Evaluation and Treatment of Polycystic Ovary Syndrome

Richard S. Legro, MD, Professor,Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey PA, 17033. : RSL1@psu.edu

Last Revised: 19 September 2009

Introduction

Polycystic ovary syndrome (PCOS) is an ovarian disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. It may be the most common female endocrinopathy in the developed world. However it most likely represents a heterogeneous disorder and one whose pathophysiology and etiology are debated. PCOS affects young women with oligo-ovulation (which can lead to oligomenorrhea), infertility, acne and hirsutism. It also has notable metabolic sequelae, including an elevated risk of diabetes and possibly cardiovascular disease, and long term treatment should also consider these factors. These multiple stigmata have lead to a multitude of treatments, the majority of which still tend to target individual symptoms. The search for the single unifying theory to this disorder will hopefully yield the single best treatment, but this quest remains one of the Holy Grails of reproductive endocrinology. This chapter will discuss the diagnosis, clinical evaluation, pathophysiology, and treatment of women with PCOS.

Diagnostic Criteria

There is no universally accepted definition of PCOS and expert generated diagnostic criteria have proliferated in recent years (Figure 1). They share a common focus on PCOS as an ovarian disorder. The definition of PCOS has largely been dependent on the technology used to ascertain the condition. Thus the earliest definition of PCOS, or the Stein Leventhal Syndrome was based on the triad of enlarged ovaries, hirsutism, and oligomenorrhea (1). As assays became available, first urinary and then serum, researchers noted gonadotropin abnormalities with elevated LH levels, and then as androgen assays evolved, elevation in androgen levels. However these multple tools to assess women with androgen excess and oligomenorrhea led to multiple diagnostic criteria (Figure 1) and often each investigative group had their own unique set, making the comparison of clinical studies often difficult if not impossible.

It was not until the early 1990s at a NIH sponsored conference on PCOS that formal diagnostic criteria were proposed and afterwards were largely utilized (2). These criteria, often referred to colloquially as “the NIH criteria” were published in the conference proceedings and received large scale acceptance in the research and clinical communities. These criteria defined PCOS as unexplained hyperandrogenic anovulation. They required the presence of oligomenorrhea AND hyperandrogenism, either clinical or biochemical along with the exclusion of phenocopies. The enduring portion of these criteria accepted by all other criteria was the exclusion of phenocopies such that PCOS remains a diagnosis of exclusion.

The improved technology and utilization of ultrasound in women’s health led to the ultrasound definiton of polycystic ovaries, defined primarily on the morphology and the number of small antral follicles (3) (Figure 2). The failure to recognize the polycystic ovary in the NIH definition of polycystic ovary syndrome led to the convening of an expert consensus conference to reconsider the NIH diagnostic criteria in Rotterdam in the Netherlands. The subsequent “Rotterdam criteria” incorporated the ultrasound determined size and morphology of the ovary into the diagnostic criteria (4, 5). Ultrasound criteria for the diagnosis of polycystic ovaries were also decided by expert consensus (Table 1)(6). However it is likely that these criteria will be revised with further study. The Rotterdam criteria have been criticized for including more mild phenotypes, for example the combination of polcystic ovaries with oligomenorrhea. These additional phenotypes may complicate the generalizability of clinical trials to treat PCOS, and may also elevate the prevalence of PCOS in the general population.

The Androgen Excess Society criteria subsequently attempted to establish hyperandrogenism as a sine qua nondiagnostic factor in combination with other stigmata of the syndrome (7). The focus on hyperandrogenism was to eliminate milder phenotypes and based on evidence that hyperandrogenism tends to track with both reproductive (i.e. acne, hirsutism, and androgenic alopecia) and metabolic (i.e. insulin resistance, dyslipidemia, and elevated cardiovascular risk) stigmata of the syndrome.

There are however unifying trends to all diagnostic criteria. Hyperandrogenism in all schemas can be established on the basis of clinical findings (eg, hirsutism or acne) and/or serum hormone measurement (most commonly serum testosterone levels). All diagnostic schemes recommend that secondary causes (such as adult-onset congenital adrenal hyperplasia, hyperprolactinemia, and androgen-secreting neoplasms) should first be excluded (discussed below under differential diagnosis). All diagnostic schemes also require more than one sign or symptom. Polycystic ovaries alone, for example, are a nonspecific finding and also are frequently noted in women with no endocrine or metabolic abnormalities (8). Insulin resistance has been noted consistently among many women with PCOS, especially in those with hyperandrogenism, but it is not included in any of the diagnostic criteria.

We can conclude that there is a thread of continuity between the varying diagnostic criteria. All agree that it is an ovarian disorder and diagnostic criteria revolve around ovarian determined stigmata, such as hyperandrogenism, oligo-ovulation, and polycystic appearing ovaries. The utility of the varying diagnostic criteria is still being debated by experts, but will ultimately be answered by well designed clinical studies.

Incidence of PCOS

The incidence of PCOS varies according to the diagnostic criteria. Polycystic ovaries on ultrasound are noted in up to 25%-30% of reproductive aged women (8, 9). Thus the vast majority of women with polycystic ovaries do not have the syndrome. Women with unexplained hyperandrogenic chronic anovulation (i.e. NIH criteria) make up approximately 7% of reproductive age women (10). There is debate as to whether minorities are disproportionately affected with PCOS (11). Other studies, for example, have shown higher rates of insulin resistance and type 2 diabetes in minorities, including Latino, Native American, and African-American populations. However the evidence for this in women with PCOS is less certain. For example in the best study of an unselected population in the U.S. i.e. women applying for jobs at an academic medical center, there were no significant differences in the prevalence of PCOS or stigmata of PCOS, such as hirsutism or elevated circulating androgen levels between white and black women (10). The broader Rotterdam criteria increase the prevalence of PCOS by 50% over the NIH criteria (12), and the prevalence according to the AES criteria is somewhere inbetween.

PCOS is increasingly associated with obesity, and the obesity epidemic worldwide has been linked to an increased prevalence of PCOS (13). There are still marked differences in the prevalence of obesity and morbid obesity among women with PCOS according to country of origin as noted in Figure 3. Obesity, and severe obesity appear to be less common in the European PCSO population (14). It appears from the published literature that the U.S. tends to have the highest prevalence of severe obesity in its population and its PCOS population. A recent large multi-center trial reported a mean BMI of 35 among its 626 study participants with PCOS (15).

Etiology and Pathophysiology

The genetic contribution to PCOS remains uncertain, and there is currently no recommended genetic screening test. While genes likely contribute to the PCOS phenotype, it is likely a complex genetic trait, and based on genome wide association studies of such diseases, for example type 2 diabetes, there are likely multiple variants which each contribute only a small portion (less than 1%) to the phenotype of the syndrome. No specific environmental substance has been identified as causing PCOS, although certain medications such as valproate have been shown in vitro (16) or in clinical series in women with epilepsy to induce hyperandrogenism (17). Obesity however likely increases its prevalence (see discussion of the pathophysiology below). Thus the epidemic of obesity has been accompanied by an increased recognition of associated disorders, such as PCOS.

There are three common theories for the etiology of PCOS, one that it is due to hypothalamic-pituitary dysfunction, the second that it is due to ovarian (and adrenal hyperandrogenism), and the third that it is primarily a disorder of peripheral insulin resistance. We will address each theory in order.

Primary Disordered Gondadotropin Secretion The first biochemical abnormality that was identified in women with PCOS was disordered gonadotropin secretion, with a preponderance of LH to FSH. As the two cell theory of the ovary evolved , i.e that thecal cells can only produce androgens under stimulation of LH, whereas granulosa cells can only aromatize androgens from the theca cells into estrogens under the influence of FSH, this preponderance of LH was thought to be the primary etiology of the syndrome. Excess LH led to excess thecal cell development and androgen production, but in the face of inadequate FSH stimulation of granulosa cell development and aromatase production, these androgens were not converted to estrogen leading to multiple abnormalities.

This theory explained the morphology of the ovary, hirsutism, and anovulation. Androgen excess led to ovarian follicular arrest in the preantral stage, as estrogen is critical to the development and selection of a dominant follicle. The ovary thus contained multiple small preantral follicles due to this ongoing process and also had increased central stroma due to excessive thecal and stromal hyperplasia from the disordered gonadotropin exposure. Secondarily this resulted in spillover of excess androgens into the circulating pool resulting in inappropriate feedback to the hypothalamic pituitary axis and a vicious feedback loop where excess LH leads to excess ovarian androgen production which in turn leads to further LH. Finally the excess circulating androgen led to stimulation of the pilosebaceous unit increases sebum production, induces terminal hair differentiation, and in rare instances in the scalp lead to pilosbaceous unit atresia and androgenic alopecia.

Studies of gonadotropin secretion in women with PCOS have established that women have augmented release of LH in response to a GnRH challenge with appropriate levels of FSH secretion (18). This has led to the use of a GnRH challenge test to diagnose PCOS by some investigative groups (19), however this requires blood tests up to 24h after the challenge and is unwieldy in a clinical setting. Similarly, random serum samples of LH tend to have poor sensitivity and specificity for diagnosing PCOS (20). This is because of the variability of serum levels due to the pulsatile excretion of the hormones, and also due to modifying factors such as concurrent medications and conditions, most importantly obesity. Obesity tends to blunt baseline LH levels and GnRH stimulated levels in women with PCOS (21), though their response remains elevated when compared to appropriate age and weight matched control women.

Primary Ovarian and Adrenal Hyperandrogenism Since most support the notion that PCOS is an ovarian disorder, it becomes therefore the prime target for the cause of the syndrome. Ovarian steroidogenesis is perturbed in the syndrome with increased circulating androgen levels frequently noted in women with stigmata of PCOS. Further intrafollicular androgen levels tend to be elevated in antral follicles supporting a lack of adequate granulosa aromatase activity (22). As noted above, a primary defect in ovarian steroidogenesis could lead through the same feedback loop noted above to disordered gonadotropin secretion and stigmata of peripheral hyperandrogenism such as acne, hirsutism, and alopecia. Thecal cells from PCOS women put into long term culture exhibit defects in steroidogenesis including hyperproduction of androgens, implying this is a permament and possibly genetic defect in the cells (23). Family studies also support a high prevalence of hyperandrogenemia and hyperandrogenism in first degree relatives of women with PCOS (24-26), further supporting a familial contribution to this stigmata. Finally 20-30% of women with PCOS have evidence of adrenal hyperandrogenism, primarily based on elevated levels of DHEAS an androgen marker of adrenal function (27), suggesting that the defect in steroidogenesis is primary, and affects both androgen secreting glands, i.e. the ovary and the adrenal. Further there is familial clustering of elevated DHEAS levels in PCOS families in both female and male relatives again supporting a heritable component to this trait (24, 26, 28).

However to date, no specific genetic abnormality has been noted in steroidogenic enzymes or factors to explain the hyperandrogenism (29). Further it is simplistic to imply that this defect is permanent. First, at least in terms of phenotype and androgen levels, it does not manifest till menarche and appears to resolve with menopause, implying this is not a constitutional phenotypic characteristic. Second, hyperandrogenism can be ameliorated by treatment with suppressive hormonal therapies, or conversely with ovulation induction. Polycystic ovaries are a recognized risk factor for ovarian hyperstimulation characterized by multiple and excessive follicular development, elevated circulating levels, and after exposure to human chorionic gonadotropin massive ovarian enlargement, vascular permeability, and accumulation of abdominal ascites. This response appears consistent more with basline inhibition of certain aspects of steroidogenesis combined with exaggerated ovarian response to a given challenge, than a primary defect in steroidogenesis per se.

Other ovarian factors than disordered steroidogenesis may contribute to PCOS. For example there appears to be an increased density of small preantral follicles in polycystic ovaries (30). This could result from increased number of germ cells in the fetal ovary or from decreased loss of oocytes with age, or from decreased rate of loss of oocytes during late gestation, childhood, and puberty. Indeed there is evidence in vitro to support increased survival and diminished atresia in a PCOS follicle (31).

Primary Disorder of Insulin Resistance Women with PCOS show multiple abnormalities in insulin action. Dynamic studies of insulin action, including hyperinsulinemic euglycemic clamps and frequently sampled intravenous glucose tolerance tests have shown that women with PCOS are more insulin resistant than weight matched control women, a defect primarily present in skeletal muscle (32, 33). Early in the ontogeny of the syndrome, as in the ontogeny of type 2 diabetes, this is characterized by increased pancreatic beta cell production of insulin to control ambient glucose levels. Thus many women with PCOS have fasting and meal challenged hyperinsulinemia (34). However this compensatory response by the pancreatic beta cell is often inadequate for the degree of peripheral insulin resistance leading to initially postpandrial hyperglycemia in these women and eventually fasting hyperglycemia (33, 35). Further the beta cell response appears to be dysschronous, implying a further beta cell defect in these women, and is responsive to treatment with insulin sensitizing agents such as thiazolidinediones (36).

Hyperinsulinemia and/or disordered insulin action may have perturbed the reproductive axis in multiple ways. First insulin may act at the hypothalamic pituitary axis to stimulate gonadotropin production. Infusions of insulin tend to have little effect on gonadotropin production in human studies, and insulin is not required for glucose transport into the nervous system. In animal cell culture models, insulin has been found to enhance pituitary gonadotropin secretion (37). However selective knock out of the insulin receptor in mouse models (the NIRKO mouse) exhibits increased food intake and fat mass, and an exaggerated response to GnRH stimulation (though their basal state in contrast to women with PCOS tends to be hypogonadotropic hypogonadism) (38). Thus the evidence for a central action on insulin may be the weakest link in the insulin resistance PCOS hypothesis in humans, perhaps because it is the most difficult to investigate.

Hyperinsulinemia is linked to ovarian and adrenal hyperandrogenism in a number of disorders of inherited insulin resistance with compensatory hyperinsulinemia including leprechaunism, the Rabson Mendenhall syndrome, and the lipodystrophies (39). These syndromes are characterized by selective tissue atrophy due to inability to utilize the primary anabolic hormone, insulin, and by excess gonadal androgen production. A less severe insulin resistance syndrome, the HAIR-AN syndrome was defined on the basis of hyperinsulinemia, hyperandrogenemia, and the presence of acanthosis nigricans (a hyperproliferative skin condition found in skin folds due to insulin excess) and is more common (40).

This link between hyperinsulinsm and hypergonadism is thought to reflect the ability of insulin in certain conditions to stimulate gonadal and adrenal androgen production. Hyperandrogenism has been further linked to insulin resistance and stigmata of the insulin resistance syndrome in women with PCOS and in PCOS family studies which have found increasing prevalence of the metabolic syndrome in family members with increasing androgen levels (41). Androgens also induce insulin resistance, best illustrated by the example of female to male transsexuals who have increased insulin resistance after supplementation with androgens (42). In vitro cultures of PCOS thecal cells have been found to overproduce androgens in response to insulin supplementation (43). Further as discussed below under therapeutic options, the use of insulin sensitizing agents, including both metformin and troglitazone have been associated with both lowering of circulating insulin levels and levels of both adrenal and ovarian androgens.

Finally increased levels of insulin are associated with the peripheral availability of sex steroids through its impact on circulating sex hormone binding globulin (SHBG). SHBG has been found to be partially regulated by circulating insulin levels with an inverse relationship (44). Decreasing levels of SHBG mean increasing levels of free and bioavailable androgens, especially since the preferred substrate of SHBG are androgens (as opposed to estrogens and progestins). Increased free androgens means increased androgen action in the periphery which can mean the pilosebaceous unit or the hypothalamic pituitary axis. Thus insulin resistance can contribute to hyperandrogenism in many ways (45).

Clinical Presentation

Women with PCOS commonly present with menstrual disorders (from amenorrhea to dysfunctional uterine bleeding) and infertility, as they have since the syndrome was first described. The compilation of presenting symptoms by Goldzieher et al from the 1960’s is still relevant to today’s presenting complaints (Figure 4) (46), though obesity is much more prevalent in the U.S. PCOS population as noted above.. Both due to the emphasis on menstrual history and its complaints of androgen excess (rare in children), PCOS classically presents at or after menarche. The phenotype in pubertal and pre-pubertal girls is debated, there is some evidence to suggest that premature pubarche places girls at increased risk for developing PCOS as they go through puberty. Premature pubarche presents in girls with hyperinsulinemia, elevated DHEAS levels. However this could only account for a small fraction of women with PCOS as the prevalence of premature pubarche is a fraction of PCOS. A national registry of all children in Denmark estimated the prevalence of premature pubarche in the Danish population at 22 to 23 cases per 10,000 girls, i.e. 0.0002% (47). At the other end of the reproductive spectrum, both menstrual irregularity (48) and hyperandrogenemia (49) appear to normalize as PCOS women approach the perimenopause and menopause. Whether these completely normalize is unknown, for instance mothers of women with PCOS have elevated testosterone levels compared to controls, suggesting that mild elevations may be familial and persist (25).

Skin disorders, especially those due to peripheral androgen excess such as hirsutism and acne, and to a lesser degree androgenic alopecia, are common in women with PCOS and frequently the presenting complaint. Obesity is frequently characterized by a centripetal distribution. This can be diagnosed by an elevated waist circumference ( > 88 cm). A history of weight gain may sometimes precede the onset of oligomenorrhea and hirsutism, leading to the suspicion that this is an acquired form of PCOS secondary to obesity. All women with PCOS should have a BMI determined at baseline and at regular visits. Other complaints which must be elicited are screens for mood disorders and depression as many women with PCOS suffer from low self esteem due to obesity, disfiguring hirsutism, and infertility.

Clinical Sequelae of PCOS

Although the endocrine and reproductive features of the disorder may improve with age, the associated metabolic abnormalities, particularly glucose intolerance, may actually worsen with age. Following we discuss common sequelae of PCOS including infertility due to ovulatory dysfunction, abnormalities of the pilosebaceous unit, certain gynecological cancers, type 2 and gestational DM, and CVD.

Infertility due to Chronic Anovulation:Women with PCOS are not generally absolutely infertile, but subfertile due to the infrequency and unpredictability of their ovulation. It is thought that in the past women with PCOS would tend to conceive later in life as ovulatory function improves (50), although many women now seek treatment prior to this. As a general rule, PCOS women represent one of the most difficult groups to induce ovulation both successfully and safely. Many PCOS women are unresponsive or resistant to ovulation induction with clomiphene citrate, and may have an inappropriate or exaggerated response to the administration of human menopausal gonadotropins (menotropins), and are at increased risk for ovarian hyperstimulation syndrome (OHSS). OHSS is a syndrome of massive enlargement of the ovaries, development of rapid and symptomatic ascites, intravascular contraction, hypercoagulability, and systemic organ dysfunction. It can be life threatening and is best prevented. Increasing obesity may blunt the risk for developing the syndrome (51). These complications occur generally following treatment with menotropins, although ovarian hyperstimulation has even been reported in women with PCOS conceiving a singleton pregnancy spontaneously, or after clomiphene or pulsatile GnRH use (52).

Skin Disorders:Skin disorders in women with PCOS revolve primarily around abnormalities of the pilosebacous unit. The development of hirsutism, acne or androgenic alopecia in PCOS has been attributed to the increased systemic and local production of androgens (see above) that activate abnormal development of the pilosebacous unit. While insulin is essential for hair follicle growth in vitro it is unclear whether the hyperinsulinemia of PCOS directly stimulates the terminalization of body hairs and the development of hirsutism (53). Generally the ontogeny of abnormalities of the pilosebaceous unit tends to proceed from acne in peri-pubertal period to hirsutism as a young adult to androgenic alopecia in the mature adult. Androgenic alopecia is luckily rare among women with PCOS and its etiology also is complex (54). Apparently similar factors which stimulate terminal midline hair in lower body regions also leads to follicular atresia in the scalp. For the most part treatments for hirsutism are also relevant for androgenic alopecia (i.e. androgen suppression and androgen antagonism). However, local vasodilators administered in a crème or lotion, i.e. minoxidil, have been shown to be effective for both male and female androgenic alopecia, whereas they have no known benefit on hirsutism.

Other skin disorders that are common include acanthosis nigricans and an increased frequency of skin tags. 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 (Figure 5). The presence of acanthosis nigricans appears to be more a sign of insulin resistance than a distinct disease unto itself.

Gynecological Cancers:Many gynecological cancers have been reported to be more common in women with PCOS including ovarian, breast, and endometrial carcinomas. However, the best case of an association between PCOS and cancer can be made for endometrial cancer, as many risk factors for this cancer are present in the PCOS patient, although the epidemiological evidence of an increased incidence in this group of women is weak (55). In an analysis of 176 patients with endometrial cancer hirsutism, increased body mass index (BMI) and hypertension were significantly more common in all patients, and nulliparity and infertility significantly more common among younger patients, compared to controls (56, 57).

Sleep Apnea Multiple groups have documented an increased risk for sleep apnea and other sleep disorders, such as sleep disordered breathing in women with PCOS (58, 59). This is surprising as sleep apnea is relatively uncommon in women, especially premenopausal women (Figure 6). Increased risk for these disorders in women with PCOS has been associated with both hyperandrogenism and insulin resistance PCOS (58, 59). It is perhaps too early to recommend universal screening in obese women with PCOS, but it should be considered in women undergoing bariatric surgery, as it is a predictor of morbidity and mortality in patients undergoing bypass surgery (60). Women with sleep disorders often complain of daytime sleepiness, fatigue after sleeping, and may snore.

Non-alchoholic fatty liver disease This disorder is fatty infiltration of the liver not due to alchohol abuse that is related to insulin resistance. Affected patients may have no symptoms, or have mild, nonspecific symptoms such as fatique or malaise. It is usually accompanied by elevated serum liver function tests, most commonly transaminases. Liver ultrasound may show steatosis, but liver biopsy remains the gold standard diagnosis and shows evidence of inflammation and fibrosis. It may respond to weight loss and insulin sensitizing therapy. The prevalence of the disorder among women with PCOS is debated. While some reports have noted an increased prevalence, a recent multi-center trial that screened over 1,000 women with PCOS found that only a small fraction (`5%) had elevated liver transaminases (15). This prevalence is comparable to that found in the U.S. population in the NHANES survey. Routine screening is probably unnecessary at this time.

Type 2 Diabetes Mellitus:The inherent insulin resistance present in many with PCOS, aggravated by the high prevalence of obesity in these individuals, places these women at increased risk for impaired glucose tolerance and type 2 DM. About 30% to 40% of obese reproductive-aged PCOS women have been found to have impaired glucose tolerance (IGT), and about 10% have frank type 2 DM based on a 2-hour glucose level > 200mg/dL (72)(61, 62). Of note is that only a small fraction of PCOS women with either IGT or type 2 DM display fasting hyperglycemia consistent with diabetes by the American Diabetes Association criteria (fasting glucose 126 mg/dL) (Figure 6). In other PCOS populations with lower rates of obesity, the prevalence of impaired glucose tolerance is also lower, though higher than control groups (63). The risk factors associated with glucose intolerance in women with PCOS—age, high body mass index (BMI), high waist–hip ratios, and family history of diabetes—are identical to those in other populations. The conversion rate to glucose intolerance over time is low per year in the range of 3-5%, which suggests re-screening every 3-5 years may be adequate to detect abnormalities (64). However, the level of insulin resistance found in PCOS women based on dynamic measures of insulin action has in other populations (i.e. children of parents with diabetes) been associated with a marked increased risk of developing type 2 DM.

Cardiovascular Disease:Many of the studies suggesting an increased incidence of CVD are inferential based on risk factor models, with little evidence of increased or premature onset of CVD events such as stroke or myocardial infarcation (65). There is a lack of prospective studies showing increased risk of cardiovascular events in women with PCOS. However a number of cohort studies including the Nurse’s Health Study have suggested an increased dose response risk of CVD disease or events in the presence of increasing oligomenorrhea although there was no determination of hyperandrogenism, so many of the cases may have had another menstrual disorder (66). In other older populations a history of irregular menses and/or hyperandrogenism has been associated with increased CV events. (67). Among postmenopausal women evaluated for suspected ischemia in the Women's Ischemia Syndrome Evaluation (WISE) study, clinical features of PCOS defined by a premenopausal history of irregular menses and current biochemical evidence of hyperandrogenemia were associated with more angiographic CAD and worsening CV event-free survival (68) (Figure 8).

The data is less robust in cohorts of women with PCOS. Studies examining subclinical atherosclerosis in premenopausal women with PCOS have detected an increased prevalence compared to controls (ranging in women with PCOS from less than 10% with increased carotid intimal medial thickness (69) to 40% with coronary artery calcification (70, 71)).

Many women with PCOS appear to form a subset of the metabolic syndrome first described by Reaven (i.e. Syndrome X or insulin resistance syndrome) consisting of insulin resistance, hypertension, dyslipidemia, glucose intolerance, and CVD (72). In fact, many PCOS women have significant dyslipidemia, with lower HDL, and higher triglyceride and LDL levels than age, sex, and weight-matched controls (73, 74). The elevation in LDL levels is somewhat atypical for the insulin resistance syndrome. PCOS women, at least in later life, also appear to have a higher risk of developing hypertension (75, 76). Metabolic syndrome appears very common among women with PCOS and in a report from the baseline cohort recruited to one large multi-center trial (including subjects with type 2 diabetes), the prevalence was 33.4% (41). The most common finding was a waist circumference greater than 88 cm in 80% followed by an abnormal high-density lipoprotein cholesterol less than 50 mg/dl (Figure 9). Conversely what most protected against the metabolic syndrome was a normal waist circumference.

Mood Disorders Women with PCOS appear to be at increased risk for diminished quality of life and mood disorders (77). A recent study noted that women with PCOS were at an increased risk for depressive disorders (new cases) compared with controls (21% vs. 3%; odds ratio 5.11 [95% confidence interval (CI) 1.26-20.69]; P<.03) (78) A validated quality of life questionnaire has been developed form women with PCOS (PCOSQ) (79). Recently a large controlled study of over 100 women (N = 1359) found a high prevalence of low quality of life in women with PCOS (77). Women with PCOS had lower quality of life on all seven factors of the modified PCOSQ (emotional disturbance, weight, infertility, acne, menstrual symptoms, menstrual predictability and hirsutism). Weight was the largest contributor to poor women for women on and off medication for their PCOS. A recent systematic review found that a meta-analysis was not possible, though it appears that weight concerns have a particular negative impact upon HRQoL (80). Few clinical studies to date have incorporated QoL measures into the trial design.

Differential Diagnosis of PCOS

The differential diagnosis of PCOS includes other causes of androgen excess (Table 1), and PCOS remains a diagnosis of exclusion. Because the work up for many of these disorders is expensive and tests have varying degrees of sensitivity and specificity, some clinical acumen must be applied in the selection of tests. Generally every women with signs and symptoms of PCOS should be screened for thryroid dysfunction, prolactin excess, and non classical congenital adrenal hyperplasia. These diagnoses occur relatively more common among women with menstrual disorders, and we have good screening tests to diagnose them. Both hyper and hypothyroidism have been associated with menstrual disturbances, though their link with hyperandrogenism is less proven. Mild elevations in prolactin are common in women with PCOS (81). A prolactin level can identify prolactinomas that secrete large amounts of prolactin and that may stimulate ovarian androgen production, but this is an extremely rare cause of hyperandrogenic chronic anovulation. Evaluating serum levels of thyroid-stimulating hormone is also useful given the protean manifestations and frequency of thyroid disease in women with menstrual disorders.

Nonclassical congenital adrenal hyperplasia, often referred to as late-onset congenital adrenal hyperplasia, can present in adult women with anovulation and hirsutism and is due almost exclusively to genetic defects in the steroidogenic enzyme, 21 hydroxylase (CYP21). In Europe and the U.S., congenital adrenal hyperplasia occurs with the highest frequency among Ashkenazi Jews, followed by Hispanics, Yugoslavs, Native American Inuit in Alaska, and Italians (82). To screen for nonclassical congenital adrenal hyperplasia due to CYP21 mutations, a fasting level of 17-hydroxyprogesterone should be obtained in the morning. A value less than 2 ng/mL is considered normal. If the sample is obtained in the morning and during the follicular phase, some investigators have proposed cutoffs as high as 4 ng/mL (83). Specificity decreases if the sample is obtained in the luteal phase due to increased progesterone production. High levels of 17-hydroxyprogesterone should prompt an adrenocorticotropic hormone (ACTH) stimulation test.

As Cushing syndrome is extremely rare (1 in 1,000,000) and screening tests are not 100% sensitive or specific (84), routine screening for Cushing syndrome in all women with hyperandrogenic chronic anovulation is not indicated. Those who have coexisting signs of Cushing syndrome, including a moon facies, buffalo hump, abdominal striae, centripetal fat distribution, or hypertension, should be screened. Proximal myopathies and easy bruising, not typically present in women with PCOS, may also help identify patients with Cushing’s.

Androgen-secreting tumors of the ovary or adrenal gland are invariably accompanied by elevated circulating androgen levels. However, there is no absolute level that is pathognomonic for a tumor, just as there is no minimum androgen level that excludes a tumor. In the past, testosterone levels above 2 ng/mL and dehydroepiandrosterone sulfate (DHEAS) levels greater than 700 µg/dL were regarded as suspicious for a tumor of, respectively, ovarian and adrenal etiology, but these cutoff levels have poor sensitivity and specificity (85).

Evaluation of women with PCOS

History and physical exam is important in evaluation of women with PCOS (Table 2). The history should focus on the onset (peri-pubertal vs acquired later in life) of oligomenorrhea, the onset and duration of the various signs of androgen excess, and concomitant medications, including the use of exogenous androgens. While many medications are associated with hypertrichosis, a generalized increase in body hair, few are associated with increased midline androgen dependent hair growth. A family history of diabetes and cardiovascular disease (especially first-degree relatives with premature onset of cardiovascular disease [male < 55 years and female < 65 years]) is important. Additionally multiple studies have shown that PCOS clusters in families, such that a sister or mother with PCOS likely increases risk for the disorder, or stigmata of the disorder in other family members. Lifestyle factors such as smoking, alcohol consumption, diet, and exercise are particularly important in these women. An astonishingly high number of women with PCOS are either current or past smokers, in one large multi-center trial 17% were current smokers during the trial and 22% had a history of smoking (15). Obviously for both fertility and prevention of cardiovascular disease, cessation should be a primary target of the treatment plan.

The physical examination should include evaluation of balding, acne, clitoromegaly, and body hair distribution, as well as pelvic examination to look for ovarian enlargement. The presence and severity of acne should be noted. Signs of insulin resistance such as hypertension, obesity, centripetal fat distribution, and the presence of acanthosis nigricans should be recorded. Other pathologic conditions associated with acanthosis nigricans should be considered, such as insulinoma and malignant disease, especially adenocarcinoma of the stomach.

The laboratory examination of patients should include tests especially at initial presentation to exclude other diagnoses as well as some measure of circulating androgen (Table 3). The best measurement of circulating androgens to document unexplained androgen excess is a subject of debate, and recent expert consensus panels have recommended standardized testosterone assays and normative values for women and children (86). Both the adrenal glands and ovaries contribute to the circulating androgen pool in women. The adrenal gland preferentially secretes weak androgens such as dehydroepiandrosterone (DHEA) or DHEAS (up to 90% of adrenal origin). These hormones, in addition to androstenedione, may serve as prohormones for more potent androgens such as testosterone or dihydrotestosterone. 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 secretion). Androstenedione, largely of ovarian origin, is the only circulating androgen that is higher in premenopausal women than men, yet its androgenic potency is only 10% of testosterone. Dihydrotestosterone is the most potent androgen, although it circulates in negligible quantities and results primarily from the intracellular 5--reduction of testosterone.

Each clinician should be familiar with the analytical performance and the normal ranges of local laboratories, as there is no standardized testosterone assay in the U.S. and the sensitivity and reliability in the female ranges are often poor (86). The present recommendation by the Androgen Excess Society is to measure free testosterone concentration either directly by equilibrium dialysis, or to calculate the free testosterone based on the total T measured accurately (e.g., by RIA using column chromatography, or by mass spectrometry) and SHBG (e.g., measured using competitive binding or a high quality immune-based assay). Evaluation of DHEAS levels may be useful in cases of rapid virilization (as a marker of adrenal origin), but its utility in assessing common hirsutism is questionable.

The Rotterdam criteria have led to increasing use of ultrasound in the initial diagnosis and evaluation of women with PCOS (Table 4). Additional information other than ovarian size that can be obtained is the exclusion of leiomyomas, most mullerian anomalies, and the determination of the thickness of the endometrium. Some studies have found very high asymptomatic rates of endometrial hyperplasia among amenorrheic women with PCOS (87).

The metabolic evaluation of women with PCOS has become a standard part of the evaluation. Exclusion of diabetes and identification of glucose intolerance can be obtained with a standard 75g oral glucose tolerance test. At the same time a fasting lipid profile can be obtained. The routine use of insulin levels in the diagnosis and management of women with PCOS is probably not indicated, as they are poor markers of insulin resistance if there is beta cell dysfunction and they have not been found to predict response to therapy.

Approach to TREATMENT OF WOMEN WITH PCOS

Treatment of women with PCOS tends to be symptom based, as there are few therapies which address the multitude of complaints with which women with PCOS present. Arguably there are currently only two therapies that address the most common complaints, i.e. (infertility, hirsutism, menstrual disorders, and obesity) and these are either weight loss ( as a result of lifestyle, medical, or surgical options or metformin therapy (Table 5). It is often difficult to treat all complaints at once, probably the most difficult one is the desire to treat both anovulatory infertility and hirsutism concurrently. Some therapies can also be counterproductive and thus contra-indicated in this situation, for instance the use of oral contraceptives because they block ovulation or the use of anti-androgens because they are potentially teratogenic in a male fetus. Because of these conundrums in clinical care, treatment tends to fall into two categories, either the treatment of anovulatory infertility or the long term maintenance treatment for PCOS related symptoms (i.e. hirsutism, menstrual disorders, obesity, etc.)

Overview of Treatment of Anovulatory Infertility One important consideration before treating subjects with anovulatory infertility is to screen the couple for other infertility factors. One large multi-center trial found that 10% of male partners of women with PCOS had co-existing severe oligospermia and close to 5% of women had bilateral occlusion of the fallopian tube or some other uterine factor (88). Obviously the presence of these factors would significantly alter therapy and their high prevalence justify pre-treatment screening. There is no evidence-based schema to guide the initial and subsequent choices of ovulation induction methods in women with PCOS. A recent ASRM/ESHRE sponsored conference recommended that before any intervention is initiated, preconceptional counseling should emphasize the importance of lifestyle, especially weight reduction and exercise in overweight women, smoking cessation, and reducing alcohol consumption (89, 90).

The recommended ASRM/ESHRE first-line treatment for ovulation induction remains the anti-estrogen clomiphene citrate (CC). Recommended second-line intervention, should CC fail to result in pregnancy, is either exogenous gonadotropins or laparoscopic ovarian surgery (89, 90). There does however appear to be some benefit of the addition of metformin to clomiphene, especially in obese subjects, so a modified first line treatment plan is presented in Figure 10. The caregiver must carefully assess the reproductive toxicitiy of all medications used in women with PCOS, since they increase ovulatory frequency and result in unexpected and unintended pregnancy and possible fetal exposure. A list of these and their FDA category is found in Table 6.

Overview of Long Term Maintenance of PCOS We use the term maintenance acknowledging that there is no known cure for PCOS, rather therapy revolves around suppression of symptoms. Therapy tends to focus on the primary chief complaint. However often the triad of hirsutism, oligomenorrhea, and obesity forms the key presenting symptoms. In that case it may make sense to choose a primary metabolic parameter upon which to base initial treatment. Glucose intolerance is the strongest risk factor for diabetes and is also an independent risk factor for cardiovascular events in women and is one potential factor to use to select initial treatment. A possible first line strategy is found in Figure 11, which allow selection of the therapies that improve the triad of PCOS symptoms. Additional targeted therapies for hirsutism and/or oligomenorrhea could be added depending on response to the initial therapy. Obviously also contraception should be considered if the patient is trying to avoid pregnancy.

Review of Efficacy of Individual Therapies on PCOS

Clomiphene Citrate Clomiphene citrate (CC) has traditionally been the first-line treatment agent for anovulatory women, including those with PCOS, and several multi-center randomized controlled trials have upheld the use of clomiphene as first line treatment (Table 6). In fact this may the area of PCOS where we have the largest and best designed studies. Clomiphene is a triphenylethylene derived nonsteroidal agent that is theorized to function at the level of the hypothalamus as an anti-estrogen to improve gonadotropin secretion. CC use is associated with hot flashes, mood changes, and rarely changes in vision thought due to pituitary swelling (thought to be a serious event and reason for discontinuing the drug). From a public health perspective, more concerning is the relatively high rate of multiple pregnancy of 7.8% after conception with clomiphene, although the majority are twins (91). However there is nevertheless a high order (triplets or more) multiple pregnancy rate of 0.9% (91). There are no trials of adequate size to comment on whether this risk is higher in women with PCOS. Six month life birth rates range from 20-40% depending on the population. Half of all women who are going to conceive using clomiphene will do so at the 50-mg starting dose, and another 20% will do so at the 100-mg/d dose (92). Most pregnancies will occur within the first six ovulatory cycles, although a constant monthly pregnancy rates was noted suggesting there may continued benefit to longer use (93). Prognostic clinical factors for live birth with clomiphene include decreased BMI, less hirsutism, younger age, and shorter duration of attempted conception (94).

Alternative clomiphene regimens have been developed, including prolonging the period of administration (95), pretreating with oral contraceptives (96) adding dexamethasone (97), and adding metformin (98). Dexamethasone as adjunctive therapy with clomiphene citrate has been shown to increase ovulation and pregnancy rates in clomiphene resistant women with PCOS (99). Finally some groups have recommended using similar compounds to clomiphene, such as tamoxifen, in lieu of clomiphene (100).

Gonadotropins Gonadotropins are frequently used to induce ovulation in women with PCOS for whom clomiphene treatment has failed. Low-dose therapy with gonadotropins offers a higher rate of ovulation, monofollicular development, with a significantly lower risk of ovarian hyperstimulation syndrome (101). Pregnancy rates are comparable with other regimens, but there have been no adequately powered trials to answer this question. This regimen is the ASRM/ESHRE consensus recommendation when using gonadotropins in women with PCOS.

Ovarian Surgery The value of laparoscopic ovarian drilling with laser or diathermy as a primary treatment for subfertile women with anovulation and PCOS is undetermined (102), and it is primarily recommended as second line infertility therapy. Neither drilling by laser or diathermy has any obvious advantage, and there is insufficient evidence to suggest a difference in ovulation or pregnancy rates when drilling is compared with gonadotropin therapy as a secondary treatment (102). Multiple pregnancy rates are reduced in those women who conceive following laparoscopic drilling. In some cases, the fertility benefits of ovarian drilling may be temporary and adjuvant therapy after drilling with clomiphene may be necessary (103). Ovarian drilling does not appear to improve metabolic abnormalities in women with PCOS (104).

Ovarian drilling may also be used to restore menstrual cyclicity in women not seeking pregnancy and there is evidence in some series of long term improvement in menses as a result of surgery (105). However these series are uncontrolled and as noted above hyperandrogenism and oligomenorrhea tend to improve with age in women with PCOS.

Aromatase Inhibitors Aromatase inhibitors such as letrozole and anastrazole have been proposed as both first and secondary treatment for ovulation induction (in women with PCOS and also for unexplained infertility) (106). Results in women with PCOS appear comparable to clomiphene from small trials (Table 7). Proposed benefits include oral administration, a shorter half life than clomiphene, more favorable effects on the endometrium, potentially higher implantation rates, and lower multiple pregnancy rates due to monofollicular ovulation. Further study of these agents are needed to verify these claims, and fetal effects need to be more completely monitored. Their use is still experimental at this point.

MetforminThe use of metformin as first line solo infertility therapy has not been supported by randomized trials. Clomiphene is roughly three times more effective at achieving live birth compared to metformin (Figure 12) (93). Meta-analysis has suggested there may be some benefit to pregnancy by adding clomiphene to metformin, particularly in obese women with PCOS compared to clomiphene alone (OR 2.67; 95% CI 1.45-4.94; number-needed-to-treat 4.6) (107). Metformin has no known human teratogenic risk or embryonic lethality in humans and appears safe in pregnancy (it is also Pregnancy Category B). There is no solid evidence that metformin use early in pregnancy prevents pregnancy loss, and the randomized trials which stopped drug with pregnancy have shown similar miscarriage rates with metformin as with clomiphene (93, 108). Currently the use of metformin alone as a first line therapy for infertility in PCOS does not appear supported by the literature.

Metformin may be most useful in the long term maintenance of PCOS. Metformin does lower serum androgens, and improves ovulatory and menstrual frequency (109). One study estimated that menstrual frequency improved by roughly a third from baseline. There may also be favorable effects at preventing the progression to diabetes. The Diabetes Prevention Program demonstrated that metformin can prevent the development of diabetes in high-risk populations (eg, those with impaired glucose tolerance) (110), and this result has been replicated for a number of anti-diabetic drugs in individuals at high risk. Metformin tends to be the drug of choice to treat glucose intolerance and elevated diabetes risk in women with PCOS because of its favorable safety profile and the familiarity a wide number of caregivers from varying specialties have with the medication. However there are no long term studies of metformin in women with PCOS to show diabetes prevention. Among women with PCOS who use metformin, glucose tolerance improves or stays steady over time (111). Metformin also may be associated with weight loss in women with PCOS, although the results in other populations are inconsistent (93, 112). Metformin is often used in conjunction with lifestyle therapy to treat PCOS. Recent studies suggest that there is limited benefit to the addition of metformin above lifestyle therapy alone (113-115).

Metformin carries a small risk of lactic acidosis, most commonly among women with poorly controlled diabetes and impaired renal function. Gastrointestinal symptoms (diarrhea, nausea, vomiting, abdominal bloating, flatulence, and anorexia) are the most common adverse reactions and may be ameliorated by starting at a small dose and gradually increasing the dose or by using the sustained-release version now available in the United States. The dose is usually 1500-2000 mg/day given in divided doses. The effects of metformin and other anti-diabetic drugs on preventing endometrial hyperplasia/neoplasia in women with PCOS are largely unknown.

Thiazolidinediones Smaller trials have shown some benefit to this class of drugs for the treatment of infertility usually in conjunction with clomiphene (116, 117). However the concern about hepatotoxicity, cardiovascular risk, weight gain, and the pregnancy Category C have limited the use of these drugs in women with PCOS. One of the thiazolidinediones, troglitazone, was removed from the market due to hepatotoxicity, and there has been increasing scrutiny of rosiglitazone because of increased cardiovascular events. Nonetheless, improving insulin sensitivity with these drugs is associated with a decrease in circulating androgen levels, improved ovulation rate, and improved glucose tolerance (36, 118-120).

Other Anti-Diabetic Drugs Other anti-diabetic drugs have been used to treat PCOS with reported improvements in circulating androgens and menstrual cyclicity as well as glycemic paratmeters. These drugs include acarbose (121), which inhibits intestinal glucose absorption and exenatide (122) a GLP-1 analogue. GLP-1 is an incretin secreted by the L cells of the intestine and it increases pancreatic beta cell insulin production. Exenatide is given as an injection, and its use is associated with weight loss which increases its appeal. One potential safety concern is the increased risk for pancreatitis on this drug. Use of these drugs is still experimental. None of the anti-diabetic agents noted are currently approved by the U.S. Food and Drug Administration (FDA) for treatment of PCOS, though metformin appears to have the safest risk/benefit ratio. There are no randomized controlled studies of treatment for 1 year or more with these agents in women with PCOS.

Combination Oral Contraceptives Oral contraceptives have been the mainstay of long-term management of PCOS among gynecologists, though there are few well designed trials in women with PCOS. They offer benefit through a variety of mechanisms, including suppression of pituitary LH secretion, suppression of ovarian androgen secretion, and increased circulating SHBG levels. Estrogen may be the most stimulator of SHBG production. Individual OC preparations may have different doses and drug combinations and thus have varying risk–benefit ratios. For instance, various progestins have been shown to have different effects on circulating SHBG levels (123), but whether that translates into a clinical benefit is uncertain. The “best” oral contraceptive for women with PCOS is unknown based on data, only on marketing hype. Oral contraceptives also are associated with a significant reduction in risk for endometrial cancer with a reduction of risk by 56% after four years of use and 67% after eight years in users compared to non-users (124), but the magnitude of the effect in women with PCOS is not known.

Because women with PCOS may have multiple risk factors for adverse effects and serious adverse events on oral contraceptives, they must be screened carefully for risk factors for these events including smoking history, presence of obesity and hypertension, and history of clotting diathesis to mention some of the important factors (Table 8). In the larger U.S. population, oral contraceptive use has not been associated with an increased risk of developing type 2 diabetes (125). There is no convincing evidence that use of oral contraceptives contributes to the risk of diabetes in women with PCOS, although there are often adverse effects on insulin sensitivity that may be dose dependent (126, 127). A low dose oral contraceptive pill is therefore recommended. Oral contraceptives may also be associated with a significant elevation in circulating triglycerides as well as in HDL levels, though these do not appear to progress over time (128). There is no evidence to suggest that women with PCOS experience more cardiovascular events than the general population when they use oral contraceptives, though risk factors for adverse events such as hypertension, obesity, clotting history, and smoking must be considered. The effect of progestins alone on metabolic risk factors varies and is not well understood.

No oral contraceptive has been approved by the FDA for the treatment of hirsutism. A number of observational or nonrandomized studies have noted improvement in hirsutism in women with PCOS who use oral contraceptives, but no studies of adequate power confirm their benefit in improving hirsutism in PCOS (129). Few studies have compared outcomes of different types of oral contraceptives, and no one type of pill has been shown to be superior in treating hirsutism in women with PCOS. A number of studies have found additive benefit when oral contraceptives are combined with other treatment modalities, most commonly spironolactone. If a woman is taking an oral contraceptive that contains drospirenone (brand name Yasmin and Yaz), a progestin with anti-mineralocorticoid properties, it may be necessary to reduce her dose of spironolactone if used as additional therapy, and evaluate her levels of potassium.

There is a theoretical benefit to treating hyperandrogenism with extended cycle formulations, as these are less likely to result in rebound ovarian function and likely to lead to more consistently suppressed ovarian steroid levels (130). However there have been few studies to uphold this in practice.

ProgestinBoth depot and intermittent oral medroxyprogesterone acetate (10 mg for 10 days) have been shown to suppress pituitary gonadotropins and circulating androgens in women with PCOS (131). No studies have addressed the long-term use of these compounds to treat hirsutism. The regimen of cyclic oral progestin therapy that most effectively prevents endometrial cancer in women with PCOS is unknown. There is also a paucity of data to address the varying risk benefit ratios of varying classes of progestins. Progestin-only oral contraceptives are an alternative for endometrial protection, but they are associated with a high incidence of breakthrough bleeding.

Intrauterine Device Recently there have been some small studies to suggest that an IUD, especially a progestin containing IUD may be useful to treat menorrhagia (132, 133), and additonally may be useful to treat endometrial hyperplasia (134). Further studies are needed, but this may be a potentially useful therapy.

Uterine Surgery:In patients with intractable uterine bleeding who have completed their child-bearing consideration may be given to either an endometrial ablation or more definitive surgical therapy with a hysterectomy. The long term risk of endometrial cancer developing in isolated pockets of endometrium after ablation remains a theoretical concern without clear data.

Statins Another area where there is emerging support in the literature for a cardiovascular and endocrine benefit in women with PCOS, is the use of statins (135). They have been shown to improve hyperandrogenemia, lipid levels, and reduce inflammation (136). However their long term effects in preventing cardiovascular disease in young women with PCOS is unknown. There are concerns about teratogenecity with the use of this drug in reproductive age women, as it is FDA pregnancy category X. The use of these drugs is still experimental in women with PCOS

Lifestyle Modification The gold standard for improving insulin sensitivity in obese PCOS women should be weight loss, diet, and exercise. It is recommended as the first line of treatment in obese women who present with infertility. 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 90-95% of patients who experience a weight decrease will relapse. Further in markedly obese individuals, the only treatment that results in sustained and significant weight reduction is bariatric surgery (137).

There is no miracle diet in women with PCOS. Hypocaloric diets result in appropriate weight loss in women with PCOS (arguing against any special defect towards weight retention). There is no clear evidence that any particular dietary composition benefits weight loss or reproductive or metabolic changes in women with PCOS (138, 139), despite the hype surrounding certain diets such as high protein diets. A recent 2y study in the general population found comparable weight loss among three types of diets of varying macronutrient composition and found comparable weight loss and similar improvement in lipid and insulin levels (140). Thus the consensus recommendations for women with PCOS to seek any type of hypocaloric diet are reasonable (89, 90).

There have been, unfortunately, few studies on the effect of exercise alone on symptoms in PCOS women (141), although it is reasonable to assume that exercise would have the same beneficial effects in PCOS women as women with type 2 DM. However the exercise program must be tailored to the degree of obesity, and the patient’s baseline fitness. Additionally there may be medical contraindications to certain form of exercise. Finally exercise alone is unlikely to result in significant weight loss without concomitant caloric reduction.

Bariatric Surgery Bariatric surgery is increasingly used in morbidly obese patients as a first line obesity therapy. The current National Institute of Health recommendations are to utilize bariaric surgery in patients with a BMI greater than 40 or with a BMI greater than 35 and serious medical co-morbidities (142). It is uncertain whether PCOS qualifies as a significant comorbidity. Women with PCOS appear to experience a dramatic improvement in symptoms after surgery, implying this may be in some subjects a “cure” for the syndrome (143, 144). However these studies are primarily case series and need further validation in prospective studies. Weight loss may result in resumed ovulation and pregnancy during the period of rapid weight loss (first 6-12 months after surgery), which has led to concern about the effects of malnutrition on the fetus and general recommendations to refrain from pregnancy for 12-24 months. However there are no clear adverse effects in women who conceive after bariatric surgery (145-147). Nonetheless this has led to a tendency to opt for gastric banding, where gastric size can be adjusted in case of pregnancy, in comparison to more permanent solutions like the more commonly used Roux-en-Y gastric bypass procedure.

Pharmacologic treatment of obesity Because weight loss generally improves stigmata of PCOS, there have been a number of studies using medications for the treatment of obesity as primary treatments of PCOS. They appear in limited and small trials to offer some benefit (148-152). The current medications approved for the treatment of obesity in the U.S. either inhibit intestinal fat absorption (orlistat, available both as a prescription drug-120 mg t.i.d.- Xenical and an over the counter treatment- 60 mg t.i.d.- Alli) or as an appetite suppressant (most commonly sibutramine (dose 5-15 mg/d), a neurotransmitter reuptake inhibitor with a central effect on appetite. The most common side effects with orlistat are GI related, especially steatorrhea and potential fat soluble vitamin deficiencies. The user must be on a low fat diet to avoid this, and vitamin supplementation is recommended. Sibutramine can be accompanied by tachycardia and hypertension, and given its mechanisms for action, the potential for interaction with many medications. These treatments for PCOS (as opposed to obesity) are of uncertain benefit.

Spironolactone Spironolactone is primarily used to treat hirsutism and appears effective, though the evidence is weak (153). It is a diuretic and aldosterone antagonist, also binds to the androgen receptoras an antagonist. It has other mechanisms of action, including inhibition of ovarian and adrenal steroidogenesis, competition for androgen receptors in hair follicles, and direct inhibition of 5--reductase activity. The usual dose is 25–100 mg twice a day, and the dose is titrated to balance efficacy while avoiding side effects such as orthostatic hypotension. A full clinical effect may take 6 months or more. About 20% of women using spironolactone will experience increased menstrual frequency (154). Because it can cause and exacerbate hyperkalemia, spironolactone should be used cautiously in women with renal impairment. Rarely, exposure has resulted in ambiguous genitalia in male infants.

Cyproterone Acetate Cyproterone acetate, not available commercially in the U.S., is a progestogen with anti-androgen properties. It is frequently combined in an oral contraceptive in other countries and is popular in the treatment of PCOS. A newer progestin from the same class, drospirenone has been marketed in the U.S. as especially effective for the treatment of female hyperandrogenism, although the data suggesting this is superior to other formulations is not based on head to head randomized trials (155).

Flutamide Flutamide, an androgen-receptor agonist, is another nonsteroidal anti-androgen that has been shown to be effective against hirsutism in smaller trials The most common side effect is dry skin, but its use has been associated with hepatitis in rare cases. The common dosage is 250 mg/d. The risk of teratogenicity with this compound is significant, and contraception should be used. Flutamide has also been combined with lifestyle and metformin therapy for treatment of PCOS and may have additive effects (156).

Finasteride Finasteride inhibits both forms of the enzyme 5--reductase (type 1, predominantly found in the skin, and type II, predominantly found in the prostate and reproductive tissues). It is available as a 5-mg tablet for the treatment of prostate cancer and a 1-mg tablet for the treatment of male alopecia. Finasteride is better tolerated than other anti-androgens, with minimal hepatic and renal toxicity; however, it has well-documented risk for teratogenicity in male fetuses, and adequate contraception should be used. Overall, randomized trials have found that spironolactone, flutamide and finasteride to have similar efficacy in improving hirsutism (153).

Ornithine decarboxylase inhibitors: These have been developed for the treatment of female hirsutism. Ornithine decarboxylase is necessary for the production of polyamines, and is also a sensitive and specific marker of androgen action in the prostate . Inhibition of this enzyme limits cell division and function in the pilosebaceous unit. Recently a potent inhibitor of this enzyme, eflornithine, has been found to be effective as a facial crème for the treatment of unwanted facial hair (157) (Brand name Vaniqa). It is available as a 13.9% crème of eflornithine hydrochloride, and is applied to affected areas twice daily. In clinical trials, 32% of patients had marked improvement after 24 weeks compared to 8% of placebo treated women, and the benefit was first noted at eight weeks. It is pregnancy category C. It appears to be well tolerated, with only about 2% of patients developing skin irritation or other adverse reactions.

Mechanical and cosmetic means of hair reduction and destruction:Mechanical hair removal (shaving, plucking, waxing, depilatory creams, electrolysis, and laser vaporization) can assist in controlling hirsutism, and often are the front line of treatment used by women.

Electrolysis (i.e. electroepilation) results in long-term hair destruction, albeit slowly (The main objective of laser therapy for hair removal is to selectively cause thermal damage of the hair follicle without destroying adjacent tissues, a process termed selective photothermolysis. In general, laser hair removal is most successful in patients with lighter skin, who have dark colored hairs, though therapies are being developed for those with darker skin. However, repeated therapies are necessary, and complete and permanent hair removal is rarely achieved. After laser-assisted hair removal, most patients experience erythema and edema lasting no more than 48 hours. Blistering or crusting may occur in some patients, as well as changes in skin pigmentation.

Conclusion

PCOS is a heterogeneous disorder with varying diagnostic criteria. The core criteria are hyperandrogenism, either clinical (i.e. hirsutism) or biochemical (i.e. elevated free testosterone or free androgen index), oligomenorrhea reflective of oligo-ovulation, and polycystic ovaries. Women with PCOS tend to be insulin resistant, obese, and at risk for diabetes and an adverse cardiovascular risk profile. Treatment tends to be symptom based, with focused treatments for infertility, obesity, hirsutism, etc. Few therapies address all signs and symptoms of the syndrome. It is hoped that a deeper understanding of the genetics and pathophysiology of the syndrome will lead to more specific therapies.