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Introduction: 11-oxygenated C19 steroids (11-oxyandrogens) have been shown to rise during adrenarche and remain higher throughout adulthood than in early childhood. The patterns of circulating 11-oxyandrogens throughout normal puberty has not yet been described. Methods: We conducted a secondary analysis of healthy youth participants, both males and females, enrolled in six prior endocrine studies (N=249). Participants were classified according to Tanner stage and body mass index (BMI). Concentrations of three adrenal-specific 11-oxygenated androgens, 11β-hydroxyandrostenedione (11OHA4), 11β-hydroxytestosterone (11OHT), and 11-ketotestosterone (11KT) were measured in fasting serum samples. Results: 11OHA4 and 11OHT increased modestly between early and late puberty in youth with normal weight (p < 0.05), whereas increases in 11KT did not reach statistically significance (p < 0.06). 11KT levels differed between sexes throughout puberty (p < 0.01), and changes in 11-oxyandrogens were small compared to the marked increases for estradiol in girls or testosterone in boys. The trajectories of 11KT and 11OHA4 changes throughout puberty differed by BMI category (p < 0.05). Conclusion: Beyond adrenarche, 11-oxyandrogens continue to rise during pubertal development. The differences in 11KT trajectories in males and females are small compared to changes in testosterone for males and estradiol for females during puberty. Obesity appears to influence the trajectories of 11-oxyandrogens during puberty.

ContextPolycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5% to15% of this population depending on the diagnostic criteria applied. It is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is highly heritable, but only a small proportion of this heritability can be accounted for by the common genetic susceptibility variants identified to date.ObjectiveThe objective of this study was to test whether rare genetic variants contribute to PCOS pathogenesis.Design, Patients, and MethodsWe performed whole-genome sequencing on DNA from 261 individuals from 62 families with one or more daughters with PCOS. We tested for associations of rare variants with PCOS and its concomitant hormonal traits using a quantitative trait meta-analysis.ResultsWe found rare variants in DENND1A (P = 5.31 × 10−5, adjusted P = 0.039) that were significantly associated with reproductive and metabolic traits in PCOS families.ConclusionsCommon variants in DENND1A have previously been associated with PCOS diagnosis in genome-wide association studies. Subsequent studies indicated that DENND1A is an important regulator of human ovarian androgen biosynthesis. Our findings provide additional evidence that DENND1A plays a central role in PCOS and suggest that rare noncoding variants contribute to disease pathogenesis.

Context Hyperandrogenemia (HA) is a consistent reproductive phenotype in women with polycystic ovary syndrome (PCOS) and their relatives. Increased testosterone levels are present in premenarchal daughters of affected women (PCOS-d). Obese girls (OB-g) without a family history of PCOS also have peripubertal HA. The sources and significance of HA in these groups remains unknown. Objective 11-oxygenated 19-carbon (C19) steroids are adrenally derived androgens that are elevated in hyperandrogenic disorders, including PCOS. We performed this study to test the hypothesis that peripheral serum 11-oxygenated steroids would differ in PCOS-d compared with OB-g suggesting distinct etiologies of HA in affected girls. Design, Setting, and Participants We compared peripheral serum 11-oxygenated steroid levels in 21 PCOS-d, 29 OB-g, and 17 lean control girls (LC) of comparable age at an academic medical center. Results Body mass index (BMI) differed by design (P Conclusions Circulating 11KT levels were similarly elevated in peripubertal PCOS-d and OB-g, suggesting an adrenal component of HA in both groups. We found that 11-oxygenated 19-carbon steroid profiles did not identify subtypes of HA girls.

Both daughters of women with PCOS (PCOS-d) and overweight girls (OW-g) are proposed to be at increased risk of PCOS because they have peripubertal increases in testosterone (T) levels, a cardinal feature of PCOS. We are testing this hypothesis by performing longitudinal studies in these girls after menarche. In adult women with PCOS, we have recently identified reproductive and metabolic subtypes using unsupervised cluster analyses. These subtypes were associated with novel PCOS susceptibility genetic loci suggesting that the subtypes reflect biologically discrete entities. We performed similar analyses in our cohort of early postmenarchal PCOS-d and OW-g to test the hypothesis that these subtypes are present in girls at risk for PCOS. Fifteen PCOS-d and 10 OW-g aged 11-16 years and with postmenarchal age less than 2 years were studied. Mothers of PCOS-d fulfilled NIH criteria for PCOS, mothers of OW-g were reproductively normal with no history of irregular menses or clinical hyperandrogenism. OW-g had a BMI above the 85th percentile for age. There was no BMI inclusion criterion for PCOS-d; four PCOS-d had a BMI above the 85th percentile. The girls were of comparable age, post-menarchal age and BMI z score. A fasting morning blood sample was drawn for T, SHBG, DHEAS, glucose and insulin. Leuprolide 10 mcg/kg SC was administered. LH and FSH levels were measured at baseline, 30 min, and 60 min following leuprolide. Unsupervised hierarchical cluster analysis adjusted for age was performed on quantitative traits including BMI, T, fasting insulin, fasting glucose, DHEAS, SHBG, and LH and FSH. These are the same quantitative traits used for clustering in adult PCOS. The clustering revealed 2 distinct PCOS subtypes: a reproductive group (41%), characterized by higher SHBG levels, LH and FSH with relatively low BMI and insulin levels, and a metabolic group (41%), characterized by higher BMI and insulin levels and lower SHBG, LH, and FSH. Jaccard coefficients indicated cluster stability (0.70 reproductive, 0.69 metabolic). There was a significant difference in the distribution of the two subgroups in PCOS-d and OW-g: PCOS-d 60% reproductive, 13% metabolic, 27% indeterminate; OW-g 25% reproductive, 50% metabolic, 25% indeterminate (Chi Sq P=0.05). We found that early postmenarchal PCOS-d and OW-g demonstrate reproductive and metabolic subtypes similar to those identified in adult women with PCOS. The majority of PCOS-d had the reproductive subtype. These findings suggest that this subtype, which is characterized by disordered gonadotropin secretion, is an early harbinger of PCOS. Longitudinal studies are ongoing to test this hypothesis.

OBJECTIVE Women with metabolic syndrome (MetS) have higher endogenous testosterone (T) levels than unaffected women. This study investigated whether hyperandrogenemia (HA) was a marker for increased cardiometabolic risk in reproductively normal premenopausal women. METHODS Reproductive hormones and metabolic parameters were assessed in 198 women with regular menses and no clinical hyperandrogenism (eumenorrheic [EM]). Hyperandrogenic EM women were compared with 110 women with NIH criteria polycystic ovary syndrome. RESULTS Twenty-two percent of EM women had HA. Levels of non-sex hormone-binding globulin (SHBG)-bound T were elevated in 68% of women, total T levels were elevated in 43% of women, and dehydroepiandrosterone sulfate levels were elevated in 30% of women. The prevalence of HA increased with BMI category (P = 0.01): 12% for BMI

Context Polycystic ovary syndrome (PCOS), a common endocrine condition, is the leading cause of anovulatory infertility. Objective Given that common disease-susceptibility variants account for only a small percentage of the estimated PCOS heritability, we tested the hypothesis that rare variants contribute to this deficit in heritability. Design, Setting, and Participants Unbiased whole-genome sequencing (WGS) of 80 patients with PCOS and 24 reproductively normal control subjects identified potentially deleterious variants in AMH, the gene encoding anti-Mullerian hormone (AMH). Targeted sequencing of AMH of 643 patients with PCOS and 153 control patients was used to replicate WGS findings. Main Outcome Measures Dual luciferase reporter assays measured the impact of the variants on downstream AMH signaling. Results We found 24 rare (minor allele frequency < 0.01) AMH variants in patients with PCOS and control subjects; 18 variants were specific to women with PCOS. Seventeen of 18 (94%) PCOS-specific variants had significantly reduced AMH signaling, whereas none of 6 variants observed in control subjects showed significant defects in signaling. Thus, we identified rare AMH coding variants that reduced AMH-mediated signaling in a subset of patients with PCOS. Conclusion To our knowledge, this study is the first to identify rare genetic variants associated with a common PCOS phenotype. Our findings suggest decreased AMH signaling as a mechanism for the pathogenesis of PCOS. AMH decreases androgen biosynthesis by inhibiting CYP17 activity; a potential mechanism of action for AMH variants in PCOS, therefore, is to increase androgen biosynthesis due to decreased AMH-mediated inhibition of CYP17 activity.

Polycystic ovary syndrome (PCOS) is a highly heritable complex trait. Parents of affected women have reproductive and metabolic phenotypes.We tested the hypothesis that there are parental effects on the heritability of fasting dysglycemia in women with PCOS.This was a cross-sectional study at an academic medical center.PARTICIPANTS included 367 women with PCOS and their parents (1101 total subjects).We compared maternal and paternal contributions to heritability of fasting dysglycemia and to transmission of the PCOS susceptibility allele of D19S884 within the fibrillin-3 gene (D19S884-A8) on fasting dysglycemia.Fathers had higher fasting glucose levels, prevalence of fasting dysglycemia and proinsulin to insulin molar ratios (P.0001), a marker of defective insulin processing, compared with mothers. Heritability of fasting dysglycemia was significant in PCOS families (h(2) = 37%, SE = 10%, P = .001). Maternal heritability (h(2) = 51%, SE = 15%, P = .0009) was higher than paternal heritability (h(2) = 23 %, SE = 23%, P = .186) of fasting dysglycemia after adjustment for age and body mass index. Within dysglycemic probands, there was increased maternal compared with paternal transmission of D19S884-A8 (maternal 84% vs paternal 45%, χ(2) = 6.51, P = .011).There was a sex difference in the parental metabolic phenotype with fathers having an increased risk of fasting dysglycemia and evidence for pancreatic β-cell dysfunction compared with mothers. However, only maternal heritability had significant effects on the prevalence of fasting dysglycemia in women with PCOS. Furthermore, there were maternal parent-of-origin effects on transmission of D19S884-A8 probands with fasting dysglycemia. These findings suggest that maternal factors, genetic and perhaps epigenetic, contribute to the metabolic phenotype in affected women.