PART III OTHER ISSUES Other IssuesPolycystic Ovary Syndrome CHAPTER 17 Polycystic Ovary Syndrome PARAMJIT T. JOSHI and ADELAIDE S. ROBB Polycystic ovary syndrome (PCOS) is a common, complex, and se- rious endocrine disorder that affects women in their reproductive years. The disorder was first recognized in 1935 by two gynecologists, Stein and Leventhal (1935). They described a group of women who had a constella- tion of infertility and several menstrual irregularities and were obese. They were also found to have enlarged ovaries with multiple cysts at laparotomy (Zawadski & Dunaif, 1992). Although it has come to be known as PCOS, the ovarian morphology is a nonspecific finding. Approximately 20% of normal women can have classic polycystic ovarian morphology on ultra - sound examination (Dunaif, 1997). Subsequently, others have reported PCOS to be a disorder characterized by ovulatory dysfunction and hyper - androgenism that is thought to have a higher prevalence in women with ep - ilepsy and, perhaps, bipolar disorder. Unlike the earlier reports by Stein and Leventhal (1935), others have noted that women with PCOS can be lean, and the symptoms of androgen excess may be absent. PCOS is the leading cause of hormonally related in - fertility and hirsutism and has been associated with multiple reproductive and metabolic disorders. Approximately 80% of women with oligomen - orrhea, the clinical consequence of chronic anovulation, have PCOS (Dunaif, 1997). PCOS is also a major risk factor for type 2 diabetes mellitus (DM) in women (Legro et al., 1999). 333 An association between the development of PCOS and the use of antiepileptic drugs was first suggested by Isojärvi et al. (1993). This sugges - tion was based on clinical observations that women with epilepsy who re - ceived an antiepileptic drug experienced an increased rate of menstrual ab - normalities. Although there are no reports of PCOS in teenage girls, use of mood stabilizers such as valproate is increasing for the treatment of bipolar disorders in children and adolescents. Three letters to the editor of the Jour - nal of the American Academy of Child and Adolescent Psychiatry (Garland & Behr, 1996; Eberle, 1998; Johnston, 1999) draw attention to this poten - tial association between use of valproate and development of PCOS in teenage girls. They stimulate awareness for both clinicians and researchers and ask for prospective studies to be conducted to shed light on this possible associ - ation between the use of mood stabilizers (specifically valproate), other antiepileptic medications, and PCOS. PCOS is associated with several reproductive, metabolic, and general health disorders, including increased risk of miscarriage, insulin resistance, hyperlipidemia, and cardiovascular disease. Endometrial, ovarian, and breast cancer have all been reported to be more common in women with PCOS (Hardiman, Pillay, & Atiomo, 2003; Balen, 2001; Coulam, Annegers, & Kranz, 1983; Schildkraut et al., 1996). Elevated levels of circulating es- trogen and the lack of cycling shedding of the endometrium are considered to be the likely etiology of the increased risk for endometrial carcinoma in women with PCOS (Rasgon, 2004; Hardiman et al., 2003; Siiteri, 1987). In a large case control study examining the relationship between endogenous steroid hormones and endometrial cancer, Potischman and colleagues (1996) found increased risk of endometrial cancer in women with de- creased sex-hormone-binding globulin (SHBG) and increased androgen lev- els. Although obesity is not always present in women with PCOS, it is a common finding, with reports of up to 50% of women with PCOS being obese, described primarily as the android-type obesity, with an increase in the waist–hip ratio (Lobo & Carmina, 2000). It has been postulated that obesity within itself may promote the development of PCOS through pe - ripheral aromatization of androgen to estrogen within adipose tissue (Franks, 1995; Siiteri, 1987). Subsequently this obesity contributes to the high rates of type 2 diabetes and hyperlipidemia and increases the risk of cardiovascular disease in women with PCOS (Rasgon, 2004). DEFINITION PCOS is characterized by both hormonal and metabolic abnormalities. Dis - parate definitions of this syndrome have been proposed. A contemporary working definition is hyperandrogenism and chronic anovulation (i.e., 334 OTHER ISSUES menstrual abnormalities and reproductive morbidity) in the absence of identifiable pituitary or adrenal pathology. Interestingly, polycystic ovaries are not necessary for the diagnosis to be made (Dunaif & Thomas, 2001; Lobo & Carmina, 2000). Many of these women have endocrine abnormalities such as elevated testosterone and/or luteinizing hormone (LH ) levels (Franks, 1995). How - ever, some women with polycystic ovaries can be entirely endocrinologi - cally normal. Moreover, approximately 10% of women with all the features of the endocrine syndrome have normal-appearing ovaries by ultrasound examination (Ehrmann et al., 1995). Accordingly, the recommended diag - nostic criteria for PCOS at the 1990 National Institutes of Health (NIH) conference on polycystic ovary syndrome (Zawadski & Dunaif, 1992) were hyperandrogenism and chronic anovulation in the absence of specific dis - eases of the ovaries, adrenals, or pituitary. It is important to differentiate this endocrine syndrome from the ovarian morphological change of poly - cystic ovaries. Outside the United States, it is still typical to diagnose women by the appearance of their ovaries on ultrasound examination. These differing diagnostic criteria for PCOS account for many of the dis- crepant findings in the literature. It appears, however, that polycystic ova- ries function abnormally, even in the absence of the peripheral endocrine syndrome, both in the steroidogenic activity of the theca interna and in the follicular responses to exogenous follicle-stimulating hormone (FSH; Franks, 1995). Therefore, the definition of PCOS differs in the United States and in Europe in the following ways: • In the United States, PCOS is defined as a metabolic syndrome, and anatomical changes need not be present to establish diagnosis. • In Europe, on the other hand, PCOS is defined as polycystic ovaries in the presence of one or more clinical signs of endocrine dysfunc - tion, such as menstrual irregularities, hirsutism, or infertility. The diagnostic criteria for PCOS on which participants agreed at the 1990 NIH–PCOS consensus conference (Zawadski & Dunaif, 1992; Duncan, 2001; Ernst & Goldberg, 2002), are as follows: • The presence of ovulatory dysfunction (polymenorrhea, oligomenor - rhea, or amenorrhea). • Clinical evidence of hyperandrogenism and/or hyperandrogenemia. • Exclusion of other endocrinopathies affecting adrenal or thyroid function, such as hyperprolactinemia, hypothyroidism, adrenal hy - perplasia, or Cushing’s syndrome. • Exclusion of anatomical findings of polycystic ovaries, multifollicu - lar ovaries, or hyperandrogenism in isolation. Polycystic Ovary Syndrome 335 However, as suggested by Chappell, Markowitz, and Jackson (1999), the diagnosis of PCOS is generally made through a combination of clinical, biochemical, and ultrasonographic findings. DIFFERENCES BETWEEN PCOS AND POLYCYSTIC OVARIES Whereas PCOS is a complex endocrine disorder characterized by metabolic and endocrine abnormalities that affects women in their reproductive years, polycystic ovaries are a common but not intrinsically pathological occurrence in 22–30% of the general female population (Luef, Abraham, Haslinger, et al., 2002; Genton et al., 2001). The accepted definition of polycystic ovaries by ultrasonographic and anatomical criteria is the pres - ence of at least 10 subcapsular follicular cysts, measuring 2–8 mm in diam - eter, arranged around or within thickened ovarian stroma (Adams et al., 1985; Adams, Polson, & Franks, 1986; Duncan, 2001). As many as 25% of women with radiological findings of polycystic ovaries have no endo- crine or menstrual irregularities, suggesting that an isolated finding of polycystic ovaries may be a normal variation and may not necessarily imply altered fertility (Genton et al., 2001). It is therefore important to distin- guish between these two conditions when interpreting clinical studies (Ernst & Goldberg, 2002). A case control study of 258 women with and without other hormonal or metabolic symptoms of PCOS, showed that there was no significant effect on fertility (Hassan & Killick, 2003). There- fore, the finding of polycystic ovaries in otherwise healthy women may not necessarily predict reproductive dysfunction (Rasgon, 2004). Other disorders that need to be considered in the differential for PCOS in - clude: nonclassic adrenal 21-hydroxylase deficiency (prevalence 1–5%), hyper - prolactinemia and Cushing’s syndrome (occasional occurrence), surreptitious androgen use (rare), extreme insulin resistance syndromes, for example, type A (rare), and ovarian and adrenal androgen-secreting neoplasms (very rare). PREVALENCE Only recently have there been studies of the prevalence of the classic endo - crine syndrome of hyperandrogenism and chronic anovulation. The preva - lence of PCOS in the general population of reproductive-age women hasbeen estimated to be between 4 and12%,withoutany differences in prevalence be - tween Caucasian and African American women (Dunaif & Thomas, 2001; Lobo & Carmina, 2000; Knochenhauer et al., 1998). However, most reports show a higher prevalence (10.5–26%) of PCOS in women with epilepsy than in the general population (Bauer et al., 2000; Bilo et al., 2001). Franks (1995) reported that 37% of women with amenorrhea and 90% with oliomenorrhea 336 OTHER ISSUES had PCOS. Bauer et al. (2000) studied 93 women with epilepsy and found that the incidence of PCOS was 10.5% in an untreated group, 11.1% in a valproate-treated group, and 10% in a carbamazepine-treated group. There are no prevalence studies in females under the age of 18 years. Valproate is an approved treatment for epilepsy syndrome. Bipolar treatment guidelines from Canada and the United States recommend valproate as a first-line strategy in the acute treatment of bipolar disorder (O’Donovan et al., 2002). Most persons with bipolar disorder require maintenance treatment, which necessitates the need for careful appraisal of long-term tolerability and safety issues. There have been reports of valproic acid inducing PCOS in females with epilepsy (Franks, 1995). These observations have initiated preliminary investigation in bipolar dis - order (Dunaif & Thomas, 2001; Knochenhauer et al., 1998; Yen, 1991). Recently, O’Donovan et al. (2002) reported that valproate-treated fe - males with bipolar disorder exhibited a high prevalence of menstrual ir - regularities and exhibited ultrasonographically confirmed polycystic ova - ries (41%). A study of ambulatory females with DSM-IV-defined bipolar disorder between the ages of 18 and 45 (10 receiving valproate mono- therapy) failed to identify any biochemical or ultrasonographic evidence of PCOS in females receiving valproate or lithium (Rasgon et al., 2000). It was noted by both groups that bipolar females exhibited a higher prev- alence of menstrual disturbances than the general population. Others have described the potential associations between PCOS and valproate (Herzog, 1996; Post et al., 2001). Although it awaits to be established whether females with bipolar dis- order manifest a higher prevalence of primary reproductive endocrine dis- orders, they appear to be more overweight or obese than the general popu- lation (Suppes, Leverich, & Keck, 2001). Valproate and several other psychotropic agents impart substantial weight gain (Ferriman & Gallwey, 1961; Roste et al., 2001). Excess weight gain may independently predispose and portend risk for subsequent reproductive endocrine and metabolic dis - orders. Various theories have been offered to explain this higher prevalence of PCOS and other reproductive disorders in these patient populations, in - cluding the effects of the disease itself and of antiepileptic drugs, especially valproate, which may directly cause PCOS or indirectly lead to the disorder by causing weight gain that triggers insulin resistance, increased testoster - one levels, and other reproductive abnormalities. CLINICAL FEATURES Hyperandrogenism and anovulation are the key features of PCOS, as de - fined by the National Institutes of Health (NIH) consensus diagnostic crite - ria. The common clinical manifestations of these abnormalities, therefore, are as follows: Polycystic Ovary Syndrome 337 Menstrual Irregularities These may manifest themselves at puberty either with delayed menarche followed by the onset of irregular periods or as the breakdown of a previ - ously regular menstrual cycle within a few years. Chronic anovulation in PCOS is associated with disordered gonadotropin secretion and presents as oligomenorrhea (8–10 menstrual cycles/year) or amenorrhea (the absence of menstrual cycles) before menopausal onset (Lobo & Carmina, 2000). Women with PCOS often are infertile, and for the few PCOS patients who become pregnant, there are increased risks of miscarriage, gestational dia - betes, and pregnancy-induced hypertension (Duncan, 2001; Lobo & Car - mina, 2000; Ernst, 2002). These menstrual irregularities are also associated with weight gain, and it is reported that approximately half of the women with PCOS are obese and that 20% of them will have either impaired glucose tolerance or type 2 diabetes by the time they reach 40 years of age (Duncan, 2001). Other risks associated with PCOS are endometrial hyperplasia or malig - nancy, hypertension, coronary heart disease, and unhealthy lipid profiles, that is, elevated levels of triglycerides and low-density lipoproteins (LDLs). Hyperandrogenism Hyperandrogenism may appear clinically as hirsutism, acne, male pattern balding, and/or male distribution of body hair or alopecia (Lobo & Carmina, 2000). The virilizing features of this illness are due to the elevated androgens (testosterone and androstenedione) and their precursors dehydro- epiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEAS; Herzog, 1996). The excess androgens are associated with subtle hyperes - trogenism (Lobo & Carmina, 2000; Dahlgren et al., 1992). It is thought that the disorder may be caused by increased steroido - genic activity that is an intrinsic defect in the ovary (Dunaif & Thomas, 2001). In vitro studies show that women with PCOS secrete increased amounts of androstenedione (an androgen) and increased amounts of 17- hydroxyprogesterone (a steroid that is an intermediate in the androgen and glucocorticoid biosynthetic pathway) from thecal cells (the androgen- producing cells of the ovary). This increased secretion by thecal cells may be a result of dysregulation of the rate-limiting enzyme in androgen biosynthesis, cytochrome P-450c17α. Reproductive Endocrine Abnormalities Reproductive endocrine abnormalities are often present, but none are path - onomonic or found in all women with the disorder. The common endocrine abnormalities include: elevation of LH in urine and serum and low normal 338 OTHER ISSUES plasma FSH, leading to an increased LH/FSH ratio (Duncan, 2001). This go - nadotropin hormonal imbalance leads to an increase in LH-stimulated ovar - ian steroidogenesis and a decrease in follicle maturation (Franks, Mason, & Willis, 2000; Rasgon, 2004). This incomplete follicle maturation in turn is thought to lead to the formation of a larger number of small, immature folli - cles and, subsequently, the formation of follicular cysts (Rasgon, 2004). Furthermore, decreases in SHBG as a result of hyperinsulinemia and hyperandrogenism, are commonly seen in this syndrome. The decreased SHBG concentration increases the bioavailable fraction of androgens and estrogens, which may increase free testosterone levels. In general, however, estrogen and FSH levels remain in the normal range (Isojärvi et al., 1995; Bauer et al., 2000; Herzog, 1996). Metabolic Abnormalities Metabolic abnormalities such as hyperinsulinemia and insulin resistance occur at greater frequency and intensity in women with PCOS. Approxi- mately 40% of women with PCOS have been shown to have impaired glu- cose tolerance tests (Ehrmann et al., 1999; Legro et al., 1999). The rates of impaired glucose tolerance vary from 31 to 35%, versus 7.8% when com- pared with the general U.S. female population (Ehrmann et al., 1999; Legro et al., 1999). Consequently, up to 20% of obese women may exhibit type 2 diabetes by age 40 years (Dunaif, 1995). Insulin resistance is independent of the effect of obesity and may occur regardless of whether the women are lean or obese compared with normal women (Franks, 1995). Further, Lobo and Carmina (2000) have shown that insulin resistance has been found to be more pronounced in women with chronic anovulation than in those who have ovulatory cycles. In women with PCOS, insulin resistance is characterized by decreased sensitivity to insulin in peripheral tissues but not hepatic resistance, unlike insulin resistance in type 2 diabetes. Hopkinson and colleagues (1998) re - ported that there was support for suggesting that decreased peripheral insu - lin sensitivity and, consequently, hyperinsulinemia were pivotal to the pathogenesis of PCOS. Hopkinson hypothesized that insulin acts in the liver to inhibit the production of insulin-like growth factor 1 (IGF-1) binding protein and SHBG, with the latter leading to an increase in free testoster - one. Therefore, according to Hopkinson, insulin resistance not only in - creases the secretion of ovarian androgen but also promotes an increase in the proportion of free (biologically active) hormone. Lipid and Lipoprotein Abnormalities These abnormalities include elevated LDLs and triglycerides, decreased lev - els of high-density lipoproteins (HDL), and apolipoproteins A-1 (Legro, Polycystic Ovary Syndrome 339 Kunselman, & Dunaif, 2001; Lobo & Carmina, 2000). Additionally, im - paired fibrinolytic activity has also been reported, as assessed by measure - ments of elevated levels of circulating plasminogen activator inhibitor levels (a potent inhibitor of fibrinolysis), which has been shown to be a risk factor for the occurrence of hypertension and myocardial infarction (Dahlgren et al., 1992; Hopkinson et al., 1998). However, decreased levels of HDL is considered to be the most characteristic lipid abnormality in women with PCOS (Hopkinson et al., 1998). Reproductive Abnormalities These abnormalities can often develop shortly after menarche in many women and can last most of their reproductive lives. In others it may ap - pear as a breakdown of a previously regular menstrual cycle, which is often associated with weight gain (Duncan, 2001). However, the most pressing concern is the occurrence of varying degrees of infertility, with PCOS iden - tified in 75% of women with anovulatory infertility (Legro et al., 2001). Women have also been reported to be at much greater risk of having multi- ple pregnancies through ovulation induction or after in vitro fertilization (Legro et al., 2001). ETIOLOGY The etiology of PCOS is not fully understood, though several authors have suggested that PCOS is caused by interactions between a variety of genetic, neuroendocrine, metabolic, and environmental factors (Rasgon, 2004; Dunaif & Thomas, 2001). Genetic Factors Familial aggregation of PCOS has been clearly established, suggesting ge - netic susceptibility (Franks, 1995; Legro & Strauss et al., 1998). Various modes of transmission have been discussed, including an autosomal domi - nant inheritance pattern based on familial aggregation of hyperandro - genism in first-degree relatives of patients with PCOS (Legro, Strauss, et al., 1998; Ernst & Goldberg, 2002). In addition, brothers of women with PCOS often show evidence of insulin resistance and elevated dehydroepian - drosterone levels, findings that might suggest their reproductive and meta - bolic phenotypes resemble those of their sisters with PCOS (Dunaif & Thomas, 2001). There is also evidence that there may be a genetic defect in ovarian and adrenal androgen biosynthesis that may synergize with a meta - bolic abnormality (Rasgon, 2004; Lobo & Carmina, 2000). Studies on women with PCOS suggest that the disorder may be caused by increased 340 OTHER ISSUES [...]... AND PCOS In Patients with Epilepsy It has been suggested that use of anticonvulsants in general and sodium valproate in particular leads to an increased incidence of polycystic ovaries and PCOS (Isojärvi et al., 199 3; Isojärvi et al., 199 5; Isojärvi et al., 199 6; Isojärvi et al., 199 8) In their initial study of 238 women with epilepsy, Isojärvi and colleagues ( 199 3) reported some symptoms of PCOS in. .. development of PCOS include an increased LH/FSH ratio and increased insulin and androgen concentrations Increased levels of 17-hydroxyprogesterone levels in thecal cells have also been implicated in playing a role in the development of PCOS Abbott, Dumesic, and Franks (2002) propose a developmental theory in understanding some of these endocrine etiological factors Accordingly, they postulated that during... luteinizing hormone in women with epilepsy Neurology, 44(2), 306–310 Dunaif, A ( 199 5) Hyperandrogenic anovulation (PCOS): A unique disorder of insulin action associated with an increased risk of non-insulin-dependent diabetes mellitus American Journal of Medicine, 98 (1A), 33S–39S Dunaif, A ( 199 7) Insulin resistance and the polycystic ovary syndrome: Mechanism and implications for pathogenesis Endocrine Reviews,... between PCOS and valproate or carbamazapine treatment in a study of 93 women with epilepsy, refuting the earlier results of Isojärvi and colleagues ( 199 3; Isojärvi et al., 199 5; Isojärvi et al., 199 6; Isojärvi et al., 199 8) In this study the diagnosis of PCOS was made using the NIH criteria and hence distinguished between polycystic ovaries and PCOS Compari- Polycystic Ovary Syndrome 3 49 sons were made... al ( 199 8) Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome Proceedings of the National Academy of Sciences of the USA, 95 (25), 1 495 6–1 496 0 Lobo, R A., & Carmina, E (2000) The importance of diagnosing the polycystic ovary syndrome Annals of Internal Medicine, 132(12), 98 9 99 3 Luef, G., Abraham, I., Haslinger, M., et al (2002) Polycystic ovaries, obesity and insulin resistance... hyperandrogenism in women taking valproate for epilepsy New England Journal of Medicine, 3 29( 19) , 1383–1388 Isojärvi, J I., Laatikainen, T J., Pakarinen, A J., et al ( 199 5) Menstrual disorders in women with epilepsy receiving carbamazepine Epilepsia, 36(7), 676–681 Isojärvi, J I., Rattya, J., Myllyla, V V., et al ( 199 8) Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy Annal of Neurology,... al., 199 6), polycystic ovaries and hyperandrogenism were seen in 79% of obese women and 65% of lean women treated with valproate This information was not reported for the carbamazapine group or control group The frequency of polycystic ovaries and hyperandrogenism in the carbamazepinetreated group was 20% and, among the normal controls, 19% Menstrual disorders were seen in 79% of the obese valproate-treated... valproate in the normally cycling rhesus monkey Journal of Clinical Endocrinology and Metabolism, 88, 290 8– 291 5 Ferriman, D., & Gallwey, J D ( 196 1) Clinical assessment of body hair growth in women Journal of Clinical Endocrinology, 21, 1440–1447 Franks, S ( 199 5) Polycystic ovary syndrome New England Journal of Medicine, 333(13), 853– 861 Franks, S., Mason, H., & Willis, D (2000) Follicular dynamics in the... result of dysregulation of the rate-limiting enzyme in androgen biosynthesis, cytochrome P-450c17a (Franks, 199 5) In order to determine whether there was a biochemical reproductive endocrine phenotype, Legro, Spielman, et al ( 199 8) studied the sisters of women with PCOS and found that there was familial aggregation of hyperandrogenemia in PCOS kindreds, with 46% of 115 sisters thus affected Only one-half... epilepsy, bipolar disorder, AEDs, and development of PCOS symptoms Further, given the number of children and adolescents who are now being prescribed AEDs both for the treatment of epilepsy and bipolar disorder, this age group should also be included in future studies Until we understand more about the associations between epilepsy and bipolar disorders, AED therapies, and PCOS, clinicians prescribing AEDs . bipolar disorders in children and adolescents. Three letters to the editor of the Jour - nal of the American Academy of Child and Adolescent Psychiatry (Garland & Behr, 199 6; Eberle, 199 8; Johnston, 199 9). hypothesized that insulin acts in the liver to inhibit the production of insulin-like growth factor 1 (IGF-1) binding protein and SHBG, with the latter leading to an increase in free testoster - one. Therefore,. cancer, Potischman and colleagues ( 199 6) found increased risk of endometrial cancer in women with de- creased sex-hormone-binding globulin (SHBG) and increased androgen lev- els. Although obesity