MENSTRUAL DISORDERS IN ADOLESCENTS
Excess Androgens and the Polycystic Ovary Syndrome
Catherine M. Gordon MD, MSc
This work was supported in part by grant no. MO1 RR2172 from the National Institutes of Health and Project #MCJ-MA 259195 from the Maternal and Child Health Bureau (Title V, Social Security Act), Health Resources and Services Administration, Department of Health and Human Services.
Department of Pediatrics, Harvard Medical School; and the Divisions of Adolescent/Young Adult Medicine and Endocrinology, Children's Hospital, Boston, Massachusetts
Hirsutism, acne, and other clinical signs of androgen excess can be a source of frustration and embarrassment for female adolescents. Clinical signs of androgen excess, particularly when accompanied by oligomenorrhea and anovulatory dysfunctional uterine bleeding, should raise suspicion of polycystic ovary syndrome (PCOS). PCOS, also referred to as functional ovarian hyperandrogenism[36] or chronic hyperandrogenic anovulation, [31] is the most common cause of hirsutism in adolescent patients; however, other causes of androgen excess, such as congenital adrenal hyperplasia (CAH) or androgen-producing tumors, must be ruled out before this diagnosis is confirmed. Because PCOS seems to begin in the perimenarchal period, familiarity with the evaluation and treatment of this disorder, as well as differentiation from other states of androgen excess, is essential for those providing care to teenagers.
I.NORMAL ANDROGEN PHYSIOLOGY IN FEMALE ADOLESCENTS AND MECHANISMS OF HIRSUTISM
In young women, hirsutism can result from increased adrenal or ovarian androgen production, an alteration in sex hormone-binding globulin (SHBG), or the use of exogenous androgens. Increased sensitivity of hair follicles to androgens can also be responsible. In the ovary, androstenedione is produced in the theca and stromal cells in response to luteinizing hormone (LH). Small amounts of dehydroepiandrosterone (DHEA) and testosterone are also produced. The major androgens secreted by the adrenal gland are androstenedione and DHEA and its sulfate (DHEAS). Testosterone is secreted in small amounts from the adrenal gland in normal women. Because of its long half-life, DHEAS has a stable concentration in the blood. This hormone is also a reliable marker of adrenal androgen production because approximately 95% of bodily production occurs within this gland. Androgens of both adrenal and ovarian origin are converted to more potent androgens (testosterone and dihydrotestosterone) in peripheral tissues. Because testosterone is carried in the plasma predominantly in association with SHBG, only a small amount of hormone is bioavailable or free. Estrogens increase the level of SHBG, whereas androgens, cortisol, and insulin decrease the level of this protein.
II.DEFINITION OF POLYCYSTIC OVARY SYNDROME AND DEVELOPMENTAL CONSIDERATIONS DURING ADOLESCENCE
PCOS is one of the most common endocrine disorders, affecting 5% to 10% of premenopausal women. [34] This syndrome is not a well-defined entity but is a spectrum of disorders associated with increased androgen production from the ovaries, adrenal glands, or both. The clinical presentation varies to include one or several of the following features: hirsutism, obesity, oligomenorrhea, anovulation, and infertility. At a 1990 National Institutes of Health consensus conference, experts attempted to identify the key features needed to diagnose PCOS, noting the following as definite criteria: hyperandrogenism, menstrual dysfunction, clinical evidence of hyperandrogenism, and the exclusion of CAH. [31] Probable criteria included insulin resistance, perimenarchal onset, an elevated LH-follicle-stimulating hormone (FSH) ratio, and polycystic ovaries by sonography.
Signs of PCOS typically date back to adolescence. PCOS can be characterized as an abnormal and exaggerated transition to puberty in four important physiologic processes: (1) maturation of the pattern of LH secretion, (2) increase in adrenal androgen production, (3) increase in body mass, and (4) onset of an adult pattern of insulin resistance. Clinical expression of PCOS appears to reflect maturational changes that occur during normal puberty in the hypothalamic-pituitary-ovarian axis. Developmental changes in LH secretion, with increased theca cell stimulation, can result in hypersecretion of androgens in female adolescents with PCOS. [50] Abnormal patterns of LH secretion, including high-amplitude LH pulses with an aberrant sleep-related pattern, have been documented in female adolescents with signs of this syndrome. [118] The expression of PCOS during adolescence may also be affected by the increasing insulin resistance that is characteristic of puberty. Insulin levels steadily increase during adolescence, suppressing levels of SHBG and amplifying the effects of sex steroids. [50] Insulin also has a direct gonadotrophic effect on ovarian steroidogenesis, [51][113] which suggests that nutritional status is closely linked to reproductive development. In young women with PCOS, the typical hyperinsulinemia of puberty can promote ovarian hyperandrogenism and anovulation. [50]
III.FEATURES AND PATHOPHYSIOLOGY
Features of PCOS include menstrual dysfunction, hyperandrogenism, increased end-organ sensitivity to androgens, hypothalamic-pituitary abnormalities, characteristic ovarian pathology, and metabolic defects (i.e., obesity, cardiovascular risks, and insulin resistance).
Menstrual Abnormalities
Menstrual abnormalities vary from amenorrhea to dysfunctional uterine bleeding resulting from anovulation. Endometrial hyperplasia can result from infrequent endometrial shedding and unopposed estrogen levels. Menarche typically occurs at a normal age, although occasionally it is delayed. An almost uniform feature is irregular menses from the time of menarche, often accompanied by hirsutism or acne. [51] In affected patients, the ovaries continue to produce estrogen, with levels generally equivalent to those of healthy, ovulating women in the follicular phase of the menstrual cycle; however, anovulatory patients with PCOS lack a midcycle estrogen elevation, [51] as well as the increase in progesterone level that occurs in the luteal phase after ovulation in normal cycling women.
Hyperandrogenism and the Pilosebaceous Unit
Hyperandrogenism, defined as an increase in the levels of one or more serum androgens (testosterone, free testosterone, DHEAS, or androstenedione), is responsible for the physical characteristics of this syndrome. [37][51][80] Hirsutism (defined as a Ferriman-Gallwey score of > 8), acne, and male-pattern balding or alopecia can result. Regardless of whether hirsutism is present, acne with either an extremely early or late age of onset or that is persistent or recalcitrant to therapy should be evaluated with an assessment of serum androgen levels. [77] The clinical manifestations of androgen excess seem to vary depending on end-organ sensitivity to androgens (Fig. 1) . In individual patients, the pilosebaceous unit needs to be taken into account. Hirsutism can result from either overproduction of androgens or an increased sensitivity of hair follicles to androgen levels. Terminal hair growth is stimulated by the increased conversion of testosterone to dihydrotestosterone from excess 5alpha-reductase within this unit or the presence of more numerous hair follicles. Interestingly, for the same level of androgen, some adolescents and women have more hirsutism than others. A study of women with PCOS from the United States, Italy, and Japan showed that a cohort of women with hirsutism had similar serum levels of LH, testosterone, and estradiol; however, levels of 3alpha-androstanediol, reflecting utilization of androgens by target tissues, were elevated in the women from Italy and the United States but were normal in the less-hirsute, Japanese women. [15] Although hormonal abnormalities are often present, serum LH and testosterone levels may be normal at the time they are drawn and should not rule out a diagnosis of PCOS.
In patients with PCOS, both the ovaries and adrenals can contribute to the elevated androgen levels seen. [74] The rate-limiting enzyme of androgen biosynthesis, cytochrome P450c17alpha, catalyzes 17alpha-hydroxylase and 17,20-lyase activities in both the ovary (Fig. 1) and the adrenals. [51] Therefore, excess activities of these enzymes result in androgen excess. In patients with PCOS, these two ovarian enzymes are overactive, evidenced by an exaggerated stimulated level of 17-hydroxyprogesterone (OHP) and androstenedione after the administration of a gonadotropin-releasing hormone (GnRH) agonist [8][36][38] and can be decreased by reducing insulin levels. [65] The contribution of the adrenals to the clinical picture of PCOS is controversial. Lucky and colleagues [78] hypothesized that selected patients with PCOS have an exaggerated adrenarche. Approximately 50% of women [15][62][67] have elevated serum DHEA and DHEAS levels. As is seen in the ovary, [8] increased activity of adrenal 17-hydroxylase and 17,20-lyase can exist, as evidenced on adrenocorticotropic hormone (ACTH) stimulation testing. [25][36][55][101] Adrenal hyper-responsiveness to even normal levels of ACTH exists in these patients [17][62][69] and may be promoted by insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) produced locally within the adrenal gland. [56] These IGFs may amplify the effects of ACTH to promote the overactivity of the adrenocortical cells responsible for adrenal androgen synthesis. [82] Hyperinsulinemia appears to amplify the adrenal response to ACTH in women with PCOS. [70] Animal and human studies have revealed that the adrenal androgens serve as precursors of ovarian androgens by intraovarian conversion; in addition, the overproduction of adrenal androgens can lead to subsequent polycystic ovarian changes and other features of PCOS. [58][60] The cause of hyperactivity of the P450c17alpha enzyme is unknown and may be the result of genetic abnormalities.
Hypothalamic and Pituitary Abnormalities
Abnormal gonadotropin secretion, noted early in adolescence in patients with PCOS, suggests the existence of a central defect. [3][118] Serum LH levels are elevated in approximately 70% of women with hyperandrogenic anovulation. [98] Patients with PCOS have an elevated LH pulse amplitude and frequency, resulting in a twofold to three-fold elevation in serum LH levels compared with those of FSH. [98] LH levels also remain tonically elevated throughout the menstrual cycle, [72] thereby stimulating theca cells to secrete androgens. LH hypersecretion is probably caused in part by acyclic estrogen production. Estrogen sensitizes the pituitary gland to GnRH, enhancing GnRH-stimulated LH synthesis and increasing the levels of pituitary LH available for release. [103] These patients have low-normal serum FSH levels, resulting in less efficient aromatization of androgens to estrogens and greater ovarian androgen over estrogen production. In contrast to LH, FSH may exhibit a greater sensitivity to negative feedback in response to estrogen, or the FSH response to GnRH may be desensitized by increased pulsatile GnRH secretion. [40][111] Both normal and elevated levels of serum inhibin have been reported in patients with PCOS and may also contribute to the mild suppression of FSH seen in patients with this disorder. [57][75][110] On GnRH stimulation testing, in which gonadotropin and steroid levels are measured in response to a single injection of GnRH analog, an exaggerated LH response and a reduced FSH response have been observed. [100] This LH secretory pattern is described as a "masculinized" pattern of LH release because it more closely resembles that seen in men compared with that of women.
Sonographic Findings
The classic ovarian pathology of PCOS is an enlarged ovary with multiple small cysts and a thickened, white capsule, but this sign is not uniformly seen and is not needed to make the diagnosis. Intraovarian hyperandrogenism, either from ovarian production or from increased circulating androgen levels from other sources, results in follicular arrest, the presumed cause of the multiple subcapsular cysts. [51] The criteria for the diagnosis of PCOS by sonography include at least 10 follicles that are 2 mm to 8 mm in diameter, arranged in a peripheral pattern, and associated with increased stroma relative to follicles ("string of pearls") (Fig. 2) . Ovaries are usually, although not always, enlarged. Two studies have addressed the population incidence of polycystic ovaries. Adams et al [2] found polycystic ovaries in 92% of women with idiopathic hirsutism, 87% with oligomenorrhea, and 26% with amenorrhea. Surprisingly, polycystic changes were documented in 22% of women who considered themselves to be normal and who reported regular cycles. [96] A similar prevalence of polycystic ovaries was found in normally cycling women in two other studies [21][44] ; however, this sonographic finding of polycystic ovaries must be considered a suggestive, but nonspecific, sign in the absence of clinical and hormonal abnormalities. As in adults, polycystic ovaries are often seen in teenagers with menstrual disturbances or hirsutism. [50] With advancing puberty, the prevalence of "polycystic ovaries" increases as the ovaries enlarge and multiple follicles become apparent. [12][95]
Obesity
Approximately half of hyperandrogenic anovulatory women are obese. [93] Estrone is the major serum estrogen in these patients, resulting from peripheral conversion of androstenedione. [7] Because the percentage of estrone conversion is related to body weight, obesity during the teenage years seems to predispose adolescents to this syndrome. Obesity also depresses levels of SHBG, allowing for increased levels of free testosterone. [112] Underlying insulin resistance, combined with obesity, may also result in the development of non-insulin-dependent diabetes mellitus (NIDDM) and other adverse metabolic sequelae of the insulin-resistance syndrome (Fig. 3)
Figure 2. Classic string of pearls morphologic characteristics of PCOS.
Cardiovascular Risks
The long-term consequences of PCOS may include an increased risk of cardiovascular disease. [59] Retrospective studies suggest an increased risk of both hypertension and coronary artery disease in aging women with PCOS. Hyperinsulinemia may contribute to this risk. [13][18] Insulin resistance has been proposed as a risk factor for coronary artery disease because of its negative impact on lipid profiles, [90][106] hypertension, [45] and NIDDM. [97] Androgens are also thought to increase cardiovascular risk independently. [59] In one study, women with PCOS had significantly lower levels of serum high-density lipoprotein cholesterol and higher triglyceride levels compared with controls, with the serum insulin level a significant explanatory variable for the total triglyceride elevation, even after controlling for age, body mass index, and sex steroids. [102] Another study reported that hyperinsulinemia, independent of obesity, contributes to lipid disturbances in patients with PCOS. [112] Thirty-one women with androgen excess were treated with a GnRH analog. Despite sex steroid suppression, lipid profiles remained abnormal and correlated with insulin resistance. A direct assessment of the dose-response relationship between insulin and PCOS revealed that insulin accounted for only 20% of the variance in lipid levels, with androgens not contributing significantly. Other hormonal and metabolic factors associated with PCOS seem to contribute beyond insulin and androgens and require further study. Although retrospective studies have suggested a significant risk for cardiovascular disease in women with PCOS, no prospective, long-term studies of those women have addressed this issue. Therefore, longitudinal studies of adolescents and young women with this syndrome are needed to determine whether identified risk factors will translate into an increased incidence of adverse cardiovascular events.
Isulin Resistance
PCOS is often associated with underlying insulin resistance (Fig. 4) , thought to confer an increased risk for NIDDM and other adverse medical sequelae. [24][28][31] The insulin resistance in patients with PCOS is selective, affecting glucose transport and other metabolic pathways in some tissues, whereas ovarian metabolic pathways are preserved. [34] High levels of insulin are thought to stimulate ovarian androgen production through both the insulin receptor and the homologous receptor for IGFs. Focus on this area began with the identification of insulin receptor mutations that result in extreme insulin resistance with diabetes mellitus, acanthosis nigricans (velvety, verrucous, hyperpigmented skin that is a marker for insulin resistance), and signs of virilization in women. [48][68] A specific syndrome of hyperandrogenism, insulin resistance, and acanthosis nigricans has been termed HAIR-AN. Insulin receptor mutations, circulating antibodies to the insulin receptor, and postreceptor signaling defects have been described in variants of this syndrome. [6][48][68] Barbieri and colleagues [6] suggested that insulin resistance was not only associated with androgen excess, but also plays a causative role in the abnormalities seen in patients with PCOS. Positive linear correlations between androgen and insulin [13][18] and numerous reports of acanthosis nigricans in hyperandrogenic women [29][47][105] have further corroborated the causative role of insulin in patients with PCOS. Two studies have also confirmed the presence of hyperinsulinemia, independent of obesity, in patients with PCOS. [18][94]
Several reports and reviews have addressed the prevalence of glucose intolerance or NIDDM in women with PCOS. [26][30][33][60] Previous studies have indicated that women with PCOS are at increased risk for NIDDM and that the diagnosis of diabetes has a strikingly earlier age of onset compared with that of the general population. [27][31][61] Significant decreases in insulin-mediated glucose uptake have been demonstrated in both lean and obese women with PCOS. [26][32][35] Pancreatic beta-Cell dysfunction also seems to be a characteristic feature of patients with PCOS. Defects in pancreatic beta-cell responses to glucose infusions [38] and decreased meal-related insulin secretory responses have been reported in these patients. [89]
Recent research has explored cellular and molecular mechanisms behind the insulin resistance associated with PCOS. Studies of insulin action in adipocytes from women with PCOS have revealed decreased insulin-stimulated glucose uptake and decreased maximal rates of glucose uptake. [20][28] This latter finding is thought to be secondary to decreased adipocyte GLUT4 glucose transporters, [99] insulin-sensitive transporters that stimulate glucose uptake into adipose and muscle cells. These defects occur in the absence of obesity, glucose intolerance, or changes in waist-to-hip ratios, [99] suggesting intrinsic abnormalities of insulin action in women with PCOS. Studies of insulin receptors isolated from cultured fibroblasts of women with this syndrome also suggest insulin resistance as an inherent defect. In 50% of these fibroblasts, decreased insulin receptor autophosphorylation was seen secondary to increased basal serine levels but decreased tyrosine autophosphorylation. [33] Serine phosphorylation of the insulin receptor has been shown to inhibit the tyrosine kinase activity of the receptor (Fig. 4) . Therefore, this defect in the initial steps of the insulin-signaling pathway may cause insulin resistance in patients with PCOS. This pattern seems to be a unique disorder of insulin action because other insulin-resistant states, such as obesity and NIDDM, are not associated with this finding; however, because 50% of the fibroblasts from women with PCOS did not have this abnormality in insulin receptor phosphorylation, [33] another defect in signal transduction may be responsible for the insulin resistance in a different subset of patients with this disorder. This area is one of active investigation.