Normal-weight Polycystic Ovary Syndrome Women Research Articles

Changes of biochemical parameters in normal weight and overweight/obese women with polycystic ovary Syndrome

Objectives: Polycystic ovary syndrome (PCOS) is an endocrine disease in reproductiveage women, which interferes with fertility, menstruation, and body composition. Some biochemical parameters change in women with PCOS, a feature which can be a consequence of the disease itself or of the accompanying obesity. This study investigated the glucose and lipid profiles, sex hormones, and hsCRP in normal weight and overweight/ obese Iranian women with and without PCOS.
 Methods: 314 women with PCOS and 138 healthy and fertile women were recruited for the study. The patients and controls were divided according to body mass index (BMI) into two groups as follows: BMI<25 Kg/m2 and BMI≥ 25 Kg/m2 . Blood samples were collected from all participants to assess fasting blood glucose, fasting insulin, lipid profile, FSH, LH, free testosterone, and hs-CRP levels. The homeostasis model of insulin resistance (HOMA-IR) was calculated for assessing insulin sensitivity.
 Results: BMI, fasting insulin, HOMA-IR, triglyceride, FT, LH, and hs-CRP levels were significantly higher in the PCOS group, while lower levels of FSH were observed in comparison to non-PCOS women. Among overweight PCOS women, hs-CRP levels were significantly elevated compared to normal-weight PCOS women. However, there was no significant difference in circulating hs-CRP levels between normal-weight and overweight participants in the control group.
 Conclusion: The study results suggest that both insulin resistance and an increase in hs-CRP may be relevant to PCOS. Moreover, the findings indicated that chronic inflammation in PCOS is not solely dependent on the pathogenesis of the disease but may be exacerbated by increased body weight.

OR35-05 Interaction of Cortisol with Testosterone Predicts Abdominal Fat Mass in Normal-weight Polycystic Ovary Syndrome Women with Normal Serum 11-Oxygenated Androgens

Abstract Disclosure: D.A. Dumesic: Consulting Fee; Self; Ferring Pharmaceuticals, Precede Biosciences, Inc, Spruce Biosciences, Inc. Grant Recipient; Self; National Institutes of Health. A.F. Turcu: None. H. Liu: None. T.R. Grogan: None. D.H. Abbott: None. G. Lu: None. D. Dharanipragada: None. G.D. Chazenbalk: None. Adrenal and ovarian steroidogenesis are interwoven with endocrine-metabolic dysfunction into polycystic ovary syndrome (PCOS). Women with PCOS and normal weight have androgen excess along with preferential abdominal adipose deposition (1,2), which is partially reversed by androgen receptor blockade (3). The role of adrenal steroids in this relationship, however, remains unclear. The present study examines whether serum levels of 11-oxygenated adrenal androgens, cortisol and/or cortisone differ between normal-weight PCOS women and body mass index (BMI)/age-matched normo-androgenic ovulatory women (controls) and whether adrenal steroids associate with abdominal adipose deposition. Twenty normal-weight PCOS women and 20 age- and BMI-matched controls underwent circulating hormone/metabolic determinations, intravenous glucose tolerance testing and total-body dual-energy x-ray absorptiometry. Clinical characteristics and hormonal values were compared between PCOS and control subjects. An unpaired Student’s t-test and Pearson correlation coefficients, adjusting for serum cortisol, were used as appropriate. Serum total/free testosterone (T) and androstenedione (A4) levels, and android/gynoid fat mass ratio, were greater in PCOS women with low-normal insulin sensitivity than in controls (all androgens P<0.001; android/gynoid fat mass ratio, P=0.026). A positive correlation of serum androgens with android/gynoid fat mass ratio was observed in all women combined (total T: R=+0.41, P=0.013; free T: R=+0.49, P=0.003; A4: R=+0.45, P=0.006). Serum 11ß-hydroxyA4 (11OHA4), 11-ketoA4 (11KA4), 11ß-hydroxyT (11OHT) and 11-ketoT (11KT), cortisol and cortisone levels were comparable between PCOS women and controls, and were unrelated to body fat distribution. Serum 11-oxygenated adrenal androgens correlated negatively with % total body fat (11OHA4: R=-0.42, P=0.011; 11KA4: R=-0.34, P=0.046; 11OHT: R=-0.36, P=0.031; 11KT: R=-0.37, P=0.027), but were no longer significant when adjusting for a concomitant negative relationship of serum cortisol with % total body fat (R=-0.45, P=0.006). Serum cortisol levels also correlated negatively with android fat mass in all women combined (R=-0.38, P=0.021) and were accompanied by a trend (P=0.075) towards reduced serum cortisol to cortisone ratio, as a marker of reduced 11β-hydroxysteroid dehydrogenase type 1 (HSD11ß1) conversion of cortisone to cortisol, in PCOS women versus controls (P=0.075). Ratios of 11KT/11KA4 and 11KT/11OHT as markers of AKR1C3and HSD11ß2 activities, respectively, did not differ by female type (both enzyme markers, P=nonsignificant). Conclusion: Reduced cortisol action, mediated in part through decreased HSD11ß1, interacts with an elevated androgens pathway to determine abdominal fat mass in normal-weight PCOS women with normal serum 11-oxygenated androgens.

Risk factors for insulin resistance related to polycystic ovarian syndrome in Iranian population

Polycystic ovary syndrome (PCOS) has significant metabolic sequelae linked to insulin resistance. This study aimed to compare clinical, metabolic, and hormonal characteristics of PCOS women with and without insulin resistance. The second aim was to compare the clinico-biochemical profiles of the various PCOS phenotypes. In this cross-sectional secondary analysis, we combined the baseline data from two separate randomized controlled trials (RCTs) in women diagnosed with PCOS. PCOS patients were categorized into the four Rotterdam PCOS phenotypes according to the presence of at least two criteria of oligomenorrhea/anovulation (O), hyperandrogenism (H), and polycystic ovary morphology (P): O–H–P, H–P, O–H, and O–P. Participants were categorized into two groups according to the homeostasis model assessment index of insulin resistance (HOMA-IR) levels: < 3.46, and ≥ 3.46. The correlation between the HOMA-IR and biometric, clinical, and biochemical variables was assessed in normal weight (BMI < 25) and overweight/obese (BMI ≥ 25) PCOS women. Then, the association between PCOS phenotypes and insulin resistance was investigated using logistic regression analysis. A total of 125 PCOS patients aged 18–40 years were included in the present study. Based on our results, the HOMA-IR index was positively correlated with diastolic blood pressure, free androgen index, and triglycerides levels; and negatively correlated with sex hormone-binding globulin in overweight/obese PCOS women. In addition, the HOMA-IR index was found to be positively correlated with alanine transaminase and negatively correlated with diastolic blood pressure in normal weight PCOS women. Moreover, individuals with O–H–P phenotype (odds ratio [OR] 2.52, 95% confidence interval [CI] 1.02–6.24) had about two-fold increased risk of insulin resistance. In conclusion, the full-blown PCOS (O–H–P) phenotype has an increased risk of insulin resistance. Accordingly, phenotype division may help physicians to predict adverse metabolic outcomes.

Interplay of Cortisol, Testosterone, and Abdominal Fat Mass in Normal-weight Women With Polycystic Ovary Syndrome.

Ovarian and adrenal steroidogenesis underlie endocrine-metabolic dysfunction in polycystic ovary syndrome (PCOS). Adipocytes express aldo-keto reductase 1C3 and type 1 11β-hydroxysteroid dehydrogenase, which modulate peripheral androgen and cortisol production. To compare serum adrenal steroids, including 11-oxygenated androgens (11-oxyandrogens), cortisol, and cortisone between normal-weight women with PCOS and body mass index- and age-matched ovulatory women with normal-androgenic profiles (controls), and assess whether adrenal steroids associate with abdominal adipose deposition. Prospective, cross-sectional, cohort study. Academic medical center. Twenty normal-weight women with PCOS and 20 body mass index-/age-matched controls. Blood sampling, IV glucose tolerance testing, and total-body dual-energy x-ray absorptiometry. Clinical characteristics, hormonal concentrations, and body fat distribution. Women with PCOS had higher serum total/free testosterone (T) and androstenedione (A4) levels and a greater android/gynoid fat mass than controls (androgens P < .001; android/gynoid fat mass ratio, P = .026). Serum total/free T and A4 levels correlated positively with android/gynoid fat mass ratio in all women combined (P < .025, all values). Serum 11ß-hydroxyA4, 11-ketoA4, 11ß-hydroxyT, 11-ketoT, cortisol, and cortisone levels were comparable between female types and unrelated to body fat distribution. Serum 11-oxyandrogens correlated negatively with % total body fat, but lost significance adjusting for cortisol. Serum cortisol levels, however, correlated inversely with android fat mass (P = .021), with a trend toward reduced serum cortisol to cortisone ratio in women with PCOS vs controls (P = .075), suggesting diminished 11β-hydroxysteroid dehydrogenase activity. Reduced cortisol may protect against preferential abdominal fat mass in normal-weight PCOS women with normal serum 11-oxyandrogens.

Randomized clinical trial: effect of low-dose flutamide on abdominal adipogenic function in normal-weight women with polycystic ovary syndrome

To examine whether low-dose flutamide administration to normal-weight women with polycystic ovary syndrome (PCOS) reduces abdominal fat deposition, attenuates accelerated lipid accumulation in newly formed adipocytes derived from subcutaneous (SC) abdominal adipose stem cells (ASCs), and/or alters glucose-lipid metabolism. A double-blind, placebo-controlled randomized clinical trial. An academic medical center. Twelve normal-weight women with PCOS and 12 age- and body mass index-matched controls. Women underwent circulating hormonal and metabolic determinations, intravenous glucose tolerance testing, total body dual-energy roentgenogram absorptiometry, and SC abdominal fat biopsy. Interventions were repeated in women with PCOS after 6-month administration of flutamide (125 mg orally daily) vs. placebo. Clinical parameters and lipid accumulation in newly formed adipocytes derived from SC abdominal ASCs invitro were compared between controls and the women with PCOS receiving flutamide vs. placebo. Serum luteinizing hormone and androgen levels as well as lipid accumulation in newly formed SC abdominal adipocytes were greater in the women with PCOS than controls. Flutamide vs. placebo reduced percent android fat, lowered serum log low-density lipoprotein and log non-high-density lipoprotein levels, and increased fasting circulating glucose levels. In all women with PCOS, changes in percent android fat positively correlated with serum log non-high-density lipoprotein and log low-density lipoprotein levels, with correlations influenced by serum free testosterone levels. Flutamide vs. placebo also attenuated lipid accumulation in newly-formed PCOS SC abdominal adipocytes invitro relative to controls, which was unrelated to serum lipid levels. Low-dose flutamide administration to normal-weight PCOS women reduces preferential abdominal fat deposition, attenuates accelerated lipid accumulation in newly-formed adipocytes derived from SC abdominal ASCs invitro, and alters glucose-lipid homeostasis. NCT01889199 (URL, clinicaltrials.gov; date of registration, 6/28/2013; enrollment date of first subject, 6/28/2013).

LOW-DOSE FLUTAMIDE ALTERS ABDOMINAL ADIPOGENIC FUNCTION IN NORMAL-WEIGHT POLYCYSTIC OVARY SYNDROME WOMEN (PCOS); A DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED CLINICAL TRIAL

In normal-weight women with polycystic ovary syndrome (PCOS), hyperandrogenism accompanies increased abdominal fat mass and accelerated subcutaneous (SC) abdominal stem cell differentiation into adipocytes in vitro (1-4). This study examined whether androgen receptor blockade by low-dose flutamide administration to normal-weight PCOS women lowers abdominal fat mass and/or reduces accelerated SC abdominal stem cell lipid accumulation during adipocyte development in vitro and if so whether such changes alter metabolism.

Potential role of d-chiro-inositol in reducing oxidative stress in the blood of nonobese women with polycystic ovary syndrome.

d-chiro-Inositol (DCI), an isomer of inositol, possesses antioxidative and endothelial protective properties. Possibly due to a deficiency of insulin mediators, polycystic ovary syndrome (PCOS) is often associated with insulin resistance (IR) and hyperinsulinemia, likely responsible for an elevated production of reactive oxygen species. We investigated oxidative-related alterations of inositol in the blood of women with PCOS before and after treatment with DCI. A total of 38 normal-weight PCOS women were investigated before and after DCI administration (500 mg/day for 12 weeks; n=38) by evaluating serum testosterone, serum androstenedione, fasting serum insulin, fasting serum glucose, and parameters of IR. From the blood, we determined biomarkers of oxidative stress: superoxide anion radicals, hydrogen peroxide, nitric oxide, and the index of lipid peroxidation. The activity of catalase and superoxide dismutase and the reduced glutathione (GSH) content in the hemolysate were also assessed. Data showed that PCOS patients' plasma underwent oxidative stress, as indicated by the higher level of prooxidants and reduced cytosolic GSH content. DCI treatment significantly improved the metabolic parameters. Also, serum values of testosterone were reduced. In conclusion, PCOS patients suffer from a systemic oxidative stress that induces endothelial dysfunction. Treatment with DCI is effective in reducing hormonal, metabolic, and oxidative abnormalities in PCOS patients by improving IR.

Serum Testosterone to Androstenedione Ratio Predicts Metabolic Health in Normal-Weight Polycystic Ovary Syndrome Women.

ContextIncreased aldo-keto reductase 1C3 (AKR1C3)-mediated conversion of androstenedione (A4) to testosterone (T) promotes lipid storage in subcutaneous (SC) abdominal adipose in overweight/obese polycystic ovary syndrome (PCOS) women.ObjectiveThis work examines whether an elevated serum T/A4 ratio, as a marker of enhanced AKR1C3 activity in SC abdominal adipose, predicts metabolic function in normal-weight PCOS women.MethodsThis prospective cohort study took place in an academic center and comprised 19 normal-weight PCOS women and 21 age- and body mass index–matched controls. Interventions included circulating hormone/metabolic determinations, intravenous glucose tolerance testing, total body dual-energy x-ray absorptiometry, and SC abdominal fat biopsy. Serum T/A4 ratios, hormone/metabolic measures, and AKR1C3 expression of adipocytes matured in vitro were compared between female types; serum T/A4 ratios were correlated with serum lipids, adipose insulin resistance (adipose-IR), homeostatic model assessment of insulin resistance (HOMA-IR) and insulin sensitivity (Si).ResultsIncreased serum T/A4 ratios (P = .040) and log adipose-IR values (P = .002) in PCOS women vs controls were accompanied by AKR1C3 messenger RNA overexpression of PCOS adipocytes matured in vitro (P = .016). Serum T/A4 ratios in PCOS women, but not controls, negatively correlated with log triglycerides (TGs: R = –0.65, P = .002) and the TG index (R = –0.57, P = .011). Adjusting for serum free T, serum T/A4 ratios in PCOS women remained negatively correlated with log TG (R = –0.57, P = .013) and TG index (R = –0.50, P = .036), respectively, without significant relationships with other metabolic measures.ConclusionAn elevated serum T/A4 ratio, as a marker of enhanced AKR1C3 activity in SC abdominal adipose, predicts healthy metabolic function in normal-weight PCOS women.

Dynamic changes in chromatin accessibility, altered adipogenic gene expression, and total versus de novo fatty acid synthesis in subcutaneous adipose stem cells of normal-weight polycystic ovary syndrome (PCOS) women during adipogenesis: evidence of cellular programming

BackgroundNormal-weight polycystic ovary syndrome (PCOS) women exhibit adipose resistance in vivo accompanied by enhanced subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes with accelerated lipid accumulation per cell in vitro. The present study examines chromatin accessibility, RNA expression and fatty acid (FA) synthesis during SC abdominal ASC differentiation into adipocytes in vitro of normal-weight PCOS versus age- and body mass index-matched normoandrogenic ovulatory (control) women to study epigenetic/genetic characteristics as well as functional alterations of PCOS and control ASCs during adipogenesis.ResultsSC abdominal ASCs from PCOS women versus controls exhibited dynamic chromatin accessibility during adipogenesis, from significantly less chromatin accessibility at day 0 to greater chromatin accessibility by day 12, with enrichment of binding motifs for transcription factors (TFs) of the AP-1 subfamily at days 0, 3, and 12. In PCOS versus control cells, expression of genes governing adipocyte differentiation (PPARγ, CEBPα, AGPAT2) and function (ADIPOQ, FABP4, LPL, PLIN1, SLC2A4) was increased two–sixfold at days 3, 7, and 12, while that involving Wnt signaling (FZD1, SFRP1, and WNT10B) was decreased. Differential gene expression in PCOS cells at these time points involved triacylglycerol synthesis, lipid oxidation, free fatty acid beta-oxidation, and oxidative phosphorylation of the TCA cycle, with TGFB1 as a significant upstream regulator. There was a broad correspondence between increased chromatin accessibility and increased RNA expression of those 12 genes involved in adipocyte differentiation and function, Wnt signaling, as well as genes involved in the triacylglycerol synthesis functional group at day 12 of adipogenesis. Total content and de novo synthesis of myristic (C14:0), palmitic (C16:0), palmitoleic (C16:1), and oleic (C18:1) acid increased from day 7 to day 12 in all cells, with total content and de novo synthesis of FAs significantly greater in PCOS than controls cells at day 12.ConclusionsIn normal-weight PCOS women, dynamic chromatin remodeling of SC abdominal ASCs during adipogenesis may enhance adipogenic gene expression as a programmed mechanism to promote greater fat storage.

SUBCUTANEOUS ABDOMINAL STEM CELL ADIPOGENESIS PREDICTS METABOLIC IMPROVEMENTS IN NORMAL-WEIGHT POLYCYSTIC OVARY SYNDROME WOMEN

Normal-weight polycystic ovary syndrome (PCOS) women have exaggerated subcutaneous (SC) abdominal adipose stem cell (ASC) differentiation into adipocytes that may be programmed. This study examines whether SC abdominal ASC differentiation into adipocytes in vitro correlates with endocrine-metabolic functions in normal-weight PCOS women versus age- and body mass index (BMI)-matched normoandrogenic ovulatory (control) women.

A Comparable Study of Ovarian Response to Controlled Ovarian Stimulation between Overweight/Obese and Normal Weight Women with Polycystic Ovary Syndrome Whom Undergone Intracytoplasmic Sperm Injection

The prevalence of obesity is increasing world-wide. Obesity is considered to have a vital role in thepathogenesis of polycystic ovary syndrome (PCOS). An assisted reproduction technique, Intra cytoplasmicsperm injection (ICSI), has been used increasingly for the infertility management in those patients. However,data regarding the effects of obesity on the outcome of this technique in PCOS patients is limited.Aim: This study compared the response to controlled ovarian stimulation (COS) between overweight/obeseand normal weight women with PCOS whom undergone ICSI.Materials and Method: 53 PCOS infertile females were included. They were divided according to theirbody mass index (BMI) into two groups: (Group I normal weight and group II overweight and obese). Bothwere included in COS/ICSI program. Assessment of total dose of gonadotropins, duration of stimulatedcycles, total number of retrieved oocytes, their quality and development of OHSS was undertaken.Results: The study showed that despite being insignificant, the total dose of gonadotropin used for stimulationof group II women was higher than that used for women in group I: 1729.06 iu vs 1380.00, p-value=0.1with a longer duration cycle 10.0 days vs 9.4, p-value=0.5, the mean total number of retrieved oocytes fromthe group II was more than that from group I women, while the mean total number of immature oocytesretrieved from group II women was significantly less than that from group I (1.7% vs 3.7%, p-value=0.04).The rate of developing OHSS in group II was more than that in group I.Conclusion: Overweight and obese PCOS women need higher doses of gonadotropin to be stimulated withlonger duration of the treatment cycle; howerever, they produce a higher number of oocytes with a highermaturity during COS. Also, they are more likely to develop OHSS when stimulated in comparison to normalweight PCOS women.

Polycystic ovary syndrome and endothelial dysfunction: A potential role for soluble lectin-like oxidized low density lipoprotein receptor-1

The aims of this study were to investigate whether serum soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1), oxidized LDL (oxLDL), paraoxonase-1(PON-1) and hydroperoxide (LOOH) levels are altered in women with polycystic ovary syndrome (PCOS) and also to determine if hyperandrogenism, insulin resistance (IR) and Anti-Müllerian Hormone (AMH) are associated with endothelial dysfunction in PCOS. A total of 46 women with PCOS and 46 non-PCOS healthy controls were recruited. Women with PCOS had significantly higher sLOX-1, oxLDL and LOOH concentrations than non-PCOS women [6.16 (3.92−13.95) vs 1.37 (0.63−4.43) ng/mL, p < 0.001; 6.48 ± 1.03 vs 3.16 ± 1.02 μU/L, p < 0.001; 2.45 (1.45−3.45) vs 1.06 (0.64−1.56) μmol/L, p < 0.001]. The mean PON-1 level of PCOS group was lower than non-PCOS group (69.47 ± 10.75 vs 104.08 ± 21.43 U/mL, p < 0.001). There was no significant difference in terms of the sLOX-1, oxLDL, LOOH and PON-1 levels between normal weight and overweight PCOS women. On univariate logistic regression analysis, Ferriman-Gallwey scale (FGS), HOMA-IR and AMH were an independent predictors of high risk group of endothelial dysfunction markers (HR-EDm). Age and BMI were not associated with HR-EDm. When incorporated into the multivariate model, endotelial dysfunction markers independently correlated with clinical hyperandrogenism (FGS) but not with AMH. In conclusion, our results indicated that an increased concentration of sLOX-1 might be an early predictor of endothelial damage in patients with PCOS. Women with PCOS have elevated sLOX-1, oxLDL, LOOH and decreased PON-1 levels, independent of BMI. Endothelial dysfunction in women with PCOS is associated with hyperandrogenism. Further studies are required to confirm our findings.

OR20-03 Transcriptional Changes in Lipid Metabolism of Adipocytes Derived from Subcutaneous Abdominal Adipose Stem Cells of Normal-Weight Polycystic Ovary Syndrome Women

Normal-weight polycystic ovary syndrome (PCOS) women exhibit increased adipose insulin resistance in vivo (1) accompanying enhanced subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes with greater lipid accumulation per cell in vitro (2). To determine whether this phenomenon is associated with abnormal adipogenic gene transcription during ASC differentiation into adipocytes, SC abdominal ASCs isolated from three non-Hispanic Caucasian normal-weight PCOS women and three age- and BMI-matched controls were cultured in adipogenic differentiation medium for 3–12 days. After RNA isolation, gene expression levels were determined by RNA sequencing at days 3, 7, and 12. Differentially expressed genes were filtered for significance (padj<0.05) and fold change (>2-fold); upstream regulator genes and gene ontology (GO) functions were determined using Ingenuity Pathway Analysis. Gene set enrichment analysis (GSEA) also was used to identify enriched cellular processes (3). Differentially expressed genes in PCOS vs. control cells were either upregulated (466, 768 and 441 genes on days 3, 7 and 12, respectively) or downregulated (742, 974 and 605 genes on days 3, 7 and 12, respectively) over time, with critical genes governing adipocyte cell differentiation in PCOS cells increased 2–6 fold at days 3, 7 and 12 (PPARγ, CEBPα, ADIPOQ, AGPAT2, FABP4, LPL, PLIN1). The predicted upstream regulator genes TGFβ1 (an adipogenic inhibitor) and TNF (a pro-inflammatory adipokine) were significantly reduced in PCOS relative to control cells at all time points. The GO functions lipid oxidation and free fatty acid (FFA) beta-oxidation were enriched amongst upregulated genes in PCOS cells across all time points, while acylglycerol synthesis was increased at days 7 and 12 alone (z>2, p<0.05, all GO functions). In parallel, GSEA showed in PCOS cells significantly increased transcripts related to oxidative phosphorylation, peroxisome activity and adipogenesis at all time points (p<0.05). Thus, adipocytes derived from SC abdominal ASCs of normal-weight PCOS women exhibit early activation of adipogenic genes, potentially underlying their exaggerated lipid accumulation in vitro, as previously described (2). These PCOS-related changes in gene expression involve an increase in both oxidative phosphorylation and FFA beta oxidation, which could disrupt the balance between energy production and lipid storage, particularly when caloric intake exceeds energy utilization.

Ovarian Expression of Adipokines in Polycystic Ovary Syndrome: A Role for Chemerin, Omentin, and Apelin in Follicular Growth Arrest and Ovulatory Dysfunction?

Adipokines are a potential link between reproduction and energy metabolism and could partly explain some infertilities related to some pathophysiology, such as polycystic ovary syndrome (PCOS). However, adipokines were predominantly assessed in blood samples, while very little is known concerning their variations in follicular fluid (FF) and ovarian granulosa cells (GCs) of PCOS women. Thus, the objectives of our study were to investigate adiponectin, chemerin, resistin, visfatin, omentin, and apelin ovarian expression in PCOS women in comparison with controls and women with only a polycystic ovary morphology. In total, 78 women undergoing an in vitro fertilization procedure were divided into three groups: 23 PCOS women, 28 women presenting only ≥12 follicles per ovary (ECHO group), and 27 control women. Each group almost equally included normal weight and obese women. Follicular fluid (FF) concentration and granulosa cells (GCs) mRNA expression of adipokines and their receptors were assessed by ELISA and RT-qPCR, respectively. Omentin levels in FF and GC were higher in PCOS than in ECHO and control women, while apelin expression was increased in both PCOS and ECHO groups. FF chemerin concentration was predominant in normal-weight PCOS women compared to BMI (Body Mass Index)-matched ECHO and control women, while GC mRNA levels were higher in the obese PCOS group than in the ECHO one. Compared to PCOS, ECHO women had increased FF adiponectin concentrations and lower plasma AMH levels. The FF concentration of all adipokines was higher in obese subjects except for adiponectin, predominant in normal-weight women. In conclusion, women with PCOS expressed higher GC chemerin and omentin, whereas the ECHO group presented higher levels of FF adiponectin and apelin and lower plasma AMH and LH concentrations. Chemerin, omentin, and apelin expression was differently regulated in women with PCOS, suggesting their possible role in follicular growth arrest and ovulatory dysfunction characterizing PCOS pathogenesis.

SUN-107 Abdominal Adipose Stem Cell Dysfunction In Vitro May Reflect Adipose Insulin Resistance In Vivo in Normal Weight Polycystic Ovarian Syndrome Women

Subcutaneous (SC) abdominal adipose stem cells (ASCs) of normal-weight polycystic ovary syndrome (PCOS) women show exaggerated development to newly-formed adipocytes in vitro (1). To determine whether this phenomenon in PCOS was related to adipose insulin resistance (adipose-IR) in vivo, 8 normal-weight PCOS women and 8 age- and BMI-balanced controls underwent circulating androgen and fasting insulin/free fatty acid (FFA) measurements. SC abdominal ASCs were isolated by fat biopsy and cultured in adipogenic medium for 12 days. ASC commitment to preadipocytes and newly-formed adipocytes derived from preadipocytes were determined by ZFP423 protein expression on day 0 and cellular lipid content by Oil Red O staining on day 12, respectively (i.e. adipogenesis). Adipose-IR was calculated as the product of fasting circulating FFA and insulin levels (2). Student’s t-test compared serum androgen levels and adipose-IR by female type; partial correlation coefficients examined associations of ZFP423 protein expression and newly-formed adipocyte lipid content with adipose-IR, adjusting for androgen levels. PCOS women had greater serum total testosterone [T] and free [f] T (P<0.005, both androgens) levels and higher adipose-IR (P=0.01) than controls. Newly-formed adipocyte lipid content positively correlated with adipose-IR in all women combined (R=0.57, P=0.02), however, significance was lost when adjusted for serum androgen levels (R=0.44, P=0.10 and R=0.36, P=0.18, for total T and fT, respectively). ZFP423 protein expression was not significantly correlated with adipose-IR in all women combined (R=-0.28, P=0.29), but was negatively correlated with adipose-IR (R=-0.64, P=0.01) after adjusting for total T levels. Using exploratory subgroup analysis, the positive relationship of newly-formed adipocyte lipid content with adipose-IR was significant in PCOS women (R=0.67, P=0.05) but not in controls (R=0.10, P=0.80). Similarly, the negative relationship of ZFP423 protein expression with adipose-IR was characteristic of PCOS women (R=-0.88, P=0.002) but not controls (R=-0.26, P=0.50). Thus, given the limited number of subjects, we hypothesize that altered SC abdominal adipogenesis contributes to increased adipose-IR in normal-weight PCOS women and that this relationship is due in part to hyperandrogenism.

MON-223 Adipose Insulin Resistance in Normal-Weight Women with Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and oligo-ovulation associated with insulin resistance (IR). Adipose-IR may underlie this PCOS phenotype and could contribute to IR by impairing insulin-mediated glucose uptake and/or lipogenesis, while diminishing insulin suppression of lipolysis. The present study examined whether adipose-IR, defined as the product of fasting circulating free fatty acid and insulin levels (1), was increased in normal-weight PCOS versus age-/BMI-balanced normo-androgenic ovulatory (control) women and, if so, whether it correlated with insulin sensitivity (Si) as measured by frequently-sampled intravenous glucose tolerance testing (FSIVGTT) and/or hyperandrogenism. Ten normal-weight PCOS women (by NIH criteria) and 18 controls (19-35 years; 19-25 kg/m2) of non-Hispanic Caucasian descent underwent serum hormone/metabolic measurements, FSIVGTT, total body dual-energy x-ray absorptiometry, and subcutaneous (SC) abdominal fat biopsy. Circulating hormone/metabolite levels, adipose-IR, Si, acute insulin response to glucose (AIRg), body fat distribution and adipocyte size distribution were compared between female types using Student’s t-test. Partial correlation coefficients examined associations between adipose-IR and outcome variables, adjusting for serum androgen levels. PCOS women exhibited greater serum LH, androstenedione (A4), total testosterone (T) and free (f) T levels than controls (P<0.05, all parameters), and demonstrated trends for increased abdominal adiposity (P=0.06) and serum triglyceride (TG) levels (P=0.09) with low-normal Si values. PCOS women also had greater (P=0.007) adipose-IR than controls, with a value of 29 pM/L*mM/L providing 94% specificity (95% CI 84%-100%) and 80% sensitivity (95% CI 55%-100%) in discriminating PCOS subjects from controls (AUC=0.81, 95% CI 0.61-1.00, P<0.001). In all women combined, adipose-IR negatively correlated with Si (P=0.01) and positively correlated with serum A4 (P=0.002), total T (P=0.004), fT (P=0.001) and fasting TG (P=0.001) levels as well as with AIRg (P=0.03) and percent small SC abdominal adipocytes (P=0.01). Relationships of adipose-IR with Si (P=0.04) and with serum TG (P=0.01) levels remained after adjusting for serum total T and fT levels, respectively, while the other correlations lost significance. Thus, in normal-weight PCOS women, adipose-IR is intimately linked with dyslipidemia and is associated with reduced Si in part through hyperandrogenism. Reference: Sondergaard E, et al. JCEM 2017;102:1193. Sources of Research Support: NIH Grants and Santa Monica Bay Woman’s Club.

MON-214 The Natural Course of Normal Weight Women with Polycystic Ovary Syndrome: An Insight into Metabolic Changes of Large Caucasian Cohort

Background: Polycystic ovary syndrome (PCOS) constitutes one of the most common endocrine diseases that should be considered as a continuum. This life span disease is originating in foetal life and through long reproductive period falling into long-term consequences extending beyond menopause. Hence, it is considered to increase diabetes risk as well cardiovascular risk and outcomes. However, the natural course of the disorder is not completely understood, and recent data suggest differences in the evolution of the disease between normal-weight and obese patients, indicating that the cardiometabolic effects may be an epiphenomenon of the obesity and not of PCOS per se. We aimed to define the evolution of normal-weight Caucasian women with PCOS through the years. Materials and Methods: In this multicenter cross-sectional case control study 763 normal-weight women with PCOS according to Rotterdam criteria and 376 age and BMI-matched controls were included. The study group was further divided into three age groups, representing women post-adolescence, of reproductive age, and of late reproductive age to menopause. All the subjects were assessed clinically, biochemically, hormonally, and with the means of pelvic ultrasound. Results: Waist circumference, WHR, FG score, glucose, lipids, gonadotropin, androgen levels as well as HOMA-IR and ovarian volume were significantly higher in the PCOS group in comparison to controls. No statistical difference was noted among PCOS women diagnosed with the Rotterdam criteria vs. those who met the NIH criteria. Age subgroup analysis showed that androgens remained significantly higher among PCOS and controls, whereas insulin and lipid levels, as well as HOMA-IR, were comparable between PCOS and controls in all age groups. Pearson correlations of studied parameters with age revealed a significant negative association of age with waist circumference, FG score, androgens (testosterone, FAI, DHEAS, D4), insulin, FSH, and HOMA-IR. Finally, multiple regression analysis of factors affecting HOMA-IR disclosed a negative association with age (r:-0.123, p: 0.001) and a positive association with BMI (r: 0.105, p: 0.004) and DHEAS (r: 0.175, p: 0.001). Conclusions: Lipids, androgens, insulin resistance, and menstrual cyclicity are gradually improved in an age-dependent manner in PCOS lean patients and age and BMI matched controls. Normal-weight PCOS women exhibit a higher degree of IR and dyslipidaemia compared to their healthy peers, but these aberrations improve gradually. If PCOS women retain their normal weight over the years, they may develop a metabolic and hormonal profile comparable to that of their peers without PCOS later in life.

Increased risk of obstructive sleep apnoea in women with polycystic ovary syndrome: a population-based cohort study

ObjectiveObesity is very common in patients with obstructive sleep apnoea (OSA) and polycystic ovary syndrome (PCOS). Longitudinal studies assessing OSA risk in PCOS and examining the role of obesity are lacking. Our objective was to assess the risk of OSA in women with vs without PCOS and to examine the role of obesity in the observed findings.DesignPopulation-based retrospective cohort study utilizing The Health Improvement Network (THIN), UK.Methods76 978 women with PCOS and 143 077 age-, BMI- and location-matched women without PCOS between January 2000 and May 2017 were identified. Hazard ratio (HR) for OSA among women with and without PCOS were calculated after controlling for confounding variables using multivariate Cox models.ResultsMedian patient age was 30 (IQR: 25–35) years; median follow-up was 3.5 (IQR: 1.4–7.1) years. We found 298 OSA cases in PCOS women vs 222 in controls, with incidence rates for OSA of 8.1 and 3.3 per 10 000 person years, respectively. Women with PCOS were at increased risk of developing OSA (adjusted HR = 2.26, 95% CI: 1.89–2.69, P < 0.001), with similar HRs for normal weight, overweight and obese PCOS women.ConclusionsWomen with PCOS are at increased risk of developing OSA compared to control women irrespective of obesity. Considering the significant metabolic morbidity associated with OSA, clinicians should have a low threshold to test for OSA in women with PCOS. Whether OSA treatment has an impact on PCOS symptoms and outcomes needs to be examined.

Metabolic characteristics of normal weight central obesity phenotype polycystic ovary syndrome women: a large-scale national epidemiological survey.

The aim was to investigate the metabolic profiles of women with normal weight but central obesity in polycystic ovary syndrome (PCOS). In total, 727 women with PCOS from a large-scale epidemiological survey were included. Diagnosis of PCOS was based on Rotterdam criteria. Subjects were categorized into four subgroups: (i) normal weight non-central obesity (NWNCO): body mass index (BMI) ≤18.5 kg/m2 to <25 kg/m2 and waist-to-hip ratio (WHR) <0.85; (ii) normal weight central obesity (NWCO): BMI ≤18.5 kg/m2 to <25 kg/m2 and WHR ≥0.85; (iii) obese non-central obesity (ONCO): BMI ≥25 kg/m2 and WHR <0.85; and (iv) obese central obesity (OCO): BMI ≥25 kg/m2 and WHR ≥0.85. BMI, WHR, blood pressure, glucose and lipid profiles were measured. NWCO subjects had significantly higher percentages of insulin resistance, high triglycerides and low high-density lipoprotein cholesterol (HDL-C) than NWNCO subjects (all P < 0.05), and similar percentages compared with ONCO subjects. Compared with the NWNCO group, the NWCO group had higher age-adjusted risks of insulin resistance, high triglycerides and low HDL-C (odds ratio [OR] = 3.83, 95% confidence interval [CI] = 2.23-6.58; OR = 1.66, 95% CI = 1.00-2.77, OR = 1.60, 95% CI = 1.11-2.30, respectively). PCOS women with normal weight but central obesity had increased risks of insulin resistance and dyslipidaemia compared with normal weight PCOS women without central obesity, suggesting that combining BMI with measurement of central obesity may provide better adiposity-related metabolic risk factor stratification in clinical practice than either method alone.

Hyperandrogenism Accompanies Increased Intra-Abdominal Fat Storage in Normal Weight Polycystic Ovary Syndrome Women.

Normal weight polycystic ovary syndrome (PCOS) women may have altered adipose structure-function underlying metabolic dysfunction. This study examines whether adipose structure-functional changes exist in normal weight PCOS women and correlate with hyperandrogenism and/or hyperinsulinemia. This is a prospective cohort study. The setting was an academic medical center. Six normal weight PCOS women and 14 age- and body mass index-matched normoandrogenic ovulatory (NL) women were included. All women underwent circulating hormone and metabolic measurements; frequently sampled intravenous glucose tolerance testing; total body dual-energy x-ray absorptiometry; abdominal magnetic resonance imaging; and SC abdominal fat biopsy. Circulating hormones and metabolites, body fat and its distribution, and adipocyte size were compared between PCOS and NL women, and were correlated with each other in all women. Circulating LH and androgen levels were significantly greater in PCOS than NL women, as were fasting insulin levels, pancreatic β-cell responsiveness to glucose, and total abdominal fat mass. Intra-abdominal fat mass also was significantly increased in PCOS women and was positively correlated with circulating androgen, fasting insulin, triglyceride, and non-high-density lipoprotein cholesterol levels in all women. SC abdominal fat mass was not significantly increased in PCOS women, but contained a greater proportion of small SC abdominal adipocytes that positively correlated with serum androgen levels in all women. Hyperandrogenism in normal weight PCOS women is associated with preferential intra-abdominal fat deposition and an increased population of small SC abdominal adipocytes that could constrain SC adipose storage and promote metabolic dysfunction.