ResearchPad - hyperandrogenism Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[SUN-019 Androgens Modulate Lipid Metabolism and Absorption in Control and Polycystic Ovary-Metabolic Syndrome Conditions]]> Introduction: In polycystic ovary syndrome (PCOS) a high plasma level of androgens has been correlated with an adverse plasma lipid profile. At present we do not know the physiological or mechanistic pathways of how androgens regulate lipid metabolism under control or PCOS conditions. We have shown flutamide, an androgen receptor (AR) inhibitor, reduces the plasma concentration of triglycerides (TG) and apoB-lipoproteins, and intestinal secretion of TG. Aim: The aim of this study was to determine the direct physiological and mechanistic effects of androgens, Testosterone (T) and dihydrotestosterone (DHT), on lipid metabolism using a PCOS-prone rodent model. Methods: Control and PCOS-prone animals were administered vehicle, T or DHT for 7 days. PCOS-prone animals also present with the Metabolic Syndrome (MetS). Following treatment animals underwent a mesenteric lymphatic cannulation procedure to determine effects on intestinal chylomicron (CM-apoB48) and lipid secretion, and absorption using radiolabelled [³H]-cholesterol and [14C]-palmitic acid.

Results: Plasma LDL-C was increased with DHT treatment in control animals, and with both T & DHT treatment in PCOS. Intestinal absorption of TG and cholesterol were increased in T and DHT treated PCOS animals but not control animals. Whereas DHT reduced intestinal CM-apoB48 secretion in both control and PCOS groups. These effects were associated with changes in genes and protein expression in lipogenic (SREBP1a/c&2, SREBP1c, SREBP-2, ACC) and steroidogenic pathways (AR, ER and SRDA51) in the liver and intestine.

Conclusion: These results demonstrate androgens modulate lipid metabolism and absorption. T and DHT differentially affect intestinal chylomicron secretion and lipid absorption in PCOS-MetS and control conditions. In conclusion, these results suggest that androgens may directly cause or exacerbate lipid and lipoprotein metabolism in conditions of hyperandrogenemia and the MetS.

<![CDATA[SUN-021 Age-Specific Multiples of the Median Level of Serum Anti-Mullerian Hormone Is a Potential Marker for Diagnosis of Polycystic Ovary Syndrome]]> Serum anti-Mullerian hormone (AMH) levels are significantly higher in women with polycystic ovary syndrome (PCOS) than in normal ovulatory women. Different diagnostic cut-off values of AMH for discriminating women with PCOS from normal controls have been proposed. This is attributed partly to the different assay methods used with different calibration, as well as the age-related changes in serum AMH levels. We propose that it may be more appropriate to use age-specific multiples of the median (MoM) of AMH value instead of a “one for all ages” cut-off as a diagnostic threshold. Hence, we conducted a retrospective study to validate the performance of age-specific MoM of AMH value in the diagnosis of PCOS. We studied on a cohort of 751 women presented to the clinic for menstrual disorders or fertility treatment, including 473 women diagnosed with polycystic ovary syndrome by the Rotterdam criteria and 278 normal ovulatory controls. Their archived serum samples, collected at the early follicular phase, were retrieved and assayed for AMH by the automated Access AMH assay. The MOM AMH of each subject was calculated based on the age-specific reference ranges recently established by our group. Our results showed that MOM AMH was significantly higher in women with PCOS compared to controls (p<0.0001). When stratified into five-yearly age groups, there was no significant difference in MOM AMH (p>0.05) among women with PCOS aged 21-25, 26-30 and 31-35 years, but those aged 36-40 years had significantly higher MOM AMH (p<0.05) compared to the other younger age groups. Among the ovulatory controls, no significant difference was observed in MOM AMH among all the age groups (p>0.05). The area under the receiver-operator characteristic curve was 0.852 (95% CI 0.825-0.877) (p<0.0001) for discriminating women with PCOS from ovulatory controls by MOM AMH. The best cut-off value of MOM AMH was 1.44, and the corresponding sensitivity and specificity were 76% and 79% respectively. At the fixed specificity of 80% and the corresponding sensitivity of 73% (with positive and negative likelihood ratios of 3.8 and 0.33 respectively), the cut-off value of MOM AMH was 1.5. In conclusion, age-specific MOM AMH is a promising surrogate of antral follicle count in the diagnosis of PCOS.

<![CDATA[SUN-018 No Difference in Breastfeeding Rates in Women with Polycystic Ovary Syndrome]]> No Difference in Breastfeeding Rates in Women with Polycystic Ovary Syndrome

Objective: Women with PCOS have increased rates of obesity and gestational weight gain compared to women without PCOS, factors which are associated with decreased breastfeeding (BF). Thus, our objective was to evaluate if women with PCOS were less likely to initiate BF.

Design: Cross-sectional analysis of participants in the PRAMS (Pregnancy Risk Assessment Monitoring System) dataset, a national questionnaire from the Centers for Disease Control (CDC) sent to postpartum mothers 2–9 months after delivery. PCOS status and BF were by self-report. Logistic regression was used to assess odds of ever BF. Length of BF was assessed using Cox proportional hazards with right censoring for women who were still BF at the time of follow-up. PRAMS complex survey design was accounted for.

Results: PCOS status was available for 14 states. Median response time was 3.7 months postpartum. Data from 16,036 participants were included which represents 855,302 women due to sample weights. 6.6% of women reported having PCOS and 83.8% reported ever BF. Compared to women with a normal BMI, women who were overweight or obese had decreased odds of BF (OR: 0.7, 95% CI: 0.6–0.9, P=0.01; OR: 0.6, 95% CI: 0.5–0.7, P<0.001 respectively); however, PCOS was not associated with BF (OR: 1.1, 95% CI: 0.9–1.3, P=0.6). In multivariate analysis, women with PCOS still were at no decreased odds of BF after adjusting for age, BMI, race, ethnicity, infertility treatment, and delivery factors (ORadj:1.1; 95% CI: 0.8–1.4; P=0.6). Variables associated with decreased odds of BF included: overweight/obesity, age ≤ 19 yrs (vs. 25–29), Black race, smoking, undesired pregnancy intent, gestational age ≤27 wks, and prior live birth. Variables associated with increased BF included: age 30–39 yrs, hospital stay 1–2 days (vs. 3–5), Hispanic ethnicity, and ≥ 3 life stressors. In multivariable Cox models, women with PCOS did not have a shorter length of BF (HRadj: 0.9, 95% CI: 0.8–1.1, P=0.3).

Conclusion: Given the rise of the national rates of obesity and clear maternal and neonatal benefits to breastfeeding, understanding the predictors of BF success is paramount. In this national survey, women with PCOS were at no decreased odds of BF, despite confirming the association between overweight/obesity and decreased BF. However, our data still supports the clinical relevance of carefully targeting women with PCOS for BF education due to the association of PCOS with increased BMI. Additional prospective studies are needed to fully understand the association between PCOS and BF.

<![CDATA[SUN-015 Developmental Programming: Depot-Specific Inflammatory State and Distribution of Thermogenic Adipocytes Programmed by Gestational Testosterone Excess]]> Prenatal testosterone excess induces insulin resistance, dyslipidemia and cardiovascular defects in ewes. Considering adipose depots influence systemic metabolic status, disruptions in visceral (VAT), subcutaneous (SAT), pericardiac (PCAT) and perirenal (PRAT) adipose depots may contribute to these metabolic defects. While the changes in PCAT and PRAT in the prenatal T-treated sheep are unknown, we found an increase in the oxidative stress and inflammatory state in the VAT but not SAT, while insulin sensitivity is maintained in both depots (Biol Reprod 2016;94:113). Although all four depots are rich in white adipocytes that specialize in lipid storage, it is not clear what underlies the depot-specific differences. A potential contributor may relate to depot-specific differences in presence of brown/beige adipocytes. Brown/beige unlike white adipocytes are thermogenically active due to their expression of uncoupled protein 1 (UCP1), which uncouples mitochondrial oxidative phosphorylation to release stored energy as heat. Because they favor lipid utilization rather than storage they promote a metabolically healthy phenotype. We hypothesized that the relative distribution of brown/beige adipocytes may contribute to the depot-specific changes in inflammatory state. To test this, adipose depots from control (n=6) and prenatal T- (100mg T propionate twice a week from days 30-90 of gestation)-treated (n=5) female sheep were studied at 21 months of age. The changes in expression of inflammatory and thermogenic adipocyte markers were assessed by real time RT-PCR and data analyzed by Student’s t-test and Cohen’s effect size analysis. Prenatal T-treatment induced 1) significant increase in inflammatory cytokine interleukin 6 in VAT and PRAT while decreasing it in PCAT 2) significant increase in tumor necrosis factor in the VAT and a trend (evident by effect size analysis only) for an increase in SAT and PCAT and 3) significant increase in PRAT and a trend toward increase in the macrophage marker CD68 expression in VAT. Among the thermogenic gene markers, the expression of UCP1 was significantly increased in VAT and PCAT with a trend for an increase in PRAT. The expression of UCP2 and PPAR gamma co-activator 1 beta (PPARGC1B) were also significantly elevated in VAT with a trend for an increase in SAT. These findings are indicative of depot-specific differences in prenatal T-induced inflammatory status with effects being pronounced in VAT compared to other depots. The increases in thermogenic markers in adipose depots do not support our hypothesis but rather are reflective of a compensatory response to promote adipose depot insulin sensitivity and may have a bearing on function of organs in the proximity of respective depots. These findings are likely of translational significance in metabolic disorders associated with hyperandrogenic state.

<![CDATA[SUN-020 Waist Circumference Is Associated with Insulin Resistance in Young Korean Women with Polycystic Ovary Syndrome]]> Polycystic ovary syndrome (PCOS) is a heterogeneous disorder and associated with metabolic disturbances such as insulin resistance (IR) and obesity which are risk factors for cardiovascular diseases. Many studies have shown that waist circumference (WC) representing abdominal obesity is an important risk factor for IR. However, there were few studies whether WC were associated with IR in young women with PCOS. We aimed to evaluate the role of WC in IR among young Korean women with PCOS. We enrolled age- and body mass index-matched women with PCOS (n = 100) and controls (n = 100). WC was measured and the 75-gram oral glucose tolerance test (OGTT) was performed. Insulin sensitivity was assessed by the Stumvoll index which was calculated from an OGTT. Multiple linear regression analysis was performed to evaluate the association between WC and IR. WC, fasting glucose, post-load 2-hour glucose, fasting insulin, and post-load 2-hour insulin did not differ between women with PCOS and controls. Women with PCOS had lower values of the Stumvoll index than the controls. In correlation analysis, WC was negatively correlated with the Stumvoll index in women with PCOS, however not in controls. In multiple regression analysis, WC was negatively associated with the Stumvoll index even after adjustment for age, total cholesterol, and total testosterone in women with PCOS. In young Korean women with PCOS, WC was negatively associated with insulin sensitivity independent of hyperandrogenemia. Simply measuring of WC could be used to screen the high risk group having IR in young women with PCOS.

<![CDATA[SUN-017 Developmental Programming: Prenatal Testosterone Treatment Induced Metabolic Defects May Involve Premature Cellular Senescence]]> Prenatal exposure to excess testosterone (T) programs peripheral insulin resistance and dyslipidemia along with tissue-specific increases in ectopic lipid accumulation, oxidative stress and insulin resistance in liver and muscle of the early adult female sheep. Prenatal T increased inflammation and oxidative stress in the visceral (VAT) but not subcutaneous (SAT) adipose tissue, with no effect on insulin sensitivity in both depots. These systemic and tissue-specific metabolic changes are reminiscent of defects such as non-alcoholic fatty liver disease (NFLAD) common among aged individuals. Because it is known that gestational insults can program premature aging of reproductive organs and chronic cardiovascular abnormalities, we hypothesized that programming of premature cellular senescence is one of the ways through which gestational T induces premature aging of metabolic systems during early adulthood. To test this hypothesis, mitochondrial oxidative phosphorylation (OXPHOS) and telomere length, as measure of cellular senescence, were assessed in liver, muscle, VAT and SAT collected from control and prenatal T- (100mg T propionate twice a week from days 30-90 of gestation) -treated female sheep at 21 months of age. Genomic DNA was subjected to TeloTAGG Telomere Length Assay (Sigma-Aldrich, St Louis, MO) and whole tissue protein lysates analyzed by immunoblot using Total OXPHOS Human WB Antibody Cocktail (ab110411, Abcam, Cambridge, MA). Data were analyzed by Student’s t test and Cohen’s effect size analysis. Prenatal T-treatment induced 1) a trend (p = 0.09) towards a large magnitude increase in shorter telomere fragments (0.08 -3.6 KB) in the liver and 2) a non-significant large magnitude decrease in shorter telomere fragments in muscle and SAT without having any effect in the VAT. Prenatal T also induced a large magnitude increase in mitochondrial OXPHOS protein complexes II and IV in liver, without having an effect at the level of the muscle, VAT and SAT. These findings are suggestive that prenatal T-treatment induced hepatic defects may involve premature cellular senescence. The relevance of parallel increase in mitochondrial OXPHOS in the liver is unclear and remains to be explored. The defects observed in the muscle and SAT may occur independent of cellular senescence or alterations in mitochondrial function. The lack of change in telomere length and mitochondrial OXPHOS in spite of increased inflammation and oxidative stress in the VAT is suggestive of a potential protective function in play, consistent with maintenance of the insulin sensitivity in this tissue. This study, therefore, raises the possibility that metabolic defects programmed by gestational insults may involve premature aging of metabolic organs in a tissue-specific manner and have translational bearing in conditions associated with hyperandrogenic states.

<![CDATA[SUN-013 Cardiometabolic Profile of Brazilian Women with Polycystic Ovary Syndrome (PCOS): A Systematic Review and Meta-Analysis]]> Introduction. PCOS is a frequent endocrine disease and its clinical expression may be influenced by ethnicity and sociocultural backgrounds. Despite its high prevalence, few studies are available regarding clinical characteristics of Brazilian women with PCOS. The aim of this study was to summarize the available evidence regarding metabolic risks in PCOS population in Brazil trough a systematic review and meta-analysis. Materials and Methods. We systematically searched EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials for studies published until July 31, 2019. Results. Eleven cross-sectional and case-control studies were selected for the present meta-analysis, including 898 women diagnosed with PCOS and 2176 controls. All used the Rotterdam criteria for the diagnosis of PCOS. Compared to controls, BMI was higher in PCOS [standardized mean difference (SMD) 0.67 (95% CI 0.29, 1.05) I²=91%], as well as waist circumference [SMD 0.88 (0.40, 1.37) I²=93%]. Systolic and diastolic blood pressure were higher in PCOS, SMD 0.66 (0.30, 1.01) I²=83%, SMD 0.55 (0.24, 0.87) I²=81%, respectively. Glucose and HOMA-IR were higher in PCOS, SMD 0.22 (0.02, 0.41) I²= 57%, SMD 0.78 (0.52, 1.04) I² =26% respectively. Regarding lipid profile, PCOS had higher values for triglyceride [SMD= 0.39 (0.14, 0.64, I² =63%)], total cholesterol [SMD 0.36 (0.15, 0.57, I²=57%)] and LDL [SMD 0.44 (0.11, 0.78, I²=82%)] and lower values for HDL [SMD -0.56 (-0.78, -0.34) I²=68%]. Conclusions. Even though the studies considered were observational, including mostly small samples, the evidence from this meta-analysis indicates women with PCOS from different regions of Brazil present worse cardiometabolic profile than women without PCOS. This systematic review and meta-analysis is registered in PROSPERO (CRD42016038537).

<![CDATA[SUN-012 Role of Leptin-Receptor Expressing Cells in the Pathogenesis of Polycystic Ovary Syndrome (PCOS)]]> Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, and is characterized by hyperandrogenism, oligo/anovulation, and/or polycystic ovaries. Many women with PCOS also suffer from adverse metabolic phenotypes, including central adiposity, insulin resistance, and glucose intolerance, which can exacerbate reproductive dysfunction. Androgens can act upon androgen receptors (AR), which are expressed in many reproductive and metabolic tissues, and contribute to the pathogenesis of PCOS. AR are highly expressed in the neuroendocrine hypothalamus in areas which regulate the hypothalamic-pituitary-gonadal axis and contribute to the central regulation of metabolism. Many phenotypes of PCOS can be modelled in rodents by administration of the non-aromatizable androgen dihydrotestosterone (DHT) during critical periods of development. Neuronal AR is key in the development of PCOS, as female mice with neuronal AR deletion who are exposed to androgen excess are protected against development of anovulation, polycystic ovaries, and metabolic abnormalities. Yet it is not known which populations of neurons confers this protection. We hypothesize that leptin-receptor (LepR) neurons participate in the pathogenesis of PCOS, as sub-populations of LepR neurons co-express AR in the hypothalamus, and LepR neurons are critical in the central regulation of energy homeostasis, and exert permissive actions on puberty and fertility. We have pre-natally androgenized (PNA) a mouse model of AR deletion specifically in LepR cells (LepRΔAR) and are conducting reproductive and metabolic phenotyping. As previously demonstrated, control PNA females show long periods of acyclicity, whereas LepRΔAR PNA female mice show a similar number of days in each stage of the estrous cycle, number of cycles, and cycle length as vehicle treated LepRΔAR females. Our findings indicate that a subpopulation of AR/LepR cells mediate the effects of prenatal androgen excess on female estrous cycles in a mouse model of PCOS-like phenotype.

<![CDATA[SUN-025 Obesity Severity and Polycystic Ovary Syndrome in an Ethnically Diverse Cohort of Adolescent Girls]]> INTRODUCTION: Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders affecting young women and may present as early as adolescence. Early recognition is important, as polycystic ovary syndrome (PCOS) is associated with increased cardiometabolic risk and type 2 diabetes mellitus. The risk of PCOS increases with obesity, but fewer studies have explored the burden of PCOS in children with obesity within healthcare settings. In this study, we examined the proportion of adolescent girls with obesity who also had diagnosed PCOS and the relationship between PCOS and obesity severity.

METHODS: From an existing cohort of nearly 8000 children age 3-17 with obesity (Body Mass Index, BMI ≥95th percentile) who were seen at pediatric well-child visits and identified for weight management based on BMI, we classified the subgroup of girls age 12-17 years who had moderate (BMI 100-119% of the 95th percentile) and severe (BMI ≥120% of the 95th percentile) obesity by PCOS status. Diagnosed PCOS was identified based on a visit diagnosis code for PCOS (ICD-9 256.4) within one year of the well child visit.

RESULTS: We identified 1478 adolescent girls (age 12-17) with obesity, among whom 76 (5%) had a PCOS diagnosis. The burden of PCOS varied by race, including 4% among white, 7% among black, 5% among Hispanic, and 8% among Asians, respectively. The proportion with diagnosed PCOS was greater in severely obese patients (9%) compared to moderately obese (3%). By race/ethnicity, the proportion with PCOS among moderately obese/severely obese girls were as follows: white 2%/8%, black 4%/10%, and Hispanic 2%/9%, respectively. The Asian population had a higher proportion of PCOS (10%) among girls with moderate obesity, as fewer Asian girls had severe obesity overall.

CONCLUSION: Among adolescent girls with obesity, the burden of PCOS varied by race/ethnicity and level of obesity. Increasing severity of obesity was associated with a greater proportion of girls having diagnosed PCOS, a trend that was reflected in white, black and Hispanic adolescent girls but not Asians, the latter due to their lower range BMI. These data highlight the prevalence of PCOS among adolescent girls with obesity and support the need for early identification and management prior to adulthood.

<![CDATA[SUN-016 Mendelian Randomization Reveals That Polycystic Ovary Syndrome Is Not a Causal Risk Factor for Type 2 Diabetes, Coronary Heart Disease, or Stroke]]>


Polycystic ovary syndrome (PCOS) is now recognized not only as a cosmetic and reproductive disorder, but also as a metabolic disorder with important consequences. The balance of the literature suggests that PCOS increases the risk of future type 2 diabetes (T2D); however, whether PCOS increases the risk of coronary heart disease (CHD) and/or stroke is more controversial. Despite a high burden of cardiovascular risk factors (which suggests a high risk of events), the mostly small and retrospective cohort studies have yielded conflicting results. Meta-analyses of these studies suggested at best a 1.4 to 2-fold increased risk of CHD and stroke, which attenuated to 1.2-1.6 when accounting for body mass index (BMI) (1,2). Given that observational studies may be biased by confounders between the risk factor and outcome (in this case, elevated BMI often present in PCOS), we performed Mendelian randomization (MR) analyses to examine the possible causal effect of polycystic ovary syndrome (PCOS) with T2D, CHD and stroke. MR uses genetic variants as instruments to represent exposures of interest to assess causality between exposures and outcomes (3). It is increasingly being used because it overcomes confounding and reverse causation, which often plague observational studies. The instrument variables for PCOS were constructed based on 14 SNPs derived from a published GWAS meta-analysis for PCOS conducted in European cohorts (10,074 cases and 103,164 controls) (4). The SNP to outcomes estimates were obtained from the DIAMANTE T2D GWAS (74,124 T2D cases and 824,006 controls) (5), the CHD GWAS meta-analysis of the UK Biobank plus CARDIoGRAMplusC4D (122,733 cases and 424,528 controls) (6) and the MEGASTROKE consortium GWAS (67,162 cases and 454,450 controls) (7). MR analyses were conducted using three methods: inverse variance weighted (IVW) (primary method), weighted median and MR Egger (sensitivity analyses). In our study, no significant association of genetically predicted PCOS with T2D (OR 0.97, CI 0.91-1.02), CHD (OR 0.99, CI 0.95-1.03) or stroke (OR 0.98, CI 0.93-1.02) was observed. Our findings suggest that PCOS is not a causal risk factor for T2D, CHD or stroke. The observed associations of PCOS with these three diseases from observational studies are likely due to confounding factors and small sample sizes. Given that MR has found that increasing BMI is causal for PCOS as well as T2D and CHD, overweight/obesity is the likely confounding variable. These results suggest a critical revision of how we counsel and manage women with PCOS.


1. Zhou Y, et al. Gynecol Endocrinol 2017; 33:904-910

2. De Groot PC, et al. Hum Reprod Update 2011; 17:495-500

3. Davey Smith G, et al. Hum Mol Genet. 2014; 23:R89-R98.

4. Day F, et al. PLoS Genet. 2018;14(12).

5. Mahajan A, et al. Nat Genet. 2018;50(11):1505-1513.

6. van der Harst P, et al. Circ Res. 2018;122(3):433-443.

7. Malik R, et al. Nat Genet. 2018;50(4):524-537.

<![CDATA[SUN-022 Metformin-Fish Oil Adjunct Therapy Improves apoB-Remnant Lipoprotein and Triglyceride Levels in Women with Polycystic Ovary Syndrome]]> <![CDATA[SUN-LB5 GnRHR ECL-2 Epitopes Targeted by Activating Autoantibodies in Polycystic Ovary Syndrome]]> 0.2). There was no significant change in activity in the OIC subjects by the addition of peaks 5 + 8 RID peptides. Conclusion: These PCOS GnRHR-AAb data confirm the presence of significant activation of the GnRHR by AAb targeted to specific epitope(s) proximate to the disulfide GnRHR-ECL2 linkage to the nearby ECL1. These data are compatible with a pathophysiological role for GnRHR-AAb in PCOS and may provide both diagnostic and therapeutic opportunities. ]]> <![CDATA[SUN-LB4 Androgenic Profiles of Patients With Severe Insulin Resistance]]> <![CDATA[SUN-LB6 Characterization of PCOS Among Flo App Users Around the World]]> <![CDATA[SUN-LB3 Relationship Between BMI and PCOS Symptoms Among Flo App Users in the United States]]> 1 year, there is a direct relationship between BMI and the percentage of women with PCOS. Moreover, when identifying symptoms and findings serving as strong predictors of a positive PCOS diagnosis, hirsutism, high glucose, and high levels of both cholesterol and glucose were the top symptoms and findings for women with BMI 18.5-34.9. Hirsutism, high glucose, and inability to conceive for > 1 year were the strongest predictors of PCOS for women with BMI 35+. Among all users with hirsutism, the percentage of women with PCOS increased 3.65 times compared to the whole cohort, making it the strongest predictor of PCOS. Understanding BMI patterns as they relate to PCOS symptoms allows for better understanding the pathophysiology of PCOS. Among women with PCOS in the United States, changes in BMI are associated with variations in the many symptoms of PCOS. ]]> <![CDATA[SUN-023 Changes in Microct Bone Density and Reduced Bone Formation in a “Postmenopausal” PCOS Rat Model]]>