ABSTRACT

Benign breast disease in women is a very common finding and results in a diagnosis in approximately one million women annually in the United States (1). An understanding of the hormonal and growth factor control of breast development and function is key to the rational and systematic evaluation and treatment of patients. A firm understanding of benign breast disease is important since sequential steps are necessary to distinguish lesions which impart a high risk of subsequent breast cancer from those which do not. This chapter will review the physiology of breast function, provide histologic examples of common lesions, and detail practical approaches to evaluation and treatment.  For complete coverage of all related areas of Endocrinology, please see our online FREE web-book, www.endotext.org.

BREAST PHYSIOLOGY IN WOMEN:

AGE RELATED CHANGES IN BREAST MORPHOLOGY

Anatomic and histologic structures of the breast undergo substantial change during the period from early adolescence to menopause (5). The normal histologic appearance represents a spectrum ranging from a predominance of ducts, lobules, and intra- and inter-lobular stroma to patterns with a predominance of fibrous change and cyst formation, a process formerly called fibrocystic disease (Figure 2). The term “fibrocystic changes” is now preferred since up to 50 to 60 percent of normal women may have this pattern histologically (6). This new term implies that women with lumpy breasts or non-discrete nodules do not have breast disease. Importantly, fibrocystic changes detected clinically incur no increased risk of breast cancer.

Specific changes in the breast, relating to stromal, ductal and glandular tissue occur as a function of age. During the early reproductive years, stromal hyperplasia may occur and produces juvenile breast hypertrophy (7) or rarely, the more significant problems of unilateral or bilateral macromastia (enlargement of breast tissue beyond what is considered normal) (8). Changes in glandular and ductal tissue occur uncommonly. In the middle reproductive years, glandular breast tissue continues to undergo changes in response to cyclic increments in plasma levels of estradiol and progesterone and, if substantial, is called adenosis. Ductal changes remain uncommon while stromal hyperplasia may occur resulting in areas of ill-defined fullness (“lumpy-bumpy” consistency) on physical exam or in firm areas requiring biopsy.

Figure 1. Influence of the cycle phase on breast total labeling index (TLI) of women less than 34 years of age according to whether cycles were natural or regulated by oral contraceptives (OC). (Reprinted with permission from Going JJ, Anderson TJ, Battersby et al. Proliferative and secretory activity in human breast during natural and artificial menstrual cycles (Am. J Pathol. 130:193-204, 1988).

Figure 2 . Simplified anatomy of the female breast illustrating the major structural components of the breast, the anatomic location of various lesions, and the histology of those lesions and corresponding sites of origin of potential lesions.

In the late reproductive period, glandular tissue may become hyperplastic with sclerosing adenosis or lobular hyperplasia. The hyperplastic glandular lesions may progress to palpable or mammographically detectable abnormalities requiring biopsy. Ductal tissue also may undergo hyperplastic change with an increase in number of ductal cells but without alterations in their appearance. This change, when associated with a 2% or greater prevalence of Ki67 positive cells, is associated with an approximately two fold increase of subsequent breast cancer (9). Further proliferative changes result in lobules approaching 100µ in diameter and called hyperplastic elongated lobular units (HELUs). With progression of the HELUs, atypical ductal or lobular hyperplasia, or ductal carcinoma in situ (DCIS) may ensue. The linear pathway illustrated in Figure 3 depicts this progression but, while considered by some to be overly simplistic, provides a useful framework. This orderly progression depends upon the number of acquired genetic mutations accumulated by clonal cells in the breast. This originally was suggested by loss of heterozygosity studies. Recent specific genetic data suggests that an average of 11 “driver” mutations and 100 bystander mutations are present in established invasive breast cancer (10). Based on the number of mutations required for cancer, current opinion suggests that breast cancer is a process that takes many years to develop with the age of menarche as the earliest factor influencing this process. The progression from the earliest neoplastic changes to invasive breast cancer is considered to take a median of 16 years with a range of 1 to 30 years based on doubling time. Careful assessment of serial mammograms allows an estimation of doubling times which range from 25 to more than 700 days (Figure 4).

Figure 3 Model of the linear progresion from normal, to hyperplastic enlogated lobular units ( HELU), to atypical ductal hyperplasia (ADH), to ductal carcinoma in situ ( DCIS), to occult invasive breast cancer ( IBC), to IBC that has exceeded detection threshold and can be diagnosed by mammogram. Kinetic modeling data suggest that it takes 10 to 20 years for the progression from atypical hyperplasia to a clinically detectable tumor

Figure 4. Cumulative frequency distribution of the doubling times of occult breast cancer obtained by serial mammograms. Figure reproduced with the permision of the author and publisher.

After the onset of menopause, glandular tissue undergoes involution and stroma and fatty tissue (i.e. approximately 97%) replace glandular elements (12).  The degree of involution is inversely related to the risk of subsequent breast cancer. When comparing the lowest with the highest quartile of involution, the relative risk of subsequent breast cancer is more than 2 fold increased I (OR 2.44 , 95% confidence interval (0.96-6.19) (1).  With aging, the degree of involution increases (1), which contributes substantially to the decrease in breast density. On histologic examination, lesions appearing dense on mammography contain a larger than normal proportion of stromal and glandular tissue.

SPECIFIC BENIGN BREAST LESIONS:

A wide variety of benign breast lesions have been described and the histologic appearance fully characterized. On a practical basis, these can be subdivided into those associated with no substantial increased risk of breast cancer ( i.e. < 1.49%), those with an increase of 1.5-2% and those with a >2% increase (Table 1) (13) .

Table 1. Relative risk of breast cancer imparted by specific benign breast lesions (Data from Reference 13)

No Increased risk:

The more common lesions Included in this category are fibrocystic changes, periductal fibrosis, hamartomas, lipomas, phylloides tumors, and neurofibromas. Another lesion is duct ectasia (Figure 5), characterized by distention of subareolar ducts and presence within them of yellowish-orange material. Penetration of the duct wall by this material may produce acute inflammatory changes in the surrounding tissues. Histologically, crystalline oval and round structures thought to be lipid in origin are present. Resolution may occur but residual periductal fibrosis and nodule formation often persist. This lesion is thought to be more frequent in cigarette smokers and represents a more chronic and extensive inflammatory process. A less common lesion is diabetic mastopathy which consists of localized or diffuse areas of fibrosis occurring in patients with diabetes (14).

Figure 5. Histological appearance of duct ectasia showing the characteristic crystalline formation of the intraluminal contents.

Abnormalities of ductal secretion may result in discharge of clear, cloudy, blue, green or black aqueous material. Stromal hyperplasia can result in nipple retraction or in palpable lesions requiring biopsy to distinguish from breast carcinoma. Histologically, the tissue may contain fibroblasts nearly exclusively or predominantly fibroblasts with admixture of glandular epithelium. Some degree of stromal hyperplasia may occur in 50-60% of normal women, particularly those in their middle and late reproductive periods. Traumatic lesions (hematomas and fat necrosis) and inflammatory conditions (granulomas and mastitis) are also not associated with an increased breast cancers (15).

1.5 To 2.0 Fold Increase In Relative Risk:

Fibroadenomas:
During the early reproductive period, glandular components of the breast may respond to cyclic hormonal stimuli in an exaggerated fashion with the development of single fibroadenomas. These consist of lobular units which grow to larger than normal size and contain both epithelial and stromal elements. Fibroadenomas range in size from slightly larger than a normal single lobular unit to larger, more discrete palpable lesions. When exceeding 5 cm, these are called giant fibroadenomas which are seen primarily at puberty or during pregnancy. The incidence of fibroadenomas peaks at age 20-24 (Figure 6). The prevalence on physical examination in young women is 2% in young women but 15-23% when evaluated prospectively at autopsy (16). When complex and containing cysts >3mm in diameter, sclerosing adenosis, epithelial calcification or papillary changes, these lesions are associated with an increased risk of breast cancer (17) (Table 1).

Figure 6. Incidence of fibrocystic breast changes and fibroadenoma by age group. (Reprinted with permission of the publisher and authors from Goehring C, Morabia A. Epidemiology of Bengin Breast Disease, with special attention to histologic types Epidemiologic Reviews 19:310-327, 1997) (16). Note that the term “fibrocystic disease” is used in the legend but this term has now been changed to “fibrocystic changes”.

Other lesions:

Hyperplasia without atypia, papillomas, papillomatosis, radial scar, blunt duct adenosis, and sclerosing adenosis are also associated with an increased risk.

Greater Than A Two-Fold Risk:

Atypical hyperplasia

This lesion can be subdivided into atypical ductal hyperplasia (figure 7) and atypical lobular hyperplasia but both impart a similar increase in relative risk of breast cancer of 3 to 4 fold (18) (Table 1). In the first ten years after diagnosis of AH, the breast tumors occur predominantly in the same breast but subsequently, occur with equal frequency in the contralateral as in the ipsilateral breast (19). These observations suggest the AH is both a precursor lesion for breast cancer and a marker of an underlying predisposing condition termed a “field defect” or alternatively a “mutator phenotype (15) When the amount of hyperplastic tissue increases according to specific criteria (20) the lesions are no longer called benign but are classified as ductal carcinoma in situ. Recent emphasis has been directed toward identification of molecular genetic markers which could predict which patients with AH are at increased risk of developing breast cancer. Over-expression of HER-2/neu is one such marker (21). The presence of aberrant p53, p21, interleukin 6, and TNF alpha and aneuploidly on flow cytometery have also been reported as markers of increased risk (22).

Figure 7. Photomicrograph of atypical ductal hyperplasia histology reprinted from Hartmann LC et al (23).

Recent data from the Mayo Clinic report the absolute rates of breast cancer during prolonged 20+ year follow-up and the important role of multifocality (23;24). As shown in Figure 8, the risk approximates 24% with one lesion, 36% with two and 47% with 3 or more lesions. The increased risk with multifocality has been confirmed in an independent cohort follow at  Vanderbilt (18;19). Although previous studies indicated that family history added to this risk (18), the updated data suggest that neither family history or other risk factors independently contribute to breast cancer risk (23). It is important to emphasize the AH appears to impart a risk of breast cancer which is lower but may approach that from BrCa1 and 2 mutations. As noted above, the presence of atypical hyperplasia imparts a risk over time of both ipsilateral and contralateral breast cancer (Figure 9).

Figure 8. Incidence of breast cancer in cohort of patients with a histologic diagnosis of atypical hyperplasia. Top panel: mean (solid line) and 95% confidence limits (dashed lines). Bottom panel: Incidence in patients with 1, 2, or 3 or more independent lesions. Reprinted with the permission of the authors and publisher from Hartmann LC et al (23).

Figure 9. Ipsilateral versus contralateral distribution of breast cancers diagnosed over time in patients initially diagnosed with atypical hyperplasia. Reproduced with the permission of the authors and publishers from Hartmann LC et al (24).

Lobular Carcinoma in situ:

Even though called lobular carcinoma in situ, this lesion is not generally considered to have reached the neoplastic stage but is analogous to atypical hyperplasia. This lesion imparts approximately a 10 fold   increase in relative risk of breast cancer developing over time. The subsequent breast cancer can occur in the same or contralateral breast; accordingly, this lesion is thought to represent a filed defect or mutator phenotype which increases breast cancer risk but the lesion itself is not a precursor of breast cancer.

Mammographic Density And Breast Cancer Risk:

The percent breast density on mammography correlates with breast cancer risk as shown on Figure 10. When comparing the lowest density category with highest, the relative risk is increased by 5.3 fold. Recent studies examined the histologic composition of dense and non-dense breast tissue. When dense lesions are biopsied and compared to areas of low density, they are found to contain a higher proportion of stroma and glandular tissue and lesser amount of fat (26). Notably, dense lesions contain more of the enzyme aromatase, when quantitated by an immunologic histologic score after staining with an aromatase monoclonal antibody (27). These findings are likely associated with a higher local production of estradiol and could explain the higher incidence of breast cancer with both of these lesions. Taking these observations together, determination of breast density assessed by Bi-RADS criteria or quantitated with a computer assisted method of determining breast density, provides the most powerful means of predicting risk of breast cancer over time (Figure 10).

Figure 10. The percentage of breast tissue which is dense on a mammogram is determined by computer assisted analysis and classified as none, <10%, 10-25%, 25-50%, 50-75%, >75%.The relative risk of breast cancer increases with each step of increased breast density. Adapted from that data of Boyd et al (25).

ETIOLOGY OF BENIGN BREAST DISORDERS

Clinical observations in women receiving estrogens and anti-estrogens suggest that hormonal events play a role in the etiology of benign breast lesions. In post-menopausal women receiving estrogens ± progestins for >8 years, the prevalence of benign breast lesions increased by 1.7 fold (95 percent CI 1.06-2.72) (28). In the Women’s Health Initiative study (WHI), the use of estrogen plus progestin was associated with a 74% increase in the risk of benign proliferative breast disease [hazard ratio, 1.74; 95% confidence interval (CI), 1.35-2.25] (29). The anti-estrogen, tamoxifen, when used for breast cancer prevention, was associated with a 28 percent (RR 0.72, 95 percent Confidence Intervals 0.65-0.79) reduction in prevalence of benign breast lesions, including adenosis, cysts, duct ectasia, and hyperplasia (30).

Underlying and acquired genetic changes are also associated with benign breast lesions. Loss of heterozygosity (LOH), a finding caused by deletions of small segments of DNA (31;32) is commonly found in benign breast lesions. Women frequently have multi-focal lesions, each of which exhibit loss of heterozygosity (LOH) of differing regions of DNA. Women with BRCA1/2 mutations are found to have a high frequency of multiple benign or malignant breast lesions when bilateral mastectomy specimens are meticulously examined (33). These findings support the current theory of an underlying predisposition to mutations in some patients as the cause of multiple breast lesions (34). In the past, this phenomenon was termed a “field effect” and more recently, a “mutator phenotype” (34).

CLINICAL MANIFESTATIONS:

Clinical presentations of benign breast disease are divided into those with pain, lumps, or breast discharge (Table 2).

Breast Pain:

Cyclic breast pain

Usually occurs during the late luteal phase of the menstrual cycle, in association with the premenstrual syndrome or independently (35-40), and resolves at the onset of menses (35;36;38). A recent study in 1171 healthy American women indicated that 11% experience moderate to severe cyclic breast pain and 58%, mild discomfort (39). Breast pain interfered with usual sexual activity in 48% and with physical (37%), social (12%), and school (8%) activity in others. A role for caffeine, iodine deficiency, alterations in fatty acid levels in the breast, fat intake in the diet, and psychological factors in the etiology of breast pain remain unproven. Non-cyclic breast pain is unrelated to the menstrual cycle. Detection of focal tenderness is helpful diagnostically and suggests a tender cyst, rupture through the wall of an ectatic duct, or a particularly tender area of breast nodularity. Acute enlargement of cysts and periductal mastitis may cause severe, localized pain of sudden onset.

Non-breast pain:

When arising from the chest wall, pain may be mistakenly attributed to the breast. Pain localized to a limited area and characterized as burning or knife like in nature suggests this possibility. Several distinct subtypes can be distinguished including localized or diffuse lateral chest wall pain, radicular pain from cervical arthritis and Tietze’s syndrome or costochondritis. The method to distinguish between breast and non-breast pain by careful physical examination is illustrated on Figure 11, panels A-D.

Figure 11. A. Focal chest wall pain—lateral. The patient is turned 90º on her side so that breast tissue is no longer under the area of palpation. The index finger elicits a focal area of pain. B. Focal chest wall pain over costochondral junctions anteriorly. C. Diffuse lateral chest wall pain. With the patient turned over 90 degrees on her side, pain is elicited over a wider area of the chest wall. D. Verification that squeezing breast tissue does not elicit pain ensures that the pain is not related to the breast but represents chest wall pain.

Breast Nodule:

Proliferation of ductal or lobular tissue causes histologic changes that are manifested by the presence of palpable lumps or nodules. Patients often present with the finding of a new breast nodule on self-exam or are found to have a lump by their health care provider. Ninety percent of these new nodules in premenopausal women are benign and usually represent fibroadenomas in the early reproductive period (16). In the middle reproductive period, focal areas of fibrosis, hyperplasia, or cyst formation are more likely. In the later reproductive period, hyperplasia, cysts, and carcinoma in situ are more common.  Some lesions present with symptoms suggesting the cause. With duct ectasia, penetration of the duct wall by lipid material may be associated with a nodule exhibiting acute redness, and causing pain, and fever; after resolution, a subareolar nodule persists.

Other specific lesions present as lumps. These include multiple papillomas, sclerosing adenosis, and radial scars. Multiple papillomas may present as breast lumps, nodules on ultrasound, or may be the cause of bloody nipple discharge and can be seen on ductography. Sclerosing adenosis is a lobular lesion with increased fibrous tissue and interspersed glandular cells. It can present as a mass or a suspicious finding on mammograms. Radial scars are a pathologic diagnosis, usually diagnosed following mammography or palpation and then biopsy. Radial scars are characterized microscopically by a fibroelastic core with radiating ducts and lobules and impart a minimally increased risk of breast cancer similar to that of proliferative changes without atypia (41).

Nipple discharge:

6.8 percent of referrals to physicians for breast concerns result from this symptom. Although particularly distressing to the patient, only 5 percent are found to have serious underlying pathology. Age is an important factor with respect to risk of malignancy (42). In one series, 3 percent of women younger than age 40, 10 percent between 40 and 60 and 32 percent >60 with nipple discharge as their only symptom were found to have a malignancy.

A careful history characterizes breast discharge as either spontaneous or expressible. On examination, one can detect by careful inspection whether the discharge emanates from a single or multiple ducts. Nipple discharge can be divided into physiologic and pathologic types. Characteristics of physiologic discharge include non-spontaneous, multiple duct, bilateral, and non-bloody. Pathologic discharge is characterized as spontaneous, serous or bloody, usually unilateral and usually single duct. Reassuring characteristics are that it must be expressed; is green yellow, brown or milky; that it is bilateral and involves multiple ducts. Spontaneous discharge, whether serous or bloody, requires careful evaluation. A hemoccult card or urine dipstick can be used to test for occult blood if the discharge is spontaneous, unilateral, and from one duct. Cytologic examination is not recommended. Milky discharge (galactorrhea) should be evaluated with measurement of a serum prolactin level. If the discharge is physiologic and the patient is under 35, only reassurance is necessary. Screening mammogram is recommended for patients over 35 with physiologic discharge. Pathologic discharge requires diagnostic mammogram, galactography (Figure 12) (43), and referral to a surgeon.

Figure 12. Galactogram illustrating space occupying lesion. A catheter is inserted into the duct from which the bloody discharge emerges. Contrast material is then injected through the catheter. The various branches of the duct are outlined.

The presence of crusting, scaling, and flaking of the nipple could be a manifestation of Paget’s disease of breast and underlying cancer or of dermatologic problems. The approach is to obtain a history of other dermatologic problems, or a history of change in soap or clothing. If absent, a diagnostic mammogram should be obtained if the patient is over 35. In a large recent series of 1251 patients with nipple discharge, 433 had unilateral discharge and 194 had no breast lump in association with this symptom. Of these, the lesions found included solitary papilloma (n=49), minimal breast cancer (n=20), fibrocystic disease(n=11), papillomatosis (n=7), lobular cancer (n=5) and duct ectasia (n=2)(42) (30A). For women with bloody discharge from a single duct, galactography is warranted. Filling defects can be due to intraductal papilloma, intraductal carcinoma, papillomatosis, debris, or air bubbles.

APPROACH TO THE PRACTICAL MANAGEMENT OF BENIGN BREAST DISEASE

A detailed history and physical exam systematically evaluates the entire breast and chest wall and focuses on areas involving the patient’s symptoms (Table 3). Diagnostic studies may then be ordered. For lumps, “The Triple Test” is recommended which includes palpation, imaging and percutaneous biopsy (either core or fine needle aspirate <FNA>). Mammography, often in conjunction with ultrasound examination (44-47) is required for evaluation of discrete palpable lesions in women over 35 whereas ultrasound provides an optional substitute in younger women (43). Round dense lesions on mammography often represent cysts which require only ultrasonography to distinguish them from solid lesions. Complex cysts containing both fluid and solid matter require biopsy.  For solid lesions, radiographically or ultrasonically directed core biopsy provides highly discriminative information regarding the presence or absence of malignancy. Core biopsy utilizes a large cutting needle deployed with a spring loaded, automated biopsy instrument and obtains tissue suitable for histologic analysis familiar to most pathologists. FNA frequently yields sufficient cellular material to allow adequate cytologic evaluation but requires an experienced cytopathologist. However, the amount of material obtained is insufficient to render a diagnosis in 35-47% of non-palpable lesions (48) and core biopsy is recommended. The exact role of MRI in evaluating breast lesions is currently being determined (49). Galactography (ductography) is useful for detection of focal lesions in a single duct. Cytology of nipple discharge is of limited value with the sensitivity of detecting malignancy only 35 to 47 percent (50).

Diagnostic Procedures

Ideally a team including a radiologist experienced in mammography, ultrasound, MRI and core needle biopsy as well as an internist, gynecologist, or surgeon with expertise in breast diseases should be involved in the evaluation of patients with breast disorders. MRI mammography, ductography, or ultrasound may be utilized (Figures 12 and 13). Information to be obtained by a focused history and physical examination are outlined on Table 3. The method of documenting whether breast pain is chest wall related is illustrated on Figure 11 A-D. Imaging has become an integral part of the management of benign breast disorders.

Imaging studies:

Mammography is useful for evaluation of palpable lesions, particularly in those over 35. Digital mammography is preferred because of its ability to penetrate through dense breast tissue which is commonly found in younger women. Ultrasound is often used as initial evaluation of a palpable mass in women under age 35. If a simple cyst is present, no further evaluation is necessary (Figure 13). If not, mammography may also be necessary to fully evaluate the lump. If the mass has findings suggestive of a fibroadenoma by ultrasound and mammography, short term follow-up and re-imaging can be considered (usually performed in 6 months). Experts are divided as to the necessity to biopsy all fibroadenomas. MRI is more sensitive than digital mammography but false positives are more common (49). Routine yearly MRI is now recommended for women whose lifetime risk of breast cancer is > 20%. As an illustration of its sensitivity, 3% of the contralateral breasts in women with diagnosed breast cancer are found to have a second lesion in the opposite breast when examined by MRI (49).

Figure 13 Upper panel illustrates by ultrasound a non-dense black area representing cyst fluid. The lower panel is the corresponding area on mammogram showing a dense area. With the combination of mammogram and ultrasound, the lesion can be shown to be a cyst.

Findings On Imaging Studies

Fibrocystic change typically presents on mammogram as round or oval, well defined masses that can be subsequently shown to represent cysts on ultrasound (Figure 13). Diffusely scattered dystrophic calcifications may also be found on the mammogram. Consequently, the goal of mammographic evaluation is to provide reassurance to the patient and physician that the risk of neoplasm is low. Aspiration of cysts is usually necessary only in a those cases where the mass does not fulfill all criteria for a simple cyst or if the cyst is painful. Biopsy may be necessary to confirm the benign nature of calcifications, particularly if clustered, linear or variously shaped.

For round masses or round calcifications on a first mammogram, the risk of cancer is less than 2%, and repeat mammography in 6 months is recommended. These lesions are termed “probably benign” using the lexicon terminology required by the Mammography Quality Standards Act (in the USA). If the risk is believed to be greater, core biopsy is recommended. Stereotactically directed core biopsy is ideal for evaluation of calcifications and provides highly discriminative information regarding the presence or absence of malignancy. If this technique is not available, insertion of a wire into the lesion radiographically followed by surgical excision or mere removal of a palpable lesion is warranted.

CLINICAL GUIDELINES FOR EVALUATION OF NODULES AND DISCHARGE

Careful examination distinguishes solitary, discrete, dominant, persistent masses from vague nodularity and thickening. Practice Guidelines of the Society of Surgical Oncology (51) recommend the following evaluation: In women less than age 35, all dominant discrete palpable lesions require referral to a surgeon. If vague nodularity, thickening or asymmetrical nodularity is present, the examination is repeated at midcycle after one or two menstrual cycles. If the abnormality resolves, the patient is reassured and if not, referred to a surgeon. Breast imaging may be appropriate. In women > age 35 with a dominant mass, a diagnostic mammogram (and frequently a sonogram) (44-47) is obtained and the patient referred to a surgeon. With vague nodularity or thickening, one obtains a mammogram with repeat physical exam at mid-cyle 1 to 2 months later and refers to surgeon if the abnormality persists. Post-menopausal women are referred for surgical consultation after a mammogram. For gross cysts (i.e. >4 cm), the guidelines suggest needle aspiration with repeat imaging within six months. If the aspirated fluid does not contain blood, the fluid is discarded without further histologic analysis unless the cyst contains solid components (i.e. complex cyst). If the fluid contains blood or if the cyst is complex, the, fluid is sent for cytology and consultation from a surgeon requested. With persistent refilling of the same cyst after aspiration, surgical consultation is warranted.

Usual practice requires “the triple test” with palpation, mammography (often in conjunction with ultrasonography) and biopsy in women over age 35 with dominant masses. When mammography is negative but a dominant mass is present, biopsy is required to rule out malignancy since lobular carcinoma may not be seen on mammograms. In those younger, mammography may be omitted if ultrasound and biopsy yield definitive information. Many experts omit biopsy in younger women with lesions characteristic of fibroadenoma on ultrasound and elect to follow carefully with serial ultrasounds at six monthly intervals for two years and yearly thereafter. Since careful studies have shown that a lesion appearing benign on mammography and ultrasound is benign >99 percent of the time, clinical judgment may allow follow-up without biopsy in experienced hands (44-47). However, other experienced surgeons disagree and believe that all fibroadenomas require diagnostic core biopsy or FNA and especially in BRCA mutation carriers in whom medullary cancer may be found. Biopsy confirmation of a fibroadenoma eliminates the need for serial ultrasounds. For those with a diagnosis of ADH (Atypical Ductal Hyperplasia) on FNA or core biopsy, excisional biopsy is then required since more complete resection often changes the diagnosis to DCIS.

Breast discharge is evaluated according to the algorithm illustrated below on Figure 14. Careful attention to several factors are necessary including determination whether the discharge arises from one duct or multiple ducts, is bloody, or is milky.

Figure 14. Algorithm to assess breast discharge.

TREATMENT OF BENIGN BREAST DISEASE IN WOMEN

The initial step in evaluating pain is to distinguish true breast pain from chest wall pain (Figure 11). Several well designed, randomized, controlled, double blind, cross over trials have validated the efficacy of medical therapy for cyclic mastalgia. Based upon these studies, we categorize therapies as definitely effective, definitely ineffective, possibly effective, and insufficiently studied. For classification as definitely effective, two or more randomized trials are required. For the category, possibly effective, one randomized trial must be positive in some respect but others may be negative. For the category definitely ineffective, prospective trials must be uniformly negative. For the category, insufficiently studied, only one randomized trial, either negative or positive is available. For full details and references see Table 162-1 in Endocrinology, Fourth Edition, LJ DeGroot and JL Jameson, editors, WB Saunders Company, Philadelphia publishers; Chapter 162 Benign Breast Disorders, RJ Santen page 2194)

Danazol, bromocriptine, and tamoxifen have been proven to be effective (52-55) (Figure 15). Linoleic acid in the form of evening primrose oil has been shown effective in two randomized trials but not in the third, the largest trial. Its role in treatment therefore remains uncertain (56-58) . Vitamin E is considered definitely ineffective and iodine and vaginal progesterone possibly effective. Medroxyprogesterone acetate, caffeine avoidance, and progesterone have not been sufficiently studied. Several other therapies have not been examined in randomized controlled trials but are likely to be beneficial since they are based upon physiologic principles. For example, precise fitting of a bra to provide support for pendulous breasts has been reported to relieve pain in observational studies. GnRH agonist analogues are used to lower LH, FSH, and estradiol levels and to create a temporary post-menopausal state (59;60). Onset of menopause is known to reduce the frequency of breast pain. This therapy is reserved for patients in whom all other measures fail and the pain is considered severe. Reduction of the dosage of estrogens in post-menopausal women or addition of an androgen to estrogen replacement therapy (e.g. Estrotestâ tablets) appears to be beneficial in reducing breast pain (personal observations of author).

Figure 15. Relative efficacy of agents to treat breast pain. These data are from the Breast Clinic in Cardiff, Wales and represent observational studies and not randomized, controlled efficacy trails.

Relative efficacy of effective therapies:

No large randomized, controlled studies have compared the relative efficacy of danazol, bromocriptine, evening primrose oil and tamoxifen. Figure 15 rank orders them according to efficacy based upon data from individual reports from the same clinic. Minimal data are available from clinical trials which involve direct head to head comparisons. It should be noted that overall responses to danazol, bromocriptine and evening primrose oil are lower in those with non-cyclic pain than those with cyclic pain. However, not all studies have carefully excluded patients with non-breast pain and therefore conclusions regarding non-cyclic pain should be considered tentative. The approach to non-breast pain is outlined in Figure 16.

Figure 16. Algorithm to treat non-breast pain

WOMEN AT HIGH RISK FOR BREAST CANCER

A major consideration for women who present with breast problems is whether they have a higher than normal risk of developing breast cancer. Certain breast lesions such as fibrocystic changes are associated with no increased risk of subsequent breast cancer (Table I). A 1.5 to 2-fold greater risk of development of breast cancer over a 20 year period of follow-up occurs with proliferative lesions including ductal hyperplasia, lobular hyperplasia without atypia, sclerosing adenosis, diffuse papillomatosis and complex fibroadenomas. A recent report also suggested that radial scars increase relative risk by 1.8, a risk similar to that found in proliferative disease without atypia. It should be noted that the Gail model for assessing breast cancer risk, which is based predominantly on reproductive factors, underestimates the long term risk of breast cancer in women with benign breast disease. On the other hand, the five year prediction is more accurate (61).

The presence of dense breast tissue on mammography has also been reported to be a predictor of increased incidence of breast cancer (Figure 10).Two components of this finding must be considered: one, the presence of high breast density makes it more difficult to read mammograms and masks the sensitivity of finding a breast cancer initially but identifies it later and two, there is an increased risk of breast cancer associated with increased breast density. With long tem follow-up studies, masking is not the explanation for the increased breast cancer risk (62).

According to classic twin studies, heritability accounts for approximately 60% of the variation in breast density (63;64). Breast cancer risk is also increased in association with high plasma estradiol and testosterone levels in postmenopausal women (62;65) and 20 kg or more weight gain (66) in the pre-menopausal years.

Another risk factor is use of hormone replacement therapy. Current data from the Women’s Health Initiative suggests a 26% increase in relative risk of breast cancer with conjugated equine estrogen (CEE) when combined with medroxyprogesterone acetate when used for an average of 7.1 years. (67). This risk is probably increased further in women starting this therapy shortly after the menopause (i.e. a short gap between onset of menopause and start of menopausal hormone therapy)(68). Starting this therapy a long time after experiencing menopause (long gap) is associated with a lesser relative risk (68). The use of estrogen alone in the WHI was associated with a trend toward reduction of risk of breast cancer at five years and a statistically significant reduction in those adhering to therapy (68). In a follow up report, after 5 years of use and 8 additional follow-up years, the reported decrease of 23% was statistically significant (69) (manson). Available data suggest that the effects of menopausal hormone therapy in the WHI is a class effect and not related to the specific type of estrogen or progestin. One study, however, suggests that use of crystalline progesterone as the progestogen is associated with a lesser risk than use of medroxyprogesterone acetate (70).

To aid in assessing breast cancer risk, a questionnaire developed by Gail, utilizes answers to 7 questions to calculate the 5 year and lifetime risk of developing breast cancer (71). This model has recognized deficiencies in that it does not consider second degree relatives with breast cancer, proliferative lesions of breast other than ADH, alcohol intake, obesity, or birth control pill and menopausal hormone therapy (MHT) use. Nonetheless, the Gail model has been prospectively validated in over 6000 women followed for an average of 4.5 years. A more recently developed model, the Tyrer–Cuzick (IBIS II) model (72) incorporates second degree relatives, obesity and use of MHT into its risk calculations and provides more robust information than the Gail model.

BREAST CANCER PREVENTION

Patients with benign breast lesions imparting an increased risk of breast cancer can be offered tamoxifen (or raloxifene) as a prevention strategy. The risk of breast cancer is determined using the Gail or Tyrer-Cuzick model and the benefits versus risks of tamoxifen evaluated. Risk factors not included in the Gail or Claus models include degree of breast density, plasma free estradiol levels, bone density, weight gain after menopause, and waist-hip ratio (25;65;66;73). Current recommendations suggest that women with a five year risk of breast cancer of over 1.67 percent and no contraindications to tamoxifen should be informed about the possibility of taking tamoxifen for five years (74-77). A recent overview has shown a 38 percent reduction of the relative risk of breast cancer with tamoxifen but benefits may be offset by increased risks of thromboembolic phenomena, endometrial cancer, and maturation of cataracts (78). The Star trial addressed whether raloxifene might be preferable to tamoxifen and (79) demonstrated relative equivalence. However, of interest was the fact that tamoxifen prevented more non-invasive breast cancers than did raloxifene (79). More intensive and frequent screening with multi-modality imaging (i.e. digital or standard mammography plus ultrasound or MRI) may be required in high risk patients. Atypical hyperplasia lesions appear to be more amenable to breast cancer prevention as reviewed from non-head-to-head studies showing prevention ranging from 62 to 75% reduction in four separate randomized studies (23) when compared to a 38% reduction in women selected to be at high risk based on reproductive factors (78).

REFERENCE LIST

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(48)   Venta LA. Image guided biopsy of non-palpable breast lesions. Harris JR LM, Morrow M OCe, editors. Diseases of the Breast second edition. 149-164. 2000. Philadelphia, Lippincott Williams and Wilkins.

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(53)   Messinis IE, Lolis D. Treatment of premenstrual mastalgia with tamoxifen. Acta Obstetricia et Gynecologica Scandinavica 1988;67(4):307-309.

(54)   O'Brien PM, Abukhalil IE. Randomized controlled trial of the management of premenstrual syndrome and premenstrual mastalgia using luteal phase-only danazol. American Journal of Obstetrics & Gynecology 1999;180(1):1-23.

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(58)   Blommers J, de Lange-De Klerk ES, Kuik DJ, Bezemer PD, Meijer S. Evening primrose oil and fish oil for severe chronic astalgia: a randomized, double-blind, controlled trial. American Journal of Obstetrics & Gynecology 2002;187(5):1389-1394.

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ABSTRACT

Contraception is important for the prevention of unintended pregnancies worldwide.  Many contraceptives also have other medical benefits, such as decreasing endometrial and ovarian cancer risk or regulating the pain and bleeding of menstruation.  It is essential for all physicians to have a basic knowledge of contraceptives, given that 99% of women in the United States will use contraception at some point in their reproductive lives.  This chapter provides an overview of the various hormonal and non-hormonal methods.   There is an emphasis placed on efficacy, pharmacology and the mechanism of action for each category of contraceptives.  Progestin-only methods include the implant, intrauterine devices (IUDs), injectables and pills. Combined estrogen-progestin methods include pills, patch and vaginal ring.  Non-hormonal methods include the copper IUD and barrier methods such as condoms or diaphragms.  Non-contraceptive benefits and contraindications for each particular method are also described.  Finally, some future developments are discussed. For complete coverage of this and all related areas of Endocrinology, please visit our FREE on-line web-textbook, www.endotext.org.

INTRODUCTION

The global population is at an all-time high at over 7 billion people. A large percentage of this population growth is in less developed countries where access to reproductive health care is limited. However, even in industrialized countries, unintended pregnancies do occur.  The rate of unintended pregnancies in the United States is higher than much of the industrialized world and approaches 50%.[i]  About 12% of these unintended pregnancies in the U.S. occur in teenagers and 75% occur in women who are poor or low income.[ii] While 2% of U.S. women have an induced abortion every year,[iii] about half of the unplanned pregnancies are carried to term.[iv] The rates of unwanted pregnancy in the United States are at least four times higher than in some countries in Europe and Japan.[v] These differences do not appear to be explained solely by exposure to the risk of pregnancy because other countries such as the Netherlands and Sweden have teenagers who engage in sexual activity earlier than most teenagers in the United States.[vi] The cost of contraception to the consumer and lack of insurance coverage for contraception had been identified as contributors to the high unintended pregnancy rate in the U.S. prior to passage of the Affordable Care Act (ACA).³  The ACA contraceptive mandate then required most insurers to cover contraception without cost-sharing beginning in August 2011.[vii]  However, not all women have insurance and the politics of contraceptive coverage are ever shifting.  Even without cost sharing, women continue to choose less effective methods and/or use methods incorrectly and inconsistently.  While the varied reasons for inconsistent contraceptive use have yet to be fully elucidated, the rate of unintended pregnancies is declining as uptake of contraception, and long-acting reversible contraception (LARC), in particular, increases.¹

There is an ever increasing variety of contraceptives available to couples. Each method has its own distinct advantages and disadvantages. The ideal contraceptive would be effective, reversible, easy to use, not coitally dependent, safe, free of side effects, and inexpensive. Because one objectively perfect method does not yet exist, the choice of a family planning method should be individualized to each couple and may change during a woman's reproductive life. Currently, methods may be non-hormonal, progesterone-containing, or estrogen- and progesterone-containing. There have been, and there will continue to be, great strides to modify and optimize these methods. This chapter will serve as a review of contraceptive options with focus on the efficacy, mechanism of action, and non-contraceptive effects.

EFFICACY AND EFFECTIVENESS

There are inherent risks in our methodology for defining the efficacy of a contraceptive method. If 100 women used a contraceptive method for a year and five became pregnant, we cannot say that the method was 95% effective. We do not know who would have become pregnant without using family planning. Thus, we rely on a failure rate to describe the effectiveness of a method. However, all failure rates are not calculated equally and have different implications.

Most estimates of a contraceptive's efficacy refer to the first year of its use. Overall, the longer a woman uses a contraceptive method, the less likely it is to fail. Thus, the failure rate in the second year is lower than the first and the failure rate in the fifth year is lower than in that of the second. There are two commonly used failure rates to compare contraceptive methods: typical use and perfect use. 'Perfect use' is a measure of efficacy if the method is used perfectly, consistently, and according to specific guidelines. It represents the efficacy of the method in the laboratory setting (method failure rate). 'Typical use' estimates the probability of pregnancy during the first year of using the method in “the real world” setting. This measure of effectiveness takes into account occasional non-use of the method, incorrect use of the method, as well as pure failure of the method. Generally speaking, methods that are coitally dependent, such as condoms and diaphragms, have a larger disparity between typical use and perfect use. The failure rate for perfect use for oral contraceptive pills is approximately 0.3%, but the typical failure rate is about 9%.[ix] Given that it is impossible to predict if women will use a method perfectly, it is appropriate to quote typical-use failure rates in clinical counseling (Table 1). Methods that are long acting and require one visit to a clinician such as an IUD or an implant have very little disparity between perfect use and typical use, and thus are the most effective methods of contraception.

Table 1:  Typical use and perfect use one-year failure rates for contraceptive methods^9,[x]^,[xi]

PHARMACOLOGY

Progestins

The major portion of the contraceptive effect in systemic hormonal methods is due to the progestin compound. Progestins confer most of the contraceptive benefit by suppressing LH and ovulation. Progestins in oral contraceptives are derived from 19 nor-testosterone and include norethindrone, norethindrone acetate, ethynodiol diacetate, norgestrel, levonorgestrel, norethynodrel, desogestrel, norgestimate, and gestodene.

Progestins should be categorized according to their active structure and their parent compound. There are three molecularly distinct types of progestins: estranes, gonanes, and pregnanes. Estranes include norethindrone, norethindrone acetate, ethynodiol diacetate, and lynestrenol. Gonanes include desogestrel, norgestimate, and gestodene. Gonanes and estranes differ in their half-life and with respect to their estrogenic and anti-estrogenic effects. Pregnanes are used in injectable methods. Drospirenone is a spironolactone analog with anti-mineralocorticoid and anti-androgenic activity.[xii]

Progestin-only methods have many documented mechanisms of action, including inhibition of ovulation, thickened and decreased cervical mucus, suppression of mid-cycle peaks of LH and FSH, inhibition of progesterone receptor synthesis, reduction in the number and size of endometrial glands, reduction in ciliary activity within the fallopian tube, and premature luteolysis (decreased functioning of the corpus luteum).[xiii]^,[xiv]^,[xv]^,[xvi] Progestins at high concentrations likely suppress the initiation of folliculogenesis at the level of the hypothalamus. At slightly lower concentrations folliculogenesis can be initiated but the progestin prevents the LH surge at the level of the pituitary and therefore prevents ovulation. At even lower concentrations, progestins alter cervical mucus, tubal motility and/or the endometrium.[xvii]

Estrogens

Estrogens primarily serve to regulate bleeding, but also inhibit FSH and prevent formation of the dominant follicle.[xviii] In contrast to the long list of progestin formulations, only a few estrogenic compounds are used in hormonal contraceptives: ethinyl estradiol (EE), mestranol, and estradiol valerate. Other estrogens, particularly estetrol, are being tested clinically in contraceptive preparations. EE is pharmacologically active whereas mestranol must be converted into EE before it becomes active. Most contraceptives currently on the market contain 35 micrograms of estrogen or less. Ethinyl estradiol is absorbed rapidly and undergoes extensive hepatic first pass metabolism. Its plasma half-life has been reported to be in the range of 10-27 hours. Its half-life in tissue, such as endometrium, appears to be longer.

MECHANISM OF ACTION

While there is a great increase in the number of hormonal contraceptive options, most of these methods are a "variation on a theme.” The mechanism of action of hormonal contraception is primarily through the suppression of ovulation, but progestational effects include:[xix]

• Inhibition of ovulation by suppressing luteinizing hormone (LH);
• Thickening of cervical mucus, thus hampering the transport of sperm;
• Possible inhibition of sperm capacitation;
• Hampered implantation by the production of decidualized endometrium with exhausted and atrophic glands.

Estrogenic effects include:[xx]

• Partial inhibition of ovulation in part by the suppression of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), depending on dose;
• Alteration of secretions and cellular structures of the endometrium within the uterus.

PROGESTIN ONLY HORMONAL CONTRACEPTIVES

Current progestin-only methods include an etonogestrel (ENG) subdermal implant, intrauterine devices, depot medroxyprogesterone acetate, and progestin-only pills.

Advantages: Progestin-only methods do not have an estrogen component, thereby decreasing the complications attributable to estrogen (such as, cardiovascular disease, venous thromboembolism, and thrombophlebitis). Specific non-contraceptive benefits of these methods include scanty or no menses, decreased menstrual cramps and pain, suppression of pain associated with ovulation, decrease in endometrial cancer, ovarian cancer, and pelvic inflammatory disease, and potential improvement of the pain associated with endometriosis. All progestin-only contraceptive methods are reversible. Non-oral administration of progestin provides long term, effective contraception, decreases the risk of ectopic pregnancy, and is not coitally dependent. Specific indications for these methods may include women who are breastfeeding, women who are at greater risk for thromboembolic events, and all women who cannot take estrogen.

Disadvantages: These methods do not protect against sexually transmitted disease and HIV, and can alter the menstrual cycle (including breakthrough bleeding with an increased number of days of light bleeding, and potential amenorrhea).

The contraindications to progestin-only contraceptives are listed in Table 2. The only absolute contraindications are pregnancy, unexplained abnormal vaginal bleeding suspicious for a serious underlying condition, and breast cancer. Active liver disease has been deleted from the list of contraindications to DMPA. In general, one should exercise care when using this method in women with acute, severe liver disease or liver tumors.

Table 2. Contraindications to Progestin-only Hormonal Contraceptives

PROGESTIN-ONLY IMPLANTS

There is one progestin-only implant available in the United States.  It is a single rod that contains 68mg of etonogestrel (ENG).  It is placed subdermally, usually in the upper extremity, in the office with local anesthesia.  It is FDA approved for up to 3 years. Small studies indicate continued efficacy for 4 or even 5 years, but insufficient numbers of obese BMI women have been included to make definitive recommendations in that cohort.[xxi]^,[xxii]  Larger studies are needed to routinely recommend extended use.

Efficacy:  The typical failure rate of the ENG implant is reported to be about 1 in 1000.  However, there are compiled data that demonstrate a Pearl Index of 0.00 (1716 women with 4103 women years of implant use and no pregnancies.[xxiii]^,[xxiv] There does appear to be a decrease in efficacy when combined with drugs that increase hepatic metabolism (Table 2).. Because of these possible interactions, the WHO classifies the implant in women taking these medications as category 2 (benefits likely outweigh the risks).

Side effects:  The most common side effect and most reported reason for removal of the implant is an irregular or unpredictable bleeding pattern^24,[xxv]. Approximately ¼ of women reported prolonged or frequent bleeding. Fortunately, most women state that menstrual flow overall decreases with each successive year of implant use and the most common patterns were infrequent bleeding and amenorrhea.[xxvi]  There appears to be a slightly increased incidence of clinically insignificant ovarian cysts in users of the implant.  Unlike the concerns with depot medroxyprogesterone and bone mineral density (BMD), limited data suggest that the ENG implant does not have any effect on BMD.[xxvii]  Weight gain, however, has not been well studied.  Some trials report an increase of BMI by less than 1%, and perhaps as many as 12% of women will report an increase in weight.  When looking at reasons why women have the implant removed, only 3-7% state it was because of weight gain.  Therefore, it appears that weight gain is clinically insignificant^25,[xxviii]^,[xxix].

Risks: The risks and contraindications are the same as those for other progestin-only methods.

Non contraceptive benefits: The ENG implant likely improves dysmenorrhea.  To date there is no randomized control trial comparing the implant to other acceptable treatments of dysmenorrhea. However, An observational study²⁶ of 315 women showed that of the 187 women who reported dysmenorrhea at baseline, 151 (81%) had improvement of their dysmenorrhea and 26 (14%) reported no change.

INTRAUTERINE DEVICES

Although intrauterine devices (IUDs) are the most widely used form of reversible contraception worldwide, they are an underutilized contraceptive method in the United States.[xxx] IUDs and implants are the most effective methods of reversible contraception (20 times as effective as the hormonal methods of the pill, patch and ring), and have high user acceptability, with few medical contraindications.[xxxi]

Mechanism of action: There are five IUDs currently available in the U.S.: a copper IUD (Paragard®) and four progestin-impregnated intrauterine systems (IUS): Liletta®, Mirena®, Kyleena®, and Skyla®. Both medicated and non-medicated intrauterine devices (IUDs) have multiple mechanisms of action that provide for contraceptive protection. Both medicated and non-medicated IUDs can alter the uterine lining so that it becomes unfavorable for implantation. Release of copper ions also alters fluid in the uterine cavity in a manner that impairs the viability of sperm, thereby inhibiting fertilization. This mechanism may be responsible for the high efficacy of copper IUDs as emergency contraception.

IUDs can also alter both sperm motility and integrity.^30,[xxxii]^,[xxxiii]^,[xxxiv] Medicated, or hormonal IUDs, can interfere with sperm motility by thickening cervical mucus. Sperm head-tail disruption has been reported in the presence of a copper IUD.³⁰ IUDs, whether hormonal or non-hormonal, do not provide protection against sexually transmitted diseases. However, it is important to recognize that IUDs are not associated with PID,[xxxv]^,[xxxvi] and that the historical associations that both physicians and the lay public maintain between IUDs and PID/tubal infertility are false.

Timing of IUD insertion: The IUD can be inserted at any point in the cycle as long as the provider is reasonably certain the patient is not pregnant. An IUD can be inserted immediately postpartum, post abortion, or as an 'interval' insertion. Interval Insertion: An 'interval' insertion is defined as insertion in women who are neither postpartum nor post abortion, or an insertion in women 6 weeks after delivery.[xxxvii] Traditionally, physicians were taught that the best time for IUD insertion was either during menses or immediately after menstruation. Limiting insertion to these time points, however, created a barrier to their use. Data now suggest that IUD insertion between cycle days 12 to 17 results in greater IUD continuation rates. The Centers for Disease Control and Prevention reviewed data from more than 9,000 copper T-200 IUD insertions and found that IUDs placed after cycle day 11 resulted in fewer IUD removals during the first 2 months of IUD use. Insertions after day 17 resulted in more frequent IUD removal due to pain, bleeding, or accidental pregnancy.[xxxviii]

Progestin-only IUD:  The 52mg LNG IUS (Mirena, Liletta) initially releases 20 mcg of levonorgestrel per day from a polymer cylinder mounted on a T-shaped frame (32mm x 32mm) containing 52 mg levonorgestrel; it is covered by a release rate-controlling membrane. Mirena is FDA approved for 5 years of use; Liletta is FDA approved for 4 years of use. However, large studies support continued efficacy for 7 years of use with either brand.[xxxix] The failure rate is low: 0.16 per 100 woman years of use. Its mechanisms of action include production of an atrophic and inactive endometrium, disturbed ovulation, and thickening of the cervical mucus. Ovulation may be inhibited in about 20% of women, but this is not the main mechanism of action. The mean number of bleeding and spotting days is initially increased but both the volume of menstrual flow and the number of days of bleeding are reduced over time.[xl] During the first year of use, about 16% of women will be become amenorrheic and average menstrual bleeding days decrease to 2 per month by 12 months of use.⁴⁰ A recent meta-analysis of randomized controlled trials reveal that LNG-20 IUS users were significantly more likely than all other IUD users to discontinue its use because of hormonal side effects and amenorrhea,[xli] so appropriate counseling is an important component of success. Initial irregular spotting or bleeding, and hormonal side effects like acne and ovarian cysts may occur in some users. In part because there is no user-dependence, the LNG-20 IUS offers much improved effectiveness over other hormonal methods.^41,31

The 19.5mg LNG IUS (Kyleena) initially releases 17.5mcg of levonorgestrel per day during the first year from a 19.5mg reservoir mounted on a smaller T-shaped frame (28 x 30mm). Consequently, it has a more narrow insertion tube.  88% women in the first year and 100% of women in the third year of use will continue to ovulate.[xlii]  Although decreased over time, average number of bleeding/spotting days is higher than with the 52mg IUS.¹¹  Kyleena is FDA approved for 5 years and there are no studies of extended use.

The 13.5mg LNG IUS (Skyla) has the same sized T frame and inserter as the 19.5mg IUS, but contains 13.5 mg of levonorgestrel, and initially releases 14mcg levonorgestrel per day, declining to 5mcg/day after 3 years. Less than 4% of women will have ovulation inhibition, and 6% of women have amenorrhea after 1 year. It is FDA approved for 3 years and there are no studies of extended use.[xliii]

Specific populations:  One population of interest is nulliparous women.  The failure rate of IUDs is low and similar for both parous and nulliparous women.  Acceptability, using the surrogate marker of continuation rate, shows a 90% retention rate in nulliparous women at one year.  As with efficacy, expulsion rates between parous and nulliparous appear to be the same, likely between 1-5% for all comers.  The risk of infection does not seem to vary between the parous and nulliparous women.[xliv] The 19.5mg and 13.5mg IUSs are marketed toward nulliparous women, but it is unknown as to whether its structural differences confer any specific benefits over the 52mg IUS in this population.

Non-contraceptive uses of 52mg LNG IUS: Multiple descriptive studies and clinical trials have been performed on the non-contraceptive benefits:[xlv]^,[xlvi]^,[xlvii]^,[xlviii]^,[xlix]^,[l]^,[li]

• Treatment of menorrhagia in women with uterine fibroids and adenomyosis
• Treatment of pain in women with endometriosis
• Alternative to hysterectomy for women with menorrhagia
• Prevention of endometrial hyperplasia in menopausal women using estrogen therapy
• Prevention of endometrial proliferation and polyps in breast cancer survivors taking tamoxifen

One such study evaluated the efficacy and performance of the LNG-IUS in 44 women with menorrhagia after medical therapy had failed.⁵¹ At 12 months, 79.5% of participants continued use of the LNG-IUS. After LNG-IUS insertion, the most common bleeding pattern at 3 months was spotting followed predominantly by amenorrhea or oligomenorrhea at 6, 9, and 12 months. Hemoglobin levels significantly increased from 10.2 g/L before insertion to 12.8 g/L at 12 months (p<0.01).

The LNG-IUS is an effective treatment for menorrhagia. It is becoming increasingly evident that the LNG-IUS is also effective in the treatment of menorrhagia due to fibroids.  All studies in a systematic review showed an increase in hemoglobin.  Early observational data shows that the LNG-IUS does not appear to decrease the size of the fibroids.  Expulsion rates also varied in these studies from 0-20%, which probably reflects the great variety of cavity size and shape among women with fibroids.[lii]^,[liii]

Another prospective study observed that the 20mcg LNG-IUS provided more effective treatment for endometrial hyperplasia than oral progestin.[liv]

PROGESTIN-ONLY INJECTABLE

Depot medroxyprogesterone acetate (DMPA; Depo-Provera®) is delivered by a deep intramuscular injection of 150 mg of medroxyprogesterone acetate (MPA) every 12 weeks.[lv] Pharmacologically active levels (>0.5mg/ml) of MPA are achieved within 24 hours of injection. Serum levels remain >1.0 ng/ml for approximately three months after administration. By the fifth month, levels drop to 0.2mg/ml.[lvi] There is also a subcutaneous preparation of Depo-Provera, which administers 104 mg of MPA.  DMPA's main mechanism of action is inhibition of ovulation.

Non-contraceptive benefits of DMPA[lvii]

Decreased risk of:

• Endometrial cancer
• Iron deficiency anemia
• Pelvic Inflammatory diseases
• Ectopic pregnancy
• Uterine Leiomyomata

Improvements of the following conditions:

• Menorrhagia/Dysmenorrhea
• Premenstrual syndrome symptoms
• Pain in women with endometriosis
• Seizures refractory to conventional anti-convulsants
• Hemoglobinopathy
• Endometrial hyperplasia
• Vasomotor symptoms in menopausal women
• Pelvic pain/dyspareunia in ovarian origin post hysterectomy
• Metastatic breast cancer
• Metastatic endometrial cancer

Efficacy: With ideal use, the failure rate is 0.3 per 100 woman-years which is similar to rates found with surgical sterilization.[lviii] Variations in body weight and concurrent medications have not been shown to alter efficacy.[lix] The typical-use failure rate is 6/100 women-years.

Side Effects: The most commonly cited side effects of DMPA are changes in menstrual patterns, weight, and mood. After 3 months of use, almost one-half of DMPA users report amenorrhea with the majority of the remaining women complaining of irregular bleeding.[lx] By the end of one year, nearly 75% of users will experience amenorrhea.[lxi] Short courses of high-dose estrogen do little to reduce bleeding among DMPA users.[lxii] In addition, early re-administration of DMPA (at 8-10 weeks instead of 12 weeks) does not reduce bleeding.[lxiii] Although many users of DMPA report weight gain, recent controlled studies show that its long-term use does not cause a significant increase in body weight.[lxiv] Product labeling for DMPA includes depression as a possible side effect. Two well-designed studies addressed the issue of depression and DMPA use. Patients followed up to one year after DMPA initiation showed no worsening of depressive symptoms compared to those who did not use Depo-Provera.[lxv]^,[lxvi] In clinical trial settings, DMPA does not cause statistically significant weight gain.[lxvii]^,[lxviii] However, African American women, Navajo Native Americans, and women with high baseline body mass index may be predisposed to weight gain with the use of this method.[lxix] Studies have shown that neither DMPA nor progestin-only injectable is associated with increased risk of breast cancer.[lxx]

Risks: A recent review showed that levels of triglyceride and total cholesterol do not change with DMPA use.⁶⁹ Seven of the ten studies that measured serum lipid levels revealed a decrease in high density lipoprotein (HDL) while three out of five studies showed an increase in mean low density lipoprotein (LDL) levels. The clinical significance of these findings remains to be determined. In contrast to combination OCs, Depo-Provera is not associated with increases in coagulation-related factors or in blood pressure.[lxxi] Recent studies provide reassuring evidence that decreases in bone mineral density in current and recent Depo-Provera users are reversible and appear to be similar to changes seen in lactation.[lxxii]

Bone loss: On November 17, 2004, the FDA placed a black box in DMPA package labeling regarding the long-term use of DMPA and bone loss. Anecdotally, this warning had an immediate impact on decreased prescription of DMPA.[lxxiii] Depot medroxyprogesterone acetate use has not been linked to menopausal osteoporosis or fractures. A cross-sectional study from the WHO demonstrated that even after four years of use, BMD in former adult DMPA users is similar to that of never users.⁷² The 2002 cohort study of BMD in adult women performed by Scholes et al.[lxxiv] demonstrated that at 3 years of follow-up, BMD of former DMPA users was comparable to that of never users of injectable contraception. While the FDA warning also specifically heightened concerns about teens and bone loss in the setting of DMPA, a 2005 report from Scholes et al.[lxxv] showed that use of DMPA in this population does not put patients at risk for osteoporosis later in life. This cohort study followed 170 adolescents (including 80 who used DMPA at baseline) and found that recovery of BMD was complete within 12 months following DMPA discontinuation. BMD was ultimately observed to be higher in the former than in the never users of DMPA. Duration of DMPA use was not observed to impact speed of BMD recovery following DMPA discontinuation.  A Cochrane review indicated that there may be a small increased risk of fracture in women with increased duration of use.[lxxvi]

PROGESTIN-ONLY ORAL CONTRACEPTIVES

Progestin-only pills, also called the 'minipill' have a dose of progestin that is very close to the threshold of contraceptive efficacy; therefore, these pills must be taken continuously at the same time each day and without a pill-free interval. Less than one percent of oral contraceptive prescriptions in the United States are for the progestin-only oral contraceptive.[lxxvii] This form of contraception is traditionally most often used in women who are breastfeeding or in women who have contraindications to estrogen.  However, most women are candidates for this method. Only one progestin-only formulation is available in the United States with 0.35mg of norethindrone per pill. It is important to note that ovulation is not always inhibited with the use of progestin-only pills. Approximately half of cycles have suppressed ovulation and thus contraceptive efficacy is dependent on the other progestin related mechanisms listed previously.⁷⁷

Efficacy: The typical failure rate of progestin-only pills is similar to that with combined oral contraceptives,[lxxviii] despite the fact that efficacy is only for 27 hours and requires consistent administration. Serum levels of progestin peak 2 hours after administration and return to near baseline levels within 24 hours.⁷⁷ Variation of only a few hours in administration can be the difference in the progestin-only pill providing its contraceptive protection. Women should be prepared to use a back-up method if they are three hours late in taking the pill, if one pill is missed or if there is a delay in its administration.  Furthermore there are data to suggest that the efficacy of progestin-only pills in the setting of rifampin, certain anticonvulsants (excluding lamotrigine) and ritonavir-boosted protease inhibitors is decreased.  The WHO subsequently categorizes progestin-only pills in these settings as risks may outweigh benefits.

Side Effects: The main side effect associated with progestin-only pills is menstrual cycle irregularity. Spotting or breakthrough bleeding, amenorrhea, and shortened length of menstrual cycles are the most common irregularities experienced. A randomized, double-blind study by the WHO showed that an average of 53% of users had frequent bleeding, 22% had prolonged bleeding, 13% had irregular bleeding, and 6% had amenorrhea within 3 months of initiation.[lxxix] Menstrual irregularity is a common reason for method discontinuation. Other less common side effects include nausea, dizziness, headache, and breast tenderness.

Risks: In general, any contraceptive method protects against ectopic pregnancy. However, if progestin-only pill users get pregnant, on average 6-10% of the pregnancies will be ectopic, higher than the rate seen in women not using any method of contraception (2%).⁷⁷ The overall risk, however, remains lower than the general population because so few women actually become pregnant (7%) while using this method of contraception.

A recent WHO case-control study of cardiovascular disease and progestin-only pill use found no significant increase in the risk of acute myocardial infarction (RR=1.0, 95%CI, 0.2-6.0), stroke (RR=1.1, 95%CI, 0.6-1.9), or venous thromboembolism (RR=1.8, 95%CI, 0.8-4.2) (34).  Thus far, progestin-only pills appear to have little or no effect on lipid metabolism, carbohydrate metabolism, hypertension, and coagulation factors.⁷⁷

COMBINED ESTROGEN AND PROGESTIN HORMONAL CONTRACEPTION

The bioavailability of progesterone is poor, so progestins derived from androgens are used instead.  There are many active progestins in addition to norethindrone.  They are classified into generations as shown in Table 3.^18,19

EXTENDED AND CONTINUOUS REGIMENS:[lxxx]

While manipulation of the timing of the pill-free-interval has been practiced by gynecologists for decades, there are now marketed ways to decrease the number of withdrawal bleeds experienced on the standard pill pack, which contains 21 active pills and 7 placebo pills (“21/7”). There are “24/4” regimens with only 4 days per month of placebo pills. Pills such as 'Seasonale' are packaged such that women take the pill for 84 consecutive days, and then stop for a week before inducing a withdrawal bleed. This method allows women to bleed only once every three months. This regimen is especially useful for women who suffer from endometriosis, heavy periods or severe PMS or menstrual cramps. Clinical trials have highlighted breakthrough bleed as an adverse effect of these extended formulations. However, many women favor the decreased number of bleeding days experienced with these newer regimens. Furthermore, there is evidence of greater ovarian suppression with potential for lower failure rates with these regimens.

Non-contraceptive Benefits of Combined Oral Contraceptives

Today there is a range of non-oral, non-daily hormonal contraceptive available, and the face of contraceptive management has changed. However, oral contraceptives have been widely used for decades, and they represent the most extensively studied drug on the market. Research regarding oral contraceptives focused on possible health risks. Many of the concerns of these health risks have been allayed. There is a large body of evidence demonstrating non-contraceptive health benefits of oral contraception. Table 3 is a list of potential non-contraceptive benefits. Specific clinical situations are described below.

Table 3. Advantages of oral contraceptives²⁰

Reduction in ovarian cancer risk: Reduction in ovarian cancer risk increases with greater oral contraceptive use although protection is provided after as little as 3 to 6 months.[lxxxi] Compared to non-users, women who have used oral contraceptives for four years or fewer have a 30% decreased risk of ovarian cancer. If they used combined OC's for 5-11 years, they have a 50% reduction of risk; if they used combined OC's for more than 12 years, there is an 80% reduction in risk. This protective effect persists for at least 15 years after OC discontinuation.[lxxxii]^,[lxxxiii] These data hold true for women at genetically increased risk of breast cancer.  The Society of Gynecologic Oncology (SGO) recommends OC use for women with BRCA1 and BRCA2 in the absence of contraindications. Given the devastating effects of this disease and our lack of success with screening and early diagnosis, the chemo-prophylactic effects of oral contraceptives should be emphasized.

Prevention of Endometrial Cancer: There is a 50% reduction in endometrial cancer risk in OC users compared with never users.[lxxxiv] Reduced risk depends on duration of OC use. The risk is reduced by 20% with 1 year of use, 40% with 2 years of use, and 60% with 4 or more years of use.[lxxxv] The actual duration of protection after discontinuation is unknown but is estimated to be at least 15 years.[lxxxvi]

Benign Breast Disease: OC use significantly reduces fibrocystic breast change and fibroadenoma development.[lxxxvii]^,[lxxxviii]^,[lxxxix] The Oxford Family Planning Association Study found a decreased risk of benign breast disease with increasing duration of use; current users, however, were at lowest risk.[xc] Fibrocystic change is significantly decreased after 1 to 2 years of use,[xci] and lasts up to 1 year after OC discontinuation.⁹⁰

Bone Mineral Density: Studies of both premenopausal and postmenopausal women seem to favor bone-sparing effects of OC's. A past history of OC use provided protection against low bone mineral density in a cross-sectional, retrospective study (OR=0.4, 95%CI, 0.2-0.5).[xcii] The same study observed increasing protection with increasing duration of use. Few studies have shown a protective effect against fracture risk-a case-control study showed that use of any OC in women after the age of 40 years provided significant protection against hip fractures during their menopause (OR=0.7;95%CI, 0.5-0.9).[xciii] Many studies, however, have not found a favorable association between OC's and bone mass.[xciv]^,[xcv] No study thus far has found a detrimental effect of OC's on bone mineral density.[xcvi]

Functional Ovarian Cysts: In general, studies of current monophasic or triphasic OC formulations demonstrate that OCs do not have a significant effect on the development of functional ovarian cysts.[xcvii]^,[xcviii]

Colorectal Cancer: A meta-analysis of pooled relative risks of colorectal cancer for ever-use of OCs from case-control studies was 0.81 (95%CI, 0.69-0.94) and from four cohort studies was 0.84 (95%CI, 0.72-0.97).[xcix] Women using high-dose OCs (with 50mcg estrogen) for greater than 96 months had a relative risk of 0.6 (95%CI, 0.4-0.9).[c] It is unclear if the results from this study apply to women using lower-dose oral contraceptives.

Relief from menstrual disorders: A randomized clinical trial of patients with dysfunctional uterine bleeding showed an 81-87% improvement in bleeding within 3 months compared to a 36-45% improvement seen in placebo treated patients.[ci] The likelihood of iron-deficiency anemia appears to be decreased in both current and past combination OC users. Anecdotal reports of treating primary dysmenorrhea with OCs document their effectiveness.[cii]

Reduction of acne: Two randomized, placebo-controlled trials showed that nearly 50% of women treated with a triphasic OCs containing norgestimate had an improvement in acne compared to 30% of women on placebo.[ciii]^,[civ] Ortho Tri Cyclen and Estrostep are approved by the FDA for the treatment of acne. Another pill that contains ethinyl estradiol and drospirenone is also effective in treating this condition, and may lead to overall improvement in facial acne.[cv] Other OCs too are being evaluated for similar use.[cvi]^,[cvii] All combination OCs likely reduce acne via an increase in sex hormone binding protein and a subsequent decrease in serum testosterone.

Reduced risk of adverse cardiovascular outcomes: In 2004, a study on the WHI database revealed that use of OCs is associated with better cardiovascular outcomes, including any cardiovascular disease, hypercholesterolemia, angina, myocardial infarction, transient ischemic attack, peripheral vascular disease, and need for cardiac catheterization. The data showed that increasing age, elevated body mass index and smoking greatly increased the risks, even in OC users.[cviii]^,[cix]

Risks

Many prescribing patterns of oral contraceptive and other hormonal contraceptive methods are based on perception rather than evidence-based medicine. Evidence-based medicine relies on the integration of clinical expertise with the best evidence from systematic review of research. As clinicians, we can use this methodology to refute misconceptions about oral contraceptives and promote many non-contraceptive benefits.[cx] However, there are some important contraindications to the use of estrogen-containing hormonal contraceptives (Table 4).

Table 4. Contraindications for the use of combined oral contraception

SPECIAL CONSIDERATIONS

Oral Contraceptive Use and The Risk of Thromboembolism

The link between estrogen use and venous thromboembolism was identified more than 20 years ago.[cxii] Since then, there has been extensive literature that describes and attempts to elucidate this risk. A summary of these data show relative risks of venous thromboembolism ranging from 2.1 - 4.4.[cxiii] It has been a demonstrated that risk increases as estrogen dose increases. Despite these risks, it is still safer for a woman to use oral contraceptives than to become pregnant. The attributable risk, or number of new cases of venous thromboembolism attributable to estrogen, is on the order of about 6 per 100,000 women years.¹¹³ This is in contrast to the risk of venous thromboembolism in pregnancy - it is estimated that there are approximately 20 cases per 100,000 pregnant women years. Table 5 provides a summary of relative risk for VTE in different populations of women.

Table 5. Relative Risk of Venous Thromboembolism (VTE)

Oral Contraceptive Use and Risk of Breast Cancer:

The relationship between OC use and breast cancer remains controversial. Two studies provide evidence that OC use is not associated with an increase in breast cancer incidence. The first study was conducted by the Collaborative Group on Hormonal Factors in Breast Disease. This group reanalyzed approximately 90% of the epidemiologic data available worldwide concerning oral contraceptive use and breast cancer risk.[cxiv]^,[cxv] The findings included a slight increase in the relative risk of localized breast cancer associated with current oral contraceptive use (relative risk 1.24, 95% CI 1.15-1.33) or oral contraceptive use within 1-4 years (relative risk 1.16, 95% CI 1.08-1.23) compared to never use. The study also demonstrated that breast cancers diagnosed in OC users were significantly less advanced than those in never users (relative risk 0.88 for spread of disease beyond the breast). They also noted there was no change in the effect of OC use associated with breast cancer by family history. Importantly, they demonstrated no overall effect of OC use that was associated with breast cancer by duration of use, dose, formulation, age at use, or age at breast cancer diagnosis. Oral contraceptive users and non-users older than 50 years have the same cumulative risk of diagnosis of breast cancer. Oral contraceptive use may accelerate the diagnosis of breast cancer but does not affect the overall risk.¹¹⁵

The second study involved over 8000 women, half of which had the diagnosis of breast cancer.[cxvi] Overall, 77% of cases and 79% of controls had ever used OCs. Ever users and current users of OCs were found not to have an increased risk of breast cancer compared to women who had never used OCs (OR 0.9, 95%CI 0.8-1.0 and 1.0, 95% CI, 0.8-1.0, respectively). The relative risk did not increase with increasing duration of OC use or higher estrogen doses. In addition, family history of breast cancer did not significantly impact risk.

In a third study,[cxvii] the authors showed an increased annual risk of breast cancer diagnosis of one per 7,690 women per year using hormonal contraception. Important limitations exist in this recent paper. The research was conducted via multiple Danish registries, which are methods of data collection, but not a study design.  Thus, these studies do not fall directly into standard epidemiologic classifications, and are subject to the biases of retrospective cohort studies. More specifically, the method of detection of the study outcome (breast cancer diagnosis) was not specified, nor was the stage of the diagnosis, nor whether or not the mortality due to breast cancer differed among women who had and had not used hormonal contraception. The clinical significance and health outcomes of higher breast cancer detection rates in the hormonal contraceptive users could not be determined. Finally and most importantly, the reference group, women who chose never to use hormonal contraception, may also make other behavioral, health and lifestyle decisions, including having additional clinical examinations, that affect their risk of cancer. This small absolute risk is unlikely to have clinical significance for women prioritizing pregnancy prevention, especially considering that previously published research[cxviii] shows that users of oral contraceptives are protected from other cancers including colorectal, endometrial, and ovarian cancer.

Oral Contraceptive Use and Liver Cancer

Non-case control studies of reproductive age women in western developed nations have reported an association between oral contraceptive and liver cancer. Recent population-based data, however, do not suggest any association between liver cancer and OC use among women in five developed nations. In addition, reassuring data from two studies in developing countries, including a large WHO study, do not support an increased risk of liver cancer with oral contraceptive use.[cxix]

Oral Contraceptive Use and Gallbladder Disease

Studies suggested in the 1970's that oral contraceptives were associated with an increased risk of gall bladder disease. Since then, numerous case-control and cohort studies have described an increased risk of benign gallbladder disease in oral contraceptive users. A meta-analysis of these studies published in 1990, however, found that few of these studies could stand up to internal validity measures. The relationship between benign gallbladder disease and oral contraceptives yields a relative risk of 1.1 with a 95% CI 1.1 - 1.2.⁸¹

Second Versus Third Generation Oral Contraceptives and Deep Vein Thrombosis.

There is no strong biological evidence that specific progestins have differential effects on VTE risk. While clotting factors may be altered differentially by specific progestins such data are not clinically relevant because we do not have a proven surrogate marker for VTE risk.[cxx] In the mid 1990's pharmaco-epidemiological studies reported that women using "third generation" oral contraceptives had a higher risk of venous thromboembolism (VTE) compared to women using "second generation" OCs.[cxxi]^,[cxxii]^,[cxxiii] Studies performed after the initial observation demonstrate a weak association between oral contraceptive use and VTE (strength of association ranges from 0.7 to 2.3). Paradoxically, larger doses of estrogen are associated with lower risks for VTE in these studies. This finding has questioned the biological plausibility of the hypothesis of associating 'new progestins’ to an increased risk of deep venous thrombosis (DVT).

It was suggested that the original studies included newer users of oral contraceptives that may have been innately at higher risk for DVT (new-user bias), thus biasing the results.^8,[cxxiv] After reanalysis of the data, the FDA issued a statement stating that the risk of DVT with the 'new progestins "is not great enough to justify switching to other products".

The association of second versus third generation progestin and the risk of VTE was further analyzed in 2 separate meta-analyses. Twelve observational studies were included in one meta-analysis of the relative risk of VTE for OCs containing either desogestrel and gestodene or levonorgestrel.[cxxv] The relative risk of VTE in users of OCs with desogestrel and gestodene v levonorgestrel was 1.7 (95% CI, 1.3-2.1), an increase of approximately 11 more cases of VTE per 100,000 women per year. When accounting for duration of use and new use (less than 1 year), this increased risk persisted. However, differences in BMI and other comorbidities that may act as confounders were not accounted for in these studies.

The results in another meta-analysis of seven cohort and case-control studies similarly show the biases in these studies. The overall adjusted odds ratio for third versus second generation oral contraceptives was 1.7 (95% CI, 1.4-2.0).[cxxvi] Among first-time users (<1 year of use), the odds ratio for third versus second generation preparations was 3.1 (95% CI, 2.0-4.6), which decreased to 2.0 (95% CI, 1.4-2.7) in longer term users (1 year of use). In this paper, the new-user effect is clearly demonstrated.

Lidegaard et al retrospectively assessed the influence of OCs on the risk of VTE in women aged 15-44 years.[cxxvii] After adjusting for age, BMI, length of OC use, and family history of coagulopathies, the odds of VTE among current second generation OC users compared to non-users was 2.9 (95% CI, 2.2-3.8) while the odds of current third generation OC users compared to nonusers was 4.0 (95% CI, 3.2-4.9). After correcting for duration of use and differences in estrogen dose, the third/second generation risk ratio was 1.3 (95% CI, 1.0-1.8; p<0.05).

If there is any increased risk of VTE with third generation OCPs, this is likely to be marginal, with small absolute risks. The majority of the risk is conferred by the estrogen, which should be factored into contraceptive decision-making. Despite the heated debate and the revealed flaws with such study designs, a similar argument is now in the literature with regard to drospirenone-containing OCPs. Several studies have investigated the risk of VTE associated with OCPs containing drosperinone vs other progestins. The EURAS study, initiated in 2001 and including more than 120,000 COC users in Europe, found comparable risk of DVT among the 3 categories of progestins.[cxxviii] This study was not only large, but also of prospective study design and the primary objective was to assess safety across COC user groups. Two other studies have shown an increased risk of VTE in drosperinone users.[cxxix]^,[cxxx] These studies are limited by flawed methodologies in a similar fashion to the studies that caused controversies around the 3^rd generation progestins. In one study[cxxxi] only 1.2% of COC users used drosperinone-containing OCPs, which results in unstable estimates.  In the other retrospective cohort study the relative risk for drosperinone-using women was elevated, but these one-year estimates are unreliable because of left censoring (women had varying risk-levels at entry to the study). The estimates of risk after the first year are in line with the EURAS study.

COC concerns for women with other risk factors:

Factor V Leiden mutation may independently increase the risk of DVT. The Factor V mutation occurs in 3-5% of Caucasians and is responsible for the majority of cases of venous thrombosis in which a mechanism is identifiable. A recent study suggested that the combination of third generation oral contraceptives and the Factor V Leiden mutation may increase the risk of DVT 30-50-fold.¹³⁰ This study has been criticized for its lack of validation and methodology.

Other inherited thrombophilias, such as the prothrombin G20210A defect, and Protein S or Protein C deficiency, have been associated with an increased risk of VTE. Multiple studies have shown that this risk increases in the setting of OC use.

A recent retrospective cohort study of patients with a documented VTE showed that compared to non-users, OC use increases the risk of thrombosis in carriers of antithrombin, protein C and protein S defects six fold.¹³¹ Interestingly, risk of VTE in carriers of Factor V Leiden was not significantly increased.

Another investigator retrospectively analyzed OC exposure and incidence of VTE in thirteen female patients with the prothrombin G20210A defect (12 of which were heterozygote for the defect).[cxxxii] All thirteen women took OCs for an average of 10 years without any thrombotic complication. Interestingly, the homozygote took OCs with a 'third generation' progestin for 6 years without a thrombotic event. Another investigator noted that of those patients who develop VTE soon after initiating OCs (<6 months), most are thrombophilic.[cxxxiii] Among women with protein C or protein S deficiency, antithrombin deficiency, Factor V Leiden or prothrombin 20210A mutations, the risk of developing a DVT during the first year of OC use was increased 11-fold (95% CI, 2.1-57.3).[cxxxiv]

A pooled analysis of 8 case-control studies revealed that the odds ratio for VTE associated with OC use was 10.25 (95% CI, 5.59-18.45) in factor V Leiden carriers and 7.14 (95% CI, 3.39-15.04) in carriers of the prothrombin G20210A mutation.¹²⁷ The crude odds ratios for VTE (not specifically analyzing the effect of OCs) were 4.9 (95%CI, 4.1-5.9) for factor V Leiden and 3.8 (95%CI, 3.0-4.9) for the prothrombin 20210A mutation.

Therefore, all healthy women who are diagnosed with a DVT while using oral contraceptives should be tested for possible Factor V Leiden mutation or Protein S or Protein C deficiency, although screening beforehand is not warranted.

Oral contraceptive use and risk of myocardial infarction: Myocardial infarction is a very rare event in non-smoking women of reproductive age. For women younger than 35 who do not smoke, the incidence of myocardial infarction is less than 1.7 per 100,000 woman years.¹¹³ This rate is notably higher between the ages of 40 and 45 years and is about 21 per 100,000 woman years. Review of the evidence shows that the association between current combined oral contraceptive use (containing 35 micrograms of ethinyl estradiol or less) and myocardial infarction is weak, with a relative risk ranging from 0.9 to 2.5. There is no evidence to support an increased or decreased risk of myocardial infarction due to past oral contraceptive use compared to no use.[cxxxv] Smoking has been identified as an independent risk factor for myocardial infarction; the combination of smoking and oral contraceptive use can be synergistic for increasing the risk of a MI.

The World Health Organization (WHO) has the following recommendations:^135,[cxxxvi]

1. Combined oral contraceptives can be use safely by women of any age who are non-smoking, normotensive, and non-diabetic.
2. For women who smoke, and are 35 years or younger, oral contraceptives containing 35 micrograms or less are recommended.
3. For women who smoke and are 35 years or older, oral contraceptive use is contraindicated.

Oral contraceptive use and risk of stroke: The link between high dose oral contraceptive pills and ischemic stroke has historically been determined with a strength of association ranging from 2.9 to 5.3.¹¹³ However, as dose of estrogen decreased, the odds ratio and relative risks in further studies all decreased as well. A summary of the data by the WHO^123,124 concludes that there is no significant increased risk of ischemic stroke in women younger than 45 years old who use oral contraceptives. Overall, the strength of association between the use of lower dose oral contraceptives and stroke is weak, with odds ratios ranging from 1.1 to 1.8, with most 95% confidence intervals including 1.0.¹¹³ There is no consistent strong evidence linking oral contraceptive use to hemorrhagic stroke. Women of any age who have migraines with aura should not take combination oral contraceptive pills.[cxxxvii] Since smoking, hypertension, and migraine headaches all are independent risk factors for stroke, it must be concluded that women with other independent risk factors may have a slightly increased risk of stroke while taking the oral contraceptive pill. There is ample evidence, however, to suggest that there is no significant increase in ischemic or hemorrhagic stroke in OC-using women with no other risk factors. Because the baseline risk of stroke is rare in reproductive aged women, the attributable risk of oral contraceptives is quite small. In summary, evidence shows that current low dose oral contraceptives are safe with regard to vascular disease for a great majority of healthy non-smoking women who seek an effective contraceptive method.

NEW DEVELOPMENTS IN COMBINED ORAL CONTRACEPTIVE PILLS

The number of combined oral contraceptive pill preparations on the market has increased in recent years. There are new formulations of pills with a dosage of estrogen as low as 20 micrograms. Some physicians use the 'Quick Start' approach to pill initiation: this allows for immediate ingestion of the first dose of the pill in the office after a negative pregnancy test regardless of menstrual cycle day. A clinical trial has shown that is approach is safe, and results in higher ultimate rate of pill use than the conventional approach that initiates pill use after the onset of menses.[cxxxviii] In general, the efficacy, side effects and cycle control of these new preparations are similar to those with 35 micrograms of estrogen. The "lower" dose pills offer the theoretical advantage of less estrogen and therefore fewer estrogen side effects and medical complications. It remains to be determined if the new "lower" dose pills confer the same non-contraceptive benefits of the "higher" dose pills. A recent Cochrane review found that there is no difference in contraceptive effectiveness for lower dose pills. Compared to the higher-estrogen pills, several COCs containing 20 μg EE resulted in higher rates of early clinical trial discontinuation (overall and due to adverse events such as irregular bleeding) as well as increased risk of bleeding disturbances (both amenorrhea or infrequent bleeding and irregular, prolonged, frequent bleeding, or breakthrough bleeding or spotting). So, while COCs containing 20 μg EE may be theoretically safer, this has not been proven and low-dose estrogen COCs have in higher rates of bleeding pattern disruptions.[cxxxix]

An oral contraceptive containing 30mcg ethinyl estradiol and 3mg drospirenone works in a manner similar to other oral contraceptives, effectively inhibiting ovulation and producing cervical mucus that is hostile to sperm motility. Unlike other progestins used in oral contraceptives, drospirenone is an analogue to spironolactone and has biochemical and pharmacologic profiles similar to endogenous progesterone.[cxl] Drospirenone has both anti-mineralocorticoid and anti-androgenic activity. Its anti-androgenic activity may leads to suppression of undesired symptoms such as acne and hirsutism. Its anti-mineralocorticoid activity balances the aldosterone-stimulating effects of estrogen, thereby potentially reducing water-retention and weight gain.

Another preparation offers a hormone-free, placebo length of only 2 days. Twenty-one days of 20mcg ethinyl estradiol and 150mcg of desogestrel is followed by 2 days of placebo and 5 days of 10mcg ethinyl estradiol. Within 18 months of use, absence of withdrawal bleeding and intermenstrual bleeding have been reported to occur in 5.5% and 12% of total cycles, respectively.[cxli] Nearly three-quarters of participants in a large, open-label study reported one or more side effects, including headache, breast pain, dysmenorrhea, and menstrual irregularities.

Psychological/behavioral effects of hormonal contraception: Data from randomized controlled trials fail to support the assertion that combined oral contraceptives cause adverse psychological symptoms. One randomized double-blind study of 462 women looked at the percentage of traditionally “hormone-related” side effects in a 6-month comparison of COC versus placebo pill users. Symptoms of emotional lability and physical symptoms of headache, nausea, breast pain, abdominal bloating, back pain, weight gain, and decreased libido were studied, and there were no differences in the incidence of these symptoms between the COC and placebo groups.[cxlii] In a 2002 review of prospective, controlled studies of the effect of COCs on mood, four studies found no significant group differences in negative affect across the entire menstrual cycle, one study found that COC users reported less negative affect across the cycle, one study found higher negative affect throughout the cycle of a monophasic but not a triphasic COC, and two studies found that COC users experienced higher positive affect.[cxliii] Common to all the studies of the psychological effects of COCs was a beneficial outcome: there was less variability in negative affect, and less negative affect during menstruation in patients taking COCs.

Many studies have focused on the role of the progestin as a contributor to dysphoric mood. Two studies have shown worsening of mood with a higher progestin to estrogen ratio.[cxliv]^,[cxlv] Thus, switching to a formulation with a lower progestin to estrogen ratio may improve mood in women who have negative mood symptoms with COCs. However, evidence regarding mood disturbances with COCs is sparse.

ALTERNATIVE METHODS

Effective, safe contraception is achieved with combination estrogen and progestin delivery via a contraceptive skin patch or a vaginal ring. The general mechanism of action of these methods is similar to that of combined oral contraceptives. These methods offer the advantage of non-daily administration, relative ease of administration, potential greater compliance and thus potential greater efficacy.

Transdermal Patch

The once-weekly contraceptive patch delivers 150mcg of norelgestromin, the active metabolite of norgestimate, and 20mcg of ethinyl estradiol daily to the systemic circulation.[cxlvi] Ten percent of American women have used or currently used the patch.[cxlvii] Typical use includes placement of the patch on the same day of each week for 3 consecutive weeks followed by a patch-free week. Serum levels of the estrogen and progestin components are maintained for 2 days beyond the recommended 7 days of wear. Therefore, patients do not have to change the patch at the exact same time each week.

The patch is composed of 3 layers: an outer protective layer of polyester, a medicated, adhesive middle layer, and a clear, polyester liner that is removed before patch application. Patients can maintain normal activity, including bathing, swimming and heavy exercise while using the patch. It is recommended that wearers avoid use of oils, creams or cosmetics that may interfere with adhesion of the patch.

Compared to OCs with 250mcg norgestimate and 35mcg ethinyl estradiol, the patch suppresses ovulation to a similar degree[cxlviii]. It is as effective as oral levonorgestrel/ethinyl estradiol in altering cervical mucus and in providing cycle control. The overall and method-failure probabilities of the transdermal patch (through 13 cycles) are 0.7% and 0.4%, respectively.¹⁴⁶ Perfect compliance (21 days of consecutive dosing followed by 7 days of no medication) was achieved in 90% of patients in the above study. However, efficacy trials of the patch have shown that participants less than 20 years age were less likely to use the patch correctly as compared with the pill.[cxlix] The noncontraceptive effects of transdermal administration have not yet been studied, but are expected to be similar to the combined oral contraceptive pill. A recent clinical trial did not demonstrate the same improved continuation rates with the "quick start" method in patch users as was seen in oral contraceptive users.[cl]

Vaginal Ring

For numerous decades, the vagina has been identified as a potential organ for drug absorption.[cli]^,[clii] The anatomy of the vagina allows for the easy placement of a ring to achieve this purpose.

A combination estrogen/progestin vaginal ring was approved for use in 2001 and was used by 6% of US women of reproductive age by 2006-2010.¹⁴⁷ It is a flexible transparent circular tube, 54 mm (2 inches) in diameter and 4 mm (1/4 inch) thick. The ring is made of ethylene vinyl acetate polymer and contains a hormone reservoir that releases 0.120 μg of etonogestrel and 0.015 μg of ethinyl estradiol each day over a three-week period.[cliii] Hormone content in the ring is sufficient to provide a "grace period" of at least 14 additional days,[cliv] so woman can leave it in place for a full month and then immediately replace it to avoid menstruation, if they so desire. Etonogestrel, also called 3-ketodesogestrel, is also a synthethormone. It is the active metabolite of desogestrel, the progestin component of commonly used oral contraceptives.

The mechanism of action of a vaginal ring is similar to other hormonal contraceptives. Initiating ring use during the first five days of a normal cycle ensures that ovulation in that cycle is suppressed. Similarly, allowing no more than seven ring-free days each month, and making sure that the ring is in place continuously, with no more than three hours out in one day are also important for efficacy.¹⁵³ Overall pregnancy rates are reported to be 0.65 per 100 woman-years (all first-year users).¹⁰³ This level of effectiveness is similar to that found for women using combined oral contraceptives. Adherence to rules for ring use was very high, with consistent and correct use reported in 90.8% of all cycles. Women using the ring also reported good cycle control, with expected withdrawal bleeding in 98% of cycles, and bleeding at other times in only 6.4% of cycles.¹⁵⁵

The ring can be placed in any position in the vagina that is comfortable. A total of 8% of women note the sensation of the ring in the vagina. If the ring is removed for intercourse it can be cleaned with water and must be replaced within three hours. Risks and adverse reactions possible with use of combined hormonal oral contraceptives also are likely to apply to the vaginal contraceptive ring. The ring does not prevent against sexually transmitted disease. Some women using the ring experienced side effects related to the device itself including vaginal discomfort or problems during intercourse, vaginal discharge, or vaginitis. These device-related problems were reported by 2-5% of women.[clv] Overall acceptability and tolerability of the ring were very high in the clinical trials performed to date.

EMERGENCY CONTRACEPTION

Emergency contraception prevents pregnancy after unprotected sexual intercourse. Emergency contraception (EC) does not protect against sexually transmitted infections. The emergency contraceptive formulations available in the United States include the CuT380A IUD,[clvi]^,[clvii]^,[clviii] ulipristal acetate (UPA) selective progesterone receptor modulator, and 150 mcg of levonorgestrel (Plan B and Plan B One-Step). Combined oral contraceptive tablets can also be used by following the “Yuzpe regimen,” which can be found on the internet for various pill formulations.

The Copper “T” IUD can be inserted up to 7 days after unprotected intercourse and is ideal for women who desire long-term contraception going forward.[clix]  It is 99% effective for emergency contraception.

The current treatment schedule for emergency contraceptive pills (ECPs) is one dose within 120 hours of unprotected intercourse.¹⁵⁸ Ulipristal acetate is more effective than levonorgestrel for emergency contraception, especially in obese women.  Estimates of effectiveness range from 62-85%.[clx] Effectiveness is sustained throughout the 120 hours after unprotected intercourse. Combined and progestin-only ECPs reduce the risk of pregnancy by about 75-88%.[clxi] Effectiveness declines with increasing delay between unprotected intercourse and initiation of treatment.[clxii]

Mechanism of action: Oral emergency contraception likely inhibits or delays ovulation.[clxiii] Some investigators have shown histological alterations in the endometrium suggesting impairment of endometrial receptivity to implantation[clxiv] while others have found no such effects.[clxv]^,[clxvi] Other possible mechanisms include interference with corpus luteum function, thickening of cervical mucus, and alterations in tubal transport of sperm, egg, or embryo.[clxvii] Emergency contraceptives do not interrupt an already established pregnancy.  The Copper “T” IUD does not have an established mechanism of action as an emergency contraceptive but likely creates a hostile environment for sperm as well as for the egg and possibly an embryo.

Progestin-only emergency contraceptives are more effective and associated with significantly less nausea and vomiting than combined emergency contraceptive pills.[clxviii] The only absolute contraindication to the use of emergency contraceptive pills is a confirmed pregnancy. The absence of contraindications is likely due to the very short duration of exposure and low total hormone content. There are no conclusive studies of women who were already pregnant when they took emergency contraceptive pills or of women pregnant after failed emergency contraception. However, there is no epidemiologic evidence that progestins are teratogenic and observational studies provide reassurance regarding birth defects.[clxix]

The FDA has granted approval for the over the counter use of progestin-only EC for prevention of pregnancy. There are no longer any restrictions on age or gender for purchasing progestin-only EC.  Evidence has been reported that making ECPs widely available does not increase risk-taking behavior or increase the incidence of unintended pregnancy.[clxx] Additionally, it has been demonstrated that women most likely to seek emergency contraception are those already concerned about or using contraception.[clxxi]^,[clxxii]

Copper IUDs can be inserted up to five to seven days after ovulation to prevent pregnancy. Insertion of a Copper IUD is significantly more effective than the use of hormonal emergency contraception. The use of a Copper IUD can reduce the risk of unintended pregnancy by more than 99%.[clxxiii]  Furthermore, 86% of parous and 80% of nulliparous women retain the IUD after insertion for emergency contraception.¹⁶²

BARRIER METHODS

Multiple forms of barrier methods are currently used: male and female condoms, the diaphragm, the contraceptive sponge, and cervical cap. Vaginal barriers are easy to use and are non-invasive. They can be used with little advance planning. Consistent and correct uses are absolutely essential for barrier effectiveness; most failures occur due to improper or inconsistent use. The 'typical use' pregnancy rate for these methods can be as high as 20-30%. The male condom has a 'typical use' failure rate of 14%. Recent studies have shown that teens were most likely to use condoms for birth control and 66% used a condom when they became sexually active.¹⁷³

Mechanism of action: Both the male and female condoms provide a physical barrier that prevents sperm and egg interaction. They are intended for one time use only. Condoms also provide some protection against HIV and STI.

Diaphragms and cervical caps use two different mechanisms, a physical barrier as well as a spermicidal chemical. They are available by prescription only, and must be sized by a health professional for a proper fit. They are always used with spermicidal agents. Diaphragm provides protection for 6 hours and cervical cap for 48 hours after insertion.

The contraceptive sponge is a disc shaped polyurethane device and contains a 1,000 mg of nonoxynol-9. It does not require prescription, and provides protection for up to 24 hours after insertion. The typical use pregnancy rate for this method is 10-40%.

Vaginal barriers have many advantages: protection against sexually transmitted infections, immediate protection without much prior planning, easy access, and no systemic side effects. Disadvantages include: discomfort with placement and use, possible latex allergy (for condoms and the orthoflex diaphragm), increased incidence of urinary tract infections and bacterial vaginosis; and associations have been reported with toxic shock syndrome. In addition, a health care provider may be required to do the initial fitting for diaphragms, necessitating an extra visit to the physician's office. A comparison of the ability of contraceptive methods to reduce sexually transmitted disease is found in Table 6.

Table 6. Contraceptive Methods and STD Protection

Barriers

Spermicides

Spermicides can be purchased without a physician's prescription in supermarkets and pharmacies. They can be used alone but are often used in conjunction with a vaginal barrier method (diaphragm, sponge, or cap). Nonoxynol-9 (N-9), the most commonly used spermicide, is an agent that destroys the sperm cell membrane, thereby immobilizing sperm. But, recent studies have shown that N-9 does not protect against STIs and HIV.[clxxiv] Spermicidal formulations include gels, creams, suppositories, film and male condoms. Pregnancy rates among typical users range from 5% to 30% in the first year of use.¹⁹ Methodology in determining these rates has not been consistent leading to skepticism of much of the data. Like the barrier methods, the effectiveness of spermicides is dependent on their consistent and correct use. Its advantages are similar to barrier methods of contraception.

Microbicides

Efforts to combine effective contraception and protection against HIV and STI transmission are of the utmost priority because the incidence of transmission of HIV and STIs is greatest in women of reproductive age.[clxxv]

Any substance that can reduce the transmission of HIV and STI when applied to the vagina is considered a microbicide.  A randomized double-blind, placebo controlled trial studied tenofovir vaginal gel in 889 women in South Africa.  The antiretroviral tenofovir gel is applied to the vagina sometime within 12 hours prior to sex and then again within 12 hours after sex.  This study showed that it cut HIV transmission by approximately 39%.  Even more encouraging were those women who were “high adherers” meaning they reported and demonstrated using the gel with >80% of each act of vaginal intercourse.  This subcategory of women showed a 54% decrease in HIV infection compared to placebo. In summary HIV incidence in the tenofovir arm was 5.6 per 100 women years vs. 9.1 per 100 women-years in the placebo arm.[clxxvi]  While this is promising, real world adherence is low, thus promoting the search for alternative delivery mechanisms, such as vaginal rings.[clxxvii]  As many as 60 potential compounds are currently under development. These formulations will probably be used as an adjunct to condoms, but may be used as primary protection for those who are unable or unwilling to use condoms consistently. These microbicides will work by either killing or immobilizing pathogens possibly by forming a barrier between pathogen and vaginal tissues, preventing the infection from entering target cells, preventing a pathogen from replicating once it has entered cells, by boosting the vagina's or rectum's own defense system or by acting like invisible condoms. The most desirable qualities of a new formula microbicide would be that it is applicable hours before sexual intercourse, it is not messy or "leaky," and spreads rapidly and evenly over the vagina and cervix.¹⁴⁸

Some compounds may increase the host natural defenses against certain sexually transmitted pathogens by maintaining the normal acidic pH of the vagina in the presence of semen. They contain lactobacillus which naturally resides in the human vagina and produces hydrogen peroxide to kill HIV and STDs. Examples are: Lactobacillus suppositories, Buffer gel, and Acid gel (ACIDFORM).

Invisible Condoms: Thermoreversible Gel - Prevents infection by forming a protective barrier after being inserted into the vagina or rectum. It is a liquid at room temperature and quickly turns into an impermeable gel inside the rectal/vaginal canal.

NATURAL FAMILY PLANNING METHODS:

Abstinence: Couples who avoid sexual intercourse are practicing abstinence. Effectiveness for preventing pregnancy is 100%, but HIV and STIs may spread through the oral or rectal mucus membrane.

Coitus Interruptus: Also known as the withdrawal method, coitus interruptus entails withdrawal of the penis from the vagina (and external genitalia) immediately prior to ejaculation. Effectiveness depends largely on the man's ability to withdraw prior to ejaculation. Its actual efficacy is difficult to measure but the probability of pregnancy among perfect users is estimated to be approximately 4% in the initial year of use.[clxxviii]

Fertility Awareness: Symptothermic method - Natural family planning methods use the signs, symptoms, and timing of a normal menstrual cycle to avoid intercourse during fertile intervals. These methods are effective because of periodic abstinence during the fertile period of a woman's menstrual cycle. The fertile period of a woman's menstrual cycle can be determined by using cycle beads, a calendar, measuring basal body temperature and monitoring cervical secretions.¹⁷⁸

Calendar Method: Estimating the fertile period during each menstrual cycle is based on 3 assumptions: (1) ovulation occurs on day 14 (±2 days) before the onset of the next menstrual flow, (2) the ovum survives for approximately 24 hours, and (3) sperm remain viable up to 5 days. Past cycle lengths give an estimate of fertile days within a given cycle. Avoidance of pregnancy is achieved by abstinence beginning about 5 days before and ending nearly 5 days after ovulation.

Basal Body Temperature: Most ovulatory cycles demonstrate a biphasic temperature pattern with lower temperatures in the first half of the cycle and higher temperatures beginning at the time of ovulation and continuing for the remainder of the cycle. Because this method does not adequately predict ovulation in advance, couples are instructed to abstain from intercourse or use a barrier method of contraception for the first half of the menstrual cycle until at least 2 days after a rise in temperature signifying ovulation.

Cervical Secretions: Changes in the character of cervical mucus can signify the fertile period of a woman's menstrual cycle. Cervical mucus that is abundant, clear or white, stretchy, and slippery represents the fertile period. Ovulation most likely occurs within 1 day of the appearance of cervical mucus that is abundant, stretchy and slippery. After ovulation, cervical secretions appear thick, cloudy and sticky. Couples are counseled to avoid intercourse when cervical secretions are first noted until 4 days after the peak of clear and slippery cervical mucus.

Couples can also use a combination of natural family planning methods (i.e., basal body temperature measurements and cervical secretion monitoring) to further avoid an undesired pregnancy. In addition, recent advances in home hormonal detection kits allow for detection of ovulation and better timing of abstinence for avoidance of pregnancy.

Lactation Amenorrhea Method (LAM) - Breastfeeding: Breastfeeding provides more than 98% protection from pregnancy in the first 6 months after birth.[clxxix] This method of contraception requires complete or nearly complete infant dependence on breast milk so that frequent suckling (at least 6-10 times per day) prevents ovulation. High frequency of feeds, long duration of each feed, night feeds, and short intervals between breastfeeds delay the return of ovulation.[clxxx]^,[clxxxi] Infant suckling disrupts the pulsatile release of gonadotropin releasing hormone (GnRH) by the hypothalamus resulting in abnormal pulsatility of LH and subsequent anovulation.[clxxxii] Ovulation however can occur even in the absence of menstruation. The probability of ovulation occurring before menstruation increases with time after delivery; the probability that women will ovulate before the resumption of menses increases from 33-45% during the first 3 months after delivery to 87-100% more than 12 months from delivery.[clxxxiii] To maintain effective contraception, another method should be used as soon as menstruation resumes, the frequency or duration of breastfeeding is reduced, food (or bottle) supplements are introduced, or the duration since delivery is 6 months. This method provides no protection against sexually transmitted diseases, but may help reduce post partum bleeding.

FUTURE DEVELOPMENTS

The near future will bring improved modifications of current methods including barrier methods, hormonal methods and intrauterine devices. Combined oral contraceptive pills using estetrol for the estrogen component are being developed in Europe.  Phase II studies using a combination of estetrol and drospirinone in a 24/4 pill show a favorable bleeding profile and have high user satisfaction.[clxxxiv]^,[clxxxv]  The next generation of contraceptives will likely be focused on new mechanisms of action. Targets include all aspects of the female and male reproductive system from gamete development to gamete delivery, fertilization and implantation. The goal of these new methods will be the interruption of key components of the system allowing safe, effective contraception with a minimum of side effects. The challenge facing the development of these new methods is allowing modification or interruption of the reproductive system with a minimum of effect on other body systems. Specifically, an optimal method would provide reversible interruption of reproductive capacity of the male and/or female without affecting the endocrine system. This is particularly important in the male as secondary sexually characteristics, and even behavior, are closely linked to any change in the hormonal milieu. Other challenges include the development of simple and cost effective methods. The next breakthrough in contraceptives will be the identification of a key molecular aspect of reproduction. If a specific receptor can be identified, an antagonist can be developed. If a critical enzyme is identified, an inhibitor can be synthesized.

Areas of interest will be in disruption of ovulation with anti-progestins or blocking the action of matrix metaloproteinases needed for the physical breakdown of the follicle. Folliculogenesis may be blocked by specific FSH antagonists, or interruption of folliculogenesis at the local level by growth differentiation factor-9. Other possible targets include blocking resumption of meiosis in the oocyte, or blocking egg activation (which is necessary before an egg is capable of fertilization and to prevent polyspermic fertilization). Finally the specific steps necessary for implantation may be identified and selectively disrupted – and research on molecules involved in implantation and angiogenesis is currently being done in mouse models.

Male hormonal contraception: male hormonal contraception may come to light in the distant future. In particular, the identification of genes in various aspects of testicular steroidogenesis, spermatogenesis and sperm maturation may provide novel targets for fertility regulation. Progestins act on the hypothalamic pituitary axis and suppress spermatogenesis and production of the hormone testosterone. It has been hypothesized that progestin implants with long acting add-back testosterone injections, oral progestagens with testosterone injections, or oral desogestrol with testosterone implants may produce azoospermia without affecting the other physiological and biological effects of testosterone.[clxxxvi] Future work will determine if these targets can be useful in developing novel strategies for male contraception.

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ABSTRACT

Amenorrhea not due to pregnancy, lactation, or menopause is a relatively common abnormality of the reproductive years and indicative of a defect somewhere in the hypothalamic-pituitary-ovarian-uterine axis. This chapter considers the various causes of amenorrhea and their treatment. It also considers the diagnosis and treatment of abnormal uterine bleeding at all stages of life.

 AMENORRHEA

Amenorrhea may be defined as 1) the absence of menstruation for 3 or more months in women with past menses (i.e., secondary amenorrhea) or 2) the absence of menarche by the age of 15 years in girls who have never menstruated (i.e., primary amenorrhea). Recent data suggest that pubertal development, and hence menarche, continues to begin earlier in American girls (3). Consequently, some clinicians would consider initiating evaluation of a girl with primary amenorrhea by age 14, particularly if 5 or more years had passed since the first evidence of pubertal development. Women who menstruate fewer than 9 times in any 12-month period (defined as oligomenorrhea) should be evaluated identically to women with secondary amenorrhea. These women are typically oligo- or anovulatory. The separation of amenorrhea into the categories primary and secondary is artificial and should not be considered in the evaluation of the amenorrheic woman. Likewise, the term “postpill” amenorrhea, sometimes used to refer to women who do not menstruate within 3 months of discontinuing oral contraceptives, conveys nothing about the cause of the amenorrhea and should not alter the evaluation.

Amenorrhea is not a diagnosis in itself but rather a sign of a disorder. In general, menses general occur at intervals of 28 ± 3 days in two-thirds of women, with a normal range of 18-40 days.

It is useful to think about 3 broad categories of amenorrhea:

1. Anatomic causes, including pregnancy, that almost always can be identified by physical examination alone.
2. Ovarian failure.
3. Chronic anovulation resulting from any of a number of endocrine disturbances.

These three categories are delineated in Table 1.

Table 1. Categories of Amenorrhea

It is generally impossible to distinguish between ovarian failure and chronic anovulation without laboratory testing.

The most important aspect of the clinical evaluation is the history and physical examination. During the physical examination, special attention should be directed toward evaluating:

1. Body dimensions and habitus.
2. Distribution and extent of terminal androgen-stimulated body hair.
3. Extent of breast development by Tanner staging and the presence or absence of any breast secretions.
4. External and internal genitalia, with emphasis on evidence of exposure to androgens and estrogens.

History, physical examination and determination of basal concentrations of follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and prolactin will identify the most common causes of amenorrhea. Administration of exogenous progestin has been recommended in the past, both as a clinical aid to diagnosis and to evaluate the biological levels of estrogen. Either progesterone in oil (100 - 200 mg im) or medroxyprogesterone acetate (5 - 10 mg orally daily for 5 - 10 days) can be given. Any genital bleeding within 10 days of the completion of these regimens is regarded as a positive test. If the test is negative (suggesting low levels of endogenous estrogen), then an estrogen and a progestin together (e.g., oral conjugated estrogen, 2.5 mg daily for 25 days, together with oral medroxyprogesterone acetate, 5-10 mg for the last 10 days of estrogen therapy) should induce bleeding if the endometrium is normal. This test will determine with certainty if the outflow tract is intact. However, the results are not always definitive. In fact, in one survey almost half the women with so-called premature ovarian failure bled in response to progestin (4). Thus, progestin challenge should never be used as the sole diagnostic test by which amenorrheic women should be evaluated. In women with evidence of hirsutism, at least total testosterone and dehydroepiandrosterone sulfate levels should be determined to rule out any serious cause (Figure 1).

Figure 1. Flow diagram for the laboratory evaluation of amenorrhea. Such a scheme must be considered as an adjunct to the clinical evaluation of the patient. CAH -= congenital adrenal hyperplasia; DHEAS = dehydroepiandrosterone sulfate; FSH = follicle-stimulating hormone; HCA = hypothalamic chronic anovulation; PCO = polycystic ovary syndrome; PRL = prolactin; T = testosterone; TSH = thyroid-stimulating hormone. Originally from Rebar RW, The ovaries. In: Smith LH Jr, ed. Cecil textbook of medicine, ed. 18. Philadelphia. WB Saunders, 1992:1367)

The World Health Organization has divided women with amenorrhea into three groups originally based upon a suggestion of Insler (5):

Group I (hypothalamic-pituitary forms of amenorrhea) consists of women with no evidence of endogenous estrogen production (based on urinary measurements), normal prolactin levels, and normal or low FSH levels.

Group II (polycystic ovary syndrome) consists of women with evidence of endogenous estrogen production (on urinary measurement) and normal levels of prolactin and FSH.

Group III (gonadal failure) consists of women with elevated FSH levels.

HYPERGONADOTROPIC AMENORRHEA (Primary Hypogonadism; Gonadal Failure; Primary Ovarian Insufficiency)

It is frequently impossible to diagnose hypergonadotropic amenorrhea, also called presumptive ovarian failure and, more recently, primary ovarian insufficiency, without the measurement of basal serum FSH levels. This is especially true because ovarian failure may occur at any time from embryonic development onward. The ovaries normally fail at the time of menopause, when virtually no viable oocytes remain. Premature ovarian failure (POF) or premature menopause generally is defined as consisting of the triad of amenorrhea, hypergonadotropinism, and hypoestrogenism in women under the age of 40 years (5a). From what is known about follicular development and atresia, it appears that premature ovarian failure can arise from abnormalities in the recruitment and selection of oocytes. The follicles may undergo atresia at an accelerated rate or a smaller than normal pool may undergo atresia at the normal rate to yield early oocyte depletion. FSH must be involved because it is the principal hormonal regulator of folliculogenesis. Circulating gonadotropin levels rise whenever ovarian failure occurs because of decreased negative estrogen feedback to the hypothalamic-pituitary unit. Gonadotropin levels sometimes increase even in the presence of viable oocytes, but the explanation for such increases is unclear. Thus, use of the term POF is inappropriate. In 5-10% of patients, spontaneous pregnancy has occurred many years after the initial diagnosis (4,6). Thus, it is more appropriate to refer to this disorder as hypergonadotropic amenorrhea, primary hypogonadism, hypergonadotropic hypogonadism, or primary ovarian insufficiency, but the term premature ovarian failure is well established in the literature.

TYPES OF PREMATURE OVARIAN FAILURE

It is now clear that POF is a heterogeneous disorder. Premature loss of oocytes could result from a reduced germ cell endowment in utero, accelerated atresia, or failure of all germ cells to migrate to the genital ridges in early development. There may be marked differences in oocyte endowment and rates of follicular atresia among women (7,8). Only now are investigators learning about the molecular factors that regulate oocyte number and development. Because information in this field is changing rapidly, it is probably impossible to provide a definitive classification of the disorder, but it is possible to enumerate many of the apparent causes (Table 1).

It is becoming clear that genetic abnormalities are perhaps the most important cause of premature ovarian failure (Table 1). Although it is estimated that only 10-15% of women with POF have a recognized genetic cause for their disorder(8a), this will no doubt increase with time. New genetic causes are identified almost monthly, and it is impossible to list all genetic causes in any such table.

Individuals with the various forms of gonadal dysgenesis typically present with hypergonadotropic amenorrhea regardless of the extent of pubertal development and the presence or absence of associated anomalies or stigmata. It is well known that cytogenetic abnormalities of the X chromosome can impair ovarian development and function. Studies of 46,XX individuals and those with various X chromosomal depletions have confirmed that two intact X chromosomes are necessary for maintenance of oocytes (9) The gonads of 45,X fetuses contain the normal complement of oocytes at 20 to 24 weeks of fetal age, but these rapidly undergo atresia so that none are typically present by the time of birth (10). Primary or secondary amenorrhea typically occurs in women with deletions in either the short or the long arm of one X chromosome.9 Mutations at independent loci on the X chromosome at Xq26-28 (POF1), Xq13.3-22 (POF2), and Xp11.2 have been identified that also are linked to POF. One gene in the POF2 region has homology to the DIA allele in Drosophila, mutants of which result in male and female infertility. A breakpoint in the last intron of the DIAPH2 gene (the homologue of the Drosophila diaphanous gene) has been associated with familial POF in women (11).

Although individuals with Turner syndrome usually are apparent on physical examination, patients with pure and mixed gonadal dysgenesis typically have no obvious identifying features. Women with pure gonadal dysgenesis, who generally present with sexual infantilism and primary amenorrhea, are of normal height and have none of the somatic abnormalities associated with Turner syndrome (12,9) Affected individuals have either a 46,XX or 46,XY karyotype. In mixed gonadal dysgenesis, a germ cell tumor or testis accounts for one gonad, with a streak, rudimentary gonad, or no gonad accounting for the other (9,13). The 45,X/46,XY karyotype is most frequent, but affected individuals may have any of several other reported karyotypes. The vast majority of affected individuals are raised as females, with mild to moderate virilization occurring at puberty. Abnormal genitalia may be noted at birth. Because of the malignant potential of intraabdominal gonads in individuals with a Y chromosomal component (14-16) the gonads should be removed.

Additional X chromosomes also are present in some women with POF (17). These women typically develop normally and may bear children early in adulthood and commonly develop POF after age 30.

Mutations in the Familial Mental Retardation-1 (FMR1) gene, located at Xq27 and which can lead to fragile X syndrome, can also lead to POF (18). Although the gene changes involved in the abnormalities associated with this gene are quite complex, the basic principles can be summarized. Normal individuals have 5-50 repeats of the cytosine-guanine-guanine (CGG) trinucleotide in the gene. Expansion of this trinucleotide to greater than 200 repeats inactivates the gene and leads to the fragile X syndrome. In addition to mild to severe mental retardation, affected males typically present with long narrow faces, increased head circumference, dysmorphic ears, prominent jaws and foreheads, and large testes. Females are less severely affected, presumably because one of the two X chromosomes is inactivated independently in every cell in the body, and only one of the chromosomes carries the mutations. Some individuals have 50-200 repeats of the CGG sequences, and these individuals are considered premutation carriers. The women who are carriers of this unstable premutation can have further expansion of the trinucleotide in their germ cells and transmit the full syndrome to their offspring; in some families, the carrier state can be transmitted for several generations before expansion occurs. Men who are premutation carriers virtually never have further expansion in germ cells but can transmit the premutation to their female offspring. It is now recognized that POF develops in about 20% of female premutation carriers (19,20). In addition, about 2% of women with sporadic POF and 14% of women with familial POF have this unstable mutation (21,22). These observations make a convincing argument for testing women with POF for mutations of FMR1. Men with the premutation are known to sometimes develop tremors and ataxia as well as more subtle neurological and emotional difficulties (the so-called Fragile X-Associated Tremor-Ataxia Syndrome, FXTAS).

Several other specific gene mutations (not necessarily located on the X chromosome) also can result in POF. These include mutations involving the inhibin alpha gene (INHA), a gene at chromosome 3q23 involving a forkhead transcription factor associated with blepharophimosis-ptosis-epicanthus inversus (BPES) type I syndrome (23,24), a family of genes associated with central nervous system leukodystrophy and ovarian failure (EIF2B) (25), the gene involving bone morphogenetic factor 15 (BMP15) which is known to play a role in folliculogenesis (26), the phosphomannomutase (PMM) gene, and the gene associated with the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (AIRE) (27).  More recently, a mutation altering a meiosis-specific subunit of the cohesion ring, which ensures correct sister chromatid cohesion, has been identified as a cause of POF in one large family (8a). No doubt other mutations will be identified as causes of POF in some affected women. Several rare inherited enzymatic defects also may be associated with premature ovarian failure. These include partial deficiencies in four enzymes in the steroidogenic pathway, 17a-hydroxylase, 17,20-desmolase, 20,22-desmolase, and aromatase, as well as galactosemia.

Girls with 17α-hydroxylase deficiency (involving the CYP17A gene) who survive to their teens present with sexual infantilism; primary amenorrhea; increased circulating levels of LH, FSH, deoxycorticosterone, and progesterone; and hypertension with hypokalemic alkalosis (28-30). Ovarian biopsy has revealed no evidence of orderly follicular maturation but instead has demonstrated numerous, large cysts and primordial follicles. Presumably, the enzyme deficiency does not permit normal follicular development. The startling observation that normal follicular growth and development with successful fertilization in vitro can be achieved with exogenous gonadotropins in individuals with 17α-hydroxylase deficiency raises significant questions about why there is no follicular development in affected girls (31).

Several case reports have described individuals with mutations in the CYP19 (aromatase P450) gene (32-34). Aromatase deficiency appears to be inherited in an autosomal recessive manner and is manifested in 46,XX individuals by female pseudohermaphroditism with clitoromegaly and posterior labioscrotal fusion at birth; enlarged cystic ovaries associated with elevated FSH levels during childhood; lack of pubertal development in association with further enlargement of the clitoris, normal development of pubic and axillary hair, and continued existence of enlarged multicystic ovaries during the teenage years; and severe estrogen deficiency, virilization, and enlarged multicystic ovaries in association with markedly elevated gonadotropin levels in adulthood. Administration of exogenous estrogen results in prompt lowering of circulating gonadotropin levels. Ovarian biopsy showed many closely packed primordial follicles in an affected 17-month old (33), but biopsy in a 13-year old showed excessive atresia (34).

Girls with galactosemia, a disorder in which galactose-1-phosphate uridyltransferase activity is decreased and that is characterized by mental retardation, cataracts, hepatosplenomegaly, and renal tubular dysfunction, also may develop premature ovarian failure with hypergonadotropinism even when a galactose-restricted diet is introduced early in infancy (35).

Data from a variety of sources indicate that abnormalities in the structure, secretion, metabolism, or action of gonadotropins can cause POF. It is now known that at least one form of premature ovarian failure is caused by mutations in the FSH receptor (FSHR). Affected individuals present with primary or secondary amenorrhea and elevated levels of FSH and may have ovarian follicles present on transvaginal ultrasound. One specific mutation on chromosome 2p (C566T: alanine to valine) in exon 7 of the FSHR was identified in several Finnish families (36,37), but the mutation must be very rare outside of Finland because it has not been detected in some other populations (38,39).

The “resistant ovary” syndrome may be the result of a gonadotropin postreceptor defect. As originally described, the Savage syndrome (named after the first patient described) consisted of young amenorrheic women with elevated peripheral gonadotropin concentrations, normal but immature follicles in the ovaries on biopsy, 46,XX karyotype with no evidence of mosaicism, complete sexual development, and hyposensitivity (i.e., resistance) to exogenous gonadotropin stimulation (40).

Altered forms of immunoreactive LH and FSH in urinary extracts from women with POF compared to those from oophorectomized and postmenopausal women have been reported, suggesting that metabolism and/or excretion of gonadotropin is altered in some cases (41). Some individuals with POF and evidence of intermittent follicular activity may have low molecular weight receptor-binding activity that antagonizes normal FSH binding (42).

Destruction of oocytes by any of several environmental insults, including ionizing radiation, various chemotherapeutic (especially alkylating) agents, and certain viral infections may accelerate follicular atresia (43). Although there is no evidence that cigarette smoking will result in POF, cigarette smokers experience menopause several months before nonsmokers.

More and more girls and young women who are treated for a variety of malignancies are surviving free of disease and subsequently presenting with transient or permanent ovarian failure. Strategies for reducing the likelihood of ovarian failure in women cured of their malignancies are being investigated by several groups. Cryopreservation of oocytes and ovarian tissue before therapy remains experimental at this point in time. Still, both males and females of reproductive age should be appraised of the potential for preserving gametes before treatment of any malignancy is initiated.

Approximately half of all individuals receiving 400-500 rads to the ovaries over four to six weeks will develop permanent ovarian failure (44). For any given dose of radiation, the older the woman, the greater the likelihood of her developing ovarian failure. It appears that about 800 rads is sufficient to result in permanent ovarian failure in all women. The transient nature of the hypergonadotropic amenorrhea in some women suggests that some follicles may be damaged but not destroyed by lower doses of radiation. To minimize the dose of radiation received by the ovaries, transposition to the pelvic sidewalls, often by laparoscopy, is recommended. One series noted preservation of ovarian function in about 90% of women undergoing transposition (45). Similarly, the older the woman at the of chemotherapy, the more likely is the ovarian failure (46). In general, it appears that the greater the number of oocytes present in the ovaries at the time of therapy with radiation or chemotherapy, the more likely it is that normal ovarian function will continue. Although the data are limited, the frequency of congenital anomalies does not appear to be increased in the children of women previously treated with chemotherapeutic agents (47).

Premature ovarian failure may be associated with a number of autoimmune disorders (4). The most common association may be with thyroiditis. Ovarian failure occurs commonly in women with polyglandular failure, including hypoparathyroidism, hypoadrenalism, and mucocutaneous candidiasis4. The heterogeneous nature of this disorder is suggested by the many different endocrinopathies that may be associated with premature ovarian failure. Autoimmune ovarian failure may occur independently of any other autoimmune disorder.

Autoimmune lymphocytic oophoritis was originally reported in association with adrenal insufficiency (Addison disease). Women with steroidogenic cell autoimmunity have lymphocytic oophoritis resulting in the ovarian failure. When POF occurs in association with adrenal insufficiency, the ovarian failure presents first about 90% of the time. The presence of antibodies to the 21-hydroxylase enzyme measured by a commercially available immunoprecipitation assay will identify women who may have occult adrenal insufficiency at the time of initial presentation as well as those who should be followed closely for the subsequent development of adrenal insufficiency (48,49). At the present time there is no good test to document the presence of antibodies to any specific ovarian antigens. The best evidence of antibodies to ovarian tissue comes from a study documenting FSH receptor antibodies in two women with myasthenia gravis and hypergonadotropic amenorrhea (50). Immunoglobulins that block the trophic actions of FSH but not LH also have been reported (51).

The thymus gland influences reproductive function (52). Congenitally athymic girls have ovaries devoid of oocytes (53). Irradiation and chemotherapeutic (especially alkylating) agents used to treat various malignancies are increasingly causes of premature ovarian failure (54-56). Inexplicably, both of these modalities have been associated with “reversible” ovarian failure. Ovulation and cyclic menses return in some individuals after prolonged intervals of hypergonadotropic amenorrhea associated with signs and symptoms of profound hypoestrogenism. Preliminary studies suggest that gonadotropin-releasing hormone analogues (but not oral contraceptive agents) may provide some protection from ovarian damage (57). Rarely, the mumps virus can affect the ovaries and cause ovarian failure (58).

DIAGNOSIS AND THERAPY OF PREMATURE OVARIAN FAILURE

Individuals with premature ovarian failure warrant thorough evaluation to eliminate potentially treatable causes and to identify associated disorders that may require therapy (5a). In general, young women who experience loss of regular menses for three or more consecutive months should be evaluated. Failure to initiate pubertal development by age 13 or begin menstruating by age 15 also warrants evaluation.

Several laboratory tests are indicated in women with POF, beginning with measurement of basal levels of prolactin, FSH, and TSH (after pregnancy is ruled out). FSH levels are typically greater than 30 mIU/ml in women with ovarian failure. If the FSH level is greater than 15 mIU/ml on initial screening, then the measurement should be repeated and serum estradiol should be measured as well to document hypogonadism. In addition, the simultaneous measurement of basal LH levels may be helpful in discerning if any oocytes remain. In general, if the estradiol concentration is greater than 50 pg/mL or if the LH level is significantly greater than the FSH level (in terms of mIU/mL) in any sample, the probability of viable oocytes is considerable. Irregular uterine bleeding, as an indication of estrogen stimulation, also provides good evidence of remaining functional ovarian follicles. It is not uncommon to identify women with intermittent menstruation, hypoestrogenism, and hypergonadotropinism. Visualization of follicles on transvaginal ultrasound also provides evidence of functional oocytes. Because a number of pregnancies have occurred after biopsy of ovaries devoid of oocytes, ovarian biopsy cannot be recommended for affected women.

Other indicated laboratory tests include measurement of thyroid-stimulating immunoglobulins (because of the frequency of thyroiditis), adrenal antibodies, fasting glucose, electrolytes, and bone density by dual-energy X-ray absorptiometry. Also indicated are an analysis of karyotype and fragile X premutation screening, particularly in the presence of a family history of mental retardation. If adrenal antibodies are detected, then a corticotropin stimulation test is indicated to identify women with adrenal insufficiency. One series evaluated 119 women with karyotypically normal spontaneous POF and found that 32 patients had hypothyroidism (27%) and 3 had adrenal insufficiency (2.5%) (59).

Even women with X-chromosomal abnormalities have delivered normal children and subsequently developed POF prior to age 40. Thus, neither parity nor age rules out the possibility of a chromosomal abnormality. Unexpected karyotypic findings that may be inherited have important implications for other family members. Also, by finding an explanation for the POF, patients with normal karyotypes may be reassured, and the patients with abnormal karyotypes can be counselled. Surgical removal of the gonads is indicated in any individual in whom a Y chromosome is identified.

Women who experience spontaneous POF are unprepared for the diagnosis. Taking the time to present the findings with sensitivity and to counsel appropriately is most important. Patients may benefit from referral to a psychologist and/or to an organization such as the Premature Ovarian Failure Support Group or Rachel’s Well ( www.rachelswell.org). Patients should be reassessed at intervals of one to two years for the presence of other disorders associated with POF.

Even in women with intermittent ovarian failure, estrogen replacement is appropriate to prevent the accelerated bone loss that occurs in affected women (4). Although exogenous estrogen may be given either as part of combined estrogen-progestin therapy or in the form of combined oral contraceptives, sequential therapy with exogenous estrogen and progestin is most physiologic. The estrogen should always be given with a progestin to prevent endometrial hyperplasia. Because women with ovarian failure may conceive while on estrogen therapy (including combined oral contraceptive agents), affected women should be counseled appropriately and cautioned to have a pregnancy test if withdrawal bleeding does not occur or if signs and symptoms suggestive of pregnancy develop. Despite these considerations, probably no other contraceptive agent is required for those women who do not wish pregnancy but who are sexually active, because pregnancy occurs in less than 10% (4). Although rare pregnancies in women with premature ovarian failure have occurred after ovulation induction with human menopausal and chorionic gonadotropins, the low likelihood should lead the physician to discourage patients from selecting such therapy. There is no evidence that ovulation and pregnancy occur more commonly in response to ovulation induction than spontaneously in these patients. Hormone replacement treatment to mimic the normal menstrual cycle, with oocyte donation for embryo transfer, provides the greatest possibility for pregnancy in women desiring pregnancy (60,61).

There are no data documenting safety of estrogen-progestin in young women with POF, but there are no reports of excessive risks either. Findings documenting risks in postmenopausal women do not apply to women with POF for whom estrogen therapy really represents replacement. Similarly, there are no data documenting the optimal form of estrogen and progestin to use in women with POF. It is important to remember that these young patients typically require twice as much estrogen as postmenopausal women to relieve any signs and symptoms of estrogen deficiency. Thus, one reasonable regimen would be 100 mm of estradiol per day by a skin patch, combined with 5-10 mg of medroyprogesterone acetate for 12 calendar days each month. The skin patch deliver a constant infusion of estradiol, avoids the first pass effect on the liver, and will maintain regular menses and be well tolerated by most patients.

CHRONIC ANOVULATION

Chronic anovulation may be viewed as a steady state in which the monthly rhythms associated with ovulation are not functional. Although amenorrhea is common, irregular menses and oligomenorrhea may occur as well. Chronic anovulation further implies that viable oocytes remain in the ovary and that ovulation can be induced with appropriate therapy.

Chronic anovulation is the most common pathological cause of oligomenorrhea or amenorrhea in women of reproductive age (Table 2). Appropriate management requires determination of the cause of the anovulation. However, anovulation can be interrupted transiently by nonspecific induction of ovulation in most affected women.

CHRONIC ANOVULATION OF CENTRAL ORIGIN

Functional Hypothalamic Chronic Anovulation (FHA)

Functional hypothalamic chronic anovulation may be defined as anovulation in which dysfunction of hypothalamic signals to the pituitary gland causes failure to ovulate. It remains unclear whether the primary abnormality is always present within the hypothalamus or sometimes occurs as a result of altered inputs to the hypothalamus. The term is used to refer to women who may be affected with suprahypothalamic or hypothalamic chronic anovulation. Although isolated gonadotropin deficiency frequently is caused by hypothalamic dysfunction, it is preferable to consider such individuals separately. However, partial forms of isolated gonadotropin deficiency may be virtually impossible to differentiate from hypothalamic chronic anovulation.

Numerous studies have documented an increased incidence of amenorrhea in women who exercise strenuously, diet excessively, or are exposed to severe emotional or physical stresses of any kind (1,62.63). Such amenorrheic persons fall into this group of women considered as having hypothalamic chronic anovulation, which is sometimes called functional amenorrhea. The diagnosis of FHA is suggested by the abrupt cessation of menses in women younger than 30 years of age who have no clinically evident anatomic abnormalities of the hypothalamic-pituitary-ovarian axis or any other endocrine abnormalities. The term hypothalamic amenorrhea was first proposed by Klinefelter and colleagues in 1943 for anovulation in which hypothalamic dysfunction is thought to interfere with the pituitary secretion of gonadotropin (64).

Although FHA is a common cause of oligomenorrhea and amenorrhea, relatively little is known about its pathophysiologic basis. The diversity of women presenting with FHA indicates that this is a heterogeneous group of disorders with similar manifestations. Compared with a matched control population, young women with secondary amenorrhea are more likely to be unmarried, to engage in intellectual occupations, to have had stressful life events, to use sedative and hypnotic drugs, to be underweight, and to have a history of previous menstrual irregularities (1). Although it has been suggested that the percentage of body fat controls the maintenance of normal menstrual cycles, it is more likely that diet, exercise, stress, body composition, and other unrecognized nutritional and environmental factors contribute in various proportions to amenorrhea.

Hormonally, basal circulating concentrations of pituitary (i.e., LH, FSH, TSH, prolactin, growth hormone), ovarian (i.e., estrogens, androgens), and adrenal hormones (i.e., dehydroepiandrosterone, DHEAS, cortisol) typically are within the normal range for women of reproductive age (65). However, mean serum gonadotropin, gonadal steroid, and DHEAS levels often are slightly decreased, and circulating and urinary cortisol levels are generally increased compared with those in normal women in the early follicular phase of the menstrual cycle (63,66). Despite low levels of circulating estrogen, affected women rarely have symptoms related to estrogen deficiency. Typically, the pulsatile secretion of gonadotropin is diminished, but these individuals respond normally to exogenous gonadotropin-releasing hormone.

In a comprehensive guideline issued in 2017, the Endocrine Society noted that one common feature of women with FHA is that all have a relative “energy deficit” (65a). The underlying cause of FHA may be a young woman’s overzealous approach to “healthy” behavior – and those habits can be difficult to change.

ANOREXIA NERVOSA, BULIMIA NERVOSA AND ATYPICAL EATING DISORDERS.

Eating disorders are common in adolescents and young women and may represent the most severe forms of functional hypothalamic chronic anovulation (67,68). Eating disorders are generally divided into three diagnostic categories: 1) anorexia nervosa, 2) bulimia nervosa, 3) binge eating disorders, and 4) other atypical eating disorders.

All eating disorders are characterized by altered eating habits or weight-control behavior. Poor nutrition can impact physical health. In addition, disturbed behavior in bulimia and anorexia is not due to any general medical disorder or any other psychiatric condition.

The constellation of amenorrhea often preceding weight loss, a distorted and bizarre attitude toward eating, food, or weight, extreme inanition, and a disordered body image makes the diagnosis of anorexia nervosa obvious in almost all cases (69-71). Demographically, 90% to 95% of anorectic women are white and come from middle- and upper-income families. In DSM-5 amenorrhea is no longer required to make the diagnosis of anorexia nervosa.

What distinguishes bulimia nervosa from anorexia nervosa is repeated binges at least once each week during which there is loss of self-control with unusually large amounts of food eaten. In most cases, binge eating is followed by compensatory self-induced vomiting or laxative abuse. Individuals with bulimia seldom have body weights that are significantly altered from ideal. Thus, body weight is the most obvious difference that distinguishes bulimia from anorexia nervosa. Many women with bulimia are ashamed or distress by their actions and are often more willing to accept treatment than individuals with anorexia. Symptoms of depression and anxiety disorders are common.

Anorexia nervosa most commonly arises in the mid-adolescent years. Self-induced dietary restrictions quickly get out of control. In some cases, the disorder is of short-standing and self-limited, whereas in others the disorder becomes well entrenched and long-standing.

Bulimia nervosa usually begins later in adolescence. Often bulimia begins similarly to anorexia. However, episodes of binge eating eventually interrupt the dietary restriction, and body weight increases to near normal levels. Women with bulimia commonly seek treatment more than five years after disease onset.

Peripheral gonadotropin and gonadal steroid levels generally are lower than in the early follicular phase of the menstrual cycle (72). As patients with anorexia undergo therapy, gain weight, and improve psychologically, sequential studies of the ultradian gonadotropin rhythms show progressive gonadotropin changes paralleling those normally seen during puberty. Initially, there is a nocturnal rise in gonadotropins, followed by an increase in mean basal gonadotropin levels throughout the 24-hour period (73-75). The responses of severely ill anorectics to GnRH are also similar to those observed in prepubertal children and become adult-like with recovery or with treatment with pulsatile GnRH (76). Because the metabolism of estradiol and testosterone is also abnormal, normalizing with weight gain, some of the gonadotropin changes may be secondary to peripheral alterations in steroids (77).

Several abnormalities indicate hypothalamic dysfunction, including mild diabetes insipidus and abnormal thermoregulatory responses to heat and cold (71). Affected individuals have altered body images as well (78).

Still other central and peripheral abnormalities exist. There is evidence of chemical hypothyroidism, with affected patients having decreased body temperature, bradycardia, low serum triiodothyronine (T3) levels, and increased reverse T3 concentrations (79,80). Circulating cortisol levels also are elevated, but the circadian cortisol rhythm is normal (81). The increased cortisol seems to be caused by the reduced metabolic clearance of cortisol as a result of the reduced affinity constant for corticosteroid binding globulin (CBG) present in such patients (82). Moreover, like women with endogenous depression, anorectics suppress significantly less after dexamethasone administration than do normal subjects (83). Anorectics also have reduced ACTH responses to exogenous corticotropin-releasing hormone (CRH), suggesting normal negative pituitary feedback by the increased circulating cortisol (84).

Although rigorous studies have not been performed in women with bulimia, presumably such individuals have endocrine disturbances similar to those of women with anorexia nervosa.

SIMPLE WEIGHT LOSS AND AMENORRHEA

Societal attitudes encourage dieting and pursuit of thinness, particularly in young women. Several reproductive problems, including hypothalamic chronic anovulation, have been associated with simple weight loss. Affected women are distinctly different from anorectics in that they do not fulfill the psychiatric criteria for anorexia. The cessation of menses does not occur before significant weight loss in such women, although this sequence is common in anorectics. The few studies that have been conducted in amenorrheic women with simple weight loss suggest that the abnormalities are similar to those observed in anorectics, but are more minor and more easily reversed with weight gain (85). Although it has been suggested that the amenorrhea in these women is secondary to metabolic defects resulting from undernutrition, the possibility of separate central defects has not been excluded (86). The importance of normal body weight to normal reproductive function is evident in studies of a tribe of desert-dwelling hunter-gatherers in Botswana (87). The weights of the women vary markedly with the season, being greatest in the summer, and the peak incidence of parturition follows exactly 9 months after the attainment of maximal weight.

EXERCISE-ASSOCIATED AMENORRHEA

Regular endurance training in women is associated with at least three distinct disorders of reproductive function: delayed menarche, luteal dysfunction, and amenorrhea (88,89). In 1992 the American College of Sports Medicine coined the term the “female athletic triad” to describe the three disorders recognized as sometimes occurring together in female athletes: disordered eating, amenorrhea, and osteoporosis (90). Activities associated with an increased frequency of reproductive dysfunction include those favoring a slimmer, lower-body-weight physique such as middle and long distance running, ballet dancing, and gymnastics. Swimmers and bicyclists appear to have lower rates of amenorrhea despite comparable training intensities. The cause of these disorders remains to be established and may involve many factors. Dietary changes, the hormonal effects of acute and chronic exercise, alterations in hormone metabolism because of the increased lean-to-fat ratio, and the psychological and physical “stress” of exercise itself may all contribute and may vary in importance in different individuals. Women engaged in endurance training frequently also have disordered attitudes toward eating, and a number of studies have documented low leptin levels and the absence of normal circadian leptin variation (91-94).

In untrained women who underwent a program of strenuous aerobic exercise (running 4-10 miles/day) combined with caloric restriction, menstrual dysfunction was induced (95). The spectrum of abnormalities in these women included luteal phase dysfunction, loss of the midcycle LH surge, prolonged menstrual cycles, altered patterns of gonadotropin secretion, and amenorrhea. Subsequent studies have indicated that luteal phase defects can occur soon after beginning endurance training in the majority of untrained women (96). However, in contrast to these findings, others observed that a progressive exercise program of moderate intensity did not affect the reproductive system of gynecologically mature (mean age, 31.4 years), untrained, eumenorrheic women (97). It was suggested that relatively young gynecologic age or an earlier age of training onset in particular adversely affects menstrual cyclicity.

Many amenorrheic athletes welcome the onset of amenorrhea. However, significant osteopenia, usually affecting trabecular bone, has been reported in these women (98-100). It appears that the loss in bone density secondary to hypoestrogenism nullifies the beneficial effects of weight-bearing exercise in strengthening and remodeling bone (99,101). Such women are at risk for stress fractures, particularly in the weight-bearing lower extremities, and bone density may remain below those of eumenorrheic athletes even after resumption of menses (102).

Stress is generally acknowledged to play a role in the cause of this form of amenorrhea, even though the term stress itself remains difficult to define. Amenorrheic runners subjectively associate greater stress with running than do runners with regular menses (103) (Fig.2).

Figure 2. Subjective stress associated with running. Subjects were asked to evaluate the stress associated with running on a scale from 0 to 10, with 10 being maximal. The means + standard errors are shown. The number of subjects in each group is shown in the bar. MDR - middle distance runners (15-30 miles per wee) with regular menses; LDR - long distance runners (>30 miles per week) with regular menses; AR = amenorrheic runners. Stress was significantly greater (p<0.001) in both long distance and amenorrheic runners compared to middle distance runners. (Data from Schwartz et al., reference 103).

However, no increase in amenorrhea was observed in a competitive group of young classical musicians, who presumably were experiencing similar stress, compared with a group of young ballet dancers, in whom the incidence of amenorrhea was quite high (104). Basal levels of circulating cortisol and urinary free cortisol excretion, indicative of increased stress, are increased in both eumenorrheic and amenorrheic runners (105) (Fig.3). It is likely even the eumenorrheic runners in this particular study had subtle reproductive abnormalities.

Figure 3. 24 Hour-urinary free cortisol excretion in normal control subjects (NC) eumenorrheic runners (R) and amenorrheic runners (AR). The number of subjects is shown in each bar. (Data from Villaneuva et al, reference 105).

Because levels of CBG, the disappearance rate of cortisol from the circulation, and the response of cortisol to adrenocorticotropin (ACTH) were not altered in the women runners compared with sedentary control subjects, secretion of ACTH and possibly of CRH must be increased in women who run. Abnormalities of the hypothalamic-pituitary-adrenal axis also are indicated by the observations that serum ACTH and cortisol responses to exogenous CRH are blunted as are the responses to meals (105,106).

The observation that amenorrheic runners also have subtle abnormalities in hypothalamic-pituitary-thyroidal function provides support for the concept that exercise-associated amenorrhea is similar to other forms of hypothalamic amenorrhea (107).

PSYCHOGENIC HYPOTHALAMIC AMENORRHEA

Amenorrhea may occur in women with a definite history of psychological and socioenvironmental trauma (86,108). The incidence of amenorrhea is quite high among depressed women, and the effects of lifestyle and nutritional status are difficult to differentiate from variables such as stress. Studies of individuals in whom a definite psychological traumatic event preceded the onset of amenorrhea have revealed low to normal basal levels of serum gonadotropins with normal responses to GnRH, prolonged suppression of gonadotropins in response to estradiol, and failure of a positive feedback response to estradiol (86,108-110). Increased basal levels of cortisol and decreased levels of DHEAS also have been noticed in women with psychogenic amenorrhea compared with eumenorrheic women (62). The mean levels of circulating cortisol are increased in such women largely because of an increase in the amplitude of the pulses of cortisol (111). Moreover, studies of depressed women have revealed abnormal circadian rhythms of cortisol and early “escape” from dexamethasone suppression (112,113).

The mechanism by which emotional states or stressful experiences causes psychogenic amenorrhea is not yet established. Evidence suggests, however, that a cascade of neuroendocrine events that may begin with limbic system responses to psychic stimuli impairs hypothalamic-pituitary activity (114). It has been suggested that increased hypothalamic b-endorphin is important in inhibiting gonadotropin secretion (114).

Psychological studies have found several social and psychological correlates of psychogenic amenorrhea: a history of previous pregnancy losses, including spontaneous abortion (115,116), stressful life events within the 6-month period preceding the amenorrhea (117,118), and poor social support or separation from significant family members during childhood and adolescence (113,118). Many women with psychogenic amenorrhea report stressful events associated with psychosexual problems and socioenvironmental stresses during the teenage years.108 Women with psychogenic amenorrhea also tend to have negative attitudes toward sexually related body parts, more partner-related sexual problems, and greater fear of or aversion to menstruation than do eumenorrheic women (117). Distortions of body image and confusion about basic bodily functions, especially sexuality and reproduction, are common (116).

DIMINISHED GONADOTROPIN-RELEASING HORMONE AND LUTEINIZING HORMONE SECRETION IN ALL FORMS

The various forms of hypothalamic chronic anovulation associated with altered lifestyles just discussed have several features in common. Altered GnRH and LH secretion seems to be the common result from altered hypothalamic input. It remains unclear if these disorders form a single disorder or several closely related disorders. Moreover, similar forms of amenorrhea are sometimes seen in women with severe systemic illnesses or with hypothalamic damage from tumors, infection, irradiation, trauma, or other causes.

TREATMENT

The treatment of patients with functional hypothalamic chronic anovulation is controversial and difficult. The Endocrine Society recommends a multidisciplinary approach including medical, dietary, and mental health support (65a). Psychological therapy and support or a change in lifestyle may cause cyclic ovulation and menses to resume. However, ovulation does not always resume, even after the lifestyle is altered. The treatment of affected women in whom menses do not resume and who do not desire pregnancy is difficult. Most physicians now advocate the use of exogenous sex steroids to prevent osteoporosis. Therapy consisting of oral conjugated estrogens (0.625-1.25 mg), ethinyl estradiol (20 mg), micronized estradiol-17β (1-2 mg), or estrone sulfate (0.625-2.5 mg) or of transdermal estradiol-17b (0.05-0.1 mg) continuously with oral medroxyprogesterone acetate (5 to 10 mg) or oral micronized progesterone (200 mg) added for 12-14 days each month is appropriate. Sexually active women can be treated with oral contraceptive agents. These women appear to be particularly sensitive to the undesired side effects of sex steroid therapy, and close contact with the physician may be required until the appropriate dosage is established. If sex steroid therapy is provided, patients must be informed that the amenorrhea may still be present after therapy is discontinued.

Some physicians believe that only periodic observation of affected women is indicated, with barrier methods of contraception recommended for fertility control. Contraception is necessary for sexually active women with hypothalamic chronic anovulation because spontaneous ovulation may resume at any time (before menstrual bleeding) in these mildly affected individuals. Women who refuse sex steroid therapy should be encouraged to have spinal bone density evaluated at intervals to document that bone loss is not accelerated. Adequate calcium ingestion should be encouraged in all affected women.

For women desiring pregnancy who do not ovulate spontaneously, clomiphene citrate (50-100 mg/d for 5 days beginning on the third to fifth day of withdrawal bleeding) can be used. However, clomiphene is frequently ineffective in these hypoestrogenic women. Treatment with human menopausal and chorionic gonadotropins (hMG-hCG) or with pulsatile GnRH may be effective in women who do not ovulate in response to clomiphene. Because the underlying defect in hypothalamic amenorrhea is decreased endogenous GnRH secretion, administration of pulsatile GnRH to induce ovulation can be viewed as physiologic; it offers the additional advantages of decreased need for ultrasonographic and serum estradiol monitoring, a decreased risk of multiple pregnancies, and a virtual absence of ovarian hyperstimulation. A starting intravenous dose of GnRH of 5 mg every 90 minutes is effective (119). After ovulation is detected by urinary LH testing or ultrasound, the corpus luteum can be supported by continuation of pulsatile GnRH or by hCG (1500 IU every 3 days for four doses). Ovulation rates of 90% and conception rates of 30% per ovulatory cycle can be expected (120). Unfortunately GnRH is no longer available in the United States because it was used so infrequently.

Cognitive behavioral therapy (CBT) has also been shown to be effective (120a).In a small trial involving 16 patients randomized to CBT or observation for 20 weeks, six women in the CBT group and only one in the observation group resumed ovulation. The CBT focused on changing attitudes towards eating habits, exercise, body image, problem-solving skills, and stress reduction.

One report noted improvements in reproductive function in a group of eight women with hypothalamic amenorrhea due to strenuous exercise or low weight who received recombinant human leptin for up to three months (121). As might be expected for a heterogeneous disorder, however, only three of the women ovulated in response to this therapy. Another study suggests that kisspeptin-54 may have utility in the future in treating hypogonadotropic hypogonadism by increasing LH pulsatility (121a).

In general, women with anorexia and bulimia nervosa should not have ovulation induced until their disease is in remission. It is clear that cognitve-behavioral therapy that focuses on modification of the specific behaviors and ways of thinking that support the patient’s eating disorder should be a part of any treatment plan (122). Addition of antidepressant drugs, especially selective serotonin reuptake inhibitors, may be of additional benefit in treating women with bulimia nervosa.

Isolated Hypogonadotropic Hypogonadism

Individuals with isolated (also termed idiopathic) hypogonadotropic hypogonadism fail to undergo pubertal maturation. Most have functional GnRH deficiency, but some appear to have abnormalities of gonadotropin deficiency localized to the pituitary gland (122a).

As originally described in 1944, Kallmann syndrome consisted of the triad of anosmia, hypogonadism, and color blindness in men (123). Women may be affected as well, and other midline defects may be associated (124-126). Because autopsy studies have shown partial or complete agenesis of the olfactory bulb, the term olfactogenital dysplasia also has been used to describe the syndrome (127). Because isolated gonadotropin deficiency may also occur in the absence of anosmia, the syndrome is considered to be quite heterogeneous.

Data indicate that in many patients the defect is a failure of GnRH neurons to form completely in the medial olfactory placode of the developing nose or the failure of GnRH neurons to migrate from the olfactory bulb to the medial basal hypothalamus during embryogenesis (128). In some patients, structural defects of the olfactory bulbs can be seen on magnetic resonance imaging (129). It appears likely that this disorder forms a structural continuum with other midline defects, with septo-optic dysplasia representing the most severe disorder.

Some individuals with isolated hypogonadotropic hypogonadism are normosmic. The molecular abnormalities identified thus far explain why some are anosmic and others are not (122a). The first mutations identified in Kallmann syndrome involve a cell surface adhesive gene, KAL1, which prevented normal development of the olfactory bulb and the neurologic tract responsible for transport of GnRH to the median eminence of the hypothalamus. Since that time, mutations in several other genes needed for development of the olfactory bulb and the neurologic tract needed for GnRH transport have been identified. Gene defects in individuals with normal smell include defects in the GnRH receptor gene, the gene responsible for GnRH production (GNRH1), the gene responsible for GnRH processing (PCSK1), and GnRH secretion (GPR54). Mutations of the KISS1-derived peptide receptor GPR54 have been particularly studied and indicate that the hypothalamic neuropeptide kisspeptin is a component of the GnRH pulse generator (122b).

Gene mutations localized to the pituitary and resulting in isolated hypogonadotropic hypogonadism include those associated with the GnRH receptor (GNRHR) and the production of the β subunit of gonadotropin. Mutations with the leptin, leptin receptor, and DAX1 genes appear to cause hypogonadotropic hypogonadism within both the hypothalamus and pituitary. These latter mutations appear to be associated with extreme obesity. There are also a number of mutations associated both with hypogonadotropic hypogonadism and other pituitary or endocrine deficiencies.

Clinically, affected individuals typically present with sexual infantilism and a eunuchoidal habitus, but moderate breast development may also occur. Primary amenorrhea is the rule. The ovaries usually are small and appear immature, with follicles rarely developed beyond the primordial stage (130). These immature follicles respond readily to exogenous gonadotropin with ovulation and pregnancy, and exogenous pulsatile GnRH can also be used to induce ovulation (131). Replacement therapy with estrogen and progestin should be given to affected women not desiring pregnancy.

Circulating LH and FSH levels generally are quite low. The response to exogenous GnRH is variable, sometimes being diminished and sometimes normal in magnitude, but rarely may be absent (132,133). Although the primary defect in most individuals appears to be hypothalamic, with reduced GnRH synthesis or secretion, a primary pituitary defect may occasionally be present. In addition, partial gonadotropin deficiency may be more frequent than has been appreciated.

Hyperprolactinemic Chronic Anovulation

About 15% of amenorrheic women have increased circulating concentrations of prolactin, but prolactin levels are increased in more than 75% of patients with galactorrhea and amenorrhea (134). Radiologic evidence of a pituitary tumor is present in about 50% of hyperprolactinemic women, and primary hypothyroidism always must be considered. Individuals with galactorrhea-amenorrhea (i.e., hyperprolactinemic chronic anovulation) frequently complain of symptoms of estrogen deficiency, including hot flushes and dyspareunia. However, estrogen secretion may be essentially normal (135). It is not clear if the hyperprolactinemia or the “hypoestrogenism” causes the accelerated bone loss seen in such individuals (136). Signs of androgen excess are observed in some women with hyperprolactinemia; androgen excess may rarely result in PCOS. In hyperprolactinemic women, serum gonadotropin and estradiol levels are low or normal.

Most hyperprolactinemic women have disordered reproductive function, and it appears that the effects on gonadotropin secretion are primarily hypothalamic. The mechanism by which hypothalamic GnRH secretion is disrupted is unknown but may involve an inhibitory effect of tuberoinfundibular dopaminergic neurons (135, 137). It has been proposed that increased hypothalamic dopamine is present in hyperprolactinemic women with pituitary tumors but is ineffective in reducing prolactin secretion by adenomatous lactotropes. The dopamine can, however, reduce pulsatile LH secretion and produce acyclic gonadotropin secretion through a direct effect on hypothalamic GnRH secretion.

It has been suggested that mild nocturnal hyperprolactinemia may be present in some women with regular menses and unexplained infertility (138). Galactorrhea in women with unexplained infertility may reflect increased bioavailable prolactin and may be treated appropriately with bromocriptine (139). Bromocriptine or cabergoline therapy may also be indicated in normoprolactinemic women with amenorrhea and increased prolactin responses to provocative stimuli (140).

Hypopituitarism

Hypopituitarism may be obvious on cursory inspection or it may be quite subtle. The clinical presentation depends on the age at onset, the cause, and the woman’s nutritional status. Loss of axillary and pubic hair and atrophy of the external genitalia should lead the physician to suspect hypopituitarism in a previously menstruating young woman who develops amenorrhea. In such cases, a history of past obstetric hemorrhage suggesting postpartum pituitary necrosis (i.e., Sheehan syndrome) should be sought (141). Failure to develop secondary sexual characteristics or to progress in development once puberty begins must always prompt a workup for hypopituitarism.

Individuals with pituitary insufficiency often complain of weakness, easy fatigability, lack of libido, and cold intolerance. Short stature may occur in individuals developing hypopituitarism during childhood. Symptoms of diabetes insipidus may be observed if the posterior pituitary gland is involved. On physical examination, the skin is generally thin, smooth, cool, and pale (i.e., “alabaster skin”) with fine wrinkling about the eyes; the pulse is slow and thready; and the blood pressure is low.

An evaluation of thyroid and adrenal function is of paramount importance in these individuals. Thyroid replacement therapy must be instituted and the patient must be euthyroid before adrenal testing is initiated. Serum gonadotropin and gonadal steroid levels typically are low in hypopituitarism. Responses to exogenously administered hypothalamic hormones often fail to localize the cause to the hypothalamus or the pituitary gland in affected patients.

Radiographic evaluation of the sella turcica is indicated in any individual with suspected hypopituitarism. The ovaries appear immature and unstimulated, but because oocytes still are present, ovulation can be induced with exogenous gonadotropins when pregnancy is desired. Exogenous pulsatile GnRH may also be used to induce ovulation if the disorder is hypothalamic. Moreover, oocytes may undergo some development, and even ovarian cysts may appear in the absence of significant gonadotropic stimulation. When pregnancy is not desired, maintenance therapy with cyclic estrogen and progestin is indicated to prevent signs and symptoms of estrogen deficiency.

CHRONIC ANOVULATION DUE TO INAPPROPRIATE FEEDBACK IN POLYCYSTIC OVARY SYNDROME (PCOS)

A Heterogeneous Disorder

In 1935, Stein and Leventhal focused attention on a common disorder in which amenorrhea, hirsutism, and obesity were frequently associated (142) (Fig.4). Since that time, this syndrome has been the topic of innumerable studies (142a,142b).

Figure 4. Facial hirsutism in a 17-year-old woman with polycystic ovary syndrome (PCOS).

With the development of radioimmunoassays for measuring reproductive hormones, it became clear that women with what is called PCOS shared several distinctive biochemical features. Compared with eumenorrheic women in the early follicular phase of the menstrual cycle, affected women typically have elevated serum LH levels and low to normal FSH levels (143). Virtually all serum androgens are moderately increased, and estrone levels are generally greater than estradiol levels (144). Ovarian inhibin physiology is normal (145). Also increased in women with PCOS are levels of anti-mullerian hormone (AMH); it appears that the more severe the disorder, the higher are the levels of AMH (145a). The increased AMH levels appear due to the increased number of small antral follicles as well as to intrinsic characteristics of the granulosa cells in PCOS.

Many women with the biochemical features of PCOS have small or even morphologically normal ovaries and are not overweight or hirsute. Not all women with PCOS present with the characteristic features.  Moreover, excess androgen from any source or increased conversion of androgens to estrogens can lead to the constellation of findings observed in PCOS (146). Included are such disorders as Cushing syndrome, congenital adrenal hyperplasia, virilizing tumors of ovarian or adrenal origin, hyperthyroidism and hypothyroidism, and obesity. In all of these disorders, the ovaries may be morphologically polycystic. Although no clinical and biochemical criteria describe the syndrome strictly, a conference convened by the National Institutes of Health (147) developed diagnostic criteria for PCOS:

1. Clinical evidence of hyperandrogenism (e.g., hirsutism, acne, androgenetic alopecia) and/or hyperandrogemia (e.g., elevated total or free testosterone).
2. Oligoovulation (i.e., cycle duration >35 days or <8 cycles per year).
3. Exclusion of related disorders (e.g., hyperprolactinemia, thyroid dysfunction, androgen-secreting tumors, 21-hydroxylase-deficient nonclassical congenital adrenal hyperplasia.)

A subsequent expert conference convened in Rotterdam, The Netherlands, in 2003 and sponsored in part by the American Society for Reproductive Medicine (ASRM) and the European Society for Human Reproduction and Embryology (ESHRE) recommended that PCOS be defined when at least two of the following three features are present: 1) oligo- and/or anovulation, 2) clinical and/or biochemical signs of hyperandrogenism, and 3) polycystic ovaries. This definition also states that other androgen excess or related disorders should be excluded prior to assigning the diagnosis of PCOS (148,149). By these criteria neither hyperandrogenism nor ovulatory dysfunction is required to make the definition of PCOS. This latter definition is now the most widely accepted; it is becoming increasingly common to spell out the phenotypes of patients reported in studies of PCOS as recommended by an NIH consensus conference in 2012 (149a).

A subsequent consensus conference on PCOS noted that there has been no overall agreement as to how to diagnose PCOS in adolescence (149b). Because both acne and irregular menstrual cycles are common in adolescents, while hirsutism develops slowly over time, it has been suggested that all three elements of the Rotterdam criteria should be present in teens in order to make the diagnosis of PCOS (149c). These investigators suggest that amenorrhea or oligomenorrhea should be present for at least two years after menarche (or until at least age 16), that the ovaries on ultrasound should be enlarged to greater than 10 cm³ (because numerous small cysts are commonly present during adolescence), and that hyperandrogenemia and not just signs of androgen excess should be present to diagnose PCOS in teenagers.

PCOS may be viewed as a state of chronic anovulation associated with LH-dependent ovarian overproduction of androgens. Clinically, the perimenarcheal onset of symptoms is a common feature. It has been estimated that PCOS affects approximately 5% of women of reproductive age, making it the most common form of chronic anovulation (150, 151). Some clinicians believe that PCOS may be the most common endocrinopathy. Although the cause of this disorder remains unknown, there is some evidence of autosomal dominant transmission in some affected individuals (152, 153). Disorders presenting similarly but with different underlying causes can be considered as having chronic anovulation with inappropriate feedback.

Polycystic Ovaries

Grossly, the ovaries of most women with PCOS are bilaterally enlarged and globular. (Fig.5)

Figure 5. Gross and cut appearance of typical polycystic ovaries. Multiple small follicular cysts are apparent in the cut section.

They are often described as having an “oyster shell” appearance because they have smooth, glistening capsules and are the appropriate color. The tunica albuginea is often thickened diffusely, and many cysts 3 to 7 mm in diameter are present on cut section. Because ovulation rarely occurs, corpora lutea may be present. Histologically, the follicular cysts are usually lined by granulosa cells and surrounded by a thickened and luteinized theca interna and are in various stages of maturation and atresia. When islands of luteinized thecal cells are found scattered throughout the ovarian stroma, not just around the follicles, the term hyperthecosis is sometimes used. The clinical syndrome accompanying this pathologic finding is typically characterized by massive obesity, severe hirsutism reflecting particularly excessive ovarian overproduction of androgens, acanthosis nigricans, glucose intolerance with insulin resistance, and hyperuricemia. (Fig.6)

Figure 6. Appearance of a woman with hyperthecosis, sometimes referred to as the HAIR-AN syndrome (hyperandrogenism, insulin resistance, acanthosis nigricans). The obesity, hirsutism, acne, and acanthosis nigricans are obvious.

Insulin action at the target cell appears defective in these patients, with some individuals having antibodies to insulin receptors and others apparently having a postreceptor defect (154, 155). PCOS and hyperthecosis appear to represent facets of the same disease process rather than two distinct entities. Some authorities, however, maintain that the two represent different disorders.

The follicles in the ovaries of women with PCOS do not mature completely. However, in vitro studies have failed to detect any primary defect in the steroidogenic capacity of polycystic ovaries (156). Although there seems to be a relative deficiency in aromatase activity in the granulosa cells of polycystic ovaries, this deficiency can be corrected by FSH in vitro and in vivo.

Other Clinical and Biochemical Features

Although all women with PCOS produce androgens at increased rates compared with eumenorrheic women, only some present with hirsutism, largely because of varying sensitivity at the level of the hair follicle. The hyperandrogenism is rarely sufficient to produce overt virilization. Signs of markedly elevated androgen levels, including clitoromegaly, temporal balding, and deepening of the voice, may suggest an androgen-producing tumor, especially if these features developed rapidly. Women with PCOS invariably are well estrogenized, with normal breast development and abundant cervical mucus on examination. Because obesity is found in only about 50% of women with PCOS, it is doubtful that obesity is central to its cause.

About 50% of women with PCOS have amenorrhea, about 30% have irregular bleeding, and about 12% have “cyclic menses” (146). No particular pattern of menstrual bleeding is characteristic of women with PCOS, although a history of oligomenorrhea is probably most common. Because only about 75% of women with PCOS are infertile, women with PCOS do ovulate occasionally.

Two other biochemical features warrant discussion. First, obese and normal-weight women with PCOS generally release increased quantities of insulin in response to a standard glucose challenge compared with weight-matched eumenorrheic individuals (157, 158). Many investigators now regard the insulin resistance as the central abnormality in the disorder, but this has not been established with certainty. Thus, regardless of body weight, 30 to 80 percent of women with PCOS experience insulin resistance and compensatory hyperinsulinemia (159). Based on studies in a very well characterized subset of obese women with the disorder, the insulin resistance present in PCOS appears to represent a postreceptor signalling aberration and differs from the insulin resistance observed in non-insulin dependent diabetes mellitus and simple obesity (118). The compensatory hyperinsulinemia that results causes exaggerated effects in other tissues as well. These effects include increased ovarian androgen secretion; excessive growth of the basal cells of the skin leading to acanthosis nigricans in some women; increased vascular and endothelial reactivity, which may lead to hypertension and vascular disease; and abnormal hepatic and peripheral lipid metabolism, which may cause dyslipidemia. Thus, it is now recognized that women with PCOS are at increased risk of cardiovascular disease and non-insulin-dependent diabetes mellitus in addition to endometrial carcinoma because of anovulation. Because treatment with a GnRH analogue reduces ovarian androgen secretion but does not correct the insulin resistance in women with PCOS, the defect in insulin action presumably is not due to abnormal sex steroid levels (160). The possibility that a defect in the secretion or action of insulin or some related growth factor is central to the cause of PCOS cannot be entirely excluded and is gaining increasing support as the cause of hyperandrogenemia in women with PCOS (161). The pivotal role of insulin resistance in PCOS is strongly suggested by the beneficial effects of insulin-sensitizing agents such as metformin, troglitazone, and D-chiro-inositol on metabolic and reproductive function, regardless of the patient’s weight (162-165).

In addition, perhaps 10% to 15% of women with PCOS have mild hyperprolactinemia in the absence of radiographic evidence of a pituitary tumor, possibly because of chronic acyclic estrogen secretion (166). Although hyperprolactinemia is associated with increased adrenal production of DHEAS, the increased adrenal androgen production seen in women with PCOS usually does not correlate with the hyperprolactinemia.

Pathophysiology of the Chronic Anovulation

A growing body of evidence indicates that disordered insulin action precedes the increase in androgens in PCOS. The administration of insulin to women with PCOS increases circulating androgen levels (161, 167). The administration of glucose to hyperandrogenic women increases circulating levels of insulin and androgen (168). Weight loss decreases levels of insulin and androgens (169). The suppression of circulating insulin levels experimentally by diazoxide reduces androgen levels (170). The suppression of androgen secretion to normal levels with GnRH agonists does not lead to normal insulin responses to glucose tolerance testing in obese women with PCOS (160, 171, 172).

The hyperinsulinemia may cause hyperandrogenemia by binding to IGF-I receptors in the ovary (173). Activation of ovarian IGF-I receptors by insulin can lead to increased androgen production by thecal cells (174). Moreover, independent of any effect on ovarian steroid production, increased insulin inhibits the hepatic synthesis of SHBG (175). Insulin directly inhibits insulin-like growth factor binding protein-1 in the liver, permitting greater local activity of IGF-I in the ovary (176).

Regardless of the cause of PCOS, it is possible to construct a rational pathophysiologic mechanism to explain the disorder (Fig.7).

Figure 7. Pathophysiologic mechanisms associated with PCOS that may help explain the chronic anovulation.

Regardless of the source or cause of androgen excess, a vicious cycle of events causing persistent anovulation commences. The androgen is converted to estrogen, primarily estrone, in the periphery. The estrogen feeds back on the central nervous system-hypothalamic-pituitary unit to induce inappropriate gonadotropin secretion with an increased LH to FSH ratio. The estrogen stimulates GnRH synthesis and secretion in the hypothalamus, causing preferential LH release by the pituitary gland. The estrogen may also increase GnRH by decreasing hypothalamic dopamine. Selective inhibition of FSH secretion by increased ovarian inhibin may also occur in PCOS. Possible inhibition of FSH secretion by increased androgen secretion has not been considered. The increased LH secretion stimulates thecal cells in the ovary to produce excess androgen. The androgen also inhibits production of SHBG, resulting in increased free androgen and predisposing affected women to hirsutism. The morphologic ovarian changes undoubtedly are secondary to hormonal changes. The absence of follicular maturation and the reduced estradiol production by the ovaries apparently result from a combination of inadequate FSH stimulation and inhibition by the increased concentrations of intraovarian androgen. The low levels of SHBG probably facilitate tissue uptake of free androgen, leading to increased peripheral formation of estrogen and perpetuating the acyclic chronic anovulation. The androgenic basis for the inappropriate estrogen feedback is partly shifted from the site of origin to the ovaries. The increased estrogens (and perhaps androgens) may also stimulate fat cell proliferation, leading to obesity. The current data suggest that there is no defect in the hypothalamic-pituitary axis in PCOS but rather that peripheral alterations result in abnormal gonadotropin secretion.

Therapy

Appropriate therapy demands that potential causes such as neoplasms be eliminated. Besides facilitating fertility, the aims of treatment in women with PCOS are three-fold: to control hirsutism, to prevent endometrial hyperplasia from unopposed acyclic estrogen secretion, and to prevent the long-term consequences of insulin resistance. The treatment must be individualized according to the needs and desires of each patient.

For the anovulatory woman with PCOS who is not hirsute and who does not desire pregnancy, therapy with an intermittent progestin (e.g., medroxyprogesterone acetate, 5 to 10 mg orally, or micronized progesterone, 200 mg orally, for 10 to 14 days each month) or oral contraceptives if she is younger than 35 years of age, does not smoke, and has no other significant risk factor should be provided to reduce the increased risk of endometrial hyperplasia and carcinoma present in such a woman because of the unopposed estrogen secretion. The woman taking progestins intermittently should be informed of the need for effective barrier contraception if she is sexually active, because these agents as administered do not inhibit ovulation, and ovulation occasionally occurs in PCOS. There is no evidence that the use of low-dose combined oral contraceptive agents increases the risks associated with insulin resistance in women with PCOS, and the benefits in preventing endometrial hyperplasia are clearly established. The progestin-containing IUD can be used both for contraception and to prevent endometrial hyperplasia, especially for women who cannot or will not take oral contraceptives.

Therapy for the woman with PCOS who is hirsute is somewhat different in some circumstances. In general, oral contraceptives provide initial therapy for affected women with mild hirsutism and provide protection from endometrial hyperplasia.

For women with PCOS who are overweight, it is reasonable to encourage lifestyle changes (149a, 176a). It is also recommended that women with PCOS be screened for diabetes, typically by an oral glucose tolerance test, although measurement of hemoglobin A1C may suffice (176a). Weight loss alone (of even less than 10%) may result in decreased insulin resistance and resumption of ovulation (177-179). However, lifestyle changes are difficult for patients to adopt. The use of insulin-sensitizing agents such as metformin is increasing but is not approved by the FDA. Whether the use of such agents will decrease the likelihood of the consequences of the metabolic alterations associated with insulin resistance is unclear. At present no data regarding the long-term safety and efficacy of these agents exist. What is clear is that only short-term trials of perhaps 3 months’ duration are needed to determine if insulin-sensitizing agents will be useful: responsive individuals will resume cyclic menstruation and ovulation in this short time frame and insulin levels will fall substantially (162,163,180,181).

Predicting which individuals with PCOS will respond is not possible at the present time. However, many clinicians believe that the therapy is low in risk, and the agents are relatively inexpensive. The use of these agents should probably be contemplated only in women with well documented insulin resistance and PCOS. Metformin should be administered only if the patient’s creatinine is normal and should be discontinued during illnesses to prevent the occurrence of lactic acidosis. Individuals should be cautioned that they may anticipate nausea or diarrhea on beginning metformin. Consequently the drug should be increased slowly to the maximal dose of 2.5 g per day orally.

For the woman with PCOS who wants to conceive, clomiphene citrate is used initially because of its high success rate and relative simplicity and inexpensiveness. A randomized trial has documented that letrozole is more effective than clomiphene in women with PCOS and a BMI >30 (181a). In fact, data are accumulating to indicate that letrozole is as effective as clomiphene in all women with PCOS, whether obese or not (181b). Both clomiphene citrate and letrozole can now be considered as first-line agents for inducing ovulation in PCOS even though letrozole is not approved for this indication by the U.S. FDA. 181b Other possible therapeutic approaches to ovulation induction include the use of gonadotropins (perhaps preceded by a GnRH analogue), FSH alone, pulsatile GnRH, and wedge resection of the ovaries at laparotomy (181c). Wedge resection or any other surgical manipulation of the ovaries should be performed only after all other methods of ovulation induction fail, an ovarian tumor is possible because of ovarian size or circulating androgen levels, or fertility is unimportant, because pelvic adhesions frequently result from surgery and may contribute to infertility. Laparoscopic ovarian follicular cautery or laser vaporization can also be used successfully to induce ovulation (182,183). However, these procedures also cause adhesion formation in a significant percentage of women. In addition, the success of medical therapy does not justify routine use of these procedures.

There are some largely uncontrolled studies suggesting that insulin-sensitizing agents, alone or in combination with clomiphene citrate, may improve both ovulatory function and fertility in some women with PCOS (162, 163,180). A trial may be warranted in women who do not respond to clomiphene before considering the use of more expensive agents to induce ovulation. However, a large randomized clinical trial documented that clomiphene citrate is more effective than metformin in inducing ovulation and resulting pregnancy; moreover, there was no further improvement when the two agents were used concurrently (183a). Metformin should not be considered as first-line therapy for women with PCOS desiring pregnancy.

CHRONIC ANOVULATION DUE TO OTHER ENDOCRINE AND METABOLIC DISORDERS

Cushing Syndrome

Along with the well-known physical manifestations in Cushing syndrome-central obesity, moon facies, and pigmented striae-are the less visible endocrinologic changes of amenorrhea, hirsutism, and infertility. The mechanisms responsible for the chronic anovulation are unclear, but several possibilities exist. The various degrees of adrenal androgen excess in Cushing syndrome of all causes together with obesity may cause excessive extraglandular conversion of androgens to estrogens in fat cells and inappropriate acyclic feedback to the hypothalamic-pituitary unit (184). The increased levels of CRH and ACTH in Cushing disease may affect the hypothalamic-pituitary secretion of GnRH and LH, as suggested for hypothalamic chronic anovulation.

Thyroid Dysfunction

As a result of significant changes in the metabolism and interconversion of androgens and estrogens, hyperthyroidism and hypothyroidism are associated with menstrual disorders ranging from excessive and prolonged uterine bleeding to amenorrhea. The altered sex steroid metabolism leads to inappropriate feedback and chronic anovulation. The changes are corrected by appropriate treatment of the underlying thyroid disease.

ABNORMAL UTERINE BLEEDING IN WOMEN OF REPRODUCTIVE AGE

Etiology

Abnormal uterine bleeding (AUB) is the most common indication for gynecologic consultation. AUB is also believed to be the indication for 80-90% of D&C procedures performed in nonpregnant women in the United States, accounting for about 350,000 procedures annually (185). By some measures AUB is the second most common indication for hysterectomy in the U.S. after uterine leiomyomas, accounting for approximately 20% or 120,000 procedures annually (186,187).

AUB may be defined as uterine bleeding occurring at unexpected times or of abnormal duration and may take any of several forms, with the bleeding altered in frequency, duration, and/or amount. Because the terminology and definitions for disturbances of menstrual bleeding are so confused, it is best to use the term AUB and then to describe the bleeding pattern as precisely as possible (187a). AUB always must be differentiated from bleeding originating in the urinary or gastrointestinal tracts. Broadly speaking, AUB can be divided into “organic causes”, which are found in perhaps 25% of cases, and so-called “dysfunctional” (or anovulatory) uterine bleeding (Table 2)

Table 2. Etiology of Abnormal Uterine Bleeding

Organic causes can be divided further into those associated with any of a number of systemic diseases and those associated with disorders of the reproductive tract. DUB may be defined as resulting from a functional abnormality of the hypothalamic-pituitary-ovarian axis and is present in the majority of women with AUB. It is perhaps best to refer to anovulatory bleeding rather than to DUB because many studies include in reports of DUB women who clearly have organic abnormalities.

The frequency of the various causes of AUB varies with the age of the patient. DUB is more common early and late in the reproductive years. Organic causes, especially neoplasms, increase with advancing age. In any woman of reproductive age, pregnancy must be ruled out, because bleeding related to complications of pregnancy is probably the most common cause of abnormal bleeding.

Different abnormalities cause AUB during the prepubertal years. Newborn girls sometimes spot for a few days after birth because of placental estrogenic stimulation of the endometrium in utero. Withdrawal of the estrogen at birth leads to sloughing of the endometrium. Accidental trauma to the vulva or vagina is the most common cause of bleeding during childhood. Vaginitis with spotting, most often because of irritation from a foreign body, also may occur. Prolapse of the urethral meatus and tumors of the genital tract also must be considered in the differential diagnosis. When the bleeding is due to the ingestion of estrogen-containing drugs (typically oral contraceptives) by children, there is rarely significant pubertal development. Of course, sexual abuse always must be considered in the young girl presenting with abnormal bleeding. Thus, it is clear that most of the prepubertal causes of bleeding are really not uterine in origin.

Although perhaps as many as half of all menstrual cycles are anovulatory when menses begin, the actual incidence of DUB in adolescents is low. Typically, anovulatory bleeding occurs at intervals longer than normal menstrual cycles, while bleeding due to organic causes tends to occur more frequently than regular menses. In most cases of anovulatory bleeding beginning in adolescence, there is spontaneous resolution. However, it is important to remember that up to 20% of patients with AUB during the teenage years have a primary coagulation disorder (188). It is also important to rule out pregnancy-related bleeding during the reproductive years.

Any woman over the age of 35 with AUB must be evaluated for a malignancy, despite the fact that most causes of such bleeding are benign. Endometrial hyperplasia clearly is a possibility in women who do not ovulate on a regular basis, even at a much earlier age than 40. The finding of endometrial hyperplasia after the menopause always should result in a search for a source of estrogen, either from exogenous therapy or from an endogenous (commonly ovarian) neoplasm.

Evaluation and Treatment

In the evaluation of the woman with AUB, obtaining a thorough history is of paramount importance. Emphasis should be placed on learning the pattern and quantity of bleeding. Because most women are poor at estimating blood loss and recalling exactly when they bled, all patients should be asked to keep a prospective menstrual calendar in which they record days and severity of bleeding. Menses lasting for more than 8 days or in which more than 80 ml of blood is lost are probably abnormal (i.e., menorrhagia). It has been estimated that up to 20% of women have excessive menstrual blood loss and that the incidence is similar for African-American and white U.S. women (189).

Obviously the physical examination also is important. The hemodynamic stability of any patient with abnormal bleeding should be assessed. The pelvic examination will rule out obvious organic causes. Warranted laboratory tests include measurement of hCG at the point of service, a complete blood count to assess hematological status, a platelet count and other coagulation studies to rule out a coagulation defect, and thyroid function studies to rule out a thyroid abnormality.

Just which patients should undergo further assessment of the endometrium is problematic, as is the type of evaluation to be undertaken. An endometrial biopsy is indicated in any woman over age 35 with AUB, in any woman with a prolonged history of irregular bleeding, and in most, if not all, women with severe bleeding. Measurement of endometrial thickness by transvaginal ultrasound appears to be of value in postmenopausal women who are not taking exogenous estrogen. Several studies have indicated that there is almost never any significant pathology when the endometrial thickness is less than 5 mm (190). Sonohysterography (SHG), sometimes termed saline infusion sonography (SIS), has become increasingly popular because it can be done in the office at the time of the initial evaluation and appears almost as accurate as hysteroscopy in diagnosing abnormalities within the uterine cavity (191,192). Some clinicians prefer hysteroscopy because it is generally superior to blind biopsy in identifying abnormalities and allows for treatment of many abnormalities at the time of diagnosis. Unfortunately it is also the most expensive of the various procedures; moreover, it is not clear that this procedure is needed to make the diagnosis in most cases. Until definitive data indicate when each of these procedures is warranted, physicians will need to exercise their individual judgment in evaluating women with AUB.

The management of AUB also requires judgment, but a few principles serve the clinician well. First, rule out an organic cause for the bleeding. Then remember that hormonal therapy can almost always stop anovulatory bleeding, but both the patient and the physician must recognize that bleeding will recur at a later (hopefully controlled and planned) time. In general, medical management is always preferred for the treatment of DUB, especially if the patient is interested in future childbearing or if menopause will occur shortly. The actual management of DUB depends on the severity of the problem, the age of the patient, and her desires regarding future fertility.

In young women, typically teenagers, with DUB, only reassurance and prospective charting may be necessary in those with mild irregular bleeding, especially because most adolescents will begin or resume regular ovulatory cycles within several months (188). In teens in whom the bleeding has been more prolonged and erratic such that there is some anemia (but the patient is hemodynamically stable), therapy must be individualized. If the young woman is sexually active (but not pregnant), a progestin-dominant oral contraceptive should control the bleeding and simultaneously provide contraception. Alternatively, a progestin such as medroxyprogesterone acetate (5-10 mg daily for 10-14 days) may be given every 30 to 60 days to induce intermittent “chemical curettage” and prevent chronic unopposed stimulation of the endometrium. However, it often takes several months before intermittent progestins can control irregular uterine bleeding. Oral iron therapy should always be provided as well. In general, the hormonal therapy can be discontinued, if desired, in 6 to 12 months. Most women will have regular menses when therapy is stopped, but thorough evaluation is warranted if irregular bleeding recurs.

In acute severe menorrhagia (with signs of acute blood loss such that the patient is hemodynamically unstable), blood transfusion may be required to restore hemodynamic stability. Once more hormonal therapy is almost always effective in controlling the bleeding. Any of several regimens may be utilized, but in general large doses of estrogen must be given initially and progestin must be added to stabilize the endometrium. For example, an oral contraceptive agent containing 35 micrograms of ethinyl estradiol may be given every 6 hours until the bleeding stops (generally within 48 hours). The dosage then may be tapered by reducing by one pill every other day (4,4,3,3,2,2,1,1 pills per day). Withdrawal bleeding may be permitted after the dosage has been reduced to one tablet each day or may be deferred for several days by continuing to administer one tablet daily. The patient then should be maintained on oral contraceptives given in the usual cyclic fashion for 6 to 12 months. If hormonal therapy cannot control the bleeding, the diagnosis of DUB should be questioned, and evaluation and biopsy of the endometrium are warranted.

Treatment of the woman over age 35 with AUB is more problematic. Organic causes of uterine bleeding are more common and mandate at least visualization if not sampling of the endometrium. Hormonal therapy with a progestin alone or with estrogen and a progestin can be used to control bleeding; combination therapy may be more effective. It is clear that low-dose combination oral contraceptive agents are effective in the majority of women with DUB (193). Hysterectomy is more commonly employed in this age group, particularly if the patient no longer desires childbearing.

A number of medications have proven effective in the treatment of menorrhagia associated with ovulatory menstrual cycles. Non-steroidal anti-inflammatory agents (NSAIDs) are clearly of benefit in some, but not all, women with increased menstrual blood loss. Five of seven randomized trials concluded that mean menstrual blood loss was less with NSAIDs than placebo, while two showed no significant difference (194). This therapy can be used for long-term treatment because side effects, mainly gastrointestinal, are mild with intermittent therapy administered only when the patient is bleeding. They can be given in combination with oral contraceptives or progestins to achieve more effective reduction in menstrual blood loss. Although not approved by the FDA for this purpose, studies from Europe indicate that progestin-containing IUDs may be the most effective therapy for menorrhagia, effecting a reduction in blood loss of as much as 90% in some women (195). The androgenic steroid danazol is also effective in reducing blood loss, even at relatively low doses of 200-400 mg per day, but side effects are common and more severe than with other medical therapies. Epsilon-aminocaproic acid (EACA), tranexamic acid (AMCA), and para-aminomethylbenzoic acid (PAMBA) are potent inhibitors of fibrinolysis and have been used effectively, particularly in Europe, to reduce menstrual blood loss, but side effects limit their utility (196,197). Tranexamic acid is now approved for use in the United States. Although extensive data are lacking, it is likely that GnRH analogs, perhaps with “add back” therapy to prevent bone loss, are very effective in reducing blood loss (198), but their expense mitigates using them except in those women who fail to respond to other methods of medical management and who wish to retain their childbearing capacity.

A few other comments are warranted. For women of reproductive age who desire childbearing, induction of ovulation is an effective means of controlling anovulatory bleeding. More than half of functional ovarian cysts, most commonly follicular and corpora luteal cysts, induce some form of menstrual irregularity, ranging from amenorrhea to menorrhagia, and most resolve spontaneously. Clearly abnormal bleeding is also a common complaint of women using hormonal and other forms of contraception. It is also important to remember that thyroid dysfunction may cause any disorder of bleeding ranging from amenorrhea to menorrhagia.

Lastly there is little if any role for the use of depot medroxyprogesterone acetate in the management of AUB. This is particularly true for the treatment of acute bleeding and for individuals in whom the cause of the bleeding has not been established with certainty. Although DMPA may be effective in some women, the drug is also known to cause irregular bleeding and may merely compound the problem. Other, more easily reversible forms of contraception are equally or more effective and should be used.

There are several approaches to the surgical treatment of abnormal uterine bleeding. The appropriate procedure depends on the individual circumstances.

Dilatation and curettage (D&C) is indicated for diagnostic purposes in those women in whom endometrial sampling is warranted but in whom endometrial biopsy in the office is not feasible or has been nondiagnostic. Although D&C has been found empirically to be effective in the management of acute uterine bleeding unresponsive to medical therapy, the therapeutic effect of the procedure is usually limited to the current bleeding episode. When D&C is performed for acute bleeding, it should be followed immediately by administration of cyclic exogenous estrogen and progestin in order to optimize long-term cycle control.

It has been estimated that the blind technique of D&C misses the diagnosis of intrauterine lesions in 10 to 25% of patients. Several studies have indicated that hysteroscopy with directed biopsy is at least as accurate as D&C in detecting endometrial abnormalities. Difficulties with hysteroscopy include its cost, the skill required to perform the procedure and evaluate what is seen, and the fact that it is not useful as a simple screening procedure. Hysteroscopy is probably most useful in individuals with AUB in whom no lesion is detected by other methods but in whom the abnormal bleeding persists.

Surgery that attempts to destroy the endometrium selectively, called endometrial ablation, has been reported for decades. Early approaches utilized thermocoagulation and irradiation. Hysteroscopic endometrial ablation can be conducted in several ways: using laser or electrical or thermal energy to coagulate or vaporize the tissue or resecting the endometrium with a loop electrode deployed via a modified urological resectoscope. Non-hysteroscopic endometrial ablation, involving blind destruction of the endometrium using computer-assisted energy delivery systems, is becoming increasingly popular because newly available approaches and those under development are less expensive than surgical approaches, require less training, and some can be performed in an office setting. Thermal balloon ablation systems are now available in the United States. Although trials comparing the various approaches are relatively uncommon, it appears that all the approved methods of endometrial ablation are equally effective (199-201). The reported incidence of complications with endometrial ablation is relatively low (200). A comprehensive survey of 87 Dutch hospitals indicates half of all complications are related to entry into the endometrial cavity (i.e., uterine perforation and cervical trauma) (202). Other complications include those related to anesthesia, failed access, hemorrhage, and the systemic absorption of distension media. Complications are more commonly encountered early in the experience of a given surgeon.

Data from several reported series suggest that endometrial ablation will result in initial amenorrhea in 50-75% of patients, acceptable reduction in blood loss in another 20-30%, and no significant reduction in blood loss in approximately 10% (199,201). Repeating the procedure a second time appears to be successful in over half the patients initially experiencing a treatment failure.

There is class I evidence from a Cochrane review that use of GnRH agonists prior to endometrial ablation results in shorter procedures, greater ease of surgery, a lower rate of post-operative dysmenorrhea, and a higher rate of post-surgical amenorrhea (203). Several randomized trials allowed a meta-analysis which documented that women undergoing hysteroscopic endometrial ablation had shorter hospital stays, fewer post-operative complications, and resumed activities earlier than those undergoing hysterectomy for increased menstrual bleeding (204). However, there was a significant advantage in favor of hysterectomy in the improvement in heavy menstrual bleeding and satisfaction rates up to 4 years after surgery compared with endometrial ablation. Moreover, rates of re-operation in women undergoing endometrial ablation increase steadily over time after the initial surgery, up to about 40% at 4 years (205). The direct costs of endometrial ablation may well be greater than hysterectomy if patients are followed long enough after their initial procedure (205). Thus, currently endometrial ablation may be an appropriate alternative to hysterectomy for the rare case of DUB or menorrhagia that is unresponsive to conservative management in a woman who is not desirous of future childbearing. Ablation may be very useful in women who are sufficiently ill such that they are poor candidates for hysterectomy.

The most common indication for the removal of uterine fibroids by myomectomy is menorrhagia, followed by pelvic pain or pressure and infertility. The reported effectiveness of myomectomy for menorrhagia is about 80%, but it is not clear what percentage of these patients have failed medical therapy. Although recurrence of myomas following myomectomy is observed in up to 50% of cases, reportedly only 10-15% of women undergoing myomectomy require subsequent surgery such as hysterectomy. MRI –guided focused ultrasound is being used increasingly to treat myomas without surgery.

The effectiveness of hysterectomy for AUB (virtually 100%) has contributed to its popularity as a primary treatment modality for this disorder. Unfortunately, the inefficiency of hysterectomy, due to its greater morbidity, mortality, and cost, makes it an inappropriate choice for management of the great majority of patients presenting with AUB. Current data would suggest that only 1-2% of women presenting with abnormal bleeding will ultimately require hysterectomy when given an appropriate trial of nonsurgical management. Hysterectomy usually should be reserved for the patient with other indications, such as leiomyomas or uterine prolapse. Hysterectomy should be used to treat persistent AUB after all other medical therapy has failed and the amount of menstrual blood loss has been documented to be excessive by some direct measurement (such as a fall in hematocrit).

ABNORMAL UTERINE BLEEDING IN POSTMENOPAUSAL WOMEN

Any bleeding in postmenopausal women not taking exogenous estrogen must be investigated. Vaginal, cervical, and rectal bleeding must be distinguished from uterine bleeding. Endometrial sampling is warranted in all postmenopausal women not on estrogen with uterine bleeding. The role of ultrasound in management continues to evolve: Many clinicians find it acceptable to defer biopsy if the endometrial thickness is less than 5 mm in diameter. In women not taking estrogen, the most common cause of uterine bleeding is endometrial atrophy.

Bleeding in postmenopausal women taking estrogen is more problematic. In women on sequential estrogen and progestogen, bleeding should occur only near the end or following the course of progestogen. If such is the case, endometrial sampling never may be indicated. An endometrial biopsy is warranted for bleeding at any other time. Despite the fact that a very few cases of endometrial cancer are associated with endometrial thickness of less than 5 mm in diameter on ultrasound, some clinicians are choosing to evaluate women with unscheduled bleeding by ultrasound alone.

When to sample women on continuous estrogen and progestogen is less clear. Sampling for bleeding occurring during the first 6 months these steroids are administered is rarely necessary. After the initial 6 months, any bleeding warrants biopsy. Biopsy would seem to be indicated at yearly intervals for women who continue to have some bleeding on continuous estrogen and progestogen.

A recent systematic review concluded that irregular bleeding was more than twice as common with a continuous as opposed to a sequential regimen, but with longer duration of treatment, continuous combined therapy was more protective than sequential therapy in preventing endometrial hyperplasia (206). There was also evidence of a higher incidence of hyperplasia under long cycle sequential therapy (progestogen every 3 months) compared to monthly sequential therapy.

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