Evaluation and Treatment of Polycystic Ovary Syndrome
Course AuthorsDaniel A. Dumesic, M.D., Mark O. Goodarzi, M.D., Ph.D., Gregory D. Chazenbalk, Ph.D., David Geller, M.D., and David H. Abbott, Ph.D. Dr. Dumesic is Professor and Division Chief of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of California Los Angeles; Dr. Goodarzi is Associate Professor, Director of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA; Dr. Chazenbalk is Associate Researcher, Department of Obstetrics and Gynecology, University of California Los Angeles; and Dr. Geller is Associate Professor of Pediatrics, Ahmanson Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA; and Dr. Abbott is Professor, Wisconsin National Primate Research Center and Department of Obstetrics and Gynecology, University of Wisconsin, Madison, WI. Within the past 12 months Drs. Dumesic, Goodarzi, Chazenbalk and Geller report no commercial conflicts of interest; Dr. Abbott has received research grants from Boehringer-Ingelheim and Viamet, and been a consultant to Viamet. Albert Einstein College of Medicine, CCME staff and interMDnet staff have nothing to disclose. Estimated course time: 1 hour(s). Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.  
Learning Objectives
Upon completion of this Cyberounds®, you should be able to:
 
Up to 70% of women with classic PCOS are insulin resistant. A crucial factor in diagnosing PCOS is the definition of PCOS itself.(1) The 1990 National Institutes of Health (NIH)-National Institute of Child Health and Human Development-Conference of PCOS in 1990 recommended that the diagnostic criteria should be clinical or biochemical hyperandrogenism with oligo-anovulation, and excluding other endocrinopathies such as non-classical congenital adrenal hyperplasia, Cushing's syndrome, thyroid dysfunction, hyperprolactinemia, androgen-producing tumors and drug-induced androgen excess.(2) In 2003, the Rotterdam consensus expanded the diagnostic criteria to include at least two of the following three features: 1) clinical or biochemical hyperandrogenism, 2) oligo-anovulation and 3) polycystic ovaries (PCO [a morphological feature of the ovary]), excluding the same previously described endocrinopathies.(3)(4) These newer Rotterdam criteria for PCOS include all patients defined by 1990 NIH criteria (i.e., classic PCOS) plus women with either 1) clinical/biochemical hyperandrogenism and PCO (i.e., ovulatory PCOS) or 2) PCO with ovulatory dysfunction (but without signs of androgen excess). The prevalence of metabolic syndrome in women with PCOS is as high as 30-45%. In 2006, the Androgen Excess (AE)-PCOS Society recommended that PCOS be defined by clinical/biochemical hyperandrogenism, with either oligo-anovulation and/or polycystic ovaries, and the exclusion of related disorders.(5)(6) Their recommendation agreed with the view of the 1990 NIH criteria that androgen excess is the key feature of PCOS. Classic PCOS patients are at increased risk of developing metabolic abnormalities, including type 2 diabetes mellitus (T2DM). Ovulatory PCOS patients tend to have a lower body mass index(7) and lesser degrees of hyperinsulinemia and hyperandrogenism than classic PCOS patients,(7)(8) while women with combined PCO and oligo-anovulation (without androgen excess) appear least affected. Up to 70% of women with classic PCOS are insulin resistant, especially those individuals who are overweight or obese,(9)(10) with PCOS and obesity exerting additive effects on insulin resistance.(11)(12) Another potential contributor to insulin resistance in the patient described above may be the use of oral contraceptive pills.(13)(14) Most PCOS women with insulin resistance have increased insulin production, leading to compensatory hyperinsulinemia that maintains euglycemia with adverse consequences. Specifically, hyperinsulinemia: stimulates ovarian theca cell androgen production which, in turn, promotes anovulation;(15) suppresses hepatic sex hormone binding globulin production, further elevating free testosterone levels; promotes acanthosis nigricans and skin tags; and underlies non-alcoholic fatty liver disease and sleep apnea.(16)(17) Moreover, insulin resistance in PCOS is a strong predictor of developing T2DM, which occurs when insulin production deteriorates and insufficient insulin levels exist to overcome insulin resistance. Women with a family history of PCOS are most likely to experience this pancreatic β-cell failure.(18)(19) Rates of impaired glucose tolerance and T2DM in PCOS approach 35% and 10%, respectively, and are higher than those for normal women of similar age (each, <3%),(20)(21)(22)(23) conferring in PCOS women a 2.5-fold increase in impaired glucose tolerance and a four-fold elevation in T2DM.(24) Reliance on fasting glucose alone to screen for T2DM in PCOS is insufficient because a fasting glucose determination in this setting is an insensitive method of diagnosing T2DM.(25) Rather, a 2-hour, post 75 g OGTT should be performed in PCOS women with a BMI >30 kg/m2; or alternatively in lean PCOS women with advanced age (>40 years), personal history of gestational diabetes or family history of T2DM,(26) although some experts recommend an OGTT in all PCOS women regardless of weight.(20) If the OGTT is normal, it can be repeated every two years or sooner if additional risk factors are identified.(20)(26) Dyslipidemia occurs in 70% of PCOS women in the United States(27) and less frequently in other countries where mean body weight is lower.(28) The most common dyslipidemia pattern in PCOS is hypertriglyceridemia, increased small dense low-density lipoprotein cholesterol (LDL-C) levels and decreased high-density lipoprotein cholesterol (HDL-C) levels.(29)(30) This dyslipidemia pattern results from insulin resistance that impairs the ability of insulin to suppress lipolysis, thereby increasing mobilization of free fatty acids from adipose stores.(29)(31)(32)(33) Increased total LDL-C levels in PCOS women are less dependent on body weight than triglycerides, small dense LDL-C and HDL-C.(28)(34)(35) Clomiphene citrate is generally the first-line therapy for anovulation in a PCOS patient. Moreover, hyperinsulinemia is a likely contributor (perhaps even the central factor) to developing the metabolic syndrome, a clustering of traits that include central adiposity, hyperglycemia, hypertension, elevated triglycerides and depressed HDL-C levels. Consequently, the prevalence of metabolic syndrome in women with PCOS is as high as 30-45%, much higher than the ~5% observed in the same age and gender group in the general population.(24)(36)(37)(38)(39) The metabolic syndrome is a risk factor for cardiovascular disease. Several cardiovascular risk factors exist with increased prevalence in PCOS including dyslipidemia, hypertension, endothelial dysfunction, increased carotid intima-media thickness, increased coronary artery calcium, elevations in inflammatory markers and decreased adiponectin. Several of these derangements improve with insulin sensitization therapy, which suggests that insulin resistance contributes to the adverse cardiovascular risk profile.(27)(29)(39)(40)(41)(42)(43)(44)(45)(46)(47) An increased risk of actual cardiovascular events in PCOS has been indirectly shown.(42)(48)(49) Along with lifestyle management such as weight loss and exercise to mitigate metabolic dysfunction, therapies that improve insulin sensitivity and reduce insulin levels have become common in the management of PCOS.(50) The most used and safest agent is metformin, which improves insulin response primarily at the liver, resulting in reduced hepatic glucose output. In PCOS, metformin therapy reduces fasting insulin levels, lowers testosterone levels and improves the lipid profile.(51)(52)(53) Other potential benefits include prevention of T2DM and cardiovascular disease (assuming these benefits, previously observed in studies of pre-diabetic and diabetic cohorts, respectively, also occur in PCOS women).(54)(55) A fasting serum lipid profile should be a component of the metabolic screening in PCOS women, as noted above. Statins and other agents targeting cholesterol synthesis, LDL-C and non HDL-C may be necessary if dyslipidemia or other risk factors persist.(26)
Although several ovulation induction strategies exist,(55)(56) two randomized clinical trials have shown that metformin does not increase the ongoing pregnancy or live-birth rates above those observed with clomiphene citrate alone;(58)(59) one trial demonstrated a disadvantage of metformin versus clomiphene citrate, except for the combined use of metformin/clomiphene in obese PCOS patients who fail to ovulate with clomiphene alone.(53)(58) Because metformin has a slower onset of action, indirectly inducing ovulation by reducing serum insulin levels, six months of metformin therapy may be needed to improve ovulation. Therefore, clomiphene citrate is generally the first-line therapy for anovulation in a PCOS patient without other infertility factors who wishes to conceive as soon as possible. Metformin (combined with diet and exercise) is an alternative strategy if the need for conception is less urgent, with the additional advantage, compared to clomiphene, of having a lower multiple birth rate.(57) The aromatase inhibitor, letrozol, also appears to be as effective as clomiphene citrate for ovulation induction in PCOS, but prospective, sufficiently powered, studies are required to confirm this observation. PCOS heritability is supported by the 5-fold increased prevalence of PCOS among mothers and sisters of women with PCOS. Gonadotropins and laparoscopic ovarian surgery are second-line interventions if clomiphene (or combined clomiphene/metformin) fail to induce ovulation.(56) in vitro fertilization is usually considered a third-line intervention under this circumstance, except if associated pathologies exist (i.e., severe endometriosis or male factor infertility, tubal damage, preimplantation genetic diagnosis).(56) With an increased risk of high-order multiple births from gonadotropin therapy, however, IVF might be a reasonable option for PCOS women who fail clomiphene therapy because such a risk can be reduced by transferring one or two embryos.(60)
Pubic and axillary hair normally develop during adrenarche, a stage of augmented adrenal androgen production distinct from puberty. Premature adrenarche (PA) in girls <7-8 years of age, (61)(62)(63)(64) however, requires an evaluation of hyperandrogenism, as discussed above, particularly since this patient continues to have irregular menses and acne, with excessive hair growth in a male distribution. She likely has PCOS because 1) her serum 17-OHP4 level is normal (<2.0 ng/mL), ruling out non-classical adrenal hyperplasia; 2) her OGTT shows impaired glucose tolerance rather than diabetes (which is diagnosed when fasting and 2-hour, post-prandial glucose levels are ≥126 and ≥200 mg/dL, respectively [20]); and 3) she does not show rapid virilization (i.e., voice deepening, temporal balding, loss of breast tissue) as signs of androgen-producing tumors. Neonates of PCOS mothers have a higher rate of hospitalization for intensive care. Girls with PA commonly develop PCOS (65) with hyperinsulinism, which appears early in life and continues throughout pubertal maturation.(66)(67)(68)(69) One longitudinal study estimated 10-20% incidence of adult PCOS in girls with earlier PA.(70) Such PA girls born small-for-gestational age also may acquire metabolic dysfunction in later life,(71)(72)(73) presumably because maladaptive responses 1) attenuate normal adipose expansion, 2) favor lipotoxicity from aberrant fat deposition and 3) induce hyperinsulinemia from insulin resistance, which in turn stimulates ovarian hyperandrogenism.(74)(75)(76)(77) Importantly, this patient likely has a family history of PCOS since her sister also has menstrual irregularity and hirsutism. Despite the lack of validated genomic associations in large population studies,(78) PCOS heritability is supported by the 5-fold increased prevalence of PCOS among mothers and sisters of women with PCOS. Adult relatives of women with PCOS disproportionately exhibit steroidogenic and metabolic abnormalities,(79)(80)(81)(82)(83)(84)(85)(86)(87)(88) and disordered insulin dynamics emerge early in maturation, similar to that observed in PA.(66)(89)(90) Recent studies of PCOS daughters reveal hyperinsulinemia across maturation stages and preceding signs of androgen excess, which suggest that insulin and other metabolic markers may facilitate the onset of hyperandrogenism in an at-risk population.(91)(92)(93) As in adults, insulin sensitizers (thiazolidinediones [TZD], metformin) improve steroidogenic and metabolic profiles in PCOS adolescents,(69)(72)(94)(95)(96)(97)(98) while restoring menstrual cyclicity and ovulation.(72)(99)(100)(101)(102) Similar benefits accompany metformin poly-therapy (101)(102) in mid-pubertal PA girls at high risk to develop PCOS, although loss of such benefits occurs following discontinuation of therapy.(103)(104) Importantly, metformin use in PCOS adolescents is not currently FDA-approved despite excellent safety profiles. Adolescent TZD use also is controversial (despite its ability in adult PCOS to mitigate insulin resistance and androgen excess) due to cardiovascular toxicity and insufficient randomized clinical trials in this age group. Anti-androgen therapy has little effect on metabolic performance. Thus, a trial of metformin may be warranted for this obese PCOS patient with impaired glucose tolerance since oligomenorrhea persists into adulthood in two-thirds of PCOS adolescents (105) and their risk of metabolic syndrome is markedly increased.(106)
Gestational androgen excess and hyperinsulinemia occur during pregnancy in PCOS and can adversely affect pregnancy outcome.(107) Given low parity, high BMI and multiple pregnancies from fertility treatment, PCOS women are at increased risk of pre-eclampsia.(108)(109) Nevertheless, singleton pregnancies in PCOS women also are at increased risk of gestational diabetes, pregnancy-induced hypertension, pre-eclampsia and perhaps preterm delivery.(108)(110) Consequently, neonates of PCOS mothers have a higher rate of hospitalization for intensive care and a greater risk of perinatal mortality unrelated to multiple births.(108) Low birth weight occurs in some ethnic groups of PCOS women.(71)(111)(112) Although the prevalence of PCOS in women born small for gestational age is twice that in women born appropriate for gestational age,(113) infant birth weight is generally normal for gestational age in PCOS (controlling for maternal BMI and multiple pregnancy).(108)(114)(115)(116) Postdatism (i.e., post term pregnancy) does not occur with any greater frequency. Hormonal changes in fetal life also may be important in the developmental origins of PCOS. In monkeys and sheep, experimentally-induced, prenatal testosterone excess programs permanent PCOS-like phenotypes(117) that mirror the increased prevalence of PCOS in women with classical congenital adrenal hyperplasia and congenital adrenal virilizing tumors. Clinical studies have yet to confirm that androgen excess during human fetal development promotes PCOS after birth, given that androgen studies of infant blood at term demonstrated conflicting results.(118)(119) Summary PCOS is a common female endocrinopathy manifested by hyperandrogenism, oligo-ovulation and polycystic ovarian morphology in its complete phenotype. After first ruling out other hyperandrogenic or oligo-ovulatory disorders, the specific PCOS phenotype is determined by which of these key features exist. Most PCOS women have insulin resistance (more severe than their body weight might produce) and multiple risk factors for cardiovascular disease including dyslipidemia, abdominal obesity, hypertension and glucose intolerance or type 2 diabetes mellitus. A subset of PCOS patients also experience anovulatory infertility due to complex endocrine abnormalities which may originate in utero and persist through puberty into adulthood. Understanding how relevant endocrine factors interact to promote optimal metabolic and reproductive function in women is the key to the development of new clinical strategies that reverse the negative metabolic and reproductive consequences of PCOS. |