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The major abnormalities of menstruation during the reproductive years number two: amenorrhea and abnormal uterine bleeding. Because any abnormality of menstruation may be associated with pregnancy, pregnancy always must be ruled out as a cause for the absence of menses.

AMENORRHEA

The prevalence of amenorrhea that is not due to pregnancy, lactation, or menopause is 3 to 4% (1,2). Amenorrhea indicates failure of the hypothalamic-pituitary-gonadal axis to
induce cyclic changes in the endometrium that normally result in menses and also may result from the absence of end organs or from obstruction of the outflow tract. It is important to remember that amenorrhea may result from an abnormality at any level of the reproductive tract. How long a woman must be amenorrheic before it is considered pathologic is arbitrary; however, any woman who presents with concerns about the absence of menses should be evaluated.

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 16 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 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 (Table 1):

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.

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)

In 1976 the WHO Scientific Group divided women with amenorrhea into two groups based upon a suggestion of Insler et al. (5):

Group I, termed Hypothalamic-Pituitary Failure, consists of women with no evidence of endogenous estrogen production (based on urinary measurements), nonelevated prolactin levels, normal or low FSH levels, and no detectable space-occupying lesion in the hypothalamic-pituitary region.

Group II, termed Hypothalamic-Pituitary Dysfunction, consists of women with a variety of menstrual cycle disturbances, including amenorrhea with evidence of endogenous estrogen production (on urinary measurement) and normal levels of prolactin and FSH. Thus, this group includes women with polycystic ovarian syndrome, who in reality may or may not have hypothalamic-pituitary dysfunction.

Although this classification scheme is still used, particularly outside the United States, its value is limited.

Hypergonadotropic Amenorrhea (Primary Hypogonadism; Gonadal Failure)

It is frequently impossible to diagnose hypergonadotropic amenorrhea, also called presumptive ovarian failure, 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. The premature loss of oocytes before age 40 results in premature ovarian failure. 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. In principle, young women with hypergonadotropic amenorrhea must be considered potentially, if only rarely, fertile.

Types of Premature Ovarian Failure

Genetic alterations or tendencies

Inherited characteristics are important in the development of premature ovarian failure (Table 1). 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 (6,7). The cause of the ovarian failure that may accompany myotonia dystrophica is unknown but may involve decreased germ cell number or accelerated atresia (8). In contrast, the premature ovarian failure associated with blepharophimosis-ptosis-epicanthus inversus (BPES) type I syndrome appears to be due to mutations in the FOXL2 forkhead transcription factor mapped to chromosome 3q23, which is involved in a variety of developmental processes and which apparently involve the ovary as well as other sites (10). An excess of X chromosomes also may be associated with decreased germ cell number or accelerated atresia. (10) Preliminary findings from an international collaborative study indicate that women with the fragile X premutation may be at significant risk of premature ovarian failure (11). Fully 16% of almost 400 premutation carriers experienced menopause prior to the age of 40. The familial occurrence of premature ovarian failure with vertical transmission has been described, suggesting autosomal dominant, sex-linked inheritance in some cases (12). All of these observations have significant implications for the reproductive counseling of affected women who had children before developing ovarian failure.

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 (13). 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 (14). Primary or secondary amenorrhea is typically occurs in women with deletions in either the short or the long arm of one X chromosome (13). Structural abnormalities of the X chromosome also can impact on ovarian function and are present in some women with premature ovarian failure (4,15,16). Even subtle molecular mutations of the X chromosome have been associated with premature ovarian failure (17).

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 (18,19). 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 (20). 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 (21-23), the gonads should be removed.

At least two separate inherited enzymatic defects also may be associated with premature ovarian failure. Girls with 17a-hydroxylase deficiency 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 (24-26). 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 17a-hydroxylase deficiency raises significant questions about why there is no follicular development in affected girls (27). 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 (28).

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 (29,30), but the mutation must be very rare outside of Finland because it has not been detected in some other populations (31,32).

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, and complete sexual development, and hyposensitivity (i.e., "resistance") to exogenous gonadotropin stimulation (33). Although the pathogenesis of this disorder remains obscure, it may be reasonable to consider affected individuals distinct from those with autoimmune disorders.

Premature ovarian failure may be associated with a number of autoimmune disorders (34). The most common association may be with thyroiditis. Ovarian failure occurs commonly in women with polyglandular failure, including hypoparathyroidism, hypoadrenalism, and mucocutaneous candidiasis (34). 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. Although the cause of autoimmune ovarian failure is unknown, circulating antibodies to ovarian tissue have been detected in many affected women, and FSH receptor antibodies have been detected in two women with myasthenia gravis and hypergonadotropic amenorrhea (35). Immunoglobulins that block the trophic actions of FSH but not LH also have been reported (36).

The thymus gland influences reproductive function (37). Congenitally athymic girls have ovaries devoid of oocytes (38). Irradiation and chemotherapeutic (especially alkylating) agents used to treat various malignancies are increasingly causes of premature ovarian failure (39-41). 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. Rarely, the mumps virus can affect the ovaries and cause ovarian failure (42).

Based on epidemiologic studies, there now appears to be an inverse dose-response relationship between the number of cigarettes smoked per day and the age at menopause. At any given age between 44 and 53 years, a woman who smokes one pack per day is more likely to have undergone menopause than a woman who smokes one-half pack per day or less (43). However, because cigarette smoking is so prevalent and premature ovarian failure so uncommon, it is difficult to believe that smoking plays any significant role in inducing early ovarian failure. Moreover, because relatively few cases of premature ovarian failure appear to be the result of environmental factors, a cause distinct from an environmental cause should be sought in any affected woman without a history of systemic disease, radiation therapy, or chemotherapy.

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. Chromosomal studies should be performed in affected women younger than 30 years of age to identify those with gonadal dysgenesis who have no signs of Turner syndrome. Surgical removal of the gonads is indicated in any individual in whom a Y chromosome is identified. Genetic studies will become more important in women with children born before the development of ovarian failure as transmissable mutations are identified. Conselling of these children regarding their future fertility will be essential. A few simple laboratory studies can rule out endocrine disorders, such as thyroid disease, hypoparathyroidism, hypoadrenalism, and diabetes mellitus. Screening tests to eliminate autoimmune dysfunction are indicated as well. Measurement of circulating LH, FSH, and estradiol concentrations on more than one occasion may help to determine if any functional oocytes remain in the ovary. 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.

Even in women with intermittent ovarian failure, estrogen replacement is appropriate to prevent the accelerated bone loss that occurs in affected women (4). The estrogen should always be given sequentially 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 develop suggestive of pregnancy. 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. 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 (44,45). Freezing of embryos (and oocytes in the near future) may be offered to women who must undergo chemotherapy and/or irradiaton for various malignancies. Embryos can be transferred to the uterus when remission is assured.

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 1). 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

Hypothalamic Chronic Anovulation. 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 (46-48). Such amenorrheic persons fall into this group of women considered as having hypothalamic chronic anovulation, which is sometimes called functional amenorrhea. The diagnosis of hypothalamic chronic anovulation 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 (49).

Although hypothalamic chronic anovulation is a common cause of oligomenorrhea and amenorrhea, relatively little is known about its pathophysiologic basis. The diversity of women presenting with hypothalamic chronic anovulation 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 (46). 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 (50). 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 (48,51). 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.

Anorexia nervosa. Anorexia nervosa may represent the most severe form of functional hypothalamic chronic anovulation. The constellation of amenorrhea often preceding the 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 (52-54). Demographically, 90% to 95% of anorectic women are white and come from middle- and upper-income families.

Peripheral gonadotropin and gonadal steroid levels generally are lower than in the early follicular phase of the menstrual cycle (55). As patients 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 (56-58). 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. (59) 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 (60).

Several abnormalities indicate hypothalamic dysfunction, including mild diabetes insipidus and abnormal thermoregulatory responses to heat and cold. (54) Affected individuals have altered body images as well (61).

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.(62,63) Circulating cortisol levels also are elevated, but the circadian cortisol rhythm is normal (64). 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 (65). Moreover, like women with endogenous depression, anorectics suppress significantly less after dexamethasone administration than do normal subjects (66). Anorectics also have reduced ACTH responses to exogenous corticotropin-releasing hormone (CRH), suggesting normal negative pituitary feedback by the increased circulating cortisol (67).

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 (68). 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 (69). The importance of normal body weight to normal reproductive function is evident in studies of a tribe of desert-dwelling hunter-gatherers in Botswana (70). 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 (71,72). 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 (73). 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.

In untrained women who underwent a program of strenuous aerobic exercise (running 4-10 miles/day) combined with caloric restriction, menstrual dysfunction was induced (74). 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 (75). 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 (76). 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 (77-79). It appears that the loss in bone density secondary to hypoestrogenism nullifies the beneficial effects of weight-bearing exercise in strengthening and remodeling bone (78,80). 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 (81).

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 (82) (Fig. 2). 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 (83). Basal levels of circulating cortisol and urinary free cortisol excretion, indicative of increased stress, are increased in eumenorrheic and amenorrheic runners (84) (Fig. 3). 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 (84,85).

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 (86).

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 week) 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 82).

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 84).

Psychogenic Hypothalamic Amenorrhea. Amenorrhea may occur in women with a definite history of psychological and socioenvironmental trauma (69, 87). 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. (69, 87-89). Increased basal levels of cortisol and decreased levels of DHEAS also have been noticed in women with psychogenic amenorrhea compared with eumenorrheic women (47). The mean levels of circulating cortisol are increased in such women largely because of an increase in the amplitude of the pulses of cortisol (90). Moreover, studies of depressed women have revealed abnormal circadian rhythms of cortisol and early "escape" from dexamethasone suppression (91,92).

The mechanism by which emotional states or stressful experiences cause 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 (93). It has been suggested that increased hypothalamic b-endorphin is important in inhibiting gonadotropin secretion (93).

Psychological studies have found several social and psychological correlates of psychogenic amenorrhea: a history of previous pregnancy losses, including spontaneous abortion; (94,95) stressful life events within the 6-month period preceding the amenorrhea; (96,97) and poor social support or separation from significant family members during childhood and adolescence (92,97). Many women with psychogenic amenorrhea report stressful events associated with psychosexual problems and socioenvironmental stresses during the teenage years (87). 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 (96). Distortions of body image and confusion about basic bodily functions, especially sexuality and reproduction, are common (95).

Diminished Gonadotropin-Releasing Hormone And Luteinizing Hormone Secretion In All Forms. The various forms of hypothalamic chronic anovulation associated with altered lifestyles have several features in common. Altered GnRH and LH secretion seems to be the common result of 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 hypothalamic chronic anovulation is controversial. 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-17b (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 still may 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 exogenous gonadotropins 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 (98). 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 (99). Unfortunately GnRH is not commercially available in the United States at this time.

Isolated Gonadotropin Deficiency. As originally described in 1944, Kallmann syndrome consisted of the triad of anosmia, hypogonadism, and color blindness in men (100). Women may be affected as well, and other midline defects may be associated (101-103). 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 (104). 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 (105). In some patients, structural defects of the olfactory bulbs can be seen on magnetic resonance imaging (106). It appears likely that this disorder forms a structural continuum with other midline defects, with septo-optic dysplasia representing the most severe disorder.

Although Kallmann syndrome is most commonly associated wtih autosomal dominant inheritance (107), kindreds have been reported that suggest autosomal recessive or X-linked form of Kallmann syndrome is due to point mutations and exon deletions of the KAL gene located on the X chromosome at location Xp22.3 (109,110). Other forms of inheritance may well be identified as more men and women with this disorder conceive as a result of newer modes of therapy, and their progeny are studied.

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 (111). These immature follicles respond readily to exogenous gonadotropin with ovulation and pregnancy, and exogenous pulsatile GnRH can also be used to induce ovulation (112). 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 (113,114). 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 (115). 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 (116). It is not clear if the hyperprolactinemia or the "hypoestrogenism" causes the accelerated bone loss seen in such individuals (117). Signs of androgen excess are observed in some women with hyperprolactinemia; androgen excess may rarely result in PCO. 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 (116,118). 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 (119). Galactorrhea in women with unexplained infertility may reflect increased bioavailable prolactin and may be treated appropriately with bromocriptine (120). Bromocriptine or cabergoline therapy may also be indicated in normoprolactinemic women with amenorrhea and increased prolactin responses to provocative stimuli (121).

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 (122). 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 should not be instituted until adrenal function is assessed and treated. Serum gonadotropin and gonadal steroid levels typically are low in hypopituitarism. Responses to exogenously administered hypothalamic hormones may 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

A Heterogeneous Disorder. In 1935, Stein and Leventhal focused attention on a common disorder in which amenorrhea, hirsutism, and obesity were frequently associated (123) (Fig. 4). With the development of radioimmunoassays for measuring reproductive hormones, it became clear that women with what is called PCO 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 (124). Virtually all serum androgens are moderately increased, and estrone levels are generally greater than estradiol levels (125). Ovarian inhibin physiology is normal (126).

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

Many women with the biochemical features of PCO have small or even morphologically normal ovaries and are not overweight or hirsute. Not all women with PCO 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 PCO (127). 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 (128) developed diagnostic criteria for PCO:

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.)

PCO 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 PCO affects approximately 5% of women of reproductive age (129,130). Although the cause of this disorder remains unknown, there is some evidence of autosomal dominant transmission in some affected individuals (131,132). 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 PCO are bilaterally enlarged and globular. (Fig. 5) 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 are rarely 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) 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 (133,134). PCO 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.

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

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.

The follicles in the ovaries of women with PCO do not mature completely. However, in vitro studies have failed to detect any primary defect in the steroidogenic capacity of polycystic ovaries (135). 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 PCO 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 PCO 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 PCO, it is doubtful that obesity is central to its cause.

About 50% of women with PCO have amenorrhea, about 30% have irregular bleeding, and about 12% have "cyclic menses" (127). No particular pattern of menstrual bleeding is characteristic of women with PCO, although a history of oligomenorrhea is probably most common. Because only about 75% of women with PCO are infertile, women with PCO do ovulate occasionally.

Two other biochemical features warrant discussion. First, obese and normal-weight women with PCO generally release increased quantities of insulin in response to a standard glucose challenge compared with weight-matched eumenorrheic individuals (136,137). Thus, regardless of body weight, 30 to 80 percent of women with PCO experience insulin resistance and compensatory hyperinsulinemia (138). Based on studies in a very well characterized subset of obese women with the disorder, the insulin resistance present in PCO appears to represent a postreceptor signalling aberration and differs from the insulin resistance observed in non-insulin dependent diabetes mellitus and simple obesity (138). 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 PCO 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 PCO, the defect in insulin action presumably is not due to abnormal sex steroid levels (139). The possibility that a defect in the secretion or action of insulin or some related growth factor is central to the cause of PCO cannot be entirely excluded and is gaining increasing support as the cause of hyperandrogenemia in women with PCO (140). The pivotal role of insulin resistance in PCO 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 (141-144).

In addition, perhaps 10% to 15% of women with PCO have mild hyperprolactinemia in the absence of radiographic evidence of a pituitary tumor, possibly because of chronic acyclic estrogen secretion (145). Although hyperprolactinemia is associated with increased adrenal production of DHEAS, the increased adrenal androgen production seen in women with PCO 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 PCO. The administration of insulin to women with PCO increases circulating androgen levels (140,146). The administration of glucose to hyperandrogenic women increases circulating levels of insulin and androgen. (147) Weight loss decreases levels of insulin and androgens (148). The suppression of circulating insulin levels experimentally by diazoxide reduces androgen levels (149). 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 PCO (139,150,151).

The hyperinsulinemia may cause hyperandrogenemia by binding to IGF-I receptors in the ovary (152). Activation of ovarian IGF-I receptors by insulin can lead to increased androgen production by thecal cells (153). Moreover, independent of any effect on ovarian steroid production, increased insulin inhibits the hepatic synthesis of SHBG (154). Insulin directly inhibits insulin-like growth factor binding protein-1 in the liver, permitting greater local activity of IGF-I in the ovary (155).

Regardless of the cause of PCO, it is possible to construct a rational pathophysiologic mechanism to explain the disorder. (Fig. 7) 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 PCO. 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 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 PCO but rather that peripheral alterations result in abnormal gonadotropin secretion.

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

Therapy. Appropriate therapy demands that potential causes such as neoplasms be eliminated. Besides facilitating fertility, the aims of treatment in women with PCO 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 PCO 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 PCO. There is no evidence that the use of low-dose combined oral contraceptive agents increases the risks associated with insulin resistance in women with PCO, and the benefits in preventing endometrial hyperplasia are clearly established.

Therapy for the woman with PCO 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 PCO who are overweight, it is reasonable to encourage lifestyle changes. Weight loss alone (of even less than 10%) may result in decreased insulin resistance and resumption of ovulation (156-158). 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 (141,142,159, 160).

Predicting which individuals with PCO 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 PCO. 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 PCO who wants to conceive, clomiphene citrate is used initially because of its high success rate and relative simplicity and inexpensiveness. Other possible therapeutic approaches to ovulation induction include the use of insulin-sensitizing agents, gonadotropins (perhaps preceded by a GnRH analogue), FSH alone, pulsatile GnRH, and wedge resection of the ovaries at laparotomy. 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 (161,162). 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.

Data indicate that insulin-sensitizing agents, alone or in combination with clomiphene citrate, may improve both ovulatory function and fertility in some women with PCO (141,142,159). A trial may be warranted in women who do not respond to clomiphene before considering the use of more expensive agents to induce ovulation.

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. (163) 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 (164). 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 (165,166).

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. 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). 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.

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.

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 (167). It is also important to rule out pregnancy-related bleeding during the reproductive years.

Any woman over the age of 40 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 (168).

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 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 (169). 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 (170,171). 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 (167). 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. 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 (172). 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 (173). 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 (174). 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 and they have not been approved for this purpose by the FDA (175,176). 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 (177), 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 lutea 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 (178-180). The reported incidence of complications with endometrial ablation is relatively low (179). 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) (181). 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% (178,180). 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 (182). 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 (183). 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 (184). The direct costs of endometrial ablation may well be greater than hysterectomy if patients are followed long enough after their initial procedure (184). 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 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.

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.

When to sample women on continuous estrogen and progestogen is less clear. Sampling for bleeding occurring during the first 6 months it is 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 (185). There was also evidence of a higher incidence of hyperplasia under long cycle sequential therapy (progestogen every 3 months) compared to monthly sequential therapy.