Metabolic health and quality of life in patients with Polycystic Ovary Syndrome: a cross-sectional study.

Polycystic ovary syndrome (PCOS), affecting 5-15% of women of reproductive age globally, is linked to metabolic complications such as insulin resistance, obesity, and non-alcoholic fatty liver disease. While metformin helps manage PCOS, reliable biomarkers for monitoring treatment response are lacking. Fetuin-B, a liver-derived protein, has emerged as a potential candidate, as previous studies have shown increased fetuin-B levels in women with PCOS. This study examined whether serum fetuin-B levels correlated with metabolic improvements in PCOS patients undergoing metformin therapy, exploring its potential as a biomarker. PCOS patients from the Fertility Center at the University Medical Center Mainz were assigned to two groups: metformin therapy (M-group) and alternative/no treatment (C-group), based on their metabolic profiles. Baseline and 24-week follow-up assessments included gonadotropins and reproductive hormone levels, metabolic markers (such as lipid profile, hepatic markers, fasting and stimulated glucose levels, and the respective derived indices), and anthropometric data, including fetuin-B. A multivariate regression analysis evaluated associations between metabolic changes and fetuin-B levels. A total of 62 PCOS patients were included (31 per group). At baseline, the M-group exhibited worse metabolic parameters compared to the C-group, including higher body mass index (BMI) (p < 0.001), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (p < 0.001), waist circumference (p < 0.001), and fatty liver index (FLI) (p < 0.001). At follow-up, the M-group showed greater improvements. Fetuin-B levels were significantly higher in the M-group at baseline (p = 0.01), but at follow-up, no significant difference was observed between the groups (M-group: 3.7mcg/mL; C-group: 4.4 mcg/mL; p = 0.13). The M-group's fetuin-B levels decreased significantly (p < 0.001), while the C-group's levels increased slightly. Changes in fetuin-B levels differed significantly between groups (p < 0.001), and regression analysis confirmed a strong association (B: 1.80; 95% CIs: 0.57-3.03; p = 0.01). This study demonstrated that metformin therapy is associated with significantly reducing fetuin-B levels in PCOS patients, underscoring its role in enhancing metabolic health. These findings highlight fetuin-B as a potential biomarker for monitoring treatment efficacy, offering a link between metabolic and reproductive health.

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, affecting 4.8 % to 18.6 % of women of reproductive age. Between 10 and 19 years of age, PCOS occurs in 3.39 % to 8.03 % of adolescents. Confirmation of diagnosis in adolescent age is difficult because manifestations of PCOS are similar to normal puberty signs (e. g., irregular menstrual cycle, acne, etc.). New evidence-based guidelines have been issued in 2018 highlighting the diagnostic criteria for establishing PCOS diagnosis in adolescents. These guidelines also recommend a separate identification of risk group patients – adolescent patients for whom both diagnostic PCOS criteria have not yet been confirmed and who should continue to be monitored. It is important to diagnose this disease as early as possible in order to initiate lifestyle adjustments and possibly also begin treatment in a timely manner.In the long term, PCOS increases the risk of developing infertility and type 2 diabetes, cardiovascular disease, insulin resistance and metabolic syndrome. Increased body weight occurring in 40–70 % of adolescents with PCOS significantly increases the risk of chronic non-communicable diseases at a later stage, and maintains PCOS symptoms. PCOS and associated symptoms reduce health-related quality of life (HRQOL). Binge eating is more common in patients with PCOS. The most effective tactics of therapy are lifestyle changes, so it is particularly important to recognise patients at increased risk of developing PCOS, to diagnose them early and to offer treatment that is most relevant to the needs of the individual and improves their quality of life.The aim of the doctoral thesis is to explore intergenerational, genetic, quality of life and binge eating aspects in teenagers with PCOS.The study contains several sections. To evaluate the intergenerational bond, 57 teenagers with PCOS and their mothers were included in Section I. The section studies the relationship between patients with PCOS and their mothers. In addition to PCOS patients, Section II also includes healthy adolescent patients and patients at risk. The role of the most common variation of protein-coding genes involved in the activity of the Hypothalamic-Pituitary-Ovarian axis (FSHR, ESR2, LHCGR, GNRHR) in PCOS development and in the PCOS clinical presentation was studied by including 63 adolescents with a diagnosis of PCOS, 67 healthy control patients and 22 patients at risk. The role of CYP21A2 gene variations in PCOS development and clinical phenotype was established in 55 PCOS patients, 49 control patients and 23 patients at risk. Additionally, components of HRQOL, binge eating and factors affecting the total HRQOL were analysed in 63 PCOS patients and 66 control patients. The study concluded that it was not possible to predict clinical symptoms associated with PCOS in adolescents based on PCOS symptoms in their mothers. The role of protein-coding gene variations that are involved in the functioning of sex hormones was also not found, in regard to PCOS development. However, it was found that the homozygous minor allele carriers within variations of specific genes (ESR2 rs4986938 and LHCGR rs2293275) had a higher total testosterone level in blood than patients who were not carriers of these alleles. The most important components that affected HRQOL in adolescents with PCOS were the diagnosis of PCOS as such, the degree of binge eating, and the percentile of the body mass index. At the same time, HRQOL was most affected by concerns about body hair and body weight. There was no difference in the frequency of binge eating between PCOS patients and adolescent control group patients.In this study, no link was found between the diagnosis of PCOS or associated symptoms in mothers and the phenotype of adolescents with PCOS. Individual alleles have been associated with the clinical presentation of PCOS. There is a better understanding of the components of HRQOL that affect PCOS the most and require particular attention in clinical practice. Further research with a larger sample-size is needed. Furthermore, longitudinal data on the population studied in this project would provide a more accurate insight into the development of the disease at a later age.

Objective To investigate whether the visceral adiposity content is associated with impaired glucose regulation (IGR), independent of insulin resistance and hyperandrogenism in women with polycystic ovary syndrome (PCOS). Methods A total of 401 PCOS patients [177 patients with normal glucose tolerance (NGT), 224 patients with IGR] and 200 healthy women matched with age, body mass index, waist circumference and waist to hip ratio in the Department of Endocrinology and Metabolism of Renji Hospital affiliated to Shanghai Jiaotong University School of Medicine from January 2015 to December 2017 were included. All subjects received 75 g oral glucose tolerance test. Insulin and sex hormone levels were measured by radioimmunoassay. Visceral adiposity content was determined by visceral adiposity index (VAI). Logistic regression was used to analyze the association between VAI and IGR. Results (1) The VAI level in PCOS patients with IGR group was higher than that in NGT group (3.7±2.6 vs 1.5±0.7, t=-11.019, P<0.05). (2) VAI was positively related with the homeostasis model assessment of insulin resistance (HOMA-IR), the glucose and insulin area under the curve (AUCglu and AUCins) (r=0.416, 0.542, 0.329, respectively, all P<0.05), but negatively related with the Matsuda index (r=-0.458, P<0.05). (3) The prevalence of IGR increased with VAI quartiles after adjustment for age, free androgen index and HOMA-IR in multivariate Logistic regression [the first quartile as a reference, the ORs of the second, third and fourth quartiles were 5.50 (95%CI: 1.15-10.47), 29.74(95%CI: 12.74-69.43) and 70.31(95%CI: 25.35-195.98), respectively; all P<0.05]. (4) The cut-off value of VAI in predicting the high risk of IGR was 1.94 (AUC=0.890, 95%CI: 0.858-0.922, sensitivity=0.826, specificity=0.853, P<0.05). Conclusions High visceral adiposity content is independently and positively related with high risk of IGR in PCOS patients. VAI>1.94 can predict the increased risk of IGR in PCOS women. Key words: Polycystic ovary syndrome; Insulin resistance; Visceral adiposity index; Impaired glucose regulation; Hyperandrogenism

Insulin resistance is one of the key factors in the pathogenesis of polycystic ovary syndrome (PCOS). The peroxisome proliferator-activated receptor gamma (PPARG) plays a role in the regulation of insulin sensitivity. The aim of the present study was to establish a possible association of the PPARG Pro12Ala polymorphism with PCOS and its effect on family and personal history, as well as on the metabolic and endocrine parameters in PCOS patients. A total of 151 PCOS patients and 179 healthy women of reproductive age were enrolled. History, body mass index (BMI), waist-to-hip ratio and the presence of phenotypic hyperandrogenism were recorded. Hormonal, metabolic and biochemical profiles were assessed. A molecular analysis for the genetic polymorphism was performed. One third (29.8%) of the PCOS patients were found to be carriers of at least one variant of the Ala allele (X/Ala), while 70.2% carried two wild-type Pro alleles (Pro/Pro), with an equal distribution observed in the control group. The PCOS patients carrying the X/Ala alleles exhibited lower serum fasting insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR) and BMI compared to Pro/Pro carriers. This finding was significant only in the lean PCOS group. The polymorphic genotype exerted no effect on history, hormonal and clinical hyperandrogenism, lipid status or C-reactive protein, leptin, adiponectin, resistin and ghrelin serum levels in women with PCOS. In conclusion, although the PPARG Pro12Ala polymorphism is not a major determinant of PCOS in the Croatian population, it may exert a positive effect on insulin sensitivity and BMI. As these associations were recorded exclusively in the lean group of patients with PCOS, this polymorphism potentially contributes to a protective role against hyperinsulinemia and obesity.

Objective: To investigate the correlation between body composition parameters, adiponectin, leptin and the adiponectin/leptin ratio and the LH/FSH ratio in women with polycystic ovary syndrome (PCOS).&#x0D; Methods: A cross-sectional study was conducted at Reproductive Cluster Yasmin, Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia, with sixty women with PCOS and sixty healthy women as controls (matched for age and BMI). Body composition parameters, including body weight, body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR), percent body fat (PBF), visceral fat area (VFA), percent subcutaneous fat (PSF) and skeletal muscle mass (SMM), were measured; levels of fasting glucose, fasting insulin, testosterone, and sex hormone binding globulin (SHBG) were measured; and homeostatic model assessment for insulin resistance (HOMA-IR) values, anti-Mullerian hormone (AMH), free androgen index (FAI), Ferriman-Gallwey (FG) score, adiponectin levels, leptin levels, adiponectin/leptin ratio, LH, FSH and LH/FSH ratio were measured.&#x0D; Results: Body composition parameters (body weight, BMI, WC, WHR, PBF, VFA, PSF, SMM) were not significantly different between women with PCOS and controls. Fasting insulin (P&lt;0.05), HOMA-IR (P&lt;0.05), AMH (P&lt;0.01), FAI (P&lt;0.01), FG score (P&lt;0.01) and LH/FSH ratio (P&lt;0.05) were higher in PCOS women. Adiponectin (P&lt;0.01) was lower in PCOS women, while leptin and the adiponectin/leptin ratio were not significantly different between groups. Most of body composition parameters, adiponectin, leptin and adiponectin/leptin ratio were correlated with HOMA-IR in both groups.&#x0D; SMM was positively correlated with the LH/FSH ratio, while body weight, BMI, WC, PBF, VFA, and PSF were inversely correlated with the LH/FSH ratio in PCOS patients but not in controls. WHR was not correlated in either group. Leptin (r=-0.278; P&lt;0.05) was negatively correlated with the LH/FSH ratio only in the PCOS group. Adiponectin (r=0.394; P&lt;0.01) and the adiponectin/leptin ratio (r=0.413; P&lt;0.01) were also positively correlated with the LH/FSH ratio only in the PCOS group. AMH was correlated with the LH/FSH ratio, whereas testosterone level, FAI, FG score, fasting insulin level and HOMA-IR value were not correlated with the LH/FSH ratio in PCOS women.&#x0D; Conclusion: Most of the body composition parameters, leptin, adiponectin and the adiponectin/leptin ratio were significantly correlated with HOMA-IR in both groups. However, correlations of those parameters with LH/FSH ratio were found only in PCOS but not in women without PCOS. Adiponectin and leptin may play a significant role in the mechanism of neuroendocrine disorders in PCOS, which is characterized by an increased LH/FSH ratio.&#x0D; Keywords: adiponectin, adiponectin/leptin ratio, body composition, HOMA-IR, leptin, LH/FSH ratio, PCOS

The aim of the study was to investigate the changes in serum glypican 4 (GPC4) and clusterin (CLU) levels in patients with polycystic ovary syndrome (PCOS) as well as their correlation with sex hormones and metabolic parameters. A total of 40 PCOS patients and 40 age-matched healthy women were selected. Serum GPC4 and CLU levels were compared between the PCOS and control groups, and binary logistic regression was used to analyze the relative risk of PCOS at different tertiles of serum GPC4 and CLU concentrations. Stepwise linear regression was used to identify the factors influencing serum GPC4 and CLU levels in PCOS patients. Serum GPC4 (1.82 ± 0.49 vs 1.30 ± 0.61 ng/mL, P < 0.001) and CLU (468.79 ± 92.85 vs 228.59 ± 82.42 µg/mL, P < 0.001) were significantly higher in PCOS patients than in healthy women after adjustment for body mass index (BMI). In the PCOS group, serum GPC4 was positively correlated with follicle-stimulating hormone, fasting plasma glucose (FPG), fasting insulin (FINS), homeostatic model assessment of insulin resistance (HOMA-IR), triglyceride, and CLU (P < 0.05), whereas serum CLU was positively correlated with BMI, FPG, FINS, and HOMA-IR (P < 0.05). Multiple stepwise linear regression analysis showed that HOMA-IR was independently associated with serum GPC4, and BMI and HOMA-IR were independently associated with CLU (P < 0.05). Serum GPC4 and CLU levels were significantly higher in PCOS patients than in healthy women, suggesting that GPC4 and CLU may be markers associated with insulin resistance in women with PCOS.

Relationship between serum apelin, visfatin levels, and body composition in Polycystic Ovary Syndrome patients

Previous studies have shown that serum zinc and adiponectin levels are associated with insulin resistance in the polycystic ovary syndrome (PCOS) patients. But there is no study to evaluate serum zinc and adiponectin levels as predictor markers of PCOS, adjusted for anthropometric, biochemical, dietary intake, and physical activity measures. Ninety-one new PCOS cases (based on the Rotterdam criteria) and 85 healthy control women participated and individually matched based on age. Food intake of all participants obtained by the food frequency and physical activity level was assessed by the International Physical Activity Questionnaires. Serum glucose, lipid profile, androgens, insulin, adiponectin, and zinc concentrations were measured at the fasting state. Weight, BMI, waist circumference, and body fat, as well as serum levels of DHEAS, insulin, TG, LDL cholesterol (LDL.C), homeostasis model assessment of insulin resistance (HOMA-IR), and LH/FSH ratio, were significantly higher in the PCOS compared with those of the healthy control women. Serum levels of zinc and adiponectin were significantly lower in the PCOS than those of the healthy control women. Results of the logistic regression model showed significant effects of adiponectin, zinc, and LH/FSH ratio on the PCOS, adjusted for anthropometric and biochemical measures (p < 0.05). In the present study, serum level of zinc had significant correlation with adiponectin in the PCOS patients, and serum levels of zinc, adiponectin, and LH/FSH ratio had significant effects on the PCOS occurrence.

Objective To explore the clinical efficacy and safety Diane-35 and metformin combined treatment for endometrial atypical hyperplasia (EAH) and early endometrial carcinoma (EEC) in polycystic ovary syndrome (PCOS) patients. Methods PCOS patients with endometrium lesion were re-cruited. All patients were treated with Diane-35 (1 tablet per day, for 21 d per month) plus metformin (1 000 mg, qd) for 6 months. Endometrial biopsies for pathological evaluation before, during and after treatment were conducted. Other clinical parameters included body weight (BW), body mass index (BMI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone (TT), sex hormone-binding globulin (SHBG), free androgen index (FAI), insulin area under curve (IAUC), homeostasis model assessment of insulin resistance (HOMA-IR) were detected as well. After successful conversion of endometrial lesions, we continued to give patients with Dydrogesterone (10 mg/d, for 14 d per month) and metformin. Results Totally 43 PCOS patients with endometrium lesion (30 EAH and 13 EEC) were re-cruited. After 6-month treatment, the endometrium in all PCOS patients was confirmed by pathological evaluation to be reversed to normal epithelia with Diane-35 plus metformin treatment. By the end of 6-month treatment, mean BMI, TT, FAI, HOMA-IR were decreased respectively (P<0.05), while SHBG were increased (P<0.05). The complete response (CR) rate was 100%. During 6-18 months of follow-up, 2 EAH patients relapsed, and both of whom did not continue to use progesterone therapy monthly; 2 EEC relapsed, who had complicated with ovary tumor. Conclusion Diane 35, a low-dose oral contraceptives with anti-androgen activity, when used in combination with metformin can completely revert the EEC and EAH to normal endometrial cell in PCOS patients, even in those who have been failure to high-dose progestin treatment before. Diane-35 with metformin combination treatment may be a good choice for the EAH and EEC in PCOS patients, which enables these patients to preserve the fertility. Key words: Polycystic ovary syndrome (PCOS); Endometrial atypical hyperplasia (EAH); Early endometrial carcinoma (EEC); Diane-35 combined with metformin

IntroductionInsulin resistance (IR) may play a central role in the pathophysiology of polycystic ovary syndrome (PCOS). Controlled ovarian stimulation (COS) in PCOS women in the setting of assisted reproductive technology (ART) is always a challenge for clinicians. However, it remains unclear whether IR in women with PCOS correlates with reduced ovarian sensitivity to exogenous gonadotropin (Gn). This study aimed to explore the association between homeostasis model assessment of insulin resistance (HOMA-IR) and ovarian sensitivity index (OSI).MethodsIn this retrospective cohort study, we explored the association between Ln HOMA-IR and Ln OSI based on smoothing splines generated by generalized additive model (GAM). Then the correlation between HOMA-IR and OSI was further tested with a multivariable linear regression model and subgroup analysis.Results1508 women with PCOS aged 20-39 years undergoing their first oocyte retrieval cycle were included consecutively between 2018 until 2022. We observed a negative association between Ln HOMA-IR and Ln OSI by using smoothing splines. In multivariable linear regression analysis, the inverse association between Ln HOMA-IR and Ln OSI was still found in PCOS women after adjustment for potential confounders (β = -0.18, 95% CI -0.25, -0.11). Compared with patients with the lowest tertile of HOMA-IR, those who had the highest tertile of HOMA-IR had lower OSI values (β = -0.25, 95% CI -0.36, -0.15).DiscussionOur study provided evidence for the inverse correlation between IR and the ovarian sensitivity during COS in PCOS women. Herein, we proposed new insights for individualized manipulation in PCOS patients with IR undergoing ART.

Polycystic ovary syndrome (PCOS) one of the most common endocrine disorders in women of reproductive age, the pathogenesis of PCOS imitated to be as a vicious cycle involving both hyperandrogenaemia and insulin resistance/hyperinsulinemia. Vitamin D deficiency (VDD) is common among women with PCOS (approximately 67%–85% women with PCOS have VDD). Vitamin D3 and CoQ10 could affect glucose metabolism and insulin sensitivity and improve metabolic abnormalities in PCOS. The study was designed to evaluate the effect of combining oral vitamin D3 tablet or CoQ10 capsule with clomiphene citrate on metabolic biomarkers in women with clomiphene citrate resistance PCOS patients. A prospective interventional randomized-controlled, open-label study include 41 PCOS patients aged range (18-34)years who are clomiphene citrate resistant divided into two groups, group 1 (n=24) whose endogenous vitamin D status less than 20ng/ml receive clomiphene citrate 100mg daily(for 5 days monthly induction) plus vitamin D 10000IU daily (2 months) and group 2 (n=17) whose endogenous vitamin D status equal or more than 20ng/ml receive clomiphene citrate 100mg daily(for 5 days monthly induction) plus CoQ10 200mg daily (2 months). Fasting blood samples were taken at baseline and 2 months after intervention to measure metabolic biomarkers [fasting serum insulin (FSI), fasting blood glucose (FBG), homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI)]. After 2 months both interventions result in non-significant change in FSI and FBG while HOMA-IR and QUICKI decreased by both interventions, but the decrease is significant only with CoQ10 supplementations. In conclusion, Vitamin D and CoQ10 supplementation result in improvement in HOMA-IR and QUICKI but the improvement was more obvious in CoQ10 group.

Serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) in IVF patients with polycystic ovary syndrome: correlations with outcome

Increased prevalence of abnormal aminotransferase levels and/or ultrasonographic evidence of hepatic steatosis (HS) have been found in women with polycystic ovary syndrome (PCOS). However, factors associated with non-alcoholic fatty liver disease (NAFLD) in PCOS are still under investigation. The aim of this case-control study was to investigate the presence of NAFLD and to assess factors associated with this condition in PCOS patients. A prospective study of 57 premenopausal PCOS patients and 60 age- and weight-matched control women, with a history of no or minimal alcohol consumption was conducted. Anthropometric variables, biochemical and hormonal parameters were determined and NAFLD was evaluated by abdominal ultrasonography and biochemical testing, after excluding causes of secondary liver disease. Insulin resistance was assessed by homeostasis model assessment of insulin resistance (HOMA-IR) and free androgen index (FAI) was calculated. PCOS patients had an increased prevalence of HS [21/57 patients (36.8%) versus 12/60 controls (20.0%), P < 0.05] and abnormal (> or =40 IU/l) serum aminotransferase levels [13/57 patients (22.8%) versus 2/60 controls (3.3%), P < 0.01] than controls. All patients and controls with metabolic syndrome had HS. Factors associated with HS were PCOS diagnosis, older age, increased BMI, waist circumference (WC), HOMA-IR and FAI values and decreased high-density lipid cholesterol and sex hormone binding globulin levels. PCOS patients had an OR of 3.55 (95% CI: 1.02-5.35) for HS versus controls, after adjustment for age, BMI and WC. NAFLD is common in PCOS patients and increased androgen bioavailability may be implicated, in combination with metabolic abnormalities. Liver evaluation is proposed in PCOS patients, especially in those with metabolic syndrome.

Aims. To compare ghrelin levels in women with polycystic ovary syndrome (PCOS) and healthy subjects and to evaluate the relationships between circulating ghrelin and the heterogeneity of clinical and biochemical manifestations of PCOS women.Methods. Forty-five women with PCOS and 20 controls were included in the study. Serum levels of ghrelin, leptin, testosterone, immune-reactive insulin (IRI), sex hormone-binding globulin, dehydroepiandrosterone sulfate, cortisol, luteinizing hormone and follicle-stimulating hormone were measured. Free androgen index and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. Body mass index (BMI) and waist-to-hip ratio (WHR) were calculated.Results. Serum ghrelin levels in PCOS patients were lower than in the control group (mean±standard error of the mean: 21.78±2.12 vs. 34.67±3.57 ng/ml; p = 0.04). In women with PCOS, a strong negative correlation was observed between ghrelin values and the clinical (BMI, WHR, waist circumference) and hormonal indices of insulin resistance (IRI and HOMA-IR). The negative correlative relationship between ghrelin and HOMA-IR disappeared after partial correlation analysis when controlling for WHR and BMI. Negative correlation existed between ghrelin and testosterone (r = −0.315; p<0.05) and between ghrelin and leptin levels (r = −0.306; p<0.05). The latter correlation disappeared after partial correlation analysis controlling for BMI, WHR and HOMA-IR.Conclusion. The ghrelin level in women with PCOS reflects the metabolic and hormonal changes which are characteristics of the syndrome. The inverse correlation between ghrelin and leptin in these women is mediated through metabolic factors.

Periodontal disease in polycystic ovary syndrome