Sebastião Freitas de Medeiros

This comprehensive review focuses on the relevance of hyperinsulinemia in women with polycystic ovary syndrome (PCOS). It highlights the most robust scientific evidence on the management of this condition within the context of PCOS. A systematic search of studies published in English language was conducted using Google Scholar, PubMed, and Cochrane databases. Keywords used alone or combined with “PCOS” included: hyperinsulinemia, incretin hormones, and dipeptidyl peptidase-4. The search strategy was complemented by manual review of references from selected articles. Glucagon-like peptide-1 receptor agonist and glucagon-dependent insulin tropic polypeptide provide various metabolic beneficial effects in addition to the weight loss. Dipeptidyl peptidase-4 inhibitors, expressed by various cells, prevent GLP-1 degradation and decreases insulin signaling in different cells, particularly in hepatocytes, and adipocytes. Regarding the management of hyperinsulinemia, the review suggests that incretin hormone agonist and dipeptidyl peptidase-4 inhibitors may represent favorable therapeutic options for addressing insulin resistance in women with PCOS, particularly those with obesity. However, this review does not explore dietary interventions and physical activity as primary strategies for managing dysglycemia in this population.

Polycystic ovary syndrome (PCOS) is frequently accompanied by visceral obesity, insulin resistance, low-grade chronic inflammation, and metabolic syndrome (MetS). These alterations promote significant dysfunction in adipose tissue and liver metabolism through cytokine production. Growing evidence indicates that the interaction between hepatokines and adipokines plays a central role in the development of metabolic and hepatic abnormalities in women with PCOS. This narrative review was conducted to analyze the relationship between adipose tissue dysfunction and liver metabolic impairment in women with PCOS, emphasizing the involvement of hepatokines and adipokines in insulin resistance, inflammation, hepatic steatosis, hepatic fibrosis and MetS. From this perspective, contemporary clinical, biochemical, and molecular studies were reviewed to evaluate how adipocyte-derived factors and hepatocyte-derived cytokines influence metabolic homeostasis in the liver and adipose tissue in women with PCOS. Increased visceral adiposity in PCOS enhances the release of free fatty acids (FFAs) to the liver, resulting in hepatotoxicity, oxidative stress, and hepatic inflammation. Several hepatokines, including fetuin-A, angiopoietin-like protein 3 (ANGPTL3), selenoprotein P(Sep-P), and hepassocin (HPS), show abnormal circulating levels in PCOS and are strongly associated with insulin resistance, dyslipidemia, and progression to hepatic steatosis. In contrast, fibroblast growth factor 21 (FGF-21), follistatin, and interleukin (IL-6) may exert dual effects. Adipokines, such as resistin, visfatin, apelin, and retinol-binding protein 4 (RBP-4), contribute to chronic inflammation, impaired glucose metabolism, androgen excess, and hepatic steatosis and fibrosis. Some of these adipokines, such as leptin and vaspin, may exert both beneficial and detrimental effects, while others, including chemerin and omentin, appear to play predominantly beneficial roles in metabolism. Reduced adiponectin-to-leptin levels further aggravate metabolic dysfunction. These changes indicate that adipose tissue–liver crosstalk is a key mechanism linking PCOS and MetS. Overall, metabolic disturbances in PCOS are strongly mediated by dysregulated communication between adipose tissue and the liver. Altered hepatokine and adipokine profiles contribute to insulin resistance, liver dysfunction, hypertension and the development of MetS in women with PCOS. Understanding these intricate interactions may support the early identification of high-risk patients and the development of targeted therapeutic strategies.

Context: Anti-Müllerian hormone (AMH) concentrations are frequently elevated in women with polycystic ovary syndrome (PCOS). However, clinical application is limited by the absence of a standardized cutoff, lack of assay harmonization, and variability across PCOS phenotypes. Objective: To compare AMH levels across the 4 PCOS phenotypes (A, B, C, D) defined by the Rotterdam criteria. Data sources: PubMed, Embase, ScienceDirect, and Web of Science were searched for studies published between January 2009 and July 2024. Reference lists of included studies were also screened. Study selection: Eligible studies included women with PCOS diagnosed by Rotterdam criteria and reported AMH levels by phenotype. Of 684 citations, 49 studies (15 535 participants) met inclusion criteria. Data extraction: Two reviewers independently extracted study characteristics, AMH values, assay type, age, and body mass index (BMI). AMH levels were converted to Beckman Coulter Gen II units. Risk of bias was assessed using ROBINS-E. Data synthesis: Random-effects meta-analyses showed highest AMH levels in phenotype A (11.49 ng/mL; standardized mean difference 3.06), followed by D (8.97), C (7.98), and B (6.25; standardized mean difference 1.36). Age and BMI were comparable. Heterogeneity was high (I2 ≈ 98%). Meta-regression adjusted for phenotype, age, BMI, and region confirmed the AMH hierarchy (A > D ≈ C > B) and identified geographic region as a significant contributor to heterogeneity. Conclusion: AMH levels differ markedly across PCOS phenotypes, with polycystic ovarian morphology exerting the greatest influence, followed by oligoanovulation and hyperandrogenism. Findings support the use of AMH in phenotype differentiation and emphasize the need for assay standardization and population-specific interpretation.

To compare anthropometric, endocrine, and metabolic parameters among White, Black, and Mixed-race women who have polycystic ovary syndrome (PCOS). This cross-sectional study enrolled 392 Brazilian women of different races, 308 women with PCOS and 84 without PCOS. The proportions of differences in races/ethnicities between groups were compared using a chi-squared test with Bonferroni adjustment for the number of comparisons. Comparisons between PCOS and control in each race group were performed using Student t test or Z test where appropriate. Differences among more than two Gaussian variables were determined using one-way analysis of variance followed by a Tukey post hoc test. Age and body mass index as possible confounders of the found results were controlled using a multinominal logistic regression. The proportions of ages and races were not different between women with PCOS and the control group (p = 0.099 and p = 0.978, respectively). Diastolic blood pressure was higher among Black women with PCOS (p < 0.001) and not different among Mixed-race (p = 0.667) or White (p = 0.133) races in the control group. Body weight, body mass index, waist circumference, waist-to-hip ratio, and fat mass were higher in Black women than in White women with PCOS (p < 0.05 for all comparisons). Free testosterone levels were higher among Black women than White women (p < 0.001) and Mixed-race women (p < 0.001) with PCOS, but the levels were not different in the control group. HbA1C was also higher among Black women with PCOS (p = 0.041). Black women with PCOS presented higher concentrations of carbohydrate and lipid than White women. Regarding hormones, free testosterone levels and free androgen index were higher among Black women than among White and Mixed-race women with PCOS. The control group did not present anthropometric, metabolic, and endocrine differences among races. The findings of the current study strongly suggest that ethnic background has a wide implication in the development of comorbidities, diagnosis, or for the clinical assistance of women with PCOS. The analysis of race/ethnicity is recommended in future studies with focus on pathophysiological, biochemical, and clinical characteristics.

Objective This study aims to evaluate antimüllerian hormone (AMH) levels across Polycystic Ovary Syndrome (PCOS) phenotypes (A, B, C, D) based on the Rotterdam diagnostic criteria. Data Sources A systematic review and meta-analysis were conducted following PRISMA guidelines. PubMed, Embase, ScienceDirect, and Web of Science were searched for studies published between January 2009 and June 2024. Study Eligibility Criteria Studies reporting AMH levels stratified by PCOS phenotypes based on the Rotterdam criteria, along with population characteristics and AMH measurement methods, were included. Animal studies, reviews, case reports, opinion articles, letters to the editor, other non-original research. and those lacking complete phenotype stratification were excluded. Study Appraisal and Synthesis Methods Study quality was assessed using the ROBINS-E tool. Primary outcomes included mean AMH levels across phenotypes, analyzed as tAMH (without assay differentiation) and bcAMH (Beckman Coulter Gen II assay). Secondary outcomes included age and BMI by phenotype. Random-effects meta-analysis was used to calculate mean levels and standardized mean differences (SMD) with 95% confidence intervals (CI). Heterogeneity was assessed using the I² statistic. Results Forty-nine studies involving 15,535 subjects revealed that AMH levels vary significantly by phenotype, being highest in A, followed by D, C, and B. For phenotype A: tAMH=9.87 ng/mL (SMD 2.97, CI 9.29–10.48); bcAMH=11.49 ng/mL (SMD 3.06, CI 10.47–12.61). For phenotype B: tAMH=5.71 ng/mL (SMD 0.98, CI 4.96–6.57); bcAMH=6.25 ng/mL (SMD 1.36, CI 5.20–7.51). There were no significant differences in age or BMI among phenotypes. High heterogeneity suggests additional factors influence AMH levels beyond phenotypic categories. Conclusions AMH levels are elevated in PCOS and vary across phenotypes, underscoring their potential to improve PCOS subtype characterization and guide management strategies. The findings highlight the need for standardizing AMH measurement techniques for consistent clinical application.

Key points • Nonclassic congenital adrenal hyperplasia (NCAH) or late onset CAH is a genetic disease with late manifestations in women, usually in late childhood, adolescence or early adulthood. • It is an important differential diagnosis of polycystic ovary syndrome. • More than 90% of the time it is due to a deficiency of the 21-hydroxylase enzyme. Other less frequent causes are mutations in genes affecting the 11-beta-hydroxylase or 3-beta-hydroxysteroid dehydrogenase enzymes. • Its diagnosis is particularly important in women who desire pregnancy. • Treatment among women with hyperandrogenism without reproductive desire can be directed toward controlling clinical manifestations. Recommendations • We recommend screening for NCAH due to 21-hydroxylase (CYP21A2) deficiency in adolescents and adult women who present signs and symptoms of hyperandrogenism (Level of Evidence A). • The diagnosis of NCAH is excluded by measuring baseline 17-OHP < 2 ng/mL ( 10 ng/mL (1,000 ng/dL) and, more frequently > 15 ng/mL (1,500 ng/ dL), the diagnosis of NCAH is established (Level of Evidence A). • When possible, we recommend CYP21A2 genotyping in women presenting 17-OHP values > 10 ng/mL (1,000 ng/dL) with the aim to confirm the diagnosis and for pre-conception counseling (Level of Evidence B). • We recommend the use of oral contraceptives (OC) associated or not with antiandrogens as the first option for treating androgenic manifestations and regularizing menstrual cycles in women who do not wish to become pregnant (Level of Evidence A). • We recommend the use of glucocorticoids in cases where conventional treatment for hirsutism is ineffective or poorly tolerated or when the post-ACTH stimulus cortisol response is less than 18 mcg/dL (Level of Evidence C). • We recommend the use of glucocorticoids that do not cross the placental barrier, such as hydrocortisone, prednisolone or prednisone for patients unable to become pregnant spontaneously or with ovulatory dysfunction and who are not at risk of affected fetuses (Level of Evidence B). • In this situation, glucocorticoid treatment must be continued during pregnancy to avoid miscarriages (Level of Evidence C). • We recommend combining ovulation inducers such as clomiphene citrate, letrozole (off-label) or gonadotropins if glucocorticoids are not sufficient to restore ovulation (Level of Evidence B). • Genetic counseling for the couple is indicated to evaluate genotyping of the partner of women with the nonclassic form to detect a serious mutation (Level of Evidence C). • We recommend referring pregnant women at risk of having female fetuses with genital defects to specialized tertiary and quaternary care centers (Level of Evidence D).

Background: Because of this prevalence and frequent association with various comorbidites, the diagnosis of polycystic ovary syndrome (PCOS) must be performed as early as possible. Despite conflicting findings, many studies have been published on adolescents with a diagnosis of polycystic ovary syndrome. Methods: The Google Scholar and PubMed data bases were searched for publications in the English language reporting on PCOS diagnosis in adolescents. Results: A comprehensive analysis of data regarding the overlay of physiological ripening of menstrual cycle characteristics, androgen levels, and ovary aspects during puberty with the established criteria to diagnose PCOS in adults revealed that are liable diagnosis of PCOS in adolescence is possibleas soon as 2-3 years postmenarche. Persistant menstrual cycle intervals shorter than 21 days or longer than 45 days, total testosterone levels >1.9-2.0 nmol/l and ovary volume >10cm³ after 15-16 years of age can be used to diagnose PCOS. Conclusion: When combined, any persistent deviation of physiological parameters in adolescents as a criterion to diagnose PCOS in adults allows a certain diagnosis of PCOS in adolescents.

Background Polycystic ovary syndrome (PCOS) is a heterogenous endocrine condition and combined oral contraceptives (COCs) have been demonstrated to be the first-line treatment to women who do not intend to become pregnant. The combination of COCs and PCOS may or may not amplify the risks of cardiovascular events. Objective To investigate whether surrogates for obesity may be influenced by the use of COCs containing different formulations in women with PCOS. Method From January 2024 a literature search was conducted in Google Scholar and Pubmed databases using PCOS, COC, and obesity terms. Hand search of randomized clinical trials in the references of obtained manuscripts was also performed. After the exclusion of reviews and articles that did not fulfill eligibility criteria, compared the results obtained before and after the use of COCs in 13 randomized clinical trials (RCTs). Random-effects model was used to estimate the standardized mean differences (SMD) and standard errors (SE). Risk of bias was examined using the Rob2 tool. Result Thirteen heterogeneous RCTs reported no difference in waist circumference with the use of different COC formulations (p = 0.714). On the contrary, body fat mass increased with the use of pill (p = 0.013). Waist triglyceride index and lipid accumulation product tended to be higher after the use of COCs (p = 0.073 and p = 0.064, respectively). Conclusion Combined oral contraceptives with different formulations might increase fat mass accumulation in women with PCOS. Lipids may also be increased in PCOS users. Because some concerns about the quality and heterogeneity identified in various RCTs, caution should be taken before a definitive conclusion regarding the use of COCs and obesity.

Background. Combined oral contraceptives (COCs) are of first line treatment of women with polycystic ovary syndrome (PCOS) who do not intend to become pregnant. PCOS is a heterogeneous condition with subphenotypes with different risks for future development of cardiovascular disease. The combination of COC and PCOS may or may not amplify the risks of cardiovascular events. Objective. To investigate whether surrogates for adiposity may be influenced by the use of COCs with different formulations in women with PCOS. Method. A literature search was conduct in Google Scholar and Pubmed databases. Hand search of randomized clinical trials in the references of obtained manuscripts was also performed. The search identified 3820 articles and 13 randomized clinical trials in which was possible to compare the results obtained before and after the use of COCs. Random-effects model was used to estimate the standardized mean differences (SMD) and standard erros (SE). Risk of bias was examined using the Rob2 tool. Result. Thirteen heterogeneous RCTs reported no difference on waist circumference with the use of different COC formulations (p = 0.714). On the contray, body fat mass increased with the use of pill (p = 0.013). Anthropometric-metabolic biomarkers waist triglyceride index and visceral adiposity index did not change but the lipid accumulation product tended to be higher after use of COCs. Conclusion. Combined oral contraceptives with different formulations might increase fat mass accumulation in women with PCOS. Lipids may also be accumulated in the PCOS users.