Association of Hyperandrogenaemia With Hypertension and Cardiovascular Events in Pre-menopausal Women- A Prospective Population-Based Cohort Study.

OBJECTIVE: The present study aimed to clarify the conflicting association of premenopausal hyperandrogenaemia (HA) with the development of hypertension and CVDs in women. DESIGN: A population-based cohort study including 5889 women. METHODS: The association of serum testosterone (T), sex hormone-binding globulin (SHBG), and free androgen index (FAI) at age 31 with blood pressure (BP) and hypertension (BP ≥140/90 mmHg and/or use of antihypertensive medication) at ages 31 and 46 and with CVDs (angina pectoris [AP] and/or acute myocardial infarction [AMI] n=74, transitory cerebral ischemia [TIA] and/or stroke n=150) and combined CVD events (AP, AMI, stroke, heart failure, or CVD mortality n=160) by age 53 was investigated. RESULTS: T and FAI were positively associated with systolic and diastolic BP at ages 31 and 46 in the multivariable model. Compared to their lowest quartile, the highest quartiles of T and FAI were positively associated with hypertension at age 31 in the multivariable model. During the 22-year follow-up, FAI was positively associated with increased risk of AP/AMI (hazard ratio [HR]:2.02, 95%CI:1.06-3.85) and overall CVD events or mortality (HR:1.54, 95%CI:1.02-2.33) in the unadjusted models. However, the significance disappeared after adjusting for BMI. CONCLUSIONS: Women with HA at premenopausal age had an elevated risk of hypertension, and together with BMI, increased risk of CVD events and CVD mortality during the 22-year follow-up. However, because of several study limitations regarding ethnicity and BMI characteristics, a longer follow-up of this cohort and future studies in ethnically diverse populations are needed to verify the results.

Hyperandrogenic eumenorrheic NON-PCOS women versus women with PCOS after the GnRH-agonist stimulation test preceded by suppression of adrenal steroidogenesis with dexamethasone.

The subject of polycystic ovary syndrome (PCOS) has been extensively covered in the literature; however, there is a paucity of data regarding eumenorrheic women with hyperandrogenism and/or hyperandrogenemia without ultrasound evidence of PCO morphology (EuHyperA), and even less data on the comparison between PCOS and EuHyperA subjects. It has previously been shown that around half of PCOS women exhibit a hyper-response of serum 17-hydroxy-progesterone (17-OHP) to the stimulation by GnRH-agonists, also indicated as functional ovarian hyperandrogenism (FOH). Often, this stimulation test is preceded by suppression of the adrenal steroidogenesis with oral dexamethasone (Dex). FOH has been associated with an increase of the P450c17 activity in the ovaries driven by elevated insulin levels. Interestingly, treatment of women with PCOS with Dex suppression and GnRH-agonist stimulation (buserelin) highlighted the possible existence of two clusters of patients: hyper-responders (HR) and normal responders (NR). In this retrospective study, we included 15 hyper-responders (HR) EuHyperA, 34 normal responders (NR) EuHyperA, 62 HR-PCOS and 45 NR-PCOS. The demographic characteristics, glucose-metabolism indices, and the hormonal response to Dex or buserelin were analyzed, with both intra-group and inter-group comparisons performed. The rate of FOH was significantly greater in PCOS than EuHyperA women. Compared to HR-PCOS, HR-EuHyperA had [i.] significantly greater age at observation; [ii.] lower cortisol, 17-OHP, Δ4-androstenedione (Δ4-ASD), total testosterone (TT), LH, and buserelin-stimulated whole curve of dehydroepiandrosterone sulfate (DHEAS), 17-OHP, Δ4-ASD and TT. Compared to NR-PCOS, NR-EuHyperA had [i.] significantly greater FSH, and buserelin-stimulated whole curve of DHEAS; [ii.] significantly lower post-HD Dex Δ4-ASD, TT, buserelin-stimulated whole curve of 17-OHP, Δ4-ASD and TT. Compared to NR-PCOS, HR-PCOS had [i.] significantly greater body mass index (BMI), homeostasis model assessment for insulin resistance (HOMA-IR), cortisol, DHEAS, Δ4-ASD, TT, FT, FAI, E2, and insulin AUC0-120min (area under the curve) at oral glucose tolerance test (OGTT); [ii] higher levels of post-LD and post-HD Dex 17-OHP, Δ4-ASD, TT, post-HD Dex DHEAS (with greater levels indicating weaker adrenal suppression), whole curve of DHEAS, 17-OHP, Δ4-ASD, TT and LH; [iii] significantly lower sex-hormone binding globulin (SHBG). Even if most of the parameters evaluated were statistically similar in the two sets of comparisons, interesting differences were observed. Women with PCOS exhibit higher androgen levels at baseline, after adrenal suppression and at the buserelin test, further to a higher ovarian volume. Of note, the percentage of women with HOMA-IR≥2.5 and serum insulin levels were greater in PCOS group compared to EuHyperA women. Moreover, within women with PCOS, the HR subgroup has higher insulin levels compared to the NR subgroup, when OGTT is performed. The alteration of the glucose-insulin balance and elevation of circulating androgens were more pronounced in PCOS, thus indicating that [i.] metabolic alterations might be crucial in the onset of PCOS itself and, [ii] EuHyperA might represent a milder form of PCOS.

Obesity is associated with hyperandrogenemia in a nationally-representative sample of U.S. girls aged 6-18 years.

CONTEXT: Studies have associated obesity with peri-pubertal hyperandrogenemia. However, these studies were performed in academic centers and could have been influenced by selection bias. OBJECTIVE: To investigate if free testosterone levels are elevated in peri-pubertal girls with obesity. DESIGN/SETTING: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2013-2016 databases. PARTICIPANTS: 1,299 girls aged 6-18 years residing in U.S. MAIN OUTCOME MEASURES: Mean free testosterone concentration (calculated from total testosterone and sex hormone-binding globulin). RESULTS: Among girls aged 6-9 years, mean (95% CI) free testosterone was 0.33 pg/ml (0.28-0.38) in healthy weight girls vs. 0.86 pg/ml (0.67-1.05) in girls with obesity. Among girls aged 10-14 years, free testosterone was 2.29 pg/ml (2.05-2.53) in healthy weight girls vs. 4.10 pg/ml (3.60-4.60) in girls with obesity. Among girls aged 15-18 years, free testosterone was 3.33 pg/ml (2.96-3.70) in healthy weight girls and 5.64 pg/ml (4.93-6.36) in girls with obesity. Girls with obesity in all age groups had higher free testosterone levels compared to healthy weight girls. In each age group, the 95% CIs for free testosterone did not overlap between healthy weight vs. obesity subgroups. A multiple regression model accounted for 42% of the variance in free testosterone (R2=0.42), and both weight and age categories were independent predictors of free testosterone (p<0.0001 for each). CONCLUSION: In a nationally-representative sample of U.S. girls, obesity is associated with elevated free testosterone, suggesting an important relationship between obesity and peri-pubertal hyperandrogenemia.

Evaluating the diagnostic accuracy of androgen measurement in polycystic ovary syndrome: a systematic review and diagnostic meta-analysis to inform evidence-based guidelines.

BACKGROUND: Biochemical hyperandrogenism is a hallmark and diagnostic feature of polycystic ovary syndrome (PCOS). However, the most accurate androgen measurement for assessing biochemical hyperandrogenism in PCOS diagnosis remains uncertain. OBJECTIVE AND RATIONALE: This systematic review aimed to assess different androgen measures [including total testosterone (TT), calculated free testosterone (cFT), free androgen index (FAI), androstenedione (A4), dehydroepiandrosterone sulfate (DHEAS), and dihydrotestosterone (DHT)] for accuracy in diagnosing biochemical hyperandrogenism in women with PCOS, to inform the 2023 International PCOS Evidence-based Guidelines. SEARCH METHODS: To update evidence from the 2018 International PCOS Guidelines, a systematic search from 3 July 2017 to 23 June 2023 was conducted across Medline (Ovid), CINAHL, all EBM, EMBASE, and PsycInfo for articles evaluating androgens in the diagnosis of biochemical hyperandrogenism. The revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) was used to assess the risk of bias and applicability. A diagnostic test accuracy meta-analysis was performed using STATA 18 software. Summary sensitivity and specificity were calculated with 95% CIs using the bivariate model, while the hierarchical summary receiver operating characteristics (ROC) model was used to produce a summary ROC curve. OUTCOMES: Of 23 studies reviewed, 18 were included in the meta-analysis, with data from 2857 participants (1650 with PCOS and 1207 controls). For diagnosing biochemical hyperandrogenism in PCOS, the pooled sensitivity, specificity, and AUC with 95% CI were for TT: 0.74 (0.63-0.82), 0.86 (0.77-0.91), and 0.87 (0.84-0.90); cFT: 0.89 (0.69-0.96), 0.83 (0.79-0.86), and 0.85 (0.81-0.88); FAI: 0.78 (0.70-0.83), 0.85 (0.76-0.90), and 0.87 (0.84-0.90); A4: 0.75 (0.60-0.86), 0.71 (0.51-0.85), and 0.80 (0.76-0.83); and DHEAS: 0.75 (0.61-0.85), 0.67 (0.48-0.81), and 0.77 (0.73-0.81), respectively. In subgroup analyses, liquid chromatography with tandem mass spectrometry (LC-MS/MS) had superior sensitivity for measuring cFT, FAI, A4, and DHEAS, and superior specificity for measuring TT, cFT, and FAI, compared to the direct immunoassay method. WIDER IMPLICATIONS: Our results directly informed the 2023 International PCOS Guideline recommendations to use TT and FT as the first-line laboratory tests to assess biochemical hyperandrogenism in the diagnosis of PCOS. cFT should be assessed by equilibrium dialysis or ammonium sulfate precipitation, or calculated using FAI. If TT or cFT are not elevated, A4 and DHEAS could also be considered, noting their poorer specificity. Laboratories should utilize LC-MS/MS for androgen measurement given its high accuracy. Future studies should focus on establishing optimal normative cut-off values in large, unselected, and ethnically diverse cohorts of women. REGISTRATION NUMBER: The review protocol was prepublished in the 2023 PCOS Guideline Technical Report (https://www.monash.edu/__data/assets/pdf_file/0010/3379591/TechnicalReport-2023.pdf).

Effects of interleukin-1 receptor antagonism in women with polycystic ovary syndrome-the FertIL trial.

Introduction: Chronic low-grade inflammation might contribute to hyperandrogenemia and metabolic complications in polycystic ovary syndrome (PCOS). The proinflammatory cytokine interleukin (IL)-1 stimulates androgen production from ovarian cells, whereas blockade of the IL-1 pathway improves cardiometabolic health. We aimed to investigate whether blocking the IL-1 pathway ameliorates hyperandrogenemia in patients with PCOS. Methods: This is a prospective, interventional, single-arm, proof-of-concept trial performed at a tertiary hospital in Switzerland (August 2018 to July 2020) in 18 premenopausal women with a diagnosis of PCOS according to the Rotterdam criteria, total testosterone levels ≥ 1.7 nmol/L, and C-reactive protein (CRP) ≥ 1.0 mg/L. Patients received 100 mg/day of the IL-1-receptor antagonist anakinra for 28 days and underwent weekly blood sampling until 1 week after the end of treatment. The primary endpoint was the change in serum androstenedione levels on day 7 of treatment, assessed with liquid chromatography-tandem mass spectrometry. Seven of these women participated in a subsequent observational sub-study (May 2021 to December 2021). Results: Median [interquartile range (IQR)] androstenedione increased by 0.5 [-0.1, 1.6] nmol/L (p = 0.048) with anakinra and by 1.3 [0.08, 2.4] nmol/L [p = 0.38] without anakinra between baseline and day 7. Anakinra reduced CRP levels on days 7, 21, and 28 (p < 0.001) but did not lead to an absolute reduction in androgens. However, four of six patients (67%) had smaller areas under the curves for androstenedione and/or testosterone during the 28-day intervention with anakinra as compared to 28 days without treatment. Discussion: Our findings suggest that anakinra suppresses IL-1-mediated chronic low-grade inflammation in PCOS and might attenuate biochemical hyperandrogenemia.

Free Androgen Index Might Not Be a Perfect Predictor of Infertility Outcomes in Patients with Polycystic Ovary Syndrome Undergoing Frozen Embryo Transfer:A Retrospective Cohort Study.

Purpose: It is well known that androgen excess impairs oocyte quality, endometrial receptivity and even embryo invasion to some extent. Free androgen index (FAI) is strongly recommended to evaluate active androgen. Previous studies have showed conflicting conclusions on the effect of hyperandrogenism on the pregnancy outcomes in patients with polycystic ovary syndrome (PCOS). This study aims to analyze the influence of hyperandrogenemia based on FAI on frozen embryo transfer (FET) outcomes in patients with PCOS. Patients and Methods: Patients diagnosed with PCOS who underwent their first FET between January 2017 and April 2022 were stratified into two cohorts using FAI, a highly recommended parameter: PCOS with hyperandrogenemia (n=73) and PCOS without hyperandrogenemia (n=255). Basic and infertility characteristics were analyzed using Student's t-test or chi-square (χ2) statistics. Logistic regression analysis was performed to verify whether FAI was helpful in predicting pregnancy outcomes in women with PCOS. Results: Body mass index (BMI), total gonadotropin (Gn), basal serum follicle-stimulating hormone (bFSH), basal serum testosterone (bT), sex hormone binding globulin (SHBG), and FAI were significantly different between the two groups. (P=0.005, P<0.001, P<0.001, P<0.001, and P<0.001, respectively). However, clinical pregnancies, abortions, and live births did not differ significantly. Further regression analyses showed that FAI was not related to clinical pregnancy, abortion, or live birth rates (adjusted odds ratio (OR)=0.978, 95% confidence interval (CI)=0.911-1.050, P=0.539; adjusted OR=1.033, 95% CI=0.914-1.168, P=0.604; and adjusted OR=0.976, 95% CI=0.911-1.047, P=0.499, respectively). Conclusion: FAI was not associated with pregnancy outcomes in patients with PCOS; that is, it did not reflect any negative effects of hyperandrogenemia on pregnancy outcomes in patients with PCOS and was not an informative clinical parameter. Therefore, more attention should be paid to the factors that influence the accuracy of FAI in reflecting androgen levels in vivo, and further discussion is needed.

Hyperandrogenemia elevates expression of apelin and apelin receptor protein in the mice pituitary.

Hyperandrogenemia is associated with polycystic ovarian syndrome (PCOS) and imbalances in the pituitary hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. Apelin and its receptor, APJ (class A, rhodopsin-like G- protein-coupled receptor), belongs to adipokines, and its expression has been shown in the pituitary. It is also well known that, hyperandrogenism and PCOS have deregulation of different adipokines. Whether hyperandrogenism also deregulates the apelin system in the pituitary has yet to be investigated. Thus, we have investigated the expression and localization of apelin and its receptor, APJ, in the letrozole-induced hyperandrogenised pituitary of female mice. Our results showed that the apelin, APJ and androgen receptor (AR) expression were upregulated in the anterior pituitary. Furthermore, the immunostaining of LH exhibited increased abundance than FSH. The circulating LH was also found to be elevated compared to FSH levels. The increased LH synthesis and secretion coincides with elevated apelin system in the pituitary of hyperandrogenised mice. Recently, a direct role of apelin has also been reported in the female pituitary, where apelin inhibits LH secretion. Thus, apelin could be one of the factors for deregulated gonadotropin secretion in hyperandrogenised conditions. However, more research is needed to fully understand the complex interactions between apelin and androgen regarding gonadotropin secretion in hyperandrogenised conditions.

CISD2 regulates oxidative stress and mitophagy to maintain the balance of the follicular microenvironment in PCOS.

OBJECTIVES: To observe the CISD2 expression among PCOS patients and to explore its profound impact on the follicular microenvironment. Moreover, we want to elucidate the intricate mechanistic contribution of CISD2 to the onset and progression of PCOS. METHODS: Oxidase NOX2, mitophagy-related proteins, and CISD2 were detected by WB. The changes in mitochondrial structure and quantity were observed by transmission electron microscopy. Mitochondrial and lysosome colocalization was used to detect the changes of mitophagy. MDA kit, GSH and GSSG Assay kit and ROS probe were used to detect oxidative stress damage. RESULTS: We found that CISD2, mitophagy and oxidase in the GCs of PCOS patients were significantly increased. Testosterone stimulation leads to the increase of oxidase, mitophagy, and CISD2 in KGN cells. CISD2 inhibition promoted the increase of mitophagy, and the activation of mitochondria-lysosome binding, while alleviating the oxidative stress. CONCLUSIONS: Inhibition of CISD2 can improve the occurrence of oxidative stress by increasing the level of mitophagy, thus affecting the occurrence and development of PCOS diseases.

The impact of hyperandrogenemia on pregnancy complications and outcomes in patients with PCOS: a systematic review and meta-analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a metabolic and reproductive disorder. Current research findings present conflicting views on the effects of different PCOS phenotypes on outcomes in pregnancy and for newborns. METHODS: This research study followed the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA). A thorough search of literature was carried out using the Cochrane Menstrual Disorders and Subfertility Group trials register, Web of Science, and EMBASE databases from their start to December 2023. The search focused on studies examining the links between hyperandrogenic and non-hyperandrogenic PCOS phenotypes and risks in pregnancy and neonatology. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using either a fixed-effects or random-effects model. RESULTS: Our analysis incorporated 10 research studies. Expectant mothers with a hyperandrogenic PCOS subtype had increased ORs for gestational diabetes mellitus (GDM) and preeclampsia (PE) compared to those with a non-hyperandrogenic PCOS subtype, with respective values of 2.14 (95% CI, 1.18-3.88, I2 = 0%) and 2.04 (95% CI, 1.02-4.08, I2 = 53%). Nevertheless, no notable differences were detected in ORs for outcomes like preterm birth, live birth, miscarriage, cesarean delivery, pregnancy-induced hypertension, small for gestational age babies, large for gestational age newborns, and neonatal intensive care unit admissions between pregnant women with hyperandrogenic PCOS phenotype and those without. CONCLUSIONS: This meta-analysis highlights that the presence of hyperandrogenism heightens the risks of GDM and PE within the PCOS population. Healthcare providers ought to be aware of this connection for improved patient management.

The gut microbial composition in polycystic ovary syndrome with hyperandrogenemia and its association with steroid hormones.

Background: Polycystic ovary syndrome (PCOS) is characterized by excess androgens, ovulatory dysfunction, and polycystic ovaries. The mechanisms underlying ovulatory and metabolic disorders in PCOS remain elusive, hampering therapeutic development. Enhanced metabolic health correlates with increased microbiota gene content and microbial diversity. We aimed to explore the impact of gut microbiota and serum steroids on PCOS regulation associated with androgen excess. Methods: The fecal samples of patients with hyperandrogenic PCOS (n = 14) and control group with PCOS (n = 14) were analyzed by 16S rRNA gene sequencing. The peripheral venous blood of all subjects was collected to detect serum hormones. The association between gut microbiota and serum hormones was analyzed with the R language. Results: Our findings reveal that the hyperandrogenic PCOS group exhibits lower richness and diversity of gut microbiota compared to the control group. Characteristic genera in PCOS patients with hyperandrogenism include Bifidobacterium, Enterobacteriaceae_unclassified, Streptococcus, Saccharimonadaceae, Enterococcus, and Eubacterium_nodatum_group. Five hormones, including 5ß-androsterone, deoxycorticosterone, corticosterone, 11-dehydrocorticosterone, and cortexolone, emerge as potential serum biomarkers for identifying patients with hyperandrogenic-PCOS (HA-PCOS). Furthermore, a lower vitamin D3 level may act as a susceptibility factor, suggesting that vitamin D3 supplementation could serve as a potential intervention for PCOS with hyperandrogenism. Conclusion: Specific fecal microbiota and serum steroids may be used as characteristic markers for clinical diagnosis of hyperandrogenic-PCOS. This research enhances our understanding of the intricate interplay among hormones, gut microbiota, and hyperandrogenemia in patients with PCOS.

Therapeutic potential of acarbose in ameliorating the metabolic and endocrinological complications of polycystic ovarian syndrome: a review.

Polycystic ovarian syndrome is a perplexed condition addressing endocrinal, cardiometabolic and gynaecological issues. It affects women of adolescent age and is drastically increasing in the Indo-Asian ethnicity over the recent years. According to Rotterdam criteria, PCOS is characterized by clinical or biochemical excess androgen and polycystic ovarian morphology; however, it has been established in the recent years that PCOS exacerbates to further serious metabolic conditions on the long term. This is a narrative literature review and not systematic review and is based on PubMed searches with relevant keywords "Polycystic ovarian syndrome AND acarbose OR metformin OR myoinositol; PCOS AND metabolic syndrome OR cardiovascular disease OR menstrual irregularity OR infertility OR chronic anovulation OR clinical hyperandrogenism" used in the title and are limited to articles published in English language with no time limits. A prominent aspect of PCOS is hyperandrogenaemia and hyperinsulinemia. About 50-70% of afflicted women have compensatory hyperinsulinemia and close to one tierce suffer from anovulation and infertility. Insulin resistance leads to metabolic complications and works with luteinizing hormone in increasing the ovarian androgen production. This excess androgen leads to clinical manifestations, irregular menstrual cycles and infertility. There isn't an entire cure, only the symptomatic clinical factors are considered rather than focusing on the underlying long-term complications. Therefore, the article focuses on a potent alpha glucosidase inhibitor, acarbose which suppresses the post meal glucose and insulin by delaying the absorption of complex carbs. It exhibits cardio-metabolic and hormonal benefits and is well tolerable in the south asian population. This review highlights the safety, effectiveness of acarbose in ameliorating the long-term complications of PCOS.

The impact of androgen levels on serum metabolic profiles in patients with polycystic ovary syndrome.

OBJECTIVE: This study aimed to investigate the impact of serum androgen levels on metabolic profiles in patients with polycystic ovary syndrome (PCOS). METHODS: We included 216 patients with PCOS and 216 healthy individuals selected as the control group. According to the measured serum androgen levels, patients with PCOS were divided into the hyperandrogenism group and non-hyperandrogenism group. Clinical metabolic indicators were assessed and compared between the two groups. Additionally, we assessed the correlation between androgen levels and clinical metabolic indicators. RESULTS: The body mass index, waist-to-hip ratio, mF-G score, and acne score, as well as T, LH, LSH/FSH, FPG, Cr, UA, TG, TC, and LDL-C levels were significantly higher in the PCOS group than in the control group. The incidence of hyperandrogenism and clinical hyperandrogenism in the PCOS group was significantly higher than that in the control group. Regarding clinical hyperandrogenism, hirsutism, acne, and acanthosis nigricans were significantly more common in the PCOS group than in the control group. Serum androgen levels were significantly correlated with the mF-G score, acne score, FSH, glucose concentration at 30 min, glucose concentration at 60 min, glucose concentration at 120 min, FINS, N120, HOMA-IR, HbA1c, AUCG, UA, TG, and hHDL-Clevels. CONCLUSION: Elevated serum androgen levels are commonly observed in patients with PCOS and are associated with multiple metabolic abnormalities. Therefore, it is recommended to regularly monitor glucose and lipid metabolism-related indicators in patients with PCOS who have elevated androgen levels.

Effect of Consultation Number on the Assessment and Treatment of Polycystic Ovary Syndrome.

Background: The basic medical education stage is not enough to support physicians to fully diagnose and evaluate polycystic ovary syndrome (PCOS). The study aims to discover the difference in treatment choice between participants with different annual consultation number of PCOS, to promote lifelong learning, and drive balanced development within healthcare. Methods: This is a multicenter cross-sectional survey. Participants' basic information, knowledge of PCOS and treatment options were collected online. According to the annual consultation number of patients with PCOS, physicians were divided into three groups: 0-50 people/yr, 50-200 people/yr, and >200 people/yr, and the results were derived from χ2 test, Fisher exact test, and multivariate logistic regression analysis. Results: The study analyzed 1689 questionnaires, and 1206 physicians (71.4%) received less than 50 women per year, 388 physicians (30.0%) with an annual number of 50-200 women, and 95 physicians (5.6%) with patient turnover for more than 200 people. Reproductive endocrinologists generally have higher access to the clinic. As the number of visits increases, more and more physicians would perceive patients as more likely to have abnormal blood glucose and heavy weight. Physicians with large numbers of consultations are more likely to use Asian or Chinese standards to assess obesity. The multivariate analysis involved variables such as age, hospital level, specialty, and patient turnover annually, and more young doctors actively assessed lipid profile (odds ratio (OR) 1.56, 95% confidence interval (CI) (1.16, 2.16)), and primary hospitals (OR 0.65 CI (0.44, 0.89)) chose OGTT for blood glucose assessment less than tertiary hospitals. Physicians in secondary hospitals are more aggressive in evaluating androgens. Conclusion: Our survey found differences in endocrine assessment, metabolic screening, and treatment in PCOS women in terms of the number of obstetrician-gynecologists who received different patient consultation numbers. The importance of continuing education for physicians is emphasized, to promote lifelong learning.

The Current and Emerging Role of Statins in the Treatment of PCOS: The Evidence to Date.

Polycystic ovary syndrome (PCOS) manifests a multifactorial pathology characterized by polycystic ovaries, menstrual cycle disorders, varying degrees of hyperandrogenism, and an ad-verse metabolic risk profile. The position of hyperandrogenism in this syndrome has been extensively studied. A multitude of mechanisms place it in the position of cause but also of consequence; therefore, ongoing research efforts are focused on identifying medications that can effectively reduce levels of androgens in women with PCOS. Moreover, lipid abnormalities are common in this population, with up to 70% of patients having dyslipidemia. Statins may have potential therapeutic benefits for women with PCOS, as they have been shown to improve insulin resistance and reduce the risk of cardiovascular disease. In addition, their role in accelerated steroidogenesis by limiting one source of cholesterol, influencing enzymatic activity, and providing several other beneficial mechanisms is widely investigated. This review aimed to provide a comprehensive overview of the pathogenesis of androgen excess and dyslipidemia in PCOS, as well as the therapeutic potential of statins.

Ovarian steroid cell tumors: what do we know so far?

Steroid cell tumors (SCT) of the ovary are rare, which has limited advances in the understanding of this enigmatic neoplasm. In this review, we summarize currently known clinicopathologic information on SCT. SCT are frequently hormonally active, leading to elevated serum and/or urine levels of androgenic hormones or their metabolites, and associated symptomatology, including virilization. The reported age at diagnosis is broad and has ranged from as young as 1 year old to 93 years old, although most patients were between ages 20 and 40 years. Most tumors are stage I and unilateral. The tumors are usually well circumscribed with a solid or solid to cystic cut surface. The tumors in one series reportedly ranged in size from 1.2 to 45 cm (average 8.4 cm). MRI is a useful imaging modality, typically showing a well delineated mass with contrast enhancement and lipid content on T2 and T1 weighted images, respectively. Microscopically, SCT display polygonal to epithelioid cells with abundant eosinophilic to vacuolated/clear cytoplasm and display an immunoprofile that is consistent with sex cord-stromal differentiation. Most cases are benign, without any recurrences after primary resection, but a subset - probably less than 20% of cases -are clinically malignant. Pathologic criteria that can specifically predict patient outcomes remain elusive, although features that correlate with adverse outcomes have been proposed based on retrospective studies. The molecular characteristics of SCTs are similarly under characterized, although there is some evidence of an enrichment for hypoxia-signaling gene mutations in SCT. In malignant SCT, the tumors generally show greater global genomic instability, copy number gains in oncogenes, and occasional BAP1 mutation. Future studies involving multi-institutional cohort and unbiased molecular profiling using whole exome/transcriptome sequencing are needed to help advance our molecular understanding of SCTs.

Susceptibility loci identified in Han Chinese influence genetic predisposition of PCOS in Indian women.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a multifactorial disorder characterized by a broad spectrum of reproductive and metabolic perturbations, necessitating early timely diagnosis and management. PCOS is a multigenic disorder and ample evidence from family based, candidate gene and genome-wide association studies (GWAS) has implicated genetic factors in development and progression of PCOS. The first GWASs in Han Chinese population revealed prominent gene loci to be strong contenders in the etiopathogenesis of PCOS. However, different ethnic and geographical settings impact the genetic association pattern of PCOS. METHODS AND RESULTS: In the current case-control replication study, we have genotyped previously identified polymorphisms viz. rs2479106 and rs10818854 of DENND1A and rs13405728 of LHCGR, rs4385527 and rs3802457 of c9orf3, rs705702 of RAB5B and rs1894116 of YAP1 in control (N = 247) and PCOS (N = 504) women by Sanger sequencing, and their association with PCOS susceptibility and its related traits was investigated. We found significant association of rs4385527 of c9orf3 and rs1894116 of YAP1 with decreased and increased PCOS susceptibility respectively in non-hyperandrogenic women. Trend towards association was also noted for rs2479106 of DENND1A and rs705702 of RAB5B. Additionally, polymorphisms also showed association with metabolic and androgen related traits in both controls and hyper- and non-hyperandrogenic women with PCOS. CONCLUSIONS: Thus, this study shows that some, but not all polymorphisms previously identified in Han Chinese women, could contribute to the genetic pathophysiology of PCOS in Indian women, accentuating essentiality of conducting replication studies to elucidate the genetic predisposition profile of PCOS.

Depletion of gut microbiota influents glucose metabolism and hyperandrogenism traits of mice with PCOS induced by letrozole.

Background: Polycystic ovary syndrome (PCOS) is a multifaceted disorder that impacts metabolism, reproduction, as well as endocrine function, characterized by excessive levels of androgen and insulin resistance. The gut microbiota has been implicated in the pathogenesis of PCOS. However, the precise mechanisms through which the gut microbiota influences PCOS still require further elucidation. Methods: The PCOS mouse model was established through the administration of letrozole to both conventional and antibiotics-treated mice. The evaluation of glucose metabolism, sex hormone levels, and ovarian morphology was conducted. Furthermore, the fecal samples from each group of mice were subjected to 16S rRNA gene sequencing, and functional prediction of gut microbiota was proceeded using PICRUSt2 to explore potential mechanisms. Results: By using letrozole-induced PCOS mice model, we manifested that antibiotic intervention significantly reduced the serum total testosterone level and ameliorated glucose intolerance. Antibiotic treatment reduced the number of amplicon sequence variants (ASVs), as well as the Shannon and Simpson index. Meanwhile, letrozole induced a significant increase in the Shannon and Simpson index instead of ASVs. Through random forest model analysis, the results revealed significant alterations in three distinct groups of microbiota, namely Clostridia_vadinBB60_group, Enterorhabdus, and Muribaculaceae after letrozole treatment. Further correlation analysis revealed a positive association between alterations in these microbiota and both serum total testosterone levels and the area under the curve (AUC) of blood glucose in IPGTT. The administration of antibiotics led to a decrease in the absolute abundance of 5 ASVs belonging to unclassified Clostridia_vadinBB60_group, unclassified Enterorhabdus, and unclassified Muribaculaceae, which exhibited a positive correlation with the levels of total testosterone in mice serum, as well as the area under the curve of blood glucose in IPGTT. Moreover, 25 functional pathways of gut microbiome were significantly discrepant between the letrozole-treated mice with and without antibiotics. Conclusion: These results suggest that disturbance of the gut microbiota may take participate in the progression of PCOS and manipulating the composition of the gut microbiota may be a therapeutic approach for managing PCOS.

The prolactin receptor gene (PRLR) is linked and associated with the risk of polycystic ovarian syndrome.

The prolactin receptor gene (PRLR) may contribute to polycystic ovarian syndrome (PCOS) since it plays important roles in physiological ovarian functions. PRLR-knockout mice have irregular cycles and subfertility and variants in or around the PRLR gene were associated in humans with female testosterone levels and recurrent miscarriage. We tested 40 variants in the PRLR gene in 212 Italian families phenotyped by type 2 diabetes (T2D) and PCOS and found two intronic PRLR-variants (rs13436213 and rs1604428) significantly linked to and/or associated with the risk of PCOS. This is the first study to report PRLR as a novel risk gene in PCOS. Functional studies are needed to confirm these results.

Prevalence of Polycystic Ovarian Syndrome and Its Link to Obesity in Adolescent Girls.

Polycystic ovarian syndrome (PCOS), also referred to as Stein-Leventhal syndrome, happens to be one of most common hormonal disorders found in females, causing large-sized ovaries with small cysts of non-ovulated oocytes in the outer medulla part of the ovary. Women suffering from PCOS often exhibit symptoms like oligomenorrhoea, elevated testosterone levels, acne, alopecia, hirsutism, sudden weight gain and many more. It can predispose a woman to developing infertility in future, and thus, difficulties in conceiving; due to the cystic changes in the ovaries, it results in anovulation and amenorrhea. The early symptoms of PCOS are being commonly observed nowadays in young women who are in their early 20s and those who are overweight or obese. The metabolic expression of PCOS increases with obesity. Obesity is a factor that is considered to contribute the most in the occurrence of various long-standing and non-transmissible illnesses apart from PCOS such as atherosclerosis, hypertension, diabetes, high blood cholesterol and even certain types of cancers. In obesity, there is an increase in the size and number of fat cells in the body. Obese and overweight young girls have a heightened likelihood of developing PCOS and its corresponding metabolic and reproductive health complications.

Obesity and Hyperandrogenemia in Polycystic Ovary Syndrome: Clinical Implications.

Polycystic ovary syndrome (PCOS) is often accompanied with metabolic disturbances attributed to androgen excess and obesity, but the contribution of each has not been defined, and the occurrence of metabolic disturbances is usually not investigated. Ninety-nine women with PCOS and forty-one without PCOS were evaluated. The clinical biomarkers of alterations related to glucose (glucose, insulin, and clamp-derived glucose disposal - M), liver (aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase), and endothelium (arginine, asymmetric dymethylarginine, carotid intima-media thickness, and flow-mediated dilation) metabolism were measured; participants were categorized into four groups according to their obesity (OB) and hyperandrogenemia (HA) status as follows: Healthy (no-HA, lean), HA (HA, lean), OB (no-HA, OB), and HAOB (HA, OB). Metabolic disturbances were very frequent in women with PCOS (≈70%). BMI correlated with all biomarkers, whereas free testosterone (FT) correlated with only glucose- and liver-related indicators. Although insulin sensitivity and liver enzymes were associated with FT, women with obesity showed lower M (coef = 8.56 - 0.080(FT) - 3.71(Ob); p < 0.001) and higher aspartate aminotransferase (coef = 26.27 + 0.532 (FT) + 8.08 (Ob); p = 0.015) than lean women with the same level of FT. Women with obesity showed a higher risk of metabolic disorders than lean women, independent of hyperandrogenemia. Clinicians are compelled to look for metabolic alterations in women with PCOS. Obesity should be treated in all cases, but hyperandrogenemia should also be monitored in those with glucose-or liver-related disturbances.