Figure 1. Prolactin – Central Nervous System Regulation.

Figure 2. Mechanisms of drug-induced hyperprolactinemia with selected examples (adopted from La Torre et al. (2). In addition to opiates, cholinomimetics, PPIs and smoking indirectly also stimulate the opioid receptors. PPIs, Protein pump inhibitors; TCAs, tricyclic anti-depressants; MAO, monoamine oxidase; SSRIs, selective serotonin reuptake inhibitors; SNRIs, serotonin-noradrenaline reuptake inhibitors.

The potency of anti-psychotics and neuroleptic-like medications to induce a rise in prolactin levels varies (Table 1). The level of prolactin increase depends on the anti-psychotic drug (different affinity and selectivity for dopamine receptors; blood-brain barrier penetrating capability, degree of serotoninergic inhibition), the dose administered, and the patient's age and sex (34,35). Lastly, polymorphisms in genes related to dopamine receptors (such as DRD1, DRD2, DRD3) (63), dopamine transporters (SLC6A3), and dopamine-metabolizing enzymes (such as monoamine oxidase and catechol-O-methyltransferase) have been associated with individual variations in response to anti-psychotic treatment and the development of side effects, including hyperprolactinemia (64).

Although direct evidence establishing the involvement of adrenergic receptors in hyperprolactinemia caused by antipsychotic and antidepressant medications remains unproven, indirect indications, as elucidated in Figure 1, suggest the potential implication of these receptors. It is plausible that adrenergic receptors might play a partial role in the hyperprolactinemia induced by these medications.

Frequency of increase to abnormal prolactin levels with chronic use: high: >50%; moderate: 25 to 50%; low: <25%; none or low: case reports. The effect may be dose-dependent. Drugs marked with blue have controversial data or decrease prolactin levels as explained in the table. Where we could not identify reliable data for the parameters in the table we added a question mark. *First-generation anti-psychotics, non-selective dopamine receptors antagonists. **Second-generation anti-psychotics.

Anti-Psychotics

Anti-psychotics are traditionally classified as first- and second-generation, but more recently a new classification taxonomy has been developed by McCutcheon et al. to express different receptor affinity of different anti-psychotics. Due to the impossibility to include in this new classification all drugs that cause hyperprolactinemia, we have used the old classification (Table 1) (139,140).

The first-generation anti-psychotics are typically associated with more severe hyperprolactinemia (2-3-fold increment), whereas second-generation drugs have lower D2 affinity and stronger blockade of 5HT2A receptors leading to milder prolactin elevations (1-2-fold), except risperidone, paliperidone, and amisulpiride. Amisulpiride has the greatest potential to cause hyperprolactinemia of all anti-psychotics (4).

The first-generation anti-psychotics, such as fluphenazine and haloperidol, act as non-selective dopamine receptors antagonists (2,10). The therapeutic effects on psychotic symptoms occur through D2 and D4 receptor binding in the mesolimbic area, while side effects are mediated by D2 blockade in the striatal area (linked to extrapyramidal effects) and in the hypothalamic infundibular system (linked to hyperprolactinemia) in more than 50% of patients. A clinical trial involving 69 patients examined the effects of various anti-psychotic medications on prolactin levels, including chlorpromazine, depot haloperidol, fluphenazine, zuclopenthixol, sulpiride, pimozide, droperidol, and flupenthixol. The study found a significant elevation in prolactin levels only in females, with a mean level of 1106 mIU/L (52 ng/mL) compared to the normal range of <480 mIU/L (22.6 ng/mL). In males, the mean prolactin levels were within the normal range, which may be attributed to the significantly lower total daily dose of chlorpromazine used in males (199.0-220.1 mg/day) compared to females (384.4-302.48 mg/day, P<0.05) (7).

Second-generation anti-psychotics with lower D2 affinity led to milder prolactin elevations (1-2-fold), except for paliperidone, risperidone, and amisulpiride whose effect on prolactin is similar to the first-generation neuroleptics. Chlorpromazine, loxapine, olanzapine and quetiapine have variable effects on prolactin secretion, while aripiprazole, clozapine, iloperidone, lurasidone have little or no effect on prolactin secretion (35).

An important factor contributing to variations in the induction of hyperprolactinemia by different anti-psychotic medications is the blood-brain barrier. Permeability glycoprotein transporter (P-gp), coded by the ABCB1 gene, is expressed in various tissues including in the cells of the blood-brain barrier. P-gp plays a role in actively transporting hydrophobic drugs with a molecular weight greater than 400 Da out of the brain, thus protecting the brain from these medications; therefore, this protein can change drug bioavailability (141,142).

The affinity of risperidone, paliperidone, and amisulpiride (prolactin rises up to 10-fold with these drugs) for P-gp is approximately twice that of olanzapine and chlorpromazine (prolactin rise is up to 3-fold with these drugs), and four times greater than haloperidol and clozapine (prolactin rise can be high initially but usually reduces with time) (143). The higher affinity of risperidone, paliperidone, and amisulpiride to P-gp could, among other mechanisms, partly explain the greater induction of hyperprolactinemia by these drugs, as P-gp does not allow them to enter the brain via the blood-brain barrier. Therefore, the portal circulation of the anterior pituitary delivers a somewhat higher concentration of these drugs to the lactotrophs, which are located outside the blood-brain barrier, to inhibit the D2 receptors (144).

Aripiprazole can act as a partial agonist at D2 receptors and display partial agonist activity at 5HT1A receptors, while also acting as an antagonist at 5HT2A receptors. Antagonism at these receptors can help to normalize prolactin levels since 5HT2A receptor activation has been associated with increased prolactin release. That is why it is considered a prolactin secretion modulator (145). Its role in prolactin levels has been investigated in a study involving both retrospective and prospective components (146). The retrospective part of the study included 30 patients undergoing risperidone treatment, when it was observed that after 6 months of treatment, prolactin levels remained high although somewhat lower than at the start of observation. In the prospective part of the study, 30 other patients were divided into two groups: one group receiving risperidone alone at a daily dosage of 2-4 mg and the other group receiving a combination of risperidone and aripiprazole at a daily dosage of 5-10 mg. The group receiving adjunctive aripiprazole exhibited significantly lower serum prolactin levels compared to the risperidone-only group at weeks1 (914±743 vs 1567±1009 mU/L), 2 (750±705 vs 1317±836 mUI/L) and 6 (658±590 vs 1557±882 mUI/L). Notably, during aripiprazole treatment, prolactin levels at weeks 1, 2, and 6 were significantly lower than at baseline (P< 0.05) (at baseline patients were treated with risperidone as monotherapy), suggesting that aripiprazole may effectively alleviate risperidone-induced hyperprolactinemia. Similar findings supporting the role of aripiprazole in reducing prolactin levels have been reported in other studies (147). Combination therapy presents a promising therapeutic approach for adjunctive treatment or for transitioning from risperidone to mitigate hyperprolactinemia (146).

More recently, a new medication SEP-363856, a trace amine-associated receptor 1 (TAAR1) and 5HT1A agonist, has been developed to treat schizophrenia. Its mechanism of action is not based on D2 antagonism, and has a favorable effectiveness and tolerability profile, without causing hyperprolactinemia (148). This category of medication serves as compelling evidence for the significant involvement of dopamine receptors in drug-induced hyperprolactinemia, and it is a future viable therapeutic choice for patients experiencing adverse effects associated with hyperprolactinemia.

DRUG-INDUCED HYPERPROLACTINEMIA IN PEDIATRIC PATIENTS

Anti-psychotic medications have been found to induce hyperprolactinemia in the pediatric population as well as in adults. In a trial involving 35 children and adolescents with early-onset psychosis, primarily diagnosed with childhood-onset schizophrenia or psychotic disorder not otherwise specified, prolactin levels were measured after a 3-week washout period, as well as after 6 weeks of treatment with haloperidol, olanzapine, and clozapine (149). Following the 6-week treatment period, haloperidol (9 of 10 patients – mean age 13.4 years) and olanzapine (7 of 10 patients– mean age 15.9 years) resulted in prolactin levels above the upper limit of normal. The mean increase was 5.2-fold for haloperidol and 2.4-fold for olanzapine. The prolactin response did not show statistically significant differences between females and males treated with haloperidol and olanzapine. Clozapine (22 patients, mean age 14.7) caused a small but significant rise in females (1.2-fold) but levels remained in the normal range for all patients. There was no rise in males. Why this difference between females and males is only on clozapine remains unclear and difficult to explain. However, in a study involving 36 girls aged 8-17 years, mean prolactin levels were higher in girls compared to boys, with the most significant increase occurring around the age of 13y, correlating with menarche. A highly significant correlation was found between increases in plasma prolactin and estradiol levels between the ages of 11 and 13 years. Girls with long menstrual cycles (>28 days) between the ages of 14 and 16 years had higher prolactin levels (p<0.05) (150). Even though the mean age of patients on clozapine was above 13 years, we do not possess information on the duration of the menstrual cycle of those girls, as if it is longer, the physiologic estrogenization because of the longer menstrual cycle can impact the range of prolactin elevation. In any case, the population sample size was relatively small to draw definitive conclusions and to provide answers why this happens only in clozapine patients (149).The authors concluded that the prolactin response in male children and adolescents treated with haloperidol or olanzapine was significantly higher than that observed in adult males. However, the prolactin response in female children and adolescents after haloperidol treatment did not differ significantly from that of adult females in similar studies, possibly due to the adult similarity of estrogen status seen in female adolescents (149). Aripiprazole in another study showed a lesser prolactin increase than olanzapine, quetiapine, and risperidone, similar to the adult population (151).

In another clinical trial involving 396 children and adolescents (aged 14.0 ± 3.1 years), the impact of anti-psychotic medications on prolactin levels was studied. The medications involved risperidone, olanzapine, quetiapine, and aripiprazole. Risperidone caused the highest incidence of hyperprolactinemia (93.5%) and had the highest peak prolactin levels (median = 56.1 ng/mL) followed in order by olanzapine, quetiapine, and aripiprazole. Menstrual disturbances were the most prevalent side effect (28.0%), particularly with risperidone (35.4%). Notably, severe hyperprolactinemia was associated with decreased libido, erectile dysfunction, and galactorrhea (152).

In conclusion, a comprehensive meta-analysis comprising 32 randomized controlled trials with a total of 4643 participants, with an average age of 13 years, has demonstrated that risperidone, paliperidone, and olanzapine are associated with a significant increase in prolactin levels among children and adolescents. Conversely, aripiprazole is linked to a notable decrease in prolactin levels in this age group. It is worth noting that haloperidol was not included in these studies, resulting in an absence of evidence regarding its prolactin-related effects in this population (153).

These findings underscore that haloperidol, risperidone, paliperidone and olanzapine are potent inducers of hyperprolactinemia in children and adolescents, mirroring observations in the adult population. A comprehensive listing of medications associated with hyperprolactinemia in children can be found in Table2.

*Aripiprazole is a partial agonist at the type 2 dopamine receptor and display partial agonist activity at the type 1A serotonin receptor (5HT1A) and antagonist at 5HT2A receptor. It can be used in combination with other psychotropic medications to reduce prolactin levels. Aripiprazole itself can sometimes cause mild hyperprolactinemia (192).

CLINICAL MANAGEMENT OF ANTI-PSYCHOTIC-INDUCED HYPERPROLACTINEMIA

Drug-induced hyperprolactinemia should be considered in the differential diagnosis of elevations of prolactin levels, sometimes greater than 200 µg/L (4260 mIU/L). Particularly when serum prolactin levels exceed 80-100 µg/L (1700-2130 mIU/L), pituitary magnetic resonance imaging (MRI) should be performed to rule out the presence of any underlying pituitary or hypothalamic masses that may contribute to hyperprolactinemia (193). According to the guidelines from the Endocrine Society, in symptomatic patients suspected of having drug-induced hyperprolactinemia, it is recommended the first test to diagnose drug-induced hyperprolactinemia is the discontinuation of the medication for 3 days or switch to an alternative drug (e.g. a prolactin-sparing anti-psychotic (e.g. aripiprazole), or an anti-psychotic with lower dopamine antagonist potency (Table 1) followed by retesting of serum prolactin levels.

However, any discontinuation or substitution of anti-psychotic agents should be done in consultation with the patient's psychiatric physician. If discontinuation is not possible or if the onset of hyperprolactinemia does not coincide with therapy initiation, obtaining a pituitary MRI is recommended (despite prolactin levels) to differentiate between medication-induced hyperprolactinemia and hyperprolactinemia caused by a pituitary or hypothalamic mass (194).

Before initiating treatment with an anti-psychotic medication, it is advised that clinicians inquire about the patient's previous treatment experience, sexual dysfunction, menstrual history (including irregularities and menopausal status), as well as any history of galactorrhea. Additionally, obtaining a baseline prolactin level is recommended before starting treatment (195). This pre-treatment screening for hyperprolactinemia can help determine whether subsequently elevated prolactin levels are due to medication-induced factors (196) and make the diagnosis easier without the need to perform further imaging.

While treatment of hyperprolactinemia in patients receiving anti-psychotics may not always be necessary, in cases where clinical hypogonadism is evident, several options are available (193). The initial step is to discontinue the drug if clinically feasible. If discontinuation is not possible, switching to a similar anti-psychotic that does not cause hyperprolactinemia is suggested. If neither of these options is feasible, cautious administration of a dopamine agonist may be considered in consultation with the patient's physician (194). It is worth noting that these interventions only result in the normalization of prolactin levels in approximately half of the patients receiving anti-psychotics, and careful psychiatric monitoring is required due to the possibility of psychosis exacerbation with dopamine agonists (193).

For patients with long-term hypogonadism demonstrated by hypogonadal symptoms or low bone mass, the use of estrogen or testosterone replacement is recommended. In rare instances where patients receiving anti-psychotics also present with a pituitary tumor, treatment options primarily revolve around tumor-specific interventions, considering especially optic chiasm compression. When a non-functioning tumor is suspected, the above options to eliminate the drug-induced component of hyperprolactinemia should be considered, with supervised short-term cessation of the medication to clarify drug-induced or tumor-derived hyperprolactinemia (193).

In addition to the interventions mentioned earlier, addressing fertility concerns in patients with drug-induced hyperprolactinemia may require further measures. Normalization of prolactin levels through medication adjustment or dopamine agonist therapy can often lead to the restoration of fertility. In situations where fertility is not spontaneously regained, fertility treatment with gonadotrophins or assisted reproductive procedures may be necessary.

NEUROLEPTIC-LIKE MEDICATIONS

Metoclopramide and domperidone are anti-emetic and gastrointestinal motility agents known also as neuroleptic-like medications which can increase pituitary prolactin secretion and breast milk production by a dopamine antagonistic action (Figure 1).

Metoclopramide is a central and peripheral D2 receptor antagonist (197). Its administration is followed by an acute increase in prolactin levels up to 15-fold above the baseline that persists in chronic administration of the drug (2). Even though the majority of patients treated with metoclopramide develop hyperprolactinemia (Table 1), related symptoms such as amenorrhea, galactorrhea, gynecomastia, and impotence remain unclear (2).

Domperidone is a peripheral D2 antagonist (it does not cross the blood-brain barrier) used for treating intestinal motility disorders, especially for the prevention of gastrointestinal discomfort with dopaminergic treatment in Parkinson's disease (198), as it antagonizes the D2 receptors in the upper gastrointestinal tract. It also reaches the D2 receptors on lactotroph cells inducing hyperprolactinemia, and can be used for stimulating lactation, for example in women with preterm infants, or an adoptive parent (199,200), and even in transgender women who wish to breastfeed (201,202). It can cause a 10-fold elevation in prolactin levels with normalization of prolactin levels after three days (85,86). Neuroleptic-like medications are summarized in Tables 1 and 3.

ANTI-DEPRESSANTS

Anti-depressants can be classified based on their structure and mechanism of action into tricyclic anti-depressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), monoamine oxidase (MAO) inhibitors, atypical anti-depressants, serotonin modulators, selective noradrenaline reuptake inhibitor, and NMDA (N-Methyl-D-Aspartate) receptor antagonists (203). Data on their ability to cause hyperprolactinemia are controversial, as described below. The two main mechanisms, both related to elevated serotoninergic tonus, explain how anti-depressants can induce hyperprolactinemia by indirect modulation of prolactin release by serotonin and serotonin stimulation of GABAergic neurons (50) Adrenergic receptors involvement in their ability to cause hyperprolactinemia remains unclear. (Figure 1).

Data on the incidence of hyperprolactinemia with anti-depressant medications, especially SSRIs, MAO inhibitors, and some TCAs, suggest that they can cause modest and generally asymptomatic hyperprolactinemia (4,193). Their ability to cause hyperprolactinemia is summarized in Table 1.

TCAs

TCAs, such as amitriptyline, desipramine, clomipramine, and amoxapine, can induce sustained mild hyperprolactinemia (2) (Table 1). They manifest their mechanism of action by blocking the reuptake of noradrenaline and serotonin, through increasing serotoninergic tonus, leading to hyperprolactinemia. Amitriptyline's ability to cause hyperprolactinemia seems to be dose-dependent. A dosage of 150-250 mg/day to 5 patients showed no effect on prolactin levels after 3-7 weeks (204), whereas a dosage of 200-300 mg/day caused a 2-fold increment of prolactin levels in two of nine chronic treated patients (88). In 13 patients with depression taking amitriptyline or desipramine, prolactin levels were studied after intravenous injection of tryptophan (serotonin precursor). It was observed that tryptophan-induced prolactin elevation was significantly increased compared with a preceding placebo period (205). A similar tryptophan test was performed with clomipramine 20 mg vs placebo in 6 normal subjects. Levels of prolactin increased after tryptophan infusion in pretreated patients with clomipramine (206),suggesting serotonin involvement in this hyperprolactinemia.

The effect of the traditional TCA imipramine on serum prolactin levels is controversial. A five-week double-blind study on patients with depression taking imipramine did not show any significant change in serum prolactin (207). However, another study in young healthy men showed that imipramine’s effect on prolactin is dose-dependent (usually therapeutic dose is 50-150 mg): oral administration of 100 mg, but not of 40 mg, led to a consistent rise in prolactin levels after 3 hours of administration, but the rise was mild (maximum 25.85 ng/mL (550 mUI/L) (91).

Data regarding nortriptyline's ability to induce sustained hyperprolactinemia are lacking. Anyway, over a 4-6 week treatment of 8 patients with nortriptyline up to 150 mg/daily, no difference was found between placebo and the medication group. In only one patient was observed a transitional 2-fold elevation in the first 2 weeks (88).

Amoxapine, which is an anti-depressant with neuroleptic properties as well, is found to increase prolactin levels in 10 patients approximately 3.5-fold compared to baseline and more than desipramine in 12 patients, where almost no difference with baseline was observed (89). The proposed mechanism of hyperprolactinemia involves the blockade of the D2 receptor in tuberoinfundibular neurons or the anterior pituitary gland (2).

SSRIs

SSRIs enhance serotonin activity via inhibition of neuronal serotonin reuptake. This could be the most prominent mechanism leading to a prolactin elevation. A review of 13 case reports showed prolactin levels between 28 and 60 ng/mL (595 and 1276 mUI/L) (52). In a French study, 27 of 159 cases (17%) had SSRI-induced hyperprolactinemia with sertraline being the most prominent, followed by fluoxetine, paroxetine and fluvoxamine. Only citalopram was found not to increase prolactin levels significantly (208). However, in another study fluoxetine, paroxetine, and fluvoxamine were found again to elevate prolactin levels, but they also found citalopram to induce hyperprolactinemia. In this study duloxetine, milnacipran, and sertraline (which was the most prominent in the previous study) were not associated with an increased risk of hyperprolactinemia (93). Fluoxetine-induced hyperprolactinemia was found in patients with major depression (4.5% of men and 22.2% of women) following 12 weeks of fluoxetine treatment (209).Differences in the ability to cause hyperprolactinemia can be attributed to the variations in the affinity of the SSRIs for dopamine, histamine, and GABA receptors.

The Nurses’ Health Study and its follow-up study assessed anti-depressant use and circulating prolactin levels in 610 women (including 267 anti-depressant users) with two measurements of prolactin an average of 11 years apart (210). In this study, mean prolactin levels were similar among SSRI users (13.2 µg/L, (280 mUI/L), 95% CI 12.2-14.4), users of other classes of anti-depressants (12.7 µg/L (270 mUI/L), 95% CI 11.0-14.6), and non-users (13.1µg/L, (278 mUI/L), 95% CI 12.8-13.4) (210). However, the duration and dosage of anti-depressant use at the time of prolactin sampling had not been assessed, as the participants had only responded as current anti-depressant users/non-users on a questionnaire.

MAO Inhibitors

Monoamine oxidase is an enzyme responsible for breaking down neurotransmitters such as serotonin, noradrenaline, and dopamine in the brain. Inhibition of this enzyme is expected to increase the levels of all those neurotransmitters. Even though increased dopamine is suspected to be related to lower prolactin levels, probably the serotonin increment prevails and that is why this class of medications is related to hyperprolactinemia; or dopamine and serotonin increment neutralize each other and no difference in prolactin levels is seen.

MAO inhibitors with serotoninergic activity (pargyline and cordyline) can cause modest and generally asymptomatic hyperprolactinemia (2,61). Phenelzine was observed to persistently increase prolactin levels in 4 of11 patients, which returned to normal during a placebo week and rose again in all 4 patients after treatment restart (88).

Atypical Anti-Depressants

Mirtazapine's mechanism of action is different from other anti-depressants, as it does not inhibit the reuptake of serotonin or noradrenaline, but it increase the release of serotonin and noradrenaline (211). In any case, prolactin levels did not show any difference in 8 healthy male subjects pre- and post-mirtazapine 15 mg oral administration (212).

Serotonin Modulators

Trazodone acts through dual inhibition of serotonin reuptake and serotonin type 2 receptors, coupled with antagonism of histamine and α-1-adrenergic receptors (213). In 12 patients with depression, 150 mg of trazodone for 3 weeks caused significantly higher prolactin levels after 12 hours, 1 week, and 2 weeks of treatment compared to baseline. Higher levels were after the first week 15,3+/-8,5 ng/mL (325 +/- 180 mUI/L) compared to baseline 9,1 +/- 5,6 ng/mL (194+/-119 mUI/L) (99).

Selective Noradrenaline Reuptake Inhibitor

Reboxetine is a selective noradrenaline reuptake inhibitor that was shown to increase prolactin in healthy men after acute administration, but this effect can be reversed if reboxetine is simultaneously administered with α2-blocker mirtazapine, suggesting a role of α2-receptors in the enhancement of prolactin release after reboxetine (214). In any case, conflicting data are present even with this drug, with one other study showing no difference between pre-treatment and after-treatment prolactin levels in patients taking up to 8 mg reboxetine for 4 weeks in 17 patients (215). This discrepancy can be due to the limited number of patients or other neuroendocrine mechanisms still less explored.

SNRI medications are described to cause only mild and rare elevations on prolactin levels, whereas (94), esketamine (NMDA receptor antagonist)is not described to cause hyperprolactinemia.

Summary

In summary, controversial data are available on anti-depressant-induced hyperprolactinemia. Routine monitoring of prolactin levels in patients taking anti-depressants is not recommended unless symptoms related to prolactin increase (in premenopausal women: menstrual cycle dysfunction leading to amenorrhea, oligomenorrhoea, anovulatory cycles, low libido, and energy; in men: erectile dysfunction, decreased energy and libido, decreased muscle mass, decreased body hair; and for both of them osteopenia, galactorrhea and infertility) occur (50,193). If the prolactin serum level is elevated (> 25 µg/L (531 mUI/L), in these patients a differential diagnosis is needed. The proposed approach is to withdraw the anti-depressant drug slowly over 2 weeks and replace it with another anti-depressant less likely to cause hyperprolactinemia, then reassess symptoms and prolactin levels after 2-4 weeks (193). If the serum prolactin remains elevated, other causes of hyperprolactinemia should be addressed by an endocrinologist. Another approach is to perform a pituitary MRI if the replacement of the anti-depressant is difficult to manage.

GASTRIC ACID REDUCERS

Histamine-Receptor Inhibitors

Histamine, a CNS neurotransmitter, binds to both H1 and H2 receptors. It can stimulate prolactin secretion via H1 receptors by inhibiting the dopaminergic system. On the contrary, histamine can also inhibit prolactin secretion via H2 receptors using a non-dopaminergic mechanism involving β-endorphin, vasoactive intestinal peptide, vasopressin, or TRH (216), all of which act as prolactin-releasing factors (49) (Figure 1).

In the French Pharmacovigilance Study, H2 receptor antagonists were found to contribute to 5% of drug-induced hyperprolactinemia, primarily with ranitidine (odds ratio = 4.43; 95% CI: 1.82–10.8) (11). Other studies have shown that H2-receptor antagonists such as cimetidine and ranitidine can elevate prolactin levels (217,218). Specifically, cimetidine caused a three-fold increase in prolactin levels after a 400 mg IV infusion, although this effect was not observed with oral administration of 800 mg cimetidine in healthy individuals (102) (Table 1,3).

Interestingly, it has been observed that systemic administration of the H2 agonist impromidine does not prevent cimetidine-induced hyperprolactinemia. In contrast, pre-administration of benzodiazepines or GABA lowered the prolactin response. This suggests that cimetidine-induced hyperprolactinemia may be mediated through neurotransmitters in the GABA-ergic system (219).

Proton-Pump Inhibitors

Proton-pump inhibitors (PPIs) have been recently reviewed regarding the risk of hyperprolactinemia and related sexual disorders observed with long-term use (220). The exact mechanism by which PPIs increase prolactin levels is not fully understood; possible explanations include inhibition of dopamine receptors, interference with other dopamine receptors, involvement of the serotoninergic pathway, modulation of the opioid pathway, and a potential role in decreasing prolactin clearance (220) (Figure 2). In addition, PPIs can increase gastrin levels in chronic use especially in females using high doses (221). As gastrin can act as prolactin-inhibitory factor (108), this antagonistic effect may explain the relatively mild hyperprolactinemia occurring with this class of drugs. Esomeprazole has a mild inhibitory effect on CYP3A4, which leads to decreased metabolism of estrogen, thereby increasing serum estrogen levels which can stimulate the production of prolactin (222). Gynecomastia, impotence, irregular menses, and galactorrhea have been described with PPI use. Hyperprolactinemia occurred less often than sexual disorders, and most cases of hyperprolactinemia were reported with omeprazole, esomeprazole, and lansoprazole use (e.g. 4-fold increment with lansoprazole) (104) (Table 1,3). Pantoprazole and rabeprazole were only sporadically associated with hyperprolactinemia. The authors assert that the occurrence of sexual dysfunction in individuals using PPIs, despite having normal prolactin levels, may be attributed to the development of low vitamin B12 levels, hypomagnesaemia and iron deficiency resulting from PPI usage. These nutritional deficiencies have been implicated in the manifestation of sexual disorders in other studies (220,223,224).

OPIOIDS

Endogenous opioids, morphine, and related drugs, activate ε-, μ-, κ- and δ- opioid receptors in the hypothalamus, modulating pituitary hormone secretion. They do not possess direct effects on pituitary cells (225,226). They inhibit the gonadal axis via ε receptors (GnRH suppression) and stimulate prolactin production by reducing the activity of tuberoinfundibular dopaminergic neurons via μ, κ and δ opioid receptors – mostly μ receptors as the μ receptor opioid antagonist naloxone prior to morphine and methadone use prevents opioid-induced hyperprolactinemia (227). Indirect stimulation of prolactin release can be mediated by stimulating prolactin-releasing factors production (the serotoninergic pathways discussed above) (228) (Figure 2). Hyperprolactinemia can then lead to additional gonadal axis suppression. In addition, opioids can modulate the corticotroph axis via κ and δ opioid receptors and the somatotroph axis via μ, κ and δ opioid receptors (226). Additionally, opioids manifest negative effects on bone health through direct inhibition of osteoblasts by opioids, gonadal axis suppression, altered mental status, and other comorbidities (chronic conditions, smoking, alcohol use) (229).

Acute intravenous or intra-ventricular administration of endogenous opioids leads to a rapid plasma prolactin increase in a dose-dependent manner (44,225). Chronic use of opioids effects on prolactin can vary: oral opioids for chronic pain increase prolactin, but morphine administered intrathecally for chronic non-cancer pain had no effect on prolactin (226). Hyperprolactinemia induced by opioids can be symptomatic: painful gynecomastia, galactorrhea, and hypogonadism have been reported in chronic opioid users. These can be alleviated with discontinuation or reduction of opioid dose, and sometimes dopamine agonists such as bromocriptine (226). Methadone induces a transient increase in prolactin levels, whereas chronic methadone users have normal basal prolactin levels (110), (Table 1, 3).

On the contrary, in a study involving six patients with hyperprolactinemia and amenorrhea, the use of naltrexone, an opioid antagonist, was investigated to determine if blocking endogenous opioids could improve the sexual axis. On the first day of naltrexone administration, significant increases were observed in the mean concentration of luteinizing hormone (LH), LH pulse amplitude, and estradiol levels compared to the control day. This indicated a prompt partial reactivation of the hypothalamic-pituitary-gonadal axis as a result of naltrexone, leading to heightened gonadotrophin levels and subsequent release of estradiol. However, it was found that the effect of opioid antagonism did not result in a sustained increase in estradiol secretion with chronic treatment. Additionally, prolactin levels continued to increase over time (mean prolactin level 255 ± 121 microgram/L), despite the initial improvement in the gonadal axis. This study demonstrated that although prolactin-induced suppression of the gonadal axis can be reversed to some extent by acute opioid antagonism, it is not an effective treatment for revitalizing the gonadal axis in the long term. Possible explanations for this lack of sustained effect include desensitization of the hypothalamic-pituitary unit for the effects of opioid receptor blockade and other disruptors of the axis, which may counteract the positive effects of opioid antagonism (230,231).

For endocrinopathies caused by opioids, including hyperprolactinemia, potential management choices include reducing or discontinuing opioid usage whenever feasible and exploring alternative pain relief therapies for chronic pain situations. Hormonal replacement therapy can be considered for hypogonadism and hypoadrenalism (226).

ANTIHYPERTENSIVES

Some antihypertensive medications including α-methyldopa, verapamil, labetalol, and reserpine, have been associated with hyperprolactinemia. This phenomenon is attributed mainly to the potential inhibition of dopaminergic pathways, highlighting the complex interplay between anti-hypertensive therapy and endocrine function. Other mechanisms are drug-specific and will be explained below.

α -methyldopa is an α-adrenergic inhibitor that leads to the suppression of monoamine synthesis, including noradrenaline, dopamine, and serotonin, which likely contributes to its anti-hypertensive effect. It causes hyperprolactinemia through the inhibition of dopamine synthesis by competitive inhibition of DOPA decarboxylase which transforms L-dopa into dopamine (61) (Figure 2). Long-term treatment resulted in elevated basal prolactin levels (3-4-fold), while a single dose of 750-1000mg reaches a peak of high prolactin level after 4-6 hours of administration (232). Gynecomastia is the most common endocrine side effect.

Calcium channel blockers are other drugs studied for their potential to cause hyperprolactinemia. The dihydropyridine class was found to have no effects on prolactin levels. Whereas, from the non-dihydropyridine class, which mainly blocks L-type of calcium channel receptors in the heart, only verapamil was found to cause 2-fold persistent hyperprolactinemia (and galactorrhea),while drug discontinuation reversed hyperprolactinemia in all patients (113). A clinical trial suggested that verapamil acts by reducing dopamine release in the tuberoinfundibular pathway through calcium influx inhibition (Figure 2), possibly by N-calcium channels which are known to be involved in the regulation of dopamine release and other neurotransmitters (233).

Labetalol is an α- and β-adrenoceptor blocker anti-hypertensive that has been reported to increase prolactin levels when administered intravenously, but not when administered orally (100 or 200 mg) as labetalol cross the blood-brain-barrier only in negligible amounts. The increase in prolactin release caused by intravenous labetalol is not readily explained by its interference with adrenergic receptors. The exact mechanism underlying this effect of the drug is currently unclear, but it is possible that labetalol's ability to block dopamine activity (anti-dopaminergic activity) might be involved in this response (234) (Figure 2). Pre-treatment with levodopa and carbidopa can prevent prolactin response after labetalol (235), suggesting dopamine pathway involvement suppression inside the blood-brain-barrier.

Reserpine is a rauwolfia alkaloid previously used for the treatment of hypertension as well as psychosis, schizophrenia, and tardive dyskinesia; it reduces dopamine by inhibiting their hypothalamic storage in secretory granules (236), and by blockade of vesicular monoamine transporter type 2 in monoamine neurons (237), leading to hyperprolactinemia. Prolactin levels are higher during treatment with reserpine than 6 weeks after discontinuation of the drug. Increased incidence of gynecomastia and breast cancer has also been reported among patients on anti-hypertensive therapy with reserpine (236). The ability of anti-hypertensives to cause hyperprolactinemia is summarized in Tables 1 and 3.

ESTROGENS

Estrogens stimulate prolactin secretion by several mechanisms: They bind to specific intracellular lactotroph cells receptors, though enhancing prolactin gene transcription and synthesis (238). They also inhibit tuberoinfundibular dopamine synthesis, stimulate lactotroph cell hyperplasia, downregulate dopamine receptor expression, and modify lactotroph responsiveness to other regulators (23,239) (Figure 2). Estrogen-induced hyperprolactinemia is dependent on the degree of estrogenization. Higher levels of estrogens in pregnancy and during ovulation increase prolactin levels with the last, contributing to a higher normal range of prolactin in pre-menopausal women.

Studies documenting the incidence of hyperprolactinemia showed that women on oral contraceptives were reported to have higher prolactin levels by 12% to 30% (240,241). Some, but not all, studies suggest that there is a dose-dependent effect (4). No increase in basal prolactin levels is reported during therapy with modern contraceptives with lower amounts of estrogen (242)or estrogen plus cyproterone acetate alone (243).

In transgender patients, estradiol or ethinyl estradiol treatment, the prolactin level rise was dependent on the dose of estrogen, duration of exposure, and alteration of SHBG levels. Estradiol infusion at levels above 10,000 pg/mL for as short as 6-7 hours significantly elevated prolactin levels by 3- to 4-fold, whereas ethinyl estradiol 2 mg/day for 1 month did not consistently elevate prolactin in all patients, which can be due to its ability to increase SHBG binding and maintaining free portion in the normal range (114) (Table 1, 3).

For women on post-menopausal hormone replacement therapies over 2.5 years, serum prolactin measured were within the normal range (244). In another study on 75 women, who were randomly assigned to three groups: control (receiving placebo), transdermal hormonal replacement (biphasic 17β-estradiol and progesterone, natural hormones), and oral ethinyl-estradiol and desogestrel, prolactin levels significantly increased in the oral group, but not in the transdermal group. There was a significant difference in hormone levels: in the oral group, estradiol levels increased five times and estrone levels eleven times. In the transdermal group, estrone and estradiol levels were increased three times (245).

GONADOTROPHINS AND GNRH AGONISTS

In addition to the known prolactin function in lactation, several studies have suggested other benefits of prolactin in oocyte development, formation of corpus luteum and its survival, steroidogenesis and implantation (246). In natural cycles there is a transient increase in late follicular phase of prolactin, but this increment is higher in stimulated cycles (246). In a cohort study were included 79 patients; 60 individuals underwent in vitro fertilization, 14 received clomiphene citrate treatment, and five patients with premature ovarian failure were administered estradiol. During the course of human menopausal gonadotrophin (hMG) treatment, a notable increase in both serum estradiol and prolactin concentrations were observed from early to late follicular days (P < 0.01). Specifically, prolactin levels increased from an initial mean value of 367±38 mIU/L (17.25±1.8 ng/mL) to 991±84 mIU/L (46.6±4 ng/mL) (Table 1). Bromocriptine effectively mitigated the increase in prolactin levels but was associated with a significant elevation in estradiol levels (P < 0.05) because prolactin itself works as a controller of estradiol increment. Clomiphene treatment led to a significant increase in serum estradiol levels (P < 0.01) but a significant decrease in serum prolactin concentrations during the late follicular phase (P < 0.01), indicating disruption of the estradiol-prolactin feedback mechanism. Among patients with premature ovarian insufficiency, serum prolactin concentrations increased concomitantly with rising serum of estradiol concentrations (after estradiol administration). Additionally, it was observed that the presence of prolactin significantly reduced estradiol production by granulosa cells (P < 0.05) (116).

An increment of prolactin levels is found even after hCG administration with a maximum prolactin level of 93.2 ng/mL; 1983 mIU/L (115).Notably, knowing that prolactin is a stress hormone, during assisted procedures it is increased, but this is a transitory increment without consequences in fertility outcome (247).

Not only gonadotrophins but also GnRH agonists are widely used during invitro fertilization to maintain a controlled and synchronized ovarian stimulation. Use of leuprolide acetate (GnRH agonist) concomitantly with hMG, resulted in higher prolactin and estradiol levels in comparison with patients receiving only hMG (prolactin 24.2 vs 16.8 ng/mL; 515 vs 358 mIU/L) (117). In another randomized study, along protocol with 0.1 mg subcutaneous triptorelin starting from day 10 of the preceding stimulation cycle and short protocol, where 0.1 mg subcutaneous triptorelin is given in the stimulating cycle, were compared. Prolactin levels were measured at 9 am in the first day of hCG administration. The long protocol correlated with higher prolactin levels (31.3 ± 16.9 vs 23.7 ± 11 ng/mL; 666 ± 359 vs 504 ± 234 mIU/L) (248).

In children, GnRH agonists are used in precocious puberty (CPP)as well as growth hormone deficiency (GHD)who do not properly respond to exogenous growth hormone treatment. In a study involving 119 children with CPP and 93 with GHD, treated with triptorelin or leuprolide, prolactin levels were measured before and every six months for 6 years for CPP group and for 2 years for GHD group. Moreover, prolactin levels were checked after 6 and 12 months of treatment withdrawal. In this study was concluded that even though prolactin levels were higher in triptorelin treated patients (only 3.8% developed hyperprolactinemia in triptorelin group which was solved after withdrawal – baseline 12.5 ± 3.7 ng/mL (266 ± 79 mIU/L) to max 45.6 ± 4.5 ng/mL; 970 ± 96 mIL/L), no significant difference was found in prolactin in basal condition and during GNRH agonist treatment in CPP and GHD (190)(Table 2).

OTHER DRUGS

A lot of other drugs have been reported to cause mild (less than 2-fold increment) increases in prolactin levels. A synthesized visualization of these mechanisms is shown in Figure 2.

The acute administration of buspirone, an anxiolytic medication, was investigated in a study involving 8 healthy volunteers. The findings revealed an increase in plasma prolactin levels across all participants compared to the baseline levels observed in 8 control subjects. During the study, blood samples were collected at 30-minute intervals over a duration of 2 hours. The zenith of prolactin levels was observed between minutes 90 and 120 for all individuals, with the maximum elevation reaching 37 ng/mL (787 mIU/L) (249). It is noteworthy that the augmentation of prolactin is believed to exhibit a dose-dependent relationship. Furthermore, it was observed that chronic usage of buspirone did not lead to significant alterations in prolactin levels, indicating a potential adaptation to the acute changes induced by the medication. The underlying mechanism responsible for this phenomenon is posited to involve both serotoninergic and dopaminergic implications (119).

Carbamazepine, a widely used anticonvulsant, was examined in a cohort comprising 4 patients with complex partial seizures undergoing chronic carbamazepine treatment (200 mg administered three times daily). Blood samples were collected at intervals of 2 hours. Additionally, a group of 5 patients with untreated epileptic seizures participated, wherein a thyrotrophin-releasing hormone (TRH) stimulation test was performed both prior to and 35-50 days post the administration of 200 mg carbamazepine three times daily. Blood samples were obtained 10, 30, and 60 minutes following intravenous injection of 200µg TRH. Furthermore, 4 normal volunteer subjects were included in the study. On the first day, a placebo was administered, followed by the administration of 400 mg carbamazepine at 8 AM on the second day. Blood samples were collected at baseline on both days and subsequently at hourly intervals until 4 PM. After a span of two weeks, a nocturnal study was conducted, spanning from 6 PM to 6 AM. The investigation revealed that there were no discernible alterations in spontaneous prolactin release or TRH-stimulated prolactin levels. However, a slight increase in sleep-entrained prolactin values was observed, while retaining the secretory circadian rhythm. Given that the release of prolactin during sleep is largely attributed to serotoninergic activity, it is plausible that the modest increment (less than 2-fold) may implicate serotoninergic modulation (working as a serotonin-releasing factor and reuptake inhibitor) facilitated by carbamazepine (120,121).

Sympathomimetic amines fenfluramine and sibutramine, formerly used for appetite suppression due to their stimulatory effect on the synaptic concentration of serotonin, have been shown to induce hyperprolactinemia as a result of increased serotoninergic activity and postsynaptic stimulation of 5HT2Areceptors. In a case report, after starting sibutramine, a 38-year-old female patient developed hyperprolactinemia (prolactin levels 46 and 89.6 ng/mL (978 and 1906 mUI/L) with amenorrhea and galactorrhea. Discontinuation of sibutramine, confirmed by a sella MRI, led to rapid normalization of prolactin levels within 15 days, and symptoms resolved during a 90-day follow-up (2,127).

Cholinomimetic drugs have been reported controversially in the literature regarding their ability to cause hyperprolactinemia. However, in collaborative studies from the National Institute of Mental Health and the University of California, San Diego, three separate experiments were conducted involving volunteers of different genders and ages. In the first experiment, nine volunteers received physostigmine salicylate at 33 µg/kg, while in the second experiment, eleven male volunteers were given 22 µg/kg of physostigmine salicylate. The third experiment involved six volunteers receiving 3 mg of arecoline hydrobromide. Placebo saline was administered in all experiments as well. It was shown that intravenous injection of physostigmine or arecoline can elevate prolactin correlating with raised β-endorphin levels in the blood. Prolactin elevation was less than 100 ng/mL (2127 mUI/L). Cholinergic activation in the hypothalamus, particularly focusing on β-endorphin, might help in explaining how peptides modify primary neurochemical effects on hormone regulation in the hypothalamus and pituitary (44).

Bucillamine, an analogue of D-penicillamine used as an antirheumatic drug in Japan, has been reported to induce hyperprolactinemia (109 ng/mL (2319 mUI/L)) after 30 months of treatment start, associated with gynecomastia and galactorrhea in one case report. The mechanism remains unclear (133).

‘Ecstasy’ (MDMA) was shown to increase prolactin secretion in rhesus monkeys by stimulating serotonin release and by direct-acting as a 5HT2A agonist (250); In nine studies, five of them observed an increase in prolactin levels due to the intervention. However, in the remaining studies, there was no significant change in prolactin levels, and these unresponsive results tended to occur when a lower dose of the intervention was used on average. This suggests a potential relationship between the dosage of the intervention and its effect on prolactin levels (135).

Smoking, particularly the consumption of high-nicotine cigarettes, has been associated with a significant acute elevation in prolactin levels, ranging from 50% to 78% above the baseline, within 6 minutes after smoking. These elevated levels persist for approximately 42 minutes and return to baseline within 120 minutes of initiating smoking (136). The underlying mechanism probably involves the stimulation of rapid prolactin release through the augmentation of endogenous opioids, which subsequently inhibits dopamine release (251). However, prolonged nicotine exposure leads to desensitization of dopamine receptors, and lowers dopamine turnover (48) probably contributing to hyperprolactinemia. It has been hypothesized that the increased incidence of osteopenia and osteoporosis could be at least partly related to this effect (252).

Recently, an association has been reported between HIV-1 protease inhibitors and the adverse effect of galactorrhea and hyperprolactinemia in four HIV-1 infected women treated with indinavir, nelfinavir, ritonavir, or saquinavir. The cause of this unexpected toxicity could be attributed to several possible mechanisms: 1) Protease inhibitors may enhance the stimulatory effects of prolactin due to their inhibition of the cytochrome P450 system, leading to longer half-life of prolactin; 2) opportunistic infections in AIDS patients may induce cytokine-driven prolactin production by pituitary or immune cells; 3) protease inhibitors might exert direct endocrine effects on the pituitary or hypothalamus (253,254). To explore mechanisms of hyperprolactinemia induced by protease inhibitors, experiments were conducted using rat pituitary cells and hypothalamic neuronal endings. The results showed that both ritonavir and saquinavir could directly stimulate prolactin secretion, while not affecting dopamine release. This suggests that these protease inhibitors might interact with specific mammalian proteins in the anterior pituitary involved in prolactin secretion, leading to the observed galactorrhea and hyperprolactinemic effect (137).

Regarding chemotherapy and immunosuppression, there are some controversial data on the effect of chemotherapy and immunosuppression on prolactin levels, as significant prolactin increases are not frequent and usually mild (2). Prolactin and growth hormone have been involved as part of a cytokine system in the recovery of the immune response after chemotherapy and bone marrow transplantation (255). In a study of 20 breast cancer patients undergoing high-dose chemotherapy and autologous stem-cell transplantation, plasma prolactin levels increased within and 30 days after transplant, yet still remaining within the normal range. The use of antiemetic drugs further raised prolactin levels. Patients in continuous complete remission after transplantation exhibited higher prolactin levels, while elevated prolactin did not impact disease-free survival, suggesting potential for further research into post-transplant immune response (256).

Radiotherapy for intracranial germ cell tumors was shown to induce hyperprolactinemia with a prevalence of 35.3% (138).

Other drug inducing hyperprolactinemia are described in Table 1.

DRUGS REPORTED TO DECREASE PROLACTIN LEVELS OR HAVE AN EQUIVOCAL EFFECT

Several medications, beyond the established treatments like cabergoline, bromocriptine, carbidopa and levodopa, have reported effects on reducing prolactin levels. For instance, pseudoephedrine, an α-adrenergic stimulant primarily affecting α1 receptors, shares structural similarities with amphetamine and moderately stimulating dopamine release in the brain by acting on D2 receptors in the pituitary, consequently lowering prolactin levels. Studies have indicated pseudoephedrine's potential to decrease milk production, at least partly attributed to its effect on prolactin levels through dopaminergic actions in the pituitary (132). Moreover, indirect evidence suggests that α-1 receptors stimulation leads to decreased prolactin levels (41).

Amphetamine was seen to produce a poor prolactin suppressant effect in either normal- or hyperprolactinemic subjects. The proposed mechanism of prolactin lowering potential is due to their ability to stimulate the release of dopamine (257). However, during the withdrawal period of cocaine use, hyperprolactinemia has been observed, probably due to a decrease in dopamine levels, leading to dysregulation in the dopamine system and increased prolactin. Moreover, during withdrawal, prolactin can be secreted as a stress hormone (129).

Guanafascine, an α2 adrenergic agonist, used to treat ADHD, has been shown to decrease prolactin levels. In a longitudinal study spanning three years involving 15 patients diagnosed with hyperprolactinemia, the noteworthy suppressive impact of guanfacine on prolactin levels suggests potential involvement of hypothalamic or extrahypothalamic adrenergic pathways in the intricate regulation of prolactin secretion (131). Even though α2 stimulation has been shown to increase prolactin levels in rats, this is not fully understood in humans making the explanation in this case confusing (42).

The impact of benzodiazepines (BDZ) on prolactin secretion is a subject of debate. Research findings have yielded conflicting results. Some studies conducted on both non-epileptic patients and healthy volunteers have not detected significant modifications in prolactin levels following BDZ treatment (258). A study on 30 adolescent patients with schizophrenia with gradually increasing doses of diazepam to a maximum of 100-400 mg/day, with 4 weeks of treatment, showed that only doses higher than 250 mg/day give a significant but mild increase in prolactin levels. Proposed mechanisms are inhibition of TIDA neurons by activation of the GABA system, or activation of the endorphin-ergic system leading to hyperprolactinemia (118). On the contrary, diazepam was found to suppress the secretion of prolactin in vitro through one of two mechanisms: it either strengthens the direct inhibitory action of GABA on prolactin release, or it hinders a benzodiazepine-sensitive Ca2+-calmodulin dependent protein kinase at micromolar concentrations leading to a reduction of prolactin secretion (259).

Moreover, phenytoin, an anticonvulsant impeding sodium channels in nerve cells, have generated conflicting data regarding their impact on prolactin levels. In animal studies, phenytoin showcased a rapid decline in both prolactin release and mRNA concentrations, functioning as a partial T3 agonist by binding to T3 nuclear receptors (260). However, clinical observations revealed elevated resting levels of prolactin in phenytoin-treated patients compared to untreated counterparts. Remarkably, responses to metoclopramide and bromocriptine remained unaltered, indicating a limited effect of phenytoin on the D2 receptors present on lactotrophs (261). Even the conclusions drawn from these findings remain contentious. Evidence suggests that phenytoin treatment may enhance the growth hormone response to levodopa, implying a phenytoin-induced dopaminergic activity at the hypothalamic-pituitary level (122). More specifically, it is postulated that phenytoin might enhance dopamine receptor sensitivity by inhibiting the Ca2+ calmodulin complex. This effect could contribute to reduced prolactin secretion (122). On the contrary, other studies have not demonstrated any notable alterations in prolactin levels due to phenytoin administration (262). The discordant outcomes surrounding phenytoin's impact on prolactin levels underscore the complexity of its effects and necessitate further investigation for conclusive insights into its mechanisms of action.

In another comprehensive study involving 126 subjects, both males and females, with generalized or partial epilepsy receiving phenobarbital as monotherapy or in combination with phenytoin or benzodiazepines, a distinct pattern emerged. Specifically, the administration of phenobarbital, either alone or in combination, resulted in elevated prolactin levels, but this elevation was found to be statistically significant only in the male participants. Notably, knowing that an epileptic attack itself can cause hyperprolactinemia, those data remain confusing. The proposed mechanism in this study is phenobarbital interaction with GABA receptors, leading to increased prolactin levels (263). However other studies do not show any change in prolactin levels (123).

Valproic acid, an anticonvulsant working as a central stimulant of GABAergic neurons, has demonstrated the ability to reduce prolactin basal levels as well as TRH-stimulated prolactin levels. This is indirect proof of the synergically acting of GABA neurons with dopaminergic tracts (124). However, in another study, no effect of valproic acid on prolactin levels was noticed during the night (264).

Lithium carbonate, a pharmaceutical agent employed as a mood stabilizer, has undergone investigation in different studies, as it decreases dopamine release and glutamate, and increases inhibitory GABA (265). One of them encompassed a longitudinal examination involving 9 patients diagnosed with bipolar disorder. The focus of this study was the assessment of plasma prolactin levels before and 12 hours after the evening administration of lithium. Evaluations were conducted on days 1, 6, 8, 13, 30, 60, and 90. Notably, this investigation yielded no discernible correlation between lithium concentration and prolactin levels, and no statistically significant alterations in prolactin levels were observed. The second part of this study adopted a cross-sectional design, involving 26 patients with an established history of long-term lithium treatment spanning durations of 3 months to 20 years. A comparative analysis revealed that prolactin levels, measured at 9 AM following a one-hour period of rest, did not demonstrate elevation in comparison to 16 controls. It is noteworthy that in both studies, lithium concentrations ranged from 0.4 to 1.4 mmol/L (normal range 0.5-1.2 mmol/L) (266). Additionally, the administration of lithium did not exert an impact on the plasma prolactin response to thyrotrophin-releasing hormone (TRH) stimulation compared to pre-treatment levels (267). The combined findings from these investigations provide compelling evidence that lithium does not contribute to hyperprolactinemia, thereby distinguishing it from medications with such an effect.

Cocaine has been shown to decrease prolactin levels beginning at 30-min following cocaine administration reaching statistical significance at the 90- and 120-minute time points (134).

Those medications are mentioned in Table 1. Their mechanism of altering prolactin levels is summarized in Figure 2.

HERBAL MEDICINES AFFECTING PROLACTIN LEVELS

In Table 4 is list of herbal medicines has been used traditionally to stimulate lactation (268). However, firm scientific evidence that they actually induce hyperprolactinemia is scarce.

Some herbs are known to decrease prolactin levels. For example, chaste tree (Vitex agnus-castus) decrease prolactin levels by activating to D2-receptors and suppressing prolactin release, as shown in in vitro experiments on lactotroph cell cultures and in in vivo animal experiments (269). Another herb, Mucuna pruriens, which is a natural source of l-dihydroxyphenylalanine (a dopamine precursor) is found to decrease prolactin levels in humans (270). Vitamin B6 (pyridoxine), by acting as a coenzyme in dopamine synthesis and aspartame, a sweetener metabolized in phenylalanine (dopamine precursor), have been shown to interfere with milk production by reducing prolactin levels (271). Ashgawanda (Withania somnifera) is found to decrease prolactin levels up to 12% (272). Moreover, oral zinc is found to decrease prolactin levels below the normal range in all 17 subjects with normal prolactin levels, in scenario of increased zinc levels in the blood (273).

While none of the mentioned herbs are currently established within clinical guidelines for specifically lactogenic or prolactin-reducing purposes, ongoing research and anecdotal evidence suggest potential roles for these botanicals as adjunctive therapies.

CONCLUSION

In summary, this review underscores the significant role of drug-induced hyperprolactinemia in causing higher prolactin levels and provides detailed insights into how pharmaceutical agents contribute to this effect. However, understanding the complex mechanisms behind drug-induced hyperprolactinemia is still a work in progress. More research is needed to delve deeper into these mechanisms and gain better insights. These efforts will contribute to refining treatment strategies and improving patient care.

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