Adult Polycystic Ovary Syndrome Research Articles

Polycystic ovary syndrome (PCOS): progress towardsabetter understanding and treatment ofthesyndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in women of reproductive age. It has a strong hereditary component estimated at 60 to 70% in daughters. It has been suggested that environmental factors during the fetal period may be involved in the development of the syndrome in adulthood. However, the underlying mechanisms of its transmission remain unknown, thus limiting the development of effective therapeutic strategies.This article highlights how an altered fetal environment (prenatal exposure to high levels of anti-Müllerian hormone) can contribute to the onset of PCOS in adulthood and lead to the transgenerational transmission of neuroendocrine and metabolic traits through alterations in the DNA methylation process.The originality of the translational findings summarized here involves the identification of potential biomarkers for early diagnosis of the syndrome, in addition to the validation of a promising therapeutic avenue in a preclinical model of PCOS, which can improve the management of patients suffering from the syndrome.

Impact of Polycystic Ovary Syndrome on Periodontal Status of Women of Adolescent and Adult Age Groups: A Cross-Sectional Study

Objective: Polycystic ovary syndrome (PCOS) is identified as the most common endocrine disorder in reproductive-aged women, and symptoms of PCOS appear during the early pubertal age. There is a gap in knowledge in recognizing the status of gingival inflammation/periodontal destruction and high-sensitivity C-reactive protein levels (hsCRP) in adolescents versus adults with PCOS. This study aimed to observe the impact of PCOS on periodontal status and systemic inflammation in adolescents and compared them with adults with PCOS. Methods: A total of 100 newly diagnosed female subjects with PCOS were enrolled into two groups: adolescents (11–19 years, n = 50) and adult females (20–40 years, n = 50). Periodontal parameters, anthropometric parameters, PCOS phenotype, hirsutism score, and serum hsCRP levels were recorded. Results: High levels of mean hsCRP, gingival index, and bleeding on probing % were observed in adolescent and adult PCOS groups, though nonsignificant between the groups (p > 0.05). Significantly more sites with probing pocket depth 3–4 mm, higher mean clinical attachment level (CAL) and sites with CAL 1–2 mm, and high frequency of patients (n = 11) with periodontitis (stage 1) were observed in adults with PCOS compared to adolescents (p ≤ 0.05). Similar and predominant prevalence of PCOS phenotype A (66%) and moderate hirsutism (46% adolescents vs. 58% adults) were observed in both groups. Conclusion: Similar levels of hsCRP and periodontal inflammation were found in adolescents and adults with PCOS. More periodontal tissue destruction was observed in adults with PCOS as compared to adolescents with PCOS.

SAT375 Impact of Flutamide on Wake vs. Sleep LH Pulse Frequency in PCOS: An Interim Analysis

Abstract Disclosure: C.K. Matingou: None. S. Kim: None. M. Gilrain: None. C.M. Burt Solorzano: None. C.R. McCartney: None. Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and ovulatory dysfunction. PCOS is also associated with luteinizing hormone (LH) excess, in part related to persistently high gonadotropin-releasing hormone (GnRH) pulse frequency. Furthermore, late pubertal girls with obesity and hyperandrogenemia did not exhibit sleep-associated decreases in LH (GnRH) pulse frequency when studied during the follicular phase, in contrast to non-hyperandrogenemic controls with or without obesity (JCEM 2014;99:2887-96). We therefore aimed to test two hypotheses: (1) sleep-associated reductions in LH pulse frequency are less pronounced in adult PCOS compared to late-follicular controls; and (2) sleep-associated reductions in LH pulse frequency are normalized in PCOS with 4 weeks of flutamide (androgen-receptor antagonist) pretreatment. To date, we have studied 5 women with PCOS (median age 30 y, BMI 42.6 kg/m2) and 5 ovulatory controls (median age 22 y, BMI 23.2 kg/m2). Subjects underwent two separate 16-hour frequent-blood-sampling studies to characterize pulsatile LH secretion, once after flutamide pretreatment (250 mg BID x 4 weeks) and once after placebo (PBO) pretreatment (BID for 4 weeks). In each study, 1500-2300 h and 2300-0700 h were designated the wake and sleep periods, respectively. The order of flutamide and PBO administration was randomized, and treatment allocation was switched after the first admission per a cross-over design. Controls were studied on cycle days 7-10, while those with PCOS were studied no earlier than cycle day 7. Serum progesterone concentrations were < 1.5 ng/dl for all admissions. With PBO pretreatment, participants with PCOS and controls exhibited the following: wake LH pulse frequency 1.19 (1.08-1.33) (median [interquartile range]) and 1.22 (0.97-1.27) pulses/h, respectively; sleep LH pulse frequency 0.93 (0.78-1.28) and 0.83 (0.78-0.99) pulses/h, respectively; and wake-to-sleep change in LH pulse frequency of -19.4 (-21.9 to +2.9) and -15.5 (-31.8 to -12.0) percent, respectively. For participants with PCOS, pretreatment with flutamide was associated with the following changes compared to PBO: wake LH pulse frequency +0.01 (-0.06 to +0.03) pulses/h; sleep LH pulse frequency +0.06 (+0.01 to +0.07) pulses/h; and wake-to-sleep LH pulse frequency change +5 (+7 to -12) percent. None of these differences were statistically significant by conservative nonparametric testing. We conclude that this interim analysis does not offer any indication that wake- and sleep-associated LH pulse frequencies are different between PCOS and late-follicular controls, nor does it suggest clear differences in wake-to-sleep changes in late-follicular LH pulse frequency between groups. Furthermore, this analysis does not seem to offer any indication that flutamide alone alters wake- and/or sleep-associated LH pulse frequencies in PCOS. Presentation Date: Saturday, June 17, 2023

Exploring the natural history of polycystic ovary syndrome: still a long road to traverse.

I read with keen interest the systematic review by Kiconco et al. (2022) that makes a sincere effort to throw light on the understanding of the natural history of polycystic ovary syndrome (PCOS). The authors found that there was consistent evidence, though from limited studies, that the level of total testosterone and dehydroepiandrosterone sulfate declined to a greater degree and the risk of gestational diabetes was higher in women with PCOS as compared to those without it. However, the evidence was found to be conflicting or insufficient for the other outcomes which are more likely to have practical long-term implications in the lives of women with PCOS. In the process of the selection of articles for the review, the participants were females of any age group and weight with a diagnosis of PCOS. The fact of extreme heterogeneity among the studies notwithstanding, it is conceptually imprecise to include women with PCOS of all age and weight categories in one common group. The international evidence-based guidelines on the assessment and management of PCOS recommends to assess the BMI in all patients and also the prevention of excess weight gain (Teede et al., 2018). Visceral adiposity is known to result in an increase in insulin resistance as well as aggravation of reproductive and metabolic features in PCOS. Obesity is significantly associated with menstrual irregularity, hyperandrogenemia and hirsutism (Rosenfield and Ehrmann, 2016). PCOS in the adolescent age group presents diagnostic challenges due to a considerable overlap of physiological features of the pubertal transition phase with the diagnostic criteria of adult PCOS (Peña et al., 2020). A meta-analysis of differentially expressed genes across various tissue types in PCOS indicated that the etiology, genetic contributors, and expression profile of genes from similar cell types are different in the obese and the lean phenotypes (Idicula-Thomas et al., 2020). Consequently, it is of paramount importance to understand the natural history of this chronic disease according to its different phenotypes.

Polycystic Ovary Syndrome: Insights from Preclinical Research.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, affecting approximately 10%. PCOS is diagnosed by the presence of at least two of these three criteria: hyperandrogenemia, oligo- or anovulation, and polycystic ovaries. The most common type (80%) of PCOS includes hyperandrogenemia. PCOS is also characterized by obesity or overweight (in 80% of US women with PCOS), insulin resistance with elevated plasma insulin but not necessarily hyperglycemia, dyslipidemia, proteinuria, and elevated BP. Although elevated compared with age-matched controls, BP may not reach levels considered treatable according to the current clinical hypertension guidelines. However, it is well known that elevated BP, even modestly so, increases the risk of cardiovascular disease. We have developed a model of hyperandrogenemia in rodents that mimics the characteristics of PCOS in women, with increases in body weight, insulin resistance, dyslipidemia, andproteinuria and elevated BP. This review discusses potential mechanisms responsible for the elevated BP in the adult and aging PCOS rat model that may be extrapolated to women with PCOS.

Ovarian expression of follicle stimulating hormone and activin receptors genes in a prenatally-androgenized rat model of polycystic ovary syndrome in adulthood.

The expression of genes involved in basic pathways, such as folliculogenesis and steroidogenesis may be affected following prenatal androgen exposure. Besides, exposure to androgens during prenatal life plays a central role in developing polycystic ovary syndrome (PCOS) in females in later life. In the present study, we aimed to examine the expression of the follicle stimulating hormone receptor (FSHR) and activin receptor (actR) genes in ovarian granulosa cells (GCs) of a prenatally-androgenized rat model of PCOS in adulthood. In the adult rat model of PCOS and their controls (n = 8 in each group), different phases of the estrous cycle were determined by vaginal smear. Total RNA was extracted from the ovarian GCs using the TRIzol protocol, a reverse transcription kit was used for complementary DNA (cDNA) synthesis, and the expression of FSHR and actR genes was measured by SYBR-Green Real-Time PCR. GraphPad Prism was used for statistical analysis of data, and the t-Student'stestwasused to compare the results between the two groups. PCOS rats had longer and irregular estrous cycles compared to controls. The expression of FSHR and actR genes were significantly decreased in the rat model of PCOS compared to control rats. In PCOS rats, genes expression ratios for FSHR and actR were 0.91 ± 0.11 times (P = 0.008) and 0.42 ± 0.13 times (P = 0.048) less than controls, respectively. Reduced expression of the FSHR and actR genes in ovarian GCs may be one of the mechanisms mediating PCOS-related disorders, especially abnormal ovarian folliculogenesis and ovulation dysfunction, following exposure to androgens during fetal life.

Health-related quality of life and binge eating among adolescent girls with PCOS

Background: Polycystic ovary syndrome (PCOS) affects 3–8% of adolescents. It is characterized by hyperandrogenism and oligoovulation/anovulation. PCOS has a negative impact on health-related quality of life (HRQoL). However, the extents to which factors influence total HRQoL of adolescents are not known. Adult PCOS patients have a higher incidence of binge eating than the general reproductive-age female population. Limited data on binge eating in adolescents with PCOS are available. Aim of this study was to investigate how PCOS and its associated factors, including binge eating, affect the HRQoL of adolescent girls. Methods: This case-control study recruited 63 adolescent girls 13–18 years of age with PCOS and 66 age-matched healthy controls. The PCOS health-related quality of life questionnaire (PCOSQ) and Binge Eating Scale (BES) were used. Multiple linear regression was executed to establish exact predictors and their effect on total HRQoL. Results: HRQoL was significantly lower in adolescents with PCOS than controls (4.9 (interquartile range (IQR) 1.5) vs. 5.8 (IQR 0.9) points). The lowest scores were found in the body hair and weight domains. BES results were not significantly higher in the PCOS group than in the control group (p = 0.727). The main predictors for total HRQoL were PCOS diagnosis per se (β = –1.002; p < 0.001), BES score (β = –0.27; p = 0.004) and body mass index (BMI) percentile (β = –0.007; p = 0.013). Conclusions: The lower HRQoL in adolescents with PCOS is attributable to the diagnosis of PCOS, BES score and BMI percentile, confirming the importance of tailoring clinical interventions and counselling to address the domains (i.e., symptoms of hirsutism and weight concerns) causing distress and lowering HRQoL. Further implementation research is required to evaluate the impact of targeted interventions on the HRQoL of adolescent girls with PCOS.

Hypertension Predisposition and Thermoregulation Delays in Adolescents with Polycystic Ovary Syndrome: A Pilot Study.

Background: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder in which clinical, sonographic, and endophenotypic features have been underinvestigated or inconclusive, especially in the early stages of the disease (adolescence/young adulthood). Objective: This prospective pilot study focused on the differences of multiple physiological functions between Greek adolescent/young adult females suffering from PCOS and age- and body mass index (BMI)- matched healthy controls. Study design: Nineteen PCOS patients and eighteen healthy controls (aged 13 to 23 years) were studied for: (i) biochemical and hormonal dysfunction by measuring circulating glucose, insulin, and androgen levels; (ii) arterial stiffness with pulse wave analysis (PWA) by Sphygmocord; (iii) intima-media thickness (IMT) by ultrasound; (iv) heart rate variability (HRV) by Task Force Monitor; and (v) QT, QRS, QT, P, QRSD by electrocardiogram (ECG). Statistical analysis included Hedge’s g correction for small samples bias, and the results are shown using the Hedge’s g effect size and 95% CI, in line with precision medicine prerequisites. Results: Significant differences in pulse wave velocity (PWV) (g = 0.964 [0.296, 1.632]), subendocardial viability ratio (SEVR) carotid (g = −0.679 [−1.329, −0.030]), pulse pressure (PP) carotid (g = 0.942 [0.275, 1.608]), systolic pressure (SP) carotid (g = 0.785 [0.129, 1.440]), free-testosterone (g = 0.677 [0.042, 0.312]), and Delta4-androstenedione (g = 0.735 [0.097, 0.373]) were observed between PCOS patients and controls. No differences were detected in the remaining endocrine and PWA or ECG biomarkers. Conclusions: Our multidisciplinary approach showed early onset of vascular dysfunction, predisposition to hypertension, thermoregulation delays, and metabolic syndrome changes in adolescent/young adult PCOS.

Genomic correlation, shared loci, and causal relationship between obesity and polycystic ovary syndrome: a large-scale genome-wide cross-trait analysis

BackgroundThe comorbidity between polycystic ovary syndrome (PCOS) and obesity has long been observed in clinical settings, but their shared genetic basis remains unclear.MethodsLeveraging summary statistics of large-scale GWAS(s) conducted in European-ancestry populations on body mass index (adult BMI, Nfemale=434,794; childhood BMI, N=39,620), waist-to-hip ratio (WHR, Nfemale=381,152), WHR adjusted for BMI (WHRadjBMI, Nfemale=379,501), and PCOS (Ncase=10,074, Ncontrol=103,164), we performed a large-scale genome-wide cross-trait analysis to quantify overall and local genetic correlation, to identify shared loci, and to infer causal relationship.ResultsWe found positive genetic correlations between PCOS and adult BMI (rg=0.47, P=2.19×10−16), childhood BMI (rg=0.31, P=6.72×10−5), and WHR (rg=0.32, P=1.34×10−10), all withstanding Bonferroni correction. A suggestive significant genetic correlation was found between PCOS and WHRadjBMI (rg=0.09, P=0.04). Partitioning the whole genome into 1703 nearly independent regions, we observed a significant local genetic correlation for adult BMI and PCOS at chromosome 18: 57630483–59020751. We identified 16 shared loci underlying PCOS and obesity-related traits via cross-trait meta-analysis including 9 loci shared between BMI and PCOS (adult BMI and PCOS: 5 loci; childhood BMI and PCOS: 4 loci), 6 loci shared between WHR and PCOS, and 5 loci shared between WHRadjBMI and PCOS. Mendelian randomization (MR) supported the causal roles of both adult BMI (OR=2.92, 95% CI=2.33–3.67) and childhood BMI (OR=2.76, 95% CI=2.09–3.66) in PCOS, but not WHR (OR=1.19, 95% CI=0.93–1.52) or WHRadjBMI (OR=1.03, 95% CI=0.87–1.22). Genetic predisposition to PCOS did not seem to influence the risk of obesity-related traits.ConclusionsOur cross-trait analysis suggests a shared genetic basis underlying obesity and PCOS and provides novel insights into the biological mechanisms underlying these complex traits. Our work informs public health intervention by confirming the important role of weight management in PCOS prevention.

BMI in childhood and adolescence is associated with impaired reproductive function-a population-based cohort study from birth to age 50 years.

What is the association between childhood and adolescent BMI and reproductive capacity in women? Adolescent girls with obesity had an increased risk of infertility and childlessness in adulthood independently of their marital status or the presence of polycystic ovary syndrome (PCOS). Girls with obesity (BMI (kg/m2)>95th percentile) more often exhibit menstrual irregularities and infertility problems as compared to those with normal weight, and premenarcheal girls with obesity have an increased risk of childlessness and infertility in adulthood. Follow-up studies on the relation between childhood and adolescence growth patterns and fertility or parity throughout the reproductive life span are limited. A prospective, population-based cohort study (the Northern Finland birth cohort 1966) was performed with 5889 women born in 1966 and followed from birth to age 50 years. Postal questionnaires at ages 31 and 46 years addressed questions on reproductive capacity evaluated by decreased fecundability, need for infertility assessment and treatment by 46 years of age. Childlessness and number of children by age 50 years were recovered from registers. Women who did not report ever having attempted to achieve pregnancy (n = 1507) were excluded. The final study population included 4382 women who attempted to achieve pregnancy before age 46 years. Data on BMI were collected by trained personnel at all stages. We assessed association with both prospectively measured BMI at various time points and with early adiposity phenotypes derived from linear mixed models including the timing and the BMI at adiposity peak (AP) and adiposity rebound (AR). Self-reported infertility assessments and treatments were assessed at ages 31 and 46 years. Data on deliveries were collected from the national birth register. Decreased fecundability was defined at age 31 years as time to achieve pregnancy over 12 months. Logistic regression analyses were conducted with adjustments for marital status, education level and smoking at age 31 years. Women with PCOS were excluded from stratification-based sensitivity analyses. Obesity at a specific age group was defined by having at least one BMI value above the 95th percentile during the related period. BMI at the age of AR (5-7 years) was not associated with fertility outcomes after adjustments, but girls with AR <5.1 years had a higher risk of remaining childless compared to girls with AR over 5.1 years (adjusted odds ratio (OR): 1.45 (1.10-1.92)). At ages 7-10 and 11-15 years, obesity was associated with decreased fecundability (adjusted OR 2.05 (1.26-3.35) and 2.04 (1.21-3.44), respectively) and a lower number of children. At age 11-15 years, both overweight and obesity were associated with a higher risk of childlessness (adjusted OR 1.56 (1.06-2.27), 1.77 (1.02-3.07), respectively), even after excluding women with PCOS. Underweight at age 11-15 years was associated with an increased risk for infertility treatment (adjusted OR 1.55 (1.02-2.36)) and a tendency for an increased risk for infertility assessment (adjusted OR 1.43 (0.97-2.10)) after excluding women with PCOS. Despite a high participation rate throughout the follow-up, some growth data for children over the different age groups were missing. Infertility outcomes were self-reported. A potential over-diagnosis of obesity may have reduced the significance of the association between childhood obesity and fertility outcomes, and the diagnosis of PCOS was self-reported. This study supports previous results showing that girls with obesity in late childhood and in adolescence displayed reduced fertility and an increased risk of remaining childless in adulthood, independently of marital history and PCOS in adulthood. These findings corroborate the body of evidence for a causal relation between early adiposity and the reproductive functions in women. We recommend reinforcing the prevention of obesity in school-age girls to reduce the risk of impaired reproductive functions. NFBC1966 received financial support from University of Oulu Grant no. 65354, Oulu University Hospital Grant no. 2/97, 8/97, Ministry of Health and Social Affairs Grant no. 23/251/97, 160/97, 190/97, National Institute for Health and Welfare, Helsinki Grant no. 54121, Regional Institute of Occupational Health, Oulu, Finland Grant no. 50621, 54231. The Finnish Medical Foundation, the North Ostrobothnia Regional Fund, the Academy of Finland (project grants 315921, 104781, 120315, 129269, 1114194, 24300796), Center of Excellence in Complex Disease Genetics and SALVE, the Sigrid Juselius Foundation, Biocenter Oulu, University Hospital Oulu and University of Oulu (75617), Jalmari ja Rauha Ahokkaan säätiö, The Finnish Medical Foundation, Medical Research Center Oulu, National Institute for Health Research (UK). M. R. J., S. S. and R. N. received funding by the Academy of Finland (#268336) and the European Union's Horizon 2020 research and innovation program (under Grant agreement no. 633595 for the DynaHEALTH action and GA 733206 for LifeCycle). The funders had no role in study design, in the collection, analysis and interpretation of the data, in the writing of the article and in the decision to submit it for publication. The authors have no conflict of interest to disclose. N/A.

Anti-Müllerian Hormone Levels in Adolescence in Relation to Long-term Follow-up for Presence of Polycystic Ovary Syndrome

ContextAnti-Müllerian hormone (AMH) measured in adolescence as biomarker for prediction of adult polycystic ovary syndrome (PCOS) is doubtful but not substantiated.ObjectiveTo investigate whether serum AMH levels and other PCOS-associated features in adolescence can predict the presence of PCOS in adulthood.Design and SettingA long-term follow-up study based on a unique adolescent study on menstrual irregularities performed between 1990 and 1997.Participants and interventionsAMH was assayed in 271 adolescent girls. Data on PCOS features were combined with AMH levels. In 160 of the 271 (59%) participants, we collected information in adulthood about their menstrual cycle pattern and presence of PCOS (features) by questionnaire 2 decades after the initial study.ResultsAMH was higher in adolescent girls with oligomenorrhea compared with girls with regular cycles, median (interquartile range): 4.6 (3.1-7.5) versus 2.6 (1.7-3.8) μg/L (P < 0.001). Women with PCOS in adulthood had a higher median adolescent AMH of 6.0 compared with 2.5 μg/L in the non-PCOS group (P < 0.001). AMH at adolescence showed an area under the receiver operating characteristic curve for PCOS in adulthood of 0.78. In adolescent girls with oligomenorrhea the proportion developing PCOS in adulthood was 22.5% (95% CI, 12.4-37.4) against 5.1% (95% CI, 2.1-12.0) in girls with a regular cycle (P = 0.005). Given adolescent oligomenorrhea, adding high AMH as factor to predict adult PCOS or adult oligomenorrhea was of no value.ConclusionsAdolescent AMH either alone or adjuvant to adolescent oligomenorrhea does not contribute as prognostic marker for PCOS in adulthood. Therefore, we do not recommend routine its use in clinical practice.

Aberrant subcutaneous adipogenesis precedes adult metabolic dysfunction in an ovine model of polycystic ovary syndrome (PCOS)

Polycystic ovary syndrome (PCOS) affects over 10% of women. Insulin resistance, elevated free fatty acids (FFAs) and increased adiposity are key factors contributing to metabolic dysfunction in PCOS. We hypothesised that aberrant adipogenesis during adolescence, and downstream metabolic perturbations, contributes to the metabolic phenotype of adult PCOS. We used prenatally androgenised (PA) sheep as a clinically realistic model of PCOS. During adolescence, but not during fetal or early life of PA sheep, adipogenesis was decreased in subcutaneous adipose tissue (SAT) accompanied by decreased leptin, adiponectin, and increased FFAs. In adulthood, PA sheep developed adipocyte hypertrophy in SAT paralleled by increased expression of inflammatory markers, elevated FFAs and increased expression of genes linked to fat accumulation in visceral adipose tissue. This study provides better understanding into the pathophysiology of PCOS from puberty to adulthood and identifies opportunity for early clinical intervention to normalise adipogenesis and ameliorate the metabolic phenotype.

Racial and ethnic differences in the metabolic response of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a highly prevalent disorder associated with insulin resistance (IR) and compensatory hyperinsulinemia. Although variations in cardiometabolic risks across race and ethnicities have been reported in the general population, racial/ethnic disparities in the metabolic dysfunction of PCOS remain relatively unstudied. To determine whether markers of metabolic function differ in nondiabetic Asian American (AS), African American (AA), Hispanic White (HW), compared to non-Hispanic White (NHW) women with PCOS. Prospective cross-sectional study in a tertiary institution. A total of 259 nondiabetic women with PCOS (by NIH 1990 criteria) who completed a 2-hour 75-g oral glucose tolerance test measuring plasma glucose and insulin levels. Basal IR and insulin secretion, assessed by the homeostasis model assessment (HOMA-IR and HOMA-β%, respectively), and two-hour hyperglycaemia and hyperinsulinemia after an oral glucose load, were compared in 21 AS, 24 AA, 53 HW and 161 NHW consecutive nondiabetic adult PCOS women. After adjusting for age and body mass index, HW and AA PCOS women demonstrated higher fasting and post-glucose challenge insulin levels, and higher HOMA-IR and HOMA-β%, than NHW women, although glucose levels were similar. In contrast, AS PCOS women had or tended to have lower HOMA-β% than any other racial/ethnic groups, lower HOMA-IR, and fasting and post-challenge insulin levels than AA or HW, and also hadhigher (albeit still normal) mean post-challenge glucose levels than NHW women with PCOS despite similar HOMA-IR, and fasting insulin and post-challenge insulin levels. Waist-hip ratio was similar across the four groups. Both HW and AA women with PCOS have increased basal state IR and higher β-cell response, and post-challenge hyperinsulinemia compared to NHW and AS subjects. The trend towards a lesser insulin response among Asian women requires further investigation. These findings suggest that the screening and management of metabolic dysfunction in PCOS should consider patients' race/ethnicity.

OR27-07 11-oxygenated C19 Steroids in Normal Weight, Overweight, and Hyperandrogenic Girls

Hyperandrogenism (HA) often begins during puberty and may be a forerunner to polycystic ovary syndrome (PCOS). PCOS women have elevated 11-oxygenated androgens (O’Reilly MW et al, JCEM 2017), but the contribution of these androgens to HA in peri-pubertal girls is unknown. To address this uncertainty, we assessed classical and 11-oxygenated steroid levels at baseline and in response to both ACTH and recombinant human chorionic gonadotropin (r-hCG) administration in peri-pubertal girls. Girls (n=35) were studied in the mid-follicular phase (as relevant): age 13.1±3.1 (7.3-18.8) y (mean ± SD [range]); BMIz 1.1±1.1 (-1.08 to +2.65); Tanner breast 3.8±1.4 (1-5); bone age 14.1±3.1 (7.3-18) y. Of pre-menarcheal (PRE) girls, 4 were normal weight (NW, BMI% 5-84) and 7 overweight (OW, BMI% ≥ 85). Of post-menarcheal (POST) girls, 10 were NW, 6 OW, and 8 HA (3 NW, 5 OW). Blood was drawn at baseline (8 am, no meds); post-ACTH (60 m after 250 mcg IV, 10 h after dexamethasone [DEX, 1 mg PO]); and post-r-hCG (24 h after 50 mcg IV, 10 h after second dose DEX). Serum concentrations of classic (dehydroepiandrosterone [DHEA], androstenedione [A4], testosterone [T], dihydrotestosterone [DHT]) and 11-oxygenated androgens (11OHA4, 11KA4, 11OHT, and 11KT) were measured by liquid chromatography-tandem mass spectrometry. Wilcoxon Rank Sum and simple Spearman correlations were used for comparisons. Unless stated otherwise, p≤0.05 for all results reported below. At baseline, 11KT was 3-fold higher than T in PRE girls (1.2±0.6 vs. 0.4±0.2 nmol/L), while they did not differ in non-HA POST girls (1.4±0.6 vs. 1.1±0.5 nmol/L). The ratio of A4/T was 6.6±2.7 and 6.0±1.6 in PRE and non-HA POST girls, respectively, while 11KA4/11KT was 3.8±1.8 and 3.7±2.9, respectively; this suggests more efficient activation of 11-oxygenated androgens. Compared to NW POST girls, OW POST girls had higher T at baseline (1.9±0.9 vs. 1.2±0.8 nmol/L) and higher A4 post-ACTH (10.0±4.3 vs. 6.6±1.5 nmol/L). Compared to non-HA POST girls, HA girls had higher T at baseline (2.2±1.1 vs. 1.1±0.5 nmol/L) and higher DHEA, A4, and T post-r-hCG (DHEA: 8.8±2.7 vs. 5.6±2.2; A4: 11.3±4.1 vs. 7.3±2.8; T: 3.4±2.9 vs. 1.2±0.6 nmol/L). 11-oxygenated androgens were not elevated in OW or HA girls. In the entire cohort, HA status correlated with DHEA, A4, and T (r=0.40, 0.54, 0.63), while hirsutism correlated with A4 and T (r=0.47, 0.57). No androgen correlated with BMIz, but T correlated with fasting insulin and HOMA-IR (r=0.37, 0.38). The ratio of classic (DHEA, A4, T) to 11-oxygenated (11OHA4, 11KA4, 11OHT, 11KT) androgens trended higher in non-HA POST girls vs. PRE girls (58%:42% vs. 44%:56%, p=0.056). From early to late puberty, there appears to be a shift away from the 11-oxygenated pathway. Most androgens in HA girls derive from the classic androgen pathway. The mechanisms of the later switch to 11-oxygenated androgen pathway predominance in adult PCOS remain to be elucidated.

Associations of childhood adiposity with menstrual irregularity and polycystic ovary syndrome in adulthood: the Childhood Determinants of Adult Health Study and the Bogalusa Heart Study.

Is high adiposity in childhood associated with menstrual irregularity and polycystic ovary syndrome (PCOS) in later life? Overall, greater childhood BMI was associated with menstrual irregularity, and greater childhood BMI and waist/height ratio (WHtR) in white but not black participants were associated with PCOS in adulthood. Increased childhood BMI has been associated with irregular menstrual cycles and PCOS symptoms in adulthood in two longitudinal population-based studies, but no study has reported on associations with childhood abdominal obesity. Few studies have investigated whether there are racial differences in the associations of adiposity with PCOS though there has been some suggestion that associations with high BMI may be stronger in white girls than in black girls. The study included 1516 participants (aged 26-41years) from the Australian Childhood Determinants of Adult Health study (CDAH) and 1247 participants (aged 26-57years) from the biracial USA Babies substudy of the Bogalusa Heart Study (BBS) who were aged 7-15years at baseline. At follow-up, questions were asked about menstruation (current for CDAH or before age 40years for BBS), ever having had a diagnosis of PCOS and symptoms of PCOS. In CDAH, a single childhood visit was conducted in 1985. In BBS, multiple childhood visits occurred from 1973 to 2000 and race was reported (59% white; 41% black). In childhood, overweight and obesity were defined by international age-sex-specific standards for BMI and WHtR was considered as an indicator of abdominal obesity. Multilevel mixed-effects Poisson regression estimated relative risks (RRs) adjusting for childhood age, highest parental and own education and age at menarche. The prevalence of childhood obesity was 1.1% in CDAH and 7.5% in BBS. At follow-up, menstrual irregularity was reported by 16.7% of CDAH and 24.5% of BBS participants. The prevalence of PCOS was 7.4% in CDAH and 8.0% in BBS participants. In CDAH, childhood obesity was associated with menstrual irregularity (RR = 2.84, 95% CI: 1.63-4.96) and PCOS (RR = 4.05, 95% CI: 1.10-14.83) in adulthood. With each 0.01 unit increase in childhood WHtR there was a 6% (95% CI: 1-11%) greater likelihood of PCOS. Overall, in BBS, childhood obesity was associated with increased risk of menstrual irregularity (RR = 1.44, 95% CI: 1.08-1.92) in adulthood. Significant interaction effects between race and childhood adiposity were detected in associations with PCOS. In BBS white participants, childhood obesity was associated with PCOS (RR = 2.93, 95% CI: 1.65-5.22) and a 0.01 unit increase in childhood WHtR was associated with an 11% (95% CI: 5-17%) greater likelihood of PCOS in adulthood. In BBS black participants, no statistically significant associations of childhood adiposity measures with PCOS were observed. The classification of menstrual irregularity and PCOS was based on self-report by questionnaire, which may have led to misclassification of these outcomes. However, despite the limitations of the study, the prevalence of menstrual irregularity and PCOS in the two cohorts was consistent with the literature. While the study samples at baseline were population-based, loss to follow-up means the generalizability of the findings is uncertain. Greater childhood adiposity indicates a higher risk of menstrual irregularity and PCOS in adulthood. Whether this is causal or an early indicator of underlying hormonal or metabolic disorders needs clarification. The stronger associations of adiposity with PCOS in white than black participants suggest that there are racial differences in childhood adiposity predisposing to the development of PCOS and other environmental or genetic factors are also important. The CDAH study was supported by grants from the Australian National Health and Medical Research Council (grants 211316, 544923 and 1128373). The Bogalusa Heart Study is supported by US National Institutes of Health grants R01HD069587, AG16592, HL121230, HD032194 and P50HL015103. No competing interests existed.

Naturally Occurring and Experimentally Induced Rhesus Macaque Models for Polycystic Ovary Syndrome: Translational Gateways to Clinical Application.

Indian rhesus macaque nonhuman primate models for polycystic ovary syndrome (PCOS) implicate both female hyperandrogenism and developmental molecular origins as core components of PCOS etiopathogenesis. Establishing and exploiting macaque models for translational impact into the clinic, however, has required multi-year, integrated basic-clinical science collaborations. Paradigm shifting insight has accrued from such concerted investment, leading to novel mechanistic understanding of PCOS, including hyperandrogenic fetal and peripubertal origins, epigenetic programming, altered neural function, defective oocytes and embryos, adipogenic constraint enhancing progression to insulin resistance, pancreatic decompensation and type 2 diabetes, together with placental compromise, all contributing to transgenerational transmission of traits likely to manifest in adult PCOS phenotypes. Our recent demonstration of PCOS-related traits in naturally hyperandrogenic (High T) female macaques additionally creates opportunities to employ whole genome sequencing to enable exploration of gene variants within human PCOS candidate genes contributing to PCOS-related traits in macaque models. This review will therefore consider Indian macaque model contributions to various aspects of PCOS-related pathophysiology, as well as the benefits of using macaque models with compellingly close homologies to the human genome, phenotype, development and aging.

Polycystic Ovary Syndrome in Adolescence.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in females, and is characterized by ovulatory dysfunction, hyperandrogenism, and polycystic ovarian morphology based on ultrasound. Controversy surrounds the optimum diagnosis and management in the adolescent population. Many patients with adult PCOS present with pathognomonic symptoms as adolescents, and there is value in early diagnosis due to the associated long-term metabolic and reproductive health sequalae. A definitive diagnosis does not need to be made prior to implementing treatment in this group of young women. The practitioner who has an adolescent presenting with signs and symptoms of PCOS, has a unique opportunity to risk stratify, screen for co-morbidities, and implement early management strategies, many of which are lifestyle modifications, to help prevent long term morbidity associated with this disease.

The ratio of anterior anogenital distance to posterior anogenital distance: A novel-biomarker for polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age. The etiopathogenesis of the disease remains uncertain. Additionally, a full consensus has not been reached regarding PCOS diagnostic criteria. Several attempts have been made to diagnose PCOS with a simple clinical biomarker, but most of them failed. This study aims to investigate the possible association between PCOS and anogenital distance (AGD), which is an important sign of intrauterine androgen exposure. A prospective cohort study was conducted on 130 women. The study group contained 65 women with PCOS whereas 65 healthy women were recruited for the control group, all between 18 and 40 years in age. The groups were compared in terms of demographics and clinical and laboratory parameters. Both anterior and posterior AGDs and associated ratios were recorded for each woman. The mean ratio of anterior AGD to posterior AGD for the PCOS and control group were 4.4 ± 1.0 and 4.9 ± 1.0, respectively (p = 0.003). Regression analysis demonstrated that this ratio significantly and positively correlated with the waist to hip ratio and negatively correlated with the free androgen index. AGD was initially used to define sexual differentiation of animals. Subsequent human studies showed that boys have longer AGDs than girls. Recent studies supporting the hypothesis that extreme prenatal androgen exposure contributes to PCOS found that AGD in adult PCOS patients was longer than control PCOS patients. However, a novel biomarker other than AGD needs to be identified to standardize these measurements. This work represents the first study to evaluate the ratio of anterior AGD to posterior AGD in PCOS patients. In this study, AGD anterior and posterior measurements were longer in PCOS patients than in controls. However, the strongest predictor of PCOS is the ratio of anterior to posterior AGD.

The role of T cells on the elevated blood pressure of female and male PCOS offspring

Prenatal factors may program the immune response in offspring of women with polycystic ovary syndrome (PCOS) and contribute to their elevated cardiovascular and renal risk. For example, PCOS women might have altered T cell concentrations which could adversely affect their offspring; however, whether adult PCOS offspring have an increase in T cells remains undetermined. We hypothesize that T cells contribute to the increase in blood pressure and proteinuria in both male and female offspring from hyperandrogenemic female (HAF) rats. Female (f) and male (m) HAF offspring (HAF‐off) and placebo offspring (Pla‐off), 24 weeks old, from HAF dams (DHT pellet 7.5mg/90d starting at 4 wks of age) or placebo dams (placebo pellet/90d) were divided into 4 groups (n=4/grp): fPla‐off, fHAF‐off, mPla‐off, mHAF‐off, respectively. We measured fat mass and lean mass by ECHO MRI, body weight, proteinuria (24h urine), and mean arterial pressure (MAP) by telemetry. We also examined the circulating and intrarenal T regulatory (CD4+CD25+FOXP3+) or Th17 effector cells (CD4+CD25‐RORγ+) by flow cytometry. MAP and proteinuria were significantly higher in male and female HAF‐off than Pla‐off (mPCOS: 121±2 mmHg vs. mPla: 112±1 mmHg; p&lt;0.05; fPCOS: 117±3 vs. fPla‐off: 109±2; p&lt;0.05) (proteinuria: fPla‐off: 4.1±1 mg/24h vs. fHAF‐off: 9.4±1.7 mg/24h; p&lt;0.05; mPla‐off: 20±2.2 mg/24h vs. mHAF: 43.7±6 mg/24h; p&lt;0.05). Female and male pups of HAF dams have similar body weights as pups of control dams. However, males of HAF dams have greater body fat mass and less lean mass, than do males of control dams (mHAF‐off: 29.57±1.07 g vs. mPla‐off: 25.95±1.33 g; p&lt;0.05, and mHAF‐off: 381.4±4.9 g vs. mPla‐off: 366.3±4.1 g; p&lt;0.05, respectively). Females of HAF dams have similar fat mass but less lean mass than do control female offspring (LM: fPla‐off: 223.3±2.5 g vs. fHAF‐off: 214.9±2.0 g; p&lt;0.05). Contrary to our hypothesis we did not find differences in circulating or intrarenal T cells between fPla‐off and fHAF‐off or mPla‐off and mHAF‐off. The exposure to hyperandrogenemia in utero life may not increases the T cells in PCOS offspring later in life and is not responsible for the increased BP. However, further preclinical studies are necessary to determine the role of the immune response and the possible mechanisms responsible for the increase in blood pressure and renal injury in PCOS offspring.Support or Funding InformationSupported by AHA14POST18640015 (ROM) and P20GM121334 (ROM and JFR).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood.

Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and corresponds with a high degree of comorbidities and economic burden. How PCOS is passed on from one generation to the next is not clear, but it may be a developmental condition. Most women with PCOS exhibit higher levels of circulating luteinizing hormone, suggestive of heightened gonadotropin-releasing hormone (GnRH) release, and Anti-Müllerian Hormone (AMH) as compared to healthy women. Excess AMH in utero may affect the development of the female fetus. However, as AMH levels drop during pregnancy in women with normal fertility it was unclear if their levels were also elevated in pregnant women with PCOS. Here, we measured AMH in a cohort of pregnant women with PCOS and control women and found that AMH is significantly more elevated in the former group versus the latter. To determine if the elevation of AMH during pregnancy in women with PCOS is a bystander effect or a driver of the condition in the offspring, we modelled our clinical findings by treating pregnant mice with AMH and followed the neuroendocrine phenotype of their female progeny postnatally. This treatment resulted in maternal neuroendocrine-driven testosterone excess and diminished placental metabolism of testosterone to estradiol, resulting in a masculinization of the exposed female fetus and a PCOS-like reproductive and neuroendocrine phenotype in adulthood. We found that the affected females had persistently hyperactivated GnRH neurons and that GnRH antagonist treatment in the adult female offspring restored their neuroendocrine phenotype to a normal state. These findings highlight a critical role for excess prenatal AMH exposure and subsequent aberrant GnRH receptor signaling in the neuroendocrine dysfunctions of PCOS, while offering a new potential therapeutic avenue to treat the condition during adulthood.