AIM:To compare clomiphene citrate (CC), metformin or the combination of CC and metformin as the first line ovulation induction drug in Asian Indian women with polycystic ovary syndrome (PCOS).METHODS:One hundred and five newly diagnosed, treatment naive PCOS women were recruited. They were randomized into any of the three groups: Group I (CC 50–150 mg/day), Group II (metformin 1700 mg/day), and Group III (CC + metformin in similar dosage to Groups I and II). Patients underwent follicular monitoring and advice on timed intercourse. The study period was 6 months, or till pregnant, or till CC resistant. Primary outcome studied was live birth rate (LBR). Secondary outcomes were ovulation rate, pregnancy rate, and early pregnancy loss rate.RESULTS:There was no significant difference among the groups in baseline characteristics and biochemical parameters. LBR was 41.6%, 37.5%, and 28.1%, respectively in Groups III, II, and I. Group III (CC + metformin) had the highest ovulation (83.3%), pregnancy (50%), and LBRs (41.6%). Group II (metformin) was as good as Group I (CC) in all the outcomes. CC + metformin (Group III) had statistically significantly higher ovulation rate as compared to CC alone (Group I) (P = 0.03; odds ratio: 95% confidence interval: 3.888 [1.08–13.997]).CONCLUSION:Thus, our study shows that metformin was as good as CC in terms of “LBR” and the combination of CC and metformin gave the highest ovulation and LBR.

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Background: Despite their higher areal bone mineral density (aBMD), adolescents with obesity (OB) have an increase in fracture risk, particularly of the extremities, compared with normalweight controls. Whereas bone parameters that increase fracture risk are well characterized in anorexia nervosa (AN), the other end of nutritional spectrum, these data are lacking in adolescents with obesity. Objective: Our objective was to compare bone parameters in adolescent girls across the nutritional spectrum, to determine whether suboptimal bone adaptation to increased body weight may explain the increased fracture risk in OB. Methods: We assessed bone endpoints in 153 adolescent girls 14-21 years old: 50 OB, 48 controls and 55 AN. We used (i) DXA to assess aBMD at the lumbar spine, proximal femur and whole body, and body composition, (ii) high resolution peripheral quantitative CT (HRpQCT) to assess bone geometry, microarchitecture and volumetric BMD (vBMD), and (iii) finite element

Background Normal-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. Results SC 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. Conclusions In 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.

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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. References: (1) Dumesic DA, et al JCEM 2019;104(6):2171–83; (2) Leung KL, et al. JES 2019;3:Supplement 1, SUN-107 (3) Subhramanian A, et al. PNAS 2005;102:43

Despite their higher areal bone mineral density (aBMD), adolescents with obesity (OB) have an increase in fracture risk, particularly of the extremities, compared with normal-weight controls (C). Whereas bone parameters that increase fracture risk are well characterized at the other end of nutritional spectrum in anorexia nervosa (AN), these data are lacking in adolescents with obesity. Our objective was to compare bone geometry, microarchitecture, density and strength estimates in adolescents across the nutritional spectrum, to determine whether suboptimal bone adaptation to increased body weight may explain the increased fracture risk in OB. We assessed bone endpoints in 153 adolescents 14-21 years old: 50 OB, 48 C and 55 AN. We used DXA to assess aBMD at the lumbar spine, proximal femur and whole body, high resolution peripheral quantitative CT (HRpQCT) to assess bone geometry, microarchitecture and volumetric BMD (vBMD), and finite element analysis to assess failure load (a strength estimate) at the distal radius and tibia. All HRpQCT and FEA analyses were controlled for age. Groups did not differ for age or height. Per design, weight and BMI were highest in OB and lowest in AN. Areal BMD Z-scores at all sites were highest in OB, intermediate in C and lowest in AN (p<0.03 for all comparisons). At the radius, cortical area and thickness increased progressively from AN to C to OB (p<0.03) while trabecular area did not differ across groups. Compared to C and AN, OB had higher cortical porosity (p<0.03), trabecular number and thickness (p<0.01). Cortical vBMD did not differ in OB vs. C but was lower in AN (p<0.0001). Trabecular and total vBMD increased progressively from AN to C to OB (p<0.04). Of note, plate BV/TV did not differ in OB vs. C, but was lower in AN (p<0.0001); rod BV/TV was higher in OB vs. C and AN (p <0.002). At the tibia, cortical area and thickness increased progressively from AN to C to OB (p<0.002), while trabecular area was higher in OB vs. AN and C (p<0.004). Compared to C and AN, OB had higher cortical porosity (p<0.007) and lower trabecular thickness (p<0.02). Trabecular number increased progressively from AN to C to OB (p<0.02). Cortical vBMD did not differ in OB vs. C but was lower in AN (p<0.02). Trabecular and total vBMD were higher in OB vs. AN and C (p<0.002). Plate BV/TV was comparable in the three groups but rod BV/TV was higher in OB vs. C and AN (p<0.0001). Finally, failure load (a strength estimate) increased from AN to C to OB for the radius and tibia (p<0.04 for all). However, after adjusting for weight, failure load was lower in OB vs. C at both sites (p<0.05), and did not differ from AN. These data demonstrate that not all bone parameters appropriately adapt to an increase in body weight, with cortical porosity, cortical vBMD, and plate BV/TV at the radius and tibia, and tibial trabecular thickness being particularly at risk. These changes may explain the higher risk for fracture in OB than controls.

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