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Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder that affects 5-20% of reproductive age women. PCOS clinical symptoms include hirsutism, menstrual dysfunction, infertility, obesity and metabolic syndrome. There is a wide heterogeneity in clinical manifestations and metabolic complications. The pathogenesis of PCOS is not fully elucidated, but four aspects seem to contribute to the syndrome to different degrees: increased ovarian and/or adrenal androgen secretion, partial folliculogenesis arrest, insulin resistance and neuroendocrine axis dysfunction. A definitive etiology remains to be elucidated, but PCOS has a strong heritable component indicated by familial clustering and twin studies. Genome Wide Association Studies (GWAS) have identified several new risk loci and candidate genes for PCOS. Despite these findings, the association studies have explained less than 10% of heritability. Therefore, we could speculate that different phenotypes and subphenotypes are caused by rare private genetic variants. Modern genetic studies, such as whole exome and genome sequencing, will help to clarify the contribution of these rare genetic variants on different PCOS phenotypes. Arch Endocrinol Metab. 2018;62(3):352-61.

Context Data on prevalence of metabolic risk factors in hyperandrogenic postmenopausal women are limited. Also, the correlation between metabolic disorders and androgen excess in this scenario is poorly understood. Objectives We aimed to assess the prevalence of obesity, hypertension, type 2 diabetes (T2D), and dyslipidemia (DLP) in postmenopausal women with hyperandrogenism of ovarian origin before and after surgical normalization of testosterone (T) levels, as well as the impact of androgen normalization on body mass index (BMI), glucose, and lipid metabolism. Design Retrospective study. Setting Tertiary health center. Participants Twenty-four Brazilian women with postmenopausal hyperandrogenism who underwent bilateral oophorectomy between 2004 and 2014 and had histologically confirmed virilizing ovarian tumor (VOT) or ovarian hyperthecosis (OH) and T-level normalization after surgery were selected. Main Outcome Measures FSH, LH, total and calculated free T, BMI, fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) serum levels were accessed before (n = 24) and 24 months after (n = 19) bilateral oophorectomy. Results At baseline, the overall prevalence rates of obesity, T2D, DLP, and hypertension were 58.3%, 83.3%, 66.7%, and 87.5%, respectively. No significant difference in prevalence was found between patients with OH and VOTs. At follow-up, FSH, LH, and total and free T levels had returned to menopausal physiologic levels, but mean BMI and mean FPG, HbA1c, LDL-C, HDL-C, and TG levels did not differ from baseline. Conclusions Postmenopausal hyperandrogenism is associated with adverse metabolic risk. Long-term normalization of testosterone levels did not improve BMI, glucose, or lipid metabolism.

Purpose Polycystic ovary syndrome (PCOS) etiology remains to be elucidated but familial clustering and twin studies have shown a strong heritable component. The purpose of this study was to identify rare genetic variants that are associated with the etiology of PCOS in a preselected cohort. Methods This prospective study was conducted among a selected group of women with PCOS. The study's inclusion criteria were PCOS patients diagnosed by Rotterdam criteria with the following phenotypes: severe insulin resistance (IR), normoandrogenic-normometabolic phenotype, adrenal hyperandrogenism, primary amenorrhea, and familial PCOS. Forty-five patients were studied by target sequencing while 8 familial cases were studied by whole exome sequencing. Results Patients were grouped according to the inclusion criteria with the following distribution: 22 (41.5%) with severe IR, 13 (24.5%) with adrenal hyperandrogenism, 7 (13.2%) with normoandrogenic phenotype, 3 (5.7%) with primary amenorrhea and 8 (15.1%) familial cases. DNA sequencing analysis identified one pathogenic variant in LMNA, three likely pathogenic variants in INSR, PIK3R1 and DLK1 and six variants of uncertain significance level with interesting biologic rationale in 5 genes (LMNA, GATA4, NR5A1, BMP15 and FSHR). LMNA was the most prevalent affected gene in this cohort (3 variants). Conclusions Several rare variants in genes related to IR were identified in women with PCOS. Although IR is a common feature of PCOS, patients with extreme or atypical phenotype should be carefully evaluated to rule out monogenic conditions.

BACKGROUND : Polycystic ovary syndrome (PCOS) is a common complex endocrine disorder, whose etiology remains to be elucidated. PCOS has a strong heritable component. Genome-wide association studies have identified several risk loci for PCOS; however, the identified candidate genes could explain less than 5% of PCOS heritability. This missing heritability might be explained by the presence of rare genetic variants with larger biological impact. High throughput sequencing (HTS) could be an interesting tool to identify these rare variants. OBJECTIVE : To identify rare genetic variants through HTS in a selection of patients with PCOS clinical relevant phenotypes or familial PCOS clusters. METHODS : Among a cohort of 130 PCOS patients, we selected 32 women presenting one or more of the following phenotypes: 1. adrenal hyperandrogenism (DHEA and/or DHEAS levels 1.5 higher the upper limit of the normal range); 2. primary amenorrhea; 3. severe insulin resistance (IR) (basal insulin >50 mUi/mL and/or after OGTT >300 mUI/mL); 4. normal androgen levels (total and free testosterone, androstenedione, DHEA and DHEAS in the normal range measured by gold standard methods). This group was studied through targeted gene sequencing panels (Miseq Illumina) including 50 genes involved in ovarian folliculogenesis, steroid hormone synthesis, gonadotropin action and insulin-signaling pathway, and genes suggested by monogenic/dygenic PCOS causes. Additional 2 families, with two PCOS sisters and their unaffected mother, were studied by exome sequencing (Hiseq Illumina). Allelic variants were considered pathogenic/potential pathogenic if they had a MAF<0.01 (Gnom AD and ExAC databases), were classified deleterious/probably deleterious by several prediction sites ( i.e . SIFT, PolyPhen 2, Mutation Taster) and affect amino acids that are highly conserved among homologues (GERP scores). RESULTS : Among the 34 PCOS index patients studied, the phenotype was distributed as following: 15 with severe IR, 10 with adrenal hyperandrogenism, 2 normoandrogenic, 3 with primary amenorrhea and 4 familial cases. Twelve variants were identified in 10 patients (29.4%), affecting 6 genes: INSR, LMNA, POMC, GATA4, FSHR, H6PD, DLK1 and SCN1A. All genes were found once, except LMNA that was found in 4 different PCOS patients with severe IR. The variants in INSR , POMC and FSHR genes were found in the severe IR group, and in GATA4 in the adrenal hyperandrogenism group. The DLK1 and SCN1A variants were found in the two families studied through exome. CONCLUSION : High throughput sequencing allowed the identification of monogenic forms of PCOS, especially in patients with severe insulin resistance. The identification of rare genetic v...