Polycystic Ovarian Syndrome

Polycystic Ovarian Syndrome

CHAPTER 29 Polycystic Ovarian Syndrome RICHARD S. LEGRO mined etiology. This concept was summarized in a 1990 National Institutes of Health—Nationa...

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Polycystic Ovarian Syndrome RICHARD S. LEGRO

mined etiology. This concept was summarized in a 1990 National Institutes of Health—National Institute of Child and Human Development (NIH-NICHD) consensus conference on PCOS [6] and has been upheld in similar proceedings in recent years. These criteria are hyperandrogenism and/or hyperandrogenemia, oligo-ovulation, and exclusion of other potential causes such as congenital adrenal hyperplasia, Cushing’s syndrome, and androgensecreting tumors [6]. This definition of hyperandrogenic chronic anovulation has also been utilized for several large series describing metabolic sequelae in PCOS [7–11], several seminal clinical trials in PCOS [12–14], and in familial and genetic studies [15], and will be the basis for the definition of PCOS used in this chapter.

ABSTRACT Polycystic ovarian syndrome (PCOS) is a common endocrinopathy, but it is poorly understood. It is a disorder of unexplained hyperandrogenic chronic anovulation and clearly heterogeneous in etiology; however, many women with PCOS are noted to have profound peripheral resistance to insulin-mediated glucose uptake. Despite evidence of familial clustering, no clear molecular or genetic mechanism has been identified to date to explain the vast majority of cases. Women with PCOS present with infertility, menstrual disorders, and hirsutism. They appear to be at increased risk for diabetes and display multiple risk factors for endometrial cancer and cardiovascular disease. Unfortunately, there are few randomized, controlled trials of any treatment in PCOS to provide us with clear treatment guidelines. Therefore, treatment tends to be symptom based, although lifestyle interventions and pharmaceutical treatments directed at improving insulin sensitivity appear to improve multiple stigmata of the syndrome. For instance, studies with these agents have shown improvements in ovulation and hirsutism.

DIFFERENTIAL DIAGNOSIS OF POLYCYSTIC OVARIAN SYNDROME The differential diagnosis of PCOS is found in Table 29.1. It is important to note that PCOS rarely presents with signs of virilization. Virilization includes the common signs of acne and hirsutism but is also accompanied by other peripheral effects such as temporal balding, clitoromegaly, deepening of the voice, breast atrophy, and changes in body contour. In virilization, balding in women tends to present with centripetal balding and frontal recession more characteristic of androgenic alopecia in men as opposed to the more indolent presentation of androgenic alopecia in women with a generalized thinning of the crown region [16]. A deepening of the voice has been reported in women with androgen-secreting tumors or who are undergoing exogenous androgen treatment (often permanent). Increase in the size of the larynx, an androgen-sensitive organ, is one factor in the voice change. Clitoromegaly, another sign of virilization, is defined as a clitoral index greater than 35 mm2 (the clitoral index is the product of the sagittal and transverse diameters of the glans of the clitoris) [17]. In a normal women these diameters are in the range of 5 mm each. The degree of clitoral enlargement correlates with the degree of androgen excess. Androgens can lead to body composition changes, especially in the upper body, with increased muscle mass

INTRODUCTION Polycystic ovarian syndrome (PCOS) is a heterogeneous and still unexplained disorder, whose etiology remains the holy grail of reproductive endocrinologists. It is also one of the most common, if not the most common, endocrinopathies in women, affecting 5% of women in the developed world [1]. PCOS was first diagnosed in situ on the basis of enlarged ovaries by pelvic examination combined with a history of amenorrhea and hirsutism [2]. An abnormal morphology was subsequently confirmed by examining histologic sections of the ovary [2]. The ovary was viewed as the prime culprit of the syndrome, and assays confirming increased androgen excretion and circulating levels appeared to validate this belief [3]. The discovery of hyperinsulinemia [4] and decreased sensitivity to insulin in women with PCOS [5] led to a deemphasis on the ovary as a diagnostic criterion. Instead, PCOS was recognized as an endocrinopathy of undeterThe Ovary

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© 2004 by Elsevier. All rights of reproduction in any form reserved.

490 TABLE 29.1

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Human Ovarian Pathophysiology: Select Aspects

Differential Diagnosis of PCOS in Women

Congenital adrenal hyperplasia (CAH) Cushing’s syndrome Androgen-producing tumor-ovary or adrenal Exogenous anabolic/sex steroids Hyperprolactinemia Severely insulin-resistant states Thyroid dysfunction

and decreased fat mass. This is accompanied by breast atrophy.

Androgen-Secreting Tumors Most commonly, virilization, especially combined with a sudden onset and rapid progression, is caused by a tumor or dysfunctional state of the ovary, and less commonly of the adrenal. The most common androgen-producing tumor in a premenopausal woman is a Sertoli-Leydig cell tumor. Any large ovarian tumor can produce androgens indirectly by causing hyperplasia of the surrounding normal stroma (i.e., benign cystic teratomas, dysgerminomas, epithelial tumors). Most ovarian androgen-secreting tumors are benign. Adrenal tumors are rare, with an estimated incidence of 2 cases per one million persons per year, which are equally divided among adenomas and carcinomas. The age of onset in adults peaks in the fifth decade. Virilization can accompany both tumors primarily producing androgens and tumors primarily producing cortisol (Cushing’s syndrome). A long history of symptoms, as in the case with an ovarian tumor, does not exclude the presence of an adrenocortical neoplasm.

Nonclassical Congenital Adrenal Hyperplasia Nonclassical congenital adrenal hyperplasia (NC-CAH) is a term referring to the milder form of adult-onset congenital adrenal hyperplasia. The CYP21 (21-hydroxylase) gene is the most commonly mutated gene in humans. It is tightly linked to the HLA locus on the short arm of chromosome 6, a frequent site of genetic recombination. Nonetheless, it remains a rare disorder in the larger population. It is estimated to be present in less than 1% of unselected hirsute women [18]. CAH occurs with the highest frequency in the U.S. population among Native Americans in Alaska. Other populations with high carrier status are Ashkenazi Jews (3.7%), Latinos (1.9%), Yugoslavs (1.6%), and Italians (0.3%) [19]. Because of the lack of 21 hydroxylation, 17hydroxyprogesterone accumulates. Because of the lack of cortisol synthesis, adrenocorticotropic hormone (ACTH) levels increase, resulting in overproduction and accumulation of cortisol precursors. These, in turn, can be shunted to androgen biosynthetic pathways, which causes excessive

production of androgens, resulting in virilization. NC-CAH can be screened for with a fasting 17-OHP level in the morning. A value less than 2 ng/mL is normal, and cutoffs as high as 4 ng/mL have been proposed recently if obtained in the morning and during the follicular phase [20]. Values above the cutoff should be screened with an ACTH stimulation test. This is performed in the early morning by giving 250 mg of Cortrosyn, a synthetic form of ACTH, intravenously after baseline 17-OHP analysis and then obtaining a 1hour value. Results are interpreted according to the nomogram of New et al. [21]. In affected patients, 1-hour stimulated 17-OHP values are generally >10 ng/mL. Phenotype is largely a result of the amount of functional enzymatic activity of the allelic variants, and those with NC-CAH have 10% to 20% activity [22]. About 70% will have oligomenorrhea, 80% hirsutism, and 40% polycystic ovaries on ultrasound [23]. Patients also appear to lack the insulin resistance of PCOS, and treatment strategies focus primarily on suppression of adrenal function.

Cushing’s Syndrome Like PCOS, Cushing’s syndrome or glucocorticoid excess most commonly occurs in the reproductive years and predominantly affects women; however, the prevalence of 2 to 5 cases per million is a fraction of the high prevalence of PCOS [24]. Nevertheless, it must be considered in the differential diagnosis of androgen excess. Coexisting signs of Cushing’s syndrome, including a moon facies, buffalo hump, abdominal striae, centripetal fat distribution, and hypertension, should be sought and further screening provided for this cause. Polycystic ovaries are commonly found in women with Cushing’s [25]. Most cases of Cushing’s syndrome (about 70%) are caused by a pituitary ACTH-secreting tumor (Cushing’s disease) [26]. Cortisol excess can be screened with a 24-hour urine for free cortisol (which better quantifies excess cortisol production than random spot blood levels, normal values < 100 mg/24 hours) or an overnight dexamethasone suppression test.

Hyperinsulinemic and/or Insulin-Resistant States Dysfunctional states of the ovary, primarily hyperthecosis, may also result in marked androgen excess and hyperinsulinemia [27]. In stromal hyperthecosis, most of the ovarian androgen overproduction results from hyperplasia of the ovarian stroma (and not from the accumulation of small follicles as is the case with PCOS). Most women with stromal hyperthecosis have severe hyperinsulinemia, which may be the stimulus for stromal androgen overproduction [28]. It has been reported in both premenopausal and postmenopausal women, often with coexisting sequelae of the insulin-resistance syndrome such as dyslipidemia

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and glucose intolerance. Surgery, consisting of oophorectomy, usually results in restoration of both normal insulin levels and androgen levels in the acquired late presentations of stromal hyperthecosis. Extreme elevations in insulin levels occur in individuals with insulin receptor defects. Many such defects have now been identified, although their overall prevalence is low. In such individuals, the elevated insulin levels may stimulate excess ovarian androgen production, resulting in what has been described as the HAIR-AN syndrome, which represents the coexistence of hyperandrogenism, insulin resistance, and acanthosis nigricans [29].

Other Causes Also in the differential diagnosis of androgen excess in an adult female are the use of exogenous androgens (e.g., anabolic steroids in a body builder) or an overdose of androgens in a postmenopausal women. Severe hirsutism and even virilization that occurs during pregnancy has its own unique differential, including benign ovarian sources such as hyperreactio luteinalis (i.e., gestational ovarian thecalutein cysts) or luteomas, and extremely rare fetoplacental sources such as aromatase deficiency resulting in androgen excess caused by the placental inability to convert precursor androgens into estrogens. Many texts also recommend

TABLE 29.2



Polycystic Ovarian Syndrome

screening subjects with menstrual disorders for hyperprolactinemia and thyroid dysfunction, which are also common in this population.

CLINICAL STIGMATA OF POLYCYSTIC OVARIAN SYNDROME AND THEIR EVALUATION A suggested laboratory evaluation of women with PCOS is provided in Table 29.2, but this remains an area where the cost effectiveness of such an extensive workup should be justified. We will begin with two common stigmata of women with PCOS that do not appear to merit routine evaluation: inappropriate gonadotropin secretion and morphology of the ovary.

Inappropriate Gonadotropin Secretion Inappropriate gonadotropin secretion (IGS) has been one of the characteristic signs of PCOS since assays were available to characterize it [30]. An excess of luteinizing hormone (LH) in the urine was first noted [31], and urinary studies also supported abnormal, erratic pulses of LH secretion in these women [32]. The availability of plasma assays allowed clear documentation of overproduction of

Tests to Consider in Women with Polycystic Ovary Syndrome

Blood Tests

Normal Range*

Purpose

<60 ng/dL*

Determine extent of androgen excess

Fasting Blood Tests 17-hydroxyprogesterone

<2 ng/mL

Evaluate for NC-CAH; use <4 ng/mL for random sample, ACTH stimulation test if abnormal

Prolactin

<20 ng/mL

Evaluate for prolactin excess

Glucose

<126 mg/dL

Screen for diabetes

Total Testosterone (consider also free or bioavailable measures)

Insulin

<20 microU/mL*

Screen for insulin resistance

Glucose-to-insulin ratio

>4.5

Screen for insulin resistance

Cholesterol

<200 mg/dL

Identify cardiovascular risk

HDL

>35 mg/dL (and preferably >45 mg/dL)

Identify cardiovascular risk

LDL

<130 mg/dL

Identify cardiovascular risk

Triglycerides

<200 mg/dL

Identify cardiovascular risk

2 h glucose >140 mg/dL— impaired glucose tolerance 2 h glucose >200 mg/dL type 2 diabetes mellitus

Identify or diagnose diabetes, repeat if abnormal

Dynamic Blood Tests Oral glucose tolerance test, give 75 g glucose in am after overnight fast

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LH, resulting in an elevated LH to follice-stimulating hormone (FSH) ratio [33]. Varying authors have recommended specific cutoff ratios as diagnostic of the syndrome. These ratios are rarely utilized because of the lack of sensitivity (>50% of women with no detectable gonadotropin abnormality) [34], especially in obese women. Pulse studies with larger numbers of women with PCOS have shown that LH pulse amplitude is inversely related to body mass index (BMI) and percentage body fat, despite an underlying increased pulse frequency of LH that is independent of body fat or composition [35, 36]. The suppression of LH levels by increasing obesity reduces the usefulness of gonadotropin levels as diagnostic criteria in PCOS. Others have criticized that the conventional measure of immunoreactive LH is not as sensitive in detecting women with PCOS, compared to bioactive LH levels; however, the latter are not routinely available [37, 38].

Ovarian Morphology Others have defined PCOS on the basis of the morphology of the ovary found on ultrasound, with multiple 2- to 8-mm subcapsular preantral follicles forming a “black pearl necklace” sign (Figure 29.1) [39]. Polycystic ovaries are found in a wide variety of unrelated disorders, including in up to 30% of women with normal menses and normal circulating androgens [40–42]. The differential diagnosis of polycystic ovaries is extensive, with some syndromes having little overlap with hyperandrogenic chronic anovulation (Table 29.3). Reports have suggested that polycystic ovaries per se may identify a group of women with some further stigmata of reproductive and metabolic abnormalities found in the

endocrine syndrome of PCOS [43, 44], but the data have not been consistent [45]. It is important to note that not all women with the endocrine syndrome of PCOS have polycystic-appearing ovaries [45], and that polycystic ovaries alone should not be viewed as synonymous with PCOS. Polycystic ovaries appear to be an independent risk factor for ovarian hyperstimulation syndrome after ovulation induction [46], and thus it may make clinical sense to document the morphology of the ovary in infertile patients seeking ovulation induction.

TABLE 29.3 Syndromes or Disease Entities That Have Been Associated with Polycystic Ovaries Hyperandrogenism Steroidogenic Enzyme Deficiencies (CAH, aromatase deficiency, etc.) Androgen-Secreting Tumors Ovarian Adrenal Exogenous Androgens Anabolic steroids Transsexual hormone replacement Hyperandrogenism and Insulin Resistance Congenital Type A syndrome Type B syndrome Leprechaunism Lipoatrophic diabetes Rabson-Mendenall Polycystic ovary syndrome(?) Acquired Cushing’s syndrome Insulin Resistance Glycogen storage diseases Other Central Nervous System Trauma/lesions Hyperprolactinemia Nonhormonal medications Valproate Heriditary Angioedema

FIGURE 29.1 Transvaginal ultrasound of a polycystic ovary. There are multiple small subcapsular follicles (“pearl necklace”) and increased central stroma. There are an absence of preovulatory follicles.

Bulimia Idiopathic (includes normoandrogenic women with cyclic menses)

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Hyperandrogenism Hyperandrogenism can be documented based on clinical stigmata of androgen excess, such as by the presence of acne, hirsutism, or androgenic alopecia. Others rely on biochemical confirmation of circulating hyperandrogenemia. Ethnic, and presumably underlying genetic, differences in population may result in the presence of hyperandrogenemia without clinical signs of hyperandrogenism [47]. HYPERANDROGENEMIA Both the adrenal glands and ovaries contribute to the circulating androgen pool in women. The adrenal preferentially secretes weak androgens such as DHEA or its sulfated “depot” form DHEA-S (up to 90% of adrenal origin). These hormones, in addition to androstenedione (often elevated in women with PCOS), may serve as prohormones for more potent androgens such as testosterone or dihydrotestosterone (DHT). The ovary is the preferential source of testosterone, and it is estimated that 75% of circulating testosterone originates from the ovary (mainly through peripheral conversion of prohormones by liver, fat, and skin, but also through direct ovarian secretion). Androstenedione, of both adrenal (50%) and ovarian (50%) origin, is the only circulating androgen that is higher in premenopausal women than in men, yet its androgenic potency is only 10% of testosterone. DHT is the most potent androgen, although it circulates in negligible quantities and results primarily from the intracellular 5areduction of testosterone. In the past, measurement of 3a-androstanediol glucuronide, a peripheral metabolite of DHT, was used as a circulating marker of androgen excess in the skin (hirsutism and acne), but its clinical use is negligible. Thus circulating testosterone levels may be the androgen of choice to measure, and their circulating levels may offer better discrimination between a control population and the affected population with PCOS. A 14% overlap in elevated androgen levels was noted between women with PCOS and a prospectively recruited cohort of cycling control women [15], versus a 20% to 30% overlap of polycystic ovaries in a normal population [40, 41]. A circulating total testosterone level was found to be the best hormonal correlate of the combined syndrome of hyperandrogenic chronic anovulation and polycystic ovaries [34]. Many prefer either a free testosterone or a bioavailable testosterone level because that better reflects the suppressive effects of hyperinsulinemia on sex hormone binding globulin [48]. Assays are reproducible and eliminate any observer bias in identifying women with androgen excess; however, given the interassay variability, it is difficult to assign a uniform and specific level of circulating testosterone, which is the cutoff for diagnosing PCOS [49].



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HIRSUTISM Hirsutism is defined as excess body hair in undesirable locations, and as such is a subjective phenomenon that makes both diagnosis and treatment difficult. Most commonly, hirsutism as associated with PCOS tends to be an androgen-dependent, midline-predominant hair growth. The pilosebaceous unit (PSU) is the common skin structure that gives rise to both hair follicles and sebaceous glands and is found everywhere on the body except the palms and soles. Before puberty the body hair is primarily fine, unpigmented vellus hair. After puberty and stimulated by the increased androgens, some of these hairs (mainly midline hair) are transformed into coarser, pigmented terminal hairs. A similar mechanism may explain the increase in acne with puberty, with increased sebum production by the sebaceous glands. One of the central paradoxes is that androgens can exert opposite effects (vellus to terminal, terminal to vellus), depending on the site of the hair follicle. It is important to note that factors other than androgen action may contribute to the development of hirsutism. Hyperinsulinemia, which accompanies many benign forms of virilization, can also stimulate the PSU both directly or indirectly by contributing to hyperandrogenemia. Hirsutism and acne, however, are heterogeneous and common disorders, similar to polycystic ovaries. Only 50% of women with hirsutism may have PCOS [50]. Hirsutism is also not invariably present in a woman with PCOS. There are, for instance, ethnic differences in target tissue sensitivity to circulating androgens and intracellular androgens [51], such that marked androgen excess may not manifest as hirsutism (e.g., in Asians) [47]. Methodology of the assessment of hirsutism and response to treatment has been poorly validated [52]. Hirsutism scores are notoriously subjective [53], and even the most frequently utilized standard of subjective hirsutism scores, the modified Ferriman-Gallwey score, relies excessively on nonmidline, non-androgendependent body hair to make the diagnosis [54]. The FDA approval of eflornithine hydrochloride cream for hirsutism was based on a Physician’s Global Assessment (PGA) scale, evaluating facial hair 48 hours after shaving on treatment compared to placebo (Vaniqa package insert). In the largest clinical trial to date in PCOS, 50% to 60% of the 400 women prospectively identified to have hyperandrogenemic chronic anovulation had no evidence of hirsutism (Ferriman-Gallwey score <6) [14]. Also, hirsutism is frequently idiopathic and accompanied by normal circulating androgen levels [51], although other studies with more thorough examination have shown idiopathic hirsutism to be rare (<10% of a hirsute population) [55].

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Chronic Anovulation In the broadest definition, PCOS has been identified with the World Health Organization (WHO) type 2 ovulatory dysfunction, or normoestrogenic anovulation. Although chronic anovulation may be the sine qua non of the syndrome, only a small percentage of women with PCOS are completely amenorrheic. Most are oligomenorrheic and experience varying intervals of vaginal bleeding. The cause of this vaginal bleeding may be physiologic (postovulatory withdrawal bleed) or pathologic. How infrequent should the menstrual bleeding be to qualify as “chronic anovulation” and how do you classify persistent anovulatory bleeding? There is no consensus here, but general guidelines are 6 to 8 spontaneous episodes of vaginal bleeding per year. The baseline endogenous ovulatory frequency is unknown in an untreated PCOS population, but the ovulation rate in the largest randomized, controlled trial in women with PCOS to date demonstrated an almost 30% ovulatory frequency in the placebo-treated arm, indicating either a significant placebo effect and/or high endogenous rate [14].

Acanthosis Nigricans Acanthosis nigricans is a dermatologic condition marked by velvety, mossy, verrucous, hyperpigmented skin. It has been noted on the back of the neck, in the axillae, underneath the breasts, and even on the vulva. Originally, it was noted in severe states of insulin resistance, such as the HAIR-AN syndrome (hyperandrogenic insulin-resistant acanthosis nigricans) [56]. These conditions with mutations in the insulin receptor may present in childhood with virilization and wasting (as opposed to obesity); however, like polycystic ovaries, its presence appears to be more a sign of insulin resistance than a distinct disease unto itself. But it can also be present in less severe states of insulin resistance, and most cases of acanthosis nigricans are not associated with mutations of the insulin receptor. There is no accepted grading system for the extent of acanthosis nigricans, as for hirsutism or alopecia. Similar to polycystic ovaries or hirsutism, other pathologic conditions are associated with acanthosis nigricans that must be considered when noted. It also has appeared in association with an insulinoma and malignant disease, especially adenocarcinoma of the stomach. Nonetheless, in most cases, the presence of acanthosis nigricans suggests compensatory hyperinsulinemia caused by an insulin-resistant state. INSULIN RESISTANCE The decrease of insulin resistance in women with PCOS compared to appropriate controls (~35 to 40 percent) is of a similar magnitude to that seen in type 2 diabetes and is independent of obesity, glucose intolerance, increases in

waist-hip-girth ratio, and differences in muscle mass [5]. This synergistic negative effect of obesity and PCOS on hepatic glucose production is an important factor in the pathogenesis of glucose intolerance in PCOS. One of the most common prevailing theories about the etiology of type 2 diabetes proposes that the primary pathogenetic defect is peripheral insulin resistance, resulting in compensatory hyperinsulinemia. Over time there is beta cell dysfunction, leading to inadequate secretion of insulin and ultimately to beta cell exhaustion, and the development of frank type 2 diabetes. There is now a relatively substantial body of literature confirming beta cell dysfunction in PCOS, although as in diabetes, there is still considerable debate regarding the primacy of the defects and their worsening over time [57]. Basal insulin levels are increased, and insulin secretory response to meals has been shown to be reduced in women with PCOS [58]. This dysfunction is also independent of obesity [59]. DETECTION OF INSULIN RESISTANCE IN WOMEN POLYCYSTIC OVARIAN SYNDROME Total body insulin sensitivity can be assessed by the euglycemic glucose clamp technique [60]. Here, exogenous insulin is infused to produce the desired insulin concentration. Glucose is infused simultaneously to maintain euglycemia. At steady state, the amount of glucose infused is equal to the amount of glucose utilized by the tissues and can be used as an index of sensitivity to insulin. The more glucose that is infused, the greater the sensitivity to insulin and vice versa. Total body insulin sensitivity can also be assessed via a modification of the intravenous glucose tolerance test known as frequently sampled intravenous glucose tolerance test (FSIGT) [61]. In this test, a bolus injection of glucose is given and blood is very frequently sampled for glucose and insulin levels. Minimal model analysis is then applied to the glucose and insulin levels obtained, and an insulin sensitivity index is derived. The precision of the model can be improved by enhancing second-phase insulin secretion with an intravenous injection of the insulin secretagogue tolbutamide or of insulin, 20 minutes after the glucose bolus. Minimal model estimates of insulin sensitivity are highly correlated with euglycemic clamp determinations of insulin action [61]. The FSIGT has been well valdiated in women with PCOS [59]. This test is substantially less labor intensive and costly to perform than the euglycemic clamp, but it still remains impractical and expensive in a clinical setting. Both of these tests have little benefit as diagnostic tests to identify insulin resistance in a PCOS population. Currently, the American Diabetes Association (ADA) does not recommend screening for insulin resistance with fasting measures of insulin or other markers of the insulinresistance syndrome [62]. Concerns about the utility of screening focus on the insulin assay variability, the lack of predictive value of fasting insulin levels, and the unclear WITH

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association between hyperinsulinemia and other metabolic sequelae (primarily cardiovascular disease) [62]. ORAL GLUCOSE TOLERANCE TESTING Oral glucose tolerance testing (OGTT) allows for the diagnosis of clinically recognized categories of glucose tolerance, including impaired glucose tolerance and type 2 diabetes. Recent studies have suggested that the prevalence rates of glucose intolerance are as high as 40 percent in women with PCOS when the less stringent WHO [63] (2-hour glucose ≥140 mg/dL) criteria are used [8, 9]. These studies are of interest because they have shown nearly identical rates of impaired glucose tolerance and type 2 diabetes among a diverse cohort, both ethnically and geographically as well as from different investigational groups. This would suggest that these abnormalities may represent a universal characteristic of women with PCOS, at least those diagnosed on the basis of hyperandrogenic chronic anovulation. Fasting glucose levels are poor predictors of glucose intolerance risks in PCOS because few women with PCOS with impaired glucose tolerance (IGT) had elevated fasting glucose values (Figure 29.2). This is supported by the limited studies of hemoglobin A1c in women with PCOS,



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which tend to be normal even in women with PCOS with IGT [64, 65]. Although diagnosing diabetes by fasting glucose using the 1997 ADA criteria may detect a more severe form of diabetes than the WHO criteria [66], this category of women with normal fasting glucoses and glucose intolerance may be exactly the subset of women (young and otherwise healthy) for whom more intensive early intervention can prevent long-term complications, such as the development of diabetes [67].

CLINICAL SEQUELAE OF POLYCYSTIC OVARIAN SYNDROME Infertility and Chronic Anovulation The most common reason that women with PCOS present to the gynecologist is because of infertility, caused by chronic anovulation [68]. As a general rule, PCOS women represent one of the most difficult groups in which to induce ovulation both successfully and safely. Many women with PCOS are unresponsive to clomiphene citrate and human menopausal gonadotropins (hMG), and this is exacerbated by the underlying obesity. On the other end

FIGURE 29.2 Scattergram of fasting blood glucose levels versus 2-hour glucosestimulated levels in 254 women with PCOS. Points on the graph are coded to reflect the World Health Organization (WHO) status based on oral glucose tolerance testing (OGTT). The dotted vertical line is the threshold for impaired fasting glucose (110 mg/dL) by the 1997 American Diabetes Association (ADA) criteria, and the dashed vertical line (126 mg/dL) is the threshold for type 2 diabetes by the same criteria. Most women with PCOS, regardless of WHO OGTT status, have normal fasting glucose levels (Adapted from reference [8]).

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of the spectrum are women with PCOS who overrespond to both of these medications. Women with PCOS are at especially increased risks of ovarian hyperstimulation syndrome (OHSS), a syndrome of massive enlargement of the ovaries and transudation of ascites into the abdominal cavity that can lead to rapid and symptomatic enlargement of the abdomen, intravascular contraction, hypercoagulability, and systemic organ dysfunction [69]. They are also at increased risk for multiple pregnancy. In addition, there is emerging evidence that baseline hyperinsulinemia may contribute to the increased OHSS risk [70, 71].

Gynecologic Cancer Endometrial cancer is the most commonly diagnosed invasive gynecologic cancer in women. Case series have identified women with PCOS at high risk for developing endometrial cancer and often at an early age [72–75]. But there is actually little solid epidemiologic evidence to link PCOS and endometrial cancer. A stronger association between PCOS and endometrial cancer may be possible if we were able to make the diagnosis of PCOS in menopausal women, but a diagnosis based on hyperandrogenic chronic anovulation becomes difficult to make after ovarian failure and cessation of menses [76]. The mechanism by which women with PCOS may be at increased risk for endometrial hyperplasia and endometrial cancer is thought to be chronic stimulation of the endometrium with weak, but bioactive estrogens, combined with the lack of progestin exposure. This condition known as “unopposed estrogen” is perhaps the clearest hormonal risk factor for endometrial cancer [77]. PCOS women have been shown to be normoestrogenic, perhaps even hypoestrogenic with elevated levels of estrone [78]. A Scandinavian study looked at a group of both premenopausal and postmenopausal women with endometrial carcinoma and found hirsutism and obesity in both groups of cases compared to controls [79]. In the younger group, they additionally noted a recent history of anovulation and infertility, two of the most common presenting complaints of women with PCOS (in addition to hirsutism and obesity) [68]. Endometrial hyperplasia has often been noted in association with anovulation and infertility, common symptoms of PCOS [74, 80, 81]. There are no systematic prospective studies of the prevalence of endometrial hyperplasia/neoplasia in a population with PCOS. Other gynecologic cancers have been reported to be more common in women with PCOS, including ovarian cancer [82] and breast cancer [83].

Type 2 Diabetes Mellitus Retrospective studies looking at diabetes prevalence over time have generally noted an increased prevalence with

age in women with PCOS. Studies from Scandinavia have shown increased rates of type 2 diabetes and hypertension compared to controls [84]. This study used a combination of ovarian morphology and clinical criteria to identify women with PCOS and found that 15% had developed diabetes compared to 2.3% of the controls [84]. A casecontrol study of PCOS in the United States has shown persistent hyperinsulinemia and dyslipidemia as women with PCOS age, although androgen levels tend to decline in older women with PCOS [85]. In a thin Dutch population, although the overall prevalence of self-reported diabetes by telephone survery was 2.3%, in women with PCOS aged 45 to 54 years (n = 32), the prevalence of diabetes was four times higher (P < 0.05) than the prevalence of this condition in the corresponding age group of the Dutch female population [86]. Adult women with PCOS have glucose intolerance rates of 40% (as defined by prevalence of either IGT or type 2 diabetes as diagnosed by a 2-hour glucose value after a 75 g OGTT [8, 9]. New data now suggest that adolescents may have soaring rates of glucose intolerance [87], comparable with adults, which appears to be mirrored in the adolescent population with PCOS [88]. Studies of large cohorts of women with PCOS have demonstrated that the prevalence rates of glucose intolerance are as high as 40 percent in women with PCOS when the less stringent WHO criteria are used (see Figure 29.2) [8, 9]. These studies are of interest because they have shown nearly identical rates of impaired glucose tolerance and type 2 diabetes among a diverse cohort, both ethnically and geographically as well as from different investigational groups.

Cardiovascular Disease Both PCOS and cardiovascular disease (CVD) are common in women, but is cardiovascular disease more common (and at an earlier age) in women with PCOS? The metabolic profile noted in women with PCOS is similar to the insulin-resistance syndrome, a clustering within an individual of hyperinsulinemia, mild glucose intolerance, dyslipidemia, and hypertension [89]. There is a prolific literature identifying obesity, dyslipidemia, glucose intolerance, and diabetes, and occasionally hypertension as risk factors for cardiovascular disease in women with PCOS [11, 90–95]. However, the metabolic syndrome X and PCOS remain distinct. When women with the metabolic syndrome are studied for reproductive stigmata of PCOS, they are no more likely to have polycystic ovaries than are other segments of the population, and less than half have a history of oligomenorrhea [96]. Nor do all women with PCOS have the metabolic syndrome. In some countries most women with PCOS (~80%) are nonobese [97], and as many as 50% of obese women with PCOS may not have docu-

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mented insulin resistance by intensive testing [98]. There is actually little published evidence supporting a link between PCOS and cardiovascular events, such as increased mortality from CVD, premature mortality from CVD, or an increased incidence of cardiovascular events (stroke and/or myocardial infarction). HYPERANDROGENIC CHRONIC ANOVULATION AND CARDIAC EVENTS A large-scale epidemiologic case-control study from the University of Pittsburgh initiated in 1992 has identified cases with PCOS primarily based on hyperandrogenic chronic anovulation (n > 200) and concurrently recruited community-based controls (n > 200) [7]. Another study from the Czech Republic with a much smaller case group (n = 28) noted a higher prevalence of self-reported coronary heart disease symptoms when compared with agematched controls (n = 752) (21% of PCOS v. 5.2% of controls, P + 0.001) [99]. This group used diagnostic criteria of both hyperandrogenic chronic anovulation and past histopathologic evidence of PCO to identify cases, but only 28 of 61 cases identified responded to the questionnaire. Several surrogate markers for atherosclerotic disease, including carotid wall thickness as determined by B-mode ultrasonography, have been studied in women with PCOS. The University of Pittsburgh performed ultrasonography of the carotid arteries on 125 women with PCOS and 142 control women from their original cohort and found a significantly higher prevalence of abnormal carotid plaque index in women with PCOS (7.2% v. 0.7% in controls) [10]. Thus most predominantly premenopausal women with PCOS (93%) had no evidence for subclinical carotid atherosclerosis. No difference was noted in the intima-media thickness between PCOS and controls until the age group 45 to 49, after which the difference increased in the oldest age groups [10]. POLYCYSTIC OVARIES AND CARDIOVASCULAR EVENTS Despite the periodic discordance between PCO and PCOS, many of the largest, best-designed studies of longterm health risks in women with PCOS have been done using ovarian morphology. In older women presently under study, ovarian morphology during their reproductive years may be retrieved from hospital records (i.e., pathology report, operative notes, etc. from a wedge resection/oophorectomy), and at least is not subject to the recall bias of a menstrual history in establishing a prior phenotype. But this method may also include a treatment bias if this wedge resection resulted in long-term benefits. Many of these women have experienced long-term resolution of their symptoms (e.g., infertility, anovulation, hirsutism) [100]; however, this benefit is not supported by short-term studies of the metabolic effects of partial



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ovarian destruction, which have shown little effect on insulin sensitivity and dyslipidemia [101]. In a study from the United Kingdom, 800 women diagnosed with PCO, primarily by histopathology at the time of an ovarian wedge resection, were followed for an average of 30 years after the procedure [102]. Observed death rates were compared to expected death rates using standardized mortality ratios. There was no increased death from cardiovascular-related causes, although there was an increased number of deaths caused by complications of diabetes in the PCO group. In a follow-up study by the same investigative group of 345 of these women with PCO and 1060 age-matched control women there was no increased long-term coronary heart disease mortality, although there was evidence of increased stroke-related mortality even after adjustment for BMI [103]. In a cohort of women with proven coronary artery disease (n = 143 and age <60 years), PCO were noted in 42% of the women, and additionally their presence was associated with more severe coronary artery stenosis (odds ratio: 1.7, 95% confidence interval: 1.1 to 2.3 of >50% stenosis with PCO compared to normal ovaries) [92]. CHRONIC ANOVULATION AND CARDIOVASCULAR EVENTS Despite the heterogeneous nature of anovulation in a reproductive-age population, some of the best epidemiologic studies of menstrual irregularity as a marker for chronic anovulation have shown an increased risk for cardiovascular events. The Dutch breast cancer screening study found a greater incidence of anovulatory cycles during the reproductive years (based on a midluteal urine sample) in women later developing cardiovascular disease [104]. Utilizing a prospective cohort design from the Nurse’s Health Study [105], 82,439 female nurses provided information in 1982 on prior menstrual regularity (at ages 20 to 35 years) and were followed through 1996 for cardiovascular events. Incident reports of nonfatal myocardial infarction, fatal CHD, and nonfatal and fatal stroke were made and confirmed by review of medical records. Compared with women reporting a history of regular menstrual cycles, women reporting usually irregular or very irregular cycles had an increased risk for nonfatal or fatal CHD. This increasing risk with increasing menstrual irregularity suggests a dose-response effect. Increased risks for CHD associated with prior cycle irregularity remained significant after adjustment for BMI and other several potential confounders, including family history of myocardial infarction and personal exercise history. There was a nonsignificant increase in overall stroke risk as well as in ischemic stroke risk associated with very irregular cycles. There was unfortunately no information on clinical or biochemical androgen excess among the study cohort to make the diagnosis of PCOS. The Nurse’s Health Study has also

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identified oligomenorrhea and highly irregular menstrual cycles as risk factors for developing type 2 diabetes, a major risk factor in itself for cardiovascular disease, especially in women [106]. Thus the increased cardiovascular risk ascribed to women with PCOS is still largely inferential, based on risk factors or surrogate markers [91, 95] or epidemiologic studies that focus on isolated stigmata of PCOS, such as PCO or chronic anovulation, that are even more heterogeneous than PCOS.

POLYCYSTIC OVARIAN SYNDROME: A LIFETIME DISORDER? The concept of PCOS as a reproductive disorder limited to the years between menarche and menopause has been shattered by its association with insulin resistance and its sequelae. This has led to the expansion of PCOS to a lifetime disorder, with premenarchal and postmenopausal phenotypes. In 1962, Neel was the first who argued for the existence of “thrifty” genes, which would have been preferred during human evolution [107]. Thrifty genes promoted an insulin-resistant phenotype, which utilized and stored energy efficiently, a survival benefit in the feastor-famine world of the hunter/gatherer. The immense resources of the Human Genome Project have led to massive searches for genes that cause type 2 diabetes and obesity. This search is still underway and is hampered by the complex genetic basis of the disorder as well as by gene-environment interactions [108]. Although many candidate genes in type 2 diabetes and obesity have been identified, pundits would claim that the lack of success in identifying specific mutations (except in rare, severe phenotypes) argues against a purely genetic cause for these conditions in the larger population. This belief has led to the development of the alternate hypothesis, that we are creatures of our environment, with the intrauterine environment exerting the greatest impact on our subsequent metabolic phenotype. The Barker hypothesis proposes that the source of insulin resistance lies in a harsh intrauterine milieu [109]. This milieu environmentally imprints our future metabolic fate. For those exposed to a nutritionally restricted womb, decreased fetal growth and birth weight are the result. The intrauterine famine results in imprinting a thrifty phenotype, where the anabolic effects of growth factors must be blunted in a nutrient-limited environment, one that ceases at birth. For instance, in the skeletal muscle, glucose is shunted to the development of more vital organs. They remain forever resistant to the effects of insulin, forming the basis for developing type 2 diabetes and cardiovascular disease in later life [110]. Studies by the proponents of this theory have shown that adults with low birth weight have an increased prevalence of impaired glucose tolerance and

type 2 diabetes [111] and have stigmata of the insulin-resistance syndrome (i.e., glucose intolerance, hypertension, and dyslipidemia) [112]. Premature pubarche, defined as the early appearance of pubic hair (before 8 years in girls and 9 years in boys), has been postulated as an early expression of PCOS in prepubescent girls [113]. Adolescent girls with premature pubarche have been noted to be hyperinsulinemic [114] and to have an increased androgen response to a gonadotropinreleasing hormone (Gn-RH) agonist [115]. Baseline DHEAS and androstenedione levels at diagnosis or premature adrenarche correlated with 17-hydroxyprogesterone (17-OHP) values after Gn-RH agonist stimulation, suggesting that functional ovarian hyperandrogenism is more common in these girls (same gene for CYP17 is expressed in both the adrenal and ovary). This sign of increased CYP17 activity is therefore the first phenotypic manifestation of this abnormality in both glands. These studies suggest that hyperinsulinemia plays a role in the hyperandrogenism found in premature pubarche and PCOS [116–118]. This hyperinsulinemia has been observed throughout all stages of puberty and cannot be explained by an increase in BMI when compared to normal subjects [119]. In one study, 45% of girls with a history of premature pubarche had ovarian hyperandrogenism [115]. These girls have subsequently developed chronic anovulation at the age of menarche [120]. Further low birth weight among girls with premature pubarche appeared to exacerbate the PCOS phenotype (Figure 29.3) [121]. At the other end of the reproductive spectrum, both menstrual irregularity [122] and hyperandrogenemia [123] appear to normalize as women with PCOS approach their late thirties and early forties. Evidence also suggests that polycystic ovaries may be more prevalent in younger women with PCOS, and that these also resolve with age [45]. Thus many of the reproductive stigmata may resolve before menopause, leading to the difficulty discussed as follows of linking long-term sequelae such as endometrial cancer and cardiovascular disease back to an earlier phenotype.

GENETIC ETIOLOGY There are several difficulties in conducting family studies in the search for genes that cause or contribute to the PCOS phenotype. PCOS is associated with infertility and low fecundity. Thus it is rare to find large pedigrees with multiple affected women with whom to perform linkage analysis. Assigning phenotypes based on hyperandrogenism or anovulation to premenarchal girls and postmenopausal women is difficult. Although a male phenotype has been postulated, there are no rigorously established clinical or biochemical features that can be

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FIGURE 29.3 Birth weight scores of postmenarcheal control girls (-, -, and -) and postmenarcheal girls with a history of precocious pubarche without ovarian hyperandrogenism and without hyperinsulinemia (+, -, and -), with ovarian hyperandrogenism and without hyperinsulinemia (+, +, and -), and with both ovarian hyperandrogenism and hyperinsulinemia (+, +, and +). Adapted from reference [121].

used to identify “PCOS males.” This makes formal segregation analysis and genetic linkage studies more difficult. The lack of animals that spontaneously develop a PCOSlike phenotype, especially mice, precludes the use of powerful tools of genetic mapping.

Family Studies The foundation of genetic studies is the evidence that disease clusters in families. None of the existing family studies of PCOS convincingly establishes a mode of inheritance either, because the number of families studied was too small, the parental phenotypes could not be firmly established, and the male phenotype is uncertain [124–133]. Moreover, the diagnostic criteria used to assign affected status differed among the studies, as did the methods with which the status of first- and second-degree relatives were ascertained. By and large, ovarian morphology determined from tissue biopsy, direct visualization, or diagnostic imaging, in association with menstrual disturbances and evidence for hyperandrogenism, have been used in most studies as the criteria for diagnosing PCOS in probands. Despite the heterogeneity in study design and the inability to obtain comprehensive phenotype information to permit

a formal segregation analysis, collectively the existing literature strongly suggests the clustering of PCOS in families, with a mode of inheritance that is not inconsistent with an autosomal-dominant pattern (Table 29.4). Nearly 50% of sisters of women diagnosed with PCOS had elevated total or bioavailable testosterone levels, suggesting that hyperandrogenemia is a dominant trait (Figure 29.4). The contribution of genetics to blood androgen levels was recently substantiated in a large population study that was not dealing with PCOS per se. The authors concluded that plasma androgen levels are “highly heritable” [134]. Several studies have shown altered and elevated levels of androgens in brothers of women with PCOS [131, 132]. It is surprising that there have been only a few studies of monozygotic twins with PCOS given the power of this approach to disclose the genetic basis of disease. Case reports have described affected sets of female twins [135, 136]. Yet, the largest available twin study did not support a strong genetic component [137]. Both mono- and dizygotic twins were studied with ultrasound, as well as with clinical and biochemical parameters. There was an unusually high incidence of polycystic ovarian morphology on ultrasound, with 50% of the study population being

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TABLE 29.4 Summary of Diagnostic Criteria for the Proband in Familial Studies of PCOS and Proposed Mode of Inheritance Author

Diagnostic Criteria for PCOS

Number Studied

Mode of Inheritance

Cooper et al. (124)

Oligomenorrhea, hirsutism, polycystic ovaries (by culdoscopy, gynecography, or wedge resection)

18 women with PCOS and their firstdegree relatives and a control group

Autosomal-dominant with reduced penetrance

Givens et al. (125)

Oligomenorrhea, hirsutism, and polycystic ovaries (examination and surgery)

3 multigeneration kindreds

(?X-linked) dominant

Ferriman and Purdie (126)

Hirsutism and/or oligomenorrhea, 60% with polycystic ovaries (by aircontrast gynecography)

381 women with PCOS and relatives and a control group

Modified dominant

Lunde et al. (127)

Clinical symptoms (menstrual irregularities, hirsutism, infertility, and obesity) and multicystic ovaries on wedge resection

132 women with PCOS and first- and second-degree relatives and a control group

Unclear, most consistent with autosomal-dominant

Hague et al. (128)

Clinical symptoms (menstrual dysfunction, hyperandrogenism, obesity, and infertility) and polycystic ovaries by transabdominal ultrasound

50 women with PCOS and 17 women with CAH and a control group

Segregation ratios exceeded autosomaldominant pattern

Carey et al. (129)

Polycystic ovaries (by transabdominal ultrasound)

10 kindreds and 62 relatives

Autosomal-dominant with 90% penetrance

Norman et al. (130)

Elevated androgens, decreased SHBG, and polycystic ovaries on ultrasound

5 families with 24 females and 8 males

Not stated

Legro et al. (131)

Elevated testosterone levels combined with oligomenorrhea (£6 menses/yr)

80 PCOS probands and 115 sisters

Hyperandrogenemia consistent with an autosomal-dominant trait

Govind et al. (132)

Polycystic ovary morphology on ultrasonograpy

29 families with 53 sisters and 18 brothers

Autosomal-dominant

Kahsar-Millar et al. (133)

Oligomenorrhea and either hirsutism or elevated testosterone levels

90 PCOS probands, 50 sisters, 78 mothers

Increased prevalence of symptoms in first-degree relatives suggesting genetic trait

affected. The authors found a high degree of discordance among the available twins for polycystic ovaries and suggested that PCOS might have a more complex inheritance pattern than autosomal-dominant, perhaps X-linked or polygenic; however, there was greater concordance among affected twins with respect to biochemical parameters, including fasting insulin levels and androgens. Hyperinsulinemia has been identified as a familial trait in PCOS families [130] and also appears to track with androgen levels in sisters of women with PCOS [138].

Phenotypes of Polycystic Ovarian Syndrome Cells Freshly isolated theca cells collected from ovaries of women with PCOS studied in short-term culture [139] and propagated PCOS thecal cells grown through multiple population doublings [140] display greater steroidogenic

activity than theca cells collected from normal ovaries (Figure 29.5). The latter studies are of importance because the long-term culture conditions and cell replication would presumably erase any effects of the in vivo hormonal milieu. The increased steroidogenic activity is caused by increased transcription of genes encoding steroidogenic enzymes, as reflected by enhanced promoter activities in cultured PCOS theca cells and increased levels of steroidogenic enzyme messenger ribonucleic acid (mRNA) in thecal tissue [140]. The biochemical phenotype displayed by PCOS theca cells is consistent with the findings from family studies, indicating genetic control of androgen production. The in vitro studies also demonstrated that the alterations in steroidogenic activity and expression of steroidogenic enzyme genes encompassed increased synthesis of progestins as well as androgens. Thus hyperandrogenemia cannot be attributed to abnormal expression of a single gene encoding a steroidogenic enzyme.

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FIGURE 29.4 Distribution of serum androgen levels in control women (control), hyperandrogenemic sisters with regular cycles (HA Sister), unaffected sisters, sisters with PCOS (PCOS Sister), and PCOS probands (Proband). (Adapted from reference [131]).

Differential patterns of phosphorylation of the bsubunit of the insulin receptor in skeletal muscle cells and fibroblasts from women with PCOS have been identified [141]. Approximately 50% of the sample population of women with PCOS studied showed the increased insulin receptor serine phosphorylation. This finding has been substantiated in ovarian tissue [142]. Although the persistent biochemical/molecular alterations in PCOS cells maintained in vitro could possibly be explained by a stable metabolic imprint (epigenetic factor) obtained in vivo, the collective observations are more simply explained by genetic differences. Moreover, the fact that several genes show altered patterns of expression suggests that the fundamental genetic abnormality in PCOS affects signal transduction pathways controlling the expression of suites of genes.



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FIGURE 29.5 Accumulation of 17OHP4, P4, and T in the Medium of Normal and PCOS Theca Cell Cultures Grown for 22 to 26 Population Doublings. Long-term cultures of normal and PCOS theca cells were grown until subconfluence and then transferred into SFM containing 5 mg/mL low-density lipoprotein, with increasing concentrations of forskolin (F) for 72 hours. After treatment the media were collected and analyzed by RIA. Results are presented as the means ± SDof steroid levels from quadruplicate theca cell cultures from three normal and three PCOS patients. (Adapted from reference [140]).

Polycystic Ovarian Syndrome Candidate Genes This conclusion raises to prominence candidate genes that are involved in cell signaling or chromosomal loci in which signal transduction genes reside, rather than candidate genes that are directly involved in steroid hormone synthesis and action, or carbohydrate metabolism and fuel homeostasis, or gonadotropin action and regulation. These genes to date have yielded few clues to the genetics of PCOS [143]. These latter group of candidate genes were selected for study because they could account for certain

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PCOS features or because they have been implicated in insulin-resistance syndromes. Although several loci have been proposed as PCOS genes, including CYP11A [144], the insulin gene al [145], and a region near the insulin receptor, the evidence supporting linkage is not overwhelming. The strongest case can be made for the region near the insulin receptor gene because it has been identified in two separate studies [146, 147]; however, the responsible gene at chromosome 19p13.3 remains to be identified. Association studies have provided several potential loci with genetic variants that may create or add to a PCOS phenotype, including Calpain 10 [148], IRS-1 and -2 [146, 147], and SHBG [149]. These are characterized by their genetic and clinical diversity. Because they are rare and their full impact on the phenotype is incompletely understood, routine screening of women with PCOS or stigmata of PCOS for these genetic variants is not indicated at this time. Currently, the treatment implications for individually identified genetic variants is uncertain and must be addressed on a case-by-case basis.

TREATMENT OF POLYCYSTIC OVARIAN SYNDROME The treatment section focuses first on therapies designed for generalized treatment of the syndrome and then on treatments directed at specific complaints. We are currently changing from a symptom-oriented treatment approach to PCOS, which often focused alternately on either suppression of the ovaries (for hirsutism and menstrual disorders) or stimulation of the ovaries (for infertility), to one that improves insulin sensitivity and treats a variety of stigmata simultaneously [150]. Multiple studies have shown that improving insulin sensitivity, be it from lifestyle modifications or from pharmacologic intervention, can result in lowered circulating androgens (primarily mediated through increased sex hormone binding globulin and less bioavailable androgen but also through decreased total testosterone), spontaneous ovulation, and spontaneous pregnancy. In other populations this improvement in insulin sensitivity can also result in a lower chance for developing diabetes; however, long-term studies documenting decreases in the incidence of such sequelae as endometrial cancer with improvements in insulin sensitivity are lacking.

GENERALIZED TREATMENTS OF POLYCYSTIC OVARIAN SYNDROME Lifestyle Modifications Obesity has become epidemic in our society and contributes substantially to reproductive and metabolic abnormalities in PCOS. Unfortunately, there are no effective

treatments that result in permanent weight loss, and it is estimated that 90% to 95% of patients who experience a weight decrease will relapse [151]. For obese patients with hirsutism, weight loss is frequently recommended as a potential benefit. Increases in SHBG through improved insulin sensitivity from weight loss may lower bioavailable androgen levels. In one study, about 50% of these women who lost weight experienced improvement in their hirsutism [152]. There have, unfortunately, been few studies on the effect of exercise alone on insulin action in hyperandrogenic women [153]. It is reasonable to assume that exercise would have the same beneficial effects in women with PCOS as women with type 2 diabetes [154]. There is much hype about the beneficial effects of diets of varying composition on insulin sensitivity, with many popular sources advocating a high-protein diet as the diet of choice for women with PCOS. Few studies support this theory, and there are theoretical concerns about the adverse effects of high protein on renal function in a population at high risk for diabetes, as well as the adverse effects of the increased fat composition of these diets on dyslipidemia.

Ovarian Suppressive Therapies Women with documented hyperandrogenemia, and stigmata of hirsutism and acne, would theoretically benefit most from this form of therapy. Suppressing the ovary has been achieved with either oral contraceptives, depot progestins, or Gn-RH analog treatment. Oral contraceptives both inhibit ovarian steroid production by lowering gonadotropins and raise SHBG through their estrogen effect, thus further lowering bioavailable testosterone. They may also inhibit dihydrotestosterone binding to the androgen receptor and 5a-reductase activity, and increase hepatic steroid clearance (because of stimulation of the P450 system). These myriad actions contribute to improving hirsutism [155]. There are theoretical reasons for choosing an oral contraceptive using a less androgenic progestin or one with specific androgen antagonistic properties (such as cyproterone acetate or drospirenone), but few studies show a clinical difference between different types of progestins. Although several oral contraceptive pills, including a triphasic oral contraceptive containing norgestimate, have been shown to improve acne and have received an FDA indication for this treatment, other pills also appear to offer similar results. A Gn-RH agonist may further lower circulating androgens, but comparative trials against other agents and combined agent trials have been mixed and have not shown a greater benefit of one or the other or combined treatment [156–159]. A Gn-RH agonist given alone results in unacceptable bone loss [159]. Glucocorticoid suppression of the adrenal also offers theoretical benefits, but deterioration in glucose tolerance is problematic for women with PCOS, and long-term effects such as osteoporosis are a significant

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concern. It may be useful as adjunctive therapy in inducing ovulation with clomiphene citrate.

Surgical Options The beneficial influence of treatment on sequelae of PCOS, especially destructive ovarian interventions such as wedge resection or ovarian drilling, has been suggested but not proven. Many argue that the best monotherapy results for the endocrine abnormalities of PCOS can be obtained through surgical destructive processes of the ovary, wedge resection or ovarian drilling [160–162]. The value of laparoscopic ovarian drilling as a primary treatment for subfertile patients with anovulation and PCOS is undetermined, according to a Cochrane review [163]. There is insufficient evidence to determine a difference in ovulation or pregnancy rates when compared to gonadotrophin therapy as a secondary treatment for clomiphene-resistant women [163], although a recent study suggested that the pregnancy rates were equivalent [164]. None of the various drilling techniques appear to offer obvious advantages [163]. The results of ovarian drilling may in some cases also be temporary [100]. Surgery, consisting of total abdominal hysterectomy and bilateral salpingo-oophorectomy, is not a usual initial treatment option for androgen excess, but may be indicated in some cases of refractory ovarian hyperandrogenism.

Insulin-Sensitizing Agents Drugs developed initially to treat type 2 diabetes have also been utilized to treat PCOS. None of these agents are currently FDA approved for the treatment of PCOS or for related symptoms such as anovulation, hirsutism, or acne. These include metformin [165–167], thiazolidinediones, and an experimental insulin sensitizer drug d-chiroinositol [13]. METFORMIN Metformin was approved for the treatment of type 2 diabetes by the FDA in 1994 but was used clinically for close to 20 years before that in other parts of the world. Several trials on metformin’s effects in women with PCOS have been published, and meta-analyses have begun to appear [168], although there has never been an adequately powered placebo-controlled dose-ranging study. Metformin is a biguanide that works primarily by suppressing hepatic gluconeogenesis, but it also improves insulin sensitivity in the periphery. Metformin has no known human teratogenic risk or embryonic lethality in humans. There have been no reported abnormalities associated with its use during pregnancy in women with diabetes [169–171], or to women with marked hyperandrogenism during pregnancy [172], or to the small number of women with PCOS who have conceived during treatment [173–175]. Some



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clinicians advocate its use during early pregnancy to reduce the miscarriage rate, but the documentation for this claim is poor [176]. Studies of longer duration with metformin in PCOS suggest long-term improvement in ovulatory function in about half of the patients [177]. Unfortunately, there have been few well-designed studies that test the effect on hirsutism. THIAZOLIDINEDIONES Thiazolidinediones are peroxisome proliferatoractivated receptor (PPAR) agonists and are thought to improve insulin sensitivity through a postreceptor mechanism. It is difficult to separate the effects of improving insulin sensitivity from that of lowering serum androgens because any “pure” improvement in insulin sensitivity can raise SHBG and thus lower bioavailable androgen. Given the long onset of action for improving hirsutism, longer periods of observation are needed. In a large multicenter trial, troglitazone has been shown to have a dose-response effect in improving ovulation and hirsutism [14]. This appeared to be mediated through decreases in hyperinsulinemia and decreases in free testosterone levels. Troglitazone has subsequently been removed from the worldwide market because of hepatotoxicity. Newer thiazolidinediones such as rosiglitazone and pioglitazone appear to be safer in terms of hepatotoxicity but have also been associated with embryotoxicity in animal studies (both are pregnancy category C), and little has been published on their effects in women with PCOS.

TREATMENT OF INFERTILITY Clomiphene Citrate Clomiphene citrate (CC) has traditionally been the firstline treatment agent for infertility in women with PCOS. It is a nonsteroidal agent and a member of a large family of triphenylethylene derivatives, which includes clorotrianisene and tamoxifen (both of which compare favorably to CC in inducing ovulation). It is a racemic mixture of two isomers, zuclomiphene (longer acting) and enclomiphene (more potent in inducing ovulation) [178]. Clomiphene has a long half-life; only 51% of the oral dose is excreted after 5 days, and the zu isomer can be detected in the serum for up to 1 month after treatment [179]. Clomiphene is thought to work as a selective estrogen receptor modulator (SERM), acting as an estrogen antagonist at the hypothalamic-pituitary axis and stimulating Gn-RH secretion. CC’s mixed estrogen agonist/antagonist effects on the lower female genital tract as well as on implantation have been more theoretically antagonist than documented. A meta-analysis showed CC to be effective in patients with ovulatory dysfunction similar to PCOS [180]. Compared with a placebo, CC was associated with increased

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ovulation. CC (all doses) was associated with an increased pregnancy rate per treatment cycle (odds ratio: 3.41, 95% confidence interval: 4.23 to 9.48) The odds ratio was better for high doses (50–250 milligrams per day) (odds ratio: 6.82, 95% confidence interval: 3.92 to 11.85) [180]. There are no clear prognostic factors to response, although increasing weight is associated with a larger dose requirement and a greater likelihood for failure [181]. Roughly 50% of women with PCOS do not respond to CC. There is no universal definition of resistance to CC, although in its simplest rendition this would involve failure to ovulate to three progressive dose increases up to 750 mg/ cycle. Alternate CC regimens have been developed, including prolonging the period of administration [182] and adding dexamethasone [183], both of which have been shown to improve response in small studies.

methods, while improving hirsutism, do not produce the dramatic results patients desire. In general, combination therapies appear to produce better results than singleagent approaches; responses with medical therapies often take 3 to 6 months to notice improvement; and adjunctive mechanical removal methods are often necessary. However, most women will experience improvement in their hirsutism. There are unfortunately no universally accepted techniques for assessing hirsutism and response to treatment. Trials have been hampered by these methodology concerns as well as by small numbers of subjects. For instance, although spironolactone has had a long and extensive use as an antiandrogen and multiple clinical trials have been published showing a benefit, the overall quality of the trials and small numbers enrolled have limited the ability of a meta-analysis to document its benefit in the treatment of hirsutism [191].

Gonadotropins Gonadotropins are also frequently utilized in both step-up and step-down regimens to induce ovulation in women with PCOS. In one of the largest trials of gonadotropins in women with PCOS to date, women were randomized to a conventional method of ovulation with more aggressive dosing and increases in FSH dosing compared to a lowdose protocol; higher pregnancy rates were achieved with the low-dose protocol (40% v. 20% for the conventional arm) [184]. There were fewer cases of multiple pregnancy and ovarian hyperstimulation in the low-dose arm and a higher percentage of monofollicular ovulation (74% v. 27%) [184]. Low-dose therapy with gonadotropins offers a high rate on monofollicular development (~50% or greater) with a significantly lower risk of OHSS (20% to 25%) leading to cycle cancellation or more serious sequelae [184–188]. A Cochrane review reports a reduction in the incidence of OHSS with FSH compared to hMG in stimulation cycles without the concomitant use of a GnRH-a (odds ratio: 0.20, 95% confidence interval: 0.08 to 0.46) and a higher overstimulation rate when a Gn-RH-a is added to gonadotropins (odds ratio: 3.15, 95% confidence interval: 1.48 to 6.70) [189]. Despite theoretical advantages, urinary-derived FSH preparations did not improve pregnancy rates when compared to traditional and cheaper hMG preparations; their only demonstrable benefit was a reduced risk of OHSS in cycles when administered without the concomitant use of a Gn-RH-a. A meta-analysis found no studies of adequate power to confirm the benefit of pulsatile Gn-RH-a to induce ovulation in PCOS [190].

TREATMENT OF HIRSUTISM Many of the aforementioned generalized treatments are also applicable to the treatment of hirsutism. Most medical

Ornithine Decarboxylase Inhibitors Ornithine decarboxylase is necessary for the production of polyamines and is also a sensitive and specific marker of androgen action in the prostate [192]. Inhibition of this enzyme limits cell division and function. Recently, a potent inhibitor of this enzyme, eflornithine, has been tested and found to be effective as a facial cream against hirsutism and has been approved by the FDA for this indication. It is given as a 13.9% cream of eflornithine hydrochloride and applied to affected areas twice a day for a minimum of 4 hours each. In clinical trials, 32% of patients showed marked improvement after 24 weeks compared to 8% of those treated with a placebo; benefit was first noted at 8 weeks. It is a pregnancy category C drug that appears to be well tolerated. A variety of adverse skin conditions occurred in 1% of subjects.

Antiandrogens and Androgen Receptor Antagonists These compounds antagonize the binding of testosterone and other androgens to the androgen receptor and are not approved by the FDA for this indication in women. As a class, therefore, they are teratogenic and pose risk of feminization of the external genitalia in a male fetus if the patient conceives. Spironolactone, a diuretic and aldosterone antagonist, also binds to the androgen receptor with 67% of the affinity of dihydrotestosterone [193]. It has other mechanisms of action, including inhibition of ovarian and adrenal steroidogenesis, competition for androgen receptors in hair follicles, and direct inhibition of 5areductase activity. There is a dose-response effect and a long period of onset: 6 months or more. About 20% of treated women will experience increased menstrual frequency, which is one reason for combining this therapy

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with the oral contraceptive [194]. Because it can cause and exacerbate hyperkalemia, it should be used cautiously in patients with renal impairment. The medication also has potential teratogenicity as an antiandrogen, although exposure has rarely resulted in ambiguous genitalia in male infants [195]. Acne has also been successfully treated with spironolactone [196]. Thus much of the treatment basis is empiric. Cyproterone acetate, not available commercially in the United States, is a progestogen with antiandrogen properties. It is frequently combined in an oral contraceptive. Flutamide is another nonsteroidal antiandrogen that has been shown to be effective against hirsutism [197]. There is a greater risk of teratogenicity with this compound, so contraception should be used.

Antiandrogens: 5a-reductase Inhibitors There are two forms of the enzyme 5a-reductase: type 1 predominantly found in the skin and type II predominantly found in the prostate and reproductive tissues. Both forms are found in the PSU and may contribute to hirsutism, acne, and balding. Finasteride inhibits both forms. It has been found to be effective for the treatment of hirsutism in women [198, 199]. Finasteride is better tolerated than other antiandrogens but has the highest and clearest risk for teratogenicity in a male fetus, so adequate contraception must be used. Randomized trials have found that spironolactone, flutamide, and finasteride all have similar efficacy in improving hirsutism [200, 201].



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CONCLUSION PCOS is a common endocrinopathy, but it is poorly understood. It is a disorder of unexplained hyperandrogenic chronic anovulation and clearly heterogeneous in etiology; however, many women are noted to have profound peripheral resistance to insulin-mediated glucose uptake. Despite evidence of familial clustering, no clear molecular or genetic mechanism has been identified to date to explain most cases. Women with PCOS present with infertility, menstrual disorders, and hirsutism. They appear to be at increased risk for diabetes and display multiple risk factors for endometrial cancer and cardiovascular disease. Unfortunately, there are few randomized, controlled trials of any treatment in PCOS to provide clear treatment guidelines. Therefore, treatment tends to be symptom based, although lifestyle interventions and pharmaceutical treatments directed at improving insulin sensitivity appear to improve multiple stigmata of the syndrome. For instance, studies with these agents have shown improvements in ovulation and hirsutism.

ACKNOWLEDGMENTS This work was supported by PHS K24 HD01476, the National Cooperative Program in Infertility Research (NCPIR) U54 HD34449, a GCRC grant MO1 RR 10732 to Pennsylvania State University and K24 HD01476.

References OTHER TREATMENTS There are several, perhaps innumerable other treatments, that have been proposed for PCOS. Many of these have come and gone, and some never arrived. Minoxidil has mild efficacy in increasing hair growth in women with alopecia. Ketoconazole is an inhibitor of the P450 enzyme system and thus inhibits androgen biosynthesis but has hepatotoxicity. Others have given aromatase inhibitors to induce ovulation and lower circulating androgens, although hirsutism has not been the primary focus to date [202]. Mechanical hair removal (e.g., shaving, plucking, waxing, depilatory creams, electrolysis, and laser vaporization) can control hirsutism, and these methods are often the front-line treatment used by women. Laser vaporization is receiving increasing attention. Hair is damaged using the principle of selective photothermolysis with wavelengths of light well absorbed by follicular melanin and pulse durations that selectively thermally damage the target without damaging surrounding tissue. Patients with dark hair and light skin are ideal candidates, and it appears to be most effective during anagen.

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