Polycystic ovary syndrome (PCOS) is one of the most common reproductive endocrine disorders in women and despite this, diagnostic challenges, delayed diagnosis, and less-than-optimal treatment regimens plague the condition. The International PCOS network, consisting of geographically diverse international experts in PCOS as well as consumers, engaged in a multi-year international evidence-based guideline development process that was jointly sponsored by the European Society for Human Reproduction and Embryology (ESHRE) and the American Society of Reproductive Medicine (ASRM). The guideline was published in 2018 and endorsed by more than 40 international societies involved in PCOS. Translation of this evidence-based guideline to medical practice and consumer groups remains a priority. However, there remain many challenges to both understanding the diagnosis and treatment of PCOS. Evidence suggests that both clinicians and consumers are not satisfied with the timeliness of diagnosis and treatment options. This review summarizes the important findings for diagnosis and treatment from the guidelines and expands on recent developments in the literature since its publication. Special attention to diagnosis at the ends of the reproductive spectrum are discussed and remaining areas of controversy are noted. Additionally, the review highlights some of the remaining challenges in the understanding and management of PCOS to help guide clinicians and investigators in this perplexing condition.

Context: Polycystic ovary syndrome (PCOS) presents in adolescence, and obesity is a common finding. The benefits and risks of alternate approaches to the management of PCOS in obese adolescent women are not clear. Objective: We investigated the effects of metformin, oral contraceptives (OCs), and/or lifestyle modification in obese adolescent women with PCOS. Design: Two small, randomized, placebo-controlled clinical trials were performed. Patients and Participants: A total of 79 obese adolescent women with PCOS participated. Interventions: In the single treatment trial, subjects were randomized to metformin, placebo, a lifestyle modification program, or OC. In the combined treatment trial, all subjects received lifestyle modification and OC and were randomized to metformin or placebo. Main Outcome Measures: Serum concentrations of androgens and lipids were measured. Results: Lifestyle modification alone resulted in a 59% reduction in free androgen index with a 122% increase in SHBG. OC resulted in a significant decrease in total testosterone (44%) and free androgen index (86%) but also resulted in an increase in C-reactive protein (39.7%) and cholesterol (14%). The combination of lifestyle modification, OC, and metformin resulted in a 55% decrease in total testosterone, as compared to 33% with combined treatment and placebo, a 4% reduction in waist circumference, and a significant increase in HDL (46%). Conclusions: In these preliminary trials, both lifestyle modification and OCs significantly reduce androgens and increase SHBG in obese adolescents with PCOS. Metformin, in combination with lifestyle modification and OC, reduces central adiposity, reduces total testosterone, and increases HDL, but does not enhance overall weight reduction.

Background: Women with obesity and infertility are counseled to lose weight prior to conception and infertility treatment to improve pregnancy rates and birth outcomes, although confirmatory evidence from randomized trials is lacking. We assessed whether a preconception intensive lifestyle intervention with acute weight loss is superior to a weight neutral intervention at achieving a healthy live birth. Methods and findings: In this open-label, randomized controlled study (FIT-PLESE), 379 women with obesity (BMI ≥ 30 kg/m²) and unexplained infertility were randomly assigned in a 1:1 ratio to 2 preconception lifestyle modification groups lasting 16 weeks, between July 2015 and July 2018 (final follow-up September 2019) followed by infertility therapy. The primary outcome was the healthy live birth (term infant of normal weight without major anomalies) incidence. This was conducted at 9 academic health centers across the United States. The intensive group underwent increased physical activity and weight loss (target 7%) through meal replacements and medication (Orlistat) compared to a standard group with increased physical activity alone without weight loss. This was followed by standardized empiric infertility treatment consisting of 3 cycles of ovarian stimulation/intrauterine insemination. Outcomes of any resulting pregnancy were tracked. Among 191 women randomized to standard lifestyle group, 40 dropped out of the study before conception; among 188 women randomized to intensive lifestyle group, 31 dropped out of the study before conception. All the randomized women were included in the intent-to-treat analysis for primary outcome of a healthy live birth. There were no significant differences in the incidence of healthy live births [standard 29/191(15.2%), intensive 23/188(12.2%), rate ratio 0.81 (0.48 to 1.34), P = 0.40]. Intensive had significant weight loss compared to standard (−6.6 ± 5.4% versus −0.3 ± 3.2%, P < 0.001). There were improvements in metabolic health, including a marked decrease in incidence of the metabolic syndrome (baseline to 16 weeks: standard: 53.6% to 49.4%, intensive 52.8% to 32.2%, P = 0.003). Gastrointestinal side effects were significantly more common in intensive. There was a higher, but nonsignificant, first trimester pregnancy loss in the intensive group (33.3% versus 23.7% in standard, 95% rate ratio 1.40, 95% confidence interval [CI]: 0.79 to 2.50). The main limitations of the study are the limited power of the study to detect rare complications and the design difficulty in finding an adequate time matched control intervention, as the standard exercise intervention may have potentially been helpful or harmful. Conclusions: A preconception intensive lifestyle intervention for weight loss did not improve fertility or birth outcomes compared to an exercise intervention without targeted weight loss. Improvement in metabolic health may not translate into improved female fecundity. Trial registration: ClinicalTrials.gov NCT02432209.

Context: Adults with polycystic ovary syndrome (PCOS) may be at increased risk for metabolic syndrome (MBS) and related cardiovascular disease. It is not clear whether PCOS diagnosed in adolescence increases the risk of MBS in this age group. Objective: The aim was to compare the prevalence and related characteristics of MBS in obese adolescents with and without PCOS. Design: We conducted a cross-sectional study of overweight and obese PCOS adolescents and BMI matched controls. Patients and Participants: A total of 74 subjects, 43 with PCOS and 31 controls, participated in the study. Interventions: Each subject underwent a physical examination and laboratory evaluation for a diagnosis of MBS. Regional fat distribution was determined by computerized tomography scan in the PCOS adolescents. Main Outcome Measures: We measured the prevalence of MBS and its components in adolescent subjects and controls. Results: The PCOS group had larger ovarian volume and higher measures of total testosterone and free androgen index than controls, but there were no differences in waist circumference, fasting glucose, blood pressure, or lipids. PCOS adolescents demonstrated more glucose abnormalities and higher plasminogen activator inhibitor-1. By pediatric criteria, 53% of the PCOS and 55% of the control adolescents had MBS. By adult criteria, 26% of PCOS and 29% of controls met diagnostic criteria for MBS. Conclusions: Obese adolescent women have a high prevalence of MBS, and PCOS does not add additional risk for MBS. There appears to be an association between MBS and visceral adiposity. PCOS is associated with increased incidence of glucose intolerance and increased plasminogen activator inhibitor-1. Our results reinforce the importance of obesity counseling in adolescents to recognize the possible risk of future cardiovascular disease in these young women.