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Objectives: There is a growing evidence indicating an impact of endocrine distrupting chemicals such as bisphenol A (BPA) on human reproduction. Its higher levels in serum or urine have been documented in women with polycystic ovary syndrome (PCOS), however the relationship to ovarian steroidogenesis remains unclear. Aim of the study was to compare urinary BPA (U-BPA) concentrations among PCOS women and control group. Second aim was to assess the relationship of U-BPA to ovarian steroidogenesis in the group with PCOS., Methods: Eighty six Caucasian women (age 28.5 ± 5.1 years) diagnosed with PCOS and 32 controls of age 24.9 ± 4.4 years were included in the study. Fasting blood samples were analyzed for biochemical parameters and steroid hormones. U-BPA was measured in the morning urine sample using high pressure liquid chromatography., Results: PCOS women had significantly higher U-BPA as compared with control group (p=0.0001). Those with high levels of U-BPA (U-BPA ≥ 2.14 ug/g creatinine) demonstrated higher serum insulin (p=0.029) and HOMA IR (p=0.037), lower serum estrone (p=0.05), estradiol (p=0.0126), FSH (p=0.0056), and FAI (p=0.0088), as compared with low-BPA group (U- BPA <2.14 ug/g creatinine). In PCOS women, U-BPA positively correlated with age (p=0.0026; R 2 =0.17), negatively with estradiol (p=0.0001, R 2 =0.5), testosterone (p=0.0078, R 2 =0.15), free-testosterone (p=0.0094, R 2 =0.12) and FAI (p=0.0003, R 2 =0.32), respectively., Conclusions: PCOS women have significantly higher U-BPA concentrations than healthy controls. U-BPA positively correlates with age and negatively with ovarian steroid hormones suggesting a possible suppressive effect of bisphenol A on ovarian steroidogenesis., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Ovarian reserve reflects the quality and quantity of available oocytes and has become an indispensable measure for the better understanding of reproductive potential. Proteomic approaches are especially helpful in discerning differential protein expression patterns associated with normal and diseased states and, thus, proteomic analyses are increasingly used to identify clinically useful biomarkers. The aim of this study was to investigate proteins secreted in the urine of patients with different ovarian reserve by proteomic techniques to identify potential markers for assessing ovarian reserve., Methods: Urine samples were obtained from patients with polycystic ovary syndrome (PCOS) and diminished ovarian reserve (DOR), and from normal control (NC)participants. We used isobaric tags for relative and absolute quantification (iTRAQ) technology combined with mass spectrometry analysis to identify candidate urinary proteins in the three groups. The selected proteins were confirmed using western blot analysis and enzyme-linked immunosorbent assay (ELISA). Diagnostic performance of the selected proteins was assessed using receiver operating characteristic analysis., Results: When Compared with NC samples, 285 differentially expressed proteins (DEPs) were identified in the DOR samples and 372 in the PCOS samples. By analyzing the intersection of the two groups of DEPs, we found 26 proteins with different expression trends in the DOR and PCOS groups. Vitamin D-binding protein (VDBP) was the key protein for the protein-protein interaction network. ELISA quantification of urinary VDBP revealed the highest levels in the PCOS group, followed by the NC group and the lowest levels in the DOR group (115.90 ± 26.02, 81.86 ± 23.92 and 52.84 ± 21.37 ng/ml, respectively; P < 0.05). As a diagnostic marker, VDBP had a sensitivity of 67.4% and a specificity of 91.8% for DOR, and a sensitivity of 93.8% and a specificity of 77.6% for PCOS., Conclusions: Urinary VDBP is closely associated with ovarian reserve and can be considered as a novel noninvasive biomarker of ovarian reserve. However, studies including large sample sizes are needed to validate these results.

Introduction and Purpose: The Urinary Neutrophil-gelatinase associated lipocalin (NGAL) levels which are a biomarker for early diagnosis of kidney damage that may develop in patients with Polycystic Ovary Syndrome (PCOS) were investigated in the study., Material and Methods: The 30 patients diagnosed with Polycystic Ovarian Syndrome between the ages of 13 and 18 who applied to the Yuzuncu Yil University General Children's Outpatient Clinic were included in the PCOS group and 30 healthy adolescents without any known acute or chronic illness and drug use were included in the control group., Findings: Urine NGAL value was 842.204 ± 21.561 in PCOS group and 775.379 ± 23.98 in control group. NGAL level in PCOS group was statistically significantly higher than control group (p: .045). When we examine the relationship between dyslipidemia and PCOS; While dyslipidemia was positive in 10 (33.7%) patients in the PCOS group, it was negative in 20 (66.7%) patients. While 1 patient had dyslipidemia, 29 patients did not have dyslipidemia in the control group. A significant relationship was found between dyslipidemia and PCOS (p: .005)., Conclusion: We found that subclinical kidney dysfunction started in early stage patients in PCOS in our study. The urine NGAL level was thought to increase in response to increased oxidative stress in PCOS. We found no relationship between, insulin resistance and urea, BUN, creatinine and NGAL levels. However, we found a negative correlation between NGAL level and LDL. In addition, dyslipidemia, insulin resistance and ALT elevation were detected in the PCOS group.

Background: Bisphenol A (BPA), a widespread industrial substance is recognized as endocrine disrupting chemical and therefore could be associated with polycystic ovary syndrome (PCOS) related metabolic disturbances., Patients: In this study 29 women of reproductive age with diagnosed PCOS were enrolled., Methods: BPA in urine samples was analyzed by gas chromatography-mass spectrometry., Results: BPA was detected in urines of 48.28% participants. The waist-to-height ratio (WtHR) was statistically significant higher in PCOS BPA+ in comparison to PCOS BPA- women (p = 0.046). PCOS BPA+ women had 6.88 times (95%Cl 1.3481-35.0600, z = 2.319, p = 0.020) higher risk for waist circumference above 80 cm and 4.95 odds (95%Cl 1.0169-24.096, z = 1.981, p = 0.048) to have WtHR over 0.5 when compared to PCOS BPA-. Statistically significant positive association between BPA urine concentrations and insulin serum levels (p = 0.038) was obtained. BPA urine values were associated with elevated HOMA-IR values and reduced HDL levels with moderate significance (p = 0.079 and p = 0.061, respectively). Also, there was 3.75 times (95%Cl 0.7936-17.7203, z = 1.668, p = 0.095) higher risk for PCOS BPA+ women to have testosterone levels above reference values., Conclusion: The obtained results suggested that the BPA exposition in PCOS women was followed by increased metabolic risk through promotion of obesity, especially the visceral type, hyperinsulinemia, insulin resistance, dyslipidemia and elevated androgen levels., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder, which affects 4-10 % women of reproductive age. Though accumulating scientific evidence, its pathogenesis remains unclear. In the current study, metabolic profiling as well as diagnostic biomarkers for different phenotypes of PCOS was investigated using non-invasive urinary GCMS based metabolomics. A total of 371 subjects were recruited for the study. They constituted the following groups: healthy women, those with hyperandrogenism (HA), women with insulin-resistance (IR) in PCOS. Two cross-comparisons with PCOS were performed to characterize metabolic disturbances. A total of 23 differential metabolites were found. The altered metabolic pathways included glyoxylate and dicarboxylate metabolism, pentose and glucuronate interconversions, and citrate cycle and butanoate metabolism. For differential diagnosis, a panel consisting of 9 biomarkers was found from the comparison of PCOS from healthy subjects. The area under the receiver operating characteristic (ROC) curve (AUC) was 0.8461 in the discovery phase. Predictive value of 89.17 % was found in the validation set. Besides, a panel of 8 biomarkers was discovered from PCOS with HA vs IR. The AUC for 8-biomarker panel was 0.8363, and a panel of clinical markers (homeostasis model assessment-insulin resistance and free androgen index) had 0.8327 in AUC. While these metabolites combined with clinical markers reached 0.9065 in AUC from the discovery phase, and 93.18 % in predictive value from the validation set. The result showed that differences of small-molecule metabolites in urine may reflect underlying pathogenesis of PCOS and serve as biomarkers for complementary diagnosis of the different phenotypes of PCOS., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Polycystic ovarian syndrome (PCOS) is the most common endocrine disease that causes reproductive abnormalities in fertile women. It is closely related to the persistent anovulatory, insulin resistance, and high androgen. However, the molecular mechanisms underlying the pathological development of PCOS are still unclear. In this study, we aimed to explore the distinctive metabolic patterns in insulin combined with human chorionic gonadotrophin induced PCOS. The dynamic changes of endogenous metabolites in the development of PCOS were studied using untargeted metabolomic approaches based on nuclear magnetic resonance. The results showed that the degree of PCOS disorder metabolites at different periods was not exactly the same. Twelve significantly differential endogenous metabolites from different time points were selected as potential biomarkers relate to pathological process of PCOS. Among them, six metabolites showed a good diagnostic accuracy with PCOS model. The arginine and proline metabolic pathway was considered as one of the most crucial pathways that affects occurrence and development of PCOS. In addition, IRS-1, Akt, PI3K, IκB, and NF-κB (p65) were significantly changed in the ovary tissue of PCOS rats, which revealed that the IRS-1-PI3K/Akt and NF-κB signal pathway may be involved in the development of PCOS. This study demonstrated that metabolomic analysis is a powerful tool for providing novel insight into understanding the pathogenesis of PCOS and provide a basic reference for the diagnosis of PCOS at the onset stage., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Polycystic Ovary Syndrome (PCOS) is a metabolic disorder prevalent globally. Female infertility cases are also on the increase during the recent times which almost matches with the increasing incidence of PCOS. The NIH-USA-defined symptoms for clinical confirmation of PCOS include oligo-ovulation, elevated androgen level and presence of cysts in the ovary. Therapeutic approaches to PCOS require confirmatory diagnostics such as measurement of hormones and ultrasound scan of the ovary, which are in part, invasive. Conversely, the volatile organic compounds (VOCs) that are present in body fluids (urine, feces, saliva, etc.) and exhaled breath are reported to be endogenously altered in diseased state, which may be indicative of diseases including cancer. We hypothesize that the hindered metabolic state in PCOS condition would conditionally alter the VOCs that eventually are excreted in urine, which may offer a template to develop a viable and non-invasive diagnostic tool., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy of women at reproductive age. Although the aetiology of PCOS remains unclear, potential effects of environmental endocrine-disrupting compounds on the development of PCOS have drawn increasing attention. The aim of the current study was to examine the association between triclosan (TCS) and PCOS, and explore possible mechanisms on how TCS may contribute to the development of clinical manifestations of PCOS., Design: Cross-sectional study., Setting: This study was conducted in one tertiary-level hospital located in Zhejiang, China., Participants: A total of 674 infertile women at 18-45 years of age were recruited in 2014-2015. Participants with (n=84) and without (n=212) PCOS with urinary TCS concentration available were included in the analyses., Methods: Urinary TCS concentration was measured using a high-performance liquid chromatography-electrospray ionisation tandem mass spectrometry. Logistic regression model was used to examine the association between TCS and PCOS. Fractional polynomial regression models were built to fit the potential non-linear relationship between TCS concentrations and luteinising hormone (LH) and LH/follicle stimulate hormone (FSH)., Results: The PCOS group had significantly higher level of TCS concentration than the non-PCOS group (the median of TCS (IQR), μg/g creatinine: 1.49 (0.68-3.80) vs 1.06 (0.52-3.02), p=0.0407). Compared with the lowest tertile, the highest tertile of TCS concentration was associated with an increased odd of PCOS (OR 2.12, 95% CI 1.12 to 3.99). After adjusting for potential confounders, the significant association remained (OR 1.99, 95% CI 1.05 to 3.79). Positive relationships were found between TCS levels and LH and LH/FSH ratio in non-PCOS participants., Conclusions: TCS exposure at a relatively low level is associated with PCOS in Chinese women. Further epidemiological studies are needed to confirm our finding, which may have important public health implications., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although the polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women with vast metabolic consequences, its etiology remains unknown and its diagnosis is still made by exclusion. This study aimed at characterizing a large number of urinary steroid hormone metabolites and enzyme activities in women with and without PCOS in order to test their value for diagnosing PCOS., Methods: Comparative steroid profiling of 24h urine collections using an established in-house gas-chromatography mass spectrometry method. Data were collected mostly prospectively. Patients were recruited in university hospitals in Switzerland. Participants were 41 women diagnosed with PCOS according to the current criteria of the Androgen Excess and PCOS Society Task Force and 66 healthy controls. Steroid profiles of women with PCOS were compared to healthy controls for absolute metabolite excretion and for substrate to product conversion ratios. The AUC for over 1.5 million combinations of metabolites was calculated in order to maximize the diagnostic accuracy in patients with PCOS. Sensitivity, specificity, PPV, and NPV were indicated for the best combinations containing 2, 3 or 4 steroid metabolites., Results: The best single discriminating steroid was androstanediol. The best combination to diagnose PCOS contained four of the forty measured metabolites, namely androstanediol, estriol, cortisol and 20βDHcortisone with AUC 0.961 (95% CI 0.926 to 0.995), sensitivity 90.2% (95% CI 76.9 to 97.3), specificity 90.8% (95% CI 81.0 to 96.5), PPV 86.0% (95% CI 72.1 to 94.7), and NPV 93.7% (95% CI 84.5 to 98.2)., Conclusion: PCOS shows a specific 24h urinary steroid profile, if neglected metabolites are included in the analysis and non-conventional data analysis applied. PCOS does not share a profile with hyperandrogenic forms of congenital adrenal hyperplasias due to single steroid enzyme deficiencies. Thus PCOS diagnosis by exclusion may no longer be warranted. Whether these findings also apply to spot urine and serum, remains to be tested as a next step towards routine clinical applicability., Competing Interests: The authors have declared that no competing interests exist.

Background: Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder, and it's diagnosis is difficult. The aim of this study was to investigate the metabolic profiles of PCOS patients by analyzing urine samples and identify useful biomarkers for diagnosis of PCOS., Methods: This study was carried out in the Department of Obstetrics and Gynecology of the Maternal and Child Health Hospital of Hunan Province from December 2014 to July 2016. In this study, the urine samples of 21 women with PCOS and 16 healthy controls were assessed through gas chromatography-mass spectrometry to investigate the urine metabolite characteristics of PCOS and identify useful biomarkers for the diagnosis of this disorder. The Student's t-test and rank sum test were applied to validate the statistical significance of the between the two groups., Results: In total, 35 urine metabolites were found to be significantly different between the PCOS patients and the controls. In particular, a significant increase in the levels of lactose (10.01 [0,13.99] mmol/mol creatinine vs. 2.35 [0.16, 3.26] mmol/mol creatinine, P = 0.042), stearic acid (2.35 [1.47, 3.14] mmol/mol creatinine vs. 0.05 [0, 0.14] mmol/mol creatinine, P < 0.001), and palmitic acid (2.13 [1.07, 2.79] mmol/mol creatinine vs. 0 [0, 0] mmol/mol creatinine, P < 0.001) and a decrease in the levels of succinic acid (0 [0, 0] mmol/mol creatinine vs. 38.94 [4.16, 51.30] mmol/mol creatinine, P < 0.001) were found in the PCOS patients compared with the controls. It was possible to cluster the PCOS patients and the healthy controls into two distinct regions based on a principal component analysis model. Of the differentially expressed metabolites, four compounds, including stearic acid, palmitic acid, benzoylglycine, and threonine, were selected as potential biomarkers., Conclusions: This study offers new insight into the pathogenesis of PCOS, and the discriminating urine metabolites may provide a prospect for the diagnosis of PCOS., Competing Interests: There are no conflicts of interest

To better understand possible effects of bisphenol A (BPA) exposure on ovarian reserve in women with polycystic ovary syndrome (PCOS), we measured creatinine adjusted urinary BPA (BPA&#95;Cre) concentrations and used regression models to evaluate the association between urinary BPA level and antral follicle count (AFC), antimullerian hormone (AMH), day-3 follicle stimulating hormone levels (FSH) and inhibin B (INHB) in 268 infertile women diagnosed with PCOS. BPA was detected in all women with a median concentration of 2.35 ng/mL (the 25th and 75th percentiles of 1.47 ng/mL and 3.95 ng/mL). A unit increase in BPA&#95;Cre was associated with a significant decrease of 0.34 in AFC (β = -0.34, 95% CI = -0.60, -0.08; p = 0.01). Likewise, BPA was negatively associated with AMH and day-3 FSH levels, but neither of them reached statistical significance. No association was observed between BPA and INHB. Our results suggest that in women with PCOS, BPA may affect ovarian follicles and, therefore, reduce ovarian reserve., Competing Interests: The authors declare no conflict of interest.

Objective: To investigate the impact of urinary albumin excretion (UAE) and cystatin C on the metabolic components of polycystic ovary syndrome (PCOS)., Methods: Seventy-five women with PCOS were divided into two groups according to metabolic syndrome as MetS + and MetS-. Clinical, metabolic and renal parameters were compared between the groups. Correlation analyses were performed between cystatin C, microalbuminuria and clinical and metabolic parameters in women with PCOS., Results: Waist/hip ratio (WHR), body mass index, LDL cholesterol, triglyceride, total cholesterol, cystatin C, UAE were significantly higher in the MetS + group compared with the MetS - one. HDL cholesterol was significantly higher in the MetS - group than the MetS + one. The UAE positively correlates with LDL cholesterol, triglyceride and total cholesterol levels. Cystatin C positively correlates with UAE, WHR, LDL cholesterol, triglyceride, total cholesterol levels., Conclusions: Evaluating UAE and cystatin C may be important for the detection of target subjects at high risk for future metabolic syndrome and cardiovascular disease.

Background: Polycystic ovary syndrome (PCOS) is an endocrine disorder whose pathogenesis remains unclear. There are also no effective biomarkers for this disease. We evaluated the metabolic changes in PCOS patients and to investigate potential metabolic biomarkers for PCOS., Methods: Twenty-two women with PCOS and 15 healthy controls were studied. Urine samples were assessed through ultra-performance liquid chromatography-mass spectrometry followed by principal component analysis and partial least squares discriminant analysis., Results: Using the presented methods, 59 urine metabolites were found at different concentrations in PCOS patients. Moreover, two novel potential biomarkers, testosterone-glucuronide and 11α-hydroxyprogesterone, and four candidate biomarkers, benzofenap, methionyl-phenylalanine, MG(18:4(6Z,9Z,12Z,15Z)/0:0/0:0) and 2-(14,15-epoxyeicosatrienoyl) glycerol, were found to show significant differences through variance analysis (P<0.01) and were identified as target metabolites. The two potential biomarkers identified in this study highly correlate to the metabolites catalyzed by the ovarian cytochrome P450c17α., Conclusions: Two novel potential urinary biomarkers, testosterone-glucuronide and 11α-hydroxyprogesterone, and four candidate urinary biomarkers, benzofenap, methionyl-phenylalanine, MG(18:4(6Z,9Z,12Z,15Z)/0:0/0:0), and 2-(14,15-epoxyeicosatrienoyl) glycerol, were identified in PCOS patients by a metabolomic approach. Further study of the biomarkers using larger populations is needed to validate these biomarkers and thereby understand the pathogenesis of PCOS, potentially allowing for its diagnosis., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to assess the association between premicroalbuminuria and metabolic syndrome in women with Polycystic Ovary Syndrome (PCOS)., Methods: In this case - control study, we analyzed the medical records of 78 women (mean age ±SD was 27.2± 2.5 years) with PCOS and 63 controls (mean age ±SD was 26.9±2.4 years) from an endocrinology outpatient center of Buali university hospital Qazvin city in Iran during 2008 to 2010. Anthropometric characteristics, Albumin/Creatinine Ratio (ACR), Lipid profile, Liver enzyme concentration and occurrence of metabolic syndrome were compared between the two groups. Premicroalbuminuria was defined as ACR>7mg/g., Results: Premicroalbuminuria was found in 53.8% of PCOS and 33.3% of control group (p value=0.015). Patients with PCOS and premicroalbuminuria had higher serum levels of fasting insulin and glucose, blood pressure and more waist circumference compared to PCOS patients who had ACR<7mg/g. Fifty percent of patients with PCOS and ACR>7mg/g fulfilled criteria of metabolic syndrome; whereas no case of metabolic syndrome was found in PCOS patients without premicroalbuminuria., Conclusions: Premicroalbuminuria is more prevalent in patients with PCOS compared to normal individuals. Metabolic syndrome is more frequently seen in patients with PCOS and premicroalbuminuria against patients with ACR<7mg/g.

Objective: This study was planned to screen polycystic ovary syndrome (PCOS) women for albuminuria and to evaluate the association between urinary albumin excretion (UAE) and metabolic disturbances of PCOS. In addition, this is the first study in the literature evaluating the association between UAE and carotid intima-media thickness (CIMT) in PCOS cases., Study Design: The study population consisted of 65 PCOS women. The study was prospectively designed and performed in a university hospital. The diagnosis of PCOS was made according to the Rotterdam criteria: exclusion criteria were hyperprolactinemia, thyroid dysfunction, adrenal dysfunction, diabetes mellitus, hypertension, and pregnancy. Blood samples were collected in the follicular phase of a menstrual cycle and serum samples were analyzed for fasting glucose, insulin, and hormone and lipid profiles. Twenty-four hour urine specimens were collected for the detection of UAE. CIMT was estimated by visual assessment of the distance between the lumen-intima and intima-adventitia interfaces., Results: The mean age and BMI were 23 years and 23 kg/m(2), respectively. The median UAE was 7 mg/day (range: 0.3-154 mg/day). The median UAE as micrograms of albumin per milligram of creatinine (uACR) was 5.6 (0.28-159). Regarding the uACR cutoff value (>6.93 μg/mg), significantly higher levels of triglycerides, 17 OH-progesterone, insulin resistance (HOMA index > 2.1) and increased CIMT were present in these cases. Microalbuminuria (uACR > 25 μg/mg) was present in 6.2%. In the regression analyses serum HDL-C levels were found to be independent predictor for uACR > 2 μg/mg (OR: 0.85) and estradiol levels were the independent predicting factor for uACR > 6.93 μg/mg even after adjustments for age and BMI were performed (OR:1.02)., Conclusions: UAE, expressed as uACR > 6.93 μg/mg, seems to be an associated sign of metabolic problems which might help in discriminating PCOS at risk of future CVD. Further studies are needed before routine use of albuminuria in PCOS cases for the detection of CVD risk., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate urinary albumin excretion (UAE) in normotensive and nondiabetic women with polycystic ovary syndrome (PCOS) in relation to their clinical, endocrine, and metabolic profiles., Design: Observational study., Setting: University fertility center., Patient(s): Sixty-three women with PCOS were evaluated., Intervention(s): Clinical assessments and urine and blood testing., Main Outcome Measure(s): Urinary albumin excretion, systolic and diastolic blood pressure, serum levels of LH, FSH, PRL, T, 17-hydroxyprogesterone, glucose, insulin, lipids, C-reactive protein, and 24-hour urinary free cortisol., Result(s): In univariate and multivariate correlation analysis, UAE correlated with diastolic blood pressure, insulin area under the curve during glucose tolerance test, PRL, and 17-hydroxyprogesterone. Overt microalbuminuria was detected in a significant proportion of subjects., Conclusion(s): Urinary albumin excretion in women with PCOS correlates well with other cardiovascular risk factors. Because the relationship between UAE and adverse cardiovascular events is continuous, evaluation of UAE in the presence of PCOS may provide clinically relevant information and may aid in selecting appropriate patients for more aggressive treatment of likely aggravating factors, such as hyperinsulinemia or borderline hypertension., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

To determine whether metformin, when given to women with polycystic ovary syndrome (PCOS), promotes folliculogenesis by prompting a drop in free sex steroids resulting in a compensatory follicle stimulating hormone (FSH) rise, we conducted a randomized, double-blind, placebo-controlled crossover clinical trial. Eight mid-reproductive age PCOS participants with mean obese body mass index (BMI) and normal glucose tolerance received 8 weeks of metformin, given in a step-up fashion to a maximum dose of 2000 mg daily or placebo with daily urine sampling, 4-6 weeks washout, and crossover to the remaining arm for 8 weeks. To confirm the effects of metformin on glucose and other metabolic markers, a hyperinsulinemic, euglycemic 3-dose clamp (physiologic: 30 mU/m(2) per minute, high: 400 mU/m(2) per minute) followed each treatment. Urinary FSH, luteinizing hormone (LH), or pregnanediol glucuronide (Pdg) did not differ by treatment. Glucose disposal, endogenous glucose production, BMI, ovulation rates, serum sex steroids, free fatty acids, and lipids did not significantly differ by treatment, despite good evidence for compliance with the protocol. During the clamp, high-dose insulin administration was associated with an acute drop in serum LH. We conclude that short-term, high-dose metformin exerts minimal effects on both metabolic markers and reproductive hormones in a small sample of overall morbidly obese women.

Objective: To determine the relationship between urinary albumin excretion and features of the metabolic syndrome in women with polycystic ovary syndrome (PCOS)., Methods: We retrospectively analyzed the medical records of 189 premenopausal women (mean age +/- SD, 28.9 +/- 7.7 years) with PCOS and 81 control patients (mean age +/- SD, 37.9 +/- 8.6 years) from a single endocrinology practice. Exclusion criteria were diabetes, heart disease, kidney disease, use of lipid-lowering agents, and use of antihypertensive agents (except spironolactone). The urine albumin-to-creatinine ratio (ACR) was measured in a random single-voided urine sample. Premicroalbuminuria was defined as an ACR >7 mg/g., Results: The prevalence of ACR >7 mg/g was 31.2% in the PCOS group (N = 189) and 35.8% in the control group (N = 81). The metabolic syndrome was noted in 16.3% (27 of 166) of patients with PCOS and in 2.9% (2 of 69) of control subjects. Nine percent of patients with PCOS who had an ACR 7 mg/g had the metabolic syndrome. Patients with PCOS who had an ACR >7 mg/g had significantly higher blood pressure and alanine aminotransferase levels than did those with an ACR 7 mg/g, no significant difference was found in frequency of use of metformin, spironolactone, or oral contraceptives., Conclusion: In women with PCOS, an ACR >7 mg/g was strongly associated with the metabolic syndrome, high blood pressure, and elevated alanine aminotransferase levels. It may be useful to consider ACR >7 mg/g as an associated sign of the presence of metabolic syndrome in women with PCOS.

Context: Women with polycystic ovary syndrome (PCOS) have anovulation due to arrested follicular maturation. The substrate (2-hydroxyestrogen) and product (2-methoxyestrogen) of catechol-O-methyl transferase (COMT) have been shown to modulate proliferation and angiogenesis of granulosa cells., Objective: The objective of the study was to evaluate COMT ovarian expression as well as the production of estrogen metabolites (2-hydroxyestrogen and 2-methoxyestrogen) in subjects with PCOS., Design: Immunohistochemistry was used to assess COMT expression in ovarian tissues. Urinary levels of 10 different estrogens and estrogen metabolites were measured using enzyme-labeled immunoassays and/or liquid chromatography with tandem mass spectrometry., Setting: The study was conducted at a tertiary university referral center., Patients and Other Participants: Ovarian tissues were obtained from six control subjects and six subjects with PCOS. Fasting first-void urinary samples were collected from 49 subjects with PCOS and 36 healthy control subjects., Main Outcome Measure(s): COMT protein expression in ovarian tissues was measured. Urinary levels of 2-hydroxyestrogen and 2-methoxyestrogen levels in PCOS patients were also measured., Results: Whereas immunohistochemistry showed that COMT was expressed in ovaries from control and PCOS subjects, its expression was significantly higher in ovaries from subjects with PCOS, in both the follicular structures and ovarian stroma. The urinary 2-hydroxyestrogen level was significantly lower in subjects with PCOS, compared with normal controls (P = 0.009). Additionally, urinary 2-hydroxyestrogen levels negatively correlated with serum insulin levels in subjects with PCOS (r = -0.333, P =0 .031)., Conclusions: Urinary 2-hydroxyestrogen is decreased in subjects with PCOS, which could be due in part to increased ovarian expression of COMT. Further studies are needed to ascertain the role of estrogen metabolism in PCOS before this information can be used in clinical settings.

Urine based gonadotropin assays provide a practical means of analyzing hormone secretion patterns. While research protocols have revealed pulsatile patterns of gonadotropins such as LH in the blood, these assays are of limited clinical use since daily venipuncture sampling is not feasible outside of a research environment. However, collection of several urine samples provides a method to achieve the same visualization of gonadotropin patterns in patients using a convenient and generally applicable technique based on analysis of the highly stable hLHbetacf for monitoring LH and hCGbetacf for monitoring pituitary hCG. We demonstrated that two different sampling techniques for analyzing these gonadotropin metabolites yielded the same information on their excretory patterns, either sampling of spot urines or collecting first morning void urines for several days. Next, we studied the core excretory patterns in several populations: menstruating and postmenopausal women from the general population, and two populations of women from a fertility center, one of which had polycystic ovaries (PCO). The PCO population was also subdivided into those with and without insulin resistance (IR). It was found that our hLHbetacf assay did not measure the form of the LH core (v-hLHbetacf) produced in subjects who were homozygous for a variant form of LH (v-LH). None of our patients tested were homozygous for the variant form of LH. It was also found that in most non-PCO (NPCO) patients, the hLHbetacf peak lasted for 7-9 days while among the PCO patients this peak frequently lasted for less than 7 days and an erratic pattern tended to appear. The overall differences in patterns between the PCO and NPCO patients were confirmed by spectral statistical methods. The prevalence of certain characteristic hLHbetacf patterns may be higher among women with PCO with a more severe clinical presentation. Use of urinary analysis of gonadotropin metabolites, especially hLHbetacf, may supplement subjective ultrasound studies with more sensitive biochemical measurements.

Context: Apparent cortisone reductase deficiency (ACRD) is a rarely ascertained condition characterized by signs of androgen excess in women or children and decreased urinary excretion of cortisol metabolites compared with cortisone metabolites. These findings suggest a deficiency of 11beta-hydroxysteroid dehydrogenase type 1 (11-HSD1; encoded by the HSD11B1 gene), which normally converts cortisone to cortisol. Common polymorphisms in both HSD11B1 and the hexose-6-phosphate dehydrogenase (H6PD) gene encoding hexose-6-phosphate dehydrogenase have been found together in ACRD patients, who carry three of a possible four minor alleles at the two loci., Objective: The objective of this study was to confirm the postulated digenic inheritance mechanism for ACRD., Design: This was a population-based association study (Dallas Heart Study). Subjects were genotyped for the 1971T>G polymorphism in intron 3 of HSD11B1 and the R453Q polymorphism in H6PD., Subjects: The study comprised 3551 individuals in a population-based sample (50% black, 35% white, and 15% Hispanic)., Main Outcome Measure: The main outcome measure was association between genotypes and risk for polycystic ovarian syndrome., Results: Both polymorphisms occurred more frequently than previously reported. Thus, ACRD genotypes (at least three of four minor alleles) occurred in 7.0% of subjects. There were no associations between genotype and body mass index; waist/hip ratio; visceral adiposity; measures of insulin sensitivity; levels of testosterone, FSH, or LH (in females); or risk of polycystic ovarian syndrome. There was no genotype effect on urinary free cortisol/cortisone or corticosteroid metabolite ratios, which were measured in 10 subjects, each carrying zero, three, or four minor alleles., Conclusions: Previously reported associations of ACRD with HSD11B1 and H6PD alleles represent ascertainment bias. However, rare severe mutations in these genes cannot be ruled out.

Hyperandrogenism, a main clinical feature of polycystic ovary syndrome (PCOS), is thought to result from enhanced ovarian and adrenal androgen generation. To investigate the contribution of peripheral steroidogenesis, we used an oral challenge with dehydroepiandrosterone (DHEA) and analyzed its downstream conversion toward androgens in eight women with PCOS (age, 20-32 yr; body mass index, 20-41 kg/m(2)) and eight healthy women matched for age and body mass index. They underwent frequent serum sampling and urine collection for 8 h on three occasions: at baseline, and after 4 d of dexamethasone (Dex; 4 x 0.5 mg/d), followed by ingestion of 100 mg DHEA or placebo. Dex induced similar significant suppression of circulating steroids in both groups. The oral DHEA challenge led to similar significant increases in the area under the concentration-time curve (0-8 h after Dex) of serum DHEA, DHEA sulfate, androstenedione, and testosterone. However, after oral DHEA, PCOS women had significantly higher increases in serum 5 alpha-dihydrotestosterone (P < 0.01), its main metabolite androstanediol glucuronide (P < 0.05), and the 5 alpha-reduced urinary androgen metabolite androsterone (P < 0.05). PCOS women also had significantly higher baseline excretion of 5 alpha-reduced glucocorticoid (P < 0.01) and mineralocorticoid metabolites (P < 0.05). Taken together, these data indicate enhanced peripheral 5 alpha-reductase activity in PCOS. Thus, not only ovary and adrenal, but also liver and peripheral target tissues, significantly contribute to steroid alterations in PCOS.

Background: Various studies have reported a prevalence of polycystic ovaries (PCO) of approximately 20% in the 'normal' population. Our aim was to investigate the frequency of ovulation and pattern of luteal phase progesterone secretion in a group of women with PCO who reported regular cycles and in whom ovulation had been established on the basis of previous investigations., Methods: Subjects collected early morning urine samples for pregnanediol-3-glucuronide measurement from day 10 of the cycle to day 1 of their next menses. Results in three consecutive cycles from women with PCO (group 1, n = 10 and 29 for patients and cycles respectively) were compared with results from two groups with normal ovaries; with either infertility (group 2, n = 10 and 30) or proven fertility (group 3, n = 6 and 19)., Results: There were considerable variations in cycle length. The median (range) was group 1: 28 (23-47); group 2: 26 (21-36) and group 3: 27 (25-38) days with more short cycles in both infertile groups. There was more variation in pregnanediol:creatinine in the normal-ovary infertile and PCO groups than in the fertile controls. Levels were higher in the early luteal phase in the fertile normal group than in either infertile group, and the mid-luteal phase peak was lower in the infertile women with normal ovaries. In summary, there was greater variability in luteal phase pregnanediol:creatinine ratios in the PCO and infertile normal-ovary groups than in women with normal ovaries and proven fertility., Conclusion: Women with PCO did not have more variation in cycle length than fertile women with normal ovaries, but there were significantly lower levels of progesterone in the early luteal phase. This may contribute to the delay in conception in these patients.

Objective: To determine melatonin production in hyperandrogenic women., Design: Controlled prospective study., Setting: Outpatients in an academic medical center., Patient(s): Twenty-two women with polycystic ovary syndrome (PCOS), 20 women with idiopathic hirsutism, and 15 age-matched individuals who had similar body mass indexes as controls., Intervention(s): Fasting blood samples and 24-hour urinary samples were obtained from all participants., Main Outcome Measure(s): All participants provided serum samples for the measurement of LH, FSH, testosterone, E(2), DHEAS, 17 alpha-hydroxyprogesterone (17-OHP), and insulin levels, as well as urinary 6-sulfatoxymelatonin (aMT6s)., Result(s): Women with PCOS had higher aMT6s, testosterone, LH/FSH ratio, and insulin values than either women with idiopathic hirsutism or control women. Testosterone inversely correlated with aMT6s in PCOS. Regression analysis revealed that only testosterone was an important determinant of aMT6s in PCOS., Conclusion(s): Women with PCOS have increased melatonin production.

Prostate-specific antigen (PSA) is a well-established tumor marker of prostatic adenocarcinoma. Human glandular kallikrein 2 (hK2), another serine protease closely related to PSA, is also gaining ground as a promising diagnostic tool in prostate cancer. The expression of these 2 proteases is known to be regulated by androgens and progestins in hormonally responsive tissues, such as the male prostate and the female breast. Previously, we have shown that serum PSA levels in normal women are very low but still detectable by ultrasensitive PSA immunoassays. We have also demonstrated that some women with hyperandrogenic syndromes have elevated serum PSA levels. In this study, we have measured urinary PSA and urinary hK2 levels in 35 polycystic ovary syndrome (PCOS) patients and compared them to those of 41 age-matched controls. We found that urinary PSA levels were significantly higher (P < 0.0001) in PCOS patients (mean +/- SE = 820 +/- 344 ng/L) than in the controls (mean +/- SE = 4.3 +/- 1.8 ng/L). Similarly, the difference between urinary hK2 of patients (mean +/- SE = 8.2 +/- 3.1 ng/L) and controls (0.5 +/- 0.3 ng/L) was also significant (P < 0.001). A weak correlation was observed between urinary PSA and serum 3 alpha-androstanediol glucuronide (r(s) = 0.42, P = 0.03) as well as between urinary PSA and serum testosterone (r(s) = 0.40, P = 0.04). The results of this study indicate that urinary PSA, and possibly urinary hK2, are promising markers of hyperandrogenism in females suffering from PCOS.

The aim of the study was to evaluate the hormonal (focusing on the urinary steroid profile) and clinical effects of chronic gonadotropin-releasing hormone (GnRH) agonist treatment in patients with polycystic ovary syndrome (PCOS) suffering from hirsutism. A long-acting GnRH agonist was administered for 6 months in eight PCOS patients. Hormonal effects were measured by determining serum luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, testosterone and estradiol concentrations, and by profiling urinary steroids using capillary gas chromatography of 24-hour urine samples. To evaluate 5 alpha-reductase enzyme activity, the ratios of androsterone to etiocholanolone and 5 alpha-tetrahydrocortisol to tetrahydrocortisol were calculated in urine samples. The ratio of androgen to cortisol metabolites was also determined before, and 3 and 6 months after therapy. LH and estradiol levels were suppressed significantly after the first injection and testosterone after the second injection of the GnRH agonist. Thus, serum testosterone was normalized. Ratios of urinary steroids reflecting 5 alpha-reductase enzyme activity (androsterone to etiocholanolone and 5 alpha-tetrahydrocortisol to tetrahydrocortisol) and the ratio of androgen to cortisol metabolites decreased significantly after 3 months of treatment. Degree of hirsutism, assessed by Ferriman-Gallwey score, diminished after 6 months, but not significantly. In conclusion, our data show that long-acting GnRH agonist treatment of PCOS patients is effective in reducing serum and urinary androgen levels, but it is not accompanied by an effective reduction in hirsutism during a 6-month treatment period. A longer or a combined treatment would be needed to achieve significant improvement in hirsutism. Gas chromatographic profiling of urinary steroids and the use of specific ratios of the excreted metabolites seems to be a sensitive tool both in the diagnosis of PCOS and in monitoring ovarian suppression.

Objective: The aetiology of enhanced adrenal androgen secretion in polycystic ovary syndrome is poorly understood. Previous reports suggest that enhanced peripheral metabolism of cortisol results in decreased negative feedback suppression of ACTH secretion, either by enhanced inactivation of cortisol by 5alpha-reductase or impaired reactivation of cortisol by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Endogenous inhibitors of hepatic 11beta-HSD1 can be extracted from urine. We have tested the hypothesis that these are increased in patients with polycystic ovary syndrome., Design: A case-control study., Patients: 57 patients with polycystic ovary syndrome and 27 healthy control women., Measurements: Aliquots from 24 h urine samples were extracted with Sep-Paks and incubated with rat liver microsomes in which 11beta-HSD1 activity was quantified by conversion of 3H-corticosterone to 3H-11-dehydrocorticosterone., Results: Inhibition of 11beta-HSD1 activity was not different in extracts from patients compared with controls (40.8 +/- 18.9 arbitrary units in patients vs. 42.7 +/- 16.6 in controls, mean (+/- SEM, P > 0.60) and did not correlate with ratios of cortisol metabolites in urine or with body mass index., Conclusions: The altered cortisol metabolism in polycystic ovarian syndrome, which is consistent with impaired 11beta-HSD1 activity, cannot be accounted for by increased production of measurable endogenous inhibitors of this enzyme.

Objective: Polycystic ovary syndrome (PCO) is one of the most common endocrine disorders affecting women. Several lines of evidence have suggested the involvement of the sympathetic nervous system (SNS) in this condition. The present work was designed to assess neurochemically SNS activity in patients during the early stages of PCO., Design and Patients: Fourteen patients with PCO (aged 14 to 21 years) were studied on a random day and 9 normal regularly cycling adolescents (aged 14 to 20 years) were studied during the early follicular phase (days 2 to 5)., Measurements: Hormonal profile was determined in basal conditions. LH and FSH were also measured after i.v. administration of 100 micrograms GnRH. Plasma concentrations of dihydroxyphenylalanine (Dopa), noradrenaline (NA), adrenaline (A), total dopamine (DA) and dihydroxyphenylglycol (DHPG) were determined in basal conditions and in response to GnRH by HPLC with electrochemical detection or a radioenzymatic method. Basal urinary Dopa, catecholamines and catechol metabolites (DHPG, vanillylmandelic acid (VMA), 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), metanephrine (MN) and normetanephrine (NMN)) were determined by HPLC with electrochemical detection., Results: Basal plasma LH, testosterone, androstenedione, oestrone and LH/FSH ratio were higher (P < 0.01) and serum sex hormone-binding globulin (SHBG) were lower (P < 0.01) in PCO patients than in control subjects. Basal and GnRH-stimulated plasma free Dopa, A, NA and total DA were similar in patients and controls. Plasma DHPG was lower (P < 0.01) in PCO patients (4.20 +/- 0.30 nmol/l) than in controls (8.0 +/- 1.0 nmol/l) throughout the study. Urinary A, NA, DA, Dopa, MN, MHPG, HVA, and VMA were similar in patients and controls. Urinary DHPG was lower (P < 0.01) in PCO patients (0.50 +/- 0.02 mumol/d) than in controls (0.73 +/- 0.09 mumol/d). On the other hand PCO patients had a higher urinary excretion of NMN than controls (PCO: 1.20 +/- 0.10; C: 0.78 +/- 0.10 mumol/d, P < 0.05)., Conclusions: Our results show the same endocrinological features in adolescent PCO patients as those reported in adults. The results also demonstrate a peripheral catecholaminergic alteration which suggests an alteration in noradrenaline deamination and/or uptake in adolescent patients. This study however does not permit us to conclude that PCO is primarily caused by this sympathetic alteration.

Objective: Prolonged period of amenorrhoea are regarded as a risk factor for the appearance of osteoporosis. Amenorrhoea is a feature of different pathological conditions with heterogeneous endocrine profiles. We evaluated bone mineral metabolism in patients with polycystic ovary syndrome (PCOS), hypothalamic amenorrhoea and idiopathic hirsutism in order to establish the relative importance for the maintenance of normal bone mass of ovulatory cycles and androgen and oestrogen production., Patients and Measurements: Bone mineral density (BMD), bone turnover markers and endocrine profile were evaluated in 51 patients with PCOS, 24 patients with idiopathic hirsutism, 26 patients with hypothalamic amenorrhoea and 35 healthy women. Body mass index (BMI) ranged between 20.1 and 31.0 kg/m2, and age from 17 to 33 years. Thirty-eight of the PCOS patients were amenorrhoeic (< 4 menstrual cycles/year)., Results: Spine and femoral BMD were significantly decreased and bone markers (serum osteocalcin, and urinary excretion of free deoxypyridinoline, cross-linked N-telopeptide and hydroxyproline) significantly increased in the patients with hypothalamic amenorrhoea, when compared to control subjects and the other two patient groups. In the sub-group of PCOS patients with amenorrhoea, spine and femoral neck BMD was significantly lower than in patients with idiopathic hirsutism and the non-amenorrhoeic PCOS patients. In all PCOS patients, spine and neck BMD were positively correlated (P < 0.05) with serum androstenedione and free testosterone levels., Conclusions: The results of this study suggest that in patients with polycystic ovary syndrome the deleterious effect on bone of amenorrhoea is balanced by androgen overproduction.

To evaluate the clinical relevance of testing pituitary-ovarian responses in patients suffering from polycystic ovary syndrome (PCOS) with the GnRH agonist nafarelin, a 1.2-mg dose of nafarelin was given intranasally to 19 women with PCOS and 15 healthy premenopausal women. The subsequent analysis of steroids in both serum and urine during the test was carried out at several time points for up to 24 h. Serum levels of 17 alpha-hydroxyprogesterone were elevated at all time points of the test in PCOS patients vs. controls [at baseline, 3.5 +/- 0.2 vs. 1.8 +/- 0.1 nmol/L (P < 0.001); at 24 h, 9.9 +/- 0.9 vs. 4.9 +/- 0.3 nmol/L (P < 0.001)]. Basal levels of androstenedione were higher in the patient group, but there was no significant change during the test in either group. Serum testosterone levels were also found to differ in PCOS patients compared with the control values at baseline (2.2 +/- 0.2 vs. 1.5 +/- 0.1 nmol/L; P < 0.05) and after nafarelin treatment (at 24 h, 3.2 +/- 0.4 vs. 1.8 +/- 0.2 nmol/L; P < 0.05). Serum estradiol levels rose significantly in both groups during the test; the posttest levels were significantly higher in PCOS than in controls. The PCOS patients displayed a significant increase in androgen and gestagen metabolites as well as in glucocorticoid metabolites excreted in the urine during the 24 h. In the control subjects, except for 17 alpha-hydroxypregnanolone, which rose significantly, none of the urinary steroids investigated showed relevant changes during the nafarelin test. The posttest excretion of allo-tetrahydrocortisol (1.4 +/- 0.2 vs. 0.3 +/- 0.1 mumol/g creatinine; P < 0.001) and the increase in 17 alpha-hydroxypregnanolone excretion (1.4 +/- 0.2 vs. 0.3 +/- 0.1 mumol/g creatinine; P < 0.001) were distinctly higher in PCOS patients than in the controls; the diagnostic sensitivity of the combination of both parameters was 89% at a 93% specificity. Thus, measurements of 17 alpha-hydroxyprogesterone levels in serum and of urinary allo-tetrahydrocortisol and 17 alpha-hydroxypregnanolone after nafarelin treatment make this stimulation test a valuable diagnostic tool for identifying PCOS patients. The significant changes in the excretion of urinary androgen and gestagen metabolites, unmasked by GnRH agonist stimulation, suggest a functional alteration of the pituitary-ovarian axis. The reason for the increased excretion of glucocorticoid metabolites after nafarelin stimulation remains to be clarified.

Background: Hyperandrogenemia is the hallmark of the polycystic ovary syndrome, yet the relative contributions of the adrenal cortex and ovary to the overproduction of androgen remain unclear. To identify possible causes of adrenocortical overactivity, we studied the metabolism of adrenal and ovarian steroid hormones in women with this disorder., Methods: We measured 24-hour urinary excretion of steroid hormone metabolites by high-resolution capillary gas chromatography in 65 women with the polycystic ovary syndrome and 45 normal women matched for body-mass index., Results: After adjustment for body-mass index, the urinary excretion of testosterone and androstenedione metabolites was 1.9 times higher in the women with the syndrome than in the normal women, and the excretion of dehydroepiandosterone metabolites (C19 steroid sulfates) and cortisol metabolites was 1.5 and 1.3 times higher, respectively (P < 0.01 for all comparisons). The affected women also had significantly higher ratios of 11-oxo (oxygenated) metabolites to 11-hydroxy metabolites of cortisol (1.4 times higher, P < 0.001) and of 11-oxo to 11-hydroxy metabolites of corticosterone (1.8 times higher, P < 0.001). In the group with the polycystic ovary syndrome, 55 percent of the nonobese women and 24 percent of the obese women had ratios above the upper limit of normal; the ratios in the obese women did not differ significantly from those in the nonobese women., Conclusions: Adrenal secretion of cortisol and androgens is increased in women with the polycystic ovary syndrome. The increases may be explained by dysregulation of 11 beta-hydroxysteroid dehydrogenase causing increased oxidation of cortisol to cortisone, which cannot be accounted for by obesity.

The adrenal participation in the pathogenesis of polycystic ovary syndrome is still under debate. In order to reappraise androgen and glucocorticoid secretion in this disease, we measured serum androstenedione, dehydroepiandrosterone-sulphate, total and free testosterone, sex hormone-binding globulin, LH, FSH, PRL, cortisol, corticosteroid-binding globulin, and urinary free cortisol in 45 women with polycystic ovary syndrome and 27 controls, subdivided in obese and normal-weight subjects. Androstenedione, total and free testosterone were significantly increased, whereas sex hormone-binding globulin tended to be reduced in patients with polycystic ovary syndrome compared with controls, reaching a significant difference between obese patients and matched controls. Free testosterone and sex hormone-binding globulin were significantly increased and reduced, respectively, in obese compared with normal-weight patients. Urinary free cortisol and serum corticosteroid-binding globulin were significantly increased (p less than 0.001) and decreased (p less than 0.005), respectively. Urinary free cortisol exceeded the upper limit of the normal range in 50% of our patients. No appreciable differences were found in PRL and cortisol levels. Besides confirming a hyperandrogenic state, our findings point to an overactivity of the hypothalamic-pituitary-adrenal axis with subsequent diminution of corticosteroid-binding globulin in polycystic ovary syndrome. They also indicate that urinary free cortisol is not a reliable index in differentiating polycystic ovary syndrome from Cushing's disease.

The patient with PCOD remains a challenge to the reproductive endocrinologist. Although successful induction of ovulation can often be achieved using standard therapeutic regimens of CC or hMG, too often this group of anovulatory patients fails to respond as expected. Over the past 10 to 15 years, alternate approaches to ovulation induction have been investigated with encouraging results. Whereas no one method is productive in all patients, these varied regimens offer us a number of options in dealing with this difficult clinical problem.

11 patients with polycystic ovary syndrome (hirsutism and oligomenorrhoea), but with no deficiency of 21-hydroxylase or 3 beta-hydroxysteroid dehydrogenase, had abnormal cortisol metabolism. The high ratio of 5 alpha to 5 beta cortisol metabolites in the urine is consistent with enhanced activity of 5 alpha-reductase. Urinary total cortisol metabolites were higher in patients than controls. Increased 5 alpha-reductase activity in liver and skin enhances hepatic cortisol metabolism at the expense of androgen excess and may be the underlying abnormality in polycystic ovary syndrome.

Urinary excretion of oestrogens in response to stimulation with a standardized dose of gonadotrophin has been used previously in the differential diagnosis of oligomenorrhoea/amenorrhoea. Patients with polycystic ovarian disease were said to have a characteristic excessive response. In the present study, some patients with laparoscopically proven polycystic ovaries did not show such an excessive response, while others with laparoscopically normal ovaries did. A high LH/FSH ratio correlated well with the laparoscopic finding of polycystic ovaries. It is concluded that where there are adequate facilities for diagnostic laparoscopy and determination of plasma gonadotrophins, there is no further place for the routine use of the standardized gonadotropin stimulation test in the evaluation of suspected polycystic ovarian disease.

Ten infertile patients with polycystic ovarian disease were treated with 18 cycles of "pure" human pituitary follicle-stimulating hormone (HP-FSH) and 10 cycles of human menopausal gonadotropin (HMG) consisting of FSH and luteinizing hormone (LH) in a 1:1 ratio. Human chorionic gonadotropin was used to trigger ovulation when optimal follicular development was achieved as judged by urinary estrogen determinations. Of the 18 cycles utilizing HP-FSH, 14 were presumptively ovulatory, 2 were conceptual, and in 5 cycles ovarian enlargement was noted. Of the 10 HMG cycles, none was ovulatory, no conceptions resulted, and 6 instances of hyperstimulation were noted. Pretreatment serum LH levels were significantly higher than normal follicular phase values. These observations suggest that endogenous LH levels in patients with polycystic ovaries are quite adequate for follicular development so that the administration of exogenous LH is unwarranted. Furthermore, the data suggest that HP-FSH or low-LH-containing HMG may prove to be an additional safe and effective nonsurgical treatment modality for patients who are anovulatory because of polycystic ovaries.

Previous studies suggested that a relative dopamine (DA) deficiency may explain the altered LH secretory dynamics that occur in patients with polycystic ovary syndrome (PCO). These studies included findings of decreased urinary excretion of homovanillic acid (HVA), a metabolite of DA, and increased urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), the major brain metabolite of norepinephrine. To further explore the role of DA in these patients, disulfiram (250 mg) was administered daily for 2 weeks to alter the conversion of DA to norepinephrine and to increase both peripheral and central DA in patients with PCO and in normal women. LH pulse frequency and amplitude and the serum LH response to GnRH were assessed before and during disulfiram administration. A dopaminergic effect during disulfiram administration was evidenced by a decrease in serum PRL in the PCO patients and an increase in urinary HVA excretion and a decrease in the ratio of 3-methoxy-4-hydroxyphenylglycol to HVA in urine in both groups (all P less than 0.05). This increase in DA did not significantly alter the serum estrogen level, the mean serum LH level, LH pulse amplitude, or serum LH responses to GnRH in either the PCO patients or the normal women. These data suggest that increasing endogenous DA does not correct the inappropriate gonadotropin secretion characteristic of PCO and places further doubt on the importance of DA in explaining the altered LH secretory dynamics in these patients.

The clinical features, ovarian pathology, and hormonal responses to dexamethasone (Dex), Dex + ethinyl estradiol (EE), and Dex + hCG were compared in 5 women with polycystic ovarian disease (PCOD) who have normal 24-hr urinary luteinizing hormone (LH levels to 5 who had elevated urinary LH levels. No differences were noted in the clinical features. There was no correlation between ovary size and LH levels. Three in the normal-LH group had hyperthecosis. Plasma androstenedione (A) was more frequently elevated in the high-LH group. Dex + EE markedly increased LH secretion in the high-LH group, suggesting increased responsiveness of the positive feedback control mechanism of LH secretion in the high-LH group. There was a greater response of A, testosterone (T), and 17-ketosteroids to Dex + hCG in the normal-LH group. Those with high-LH levels did not exhibit a significant increase in A, T, and 17-KS with hCG. The limitations and usefulness of the Dex + hCG test are discussed. The hypothesis is advanced that the increased LH secretion in the high-LH group is due at least in part to positive feedback resulting from the increased A levels. The amount of 17beta-oxidoreductase activity in the ovary may influence LH secretion in PCOD.

One hundred and one patients with polycystic ovary syndrome (PCO) were treated during an 11-year interval. Sixty-seven cases were classified as typical PCO with enlarged ovaries of probable ovarian origin (Type I) and 34 as atypical PCO of probable adrenal origin (Type II). Fifty-five patients were treated for anovulatory infertility with clomiphene citrate or other endocrine therapy as indicated. There was a 91% ovulatory response and 51% conception rate from therapy in cases of Type I PCO. In Type II PCO, adrenal suppressive therapy resulted in a 55% ovulatory response. Our data support the concept that anovulation of ovarian origin as seen in PCO Type I responds to clomiphene therapy, while anovulation secondary to adrenal hyperandrogenization should be treated by adrenal suppressive therapy.

The proportion of 20 alpha/20 beta-epimers of the urinary C21-steroid metabolites was estimated in normal volunteers and in patients with congenital adrenal hyperplasia (CAH), postpubertal virilizing syndrome (PVS) and polycystic ovary syndrome (POS). In the normal individuals 20 alpha- and 20 beta-epimers of 5 beta-pregnane-3 alpha, 17 alpha, 20-triol (pregnanetriol) and 5-pregnene-3 beta, 17 alpha, 20-triol (5-pregnenetriol) were measured. In the other case 20 alpha- and 20 beta-epimers of the characteristic, representative metabolites were also investigated. In 26 of 27 normal persons and in all the patients with normotensive CAH, PVS and POS the 20 beta-epimer comprised 0-10% of the total pregnanetriol. The 20 beta-epimer of 5-pregnenetriol was found in only one normal case (6% of the total). The percentage of 20 beta-epimers of 3 alpha, 17 alpha, 20-trihydroxy-5 beta-pregnan-11-one, 5 beta-pregnane-3 alpha, 11 beta, 17 alpha, 20-tetrol (in the normotensive CAH, PVS and POS) and 5 alpha- or 5 beta-pregnane-3 alpha, 17 alpha, 20, 21-tetrol (in the hypertensive CAH) varied from nil to 76%. The effect of functional groups and the stereochemistry of the molecule on the direction of C-20-keto group reduction is discussed; the existence of additional factors determining this reduction in certain pathological conditions is suggested.

The authors studied 158 young women with the syndrome of sclerocystic ovaries (SCO) and 40 healthy subjects. The patients showed a high rate of vegetovascular dystonia, predominantly according to the hyperparasympathicotonic type, cardialgia and dyspnea. In 54.5% of the patients lipid metabolism disturbances of the atherogenic nature were elicited, being most pronounced in the hypothalamic-pituitary form of the disease. It is postulated that in cases of the SCO syndrome, the deficit of estrogens and pregnanediol decreases "immunity" of females to the development of atherogenic dyslipoproteinemias while a relative or absolute hyperandrogenia accounts for the transformation of the "female" type of the lipid spectrum into the "male" type with lower levels of cholesterol of high density lipoproteins (LP) and higher levels of TG, and cholesterol of very low density LP and of low density LP. It is recommended that the SCO syndrome should be included into the risk factors for atherosclerosis and coronary heart disease.