Polycystic ovary syndrome (PCOS) is a heterogeneous and enigmatic disorder that is typically characterized by the presence of a combination of ovulatory dysfunction, hyperandrogenism, and polycystic-appearing ovarian morphology. Although it has now been over 80 years since Stein and Leventhal1 first described this clinical syndrome and it is one of the most common endocrinopathies encountered by gynecologists, its pathophysiology is still not completely understood and it has no universally accepted definition.
Diagnosis of PCOS
Three expert groups have proposed separate criteria for the diagnosis of PCOS. The earliest proposed criteria were by the NIH in 1990 which required the presence of oligomenorrhea or amenorrhea and clinical or laboratory evidence of hyperandrogenism.2 These criteria were extended further in the most widely used diagnostic criteria, the Rotterdam Consensus Criteria,3 which requires 2 of 3 features: oligomenorrhea or amenorrhea, clinical or laboratory evidence of hyperandrogenism, and polycystic-appearing ovaries on ultrasound (defined as >12 follicles between 2 and 9 mm in diameter in at least one ovary or an ovarian volume >10 cm3). Finally, the 2006 Androgen Excess Society requires the presence of hyperandrogenism and ovarian dysfunction, which can either be oligomenorrhea or polycystic-appearing ovaries or both.4
Notably, in 2012 an NIH consensus panel recommended that the 2003 Rotterdam criteria be adapted but with the caveat that different phenotypes be utilized (Phenotype A-D) that are based on which of the criteria qualify the patient for the diagnosis of PCOS.5 Furthermore, they suggested that “the name ‘PCOS’ is a distraction and an impediment to progress” and that a new name assignment is warranted for the syndrome that would capture its complexity and impact on metabolism, endocrinology, and reproduction. Indeed, numerous experts and consensus groups are working on reorganizing and restructuring the syndrome to devise a nomenclature and classification that better fits the spectrum of the disease. Previous suggestions have included hyperandrogenic chronic anovulation,6 metabolic reproductive syndrome,7 and more recently as polyfollicular ovarian syndrome with metabolic features or polyfollicular syndrome with metabolic dysfunction and/or hyperandrogenic manifestations.8
As there are competing diagnostic criteria for defining PCOS, the incidence of the disease will vary depending on the criteria being used. With the widely used and most expansive and inclusive Rotterdam criteria, the prevalence ranges from 5% to 20% of the population.9 Using the 1990 NIH criteria, the prevalence is reported to be 5% to 10% and with using the Androgen Excess Society the prevalence is 10% to 15%.9
Evaluation of PCOS
Patients with PCOS may clinically present with a variety of symptoms including hyperandrogenism, menstrual disorders, metabolic dysfunction, and infertility. The most common presenting feature of hyperandrogenism is hirsutism. Hirsutism is identified by the presence of excess terminal hairs that grow >5 mm in length in a male-like pattern of distribution over the body (upper lip, chin, midsternum, upper and lower abdomen, upper and lower back, and buttocks). It can be clinically quantified using the Ferriman and Gallwey,10 or a modified Ferriman and Gallwey score which takes into consideration the patient’s ethnic background.11,12 In addition to hirsutism, other manifestations of hyperandrogenism in women with PCOS may be acne or, to a lesser degree, androgenic alopecia.13 Although there is little utility in obtaining circulating androgen levels in patients who are overtly hirsute, there is a value of measuring biochemical androgen levels in many cases. A total testosterone level and free testosterone level should be assessed, and DHEA-S and androstenedione levels can be considered as well,14 though care must be taken to interpret these values appropriately.
Menstrual disorders are commonly described as irregular, infrequent, or scant or absent menstrual bleeding that often is an extension of postmenarche menstrual irregularity that never normalized. However, in some women the menstrual manifestations may present in adulthood as well. Notably, the presence of regular menstrual cycles does not exclude PCOS as cycles may become regular as women with PCOS age in some cases.15 With both menstrual dysfunction and hyperandrogenism, the severity of symptoms directly correlates with the degree of insulin resistance.16,17 Infertility ensues primarily because of anovulation or oligo-ovulation.
The classical ovarian morphology (Fig. 1) detected on transvaginal ultrasonography is that of an increased number of antral follicles or an increased ovarian volume as delineated by the Rotterdam consensus conference as stated above. It should be emphasized though that polycystic-appearing morphology alone should not be regarded as indicative of PCOS as it is frequently found in otherwise normal young women in the general population.
A clinical suspicion of PCOS should be raised in any woman who presents with signs or symptoms of hirsutism or oligomenorrhea. The subsequent assessment will attempt to diagnose the condition based on the established diagnostic criteria and identification of the specific phenotype as difference phenotypes are associated with varying degrees of metabolic or other types of dysfunction. The differential diagnosis of PCOS must include other causes of androgen excess and ovulatory dysfunction such as thyroid disease, prolactin disorders, nonclassical forms of congenital adrenal hyperplasia, exogenous androgens, androgen-secreting tumors, genetic defects of insulin action, Cushing syndrome, and primary hypothalamic and primary ovarian dysfunction.18
In the evaluation of a patient with suspected PCOS, a detailed history should be obtained with emphasis on the onset and duration of symptoms of menstrual dysfunction and androgen excess, and medication history. As part of the physical examination, a waist circumference should be obtained and a careful body inspection performed to detect the presence of acne, hirsutism, central obesity, alopecia, clitoromegaly, and acanthosis nigricans. Pelvic examination may reveal ovarian enlargement. Transvaginal pelvic ultrasonography is important in the evaluation of women with suspected PCOS as polycystic-appearing ovaries are a component of most diagnostic criteria. All women should be screened for metabolic syndrome which is defined as: elevated blood pressure ≥130/85 mm Hg, increased waist circumference ≥35 inches, elevated fasting glucose ≥100 mg/dL, decreased HDL less than or equal to 50 mg/dL, and elevated triglyceride level ≥150 mg/dL.19
The initial laboratory biochemical evaluation in women or adolescents who present with symptoms concerning for PCOS should include a serum total testosterone, sex hormone binding globulin (SHBG), and free testosterone. Free testosterone is more sensitive than total testosterone for detection of hyperandrogenism; however, it is only more reliable if calculated from total testosterone and SHBG (as opposed to measuring free testosterone directly by equilibrium dialysis). There are no established androgen level cutoffs that would suggest an androgen-secreting tumor.20 As PCOS is a diagnosis of exclusion, a laboratory work-up for other causes of hyperandrogenemia and non-androgenic causes of anovulation is warranted. Obtaining a serum hCG, FSH, LH, prolactin, and TSH are appropriate as an initial step, as well as an early morning follicular phase 17-hydroxyprogesterone (17-OHP) to rule out nonclassical congenital adrenal hyperplasia because of 21-hydroxylase deficiency in appropriately selected patients (for example, in at-risk populations such as Ashkenazi Jews). A truly elevated 17-OHP should be followed-up with an ACTH stimulation test.21 Rare disorders such as Cushing syndrome or acromegaly can be considered in the appropriate clinical context.
A slightly elevated LH to FSH ratio is common in PCOS because of increased LH concentrations and low-normal FSH concentrations.22 The increase in serum LH is a consequence of an abnormal LH secretory mechanism in which there is an increase in LH pulse frequency and amplitude in patients who are anovulatory. The decreased in FSH is because of a concurrent increase in GnRH pulse frequency and negative feedback effects of elevated estrogen levels derived from peripheral aromatization and from increased inhibin B levels. Abnormal thyroid function may alter testosterone levels by altering SHBG levels and elevated prolactin may be caused by a prolactinoma. DHEA-S is another useful biochemical marker as when it is elevated it suggests an androgen-secreting tumor most likely originating from the adrenal gland. Although elevated AMH levels have been associated with PCOS, there are no cutoff values that are currently established that would aid in the diagnosis of PCOS.
Insulin resistance and an abnormal compensatory hyperinsulinemia are key features of the pathophysiology of PCOS and these features result in an increased risk of impaired glucose tolerance and type 2 diabetes mellitus in these patients.23 As such, women with a diagnosis of PCOS should be screened for impaired glucose tolerance and type 2 diabetes with a fasting glucose level followed by a 2-hour oral glucose tolerance test after administration of a 75 g glucose load. Women with PCOS should also be screened for dyslipidemia because of the increased risk of metabolic syndrome and its subsequent cardiovascular risk. Rescreening for features of the metabolic syndrome and cardiovascular risk should be done periodically as there is a nearly 20% risk of developing impaired glucose tolerance yearly in patients with PCOS.24
In addition to long-term consequences of insulin resistance, metabolic syndrome, diabetes, and cardiovascular disease in women with PCOS, there are several more conditions for which these women are at risk. As patients with PCOS are typically obese, conditions associated with obesity and anovulation have a higher prevalence in this population such as endometrial cancer, endometrial hyperplasia, obstructive sleep apnea, nonalcoholic fatty liver disease, and mood disturbances including anxiety and depression.25 Obesity and hirsutism have also been associated with a reduced quality of life.26
The association between PCOS and insulin resistance, and thus risk of developing metabolic syndrome and type II diabetes, has been clearly established. No prospective studies thus far have documented a clear link between PCOS and cardiovascular events, though some studies with premenopausal women have suggested a relation between increasing level of oligomenorrhea and independent cardiovascular risk factors, such as increased prevalence of subclinical atherosclerosis compared to controls.27–29 It is still unclear how and why women with PCOS do not seem to exhibit a higher incidence of myocardial infarctions despite the increased prevalence of abnormal vasculature.
Though reproductive and metabolic implications may seem to have two disparate focuses, the general principle of therapy in PCOS is to optimize health first, before commencing treatment for infertility. Nonpharmacologic lifestyle changes have been shown to attenuate some of the metabolic perils associated with PCOS and can additionally lead to a sense of better physical well-being in these women.30 An increase in exercise combined with dietary changes, particularly caloric restriction, has consistently been shown to reduce the risk of developing type II diabetes equal to or better than pharmacologic agents.31 Up to 80% of women with PCOS are overweight or obese. In this population, even modest weight loss—as little as 5% body weight change—has been associated with enhancements in overall health including improved glucose and lipid levels. In the obese PCOS population, weight loss itself, regardless of modality—be it medication, gastric bypass, or diet and exercise—has been associated with improved pregnancy rates as well as decreased hirsutism.32–35
Although much of the focus on therapy for women with PCOS appropriately centers on enhancing metabolic management and fertility treatments, cosmetic medical issues may profoundly impact the quality of life and psychological well-being of women with PCOS and in fact are the most common reason for women presenting for medical care. Hirsutism and acne are the most common physical manifestations of hyperandrogenism. Although there is no clear first-line treatment for hirsutism, lifestyle interventions to improve this condition primarily center around mechanical hair removal including shaving, plucking, waxing, electrolysis, and laser vaporization; depilatory creams are also often utilized. The combination of an FDA-approved topical pharmacologic agent, Eflornithine, an inhibitor of the enzyme ornithine decarboxylase, used 2 times daily in combination with laser therapy has been shown to be superior to laser alone in the treatment of hirsutism.36 The treatment of acne centers primarily around pharmacologic interventions aimed at decreasing circulating androgens in addition to topical treatments by dermatologists.
Although most treatments for fertility related to anovulation or oligo-ovulation in women with PCOS focus on pharmacologic intervention, surgical interventions have been attempted as an alternative to restore ovulatory cycles. Ovarian wedge resection was the earliest surgical intervention proposed, first described by Stein and Cohen in 1935.37 Although many studies showed this technique to be successful in terms of ovulation induction, wedge resection is associated with significant adhesion formation which itself is fraught with potential fertility implications. As a surgical alternative, laparoscopic ovarian drilling (LOD) was first described by Gjönnaess38 in 1984 and has been widely used since that time. LOD typically employs monopolar or bipolar electrocautery, or laser, to effectively drill an undefined number of holes into the ovarian cortex.39,40 This surgical procedure is currently recommended only as a second-line therapy in clomiphene-resistant women with anovulatory infertility.18 A Cochrane review of 25 randomized controlled trials found that LOD was equivalent to other pharmacologic ovulation induction therapies in terms of live birth rate, long-term cost, and quality of life, however notably resulted in a lower rate of multiple pregnancy.41 Despite the improvement in risk of multiple pregnancy, this procedure is not recommended first line given the underlying surgical risks in addition to risk of periovarian adhesion formation.
Pharmacologic therapies are routinely utilized alongside nonpharmacologic interventions to manage the overall health of women with PCOS. The specific interventions and medications employed to manage this condition will differ among patients based on their individual characteristics and goals of treatment. Pharmacologic treatments may be divided into treatment for counteracting hyperandrogenism, managing endometrial effects of ovulatory dysfunction, improving metabolic status, and treatment of infertility via ovulation induction.
COMBINED ORAL CONTRACEPTIVES
Unless otherwise contraindicated, combination low-dose oral contraceptive pills (OCPs) are regarded as first line therapy in women with PCOS who are not actively attempting to become pregnant. OCPs increase circulating levels of sex hormone binding globulin (SHBG) and decrease ovarian androgen secretion, leading to decreased levels of circulating androgens. They also suppress luteinizing hormone secretion from the pituitary, and additionally may stabilize the endometrium to minimize the risk of endometrial hyperplasia.14,18
Specific antiandrogens are often employed to target androgenic hirsutism, acne, and alopecia. Spironolactone, an androgen receptor blocker and inhibitor of androgen biosynthesis, is the preferred first-line treatment specifically for hirsutism. Flutamide, another androgen receptor blocker, and finasteride, a 5α-reductase inhibitor are alternative treatments for hirsutism, with finasteride also often used to treat for androgenic alopecia. These antiandrogens can be combined for synergistic effect with one another because of different mechanisms of action and combined with OCPs. If not being used simultaneously with OCPs, patients must be counseled on the need for effective contraception during use as they have been shown to be teratogenic.42,43
Because of chronic oligo-ovulation or anovulation, women with PCOS are at increased risk for endometrial hyperplasia and thus endometrial carcinoma. To minimize this risk, regular administration of progestins are recommended in patients not actively attempting to become pregnant. No one regimen has been deemed superior to others, but options for management include cyclic or continuous oral progestins, progestin-containing intrauterine devices, and injectable progestins such as depot medroxyprogesterone acetate.18
For metabolic management of this disease, first line therapy is lifestyle interventions including weight loss along with diet changes and exercise as discussed previously. In women with evidence of glucose intolerance, elevated insulin levels, or strong family history of diabetes, medical management with insulin sensitizers, most commonly metformin, is often dually warranted. In addition to its metabolic impact on improved insulin sensitivity and glucose tolerance, metformin also decreases circulating androgen levels. Furthermore, metformin has been suggested to improve ovulatory function.44 A meta-analysis in 2004 found that metformin was better than placebo for menstrual cycle regulation in noninfertile PCOS patients, as well as better than placebo for ovulation induction in the infertile PCOS population.45 However, this same study revealed that pregnancy rates were not improved using metformin. Further studies revealed inferiority of metformin when compared directly to other oral ovulation inductions such as clomiphene citrate and letrozole in terms of ovulation, pregnancy rates, and live birth rates in women with PCOS.39,46 Given these findings, metformin is not recommended alone as a first line drug for fertility treatment, but is used in this population largely for its metabolic benefits. In addition, combination therapy of metformin plus clomiphene may be considered in women who are resistant to clomiphene alone, though there remains insufficient evidence of an increase in live birth rates in this setting.46
For women with PCOS seeking ovulation induction for pregnancy, the most widely used first-line therapy has traditionally been the oral antiestrogenic agent clomiphene citrate. Clomiphene is a selective estrogen receptor modulator (SERM), blocking estradiol receptors in the hypothalamus and inducing a change in GnRH pulse frequency, leading to an increased release of FSH from the anterior pituitary and subsequent follicular development.39 The original multicenter pregnancy in polycystic ovary syndrome (PPCOS I) trial showed a clear benefit of clomiphene compared to metformin alone in achieving live birth, however also confirmed that a higher risk of multiple births is a complication (Fig. 2).46 In the practical administration of clomiphene citrate, the starting dose is typically 50 mg for 5 days in the early follicular phase, with a stair step approach for lack of response up to a dose of 150 mg. Patient weight must be considered when considering a starting dose.
Letrozole, an aromatase inhibitor, is also known to be effective for ovulation in women with PCOS. This medication is administered similarly to clomiphene, for 5 days in the early follicular phase, starting with a dose of 2.5 mg and increasing in a stepwise manner as needed for lack of response to a maximum dose of 7.5 mg. A large follow-up study to PPCOS I, the PPCOS II trial, compared clomiphene citrate directly to letrozole in the infertile PCOS population, and reported an increased live birth rate and ovulation rate in this population (Fig. 3).47,48 It is worth noting however that the mean BMI in this study was above 35 kg/m2, and thus the current recommendation for the utilization of letrozole as a first-line treatment over clomiphene should apply to the obese PCOS population. Further studies are needed to elicit if there is a benefit of one oral agent over another in the non-obese PCOS population. In addition, there has more recently been suggestion that perhaps a combination of letrozole and clomiphene may act synergistically to improve ovulation rates in women with PCOS49; however, sample size in a recent study was limited and more studies are needed to examine this finding and whether this correlates with enhanced live birth rates.
In patients resistant to oral ovulation induction agents or after failures of therapy, injectable gonadotropin therapy may be used as second-line treatment. Gonadotropin therapy has been associated with a clear increased risk of multiple pregnancy, as well as an increased risk of ovarian hyperstimulation syndrome (OHSS), a risk amplified in the PCOS population. OHSS is generally an iatrogenic condition except in rare cases, and is a serious and potentially life-threatening condition involving increased capillary permeability, third spacing of fluid with resultant ascites, pulmonary edema, renal failure, risk of venous thromboembolism, as well as obstetric complications including increased risk of spontaneous abortion.50 This disease state generally occurs as the result of controlled ovarian hyperstimulation with gonadotropins for either ovulation induction or in vitro fertilization (IVF). Although the underlying etiology of polyfollicular ovaries and thus inherent risk of OHSS exists, there are strategies that we can employ during treatment to minimize the incidence of this disease state.
The risk of OHSS can be attenuated by gentle stimulation with gonadotropins along with close monitoring of estradiol levels in addition to transvaginal ultrasound throughout stimulation. The employment of a low-dose sliding scale hCG trigger, or use of a GnRH agonist, namely Leuprolide, either alone or in combination with hCG as part of a dual trigger can significantly attenuate this risk and should always be considered.50,51
In women with PCOS undergoing IVF, there is evidence suggesting that live birth rates may be higher and the risk of OHSS lower when frozen, rather than fresh, embryo transfer is performed. A multicenter trial of over 1500 infertile women with PCOS undergoing day three embryo transfer of up to two embryos revealed a higher rate of live birth, along with a lower risk of OHSS and lower frequency of miscarriage in these patients compared with women who underwent fresh embryo transfer immediately following IVF stimulation.52 This is proposed to be because of the interval “rest” period allowing the hyperstimulated ovary to return to a baseline size, as well as the hormonal milieu to return to a less stimulated state. Interestingly, the women in the frozen embryo transfer cohort had a higher incidence of preeclampsia later in pregnancy. These findings suggest a potential benefit for this population of infertile women with PCOS to undergo embryo cryopreservation cycles upfront after IVF stimulation with gonadotropins, with an interval plan for frozen embryo transfer to both improve pregnancy rates and minimize the medical risk of OHSS.
PCOS remains one of the most intriguing endocrine disorders that physicians encounter even though it was first described over 80 years ago. Although the diagnostic criteria, nomenclature, and ideal therapeutic strategies are areas of active and ongoing debate, there is no doubt that we have made tremendous progress in improving the quality of life and reproductive outcomes of women who suffer from this wide-ranging disorder.
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