Lean Polycystic Ovary Syndrome Women Research Articles

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<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<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<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.

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.

The Associations Between Alanine Aminotransferase and Other Biochemical Parameters in Lean PCOS

To explore the associations of alanine aminotransferase in lean women of polycystic ovary syndrome (PCOS) with other biochemical parameters and the potential risk factors. This is a retrospective cohort study with lean PCOS (n = 91) and healthy controls (n = 45); we reviewed the electrical records and databases of the PCOS patients in our infertility clinic between January 2019 and September 2021; independent t-test, linear correlation analysis, and multiple linear regression were used to explore the associations. Higher levels of luteinizing hormone, total testosterone, thyroid stimulating hormone, platelet count, lymphocyte count, homocysteine, alanine aminotransferase (ALT), and uric acid were identified in lean PCOS patients, while follicle-stimulating hormone level was lower in in lean PCOS as expected (P < 0.05). Of note, the linear correlation showed that BMI, total testosterone, white blood cell count, lymphocyte count, aspartate aminotransferase, and uric acid were positively associated with alanine aminotransferase (r = 0.232, 0.318, 0.218, 0.388, 0.602, 0.353 respectively, P < 0.05). After multiple linear regression was performed, total testosterone and aspartate aminotransferase were independently and positively correlated with alanine aminotransferase in lean PCOS (B = 0.251, 0.605 respectively, P < 0.05). Higher level of ALT was identified in the lean PCOS. BMI, white blood cell count, lymphocyte count, aspartate aminotransferase, uric acid, and total testosterone were positively correlated with ALT in lean PCOS. Total testosterone and aspartate aminotransferase were independently and positively associated with ALT in lean PCOS after multiple linear regression. There might exist a potential risk of afflicting liver impairment for the lean PCOS women in the earlier period. Early examination and intervention might be necessary to prevent or delay the progression of the liver disease as soon as the diagnosis of PCOS.

Assessment of clinical, biochemical, and hormonal profile of lean versus overweight polycystic ovarian syndrome patients: A cross-sectional study

Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder having escalation in its prevalence. This study was planned to understand the clinical, biochemical, and hormonal profile of lean versus overweight patients diagnosed newly with PCOS. Materials and Methods: A cross-sectional study was conducted for 1 year in the Department of Endocrinology of a tertiary care hospital. A total of 50 female patients newly diagnosed to have PCOS by the Rotterdam criteria 2003 were enrolled for the study. Assessment of clinical characteristics, biochemical, and hormonal profile was done. Results: Fasting serum insulin levels and homeostasis model assessment-insulin resistance signifying insulin resistance were higher in overweight compared to the lean PCOS. Insulin resistance was present in 50% of lean PCOS and 82% of overweight PCOS. Glucose abnormalities were noted in 13.7% of lean PCOS and 32.2% of overweight PCOS. Conclusion: Obese women with PCOS have a higher risk of increased obesity, impaired glucose tolerance, and insulin resistance as compared to lean PCOS women.

Serum pregnancy-associated placental protein-a (PAPP-A) levels are increased in polycystic ovary syndrome (PCOS) in women with oligo-anovulation

Background/Aim: Pregnancy associated placental protein-A (PAPP-A) is a zinc-binding metalloproteinase with a key role in insulin like growth factor (IGF) pathway, and potential atherogenic effects. There is little information in the literature regarding PAPP-A levels in Polycystic ovary syndrome (PCOS). We aimed to investigate the serum PAPP-A levels among non-obese women with PCOS as a cardiovascular risk marker. Methods: Non-obese women of reproductive age (18-35 years of age) diagnosed with PCOS according to Rotterdam Consensus Conference criteria were included in this case-control study. Serum PAPP-A levels were compared with independent samples t-test between two main groups (PCOS and control) and investigated in PCOS subgroups as PCOS patients were further classified according to main phenotypes (hyperandrogenism and oligo-anovulation). Results: A total of 41 women with PCOS and 40 age- and body mass index- matched controls were included in the analysis. The serum PAPP-A levels of the control and PCOS groups, and of PCOS patients with hyperandrogenism were similar (P=0.128, P=0.261, respectively). However, the serum PAPP-A levels of those with oligo-anovulation was higher than those without (P=0.006), and that of women without oligo-anovulation was comparable to that of the control group (P=0.613). Conclusion: Lean and young PCOS women with oligo-anovulation had increased serum levels of PAPP-A when compared to women without. Prospective studies are needed to uncover the long-term cardiovascular risk of elevated PAPP-A levels in PCOS women with oligo-anovulation.

Comparison of serum adiponectin and osteopontin levels along with metabolic risk factors between obese and lean women with and without PCOS.

The objective of this study was to investigate the possible relation between serum adiponectin and osteopontin levels as metabolic risk markers among women with different polycystic ovary syndrome (PCOS) phenotypes. In a University Hospital setting PCOS patients diagnosed according to Rotterdam Consensus Conference criteria with body mass index (BMI) between 18 and 35 were recruited. Overall, 57 PCOS patients and 57 age- and BMI-matched healthy controls were included in the study. Luteinising hormone (LH) to follicle-stimulating hormone FSH ratio (LH/FSH), free androgen index (FAI), and dehydroepiandrosterone sulphate (DHEAS-S) was found to be significantly higher in women with PCOS. There was significant interaction between PCOS status and obesity for serum adiponectin levels. Although mean adiponectin and osteopontin levels were similar among cases and controls, a further two-way ANOVA comparison within lean and obese subgroups revealed adiponectin to be significantly lower in lean PCOS women than in lean controls. LH/FSH ratio and adiponectin levels were all found to differ between lean counterparts; however, they did not show any correlation with metabolic markers [cholesterol, homeostatic model assessment (HOMA) or C-reactive protein (CRP) levels] in overall lean women or in the lean PCOS subgroup. Serum adiponectin levels in lean PCOS women were significantly lower than those in lean controls. On the other hand, mean adiponectin and osteopontin levels were similar in PCOS cases and controls overall.

Metabolomic biomarkers of polycystic ovary syndrome related-obesity: a review of the literature

Abstract Background and objectives: Polycystic ovary syndrome (PCOS) displays a phenotype-dependent cardio-metabolic risk. By performing a systematic search of the literature, we aimed to summarize metabolomic signatures associated with obesity in PCOS women. Data sources and study eligibility criteria: We conducted a comprehensive search including: Embase, PubMed, and Web of Science until 31st of May 2019. We used the terms: metabolomics and polycystic ovary syndrome. We excluded the following papers: animal studies, studies that included only lean PCOS women, reviews, meta-analyses, results of interventional studies, those that did not apply metabolomic techniques. Results: The lipid signature in obese women with PCOS showed increased levels of free fatty acids (carnitine, adipic acid, linoleic acid, oleic acid) and lower levels of lysophosphatidylcholines and glycerolphosphocholine compared with non-obese PCOS women. Regarding carbohydrate metabolism, a decrease in citric and lactic acid levels characterized obese PCOS women. Decreased lactic acid in obese PCOS women suggests augmented insulin stimulated glucose muscle use in lean, but not in obese women. Considering amino acid metabolomic markers, valine, glycine, serine, threonine, isoleucine and lysine were higher in obese PCOS women. Patients with visceral obesity presented a diminished uptake of essential amino acids, BCAA, leucine and serine in the skeletal muscle. α-ketoglutarate was significantly higher in obese women with PCOS in comparison with lean women with PCOS, distinguishing these 2 subgroups of PCOS with high ‘predictive accuracy’. Limitations: Overall, a small number of studies have focused on the impact of obesity on the metabolic fingerprints of PCOS women. There is need for properly controlled, high-quality studies. Conclusions: There is compelling evidence of significant alterations in carbohydrate, lipid, and amino acid metabolism in women with PCOS and obesity. Metabolomics may identify new metabolic pathways involved in PCOS and improve our understanding of the complex relation between PCOS and obesity in order to personalize PCOS therapy.

Insulin resistance, androgens, and lipids are gradually improved in an age-dependent manner in lean women with polycystic ovary syndrome: insights from a large Caucasian cohort.

Polycystic ovary syndrome (PCOS), considered a lifelong condition, manifests mainly as a cluster of hyperandrogenic symptoms during the early reproductive years, with the affected woman gradually developing an adverse cardiometabolic profile over the years. However, some data point to the possibility of differences in the evolution of PCOS according to a woman's weight. The aim of the present study was to evaluate the metabolic and hormonal profiles of women with PCOS over time. A total of 763 lean women with PCOS (BMI 20-25kg/m2) and 376 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. All subjects were assessed clinically, biochemically, and hormonally. Waist circumference, lipids, androgens, and insulin resistance index (homeostasis model assessment of IR index (HOMA-IR)) were significantly higher in the PCOS group compared with controls. Age subgroup analysis showed a progressive decrease of HOMA-IR and waist circumference, and lipid levels were comparable between PCOS and controls in all age groups. Androgens remained significantly higher in PCOS, but they gradually decreased through time. A significant negative association of age with waist circumference, androgens, insulin, and HOMA-IR was revealed. Univariate and multivariate regression analysis disclosed a strong correlation of HOMA-IR with age (p = 0.014, β - 0.19, SE coefficient 0.008) as a single parameter or in combination with total cholesterol (TC) (p < 0.001, age: β - 0.023, SE 0.10; TC: β 0.084, SE 0.027). Insulin resistance, androgens, and lipids are gradually improved in an age-dependent manner in lean PCOS women. We hypothesize that if these women do not gain weight with the passage of time, there is a high probability that their cardiometabolic risk will be attenuated.

Prevalence of hyperandrogenism in Iraqi women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a mainly common endocrine disorder. Hyperandrogenism is the major standard in the diagnosisof PCOS development.Eighty women diagnosed with PCOS and twenty healthy women(aged 20-40 years)were enrolled in this study which was conducted at the infertility clinic of Kamal AL-Samaraay Hospital/ Baghdad. The diagnosis of PCOS was made according to the Rotterdam criteria. Body mass index (BMI, Kg/m2)was calculated by a specific formula. History of menstrual irregularity, hirsutism, acne, and alopecia was taken. Hormone levels in serum, namely luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone were measured in all patients and control subjects.There was a statistically significant difference (P &lt;0.05) in the BMI between the PCOS and control women.Also, the prevalence of overweight and obesity was much higher in PCOS women than in their matching control. The serum levels of LH, FSH, and testosterone were significantly different (P &lt;0.05) in PCOS as compared to healthy women. Clinical hyperandrogenism (hirsutism and alopecia) were present in most of PCOS women, while acne wasa less useful clinical sign of hyperandrogenism.Inaddition, the prevalence of hirsutism and alopecia was increased in obese when compared with overweight and lean PCOS women.

Effects of Metformin Treatment on Soluble Leptin Receptor Levels in Women with Polycystic Ovary Syndrome

The effects of metformin treatment on soluble leptin receptor (sOB-R) levels in women with polycystic ovary syndrome (PCOS) were investigated. This prospective and open-label study was conducted by the Department of Obstetrics & Gynecology at Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, China. Fifty-five women with PCOS and insulin resistance (IR) were treated with metformin for 6 months. According to body mass index (BMI), the patients were divided into two groups: lean PCOS group (BMI <23 kg/m2, n=34) and overweight or obese PCOS group (BMI ≥23 kg/m2, n=21). Before and after treatment, serum luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), androstenedione (A), dehydroepiandrosterone sulfate (DHEAS), insulin and sOB-R levels were determined. Thirty-one BMI-matched ovulatory women served as controls. The results showed: (1) The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), androgen levels and hirsutism scores were higher, and sOB-R levels were lower in PCOS groups than in control group. A subgroup analysis of lean and overweight or obese PCOS patients revealed there was significant difference in sOB-R level between lean PCOS group and overweight or obese PCOS group. There were no significant differences in anthropometric parameters between lean PCOS patients and BMI-matched controls. However, sOB-R level was significantly lower in lean PCOS women than in controls. (2) There was no correlation between sOB-R level and BMI, waist and hip circumference, total testosterone, androstendione, DHEAS, LH or hirsutism scores in PCOS patients, but there was a significant negative correlation between sOB-R and HOMA-IR. (3) After treatment with metformin for 6 months, serum insulin levels decreased, and sOB-R levels increased significantly (P<0.01). It was suggested that considering low sOB-R levels supposedly compensate diminished leptin action, PCOS per se might cause leptin resistance. It is likely that reduction of hyperinsulinemia produced by metformin effectively improves the sOB-R levels in PCOS.

OR33-1 Metabolic Inflexibility in Obese versus Lean Women with Polycystic Ovary Syndrome (PCOS): Is PCOS Status or Adiposity the Critical Factor?

Metabolic flexibility reflects the ability to switch from lipid to carbohydrate oxidation during insulin stimulation manifested in increased respiratory quotient (∆RQ). Obese adolescent girls with PCOS have metabolic inflexibility compared with their non-PCOS obese peers (JCEM 2018, PMID 29220530). To examine if metabolic inflexibility is also present in lean PCOS or is unique to obese PCOS, we investigated metabolic flexibility in lean and obese women (ages 18-42 yrs.) with PCOS. Data in 24 obese (body mass index, BMI 33.4 ± 4.7 [SD] kg/m2) and 15 lean (BMI 22.7 ± 2.0 kg/m2) PCOS women (diagnosed by the Rotterdam criteria), and 14 obese (BMI 32.5 ± 5.0 kg/m2) and 16 lean (22.9 ± 1.4 kg/m2) control women without PCOS were examined. RQ and lipid oxidation, by indirect calorimetry, were analyzed at fasting and during a hyperinsulinemic-euglycemic clamp. The relationship between metabolic flexibility (assessed as ∆RQ from fasting to hyperinsulinemia) and clamp insulin sensitivity (IS), sex hormones, C-reactive protein (CRP), BMI and leptin concentrations was evaluated. Despite similar BMI and leptin levels, obese PCOS women had lower ∆RQ compared with obese control women (0.07 ± 0.04 vs. 0.11 ± 0.04, p< 0.0001). However, ∆RQ was not different between obese and lean PCOS women, nor was fasting lipid oxidation and suppression in lipid oxidation during hyperinsulinemia. Insulin sensitivity was lower (3.9 ± 1.4 vs. 7.4 ± 2.6 mg/Kg/min per mU/L, p< 0.0001), and CRP and leptin concentrations were higher in obese PCOS vs. lean PCOS (3.34 ± 1.87 vs. 1.29 ± 1.18 mg/L; and 33.6 ± 11.0 vs. 12.4 ± 8.5 ng/L, respectively, all p< 0.05). In the total cohort, ∆RQ correlated with free androgen index (r = -0.359), androstenedione (r = -0.271), and IS (r = 0.452) (all p< 0.05). Multiple regression analysis in the total cohort revealed that the best predictor of metabolic flexibility was PCOS status (partial r = -0.243, p= 0.05) independent of BMI and age. In PCOS women, IS (partial r = 0.503, p= 0.002) and baseline RQ (partial r = -0.489, p= 0.003) explained 46% of the variance in metabolic flexibility with no significant effect of BMI and age. Findings were similar in non-PCOS women (model R2 = 0.750, p= 0.001). Replacing BMI with leptin in the models for PCOS or control women did not change the results. In conclusion, our data suggest that PCOS status, rather than adiposity plays a role in the metabolic inflexibility observed in women with PCOS. It remains to be determined if the lack of a difference in metabolic inflexibility between obese and lean PCOS women applies across the lifespan and holds true in adolescents too, or if metabolic flexibility differs early in the course of PCOS between obese and lean adolescents, but the difference fades as they get older and enter womanhood. Sources of Research Support: Juselius Foundation and Academy of Finland

Reproductive and Behavior Dysfunction Induced by Maternal Androgen Exposure and Obesity Is Likely Not Gut Microbiome-Mediated.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder of unclear etiology in women and is characterized by androgen excess, insulin resistance, and mood disorders. The gut microbiome is known to influence conditions closely related with PCOS, and several recent studies have observed changes in the stool microbiome of women with PCOS. The mechanism by which the gut microbiome interacts with PCOS is still unknown.We used a mouse model to investigate if diet-induced maternal obesity and maternal DHT exposure, mimicking the lean and obese PCOS women, cause lasting changes in the gut microbiome of offspring. Fecal microbiome profiles were assessed using Illumina paired-end sequencing of 16S rRNA gene V4 amplicons.We found sex-specific effects of maternal and offspring diet, and maternal DHT exposure on fecal bacterial richness and taxonomic composition. Female offspring exposed to maternal obesity and DHT displayed reproductive dysfunction and anxietylike behavior. Fecal microbiota transplantation from DHT and diet-induced obesity exposed female offspring to wild-type mice did not transfer reproductive dysfunction and did not cause the expected increase in anxietylike behavior in recipients.Maternal obesity and androgen exposure affect the gut microbiome of offspring, but the disrupted estrous cycles and anxietylike behavior are likely not microbiome-mediated.

Elevated PAPP-A levels in lean patients with polycystic ovary syndrome

ObjectivesThis study aimed to evaluate the serum concentrations of PAPP-A (pregnancy associated placental protein-A), a biomarker which is associated with cardiovascular disease, in patients with polycystic ovary syndrome (PCOS). Materials and MethodsA total of 62 women with PCOS, and 68 age and body mass index (BMI) matched controls were eligible for the study. Hirsutism scores, hormonal and metabolic profile as well as PAPP-A levels were assessed in each subject. ResultsWomen with PCOS and controls yielded similar median serum levels of PAPP-A (1.7 ng/ml versus 1.8 ng/ml, respectively, p = 0.328). However, when patients were compared based on BMI; subgroup analyses found that among women with BMI<27 kg/m2, patients with PCOS exhibited higher PAPP-A levels than controls (2.1 ng/ml versus 1.8 ng/ml, respectively, p = 0.018). When women with PCOS were evaluated in their own based on BMI, lean PCOS women showed higher levels of PAPP-A (2.1 ng/ml versus 1.5 ng/ml, p = 0.002). PAPP-A levels were negatively correlated with age (p = 0.031, r = −0.189), BMI (p = 0.002, r = −0.265) and triglyceride levels (p < 0.001, r = −0.3). ConclusionThe data of the present study suggested that PAPP-A might be a clinical indicator in PCOS, in which the risks of metabolic syndrome and cardiovascular event are increased. Especially a group of young patients with BMI <27 kg/m2 might benefit from the cardiovascular risk evaluation using PAPP-A, supplying prognostic information for high risk in the development of cardiovascular disease.

Serum adipokine (apelin) in lean and obese polycystic ovary syndrome patients before and after metformin treatment

Abstract Background Polycystic ovary syndrome (PCOS) is a common disorder in the childbearing period. Apelin is a regulator of glucose metabolism and is associated with insulin resistance (IR). Metformin is used in PCOS, but its effects on serum apelin in PCOS patients are unknown. Aim To compare serum apelin levels in lean and obese PCOS women and to evaluate the effects of metformin treatment on serum apelin levels, clinical and metabolic parameters, and hormone profile in these patients. Methods A prospective interventional study involving 59 PCOS patients (38 obese and 21 lean) was conducted. Body mass index (BMI), serum apelin, glucose, insulin, FSH, LH and testosterone levels were measured, and HOMA-IR was calculated before and after six months of metformin treatment. Results Significantly higher BMI and serum apelin (P Conclusion Serum apelin levels were higher in obese than lean PCOS patients. Metformin treatment improved insulin sensitivity and decreased serum apelin, LH and testosterone levels in both groups; lean PCOS patients showed better response to metformin treatment.

Circulating Levels of Vitamin D3 and Leptin in Lean Infertile Women with Polycystic Ovary Syndrome.

Objective:The objective of this study is to measure levels of Vitamin D3 and leptin and assess their relation of each to the pathogenesis of polycystic ovary syndrome (PCOS).Design:This was a cohort observational study.Settings:This study was conducted at the Department of Obstetrics and Gynecology, Tanta University.Materials and Methods:Ninety lean women were enrolled in this study and were allocated into two groups with 45 patients in each group: the first group (study group) who are lean women with PCOS and the second group (control group) who are the lean infertile patients without PCOS. Blood samples were collected and tested for study parameters.Results:There were no significant differences regarding demographic characteristics between both groups. The differences were in ovarian volume and hormonal profiles. Serum leptin was found to be significantly increased in lean PCOS than in control groups. Vitamin D3 levels were found to be lower in the lean PCOS group than in control group.Conclusion:Lean PCOS women are a unique group with specific hormonal profiles different from the typical PCOS profiles. Leptin and Vitamin D3 may have a role in the pathogenesis of lean PCOS, but large studies are still required regarding this unique group.

Women with polycystic ovary syndrome demonstrate worsening markers of cardiovascular risk over the short-term despite declining hyperandrogenaemia: Results of a longitudinal study with community controls.

To compare age-associated changes in cardiovascular risk markers in lean and obese reproductive-aged women with polycystic ovary syndrome (PCOS) with community controls. Longitudinal study at an academic medical centre PATIENTS: Patients diagnosed with PCOS by 2004 Rotterdam criteria in a multidisciplinary clinic were systematically enrolled from 2006-2014 in a PCOS cohort study and subsequently agreed to participate in a longitudinal study. The comparison controls were from the prospective, longitudinal Ovarian Aging (OVA) study, which consists of healthy women with regular menstrual cycles recruited from 2006 to 2011. Cardiovascular risk markers and hormone parameters at baseline and follow-up. Obese and lean PCOS (n=38) and control women (n=296) completed two study visits. The follow-up time (3.5±1.5 vs 4.0±0.8years, P=.06) and magnitude of BMI gain (+0.1kg/m2 /y [-0.11, 0.36] vs +0.26 [-0.18, 0.87] P=.19) did not differ between obese and lean PCOS and controls. In PCOS subjects, total testosterone decreased in both obese and lean, but the decrease was greater in obese subjects (-0.09nmol/L per year; 95% CI: -0.16, -0.02 vs -0.04nmol/L per year; 95%CI: -0.11, 0.03). Compared to their respective controls, obese and lean PCOS saw worsening triglyceride (TG) levels (P<.05) and HOMA-IR (P<.05) over time, but there was no difference in change in LDL, HDL, fasting glucose, C-reactive protein or ALT. In a longitudinal study, reproductive-aged women with PCOS demonstrated declines in biochemical hyperandrogenaemia over time. Despite this, PCOS subjects experienced steeper increases in cardiovascular risk factors associated with insulin resistance, including triglycerides and HOMA-IR.

Early miscarriage rate in lean polycystic ovary syndrome women after euploid embryo transfer – a matched-pair study

The early miscarriage rate is reported to be higher in patients with polycystic ovary syndrome (PCOS) compared with non-PCOS patients. However, whether PCOS is an independent risk factor for early miscarriage is still controversial; to what extent embryonic aneuploidy accounts for miscarriages of PCOS is still unknown. In this 1:3 matched-pair study, 67 lean PCOS patients and 201 controls matched for age, body mass index (BMI) and embryo scores undergoing a single euploid blastocyst transfer in vitrified-warmed cycles were analysed. Clinical pregnancy, early miscarriage and live birth rates were compared. Logistic regression analysis was performed to further evaluate the factors associated with early miscarriage and live birth. Clinical pregnancy rates were 50.7% in PCOS and 55.2% in control groups. Early miscarriage rate was significantly (P = 0.029) increased in the PCOS group compared with controls; non-PCOS patients had a significantly higher live birth rate than PCOS patients, P < 0.001. Further regression analyses showed that PCOS was significantly associated with a higher risk of early miscarriage and decreased chance of live birth. In conclusion, PCOS in women undergoing pre-implantation genetic diagnosis may, independently from BMI and karyotype, increase the risk of miscarriage.

Distinct response of fat and gastrointestinal tissue to glucose in gestational diabetes mellitus and polycystic ovary syndrome.

Gestational diabetes mellitus (GDM) and polycystic ovary syndrome (PCOS) are distinct pathologies with impaired insulin sensitivity as a common feature. The aim of this study was to evaluate the response of fat tissue adipokines and gastrointestinal incretins to glucose load in patients diagnosed with one of the two disorders and to compare it with healthy controls. Oral glucose tolerance test (oGTT) was performed in 77 lean young women: 22 had positive history of GDM, 19 were PCOS patients, and 36 were healthy controls. Hormones were evaluated in fasting and in 60 min intervals during the 3 h oGTT using Bio-Plex ProHuman Diabetes 10-Plex Assay for C-peptide, ghrelin, GIP, GLP1, glucagon, insulin, leptin, total PAI1, resistin, visfatin and Bio-Plex ProHuman Diabetes Adipsin and Adiponectin Assays (Bio-Rad). Despite lean body composition, both PCOS and GDM women were more insulin resistant than controls. Significant postchallenge differences between the GDM and PCOS groups were observed in secretion of adipsin, leptin, glucagon, visfatin, ghrelin, GIP, and also GLP1 with higher levels in GDM. Conversely, PCOS was associated with the highest resistin, C-peptide, and PAI1 levels. Our data suggest that decreased insulin sensitivity observed in lean women with GDM and PCOS is associated with distinct hormonal response of fat and gastrointestinal tissue to glucose load.

Microvascular endothelial function in lean versus obese women with polycystic ovary syndrome: role of the endothelin B receptor

Polycystic ovary syndrome (PCOS) affects 10% of women and is associated with myriad cardiovascular risk factors, including obesity and endothelial dysfunction. PCOS is also associated with elevated levels of plasma endothelin‐1 (ET‐1), one of several circulating indicators of endothelial injury and dysfunction. Women with PCOS have reduced vasodilatory responses to ET‐1 as mediated through the endothelin receptor subtype B (ETBR). We hypothesized that impairments in ETBR‐dependent and independent vasodilation are more severe in obese than in lean women with PCOS. We tested 3 lean (age 30 ± 6 y; BMI 23 ± 1 kg/m2) and 3 obese (33 ± 5 y; 36 ± 4 kg/m2) women diagnosed with PCOS according to the Rotterdam criteria. We assessed cutaneous vascular conductance (CVC) with laser Doppler flowmetry during intradermal microdialysis perfusions of ET‐1 (1, 3, 4, 5, and 7 pmol) with either lactated Ringer's solution, ETBR inhibition (BQ‐788), or nitric oxide inhibition (L‐NMMA). Dose‐response curves (%CVCmax) as a function of the log concentration of ET‐1 demonstrated reduced vasodilatory responses in lean PCOS (logEC50 0.61 ± 0.07) relative to obese PCOS (logEC50 0.52 ± 0.47). Inhibition of ETBR decreased the ET‐1‐induced vasodilation in both lean (i.e., logEC50 0.66 ± 0.11) and obese (logEC50 0.62 ± 0.21) groups. Contrary to our hypothesis, this inhibition was two‐fold greater in obese PCOS women, indicating a greater role for ETBR‐induced vasodilation under basal conditions relative to lean PCOS. Conversely, nitric oxide inhibition had little effect in either lean (logEC50 0.61 ± 0.32) or obese PCOS women (logEC50 0.54 ± 0.18) compared to ET‐1 alone. Our data suggest that impairments to endothelial function are more severe in lean than obese women with PCOS, and that ETBR plays an important role in this potentially adverse cardiovascular outcome.Support or Funding InformationSupported by The John B. Pierce Laboratory and the American Heart Association (15POST24990003).

Assessment of circulating betatrophin concentrations in lean glucose-tolerant women with polycystic ovary syndrome

The aims of the current study were to investigate the betatrophin levels in lean glucose-tolerant women with polycystic ovary syndrome (PCOS), and to explore the relationships between these levels and antropometric, hormonal and metabolic parameters. The study population consisted of 50 lean (body mass index [BMI] < 25 kg/m2) women diagnosed with PCOS using the Rotterdam criteria, and 60 age- and BMI-matched healthy controls without any features of clinical or biochemical hyperandrogenism. Before recruitment, glucose tolerance was evaluated in all of the subjects using the 2-h 75 g oral glucose-tolerance test, and only those exhibiting normal glucose tolerance were enrolled. Serum betatrophin levels were significantly higher in women with PCOS (median 322.3; range 44.7–1989.3 ng/L) compared to the controls (median 199.9; range 6.2–1912.9 ng/L; p = .005). In the control group, no significant correlation was evident between betatrophin levels and clinical or biochemical parameters. In the PCOS group, betatrophin levels were positively correlated with prolactin levels (r = .286, p = .046) and negatively correlated with BMI (r = −.283, p = .049), waist/hip ratio (r = −.324, p = .023), and low-density lipoprotein cholesterol levels (r = −.385, p = .006).Impact statementWhat is already known on this subject: Several studies have suggested that primary alteration in beta-cell function is a pathophysiological feature of PCOS, and insulin resistance is the most significant predictor of beta-cell dysfunction independent of obesity.Betatrophin is a circulating protein that is primarily expressed in the liver in humans. Early experimental investigations demonstrated that overexpression of betatrophin significantly promoted pancreatic beta-cell proliferation, insulin production and improved glucose tolerance. Few studies have investigated the association between PCOS and betatrophin. However, in contrast to our study, the authors included overweight/obese patients and glucose tolerance was not evaluated before recruitment.What the results of this study add: Our results showed that serum betatrophin levels were significantly higher in lean glucose-tolerant PCOS women than in age- and BMI-matched healthy controls.What are the implications of these findings for clinical practice and/or further research: Elevated betatrophin levels in PCOS women, in the absence of obesity and glucose intolerance, may reflect a compensatory mechanism in order to counteract metabolic syndrome-related risk factors.