Androgens In Polycystic Ovary Syndrome Research Articles

P-590 Discriminatory value of steroid hormones on polycystic ovary syndrome in women with infertility and obesity

Abstract Study question Which steroid hormone (ratio) has the highest discriminatory value in the biochemical diagnosis of polycystic ovary syndrome (PCOS) in women with infertility and obesity? Summary answer Androstenedione (A4) is a potentially useful discriminatory biomarker for PCOS in women with obesity, whereas Testosterone (T)/Dihydrotestosterone (DHT) and 11-oxygenated androgens are not. What is known already The best biomarker to assess biochemical hyperandrogenism in PCOS is still under discussion. Serum total or free T, followed by Free Androgen Index (FAI), and Dehydroepiandrosterone Sulfate (DHEA-S) are the most widely used biomarkers. T/DHT ratio has been proposed as a useful biomarker for PCOS. Moreover, a recent study demonstrated 11-oxygenated androgens represent the majority of circulating androgens in PCOS. Whether this is also relevant in women with obesity is unclear. We aimed to assess the discriminatory value of different steroid hormones and their ratios for PCOS as well as adverse metabolic phenotype within PCOS in women with obesity. Study design, size, duration We used the baseline data and samples originating from an RCT that examined whether a six-month lifestyle intervention prior infertility treatment in women with obesity improved live birth rate, compared to prompt infertility treatment. In total of 577 women with obesity were randomized between 2009 and 2012. Women were diagnosed with PCOS according to the Rotterdam criteria. Metabolic syndrome was diagnosed based on the revised criteria of the National Cholesterol Education Program. Participants/materials, setting, methods Women with PCOS comprised the study group (N = 132). Ovulatory women with idiopathic, tubal or male factor infertility were the control group (N = 83). Women were excluded when blood sampling was performed in the luteal phase or when baseline samples were unavailable. The steroid hormones were measured using LC-MS/MS. 11β-hydroxyandrostenedione (11OHA4) and 11-ketotestosterone (11KT) were analyzed using LC-MS/MS in a separate method. The discriminatory value was based on receiver operator characteristic (ROC) curves with adjustment for age. Main results and the role of chance The mean age was 28.1 years in the PCOS group and 30.9 years in the control group (p < 0.001). BMI was not significantly different (36.0±3.2 versus 35.7±3.5, p = 0.51). Among the tested steroid hormones (ratios), SHBG, A4, T, DHT, 11KT, FAI, T/DHT ratio, and T/A4 ratio showed statistically significant differences between the PCOS and the control group. DHEA, DHEA-S, 11OHA4 did not differ between the groups. The crude AUCs of FAI, T, A4, T/DHT ratio, SHBG, 11KT, T/A4 ratio, and DHT in ROC analysis for representing PCOS were 0.85, 0.84, 0.81, 0.70, 0.62, 0.59, 0.58, and 0.57 respectively. Among the markers with crude AUCs≥0.70, the incremental value of the marker A4 (AUC difference: 0.14, 95%CI: 0.07 to 0.21), T (0.18, 95%CI: 0.10 to 0.25), and FAI (0.18, 95%CI: 0.10 to 0.25) in addition to age showed significant improvement, but T/DHT ratio (0.02, 95%CI: –0.01 to 0.04) did not. However, the combination of A4 together with T or FAI did improve discriminatory value of individual T or FAI (AUC difference: –0.001, 95%CI: –0.004 to 0.003 and 0.007, –0.007 to 0.02, respectively). None of the measured steroid hormones (ratios) have promising discriminatory value for adverse metabolic phenotype within PCOS in women with obesity. Limitations, reasons for caution This is a post-hoc analysis and no power calculation was performed. There was a significant difference in age between women with and without PCOS, and residual confounding might exist. All PCOS patients in this analysis were infertile and obese, and it is conceivable that milder PCOS phenotypes are not represented. Wider implications of the findings T/DHT ratio and 11-oxygenated androgens might not serve as a promising discriminatory biomarker for PCOS in women with obesity, nor for adverse metabolic phenotype within PCOS in these women. A4 is a potential biomarker for PCOS diagnosis in women with infertility and obesity, however, its utility potency needs further validation. Trial registration number NTR 1530

Dihydrotestosterone- A Potential Biomarker of Hyperandrogenaemia in Polycystic Ovary Syndrome: A Case-control Study from North India

Introduction: Polycystic Ovary Syndrome (PCOS) is a complex reproductive disorder characterised by hyperandrogenism, ovulatory dysfunction and polycystic/enlarged ovary. Although clinical and/or biochemical hyperandrogenism is one of the major features of PCOS, biochemical hyperandrogenism in the form of high testosterone and/or Free Androgen Index (FAI) is rarely observed in the Asian Indians. Aim: To assess various androgens to determine best available biomarker of androgens in PCOS from North India. Materials and Methods: This case-control study was conducted at Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India, between January 2016 to December 2019. During this period 137 female with PCOS and 49 female as control were included. Serum total testosterone (T), FAI, Dehydroepiandrosterone Sulphate (DHEAS), androstenedione and Dihydrotestosterone (DHT) were measured besides assessment of hirsutism using the FerrimanGallwey (FG) scale. Statistical differences were derived using Mann-Whitney U test, Receiver Operating Characteristic (ROC) curve analysis and Spearman’s correlation test. Results: There were 87 PCOS cases with phenotype A, 25 PCOS cases with phenotype B, 10 PCOS cases with phenotype C and 15 PCOS cases with phenotype D. The mean age was 23.7 years in the PCOS group and 26.2 years in the control group. The mean body mass index in the PCOS group was 25.23 kg/m2 and in the control was 22.6 kg/m2 . FG score of ≥9 was observed in 75.9% PCOS cases. High (mean+2SD) levels of T (≥0.51 ng/ mL), FAI (≥2.55), DHEAS (≥309 ug/dL), androstenedione (≥2.2 ng/mL) and DHT (≥462 pg/mL) were observed in 35.29%, 56.25%, 14.18%, 18.62% and 61.38%, cases, respectively. Mean DHT value was 584.27 pg/mL in study group whereas in control was 257.16 pg/mL (p-value <0.0001) and area under ROC curve was 0.895. Similarly, area under ROC curve was 0.86, 0.817, 0.721 and 0.63 for FAI, testosterone, DHEAS and androstenedione, respectively. Spearman’s correlation test of androgens with body mass index, age and FG Score did not find any associations with DHT. Conclusion: Dihydrotestosterone (DHT) is best available biomarker and can be considered as diagnostic biomarker of hyperandrogenemia in PCOS women from north India.

The effect of chamomile on menstruation pattern and serum androgens in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is associated with menstrual disorders and hyperandrogenism, which is considered to be a common cause of hirsutism and infertility. Chamomile has been used as a medicinal herb known for its menstrual property. This study aimed to investigate the effect of chamomile on the menstruation pattern and serum androgens in PCOS women. This study was a randomized clinical trial, conducted on 80 women during their reproductive age with PCOS from April 2014 to August 2015. They were divided into intervention and control groups. The intervention group received a chamomile capsule (containing 370 mg dried powder of German chamomile flower) three times a day for 12 weeks, while the control group received placebo (starch-based capsules) with the same prescription order. Menstrual questionnaires as well as the androgens of testosterone and dehydroepiandrosterone were examined before and after 3 months. The primary outcome in the chamomile capsules user group, the number of participants with normal menstrual cycles significantly increased (p<0.001). In addition, a significant improvement in the number of menstrual cycles after the chamomile therapy was observed. A significant decrease was observed in testosterone levels in the intervention group. However, there was no significant change in the level of hormone dehydroepiandrosterone sulfate in both intervention and control groups (P = 0.423). Chamomile can have a significant impact on menstrual regulation and decrease the total testosterone levels in women of reproductive age with polycystic ovary syndrome. It is recommended that careful, large randomized controlled trials should be conducted to understand the mechanisms of action of chamomile and its effects on menstruation process.

Potential Health Benefits of Curcumin on Female Reproductive Disorders: A Review.

Curcumin is one of the main polyphenolic compounds in the turmeric rhizome. It possesses antioxidant, anti-inflammatory, anti-cancer, anti-arthritis, anti-asthmatic, anti-microbial, anti-viral and anti-fungal properties. This review aims to provide an overview of the potential health benefits of curcumin to treat female reproductive disorders, including polycystic ovary syndrome (PCOS), ovarian failure and endometriosis. Comprehensive information on curcumin was retrieved from electronic databases, which were MEDLINE via EBSCOhost, Scopus and Google Scholar. The available evidence showed that curcumin reduced the high level of androgen in PCOS. Studies in rodents suggest that curcumin resulted in the disappearance of cysts and the appearance of healthy follicles and corpora lutea. Furthermore, animal studies showed curcumin improved the overall function of the ovary in ovarian diseases and reversed the disturbance in oxidative stress parameters. Meanwhile, in vitro and in vivo studies reported the positive effects of curcumin in alleviating endometriosis through anti-inflammatory, anti-proliferative, anti-angiogenic and pro-apoptotic mechanisms. Thus, curcumin possesses various effects on PCOS, ovarian diseases and endometriosis. Some studies found considerable therapeutic effects, whereas others found no effect. However, none of the investigations found curcumin to be harmful. Curcumin clinical trials in endometriosis and ovarian illness are still scarce; thus, future studies need to be conducted to confirm the safety and efficacy of curcumin before it could be offered as a complementary therapy agent.

SARS-CoV-2 Viral Entry Proteins in Hyperandrogenemic Female Mice: Implications for Women with PCOS and COVID-19.

SARS-CoV-2, the causative agent of COVID-19, infects host cells using the angiotensin I converting enzyme 2 (ACE2) as its receptor after priming by host proteases, including TMPRSS2. COVID-19 affects multiple organ systems, and male patients suffer increased severity and mortality. Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is associated with obesity and cardiometabolic comorbidities, both being risk factors associated with severe COVID-19 pathology. We hypothesize that elevated androgens in PCOS regulate SARS-CoV-2 entry proteins in multiple tissues increasing the risk for this population. Female mice were treated with dihydrotestosterone (DHT) for 90 days. Body composition was measured by EchoMRI. Fasting glucose was determined by an enzymatic method. mRNA and protein levels of ACE2, Tmprss2, Cathepsin L, Furin, Tmprss4, and Adam17 were quantified by RT-qPCR, Western-blot, or ELISA in tissues, serum, and urine. DHT treatment increased body weight, fat and lean mass, and fasting glucose. Ace2 mRNA was upregulated in the lung, cecum, heart, and kidney, while downregulated in the brain by DHT. ACE2 protein was upregulated by DHT in the small intestine, heart, and kidney. The SARS-CoV-2 priming proteases Tmprss2, Cathepsin L, and Furin mRNA were upregulated by DHT in the kidney. ACE2 sheddase Adam17 mRNA was upregulated by DHT in the kidney, which corresponded with increased urinary ACE2 in DHT treated mice. Our results highlight the potential for increased cardiac, renal, and gastrointestinal dysfunction in PCOS women with COVID-19.

The correlation between vitamin D, glucose homeostasis and androgen level among polycystic ovary syndrome patients: a cross-sectional study

Background: Polycystic ovary syndrome (PCOS) is one of the most common systemic reproductive endocrine diseases. This study is aimed at determining vitamin D (vit D) status and establishing whether serum 25-hydroxy vitamin D [25(OH)D] is associated with glucose homeostasis and the level of androgen in PCOS. Material and Methods A total of 290 women with PCOS participated in this cross-sectional study. Glucose homeostasis was assessed by a 75-g oral glucose tolerance test and the concentration of serum 25-hydroxy vitamin D was determined among all subjects. The homeostasis model assessment of insulin resistance (HOMA-IR) was taken as the indicator of insulin resistance. Beta cell function was estimated using the insulinogenic index and the disposition index. Free androgen index (FAI) was used to represent the androgen level. Results In our study, 7.2% of the patients had Vit D severe deficiency, 75.2% had Vit D deficiency and 15.5% had vit D insufficiency. The level of serum 25(OH)D showed a significant positive association with insulinogenic index (r = 0.147, p < .05), disposition index (r = 0.280, p < .05), and SHBG (r = 0.178, p < .05) but exhibited a negative association with HOMA-IR (r = −0.198, p < .05), FAI (r = −0.178, p < .05). Adjusted age and BMI, 25(OH)D would be the dependent variable on disposition index [B = 0.259, 95%CI(0.041,0.477)] and FAI [B = −0.125, 95%CI(−0.232, −0.017)]. Conclusions According to our results, the low levels of serum 25(OH)D were common in women with PCOS, which was speculated to be associated with glucose homeostasis and the androgen level.

Prenatal androgen exposure causes a sexually dimorphic transgenerational increase in offspring susceptibility to anxiety disorders

If and how obesity and elevated androgens in women with polycystic ovary syndrome (PCOS) affect their offspring’s psychiatric health is unclear. Using data from Swedish population health registers, we showed that daughters of mothers with PCOS have a 78% increased risk of being diagnosed with anxiety disorders. We next generated a PCOS-like mouse (F0) model induced by androgen exposure during late gestation, with or without diet-induced maternal obesity, and showed that the first generation (F1) female offspring develop anxiety-like behavior, which is transgenerationally transmitted through the female germline into the third generation of female offspring (F3) in the androgenized lineage. In contrast, following the male germline, F3 male offspring (mF3) displayed anxiety-like behavior in the androgenized and the obese lineages. Using a targeted approach to search for molecular targets within the amygdala, we identified five differentially expressed genes involved in anxiety-like behavior in F3 females in the androgenized lineage and eight genes in the obese lineage. In mF3 male offspring, three genes were dysregulated in the obese lineage but none in the androgenized lineage. Finally, we performed in vitro fertilization (IVF) using a PCOS mouse model of continuous androgen exposure. We showed that the IVF generated F1 and F2 offspring in the female germline did not develop anxiety-like behavior, while the F2 male offspring (mF2) in the male germline did. Our findings provide evidence that elevated maternal androgens in PCOS and maternal obesity may underlie the risk of a transgenerational transmission of anxiety disorders in children of women with PCOS.

Simultaneous quantitation of four androgens and 17-hydroxyprogesterone in polycystic ovarian syndrome patients by LC-MS/MS.

BackgroundDue to the low concentration of androgens in women and the limitation of immunoassays, it remains a challenge to accurately determine the levels of serum androgens in polycystic ovary syndrome (PCOS) patients for clinical laboratories. In this report, a liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method was developed and validated for simultaneous quantitation of testosterone (T), androstenedione (A4), dehydroepiandrosterone sulfate (DHEAS), dihydrotestosterone (DHT), and 17‐hydroxyprogesterone (17‐OHP) that are associated with PCOS.MethodsThe serum samples were processed by protein precipitation and solid phase extraction before analysis with the in‐house developed LC‐MS/MS. The chromatographic separation was achieved with a C18 column, using a linear gradient elution with two mobile phases: 0.02% formic acid in water (phase A) and 0.1% formic acid in methanol (phase B). The separated analytes were detected by positive or negative electrospray ionization mode under multiple reaction monitoring (MRM).ResultsThe assay for all the five analytes was linear, stable, with imprecision less than 9% and recoveries within ±10%. The lower limits of quantification were 0.05, 0.05, 5, 0.025, and 0.025 ng/mL for T, A4, DHEAS, DHT, and 17‐OHP, respectively. In the receiver operating characteristic curve (ROC) analyses with the PCOS (n = 63) and healthy (n = 161) subjects, the AUC of the four‐androgen combined was greater than that of any single androgen tested in PCOS diagnosis.ConclusionsThe LC‐MS/MS method for the four androgens and 17‐OHP showed good performance for clinical implementation. More importantly, simultaneous quantitation of the four androgens provided better diagnostic power for PCOS.

Hormonal and metabolic features of the androgenic phenotypes of polycystic ovary syndrome and non-classic adrenal hyperplasia with various polymorphic variants in the CYP17A1 gene

The CYP17A1 gene encodes the most important stages of sex steroid biosynthesis by the adrenal glands and ovaries. The objective of this study was to evaluate the hormonal and metabolic status of patients with hyperandrogenia and the CYP17A1 rs743572 gene polymorphism. We examined 106 women with polycystic ovary syndrome androgen phenotypes A, B, and C and 28 women with latent non-classic congenital adrenal hyperplasia. It was found that there were no significant differences in the frequency of CYP17A1 alleles and genotypes between the three phenotype groups of patients with polycystic ovary syndrome. Body mass index and insulin resistance after glucose loading were comparable in individuals with these phenotypes of polycystic ovary syndrome. The CYP17A1 gene polymorphism in patients with different polycystic ovary syndrome phenotypes and in individuals with latent non-classic congenital adrenal hyperplasia did not associate with the concentration of estradiol and androgens in the blood. Neither did LH / FSH ratio differ between groups with different allelic variants of the CYP17A1 gene. These results show that patients with different polycystic ovary syndrome phenotypes do not require differentiated therapy. Serum levels of DHEA-S and cortisol were elevated in 38.7% of women with polycystic ovary syndrome without non-classic congenital adrenal hyperplasia, which indicates an adrenal cause of hyperandrogenia. We suppose that in the diagnosis of polycystic ovary syndrome, it is necessary to define not only phenotypes, but also a suprarenal source of androgens. The therapy of these patients may require application of corticosteroids besides the usual methods in planning of pregnancy.

Role of Obesity and Adrenergic Activation in the Androgen‐Induced Cardiometabolic Abnormalities in PCOS

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. PCOS is diagnosed by the combination of hyperandrogenemia, oligo/anovulation, and polycystic ovaries. PCOS is also associated with cardiometabolic abnormalities such as: obesity, insulin resistance, dyslipidemia, increased blood pressure (BP), and renal injury. In PCOS, obesity worsens the metabolic outcomes and evidence suggests that the sympathetic nervous system activation increases BP. However, the mechanisms responsible for elevated BP in women with PCOS are still unclear. We tested the hypothesis that obesity, by activating the sympathetic nervous system, mediates the androgen‐induced cardiometabolic abnormalities in PCOS.Four‐week old female SD rats were randomized to subcutaneously receive dihydrotestosterone (DHT, 7.5 mg/ 90 days) pellets (DHT) or sham surgeries (control). Then, DHT animals were assigned to have access to food either ad libitum or on a daily pair‐feeding schedule based on control food intake (PF‐DHT). Body composition (by EchoMRI) and proteinuria were determined every 4 weeks. At the end of the experiment, α1,β1,2‐adrenergic receptor antagonism response was assessed measuring BP by radiotelemetry in conscious, freely moving animals using propranolol (10mg/kg/d) and terazosin (10mg/kg/d) subcutaneously for 14 days.DHT rats had increased daily food intake (18.7 ± 0.1 vs 15.2 ± 0.1 g, p&lt;0.0001) compared to control. During pair‐feeding, food intake in PF‐DHT was decreased to the same level as control. DHT rats had higher BW, fat, and lean mass compared to control. Pair‐feeding abolished the increase in fat mass (12.5 ± 1.7 vs 22 ± 2.5 g, p&lt;0.001) and attenuated the increase in BW (269 ± 6 vs 308 ± 7 g, p&lt;0.001) and lean mass induced by androgens in PCOS. DHT rats had higher BP and proteinuria compared to control. In PCOS, pair‐feeding normalized BP (103.8 ± 0.6 vs 109.6 ± 0.7 mmHg, p&lt;0.0001) and ameliorated the androgen‐induced increase in proteinuria (11.8 ± 1 vs 31.3 ± 2 mg/24h, p&lt;0.0001). Acute adrenergic antagonism caused a bigger BP decrease in control than in DHT (88.1 ± 0.7 vs 93 ± 0.8 mmHg, p&lt;0.05) or in PF‐DHT (88.1 ± 0.7 vs 93 ± 0.5 mmHg, p&lt;0.05). Chronic adrenergic antagonism, however, normalized BP in PF‐DHT (95.5 ± 0.2 vs 97.3 ± 0.3 mmHg, p&lt;0.05), but it did not in DHT (95.5 ± 0.2 vs 100.1 ± 0.3 mmHg, p&lt;0.05).DHT rats showed increased food intake, fat mass, BP, and proteinuria compared to control rats. PF‐DHT rats had decreased fat mass, BP, and proteinuria compared to ad libitum‐fed DHT. In PCOS, the BP lowering effect of acute adrenergic antagonism is blunted by androgen‐excess independently of obesity. Chronic adrenergic antagonism, however, normalizes BP in PCOS in absence of obesity. In summary, obesity plays a key role mediating the negative cardiometabolic consequences of hyperandrogenemia in women with PCOS. Chronic adrenergic antagonism in addition to weight loss may be a promising therapeutic approach for androgen‐induced hypertension in PCOS.Support or Funding InformationNIH P20 GM‐121334 (L.L.Y.C. and D.G.R) and NIH R21 DK‐113500 (D.G.R.)

MON-203 Local Activation of 11-Oxygenated Androgens by AKR1C3 Is the Predominant Source of Androgens in Human Female Adipose Tissue

Polycystic ovary syndrome (PCOS) affects 10% of women and is a lifelong metabolic disorder, with increased risk of type 2 diabetes, fatty liver and cardiovascular disease. Androgen excess is an important driver of metabolic risk. Excess androgen activation in adipose tissue from PCOS women, through conversion of androstenedione (A4) to testosterone (T) by the enzyme AKR1C3, has been shown to drive insulin resistance and lipotoxicity, with insulin upregulating AKR1C3 further. Recent work has shown that 11-oxygenated androgens including 11-ketotestosterone (11KT), which binds and activates the androgen receptor with similar potency to T, constitute the majority of circulating androgens in PCOS, and that AKR1C3 can activate 11-ketoandrostenedione (11KA4) to 11KT with even higher efficiency than A4 to T. This raises the possibility that 11KT is more relevant than T in mediating excess androgen effects in PCOS. Here, we examined the contributions of classic and 11-oxygenated androgen pathways to intra-adipose androgen activation and the functional significance of the involved enzymes. To this end, we performed ex vivo primary adipose tissue incubations with corresponding subcutaneous (sc) and omental (om) adipose tissue obtained from eight women undergoing bariatric surgery (age range 32-59 years; BMI range 44-57). Incubations carried out with 100nM A4 and 11KA4, respectively, revealed significantly higher AKR1C3-mediated conversion of 11KA4 to 11KT than conversion of A4 to T, both in sc and om tissue. We observed a significant reduction of both 11KT and T generation after the addition of a selective AKR1C3 inhibitor to the primary tissue incubations. Conversely, co-incubation with a selective HSD11B1 inhibitor significantly enhanced the activation of 11KA4 to 11KT by decreasing the inactivation of 11KA4 to 11β-hydroxyandrostenedione; HSD11B1 inhibition had no impact on classic androgen pathway activation of A4 to T. Supernatants and tissues are currently undergoing investigation by mass spectrometry and NMR spectroscopy to determine the differential impact of T and 11KT generation on the adipose-specific global metabolome and lipidome. We conclude that local activation of 11-oxygenated androgens is the predominant source of androgen exposure in adipose tissue. AKR1C3 inhibition presents a promising tool to reduce androgen burden in PCOS, with effective reduction in both classic and 11-oxygenated pathway androgen biosynthesis in adipose tissue.

A review of androgen in polycystic ovary syndrome with nonalcoholic fatty liver disease

A growing number of studies have suggested that androgen in women with polycystic ovary syndrome (PCOS) exists a significant impact on the development of non-alcoholic fatty liver disease (NAFLD). We should pay more attention to the metabolism and function of androgens in PCOS women, as well as the effect and mechanism of androgens on NAFLD progression in PCOS women. This article briefly reviews and comments on this issue. Key words: Polycystic ovary syndrome; Androgens; Insulin resistance; Inflammation; Non-alcoholic fatty liver disease

Altered amino acids concentrations in polycystic ovary syndrome women with non-alcoholic fatty liver disease

Prevalence of Non-alcoholic fatty liver disease (NAFLD) increased in females with polycystic ovary syndrome (PCOS). Dysfunction of amino acids metabolism has been found in NAFLD. We aim to explore the association between plasma concentrations of amino acids and NAFLD in PCOS women. Cross-sectional study Diagnosis of PCOS was based on the Rotterdam criteria. A subgroup of 157 PCOS women from a metabolomics study was included. Plasma samples from subjects were tested using the gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS). NAFLD status was evaluated by a fatty liver index (FLI). FLI was calculated using body mass index (BMI), waist circumference, triglycerides, and gamma-glutamyl transferase, using a cut-off <30 for excluding, 30≤FIL<60 for suspecting, and ≥60 for confirming hepatic steatosis. Accordingly, subjects were divided into three groups based FLI values. Endocrine hormones, metabolic parameters, anthropometric measurements, and oral glucose tolerance tests were performed. Our results showed that altered metabolism of glucose, lipid, amino acids and androgen in PCOS with hepatic steatosis. Levels of alanine and branched-chain amino acid (BCAA) increased in subjects with FLI≥60, while threonine decreased. Correlation analysis showed that alanine and BCAA were positively associated with FLI, and glycine and serine were negatively correlated with FLI. After adjusting age, BMI, free androgen index (FAI) and homeostasis model assessment of insulin resistance (HOMA-IR), we found alanine and BCAA were positively associated with FLI. In addition, valine and isoleucine were positively associated with C-reation protein. Altered plasma amino acids levels were found in PCOS with NAFLD. BCAA was strongly associated with NAFLD in PCOS independent of age, BMI, FAI and IR. Chronic inflammation may be an underlying mechanism for BCAA inducing NAFLD in PCOS.

Follicular hyperandrogenism and insulin resistance in polycystic ovary syndrome patients with normal circulating testosterone levels.

Polycystic ovary syndrome (PCOS) is a common reproductive disease with high heterogeneity. The role of excess androgen in PCOS etiology remains disputed, since around 20%–50% of PCOS women do not display hyperandrogenemia. The microenvironment of the ovary critically influences follicular development. In the present study, we assessed the role of androgen in PCOS by investigating whether excessive follicular fluid androgen was present in PCOS patients with normal serum androgen levels and influenced by follicular fluid insulin resistance (IR). Follicular fluid samples of 105 women with PCOS and 105 controls were collected. Levels of steroid hormones, glucose and insulin in the follicular fluid were examined and compared with data from serum biochemistry tests. We found that 64.9% (63/97) of PCOS patients with normal serum androgen levels displayed abnormally high follicular fluid androgen level. The follicular fluid androgen level was positively correlated with follicular fluid IR within a certain range and follicular fluid estrogen-to-testosterone (E2/T) ratio was significantly reduced in these patients. These results indicated that there existed a subgroup of PCOS patients who displayed excessive follicular fluid androgen and IR despite their normal circulating testosterone (T) levels. Our study highlights the importance of ovary hyperandrogenism and IR in the etiology of PCOS.

Study of Visceral and Subcutaneous Abdominal Fat Thickness and Its Correlation with Cardiometabolic Risk Factors and Hormonal Parameters in Polycystic Ovary Syndrome.

Aim of the Study:This study aimed to compare the different adiposity parameters, namely visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) between patients with polycystic ovary syndrome (PCOS) and controls. In addition, it aimed to correlate these adiposity indices with hormonal parameters as well as cardiovascular (CV) risk factors in patients with PCOS.Materials and Methods:Newly diagnosed PCOS patients of reproductive age group according to Rotterdam criteria were included. Age- and body mass index (BMI)-matched healthy females with normal menstrual cycles were taken as controls. All the study participants underwent detailed clinical, biochemical, and hormonal evaluation. Transabdominal ultrasound (US) was performed for detailed ovary imaging and assessment of adiposity (SAT and VAT) parameters.Results:A total of 58 PCOS patients and 40 age- and BMI-matched controls were included. PCOS patients had significantly higher levels of androgens (P < 0.001), elevated highly sensitive C-reactive protein (P = 0.007), and higher degree of insulin resistance (P < 0.001) than controls. PCOS patients had a mean SAT of 2.37 ± 0.7 cm and mean VAT of 8.65 ± 1.78 cm. These parameters were significantly higher than controls who had a mean SAT of 2.01 ± 0.7 cm (P = 0.014) and mean VAT of 7.4 ± 1.89 cm (P = 0.003), despite both groups having similar BMI. Among PCOS cohort, VAT correlated positively with total testosterone (r = 0.295, P = 0.025) and negatively with dehydroepiandrosterone sulfate (r = −0.210, P = 0.114). However, no significant correlation was observed between SAT and androgens in PCOS group.Conclusion:PCOS patients, whether obese or nonobese, had elevated visceral adiposity than controls. VAT correlated positively with adverse CV risk factors and testosterone in PCOS patients. Hence, a simple and inexpensive ultrasonography screening of visceral fat may identify women who have adverse metabolic profile and enhanced CV risk.

Effects of orlistat on serum androgen levels among iranian obese women with polycystic ovarian syndrome.

IntroductionPolycystic ovary syndrome is one of the most common endocrinopathies in young women, and it affects 6% to 8% of women in reproductive age. Hyperandrogenism is the hallmark of polycystic ovary syndrome. The aim of the present study was to evaluate the effects of orlistat on weight loss and serum androgen levels among Iranian women with polycystic ovary syndrome.MethodsThe present study was carried out in the clinic of Infertility and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Thirty-two patients with polycystic ovary syndrome were randomly enrolled. We measured serum androgens (Testosterone, 17α-hydroxyprogesterone, dehydroepiandrosterone and sex hormone-binding globulin) before and after 12 weeks of treatment with orlistat. We used the Rotterdam Criteria for all patients and transvaginal sonography was performed.ResultsThe mean age of patients was 27.75±6.22 and the mean body mass index was 32.69±0.94 kg/m2. Comparing with baseline, treatment with orlistat resulted in a significant reduction in weight, BMI, and waist circumference (p=0.001). We also found a remarkable reduction in total testosterone levels (p>0.001). Treatment improved the sex hormone-binding globulin plasma levels, but the improvement was not statistically significant. There was no reduction in other androgen levels.ConclusionThis study showed a significant reduction of weight and total testosterone level - the most important androgen in polycystic ovary syndrome - after 12 weeks of treatment with orlistat. Therefore, it seems that a short course of orlistat can be useful in the management of patients with polycystic ovary syndrome.

Free testosterone and dehydroepiandrosterone sulfate serum levels in polycystic ovary syndrome women

Objectives: This study designed to detect the prevalence of ovarian and/or adrenal hyperandrogenism in women with Polycystic Ovary Syndrome (PCOS).Materials: One hundred PCOS women included in this cross sectional study after informed consent and approval of the study by local institute ethical committee. Diagnosis of PCOS based on the Rotterdam ESHRE criteria. Studied women underwent complete physical examination with calculation of body mass index (BMI) and assessment of hirsutism by modified Ferriman Gallway score. Clotted blood sample taken from studied women for measurement of serum total testosterone, sex hormone binding globulin (SHBG) and dehydroepiandrosterone sulfate (DHEAS) to detect the prevalence of ovarian and/or adrenal hyperandrogenism in PCOS women. Results: 66% of studied PCOS women presented with hirsutism, 22% of studied PCOS women presented with menstrual irregularities (hypomenorrhea, oligomenorrhea) and dysmenorrhea was the presenting symptom in 12%. Free testosterone was elevated in 50 cases of studied women; DHEAS was elevated in 30 cases of studied women while the remaining 20 cases had elevated both free testosterone and DHEAS. Mean free testosterone was 2.6±1.8 pg/ml and mean DHEAS was 5.5±3.8 mg/l. Conclusion: The ovary is the main source of excess androgen in PCOS (50% of studied women) and excess adrenal androgen found in 30% of studied PCOS women, further large studies recommended to confirm this finding.

11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome.

Context:Androgen excess is a defining feature of polycystic ovary syndrome (PCOS), but the exact origin of hyperandrogenemia remains a matter of debate. Recent studies have highlighted the importance of the 11-oxygenated C19 steroid pathway to androgen metabolism in humans. In this study, we analyzed the contribution of 11-oxygenated androgens to androgen excess in women with PCOS.Methods:One hundred fourteen women with PCOS and 49 healthy control subjects underwent measurement of serum androgens by liquid chromatography-tandem mass spectrometry. Twenty-four–hour urinary androgen excretion was analyzed by gas chromatography-mass spectrometry. Fasting plasma insulin and glucose were measured for homeostatic model assessment of insulin resistance. Baseline demographic data, including body mass index, were recorded.Results:As expected, serum concentrations of the classic androgens testosterone (P < 0.001), androstenedione (P < 0.001), and dehydroepiandrosterone (P < 0.01) were significantly increased in PCOS. Mirroring this, serum 11-oxygenated androgens 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone were significantly higher in PCOS than in control subjects, as was the urinary 11-oxygenated androgen metabolite 11β-hydroxyandrosterone. The proportionate contribution of 11-oxygenated to total serum androgens was significantly higher in patients with PCOS compared with control subjects [53.0% (interquartile range, 48.7 to 60.3) vs 44.0% (interquartile range, 32.9 to 54.9); P < 0.0001]. Obese (n = 51) and nonobese (n = 63) patients with PCOS had significantly increased 11-oxygenated androgens. Serum 11β-hydroxyandrostenedione and 11-ketoandrostenedione correlated significantly with markers of insulin resistance.Conclusions:We show that 11-oxygenated androgens represent the majority of circulating androgens in women with PCOS, with close correlation to markers of metabolic risk.

Androgens in polycystic ovary syndrome: lessons from experimental models.

There is substantial evidence to support a role for androgens acting via the androgen receptor in the development of the pathological disorder, polycystic ovary syndrome (PCOS). PCOS is the most common endocrine condition in women, but its etiology remains unknown. This review focuses on how animal experimental models of PCOS are providing strong evidence to support hyperandrogenism as an important mediator in the development of PCOS characteristics. A variety of animal models for PCOS have now been established by increasing androgen exposure, supporting a role for androgens in the pathogenesis of PCOS. However, some androgens can be aromatized into estrogens leading to confusion on which PCOS traits are primary mediated via androgenic (mediated via the androgen receptor) or estrogenic (mediated via the estrogen receptor) mechanisms. Recent findings from studies comparing the induction of PCOS by aromatizable and nonaromatizable androgens, as well as androgen receptor knockout mouse models have enhanced our understanding of the mechanisms underlying PCOS, and verify that androgen receptor-mediated actions play a key role in the development of PCOS. Animal models have provided strong evidence to support that androgen receptor-mediated actions are key mediators in the development of PCOS traits.

Visual-spatial cognition in women with polycystic ovarian syndrome: the role of androgens

Are women with polycystic ovary syndrome (PCOS) better at three-dimensional mental rotation than other women? Women with PCOS scored significantly higher on a mental rotation task than a female control group. PCOS is a condition characterized by elevated testosterone levels. Some researches have found that three-dimensional mental rotation task performance is positively correlated with testosterone levels. This cross-sectional study was conducted between June 2006 and January 2009. The participants were 69 women with PCOS and 41 controls recruited from five gynaecology clinics in London. The control group consisted of non-PCOS women of comparable subfertility to PCOS group. These groups sizes gave roughly 80% power to detect moderate effect sizes for the main statistical test. Participants were recruited at London gynaecology clinics. The women were aged between 18 and 43. PCOS was diagnosed based on the Rotterdam criteria. Controls were women who experienced some degree of subfertility. Blood samples from participants were frozen for up to 4 months until being assayed by direct electrochemiluminescence. The mental rotation task was undertaken electronically. Some questionnaires and other tasks were completed as control measures. Women with PCOS scored significantly higher than controls: median (range) 3.00 (0-9) and 2.00 (0-8), respectively (U = 1147.500, N1 = 69, N2 = 41, P < 0.047). Within the PCOS group, circulating levels of testosterone were significantly positively correlated with three-dimensional scoring (rs = 0.376, n = 56, P < 0.002), whereas estradiol was significantly negatively correlated with three-dimensional scoring (rs = -0.473, n = 29, P < 0.010). In the control group, the relationship between sex hormones and mental rotation was non-significant. Other factors, including general intelligence and social class, did not account for these findings. A subgroup analysis comparing hyperandrogenic PCOS cases, non-hyperandrogenic PCOS cases and controls, in which age and body mass index were controlled for using ANCOVA, found a non-significant difference in three-dimensional scoring between the three groups (F = 1.062, d.f. = 1, 73, P < 0.351). The small number of women in the control group meant that correlations were underpowered in this group. This study is the first to find a benefit of PCOS in visuospatial cognition, and the first to find a link between visuospatial cognition and sex hormones in PCOS. The fact that the correlations went in the opposite direction in the PCOS group compared with the controls might suggest the influence of increased prenatal exposure to androgen in PCOS. The assays for this study were funded by the Department of Psychology, City University London. All authors report no conflicts of interest.