Lean Polycystic Ovary Syndrome Research Articles

Mechanism of elevated LH/FSH ratio in lean PCOS revisited: a path analysis

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting 5–20% of reproductive-age women. However, the treatment of PCOS is mainly based on symptoms and not on its pathophysiology. Neuroendocrine disturbance, as shown by an elevated LH/FSH ratio in PCOS patients, was thought to be the central mechanism of the syndrome, especially in lean PCOS. LH and FSH secretion are influenced by GnRH pulsatility of GnRH neurons in the hypothalamus. Kisspeptin is the main regulator of GnRH secretion, whereas neurokinin B (NKB) and dynorphin regulate kisspeptin secretion in KNDy neurons. This study aims to deepen the understanding of the neuroendocrine disorder in lean PCOS patients and its potential pathophysiology-based therapy. A cross-sectional study was performed at Dr. Cipto Mangunkusumo Kencana Hospital and the IMERI UI HRIFP cluster with 110 lean PCOS patients as subjects. LH, FSH, LH/FSH ratio, kisspeptin, NKB, dynorphin, leptin, adiponectin, AMH, fasting blood glucose, fasting insulin, HOMA-IR, testosterone, and SHBG were measured. Bivariate and path analyses were performed to determine the relationship between variables. There was a negative association between dynorphin and kisspeptin, while NKB levels were not associated with kisspeptin. There was no direct association between kisspeptin and the LH/FSH ratio; interestingly, dynorphin was positively associated with the LH/FSH ratio in both bivariate and pathway analyses. AMH was positively correlated with the LH/FSH ratio in both analyses. Path analysis showed an association between dynorphin and kisspeptin levels in lean PCOS, while NKB was not correlated with kisspeptin. Furthermore, there was a correlation between AMH and the LH/FSH ratio, but kisspeptin levels did not show a direct significant relationship with the LH/FSH ratio. HOMA-IR was negatively associated with adiponectin levels and positively associated with leptin and FAI levels. In conclusion, AMH positively correlates with FAI levels and is directly associated with the LH/FSH ratio, showing its important role in neuroendocrinology in lean PCOS. From the path analysis, AMH was also an intermediary variable between HOMA-IR and FAI with the LH/FSH ratio. Interestingly, this study found a direct positive correlation between dynorphin and the LH/FSH ratio, while no association between kisspeptin and the LH/FSH ratio was found. Further research is needed to investigate AMH and dynorphin as potential therapeutic targets in the management of lean PCOS patients.

Biomarkers identification in follicular fluid in relation to live birth in in vitro fertilization of women with polycystic ovary syndrome in different subtypes by using UPLC-MS method

BackgroundPolycystic ovary syndrome (PCOS) is a common infertility disorder which affects reproductive-aged women. However, metabolic change profiles of follicular fluid (FF) in lean and obese women diagnosed with and without PCOS remains unclear. Methods95 infertile women were divided into four subgroups: LC (lean control), OC (overweight control), LP (lean PCOS), and OP (overweight PCOS). The FF samples were collected during oocyte retrieval and assayed by ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS) metabolomics. ResultsA total of 236 metabolites were identified by metabolic analysis. The pathway enrichment analysis revealed that the glycerophospholipid metabolism (impact = 0.11182), ether lipid metabolism (impact = 0.14458), and primary bile acid biosynthesis (impact = 0.03267) were related to metabolic pathway between PCOS and control. Correlation analyses showed that epitestosterone sulfate was found positively correlated with fertilization rate in PCOS, while falcarindione, lucidone C. and notoginsenoside I was found to be negatively correlated. The combined four biomarkers including lucidone C, epitestosterone sulfate, falcarindione, and notoginsenoside I was better in predicting live birth rate, with AUC of 0.779. ConclusionThe follicular fluid of women with PCOS showed unique metabolic characteristics. Our study provides better identification of PCOS follicular fluid metabolic dynamics, which may serve as potential biomarkers of live birth.

BMI and Polycystic Ovary Syndrome: Demographic Trends in Weight and Health.

Introduction Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women in adolescence and reproductive age. The distribution of PCOS across different body mass index (BMI) categories can vary, and research has shown associations between PCOS and weight status. This study tries to evaluate the distribution of PCOS in relation to BMI in women attending the PCOS clinic in a tertiary hospital in eastern India. Methodology This hospital-based cross-sectional study was carried out in the gynecology outpatient departmentof a tertiary care center. The study population included all the women in the age group between 15 and 45 years diagnosed as having PCOSusing the Rotterdam definition. The various physical, clinical, and biochemical parameters were measured in the study population and compared among the obese and lean PCOS patients. Results and discussion A total of 143 women were included in the study. The mean age of the study population was 26.8 years. Among these, the underweight and normal weight patients were categorized as lean PCOS patients, 35 in number (24.5%), and overweight and obese patients were categorized as obese PCOS patients, 108 in number (75.5%). All the physical parametermeasures like age (mean = 28.05, SD = 5.722), height (mean = 153.384, SD = 6.679), weight (mean = 68.182, SD = 11.501), waist circumference (mean = 95.135, SD = 10.291), hip circumference (mean = 101.47, SD = 9.320), waist-to-hip ratio (mean = 0.940, SD = 0.0831), and neck circumference (mean = 34.85, SD = 2.445) were significantly higher in the obese group as compared to the lean group. Menstrual irregularity was significantly more common in the obese PCOS patients as compared to the lean PCOS group (p = 0.02). There was a significant difference (p < 0.05) between the obese and lean PCOS patients when the biochemical parameters like fasting insulin, fasting glucose, and homeostatic model assessment of insulin resistance (HOMA-IR) were compared. There is a strong link between obesity, insulin resistance, and PCOS. Obesity can exacerbate insulin resistance, a common feature of PCOS, leading to increased levels of insulin and androgens. Conclusion The demographic distribution of PCOS in relation to BMI is essential for tailoring interventions and treatments.

Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry

BackgroundPolycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case–control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes.ResultsThe study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m2). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10–12) and rs2228260 within XBP1 (P = 3.68 × 10–8). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10–6). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10–9) and a gene-based association was identified with ERBB4 (P = 1.59 × 10–6). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata.ConclusionsGenetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.

#187 : The Correlation Between Insulin Resistance with Serum Androgens Levels in Lean Women With and Without PCOS

Background and Aims: Polycystic Ovarian Syndrome (PCOS) is a multifactorial disease resulting from the interaction of multiple predisposing genetic variations and environmental factors. Insulin resistance and hyperinsulinemia contribute to hyperandrogenism and impaired gonadotropin secretion by reducing sex hormone binding globulin (SHBG) levels and increasing testosterone bioavailability. However, this insulin resistance is not always present in PCOS patients, especially in lean PCOS patients. This study aims to determine whether insulin resistance correlates with serum androgens levels. Method: We collected 25 samples from lean women with PCOS, and 25 samples from lean women without PCOS. Peripheral whole blood samples will be taken from all samples. Data collected include Anthropometric data, Hormonal profile (using ELISA method), and HOMA-IR value. Results: The result showed that median(min-max) ages for patients was 25(17-34) years. In lean women with PCOS, there was a positive relationship between HOMA-IR with FAI (p=0.017, r=0.472) and negative relationship with SHBG (p=0.001, r=-0.610). Also, in lean women without PCOS, there were no correlation between HOMA-IR with FAI, and HOMA-IR with SHBG (p&gt;0.05) Conclusion: This study shows that there was a correlation between insulin resistance and some serum androgens in lean women with PCOS, but there was no correlation between HOMA-IR with FAI, and HOMA-IR with SHBG in lean women without PCOS. Therefore, the results of this study are hoped to explain the correlation of insulin resistance with serum androgens in lean PCOS patients and can be the basis for further research to find the right solution for the treatment of PCOS patients.

Effect of hyperlipidemia on the outcome of in vitro fertilization in non-obese patients with polycystic ovary syndrome.

It is little known whether hyperlipidemia alone has adverse effects on the outcome of in vitro fertilization (IVF) in patients with polycystic ovarian syndrome (PCOS). The PCOS patients with body mass index (BMI) < 30 kg/m2 were performed IVF or intracytoplasmic sperm injection treatment, including 208 fresh cycles and 127 frozen embryo transfer (FET) cycles. All the patients were divided into hyperlipidemia and control groups, and embryo quality and pregnancy outcomes between the two groups were compared. In the fresh cycles, total gonadotropin dosage in the control group was significantly lower than that in the hyperlipidemia group, and serum estradiol levels on trigger day were reversed (P < 0.05). The embryo fragment score was positively correlated with serum low-density lipoprotein level (r = 0.06, P < 0.05) and negatively with serum high-density lipoprotein (HDL) and lipoprotein A levels (r = -0.489 and -0.085, P < 0.01). Logistic regression analysis found that HDL was beneficial for clinical pregnancy (OR = 0.355, 95% CI: 0.135-0.938, P < 0.05). In the FET cycles, there were no differences in pulse index, systolic/diastolic ratio and serum estradiol and progesterone levels between the two groups, but resistance index in the hyperlipidemia group was significantly higher than that in the control group (P < 0.05). Hyperlipidemia may increase the dosage of gonadotropin and have adverse effect on the embryo quality, endometrial receptivity, and clinical outcomes of lean PCOS patients. It is recommended that the non-obese patients with hyperlipidemia and PCOS perform lipid-lowering treatment before undergoing embryo transfer.

Effect of Dietary Regimen on the Development of Polycystic Ovary Syndrome: A Narrative Review.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 4%-20% of women worldwide. The pathogenesis of PCOS is still unconfirmed. Some risk factors for the disease are obesity, insulin resistance, genetic factors, and diet. Our aim is to review studies investigating the role of diet in the development of PCOS. We looked into studies published in different databases, such as PubMed, Scopus, Google Scholar, and Web of Science, using specific keywords as per our study topic. High-carbohydrate, high-fat diets, low-fiber diets, high glycemic index and glycemic load, and Western diets were associated with a higher risk of PCOS. Some vitamins, such as Vitamin D and B9, the Dietary Approaches to Stop Hypertension (DASH) diet, fruits, nuts, and seeds, such as pumpkin and sunflower, are associated with a lower risk of PCOS. The Alternate Healthy Eating Index-2010 (AHEI-2010) diet reduces the risk of hyperandrogenic or oligoanovulatory phenotypes. The review revealed that unhealthy diets encompass high levels of carbohydrates, animal proteins, fats, and processed foods. Despite inconsistent results from certain studies claiming no disparity in the dietary patterns between PCOS patients and healthy controls, the majority of researchers have amassed sufficient evidence linking nutrition to the incidence of PCOS. The review also underscores the significance of the interplay between genes and the environment in the prevalence of PCOS. Individuals possess a genetic predisposition to the condition from birth, and subsequent exposure to detrimental environmental factors, particularly diet and inactivity, trigger epigenetic changes that contribute to the development of the disorder. This study further illuminated the existence of the "lean PCOS" phenomenon, wherein roughly 20% of global PCOS cases exhibit clinical manifestations of the syndrome but maintain a normal or below-average weight. To sum up, the collective body of assessed research indicates that women with PCOS tend to share similar dietary habits, characterized by the consumption of numerous unhealthy foods such as processed foods, animal proteins, carbohydrates, and fats. While some studies present conflicting findings, these contradictions underscore the necessity for further investigation employing extensive cohorts.

Comparison of Central Fat Accumulation Indices with Body Mass Index in Women with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is an endocrinopathic disorder commonly affecting women in the reproductive age group, predisposing them to risk of metabolic syndrome. Currently, body mass index (BMI) is used as a marker to assess obesity. However, it is the central obesity which is a prevalent characteristic of PCOS which goes undetected in many women who exhibit an apparently lean PCOS. Recently, indices, such as body fat percentage (BFP), visceral adiposity index (VAI) and lipid accumulation product (LAP), have been deemed more effective, as they present formulas, anthropometric indices and biochemical measures. The aim of this study was to compare the other central fat accumulation indices-VAI, LAP and BFP with BMI in women with PCOS. The descriptive type of cross-sectional study was conducted in a tertiary care hospital which included 110 women, aged 18-40year fulfilling the Rotterdam criteria for diagnosis of polycystic ovary syndrome. Height, weight and lipid profile were measured, and BMI, LAP and VAI were calculated. Body fat percentage was measured by the body fat analyser using the bioelectrical impedance method. All indices were then compared. BMI showed a significant positive correlation with BFP (r = 0.68). VAI and LAP showed significant correlation with each other (p < 0.05). LAP and VAI were found to weakly correlate with BFP. However, lean PCOS also had higher values of visceral adiposity indices and hence did not show strong correlation. Central fat accumulation indices should be integral in assessing body fat distribution. BFP, VAI and LAP assess fat distribution and function both and, hence, present complete information at low cost.

Insulin level, lipid profile, and HOMA index in lean and obese patients with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a prevalent endocrinopathy characterized by insulin resistance, hyperinsulinemia, and increased ovarian androgen production. While obesity has been linked to the pathogenesis of PCOS, the condition is also observed in individuals with normal BMI. This cross-sectional study aimed to evaluate the biochemical profile of lean and obese patients with PCOS. Fifty female patients with previously diagnosed PCOS were included in the study, attending the outpatient clinic at AL-Zahraa Teaching Hospital in Al-Najaf between September 2021 and March 2022. Blood samples were collected from each patient to assess insulin levels, lipid profiles, and fasting blood sugar. The results showed a comparable percentage of lean and obese PCOS patients, with a slightly higher proportion of obese individuals. Statistically significant differences were observed in obese patients with higher fasting blood sugar levels, insulin, HDL cholesterol, and triglycerides. Additionally, the HOMA index, an indicator of insulin resistance, was higher in obese individuals. Lean PCOS patients exhibited metabolic, hormonal, and hematopoietic dysregulations comparable to or less pronounced than those affecting the obese phenotype. Regardless of BMI, insulin resistance is part of PCOS and must be treated immediately.

Obesity and hyperandrogenism are implicated with anxiety, depression and food cravings in women with polycystic ovary syndrome.

PCOS is associated with mood/eating disorders. Negative body image due to obesity, acne, hirsutism seems to play significant role, but hormonal derangements are probably implicated. To investigate the relation between insulin resistance (IR), obesity and hyperandrogenism with mood and eating disorders in women with PCOS. Forty-nine (60.5%) PCOS women and 32(39.5%) age- and BMI-matched healthy controls were enrolled. Emotional/food disorders were evaluated by using self-administered questionnaires: Eating Attitudes Test (EAT)-26, Beck Depression Inventory-II (BDI-II), Hamilton anxiety scale (HAS) and Food Craving Questionnaire-Trait (FCQ-T). The two groups had no significant differences regarding age, BMI and HOMA2-IR. PCOS women had significantly higher DHEA-S (p < 0.0001), Δ4Α (p < 0.0001) and Testosterone (p < 0.0001). When the two groups were subclassified according to the BMI, in lean (BMI < 25 kg/m2) or overweight (BMI ≥ 25 kg/m2), no significant differences were found with respect to EAT-26 and HAS. BDI-II was associated with obesity (overweight vs lean PCOS: 20.5 ± 6.4 vs 9.8 ± 3.9; p = 0.037) and hyperandrogenism (overweight PCOS vs overweight controls: 20.5 ± 6.4 vs 14.8 ± 8.1; p < 0.0001; lean PCOS vs overweight controls: 16.7 ± 4.7 vs 14.8 ± 8.1; p = 0.01). Additionally, a significant correlation between BDI-II and DHEA-S (rho = 0.305; p = 0.006), Δ4Α (rho = 0.259; p = 0.02) and Testosterone (rho = 0.328; p = 0.003) was reported. FCQ-T was associated with obesity (overweight PCOS vs lean PCOS: 47.6 ± 9.9 vs 29.3 ± 8.9; p < 0.0001; overweight controls vs lean PCOS: 45.5 ± 15.7 vs 29.3 ± 8.9; p < 0.0001), whereas a correlation between FCQ-T and BMI (rho = 0.593; p = 0.0001), waist circumference (rho = 0.554; p = 0.0001) and HOMA2-IR (rho = 0.328; p = 0.003) was documented. Obesity and hyperandrogenism increase the risk of depression and food cravings in women with PCOS, leading to a vicious circle of further aggravation of obesity and metabolic syndrome.

Obesity and PCOS radically alters the snRNA composition of follicular fluid extracellular vesicles.

The ovarian follicle consists of the oocyte, somatic cells, and follicular fluid (FF). Proper signalling between these compartments is required for optimal folliculogenesis. The association between polycystic ovarian syndrome (PCOS) and extracellular vesicular small non-coding RNAs (snRNAs) signatures in follicular fluid (FF) and how this relates to adiposity is unknown. The purpose of this study was to determine whether FF extracellular vesicle (FFEV)-derived snRNAs are differentially expressed (DE) between PCOS and non-PCOS subjects; and if these differences are vesicle-specific and/or adiposity-dependent. FF and granulosa cells (GC) were collected from 35 patients matched by demographic and stimulation parameters. FFEVs were isolated and snRNA libraries were constructed, sequenced, and analyzed. miRNAs were the most abundant biotype present, with specific enrichment in exosomes (EX), whereas in GCs long non-coding RNAs were the most abundant biotype. In obese PCOS vs. lean PCOS, pathway analysis revealed target genes involved in cell survival and apoptosis, leukocyte differentiation and migration, JAK/STAT, and MAPK signalling. In obese PCOS FFEVs were selectively enriched (FFEVs vs. GCs) for miRNAs targeting p53 signalling, cell survival and apoptosis, FOXO, Hippo, TNF, and MAPK signalling. We provide comprehensive profiling of snRNAs in FFEVs and GCs of PCOS and non-PCOS patients, highlighting the effect of adiposity on these findings. We hypothesize that the selective packaging and release of miRNAs specifically targeting anti-apoptotic genes into the FF may be an attempt by the follicle to reduce the apoptotic pressure of the GCs and stave off premature apoptosis of the follicle observed in PCOS.

ART outcomes in lean compared to obese phenotypes of polycystic ovarian syndrome.

To investigate differences in reproductive outcomes among IVF patients with lean compared to obese polycystic ovarian syndrome (PCOS) phenotypes. A retrospective cohort study of patients with PCOS who underwent IVF in a single, academically affiliated infertility center in the USA between December 2014 and July 2020. The diagnosis of PCOS was assigned based on Rotterdam criteria. Patients were designated as lean (< 25) or overweight/obese (≥ 25) PCOS phenotype based on BMI (kg/m2) at cycle start. Baseline clinical and endocrinologic laboratory panel, cycle characteristics, and reproductive outcomes were analyzed. The cumulative live birth rate included up to 6 consecutives cycles. A Cox proportional hazards model and Kaplan-Meier curve for estimating live birth rates were used to compare the two phenotypes. A total of 1395 patients who underwent 2348 IVF cycles were included. The mean (SD) BMI was 22.7 (2.4) in the lean and 33.8 (6.0) in the obese group (p < 0.001). A number of endocrinological parameters were similar between lean and obese phenotypes: total testosterone 30.8ng/dl (19.5) vs 34.1 (21.9), p > 0.02 and pre-cycle hemoglobin A1C 5.33% (0.38) vs 5.51% (0.51) p > 0.001, respectively. The CLBR was higher in those with a lean PCOS phenotype: 61.7% (373/604) vs 54.0% (764/1414) respectively. Miscarriage rates were significantly higher for O-PCOS patients (19.7% (214/1084) vs 14.5% (82/563) p < 0.001) and the rate of aneuploids was similar (43.5%, 43.8%, p = 0.8). A Kaplan-Meier curve estimating the proportion of patients with a live birth was higher in the lean group (log-rank test p = 0.013). After adjusting for potential confounders, the lean phenotype was associated with an increased hazard ratio for live birth: HR = 1.38 p < 0.001. Lean PCOS phenotype is associated with a significantly higher CLBR compared to their obese counterparts. Miscarriage rates were significantly higher among obese patients, despite comparable pre-cycle HBA1C and similar aneuploidy rates in patients who underwent PGT-A.

Leptin Inhibition Ameliorates Renal Mitochondrial Dysfunction And Associated Renal Injury In Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and polycystic ovaries. Renal injury, increased central adiposity and higher circulating levels of the adipokine leptin are common characteristics of PCOS. Leptin has direct renal fibrotic, hypertrophic, and albuminuric effects and can cause renal mitochondrial dysfunction and oxidative stress leading to chronic kidney disease development. Despite increased circulating leptin level in both lean and obese PCOS women, its role in PCOS-mediated renal damage remains unknown. In a well-characterized mouse model of PCOS, we aimed to test the hypothesis that hyperandrogenemia increases central adiposity leading to hyperleptinemia, which via leptin receptors induces intrarenal mitochondrial oxidative stress and dysfunction causing renal injury. Methods: Three-week-old peripubertal female mice were implanted with Silastic tubes filled with the non-aromatizable androgen dihydrotestosterone (DHT, 8 mg) or vehicle for 12 weeks. Eight weeks post-Silastic tubes implantation, the animals were treated with the leptin receptor antagonist (LepR-Ant) pegylated leptin (2 mg/kg, ip, 3x/week) for 4 weeks. Body weight, fat mass (EchoMRI), kidney weight (gravimetry), plasma leptin (ELISA), the glomerular filtration rate (GFR, transcutaneous fluorescence), as well as the renal injury markers urinary albumin to creatinine ratio (UACR, clinical chemistry analyzer), NGAL, and KIM1 (ELISA) were measured. Freshly isolated kidney mitochondria were used to measure mitochondrial reactive oxygen species (mtROS) by Amplex Red assay. Moreover, mitochondrial complex I and complex II-driven respiration and complex IV activity were assessed using Oroboros Fluorespirometer. Results: DHT significantly (p&lt;0.05) increased body weight (31.6 ± 2.3 vs. 23.6 ± 0.5 g), fat mass (3.5 ± 0.6 vs. 1.9 ± 0.4 g), kidney weight (365.6 ± 13.1 vs. 257.1 ± 3.7 mg), leptin (3.7-fold), UACR (1013.3 ± 56.4 vs. 658.9 ± 103.6 μg albumin/g creatinine), NGAL (6-fold), and KIM1 (3.7-fold). Moreover, PCOS mice had significantly (p&lt;0.05) lower GFR (1067.2 ± 59.9 vs. 1335.6 ± 60.3 uL/min/100g body weight), higher mtROS driven by complexes I (3.8 ± 0.8 vs. 2.0 ± 0.3 % electron leak) and III (8.0 ± 1.8 vs. 3.7 ± 0.9 % electron leak), as well as lower complexes I, II, and IV respiration (43-71%). The LepR-Ant had no effect on kidney weight or GFR; however, it abolished DHT-induced increases in body weight and fat mass. Excitingly, the LepR-Ant inhibited mtROS generation and completely restored complex I and II respiration, which was associated with a significant reduction in the urinary renal injury markers UACR, NGAL, and KIM-1 levels (40-60%, p&lt;0.05). Conclusion and significance: Our findings suggest that leptin via its receptor activation plays a significant role in the renal outcomes in PCOS by inducing mitochondrial dysfunction. Leptin receptor blockade could be a novel therapeutic approach to ameliorate renal injury in PCOS. Supported by NIH grants NIGMS P20GM121334 to KSE, LLYC, and DGR, NIGMS P20GM104357, NHLBI P01HL51971, and American Heart Association Predoctoral Fellowship 903804 (A.M.H.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Serum Phoenixin-14 levels of women with polycystic ovary syndrome increase proportionally with BMI.

This study aimed to compare serum PNX-14 values of women with PCOS classified as lean or overweight according to the BMI values. Fifty lean or overweight women diagnosed with PCOS according to the revised Rotterdam criteria were included in the study. They were divided into two groups according to their BMI values. Thirty patients with BMI values of 18.5-24.9 kg/m2 constituted the normal-weight PCOS group. Twenty patients with BMI values of 25-29.9 kg/m2 formed the overweight PCOS group. Thirty patients with regular menstrual cycles who did not exhibit clinical and laboratory findings of PCOS were selected as the control group. The patients in the control group were also divided into two different groups as normal weight (n=17) and overweight (n=13). In anovulatory PCOS group, blood samples were collected on the third day of progesterone withdrawal bleeding. Both in ovulatory PCOS and control groups, blood samples were collected on the third day of spontaneous menstrual cycle. In addition to basal hormonal parameters, serum phoenixin-14 concentrations were measured by enzyme-linked immunosorbent assay. LH values of the overweight or lean PCOS group were significantly higher than the overweight or lean non-PCOS group (p<0.01). The LH/FSH ratios of the lean and obese PCOS groups were significantly higher than the non-PCOS control group (p<0.01). Testosterone levels of both lean and obese PCOS groups were significantly higher than non-PCOS groups (p<0.02). The HOMA-IR value of the obese PCOS group was significantly higher than the lean PCOS group (p<0.03). The HOMA-IR values of the patients in the PCOS group were significantly higher than the non-PCOS controls. Phoenixin-14 levels of the obese PCOS group were approximately three times higher than the lean PCOS group (p<0.01). Phoenixin-14 levels of the obese non-PCOS group were also three times higher than the lean non-PCOS group (p<0.01). Serum Phoenixin-14 levels of patients in the lean PCOS group were significantly higher than in the lean non-PCOS group (9.11±2.09 pg/mL vs. 2.04±0.11 pg/mL, p<0.01). Serum Phoenixin-14 levels of the patients in the obese PCOS group were significantly higher than in the obese non-PCOS group (27.4±3.04 pg/mL vs. 6.44±1.09 pg/mL, p<0.01). A positive and significant correlation was found between serum PNX-14 levels and BMI, HOMA-IR, LH, and testosterone levels in both lean and obese PCOS patients. This study showed for the first time that serum PNX-14 levels are significantly increased in lean and obese PCOS patients. The increase in PNX-14 showed a proportional trend with BMI levels. Serum PNX-14 levels were correlated positively with serum LH, testosterone, and HOMA-IR.

The Efficacy of Metformin Treatment on Insulin Resistance and Hyperandrogenism in Lean Women with Polycystic Ovary Syndrome: A Literature Review

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in premenopausal women, characterized by insulin resistance and hyperandrogenism. Previous studies have investigated the use of metformin, a well-known insulin sensitizer, on lean PCOS patients, but it remains unclear as to how effective the treatment is. This literature review was carried out to better assess the effects of metformin on lean PCOS patients. Methods: Related literature was fully searched using MEDLINE, EMBASE, Web of Science, and COCHRANE for metformin therapy on lean women with PCOS (last updated May 2022). A review was performed to evaluate the effects of continued metformin treatment on relevant hormonal and metabolic indicators in these women. Results: A total of fourteen studies among 300 related articles were included in the review. Significant changes in total testosterone, sex hormone binding globulin (SHBG), blood insulin, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) were reported in majority of the studies. Several studies observed significant changes in Body Mass Index (BMI), luteinizing hormone (LH), and blood glucose. Nearly none of the studies assessed reported significant changes in follicle-stimulating hormone (FSH) and androstenedione. Discussion: Current literature around the efficacy of metformin treatment on lean PCOS patients remains unclear and uncertain. The majority of studies reviewed indicate that metformin treatment significantly ameliorated total testosterone, SHBG levels, and insulin resistance in lean patients with PCOS. However, the mechanisms and effects of metformin on other treatment outcomes in lean PCOS women is unclear. Conclusion: Metformin may be a putative treatment for lean PCOS women with significant insulin resistance and/or hyperandrogenism. More research involving larger sample sizes and a greater number of clinical outcomes is required.

Adipocytokines in polycystic ovary syndrome (PCOS): A systematic review and meta-analysis

&lt;abstract&gt; &lt;p&gt;The central tenet in PCOS is predicting the development of the development of metabolic syndrome is Insulin resistance (IR). Adipocytokines are hormones produced by adipose cells that help to regulate insulin secretion and resistance in the body. This study discusses the effect of different adipocytokines and their patterns (increased or reduced) in predicting insulin resistance in obese and lean PCOS patients. A systematic review and meta-analysis were performed which identified relevant studies from 2010 to 2020. Data was analyzed using Review Manager Version (RevMan) 5.4 software. A fixed-effect model was fitted to estimate the pooled effect of adipocytokines. I&lt;sup&gt;2&lt;/sup&gt; test statistics were done to test the heterogeneity of included studies. Of 17 selected studies with 1504 participants, there is considerably lower levels of adiponectin among women with PCOS as compared with healthy controls with mean difference of −3.79 (95% CI = 3.97–3.60, I&lt;sup&gt;2&lt;/sup&gt; = 73%; P = 0.005). In comparison to their healthy counterparts, leptin levels were shown to be higher in women with PCOS with mean difference of 3.64 (95% CI = 3.20–4.08, I&lt;sup&gt;2&lt;/sup&gt; = 97%; P = 0.00001). Leptin concentration was shown to be directly related to IR and BMI. After controlling for BMI and age-related effects, adiponectin levels appear to be lower in women with PCOS compared to non-PCOS controls but leptin levels appear to be higher. In conclusion, increased in adipocytokines such as leptin, visfatin and chemerin predict IR among both obese and lean PCOS whereas decreased levels of zinc-alpha2 glycoprotein predict IR. Adipocytokines can be potential predictive serum biomarkers of insulin resistance (IR) in PCOS.&lt;/p&gt; &lt;/abstract&gt;

Comparison of Endocrine and Metabolic Profile of Obese and Lean PCOS Women with Infertility

Comparison of Endocrine and Metabolic Profile of Obese and Lean PCOS Women with Infertility

PSUN123 Increased Expression of Insulin Signaling Intermediates After Six-Months Of Medical Care In Women With Obesity And Polycystic Ovary Syndrome

Abstract Background Recently an androgen-induced obesity-independent mechanism of insulin resistance in a mouse model mimicking lean polycystic ovary syndrome (PCOS) was discovered. To date there is little to no data on the mechanism of insulin resistance or molecular insulin signaling in adipose tissue of women with PCOS undergoing Vertical Sleeve Gastrectomy (VSG). Does the mechanism of androgen receptor (AR)-mediated regulation of insulin signaling seen in the lean PCOS mouse model occur in adipose tissue of women with obesity and PCOS? Objective We hypothesize that in women with obesity and PCOS, those with higher levels of free androgen index will display more dysregulation in the insulin signaling pathway in adipose tissue. More specifically, we believe that visceral more than subcutaneous adipose tissue in the women in the study will display more dysregulation; and lastly that VSG will alleviate insulin signaling dysregulation. Briefly, insulin activates insulin receptor (IR) which leads to activation of phospho-AKT which increases phosphorylated forkhead box 01 (p-FOXO1, gluconeogenesis regulation) and transcriptionally regulates acetyl co-A carboxylase (ACC, de novo lipogenesis (DNL) regulation). Methods This is a nested mechanistic study within a randomised controlled clinical trial. We performed molecular analyses (Western blots for protein and qPRC for mRNA expression, respectively, n = 3-4/group) exploring intermediates in the insulin signaling pathway (IR, p-AKT, p-FOXO1, and ACC) in (i) visceral and subcutaneous (SubQ) adipose tissue from women with obesity and PCOS before VSG bariatric surgery (n = 3/group); and (ii) SubQ WAT from women with obesity and PCOS at baseline and six-months after medical intervention with metformin (MTF) and lifestyle modification. Results Subcutaneous (SubQ) white adipose tissue (WAT) displayed similar levels of p-ACC compared to visceral WAT from women pre-VSG. Six months of medical care increased p-ACC in SubQ WAT by 5-fold compared to baseline. IR displayed similar expression in the visceral compared to SubQ WAT in women pre-VSG. IR expression increased by 20-fold at 6-months of medical care compared to baseline in SubQ WAT. p-FOXO1 displayed similar expression in the visceral compared to SubQ WAT. However, p-FOXO1 was decreased at 6-months of medical care compared to baseline. p-AKT levels were similar in visceral compared to SubQ WAT pre-VSG. However, p-AKT levels were significantly increased by 4-fold at 6-months of medical care compared to baseline. Conclusion None of the insulin signaling intermediates measured were different in visceral compared to SubQ in women with obesity and PCOS. Additionally, the findings indicated lowered DNL, lowered regulation of gluconeogenic genes and thus lowered gluconeogenesis, and increased insulin action in SubQ WAT in women with obesity and PCOS after 6-months of medical care. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Evaluation Of Oxidative Stress And Its Association With Pro-Inflammatory Cytokines In Obese, And Non-Obese PCOS Subjects

Introduction: Polycystic ovarian syndrome (PCOS) is a common endocrinological disorder of reproductive age female. The etiology of PCOS is not completely understood. Several publications nowadays demonstrate the relationship between chronic low-grade inflammation and mitochondrial dysfunctions induced by oxidative stress.&#x0D; Methods: This hospital based cross-sectional study, was conducted among reproductive age females. The study includes 73 obese PCOS, 55 Lean PCOS subjects and 15 non-obese PCOS subjects on the basis on transvaginal sonography and BMI. The anthropometric parameters were: BMI, Waist Hip Ratio (WHR), systolic and diastolic blood pressure by sphygmomanometer. Serum samples were collected to measure: oxidative stress (MDA), lipid profile, and pro-inflammatory cytokines (HsCRP, IL-6, IL-18 &amp; TNF-α).&#x0D; Results: The BMI and MDA levels were significant in obese-PCOS and lean PCOS group (p &lt;0.001). Whereas, in the obese-PCOS and non-PCOS obese group MDA, triglycerides, HDL, VLDL, IL-6, IL-18, and TNF-α were significant respectively.&#x0D; Conclusion: It concluded from this study that obesity may contribute to dyslipidemia and elevated oxidative stress levels in reproductive age females irrespective of PCOS. Therefore, obesity in addition to known features such as dyslipidemia, hypertension and disturbed oxidative stress response, may be contributing factors to increase the risk of future cardiovascular diseases in obese women.

PRENATAL ANDROGEN EXPOSURE IN MICE LEADS TO A METABOLICALLY DISTINCT PCOS WITHOUT OBESITY

Our objective was to elucidate the mechanisms of glucose metabolism in a lean polycystic ovary syndrome (PCOS) mouse model.