infected patients (117, 118). Although some of these could contribute to vertical transmission as well as affect fertility, the role of the viruses needs to be clarified with further research (119, 120).

HIV infects the testis early during the course of the disease, targeting testicular leucocytes and germ cells, but is not associated with any apparent morphological changes (121). Viral infection of the germ cells is important in vertical transmission of the disease. Further, HIV-2 and SIV but not HIV-1 are known to damage Leydig cells and reduce testosterone levels (122). HIV/AIDS also make the testes more susceptible for opportunistic infections like CMV, EBV and TB (123). Some evidence has emerged for an oncogenic effect of HIV and EBV infection on human testis but further research is needed (124). 

Although viral orchitis induces humoral immune response and result in anti-sperm antibodies, their causal link to subfertility or hypogonadism is unclear (110, 125).

OVARIES

Viruses affect ovaries through similar mechanisms as the testes; direct invasion and innate immune mediated oophoritis, resulting in changes in estrogen/progesterone to cause varying degrees of hypogonadism as well as affect fertility (126, 127). Mumps, Zika, HIV, and CMV viruses have been documented in the literature as common viral culprits affecting the ovaries and the clinical manifestations range from being silent infections to oophoritis resulting in premature menopause (126-128).

Further, some viruses (e.g. CMV) had been implicated in ovarian carcinogenesis but further studies need to clarify the exact causal effect and pathogenesis (129).

Viral Protein Mediated Modulation of Hormone System

New insights have shown that the viral genomes can produce viral peptide sequences that possess homology with human hormones, growth factors, and cytokines. Such viruses may affect human physiology not by infecting and damaging tissues nor by eliciting immune responses but by producing molecules which mimic the action of functional molecules. Recent research pointed out that viruses belonging to Iridoviridae family, which commonly infect fish, but have been also identified in the human virome (blood and feces), produce viral insulin like peptide (VILP), which has homology to human insulin/ IGF-1 (130). These VILPs could compete with endogenous ligands, stimulate or impair post receptor signaling in an autocrine, paracrine, and endocrine basis. They bind to human receptors and stimulate downstream signaling, increase glucose uptake by adipocytes in vitro and in vivo, and stimulate cell proliferation and growth, but less potently than human insulin/IGF-1 (130-132). The role of VILPs are not fully understood and further research is needed to explore the links between VILP and T1DM, insulin resistance, and certain neoplastic growths in association with viral infections.

Other “viral hormones” have also been identified, with structural and/or functional homology to human hormones including IGF-1 and IGF-2, endothelin-1 (ET1), endothelin-2, TGF-β1 and TGF-β2, fibroblast growth factors 19 and 21, inhibin, adiponectin, resistin, adipsin, and irisin in various viruses (132). However, their exact role in altering human physiology in a beneficial or harmful manner is yet to be identified.

Certain virus genome encoded proteins may alter the human genomic expression of particular hormones. A classic example is HTLV-1 infected cells producing PTHrP causing hypercalcemia by trans-activation of the PTHrP gene through the TAX viral gene product (133). Certain viral products act at the cellular receptor/post receptor level, resulting in alterations of intracellular hormonal signaling pathways. HIV-1 related Vpr and Tat protein may induce hypersensitivity of the glucocorticoid receptor (GR) resulting in lipodystrophy and insulin resistance (134). A similar mechanism is suggested for Paget’s disease, where there is a possible mumps viral peptide (Nucleocapsid transcript) induced hypersensitivity of osteoclastic receptors to vitamin D (135).  Inactivation of hormone receptor / post receptor signaling may be seen with some viruses; RSV protein miR-29a down regulates GR receptors (136); poxvirus MCV MC013L protein induces inhibition of glucocorticoid nuclear receptor transactivation (137), and E1A protein produced by Adenovirus blocks the action of glucocorticoids on transcription activity genes (138) resulting in resistance to glucocorticoids. As illustrated by the above examples, viral encoded proteins may affect the human endocrine system through alteration of endocrine signaling systems.

VIRAL INFECTIONS AS A COMPLICATION OF ENDOCRINE DISEASES

HPA Axis

Patients with untreated or undertreated adrenal insufficiency are at a higher risk of infections as well as 5-fold higher mortality from infection compared to the normal population (139, 140). Impaired innate immune function, especially with lower natural killer cells among patients with adrenal insufficiency has the potential to make them more susceptible to invading pathogens and cause a higher rate of death following viral infections (141-143). On the other hand, among patients with undiagnosed glucocorticoid deficiency, the initial HPA axis response to increase the level of glucocorticoids in response to the immune mediators will be altered, hence appropriate shaping of the downstream immune response will not take place. This may result in overactive immune response to the viral infections, affecting mortality and morbidity. Replacement regimes which restore physiological glucocorticoid secretion patterns have been shown to reduce susceptibility to infections as well as to improve mortality among patients with adrenal insufficiency (144). Therefore, appropriate steroid treatment regimens should be employed in patients with deficiencies in the HPA axis depending on their clinical state (Doubling steroid dose in mild viral infections, up to 200mg/24-hours hydrocortisone in moderate-severe viral infections) (145).

Stress induced hypercortisolemia and elevated epinephrine levels, which occur as a physiological mechanism, could mediate latent viral reactivation (HSV, EBV, VZV) through IL-6 mediated pathways, precipitating viral infections (146-148). However, the level of stress may also determine the threshold for reactivation (e.g. low stress levels precipitating VZV,  high stress levels precipitate an increase in HSV-1 DNA load) (148).

Viral infections have an increased prevalence and more severe disease course among patients who are immunosuppressed compared to the general population (149). Cushing’s syndrome or over treatment with steroids impair immune function and are considered as an immunocompromised state with high susceptibility for severe viral infections. Further, the high glucocorticoid levels may mask the initial symptoms of viral infection, delaying medical treatment and would lead to a clinical course which is more difficult to predict than in the normal population (150, 151). In addition, concordant viral infection may precipitate adrenal crisis in patients on glucocorticoid replacement therapy, which adds to the increased mortality from viral illness (139).

Pituitary

HYPOPITUITARISM

Several anterior pituitary hormones have immunoregulatory roles (152). GH, PRL, TSH, and gonadotrophins show stimulatory effects on immune cells while gonadal steroids tend to suppress immune mechanisms (153-156). Patients with multiple deficiencies of anterior pituitary hormones would therefore have variable alterations in their immune systems and show an increased susceptibility for infections and an increased tendency to develop serious infections (157).

HYPERPROLACTINEMIA

Elevated prolactin levels act as immunomodulators and enhance the host innate and adaptive immune system. Thus, prolactin may protect the host from viral infections as well as help in containing viral infections (52-54).

Thyroid Gland

Thyroidal diseases have not been shown to increase the susceptibility to viral infections.

Parathyroid Glands

HYPERPARATHYROIDISM

Several in vivo and in vitro studies have demonstrated the immunomodulatory effect of parathyroid hormone. PTH receptors had been identified on cells involved in immune pathways, including neutrophils and B and T lymphocytes (158). In patients with CKD and secondary hyperparathyroidism, elevated PTH has been shown to affect immune cells causing impaired migration, reduced phagocytic and bactericidal activity, and inhibited granulocyte chemotaxis (159, 160). T and B lymphocyte proliferation and antibody production are also affected by PTH. Thus, PTH may reduce the host response to viral infections and increase the susceptibility for severe viral infections (159).

Gonads

Gender had been one of the key epidemiological factors determining the prevalence and intensity of human viral infections, with men tending to be more susceptible (161). It was shown that females mount a stronger innate and adaptive immune response than males, giving rise to the above differences (162). Rodent studies had demonstrated that in addition to the influence of the sex chromosomes on immune cells, sex hormones also account for this difference through their effects on the immune systems by influencing cell signaling pathways resulting in differential production of cytokines / chemokines and also enhancing T-cell populations and adaptive immune systems through receptors on immune cells (163-165).

Low testosterone levels negatively impact the outcome of certain viral infections. Low levels seen in elderly men and in young men with hypogonadism result in higher morbidity and a worse clinical course following certain viral infections (e.g. Influenza) and antibody response is reduced compared to young healthy males (166). Furthermore, treatment with testosterone has been shown to reduce mortality and improve disease course in both young and elderly males with hypogonadism (166). These changes were mainly due to alterations in the immune response by testosterone receptor mediated leukocyte contraction to limit inflammation (monocytes, CD8+ T cells, degranulation and reduced cytokine production) rather than limiting viral replication (165, 167).

Estrogen acts as a potent anti-inflammatory hormone that reduces the severity of viral infections such as the influenza virus. Estrogen alters the production of chemokines, target organ recruitment of neutrophils, and cytokine responses of virus-specific CD8 T cells to protect against severe influenza (168). Estrogen shows bipotential effects; small or cyclical amounts enhancing proinflammatory cytokine responses and high or sustained circulating levels reducing production of proinflammatory cytokines and chemokines (169). Female hypogonadism in the form of natural menopause or pathological hypogonadism in young women has been shown to increase susceptibility for viral infections while the use of hormonal replacement therapy or estrogen replacement has reduced viral infections and hospital admissions (170).

Diabetes

Chronic hyperglycemia is known to be associated with altered innate immune response with reduced chemotaxis, phagocytosis, killing by polymorphonuclear cells and monocytes/macrophages, a reduced response of T cells, reduced neutrophil function, and varying disorders of humoral immunity (171). These defects in immune response predisposes patients with diabetes, especially individuals with poor glycemic control, to different viral infections as well as results in a more severe disease (172). Respiratory viruses like influenza  are known to affect patients with diabetes commonly and have a sixfold higher risk of hospitalization compared to non-diabetics (173). Further, SARS-CoV-2 virus also tends to result in more severe infections in patients with poorly controlled diabetes (174).

ENDOCRINE PARAMETERS AS MARKERS OF SEVERE VIRAL INFECTION

Severe systemic viral infections tend to cause changes in thyroid profile, which is known as Non-Thyroidal Illness (NTI)/ Sick Euthyroid syndrome. Classic changes in the thyroid profile are low T3 and normal/low TSH and fT4 levels. Low T3 levels and the presence of NTI has been associated with severe viral infections and poor outcomes in several viral infections (e.g., CNS viral infections, SARS-Cov-2) (60, 175).

Among many other markers of disease severity, low serum calcium level is also a predictor for severe disease and worse clinical outcome among patients with Dengue and SARS-COV-2 infections (82, 176, 177). The above markers could be used in addition to the usual clinical parameters for assessment and prediction of disease severity and prognosis.

COVID-19 AND THE ENDOCRINE SYSTEM

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has spread across the globe rapidly since the end of 2019 (Corona virus disease 2019; COVID-19), causing an unprecedented pandemic with significant mortality and morbidity. Because of the novelty of the disease, the possible impact on the endocrine system is not fully understood. However, emerging evidence support that COVID-19 has significant effects on the endocrine system. Additionally, patients with certain endocrinopathies face a worse outcome from COVID-19 infections.

SARS-CoV-2 virus uses the host angiotensin-converting enzyme 2 (ACE2) as the receptor for fusion and entry into human cells in order to complete its life cycle (178). Lung is the principal target of COVID-19 virus due to an abundancy of ACE2 receptors and is responsible for the main symptoms of the disease but many endocrine organs (hypothalamus, pituitary, thyroid, pancreas, adrenals, gonads) also express ACE2 receptors abundantly and this predisposes viral entry into endocrine organs and subsequent viral induced changes (179, 180). Possible pathogenic mechanisms are direct viral entry and destruction of cells, inflammation induced cellular dysfunction, and immune/antibody mediated hormonal dysfunction.

COVID-19 and Endocrinopathies

Data on the impact of COVID-19 infections on endocrine organs are emerging. Previous SARS viral infection outbreaks have revealed a spectrum of endocrinopathies which span from asymptomatic disease to gross hypofunction of endocrine organs (hypothalamus, pituitary, thyroid, adrenals, pancreas and gonads). Considering the similarities of other SARS viruses and SARS-Cov-2 (COVID-19) in structure and pathogenic mechanisms, we can assume that a similar spectrum of diseases can be expected during COVID-19 pandemic.  Table 3 outlines a summary of available data on the impact of COVID-19 infection on endocrine organs.

* Evidence based on SARS-Cov-1/ SARS virus infections

† Need further scientific evidence to establish the effect of infection on endocrine dysfunction

In addition to the COVID-19 virus induced hormonal changes, certain pre-existing endocrinopathies may influence the disease course of COVID-19. Patients with immunocompromise due to active Cushing’s disease or long term poorly controlled diabetes are more prone for severe COVID-19 infections and have an increased morbidity and mortality (174, 202). Therefore, care must be taken to treat these patients to achieve good control of their disease state as well as to recognize the increased severity of COVID-19 infections. Patients with adrenal insufficiency are also considered to have an increased risk of  more severe COVID-19 infections with a higher complication risk, including adrenal crisis and mortality (139, 203). Careful management of glucocorticoid replacement would minimize the risk.

CONCLUSION

Viruses, being one of the common infective agents affecting humans, play an important role related to physiological and pathological changes in the endocrine system. Through different mechanisms; direct and indirect, viruses influence endocrine organs causing hypo- or hyperfunction. Such changes can result in transient or permanent changes in endocrine glands. On the other hand, certain endocrinopathies may affect the course of viral infections, by altering immune mechanisms. Therefore, thorough knowledge of the interaction of viruses with the endocrine system is important and further research is warranted to gain more detailed insights.

REFERENCES

1. Microbiology by numbers. Nature Reviews Microbiology. 2011;9(9):628-.
2. Rohwer F, Prangishvili, D. Lindell, D. Roles of viruses in the environment. . Environ Microbiol. 2009;11:2771–4.
3. D.J. G. Endogenous retroviruses in the human genome sequence. Genome Biology 2001;2:171.
4. Nexø BA, Villesen P, Nissen KK, Lindegaard HM, Rossing P, Petersen T, et al. Are human endogenous retroviruses triggers of autoimmune diseases? Unveiling associations of three diseases and viral loci. Immunologic research. 2016;64(1):55-63.
5. Gonzalez-Cao M, Iduma P, Karachaliou N, Santarpia M, Blanco J, Rosell R. Human endogenous retroviruses and cancer. Cancer biology & medicine. 2016;13(4):483-8.
6. Hannigan GD, Meisel JS, Tyldsley AS, Zheng Q, Hodkinson BP, SanMiguel AJ, et al. The human skin double-stranded DNA virome: topographical and temporal diversity, genetic enrichment, and dynamic associations with the host microbiome. mBio. 2015;6(5):e01578-15.
7. Abeles SR, Robles-Sikisaka R, Ly M, Lum AG, Salzman J, Boehm TK, et al. Human oral viruses are personal, persistent and gender-consistent. The ISME journal. 2014;8(9):1753-67.
8. Guerrant RL, Walker DH, Weller PF. Tropical Infectious Diseases: Principles, Pathogens and Practice E-Book: Elsevier Health Sciences; 2011.
9. N. James MacLachlan EJD. Virus Replication.Fenner's Veterinary Virology. 5th Edition ed: Academic Press; 2017. p. 17-45.
10. Dimitrov DS. Virus entry: molecular mechanisms and biomedical applications. Nature Reviews Microbiology. 2004;2:109-22.
11. Kino T, Chrousos GP. Virus-mediated modulation of the host endocrine signaling systems: clinical implications. Trends Endocrinol Metab. 2007;18(4):159-66.
12. Scott N. Muller BTR. Immune response to viruses. Clinical immunology. 2008:421-31.
13. Wittek A.E. QGVJ. Immunology of viral infections In: R.B B, editor. Textbook of Human Virology 2nd edn. 2nd edition ed: Mosby-Year Book; 1991. p. 116–55.
14. Vemuri RS, E.M.; Chieppa, M.; Eri, R.; Kavanagh, K. . Beyond Just Bacteria: Functional Biomes in the Gut Ecosystem Including Virome, Mycobiome, Archaeome and Helminths. Microorganisms 2020;8:483.
15. M.B. O. Molecular mimicry and immune-mediated diseases. FASEB J. 1998;12:1255–65.
16. Silverman MN, Pearce BD, Biron CA, Miller AH. Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection. Viral Immunol. 2005;18(1):41-78.
17. Leung DY, Hamid Q, Vottero A, Szefler SJ, Surs W, Minshall E, et al. Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta. The Journal of experimental medicine. 1997;186(9):1567-74.
18. Dhabhar FS, McEwen BS. Stress-induced enhancement of antigen-specific cell-mediated immunity. The Journal of Immunology. 1996;156(7):2608-15.
19. Dhabhar FS, Malarkey WB, Neri E, McEwen BS. Stress-induced redistribution of immune cells—From barracks to boulevards to battlefields: A tale of three hormones–Curt Richter Award Winner. Psychoneuroendocrinology. 2012;37(9):1345-68.
20. Dhabhar FS, McEwen BS. Acute stress enhances while chronic stress suppresses cell-mediated immunityin vivo: A potential role for leukocyte trafficking. Brain, behavior, and immunity. 1997;11(4):286-306.
21. Miller AH, Spencer RL, Pearce BD, Pisell TL, Tanapat P, Leung JJ, et al. 1996 Curt P. Richter Award. Effects of viral infection on corticosterone secretion and glucocorticoid receptor binding in immune tissues. Psychoneuroendocrinology. 1997;22(6):455-74.
22. Ben-Hut T, Conforti N, Itzik A, Weidenfeld J. Effects of HSV-1, a neurotropic virus, on the hypothalamic-pituitary-adrenocortical axis in rats. Brain Research. 1995;702(1):17-22.
23. Pekic S, Popovic V. DIAGNOSIS OF ENDOCRINE DISEASE: Expanding the cause of hypopituitarism. European journal of endocrinology. 2017;176(6):R269-r82.
24. Schaefer S, Boegershausen N, Meyer S, Ivan D, Schepelmann K, Kann PH. Hypothalamic-pituitary insufficiency following infectious diseases of the central nervous system. European journal of endocrinology. 2008;158(1):3-9.
25. Tsiakalos A, Xynos ID, Sipsas NV, Kaltsas G. Pituitary Insufficiency after Infectious Meningitis: A Prospective Study. The Journal of Clinical Endocrinology & Metabolism. 2010;95(7):3277-81.
26. Dhanwal D, Kumar S, Vyas A, Saxena A. Hypothalamic pituitary dysfunction in acute nonmycobacterial infections of central nervous system. Indian Journal of Endocrinology and Metabolism. 2011;15(7):233-7.
27. Tanriverdi F, Alp E, Demiraslan H, Dokmetas HS, Unluhizarci K, Doganay M, et al. Investigation of pituitary functions in patients with acute meningitis: a pilot study. Journal of endocrinological investigation. 2008;31(6):489-91.
28. Partanen T KM, Leisti P, Salmela P, Pääkkö E, Karttunen A, Sintonen H, Risteli L, Hautala N, Vapalahti O, Vaheri A, Kauma H, Hautala T. . Long-term hormonal follow-up after human Puumala hantavirus infection. Clin Endocrinol (Oxf) 2016;84:85-91.
29. Leow MK KD, Ng AW, Ong KC, Kaw GJ, Lee LS. Hypocortisolism in survivors of severe acute respiratory syndrome (SARS). Clin Endocrinol (Oxf). 2005;63(2):197-202.
30. Sullivan WM, Kelley GG, O'Connor PG, Dickey PS, Kim JH, Robbins R, et al. Hypopituitarism associated with a hypothalamic CMV infection in a patient with AIDS. The American Journal of Medicine. 1992;92(2):221-3.
31. Chapter 20 Hypothalamic infections. In: Swaab DF, editor. Handbook of Clinical Neurology. 80: Elsevier; 2004. p. 91-9.
32. Somasundaram NP, Ranathunga I, Ratnasamy V, Wijewickrama PSA, Dissanayake HA, Yogendranathan N, et al. The Impact of SARS-Cov-2 Virus Infection on the Endocrine System. Journal of the Endocrine Society. 2020;4(8).
33. Pekic S, Miljic D, Popovic V. Infections of the Hypothalamic-Pituitary Region.Endotext [Internet]: MDText. com, Inc.; 2018.
34. Aita K, Shiga J. Herpes simplex virus types 1 and 2 infect the mouse pituitary gland and induce apoptotic cell death. Archives of virology. 2004;149(12):2443-51.
35. Hautala T, Sironen T, Vapalahti O, Pääkkö E, Särkioja T, Salmela PI, et al. Hypophyseal hemorrhage and panhypopituitarism during Puumala Virus Infection: Magnetic Resonance Imaging and detection of viral antigen in the hypophysis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2002;35(1):96-101.
36. Sellmeyer DE, Grunfeld C. Endocrine and metabolic disturbances in human immunodeficiency virus infection and the acquired immune deficiency syndrome. Endocrine reviews. 1996;17(5):518-32.
37. Yousuf T L, L. Bacal, A. Krikorian, A. A novel association between pituitary tumor apoplexy and influenza A. AACE Clinical Case Rep 2016. 2016;2:e143-e5.
38. Suh DC, Park JS, Park SK, Lee HK, Chang KH. Pituitary hemorrhage as a complication of hantaviral disease. AJNR American journal of neuroradiology. 1995;16(1):175-8; discussion 9-80.
39. Figurnov VA, Marunich NA, Gavrilov AV, Figurnova EV. [Late consequences of hemorrhagic fever with renal syndrome in a woman who had it during pregnancy]. Klinicheskaia meditsina. 2007;85(5):71-2.
40. Raj H, Kamalanathan S, Sahoo JP, Kadhiravan T. Varicella causing remission of Cushing's disease. BMJ case reports. 2018;2018:bcr2018225867.
41. Pal R. COVID-19, hypothalamo-pituitary-adrenal axis and clinical implications. Endocrine. 2020;68(2):251-2.
42. Yoon JW, Choi DS, Liang HC, Baek HS, Ko IY, Jun HS, et al. Induction of an organ-specific autoimmune disease, lymphocytic hypophysitis, in hamsters by recombinant rubella virus glycoprotein and prevention of disease by neonatal thymectomy. J Virol. 1992;66(2):1210-4.
43. Hägg E, Aström L, Steen L. Persistent hypothalamic-pituitary insufficiency following acute meningoencephalitis. A report of two cases. Acta medica Scandinavica. 1978;203(3):231-5.
44. Kupari M, Pelkonen R, Valtonen V. Post-encephalitic hypothalamic-pituitary insufficiency. Acta endocrinologica. 1980;94(4):433-8.
45. Lim AKH, Paramaswaran S, Jellie LJ, Junckerstorff RK. A Cross-Sectional Study of Hyponatremia Associated with Acute Central Nervous System Infections. Journal of Clinical Medicine. 2019;8(11):1801.
46. Grajecki DS, Haas CS, Hubold C, Lehnert H. Sucessfull treatment of EBV-associated SIADH with V2 receptor antagonist. Exp Clin Endocrinol Diabetes. 2013;121(03):P68.
47. Kuriki A, Ishihara K, Satoh H, Sugie M, Kato H, Kawamura M. [Syndrome of inappropriate secretion of anti-diuretic hormone associated with limbic encephalitis due to herpes simplex virus infection--a case report]. Rinsho shinkeigaku = Clinical neurology. 2008;48(3):184-90.
48. Ahn HJ, Chung JH, Kim DM, Yoon NR, Kim CM. Hemorrhagic fever with renal syndrome accompanied by panhypopituitarism and central diabetes insipidus: a case report. Journal of neurovirology. 2018;24(3):382-7.
49. Moses AM, Thomas DG, Canfield MC, Collins GH. Central Diabetes Insipidus due to Cytomegalovirus Infection of the Hypothalamus in a Patient with Acquired Immunodeficiency Syndrome: A Clinical, Pathological, and Immunohistochemical Case Study. The Journal of Clinical Endocrinology & Metabolism. 2003;88(1):51-4.
50. Lee YJ, Yang D, Shyur SD, Chiu NC. Neurogenic diabetes insipidus in a child with fatal Coxsackie virus B1 encephalitis. Journal of pediatric endocrinology & metabolism : JPEM. 1995;8(4):301-4.
51. Madhoun ZT, DuBois DB, Rosenthal J, Findlay JC, Aron DC. Central diabetes insipidus: a complication of herpes simplex type 2 encephalitis in a patient with AIDS. Am J Med. 1991;90(5):658-9.
52. Borba VV, Zandman-Goddard G, Shoenfeld Y. Prolactin and Autoimmunity. Frontiers in Immunology. 2018;9(73).
53. Parra A, Ramírez-Peredo J, Larrea F, Cabrera V, Coutiño B, Torres I, et al. Decreased dopaminergic tone and increased basal bioactive prolactin in men with human immunodeficiency virus infection. Clin Endocrinol (Oxf). 2001;54(6):731-8.
54. Ochoa-Amaya JE, Malucelli BE, Cruz-Casallas PE, Nasello AG, Felicio LF, Carvalho-Freitas MI. Acute and chronic stress and the inflammatory response in hyperprolactinemic rats. Neuroimmunomodulation. 2010;17(6):386-95.
55. McGill F, Griffiths MJ, Bonnett LJ, Geretti AM, Michael BD, Beeching NJ, et al. Incidence, aetiology, and sequelae of viral meningitis in UK adults: a multicentre prospective observational cohort study. The Lancet Infectious Diseases. 2018;18(9):992-1003.
56. Czupryna P, Moniuszko A, Garkowski A, Pancewicz S, Zajkowska J. Comparison of hyponatremia and SIADH frequency in patients with tick borne encephalitis and meningitis of other origin. Scandinavian Journal of Clinical and Laboratory Investigation. 2016;76(2):159-64.
57. Swart RM, Hoorn EJ, Betjes MG, Zietse R. Hyponatremia and Inflammation: The Emerging Role of Interleukin-6 in Osmoregulation. Nephron Physiology. 2011;118(2):p45-p51.
58. Scheinpflug K, Schalk E, Reschke K, Franke A, Mohren M. Diabetes insipidus due to herpes encephalitis in a patient with diffuse large cell lymphoma. A case report. Exp Clin Endocrinol Diabetes. 2006;114(1):31-4.
59. Torres AM, Kazee AM, Simon H, Knudson PE, Weinstock RS. Central diabetes insipidus due to herpes simplex in a patient immunosuppressed by Cushing's syndrome. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2000;6(1):26-8.
60. Zou R, Wu C, Zhang S, Wang G, Zhang Q, Yu B, et al. Euthyroid Sick Syndrome in Patients With COVID-19. Frontiers in Endocrinology. 2020;11(798).
61. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, et al. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 2014;24(12):1670-751.
62. Kojima M, Nakamura S, Oyama T, Sugihara S, Sakata N, Masawa N. Cellular composition of subacute thyroiditis. an immunohistochemical study of six cases. Pathology, research and practice. 2002;198(12):833-7.
63. Eylan E, Zmucky R, Sheba C. Mumps virus and subacute thyroiditis; evidence of a causal association. Lancet (London, England). 1957;272(6978):1062-3.
64. VOLPÉ R, ROW VV, EZRIN C. Circulating Viral and Thyroid Antibodies in Subacute Thyroiditis1. The Journal of Clinical Endocrinology & Metabolism. 1967;27(9):1275-84.
65. Volpé R. The management of subacute (DeQuervain's) thyroiditis. Thyroid. 1993;3(3):253-5.
66. Desailloud R, Hober D. Viruses and thyroiditis: an update. Virol J. 2009;6:5-.
67. Dumoulin F, Liese H. Acute hepatitis E virus infection and autoimmune thyroiditis: yet another trigger? BMJ case reports. 2012;2012.
68. Mori K, Yoshida K. Viral infection in induction of Hashimoto's thyroiditis: A key player or just a bystander? Current opinion in endocrinology, diabetes, and obesity. 2010;17:418-24.
69. Davies TF. Infection and Autoimmune Thyroid Disease. The Journal of Clinical Endocrinology & Metabolism. 2008;93(3):674-6.
70. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annual review of immunology. 2003;21:335-76.
71. Burch HB, Nagy EV, Lukes YG, Cai WY, Wartofsky L, Burman KD. Nucleotide and amino acid homology between the human thyrotropin receptor and the HIV-1 Nef protein: identification and functional analysis. Biochemical and biophysical research communications. 1991;181(1):498-505.
72. Akahori H, Takeshita Y, Saito R, Kaneko S, Takamura T. Graves' Disease Associated with Infectious Mononucleosis due to Primary Epstein-Barr Virus Infection: Report of 3 Cases. Internal medicine (Tokyo, Japan). 2010;49:2599-603.
73. Wang W, Ye Y, Yao H, Sun L, Wang A, Wang Z. Evaluation and observation of serum thyroid hormone and parathyroid hormone in patients with severe acute respiratory syndrome. J Chin Antituberculous Assoc. 2003;25:232-4.
74. Ciampolillo A, Marini V, Mirakian R, Buscema M, Schulz T, Pujol-Borrell R, et al. Retrovirus-like sequences in Graves' disease: implications for human autoimmunity. Lancet (London, England). 1989;1(8647):1096-100.
75. Mulcahy HEM, F.E. Freaney, R. Hegarty J.E. Parathyroid crisis and acute viral hepatitis B infection. Postgrad Med J. 1993;69:408-10.
76. Hellman P, Albert J, Gidlund M, Klareskog L, Rastad J, Akerström G, et al. Impaired parathyroid hormone release in human immunodeficiency virus infection. AIDS research and human retroviruses. 1994;10(4):391-4.
77. Elkattawy SA, R. Ayad, S. A Novel Case of Hypoparathyroidism Secondary to SARS-CoV-2 Infection. Cureus 2020;12(8):e10097.
78. Sandhu S, Desai A, Batra M, Girdhar R, Chatterjee K, Kemp EH, et al. Severe Symptomatic Hypocalcemia from HIV Related Hypoparathyroidism. Case Reports in Endocrinology. 2018;2018:8270936.
79. Singh A, Dnyanesh D. The prevalence of hypocalcemia in children with dengue infection: A 1-year cross-sectional study. Indian Journal of Health Sciences and Biomedical Research. 2019;12:166.
80. Sobel R, Einhorn S, Maislos M, Shainkin-Kestenbaum R, Shany S, Horowitz J. Transitory Hypocalcemia Complicating Measles. Archives of Internal Medicine. 1985;145(11):2043-4.
81. Jia-Kui S, Wen-Hao Z, Lei Z, Ying L, Jing-Jing L, Xiao-Hua K, et al. Research Square. 2021.
82. Liu J, Han P, Wu J, Gong J, Tian D. Prevalence and predictive value of hypocalcemia in severe COVID-19 patients. Journal of Infection and Public Health. 2020;13(9):1224-8.
83. Antonelli A, Ferrari SM, Di Domenicantonio A, Ferrannini E, Fallahi P. Chapter 53 - Viral Infections and Type 1 Diabetes. In: Shoenfeld Y, Agmon-Levin N, Rose NR, editors. Infection and Autoimmunity (Second Edition). Amsterdam: Academic Press; 2015. p. 877-89.
84. Masini M, Campani D, Boggi U, Menicagli M, Funel N, Pollera M, et al. Hepatitis C Virus Infection and Human Pancreatic β-Cell Dysfunction. Diabetes Care. 2005;28(4):940-1.
85. Capua I, Mercalli A, Pizzuto MS, Romero-Tejeda A, Kasloff S, De Battisti C, et al. Influenza A Viruses Grow in Human Pancreatic Cells and Cause Pancreatitis and Diabetes in an Animal Model. Journal of Virology. 2013;87(1):597-610.
86. Sarmiento L, Frisk G, Anagandula M, Hodik M, Barchetta I, Netanyah E, et al. Echovirus 6 Infects Human Exocrine and Endocrine Pancreatic Cells and Induces Pro-Inflammatory Innate Immune Response. Viruses. 2017;9(2):25.
87. Ginsberg-Fellner F, Witt ME, Fedun B, Taub F, Dobersen MJ, McEvoy RC, et al. Diabetes mellitus and autoimmunity in patients with the congenital rubella syndrome. Reviews of infectious diseases. 1985;7 Suppl 1:S170-6.
88. Rawla P, Bandaru SS, Vellipuram AR. Review of Infectious Etiology of Acute Pancreatitis. Gastroenterology Res. 2017;10(3):153-8.
89. Zhi M, Zhu X, Lugea A, Waldron RT, Pandol SJ, Li L. Incidence of New Onset Diabetes Mellitus Secondary to Acute Pancreatitis: A Systematic Review and Meta-Analysis. Front Physiol. 2019;10:637-.
90. Boettler T, von Herrath M. Protection against or triggering of Type 1 diabetes? Different roles for viral infections. Expert Rev Clin Immunol. 2011;7(1):45-53.
91. Christen U, von Herrath MG. Do viral infections protect from or enhance type 1 diabetes and how can we tell the difference? Cellular & Molecular Immunology. 2011;8(3):193-8.
92. Zhao G, Vatanen T, Droit L, Park A, Kostic AD, Poon TW, et al. Intestinal virome changes precede autoimmunity in type I diabetes-susceptible children. Proceedings of the National Academy of Sciences. 2017;114(30):E6166-E75.
93. Pusch E, Renz H, Skevaki C. Respiratory virus-induced heterologous immunity. Allergo Journal. 2018;27(3):28-45.
94. Paolo WF, Nosanchuk JD. Adrenal infections. International Journal of Infectious Diseases. 2006;10(5):343-53.
95. Potratz D, Brake B, Dienes H, Schulz TF, Hosp M, Dierich M, et al. Herpes simplex virus type 1 and 2 in the adrenal glands: replication and histopathology. Archives of virology. 1986;90(3-4):207-22.
96. Ding Y, He L, Zhang Q, Huang Z, Che X, Hou J, et al. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS‐CoV) in SARS patients: implications for pathogenesis and virus transmission pathways. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland. 2004;203(2):622-30.
97. Wheatland R. Molecular mimicry of ACTH in SARS–implications for corticosteroid treatment and prophylaxis. Medical hypotheses. 2004;63(5):855-62.
98. Lee C-W, Suarez DL, Tumpey TM, Sung H-W, Kwon Y-K, Lee Y-J, et al. Characterization of highly pathogenic H5N1 avian influenza A viruses isolated from South Korea. Journal of virology. 2005;79(6):3692-702.
99. Mahanty S, Bray M. Pathogenesis of filoviral haemorrhagic fevers. The Lancet infectious diseases. 2004;4(8):487-98.
100. Ventura KC, Hawkins H, Smith MB, Walker DH. Fatal neonatal echovirus 6 infection: autopsy case report and review of the literature. Modern Pathology. 2001;14(2):85-90.
101. Pinching AJ. Cytomegalovirus infection in the acquired immune deficiency syndrome. Journal of Antimicrobial Chemotherapy. 1989;23(suppl_E):31-6.
102. Glasgow BJ, Steinsapir KD, Anders K, Layfield LJ. Adrenal pathology in the acquired immune deficiency syndrome. American Journal of Clinical Pathology. 1985;84(5):594-7.
103. Hofbauer LC, Heufelder AE. Endocrine implications of human immunodeficiency virus infection. Medicine. 1996;75(5):262-78.
104. Welch K, Finkbeiner W, Alpers CE, Blumenfeld W, Davis RL, Smuckler EA, et al. Autopsy findings in the acquired immune deficiency syndrome. Jama. 1984;252(9):1152-9.
105. Salim YS, Faber V, Wiik A, Andersen PL, HØIer‐Madsen M, Mouritsen S. Anti‐corticosteroid antibodies in AIDS patients. Apmis. 1988;96(7‐12):889-94.
106. Eledrisi MS, Verghese AC. Adrenal insufficiency in HIV infection: a review and recommendations. The American journal of the medical sciences. 2001;321(2):137-44.
107. Marik PE, Kiminyo K, Zaloga GP. Adrenal insufficiency in critically ill patients with human immunodeficiency virus. Critical care medicine. 2002;30(6):1267-73.
108. Rodrigues D, Reis M, Teixeira V, Silva-Vergara M, Correia Filho D, Adad S, et al. Pathologic findings in the adrenal glands of autopsied patients with acquired immunodeficiency syndrome. Pathology-Research and Practice. 2002;198(1):25-30.
109. Ohsawa M, Tomita Y, Hashimoto M, Yasunaga Y, Kanno H, Aozasa K. Malignant lymphoma of the adrenal gland: its possible correlation with the Epstein-Barr virus. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc. 1996;9(5):534.
110. Masarani M, Wazait H, Dinneen M. Mumps orchitis. J R Soc Med. 2006;99(11):573-5.
111. Barták V. Sperm count, morphology and motility after unilateral mumps orchitis. Journal of reproduction and fertility. 1973;32(3):491-4.
112. Wu H, Shi L, Wang Q, Cheng L, Zhao X, Chen Q, et al. Mumps virus-induced innate immune responses in mouse Sertoli and Leydig cells. Scientific Reports. 2016;6(1):19507.
113. Casella R, Leibundgut B, Lehmann K, Gasser TC. Mumps orchitis: report of a mini-epidemic. The Journal of urology. 1997;158(6):2158-61.
114. Adamopoulos DA, Lawrence DM, Vassilopoulos P, Contoyiannis PA, Swyer GI. Pituitary-testicular interrelationships in mumps orchitis and other viral infections. Br Med J. 1978;1(6121):1177-80.
115. Craighead JE. CHAPTER 1 - Enteroviruses. In: Craighead JE, editor. Pathology and Pathogenesis of Human Viral Disease. San Diego: Academic Press; 2000. p. 1-28.
116. Matusali G, Houzet L, Satie A-P, Mahé D, Aubry F, Couderc T, et al. Zika virus infects human testicular tissue and germ cells. The Journal of Clinical Investigation. 2018;128(10):4697-710.
117. Huang JM, Huang TH, Qiu HY, Fang XW, Zhuang TG, Qiu JW. Studies on the integration of hepatitis B virus DNA sequence in human sperm chromosomes. Asian journal of andrology. 2002;4(3):209-12.
118. Joguet G MJM, Matusali G, Hamdi S, Walschaerts M, Pavili L, Guyomard S, Prisant N, Lamarre P, Dejucq-Rainsford N, Pasquier C, Bujan L. Effect of acute Zika virus infection on sperm and virus clearance in body fluids: a prospective observational study. The Lancet Infectious Diseases. 2017;17 (11):1200-8.
119. Feldmann H. Virus in Semen and the Risk of Sexual Transmission. New England Journal of Medicine. 2018;378(15):1440-1.
120. Li D, Jin M, Bao P, Zhao W, Zhang S. Clinical Characteristics and Results of Semen Tests Among Men With Coronavirus Disease 2019. JAMA Network Open. 2020;3(5):e208292-e.
121. Le Tortorec A, Satie A-P, Denis H, Rioux-Leclercq N, Havard L, Ruffault A, et al. Human prostate supports more efficient replication of HIV-1 R5 than X4 strains ex vivo. Retrovirology. 2008;5(1):119.
122. Willey S, Roulet V, Reeves JD, Kergadallan M-L, Thomas E, McKnight Á, et al. Human Leydig cells are productively infected by some HIV-2 and SIV strains but not by HIV-1. Aids. 2003;17(2):183-8.
123. Yuan J. Genitourinary Presentation of Tuberculosis. Reviews in urology. 2015;17(2):102-5.
124. Garolla A, Vitagliano A, Muscianisi F, Valente U, Ghezzi M, Andrisani A, et al. Role of Viral Infections in Testicular Cancer Etiology: Evidence From a Systematic Review and Meta-Analysis. Frontiers in endocrinology. 2019;10:355-.
125. Naz RK, Ellaurie M, Phillips TM, Hall J. Antisperm antibodies in human immunodeficiency virus infection: effects on fertilization and embryonic development. Biology of reproduction. 1990;42(5-6):859-68.
126. Morrison JC, Givens JR, Wiser WL, Fish SA. Mumps oophoritis: a cause of premature menopause. Fertility and sterility. 1975;26(7):655-9.
127. Morelli F, Souza RP, Cruz TEd, Damke GMZF, Damke E, Suehiro TT, et al. Zika virus infection in the genital tract of non-pregnant females: a systematic review. Revista do Instituto de Medicina Tropical de São Paulo. 2020;62.
128. Manfredi R, Alampi G, Talò S, Calza L, Tadolini M, Martinelli GN, et al. Silent oophoritis due to cytomegalovirus in a patient with advanced HIV disease. International journal of STD & AIDS. 2000;11(6):410-2.
129. Ingerslev K, Hogdall E, Schnack TH, Skovrider-Ruminski W, Hogdall C, Blaakaer J. The potential role of infectious agents and pelvic inflammatory disease in ovarian carcinogenesis. Infectious Agents and Cancer. 2017;12(1):25.
130. Altindis E, Cai W, Sakaguchi M, Zhang F, GuoXiao W, Liu F, et al. Viral insulin-like peptides activate human insulin and IGF-1 receptor signaling: A paradigm shift for host–microbe interactions. Proceedings of the National Academy of Sciences. 2018;115(10):2461-6.
131. Irwin DM. Viral Insulin/IGF-1–Like Peptides: Novel Regulators of Physiology and Pathophysiology? Endocrinology. 2018;159(11):3659-60.
132. Huang Q, Kahn CR, Altindis E. Viral Hormones: Expanding Dimensions in Endocrinology. Endocrinology. 2019;160(9):2165-79.
133. Watanabe T, Yamaguchi K, Takatsuki K, Osame M, Yoshida M. Constitutive expression of parathyroid hormone-related protein gene in human T cell leukemia virus type 1 (HTLV-1) carriers and adult T cell leukemia patients that can be trans-activated by HTLV-1 tax gene. The Journal of experimental medicine. 1990;172(3):759-65.
134. Kino T, De Martino MU, Charmandari E, Mirani M, Chrousos GP. Tissue glucocorticoid resistance/hypersensitivity syndromes. The Journal of steroid biochemistry and molecular biology. 2003;85(2-5):457-67.
135. Roodman GD, Windle JJ. Paget disease of bone. The Journal of clinical investigation. 2005;115(2):200-8.
136. Glantschnig C, Koenen M, Lozano MG, Karbiener M, Cummins C, Blüher M, et al. A miR-29a-driven negative feedback loop regulates the glucocorticoid receptor in health and disease. Diabetologie und Stoffwechsel. 2018;13(03):LB FV 7.
137. Chen N, Baudino T, MacDonald PN, Green M, Kelley WL, Burnett JW, et al. Selective inhibition of nuclear steroid receptor function by a protein from a human tumorigenic poxvirus. Virology. 2000;274(1):17-25.
138. Brockmann D, Esche H. The multifunctional role of E1A in the transcriptional regulation of CREB/CBP-dependent target genes. Current topics in microbiology and immunology. 2003;272:97-129.
139. Puig-Domingo M, Marazuela M, Giustina A. COVID-19 and endocrine diseases. A statement from the European Society of Endocrinology. Endocrine. 2020;68(1):2-5.
140. Bergthorsdottir R, Leonsson-Zachrisson M, Odén A, Johannsson G. Premature mortality in patients with Addison’s disease: a population-based study. The Journal of Clinical Endocrinology & Metabolism. 2006;91(12):4849-53.
141. Quinkler M, Ekman B, Zhang P, Isidori AM, Murray RD, Investigators EA. Mortality data from the European Adrenal Insufficiency Registry—Patient characterization and associations. Clinical endocrinology. 2018;89(1):30-5.
142. Tresoldi AS, Sumilo D, Perrins M, Toulis KA, Prete A, Reddy N, et al. Increased infection risk in Addison’s disease and congenital adrenal hyperplasia: a primary care database cohort study. The Journal of Clinical Endocrinology & Metabolism. 2020;105(2):418-29.
143. Bancos I, Hazeldine J, Chortis V, Hampson P, Taylor AE, Lord JM, et al. Primary adrenal insufficiency is associated with impaired natural killer cell function: a potential link to increased mortality. European journal of endocrinology. 2017;176(4):471.
144. Isidori AM, Venneri MA, Graziadio C, Simeoli C, Fiore D, Hasenmajer V, et al. Effect of once-daily, modified-release hydrocortisone versus standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal insufficiency (DREAM): a single-blind, randomised controlled trial. The lancet Diabetes & endocrinology. 2018;6(3):173-85.
145. Isidori AM, Arnaldi G, Boscaro M, Falorni A, Giordano C, Giordano R, et al. COVID-19 infection and glucocorticoids: update from the Italian Society of Endocrinology Expert Opinion on steroid replacement in adrenal insufficiency. Journal of endocrinological investigation. 2020;43(8):1141-7.
146. Ives AM, Bertke AS. Stress Hormones Epinephrine and Corticosterone Selectively Modulate Herpes Simplex Virus 1 (HSV-1) and HSV-2 Productive Infections in Adult Sympathetic, but Not Sensory, Neurons. Journal of Virology. 2017;91(13):e00582-17.
147. Noisakran S, Halford WP, Veress L, Carr DJJ. Role of the Hypothalamic Pituitary Adrenal Axis and IL-6 in Stress-Induced Reactivation of Latent Herpes Simplex Virus Type 1. The Journal of Immunology. 1998;160(11):5441-7.
148. Uchakin PN, Parish DC, Dane FC, Uchakina ON, Scheetz AP, Agarwal NK, et al. Fatigue in Medical Residents Leads to Reactivation of Herpes Virus Latency. Interdisciplinary Perspectives on Infectious Diseases. 2011;2011:571340.
149. Englund J, Feuchtinger T, Ljungman P. Viral infections in immunocompromised patients. Biol Blood Marrow Transplant. 2011;17(1 Suppl):S2-S5.
150. Pivonello R, Ferrigno R, Isidori AM, Biller BMK, Grossman AB, Colao A. COVID-19 and Cushing's syndrome: recommendations for a special population with endogenous glucocorticoid excess. Lancet Diabetes Endocrinol. 2020;8(8):654-6.
151. Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BM, Colao A. Complications of Cushing's syndrome: state of the art. The Lancet Diabetes & Endocrinology. 2016;4(7):611-29.
152. Berczi I. Pituitary hormones and immune function. Acta Paediatrica. 1997;86(S423):70-5.
153. Postel-Vinay M-C, de Mello Coelho V, Gagnerault M-C, Dardenne M. Growth hormone stimulates the proliferation of activated mouse T lymphocytes. Endocrinology. 1997;138(5):1816-20.
154. Yu-Lee L-Y. Molecular actions of prolactin in the immune system. Proceedings of the Society for Experimental Biology and Medicine. 1997;215(1):35-52.
155. Fabris N, Mocchegiani E, Provinciali M. Pituitary-Thyroid Axis and Immune System: A Reciprocal Neuroendocrine-lmmune Interaction. Hormone Research in Paediatrics. 1995;43(1-3):29-38.
156. Grossman CJ. Interactions between the gonadal steroids and the immune system. Science. 1985;227(4684):257-61.
157. Sharma MD, Sagar B, Wang S, Clinton White A, Jr., Balasubramanyam A. High Frequency of Serious Infections in Patients with Panhypopituitarism: A Case-Control Study. Clinical Infectious Diseases. 2001;32(1):153-8.
158. Bialasiewicz AA, Jüppner H, Diehl V, Hesch R-D. Binding of bovine parathyroid hormone to surface receptors of cultured B-lymphocytes. Biochimica et Biophysica Acta (BBA)-General Subjects. 1979;584(3):467-78.
159. Shurtz-Swirski R, Shkolnik T, Shasha SM. Parathyroid hormone and the cellular immune system. Nephron. 1995;70(1):21-4.
160. El Kelany MA, Maklad SS, El Fouhil DF, El Etreby EA, Saleh LH, El Sheikh NA. Immunomodulatory effects of secondary hyperparathyroidism on circulating CD4+ and CD8+ T-lymphocytes in chronic renal failure patients. The Egyptian journal of immunology. 2009;16(2):71-82.
161. Klein SL. Sex influences immune responses to viruses, and efficacy of prophylaxis and treatments for viral diseases. Bioessays. 2012;34(12):1050-9.
162. Klein SL, Jedlicka A, Pekosz A. The Xs and Y of immune responses to viral vaccines. The Lancet infectious diseases. 2010;10(5):338-49.
163. Hewagama A, Patel D, Yarlagadda S, Strickland FM, Richardson BC. Stronger inflammatory/cytotoxic T-cell response in women identified by microarray analysis. Genes & Immunity. 2009;10(5):509-16.
164. Kovats S, Carreras E, Agrawal H, Klein S, Roberts C. Sex hormones and immunity to infection. 2010.
165. Tuku B, Stanelle-Bertram S, Sellau J, Beck S, Bai T, Kouassi NM, et al. Testosterone Protects Against Severe Influenza by Reducing the Pro-Inflammatory Cytokine Response in the Murine Lung. Frontiers in Immunology. 2020;11(697).
166. Steeg LGv, Vermillion MS, Hall OJ, Alam O, McFarland R, Chen H, et al. Age and testosterone mediate influenza pathogenesis in male mice. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2016;311(6):L1234-L44.
167. vom Steeg LG, Dhakal S, Woldetsadik YA, Park H-S, Mulka KR, Reilly EC, et al. Androgen receptor signaling in the lungs mitigates inflammation and improves the outcome of influenza in mice. PLOS Pathogens. 2020;16(7):e1008506.
168. Robinson DP, Hall OJ, Nilles TL, Bream JH, Klein SL. 17β-estradiol protects females against influenza by recruiting neutrophils and increasing virus-specific CD8 T cell responses in the lungs. Journal of virology. 2014;88(9):4711-20.
169. Straub RH. The complex role of estrogens in inflammation. Endocrine reviews. 2007;28(5):521-74.
170. Costeira R, Lee KA, Murray B, Christiansen C, Castillo-Fernandez J, Ni Lochlainn M, et al. Estrogen and COVID-19 symptoms: associations in women from the COVID Symptom Study. medRxiv. 2020:2020.07.30.20164921.
171. Geerlings SE, Hoepelman AI. Immune dysfunction in patients with diabetes mellitus (DM). FEMS immunology and medical microbiology. 1999;26(3-4):259-65.
172. Muller LM, Gorter KJ, Hak E, Goudzwaard WL, Schellevis FG, Hoepelman AI, et al. Increased risk of common infections in patients with type 1 and type 2 diabetes mellitus. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2005;41(3):281-8.
173. Diepersloot R, Bouter KP, Beyer W, Hoekstra J, Masurel N. Humoral immune response and delayed type hypersensitivity to influenza vaccine in patients with diabetes mellitus. Diabetologia. 1987;30(6):397-401.
174. Singh AK, Gupta R, Ghosh A, Misra A. Diabetes in COVID-19: Prevalence, pathophysiology, prognosis and practical considerations. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2020.
175. Tong Q, Xiang W, Ye H, Zhang H, Chen Y, Chen W, et al. T3 level may be a helpful marker to predict disease prognosis of acute central nervous system viral infections. The International journal of neuroscience. 2019;129(2):139-45.
176. Constantine G, Rajapakse S, Ranasinghe P, Parththipan B, Wijewickrama A, Jayawardana P. Hypocalcemia is associated with disease severity in patients with dengue. Journal of infection in developing countries. 2014;8:1205-9.
177. Manjunath VG, Balla S, Kumar J. Serum ionic calcium levels and hypocalcemia in dengue fever in children and its correlation with its severity: case control study. 2019. 2019;6(3):5.
178. Jin Y, Yang H, Ji W, Wu W, Chen S, Zhang W, et al. Virology, epidemiology, pathogenesis, and control of COVID-19. Viruses. 2020;12(4):372.
179. Lazartigues E, Qadir MMF, Mauvais-Jarvis F. Endocrine Significance of SARS-CoV-2’s Reliance on ACE2. Endocrinology. 2020;161(9).
180. Zinserling VA, Semenova NY, Markov AG, Rybalchenko OV, Wang J, Rodionov RN, et al. Inflammatory Cell Infiltration of Adrenals in COVID-19. Horm Metab Res. 2020;52(09):639-41.
181. Pascual-Goñi E, Fortea J, Martínez-Domeño A, Rabella N, Tecame M, Gómez-Oliva C, et al. COVID-19-associated ophthalmoparesis and hypothalamic involvement. Neurology - Neuroimmunology Neuroinflammation. 2020;7(5):e823.
182. Nampoothiri S, Sauve F, Ternier G, Fernandois D, Coelho C, Imbernon M, et al. The hypothalamus as a hub for SARS-CoV-2 brain infection and pathogenesis. bioRxiv. 2020:2020.06.08.139329.
183. Chen M, Zhou W, Xu W. Thyroid function analysis in 50 patients with COVID-19: a retrospective study. Thyroid. 2020.
184. Rajevac H, Bachan M, Khan Z. DIABETES INSIPIDUS AS A SYMPTOM OF COVID-19 INFECTION: CASE REPORT. Chest. 2020;158(4):A2576-A.
185. Yousaf Z, Al-Shokri SD, Al-Soub H, Mohamed MFH. COVID-19-associated SIADH: a clue in the times of pandemic! Am J Physiol Endocrinol Metab. 2020;318(6):E882-E5.
186. Uddin Chowdhury MR, Akter KS, Moula MM, Kabir MA, Bhuiyan SI, Das BC. COVID-19 presented with syndrome of inappropriate ADH secretion(SIADH): A case report from Bangladesh. Respiratory Medicine Case Reports. 2020;31:101290.
187. Ravioli S, Niebuhr N, Ruchti C, Pluess E, Stoeckli T, Lindner G. The syndrome of inappropriate antidiuresis in COVID-19 pneumonia: report of two cases. Clinical Kidney Journal. 2020.
188. Brancatella A, Ricci D, Cappellani D, Viola N, Sgrò D, Santini F, et al. Is Subacute Thyroiditis an Underestimated Manifestation of SARS-CoV-2 Infection? Insights From a Case Series. The Journal of Clinical Endocrinology & Metabolism. 2020;105(10):e3742-e6.
189. Brancatella A, Ricci D, Viola N, Sgrò D, Santini F, Latrofa F. Subacute thyroiditis after SARS-CoV-2 infection. The Journal of Clinical Endocrinology & Metabolism. 2020;105(7):dgaa276.
190. Mateu-Salat M, Urgell E, Chico A. SARS-COV-2 as a trigger for autoimmune disease: report of two cases of Graves’ disease after COVID-19. Journal of endocrinological investigation. 2020;43(10):1527-8.
191. Muller I, Cannavaro D, Dazzi D, Covelli D, Mantovani G, Muscatello A, et al. SARS-CoV-2-related atypical thyroiditis. The Lancet Diabetes & Endocrinology. 2020;8(9):739-41.
192. Ceriello A, De Nigris V, Prattichizzo F. Why is hyperglycaemia worsening COVID‐19 and its prognosis? Diabetes, Obesity and Metabolism. 2020;22(10):1951-2.
193. Yang J-K, Lin S-S, Ji X-J, Guo L-M. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta diabetologica. 2010;47(3):193-9.
194. Szatmary P, Arora A, Raraty MGT, Dunne DFJ, Baron RD, Halloran CM. Emerging phenotype of severe acute respiratory syndrome-coronavirus 2–associated pancreatitis. Gastroenterology. 2020;159(4):1551-4.
195. Reddy PK, Kuchay MS, Mehta Y, Mishra SK. Diabetic ketoacidosis precipitated by COVID-19: A report of two cases and review of literature. Diabetes Metab Syndr. 2020;14(5):1459-62.
196. Iuga AC, Marboe CC, M. Yilmaz M, Lefkowitch JH, Gauran C, Lagana SM. Adrenal Vascular Changes in COVID-19 Autopsies. Archives of Pathology & Laboratory Medicine. 2020;144(10):1159-60.
197. Frankel M, Feldman I, Levine M, Frank Y, Bogot NR, Benjaminov O, et al. Bilateral Adrenal Hemorrhage in Coronavirus Disease 2019 Patient: A Case Report. The Journal of Clinical Endocrinology & Metabolism. 2020;105(12):3745-9.
198. Gagliardi L, Bertacca C, Centenari C, Merusi I, Parolo E, Ragazzo V, et al. Orchiepididymitis in a boy with COVID-19. The Pediatric infectious disease journal. 2020;39(8):e200-e2.
199. Illiano E, Trama F, Costantini E. Could COVID‐19 have an impact on male fertility? Andrologia. 2020:e13654.
200. Ma L, Xie W, Li D, Shi L, Mao Y, Xiong Y, et al. Effect of SARS-CoV-2 infection upon male gonadal function: A single center-based study. medRxiv. 2020:2020.03.21.20037267.
201. Li H, Xiao X, Zhang J, Zafar MI, Wu C, Long Y, et al. Impaired spermatogenesis in COVID-19 patients. EClinicalMedicine. 2020;28.
202. Serban AL, Ferrante E, Carosi G, Indirli R, Arosio M, Mantovani G. COVID-19 in Cushing disease: experience of a single tertiary centre in Lombardy. Journal of endocrinological investigation. 2020.
203. Arlt W, Baldeweg SE, Pearce SH, Simpson HL. Clinical management guidance during the covid-19 pandemic adrenal insufficiency. European journal of endocrinology. 2020:1-21.

ABSTRACT

Protozoa are parasitic organisms that are among the most important pathogens worldwide. They are classified into four groups and in infected persons, the disease process may be asymptomatic. Of the four groups, Flagellates and Sporozoa are implicated in the causation of endocrine dysfunction and metabolic abnormalities. The disease condition caused by the flagellates include Giardiasis, Leishmaniasis, and Trypanosomiasis and all cause endocrine abnormalities that range from growth retardation, hypogonadism, adrenal insufficiency, thyroid dysfunction which is largely a resultant effect of the sick euthyroid syndrome, and the syndrome of inappropriate ADH secretion. The Sporozoan disease that notably give rise to metabolic abnormalities is malaria especially severe malaria which is commonly caused by P Falciparum infection. Hypoglycemia is one of the defining criteria for severe malaria and in Africa where malaria is endemic the reported prevalence rate of hypoglycemia in children is as high as 60%. Other abnormalities which are infrequently reported requiring treatment albeit temporarily are hyperglycemia, hypocalcemia, and diabetes insipidus. Adrenal insufficiency when is present is a poor prognostic factor in severe malaria. Toxoplasmosis is acquired or vertically transmitted and may present with neuroendocrine manifestations and adrenal insufficiency resulting from infiltration of the affected endocrine organs with the parasites.

PROTOZOA

A parasite is an organism that lives on or in a host organism and gets its food from or at the expense of its host. The three main classes of parasites that can cause disease in humans include helminths, protozoa, and ectoparasites.

Protozoa are microscopic, one-celled organisms that can be free-living or parasitic in nature. Their ability to multiply in humans contributes to their survival and also permits serious infections to develop from just a single organism. Transmission of protozoa that live in a human’s intestine to another human typically occurs through a fecal-oral route and for those that live in the blood or tissue of human’s transmission to other humans is via an arthropod vector (1). Protozoa that are infectious to humans are classified into four groups based on their mode of movement;

Mastigophora – the flagellates, e.g., Giardia, Leishmania, Trypanosoma

Sporozoa – organisms whose adult stage is not motile e.g., Plasmodium, Cryptosporidium, Toxoplasma gondii,

Ciliophora – the ciliates, e.g., Balantidium

Sarcodina – the ameba, e.g., Entamoeba

MASTIGOPHORA  

Mastigophora is a phylum of protozoans of the Kingdom Protista, consisting mainly of free-living flagellated unicellular organisms that reproduce by binary fission and whose habitat includes fresh and marine waters. Leishmania and Trypanosoma live in the blood, lymph, and tissue spaces and are typically transmitted from one host to another by blood feeding arthropods.

Giardiasis 

This is a diarrheal illness that is caused by Giardia (also known as Giardia intestinalis, Giardia lamblia, or Giardia duodenalis). It is a microscopic parasite and is the most common cause of protozoa associated diarrhea worldwide. The prevalence rate of Giardiasis is higher in developing countries than in the developed countries of the world with Giardia species being endemic in areas of the world that have poor sanitation and high-risk groups including immunocompromised individuals (2-3).

MODE OF TRANSMISSION

The parasite is found on surfaces or in soil, food, or water that has been contaminated with feces from infected humans or animals. Infection is transmitted commonly through ingestion of infectious G lamblia cysts. In the intestine, excystation occurs and trophozoites are released into the feces. A summary of the transmission of the parasite is shown in Figure 1.

Giardia infrequently is transmitted sexually specifically through oral-anal practices. The incubation period is 3-35 days but 7-10 days on the average.

Figure 1. Life Cycle of Giardia. Source- Centers for Disease Control and Prevention

CLINICAL PRESENTATION

The clinical manifestations include acute or chronic diarrheal disease, but the infection may be asymptomatic even in children. In a Nigeria Study (3) that evaluated stool samples of children aged between 0-5 years, about half-(41%) were positive for G. lamblia. The extraintestinal manifestations of Giardiasis include allergic presentations resulting from immune system activation, and long-term consequences such as ocular pathologies, arthritis, allergies, growth failure, muscular, and metabolic complications (4-5).

ENDOCRINE AND METABOLIC ABNORMALITIES

The complications relating to endocrine and metabolic dysfunction include growth failure and hypothyroidism. The Nigerian Report described above showed a positive association between asymptomatic giardiasis and malnutrition. The relation between Giardiasis and growth failure is explained mainly by malabsorption leading to protein energy malnutrition and micronutrient deficiencies. Other than nutritional status, other contributory factors to growth stunting in children include sanitary and socio-economic conditions, loss of intestinal surface area, and maldigestion (4-5).

Giardia infection has no direct effect or impact on thyroid function but has been reported to indirectly affect thyroid status. Worsening of hypothyroidism related to malabsorption of levothyroxine tablets occasioned by the presence of Giardia infection has been documented in the literature (6-7).

DIAGNOSIS AND MANAGEMENT

The diagnosis is made by demonstration of cysts or trophozoites in stool samples. Other means of diagnosis include small bowel biopsy and stool ELISA. The mainstay of treatment is metronidazole. Patients with stunted growth often experience catch- up growth following treatment of giardiasis.

Leishmaniasis  

Leishmaniasis is a poverty related protozoal disease caused by the Leishmania donovani complex. There are 3 main forms of leishmaniases – visceral (also known as kala-azar, the most serious form of the disease), cutaneous (the most common), and mucocutaneous. The clinical spectrum of leishmaniasis ranges from a self-resolving cutaneous ulcer to a mutilating mucocutaneous disease and even to a lethal systemic illness. In Nigeria cutaneous leishmaniasis is the commonly occurring type and has been noted to occur in Northern Nigeria especially in areas bordering the Niger Republic.

MODE OF TRANSMISSION

Leishmania spp. is a parasite with a dimorphic life cycle that is controlled by the passage from vector to host .All three forms of Leishmaniasis are transmitted by the bite of infected female sand fly. The vector phase of the life cycle begins when the vector ingests blood containing the parasites with the parasites undergoing differentiation and ultimately becoming promastigotes and pass into the proboscis where where they can inoculate the host during feeding of the vector (8). These human and vector stages of Leishmania are shown in Figure 2. Infiltration of the reticuloendothelial system by amastigotes leads to the biochemical and clinical features of the disease.

Vertical transmission of visceral leishmaniasis may occur during pregnancy while cutaneous leishmaniasis may be transmitted through physical contact. Transmission via contaminated needles, blood transfusion, sexual intercourse and vertical transmission are modes of transmission that are documented albeit infrequently (8).

Figure 2. Life cycle of Leishmania. Source -CDC

CLINICAL PRESENTATION

Visceral Leishmaniasis (VL) may present with fever, malnutrition, weight loss , hepatosplenomegaly and death if treatment is delayed or sub-optimal. Cutaneous Leishmaniasis presents with skin ulceration and nodules and the Mucocutaneous form of Leishmaniasis with skin and mucous involvement.

ENDOCRINE AND METABOLIC ABNORMALITIES

Evidence of involvement of several endocrine organs- pituitary, adrenal, thyroid, and sex glands- via histopathologic studies have been documented in VL (9). However abnormal endocrine function tests in some instances without clinical manifestations have been documented.

Reports from Africa and Europe show that thyroid function may be affected in VL but the abnormalities detected are most likely a result of euthyroid sick syndrome (ESS) or non-thyroidal illness (NTI) with no clinical presentation of thyroid disease (10-12). VL has been reported to present with primary adrenal insufficiency in with clinically overt features and in some cases biochemical evidence without clinical features may occur. Primary adrenal insufficiency (AI) was reported in VL in a patient without HIV infection and a patient with concomitant HIV infection and was attributable to parasitic infiltration of the organ (13-14). A Brazilian Series reported a prevalence rate of AI to be about 50% in persons with VL (12). In the Brazilian Report (12) that compared hormonal parameters between persons with chronic leishmaniasis and control subjects, the following were noted in some of the subjects with leishmaniasis; a) features of pituitary dysfunction characterized by low TSH, low T4, and low T3 levels (ESS/NTI), b) elevated ACTH with normal cortisol levels, c) high FSH, LH, and low testosterone levels. Other endocrine abnormalities include low parathyroid hormone (PTH) and decreased total and ionized calcium levels.

An unusual presentation of VL is adrenal cysts which has been reported to come to clinical attention because of the mass effect (15-16). The Syndrome of inappropriate ADH secretion (SIADH) is often reported in VL with hyponatremia documented as a significant contributory factor to mortality of the disease (17). The endocrine and metabolic abnormalities of Leishmaniasis and potential mechanisms underlying their occurrence are shown in Table 1. 

DIAGNOSIS AND TREATMENT

A combination of clinical symptoms and laboratory parameters clinches the diagnosis. The laboratory tests involve the detection of the parasites in samples taken from the base of the ulcer and dermal scrapings- Wright ‘s stain detects round or ovoid parasite in the cytoplasm of macrophages.

Polymerase chain reaction for detection of the parasite in peripheral blood and bone marrow samples IS diagnostic. Other tests to support the diagnosis is the Leishman test, which essentially refers to observation of a delayed tuberculin type of reaction following an Intradermal injection of leishmanial antigen.

The mainstay of treatment is the pentavalent antimony compounds. Other pharmacotherapies include amphotericin B, oral miltefosine, pentamidine, and antibiotics. Treatment is individualized, thus persons with associated endocrine/metabolic dysfunction are treated on a case-by-case basis.

Trypanosomiasis  

This is an anthropozoonosis caused by a protozoan hemoflagellate. Trypanosoma cruzi in American trypanosomiasis, also known as Chagas disease, is transmitted to human host by a tick. Human African trypanosomiasis (HAT) also known as sleeping sickness is caused by Trypanosoma brucei gambiense in West and Central Africa andTrypanosoma brucei rhodosiense in East Africa is transmitted to human hosts by bites of infected tsetse flies.

Figure 3. The pathogen in human African trypanosomiasis

MODE OF TRANSMISSION

In HAT the tsesefly (glossina specie) injects metacyclic trypomastogotes into the skin and these pass into the blood stream and are subsequently carried to other parts of the body and body fluids. The tsetsefly becomes infected when it bites an infected person. Trypanosoma brucei gambiense may also be acquired congenitally from an infected mother.

Chagas disease is transmitted by a group of blood-feeding insects known as kissing bugs or triatomid bugs. The pathogen normally circulates between bugs and wild animals in sylvatic habitats; infected bugs in domestic habitats can transmit Chagas to humans and domestic animals (dogs, guinea pigs). Details of the life cycle and transmission of the pathogen is shown in Figure 4.

Figure 4. Transmission of Chagas Disease

CLINICAL PRESENTATION

Trypanosomiasis may cause acute illness but on the other hand the infection may be asymptomatic. Chagas disease (CD) presents in three phases: acute, indeterminate, and chronic. The acute phase occurs immediately following infection and is usually asymptomatic in most people but when symptomatic, presentation is essentially those of malaise and skin lesions. The indeterminate phase is usually asymptomatic but may progress to a chronic phase where organ systems mainly the heart and sometimes the gastrointestinal tract are affected.

HAT is characterized by an early hyper-hemolytic phase in which the trypanosomes are restricted to the blood and the lymphatic system and also characterized by organomegaly and lymphadenopathy. This is followed by a late phase or the meningo-encephalitic stage characterized by neuro-psychiatric and endocrinal disorders.

ENDOCRINE AND METABOLIC ABNORMALITIES   

These occur infrequently and includes systemic neuroendocrine manifestations in the sympathetic and parasympathetic ganglia. In HAT, documented endocrine abnormalities include adrenal insufficiency, hypothyroidism, and hypogonadism in the absence of autoantibodies (18). Some authors have reported thyroid dysfunction specifically hypothyroidism in untreated HAT (19).

Adrenal insufficiency in trypanosomiasis may be primary or secondary and this is seen especially in untreated cases (20). The adrenal may serve as a reservoir for the T. cruzi infection and some investigators have noted a correlation between Chagasic myocarditis and infection within the central vein of the adrenal gland (21).

Secondary hypogonadism in both sexes had also been demonstrated in some reports which clearly showed that in the majority of the cases, the pathology was not at the level of the pituitary gland but rather an extra pituitary origin (22). Clearly, primary hypogonadism was not demonstrated to be a contributory factor to cases of hypogonadism in persons with trypanosomiasis.

Metabolic abnormalities are infrequently reported however a case of spurious hypoglycemia (23) has been documented in which hypoglycemia was attributable to invitro utilization of glucose by the parasite. The metabolic and endocrine abnormalities are shown in Table 2.

DIAGNOSIS  

Diagnosis of HAT involves a three-tiered approach for infections due to T.b. Gambiense and a two-tiered approach for that due to T.b. rhodosiense. The three steps for gambiense HAT include a screening test, diagnostic confirmation, and stage determination while that for rhodesiense HAT are diagnostic confirmation and stage determination. Screening is for gambiense HAT involves serology - CATT (Card Agglutination Test for Trypanosomiasis), which detects the presence of specific antibodies in the patient’s blood or serum. Diagnostic confirmation is done to detect the presence of trypanosomes in lymph node aspirates, chancre smear, or in blood. Stage determination is via the detection of trypanosomes (after centrifugation) and white cell count in the cerebrospinal fluid (lumbar puncture):Hemolymphatic stage is characterized by the absence of trypanosomes AND ≤ 5 white cells/mm³ and the Meningoencephalitic stage is defined by evidence of trypanosomes OR > 5 white cells/mm³.

Diagnosis of Chagas disease is via identification of Trypanosoma cruzi by direct microscopy of fresh blood or blood concentrated by the microhematocrit method. Serological tests for anti-Trypanosoma cruzi antibodies are performed for cases of suspected disease but no definitive diagnosis by microscopy.

PHARMACOTHERAPY FOR TRYPANOSMIASIS

Acute or chronic Chagas disease can be treated with either benznidazole or nifurtimox for those without cardiac or GIT complications. Drugs employed in the management of HAT include Nifurtimox, Eflornithine, Melarsoprol, Pentamidine, and Prednisolone (24).

SPOROZOANS

Sporozoans are a group of non-flagellated, non-ciliated and non-amoeboid protists that are responsible for diseases such as malaria and toxoplasmosis.

Malaria

Malaria is an infection caused by single-celled parasites that enter the blood through the bite of an Anopheles mosquito. These parasites, called plasmodia, belong to at least five species; P falciparum, P vivax, P ovale, P malariae and P knowlesi. Plasmodium parasites spend several parts of their life cycle inside humans and another part inside mosquitoes. During the human part of their life cycle, Plasmodium parasites infect and multiply inside liver cells and red blood cells.

Malaria infection begins when an infected female Anopheles mosquito bites a person, injecting Plasmodium parasites, in the form of sporozoites, into the bloodstream and then to the liver. In the liver, asexual multiplication of the sporozoites take place and these are released from the liver as merozoites which invade the red blood cells and multiply within the red cells until the cells burst and the released merozoites invade more red cells with the cycle repeating itself and causing fever. Some of the merozoites leave the cycle of asexual multiplication and instead of replicating within the cells develop into sexual forms of the parasites known as gametocytes. Following the bite of an infected person, gametocytes are ingested by the mosquito and develop into gametes which ultimately become sporozoites which travel to the mosquito’s salivary glands (25).

CLINICAL PRESENTATION

Uncomplicated malaria presents with fever, headache, and generalized malaise. Severe malaria refers to the demonstration of asexual forms of the malaria parasites (commonly P falciparum) in a patient with a potentially fatal manifestations or complications of malaria. Severe malaria is characterized by altered mentation, severe hemolysis, some metabolic abnormalities, and organ complications.

ENDOCRINE AND METABOLIC ABNORMALITIES

Hypoglycemia is commonly documented in severe malaria and hyperglycemia although infrequently reported is seen in severe malaria as well as uncomplicated malaria. Hypocalcemia is also reported in severe malaria as well as in cases of uncomplicated malaria.

Hypoglycemia may be iatrogenic due to quinine administration or due to increased glucose turnover secondary to increased glucose uptake resulting from anaerobic glycolysis and alterations in glucose production in severe malaria (26). Nigeria Reports have hypoglycemia (blood glucose <2.2mmol/L) documented in 60% of children diagnosed with severe malaria (27). Hyperglycemia on the other hand infrequently occurs in persons with malaria and it may present in uncomplicated malaria or severe malaria due to P falciparum infection. The causes of hyperglycemia sometimes necessitate the temporary use of insulin and is multifactorial. These include release of counter-regulatory hormones in response to the stress of the underlying malaria disease condition and pro inflammatory cytokines which increase blood glucose (28). Other proposed reasons for hyperglycemia are reduced sensitivity to insulin and increased gastric and small intestine permeability for sucrose in malaria patients (29-30).

Hypocalcemia is reported in severe malaria as well as in cases of uncomplicated malaria. It has been shown that there is an inverse relationship between parasite load and calcium levels with calcium levels returning to normal following treatment and parasite clearance (31). Altered magnesium metabolism and disturbed parathyroid gland function have been documented as possible reasons for hypocalcemia in malaria (32).

The pituitary-thyroid axis may be depressed in severe malaria and this is most likely attributable to adaptations of the pituitary-thyroid axis to the underlying illness. A Report has noted suppressed T4 and TSH levels with a poorly responsive pituitary gland to TRH stimulation as evidenced by low TSH levels following stimulation (33-34).  Another possible mechanism underlying the secondary hypothyroidism is parasitic sequestration within the hypothalamo-pituitary portal system (35).

Clinical and biochemical parameters of central diabetes insipidus which in some cases warranted treatment has been reported in severe malaria. The suggested mechanism is obstruction of the neurohypophyseal microvasculature (36-37).

Primary and secondary adrenal insufficiency which may present with subnormal cortisol levels and in some cases overt features of hypocortisolemia may be seen in severe malaria. Primary adrenal insufficiency may be due to necrosis or impaired circulation due to sequestration of parasites. Some reports have results suggestive of cytokines playing a role in modulating the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency. Other potential mechanisms for secondary adrenal insufficiency are erythrocyte sequestration within the hypothalamic -pituitary portal system, altered setpoint for cortisol inhibition of ACTH, and production of a peptide like mammalian somatostatin which has been found to inhibit ACTH secretion in vitro (38-39).

DIAGNOSIS AND TREATMENT

Direct microscopy employed on thin and thick blood films enable parasite detection, species identification, quantification, and monitoring of parasitemia. Serology via the rapid diagnostic tests which detects the parasite antigen can be employed.

Figure 5: Giemsa-stained peripheral blood smear. Arrow A showing a classic, ring-shaped trophozoite of Plasmodium falciparum. Arrow B showing a classic, headphone-shaped trophozoite of P. falciparum. Arrow C showing two trophozoites of P. falciparum within the same red blood cell. (Reproduced from BMJ Case Reports (Surce-Parikh et al. Classic image: peripheral blood smear in a case of Plasmodium falciparum cerebral malaria http://dx.doi.org/10.1136/bcr-2014-205820

Severe malaria regardless of the infecting specie is treated with intravenous Artesunate and interim oral treatment, artemether -lumefantrine. Other oral antimalarial drugs are Atovaquone-proguanil, Quinine. and Mefloquine.

Toxoplasmosis

Toxoplasmosis is an infection with Toxoplasma gondii, an obligate intracellular protozoon, which is ingested in the form oocysts in material contaminated by feces from infected cats. Oocysts may also be transported to food by flies and cockroaches.

TRANSMISSION  

It is primarily an intestinal parasite in cats and has a wide host of intermediate hosts including sheep and mice and exists in three forms: oocysts, tachyzoites, and bradyzoites. Oocysts are only produced in the definitive host – the cat. When passed in the feces and then ingested, the oocysts can infect humans and other intermediate hosts where they develop into tachyzoites- rapidly multiplying trophozoite form of T. gondii. They divide rapidly in cells, causing tissue destruction and spreading the infection. The transmission of toxoplasmosis is shown in Figure 5. Tachyzoites in pregnant women are capable of infecting the fetus. Eventually tachyzoites localize to muscle tissues and the CNS where they convert to tissue cysts, or bradyzoites which is the dormant stage. This is thought to be a response to the host immune reaction. Ingestion of cysts in contaminated meat is also a source of

infection, as bradyzoites transform back into tachyzoites upon entering a new host.

Figure 5. Mode of transmission of toxoplasmosis

CLINICAL PRESENTATION

Toxoplasmosis is often asymptomatic or associated with mild self-limiting symptoms except in immunocompromised persons and sometimes in cases that are congenitally transmitted via the transplacental route (congenital toxoplasmosis).

CNS toxoplasmosis is one of the most common and important opportunistic infections in patients who are immunocompromised -the clinical manifestations are often nonspecific, with the most common presenting symptoms being headache, lethargy, fever, and focal neurologic signs. In congenital toxoplasmosis (CT), chorioretinitis is the most common manifestation and may cause seizure, hydrocephalus, and psychomotor delay.

ENDOCRINE AND METABOLIC ABNORMALITIES

Endocrine defects in toxoplasmosis are usually neuroendocrine in nature and may occur in congenital toxoplasmosis as well as acquired toxoplasmosis. Endocrine manifestations of   Toxoplasmosis include hypogonadotropic hypogonadism, precocious puberty, short stature, and diabetes insipidus. Documented hormonal abnormalities in persons with congenital toxoplasmosis result from hypothalamo-pituitary dysfunction and include growth hormone, gonadotropin, and ADH deficiency (40-41) (Figure 6).

Figure 6. Computerized tomography of brain showing dilated ventricles with multiple subependymal and parenchymal calcifications (arrow). (Source: Mohammed S et al; Congenital toxoplasmosis presenting as central diabetes insipidus in an infant: a case report BMC Res Notes. 2014; 7: 184.

Hypogonadotropic hypogonadism may occur transiently as a result of the modulation of the hypothalamus-pituitary axis by cytokines. Trypanosomiasis which is seen as a ring enhancing lesions in the brain during MRI imaging is an organic cause of the neuroendocrine abnormalities noted in some series (42-44).

Toxoplasmosis has been suggested as a possible risk factor for type 2 diabetes mellitus. Some Researchers have suggested that Toxoplasma gondii directly effects pancreatic cells through beta cell destruction (45-46).

DIAGNOSIS AND TREATMENT  

Diagnosis is made via direct detection of the parasites in body fluid and tissue samples.

Serology and molecular techniques are also employed in the diagnosis. Imaging preferable MRI is of use in suspected CNS involvement. Pyrimethamine, Sulfadiazine and Trimethorprin, and sulfamethoxazole are pharmacotherapies for managing toxoplasmosis.

BALANTIDIASIS

Balantidiasis is a disease caused by Balantidium coli, a ciliated protozoan and the only ciliate known to be capable of infecting humans. It is transmitted via contaminated water or food through cysts often associated with swine, the primary reservoir host. Endocrine and metabolic dysfunction or abnormalities are not documented in Balantidiasis.

SARCODINA

Amoebiasis is a diarrhea illness caused by infection with Entamoeba histolytica and is acquired by fecal-oral transmission. In some instances, extraintestinal diseases may occur but endocrine and metabolic dysfunction are not known to occur.

CONCLUSION

Protozoal infections are rare but significant causes of metabolic and endocrine abnormalities. The possibility of protozoal infections as possible causes of these abnormalities should be sought out in regions where these infections are prevalent especially after exclusion of other commonly occurring causes.

REFERENCES

1. Mousa HA. The Hidden Scene behind the High prevalence of Giardiasis and other infectious diseases in developing countries. J Infect Dis Ther 2014; 2:e106. doi:10.4172/2332-0877.
2. Werner Espelage , Matthias an der Heiden, Klaus Stark, Katharina Alpers. Characteristics and risk factors for symptomatic Giardia lamblia infections in Germany. BMC Public Health. 2010;10:41. doi: 10.1186/1471-2458-10-41.
3. Inabo HI, Yau B, Yakubu SE Asymptomatic Giardiasis and Nutritional Status of Children in Two Local Government Areas in Kaduna State, Nigeria. Sierra Leone Journal of Medical Research; 2011;3:157-162.

4       Jeffrey R. Donowitz, Masud Alam, Mamun Kabir, Jennie Z. Ma, Forida Nazib, James A. Platts-Mills, Luther A. Bartelt, Rashidul Haque, William A. Petri, Jr, A Prospective Longitudinal Cohort to Investigate the Effects of Early Life Giardiasis on Growth and All Cause Diarrhea, Clinical Infectious Diseases, 2016;63(6) 792–797.

5. Simsek Z, Zeyrek FY, Kurcer MA Effect of Giardia infection on growth and psychomotor development of children aged 0-5 years. Journal of Tropical Pediatrics 2004;50(2):90-3.
6. Radaeli Rde F, Diehl LA. Increased levothyroxine requirement in a woman with previously well-controlled hypothyroidism and intestinal giardiasis. Arq Bras Endocrinol Metabol 2011;55:81-4.
7. Seppel T, Rose F, Schlaghecke R. Chronic intestinal giardiasis with isolated levothyroxine malabsorption as reason for severe hypothyroidism - implications for localization of thyroid hormone absorption in the gut. Exp Clin Endocrinol Diabetes. 1996;104:180-2.
8. Miroslava Avila-García, Javier Mancilla, Enrique Segura-Cervantes and Norma Galindo-Sevilla (March 19th 2014). Transmission to Humans, Leishmaniasis - Trends in Epidemiology, Diagnosis and Treatment, David M. Claborn, IntechOpen, DOI: 10.5772/57271.https://www.intechopen.com/books/leishmaniasis-trends-in-epidemiology-diagnosis-and-treatment/transmission-to-humans
9. Meleney HE. The histopathology of kala-azar in the hamster, monkey and man. Am J Pathol. 1925;1:147–168.
10. Nahid R. Yousif, Rimaz E. Gurashi, Mohamed A. El Tahir, Safa Wadidi. Abd El Karim A. Abdrabo. Evaluation of Thyroid Function among Visceral Leishmaniasis Sudanese Patients. African Journal of Medical Sciences, 2018; 3 (8) .
11. Al-Ezzy AI, Abood WN. Correlation of Rk39-Specific Antibodies and Thyroid Function in Patients with Visceral Leishmaniasis. Eurasian J Med. 2016;48(3):181-185.
12. Frederico Araujo Lima Verde, Francisco Agenor Araujo Lima Verde, Augusto Saboia Neto, Paulo César Almeida, Emir Mendonça Lima Verde. Hormonal Disturbances in Visceral Leishmaniasis (Kala-Azar) Am J Trop Med Hyg. 2011; 84(5): 668–673.
13. Mondain-Miton V, Toussaint-Gari M, Hofman P, Marty P, Carles M, De Salvador F, et al. Atypical leishmaniasis in a patient infected with human immunodeficiency virus, Clin Infect Dis 1995;21:663-665.
14. Kaneria MV, Jagtap S, Modi C, Kamath S. Atypical presentation of Visceral Leishmaniasis. JAPI 2005;53
15. Brandonisio O, Fumarola L, Spinelli R, Gradoni L. Unusual presentation of leishmaniasis as an adrenal cystic mass. Eur J Clin Microbiol Infect Dis. 2002 ;21(9):682-3.
16. Brenner DS, Jacobs SC, Drachenberg CB, Papadimitriou JC. Isolated visceral leishmaniasis presenting as an adrenal cystic mass. Arch Pathol Lab Med. 2000 ;124(10):1553-6.
17. Daher EF, Soares DS, Filho SL, et al. Hyponatremia and risk factors for death in human visceral leishmaniasis: new insights from a cross-sectional study in Brazil. BMC Infect Dis. 2017;17(1):168.
18. Reincke M, Arlt W, Heppner C, Petzke F, Chrousos GP, Allolio B. Neuroendocrine dysfunction in African trypanosomiasis. The role of cytokines. Ann N Y Acad Sci. 1998 ;840:809-21.
19. Reincke M, Allolio B, Petzke F, Heppner C, Mbulamber D, Vollmer D et al. Thyroid dysfunction in African trypanosomiasis: a possible role for inflammatory cytokines. Clin Endocrinol (Oxf) 1993;39(4): 455-461
20. Reincke M, Allolio B, Petzke F, Heppner C, Mbulamber D, Vollmer D et al. Impairment of Adrenocortical Function Associated with Increased Plasma Tumor Necrosis Factor-Alpha and Interleukin-6 Concentrations in African Trypanosomiasis. Neuroimmunomodulation 1994;1:14–22.
21. Paolo WF, Nosanchuk JD. Adrenal Infections International journal of infectious diseases. 2006; 10(5): 343-353)
22. Boersma A, Noireau F, Hublart M. Gonadotropic axis and Trypanosoma brucei gambiense infection, Annales de la Société belge de médecine tropicale 1989;69(2):127-35.
23. Nieman, Roger E., et al. “Severe African Trypanosomiasis with Spurious Hypoglycemia.” The Journal of Infectious Diseases, 1989; 159:360-362.
24. Pan American Health Organization. Guidelines for diagnosis and treatment of Chagas disease. Washington, D.C. 2019.
25. Baer K, Klotz C, Kappe SH, et al. Release of hepatic Plasmodium yoelii merozoites into the pulmonary microvasculature. PLoS Pathogens. 2007;(11):e171.
26. Planche T, Dzeing A, Ngou-Milama E, Kombila M, Stacpoole PW. Metabolic complications of malaria. Curr Top Microbiol Immunol 2005;295:105-36.
27. Osonuga OA, Osonuga Ifabunmi, Derkyi-Kwarteng L. Prevalence of hypoglycemia among severe malaria children in rural Africa population, Asian Pacific Journal of Tropical Disease 2011; 1(3):192–194.
28. Kiely A, McClenaghan NH, Flatt PR, Newsholme P. Pro-inflammatory cytokines increase glucose, alanine and triacylglycerol utilization but inhibit insulin secretion in a clonal pancreatic beta-cell line. J Endocrinol. 2007 ;195(1):113-23.
29. Singh Y, Joshi SC, Satyawali V, Gupta A. A case of severe falciparum malaria presenting with hyperglycemia. J Med Trop 2014;16:39-41
30. Singh Yatendra, Joshi Subhash C., Satyawali Vivekanand, Gupta Abhisek .A case of severe falciparum malaria presenting with hyperglycemia. Journal of Medicine in the Tropics 2014:16:39-41.
31. Prabha MR, Pereira P, Chowta N, Hegde BM. Clinical implications of hypocalcemia in malaria. Indian J Med Res. 1998;108:62-5..
32. Singh PS, Singh N. Tetany with Plasmodium falciparum infection. J Assoc Physicians India. 2012;60:57-8. .
33. Feinsod FM, Heinrich G Malaria infection presenting with symptoms of thyroid insufficiency and amenorrhoea. Trans R Soc Trop Med Hyg 1981;75(1):117-8.
34. Davis,TM, Supanaranond W, Pukrittayakamee S,Krishna S,  Hart GR,  Burrin JR, et al. The pituitary-thyroid axis in severe falciparum malaria: evidence for depressed thyrotroph and thyroid gland function.  Trans R Soc Trop Med Hyg 1990;84(3):330-5.
35. Selvaraj V. Hypopituitarism: A rare sequel of cerebral malaria – Presenting as delayed awakening from general anesthesia. Anesth Essays Res. 2015; 9(2): 287–289.
36. Premji R, Roopnarinesingh N, Cohen J, Sen S. Cerebral Malaria: An Unusual Cause of Central Diabetes Insipidus 2016 |Article ID 2047410 | https://doi.org/10.1155/2016/2047410.
37. Grimwade K, French N, Mthembu D, Gilks C. Polyuria in association with Plasmodium falciparum malaria in a region of unstable transmission. Trans R Soc Trop Med Hyg. 2004 ;98(4):255-60.
38. Timothy M. E. Davis, Li Thi Anh Thu, Tran Quang Binh, Ken Robertson, John R. Dyer, Phan Thi Danh, Desiree Meyer, Miles H. Beaman, Trinh Kim Anh. The hypothalamic-pituitary-adrenocortical Axis in Severe Falciparum Malaria: Effects of Cytokines, The Journal of Clinical Endocrinology & Metabolism, 1997; 82, (9):3029–3033.
39. Mohapatra MK, Barihar PK, Mohapatra A.Adrenal insufficiency in severe falciparum malaria: its outcome and prediction by discriminant score. IJCMR 2019;6(9):148-155.
40. Mohamed, S., Osman, A., Al Jurayyan, N.A. et al. Congenital toxoplasmosis presenting as central diabetes insipidus in an infant: a case report. BMC Res Notes 2014;( 7): 184 https://doi.org/10.1186/1756-0500-7-184
41. Suresh Babu, P.S., Nagendra, K., Sarfaraz Navaz, R. et al. Congenital toxoplasmosis presenting as hypogonadotropic hypogonadism. Indian J Pediatr 2007; 74: 577–579.
42. Massa G, Vanderschueren-Lodeweyckx M, Van Vliet G, Craen M, de Zegher F, Eggermont E. Hypothalamo-pituitary dysfunction in congenital toxoplasmosis. Eur J Pediatr. 1989 ;148(8):742-4.
43. Oktenli C, Doganci L, Ozgurtas T, Araz RE, Tanyuksel M, Musabak U. Transient hypogonadotrophic hypogonadism in males with acute toxoplasmosis: suppressive effect of interleukin-1b on the secretion of GnRH.Human Reproduction 2004;19(4):859-866
44. Setian N, Andrade RSF, Kuperman H, Della Manna T, Dichtchekenian V, and Damiani D. Precocious Puberty: An Endocrine Manifestation in Congenital Toxoplasmosis. Journal of Pediatric Endocrinology and Metabolism. 2002;15:9, https://doi.org/10.1515/JPEM.2002.15.9.1487
45. Hamidreza Majidiani, Sahar Dalvand, Ahmad Daryani, Ma de la Luz Galvan-Ramirez, Masoud Foroutan-Rad. Is chronic toxoplasmosis a risk factor for diabetes mellitus? A systematic review and meta-analysis of case–control studies. The Brazilian Journal of Infectious Diseases, 2016;20(6):605-609.
46. Shahnaz Shirbazou, Ali Delpisheh, Rahim Mokhetari, and Ghafor Tavakoli. Serologic Detection of Anti Toxoplasma gondii Infection in Diabetic Patients. Iran Red Crescent Med J. 2013 15(8): 701–703.