Hyperandrogenism In Polycystic Ovary Syndrome Research Articles

The efficacy of gonadotropin-releasing hormone (GNRH) agonist before frozen embryo transfer in improving pregnancy outcome and decreasing miscarriage rate in hyperandrogenic polycystic ovary syndrome women: a randomized clinical trial.

The hyper androgenic status is a major complication of polycystic ovarian syndrome (PCOS) that deteriorates endometrial function and increases miscarriage rate. This study was conducted to investigate the efficacy of GnRH agonist before frozen-thawed embryo transfer in improving pregnancy outcome in infertile women with PCOS. This single-blind, randomized controlled trial was performed at Dr Shariati hospital and Omid Fertility Clinic in Tehran, Iran. In the study were included 178 PCOS women. Patients were then divided into two groups of control and intervention. All women received the standard treatment for the preparation of the endometrial using estradiol valerate at dose of 6-8 mg/day. The intervention group also received diphereline, as GnRH agonist, at two doses, 8 weeks before starting the endometrial preparation. Chemical pregnancy in intervention group was 47.7% compared to 35.6% in the control group, revealing no significant difference between two groups. No statistically significant difference was observed between two groups concerning clinical pregnancy rate (43.2% vs. 27.3%). However, rate of ongoing pregnancy was 42.0% in intervention group but 18.0% in the control group, suggesting a significant difference (P=0.001). The rate of miscarriage in the intervention group was 2.6% and in the control group was 33.3%, which was significantly lower (P=0.001). It can be concluded that endometrial preparation using GnRH improves ongoing pregnancy and decreases miscarriage rate. It seems that reduction of androgen level in PCOS patients affects the endometrium and improves the receptivity and implantation of the embryo, resulting in better pregnancy outcomes by reducing the miscarriage rate.

Effects of continuous and intermittent aerobic physical training on hormonal and metabolic profile, and body composition in women with polycystic ovary syndrome: A randomized controlled trial.

To evaluate the effects of continuous (CA) and intermittent (IA) aerobic training on hormonal and metabolic parameters and body composition of women with polycystic ovary syndrome (PCOS). Prospective, interventional, randomized study. Randomized controlled training (RCT) with sample allocation and stratification into three groups: CAT (n=28) and IAT (n=29) training and no training [control (CG), n=30]. Before and after 16weeks of intervention (CAT or IAT) or observation (CG), hormonal and metabolic parameters, body composition and anthropometric indices were evaluated. Aerobic physical training on a treadmill consisted of 30- to 50-minute sessions with intensities ranging from 60% to 90% of the maximum heart rate. In the CA group, there was reduction in waist circumference (WC) (P=.045), hip circumference (P=.032), cholesterol (P≤.001), low-density lipoprotein (P=.030) and testosterone (P≤.001). In the IAT group, there was a reduction in WC (P=.014), waist-to-hip ratio (P=.012), testosterone (P=.019) and the free androgen index (FAI) (P=.037). The CG showed increases in WC (P=.049), total body mass (P=.015), body fat percentage (P=.034), total mass of the arms (P≤.001), trunk fat percentage (P=.033), leg fat percentage (P=.021) and total gynoid mass (P=.011). CAT and IAT training reduced anthropometric indices and hyperandrogenism in PCOS, whereas only IAT training reduced the FAI. Furthermore, only CAT training improved the lipid profile.

OR31-05 Emergence of Ovarian Hyperandrogenism and Luteal Insufficiency Following ESR1 Knockdown in the Mediobasal Hypothalamus of Adult Female Rhesus Monkeys

Diminished estradiol (E2) negative feedback action by neuronal ESR1 in the arcuate nucleus (ARC) of the mediobasal hypothalamus (MBH) is hypothesized to cause gonadotropin-releasing hormone (GnRH) hypersecretion, and thus LH excess, contributing to ovarian hyperandrogenism in polycystic ovary syndrome (PCOS). In primates, including humans, however, the mediating estrogen receptor is unknown. Thus, to test the hypothesis that diminished E2 action on ARC ESR1 contributes to female primate ovarian hyperandrogenism, eleven, ovary intact, adult female rhesus macaques, pair housed with female peers, received five 12µl MRI-guided MBH infusions into the rostral-to-caudal extent of both right and left ARC. Each infusion comprised gadolinium contrast agent and ~3-4 x 1010 adeno-associated virus 8 (AAV8) particles containing either a shRNA specific for ESR1 (n=6, ERaKD) or scrambled shRNA (n=5, control). Mid-surgery MRI scans identified targeting accuracy. 2-2.5 years following AAV8 infusion, EIA-determined P4 values were obtained from twice weekly serum samples; samples obtained during the follicular phase of menstrual cycles or anovulatory periods were submitted to liquid chromatography, tandem mass spectrometry (LCMS) for additional steroid hormones. LCMS-determined values were also obtained 0 hours (h) and 24 h following an IM injection of 200IU hCG. Both ERaKD (28.5 ± 1.3 days, mean ± SEM) and control (34.0 ± 3.3 days) female groups exhibited comparably regular menstrual cycles. ERaKD exhibited higher circulating levels of LH (2.8 ± 0.2 ng/ml, p=0.03), androstenedione (A4, 0.43 ± 0.03 ng/ml, p=0.03) and testosterone (T, 0.23 ± 0.03 ng/ml, p=0.09), and LH/FSH ratio (1.7 ± 0.2, p=0.05) compared to controls (LH, 2.1 ± 0.4; A4, 0.30 ± 0.05; T, 0.18 ± 0.01 ng/ml; LH/FSH 1.3 ± 0.2). Following an ovarian androgen-stimulating hCG injection, ERaKD 24-h peak levels for T (0.28 ± 0.01 ng/ml) were higher (p=0.03) compared to controls (0.21 ± 0.01 ng/ml). In addition, luteal insufficiency emerged in ERaKD females, with mean (2.4 ± 0.3 ng/ml), peak (3.6 ± 0.4 ng/ml) and area-under-the-curve (AUC, 23.2 ± 4.2 ng/ml/days) P4 values diminished compared to controls (mean, 3.6 ± 0.1, p=0.01; peak 5.7 ± 0.1 ng/ml, p=0.01; AUC, 43.7 ± 6.7 ng/ml/days, p=0.03). Taken together, these results suggest that knockdown of ARC ESR1 disrupts Gn stimulation of ovarian function, contributing to female monkey ovarian hyperandrogenism and menstrual cycle impairment emulating PCOS in women.

MON-040 11-Oxygenated C19 Steroids in Polycystic Ovarian Syndrome

BACKGROUND: Polycystic ovarian syndrome (PCOS), an endocrine and reproductive disorder consisting of hyperandrogenism, menstrual dysfunction and ovarian changes, affects 6–20% of reproductive aged women worldwide. While hyperandrogenemia is traditionally determined by evidence of elevated testosterone (T), this hormone can be difficult to accurately measure in women with relatively lower circulating levels compared to men. Recent studies have suggested that four adrenal androgens known as 11-oxygenated C19 steroids (11OxyAs), specifically 11-ketotestosterone (11KT), may be good alternative markers for hyperandrogenism in PCOS. Using a multiethnic population seeking evaluation for PCOS symptomatology, we sought (1) to investigate the utility of 11OxyAs to differentiate women with and without NIH PCOS relative to classical androgens such as T, androstenedione (A4) and DHEAS levels, and (2) to evaluate the relationship of 11OxyAs to clinical findings of androgen excess. Methods: Using the University of California, San Francisco PCOS Tissue Bank, serum samples from 131 women seen for a PCOS evaluation were selected sequentially and identified as PCOS or non-PCOS (controls) based on meeting NIH criteria at the time of evaluation. In addition to obtaining gonadotropin and metabolic profiles, classical androgens and 11OxyAs were measured using mass spectrometry. The relationship of these androgens to modified Ferriman-Gallwey (mFG) scores and ovarian morphology were also assessed. Results: Out of 131 women selected, 83 met NIH PCOS criteria at the time of evaluation and 48 did not (controls). Age and BMI did not differ among the two groups. As expected, total T, A4 and LH were all significantly higher in NIH PCOS. A trend towards higher HOMA-IR levels was also seen in NIH PCOS, but this did not reach statistical significance (3±3.9 mg/dL vs. 1.9±1.7 mg/dL, p = 0.12). No difference was seen in all four 11OxyAs between NIH PCOS and controls. Unlike previous studies, we also did not find mean 11KT levels to exceed that of T in both controls (T 393±143 pg/mL vs. 11KT 389±206 pg/mL) and PCOS (T 530±245 pg/mL vs. 11KT 388±201 pg/mL). In addition, no relationship was seen between HOMA-IR and 11β-hydroxyandrostenedione (11OHA4) or 11-ketoandrostenedione (11KA4) levels. Within PCOS, DHEAS and A4 were noted to have a weak but inverse relationship to BMI (r2 0.05 p = 0.05; r2 0.08 p = 0.007), whereas no correlation was seen between any of the four 11OxyAs or T and BMI. Lastly, 11OxyAs, T, and A4 levels did not predict mFG scores or polycystic ovarian morphology. Conclusions: 11OxyAs levels were not statistically higher among women with NIH PCOS compared to at risk women who did not meet NIH criteria. There was no significant relationship between these androgens and mFG scores or ovarian morphology. Further studies are necessary to show the utility of 11OxyAs levels as a marker for hyperandrogenism or metabolic risk.

MON-022 Dissecting the Interplay Between Diet and PCOS Pathology on Gut Microbiota in a PCOS Mouse Model

The gut microbiome has been implicated in the development of metabolic disorders such as obesity and type-2 diabetes, and more recently polycystic ovary syndrome (PCOS). PCOS is a heterogeneous disorder with reproductive, endocrine and metabolic irregularities, and clinical and animal studies have reported that PCOS causes a decrease in microbial diversity and composition. Diet is an important regulator of the gut microbiome, and a recent study identified that alterations in macronutrient balance impact gut microbial communities which correlate with different metabolic health outcomes (1). We have identified that macronutrient balance impacts the development of PCOS traits. Therefore, to investigate the interplay between macronutrient balance and a PCOS environment on the gut microbiome, we analyzed the intestinal microbiome from fecal pellets of control and DHT-induced PCOS mice exposed to 10 different diets that varied systematically in protein (P), carbohydrate (C) and fat (F) content. The amount of dietary P, C and F consumed significantly altered alpha and beta diversity of the gut microbiota of pooled control and PCOS mice (P<0.0001). Alpha diversity between control and PCOS mice on the same diet did not differ significantly, and hence was only affected by diet composition. However, beta diversity was significantly altered between control and PCOS mice (P<0.05). We performed DESeq2 analysis and identified an operational taxonomic unit (OTU) within Bacteroides (OTU3) to be the most differentially abundant OTU between control and PCOS mice, with a significant decrease in PCOS mice compared to controls (control: 7.88 and PCOS: 5.38; fold change = 1.464; P<0.0001). The consensus sequence of Bacteroides OTU3 was found to share 99.2% similarity to Bacteroides acidifaciens. B. acidifaciens is associated with obesity with elevated levels reported to prevent the onset of obesity (2). Thus, we then investigated the influence of P, C and F on the relative abundance of Bacteroides OTU3 and revealed an association with C consumption, with increasing levels of C leading to increased levels of Bacteroides OTU3 (Carb: r= 0.22, p=0.0028, q=0.015). These findings demonstrate that diet exerts a stronger influence over the gut microbiome than PCOS pathology. However, the hyperandrogenic PCOS environment does lead to changes in gut microbiota beta diversity, with a specific decrease in an obesity-associated (2) Bacteroides species in PCOS mice that is also responsive to levels of C consumption. Reference: (1) Holmes et al., Cell Metabolism. 2017; 25(1): 140-151. (2) Yang et al., Mucosal Immunology. 2017, 10 (1), 104-116.

Pigment epithelium-derived factor (PEDF) negates hyperandrogenic PCOS features.

Polycystic ovary syndrome (PCOS), one of the most common female endocrine disorder, is a prevalent cause of infertility. Hyperandrogenism is a key feature in PCOS and is correlated with increased expression of VEGF and cytokines in the ovaries. We have previously shown that pigment epithelium-derived factor (PEDF), an endogenous protein, presents potent anti-angiogenic and anti-inflammatory activities in the ovary and negates the effects of cytokines and VEGF. Additionally, PEDF plays a role in both pathophysiology and treatment of ovarian-hyperstimulation syndrome (OHSS), frequently seen in PCOS patients. We established hyperandrogenic-PCOS models, both in vivo, using mice exposed prenatally to dihydrotestosterone (DHT) and, in vitro, using human primary granulosa cells (hpGCs) and human granulosa cell line (KGN). In PCOS-induced mice, the mRNA levels of I l-6, V egf and Amh were higher than those of control; yet, treatment with rPEDF decreased these levels. Moreover, treating OHSS-induced PCOS-mice with rPEDF alleviated all OHSS symptoms. Stimulation of hpGCs with DHT resulted in downregulation of PEDF mRNA expression, concomitantly with a significant increase in IL-6 and IL-8 mRNAs expression. However, co-stimulation of DHT with rPEDF attenuated the increase in cytokines expression. The anti-inflammatory effect of PEDF was found to be mediated via PPARγ pathway. Our findings suggest that rPEDF treatment may normalize the ovarian angiogenic-inflammatory imbalance, induced by PCOS-associated hyperandrogenism. Moreover, the therapeutic potency of PEDF in preventing OHSS symptomes offers a rationale for using PEDF as novel physiological treatment for PCOS sequels.

Decreased microRNA-125b-5p disrupts follicle steroidogenesis through targeting PAK3/ERK1/2 signalling in mouse preantral follicles

BackgroundHyperandrogenism is one of the major characteristics of polycystic ovary syndrome (PCOS). Abnormal miR-125b-5p expression has been documented in multiple diseases, but whether miR-125b-5p is associated with aberrant steroidogenesis in preantral follicles remains unknown. MethodsSteriod hormone concentrations and miR-125b-5p expression were measured in clinical serum samples from PCOS patients. Using a mouse preantral follicle culture model and a letrozole-induced PCOS mouse model, we investigated the mechanism underlying miR-125b-5p regulation of androgen and oestrogen secretion. ResultsThe decreased miR-125b-5p expression was observed in the sera from hyperandrogenic PCOS (HA-PCOS) patients. In mouse preantral follicles, inhibiting miR-125b-5p increased the expression of androgen synthesis-related genes and stimulated the secretion of testosterone, while simultaneously downregulating oestrogen synthesis-related genes and decreasing oestradiol release. Ectopically expressed miR-125b-5p reversed the effects on steroidogenesis-related gene expression and hormone release. Mechanistic studies identified Pak3 as a direct target of miR-125b-5p. Furthermore, inhibiting miR-125b-5p facilitated the activation of ERK1/2 in mouse preantral follicles, while inhibiting Pak3 abrogated this activating effect. These results were recapitulated in letrozole-induced PCOS mouse ovaries. Of note, inhibiting PAK3 antagonised the positive effect of miR-125b-5p siRNA on the expressions of androgen synthesis-related enzymes and testosterone secretion. Luteinizing hormone (LH) inhibited miR-125b-5p expression, and stimulated Pak3 expression. ConclusionHigh serum LH concentrations in PCOS patients repress miR-125b-5p expression, which further increases Pak3 expression, leading to activation of ERK1/2 signalling, thus stimulating the expression of androgen synthesis-related enzymes and testosterone secretion in HA-PCOS.

Effects of metformin alone and in combination with spironolactone on hyperandrogenism in polycystic ovarian syndrome

Objective To evaluate the efficacy of combined therapy with metformin and low-dose spironolactone as compared with metformin alone on the clinical and endocrine-metabolic alterations of patients with polycystic ovarian syndrome (PCOS). Background PCOS is the most common endocrinological disorder in reproductive-age women. Thus, at least theoretically, metformin plus spironolactone therapy may be an effective and safe combination for PCOS. Patients and methods A prospective randomized comparative study was carried out on 48 patients with the PCOS in Obstetrics and Gynecology Department, Menoufia University Hospital, and Al-Shohadaa Hospital, Egypt, from the period of May 2016 till January 2018. Detailed history, laboratory investigations, obstetric examination, and follow-up were done. Results Mean hirsutism score and BMI (kg/m2) were 10.8 ± 3.9 and 26.8 ± 2.2, respectively, before treatment, which decreased significantly to 7.6 ± 2.4 and 22.10 ± 1.92, respectively, after 6 months of treatment. Luteinizing hormone, follicle-stimulating hormone, free testosterone, dehydroepiandrosterone sulfate, fasting glucose, fasting insulin, and homeostasis model assessment of insulin resistance were decreased significantly after 6 months of treatment as compared with before treatment among women who received metformin + hypocaloric diet and received metformin + spironolactone + hypocaloric diet before treatment. Free testosterone was decreased in group B (58.2 ± 9.1) more than group A (73.6 ± 12. 9). Conclusion The results confirm the beneficial effects of metformin in patients with PCOS. It also proves that the addition of low-dose spironolactone induces a more marked reduction of clinical and biochemical hyperandrogenism in patients with PCOS present with hyperandrogenic conditions.

Body Composition, Serum Concentrations of Androgens and Insulin Resistance in Different Polycystic Ovary Syndrome Phenotypes.

Insulin resistance and hyperandrogenemia observed in polycystic ovary syndrome (PCOS) are associated with metabolic disturbances and could be connected with body composition pattern. To date, several studies defining the parameters of body composition using dual energy X-ray absorptiometry (DXA) method in the group of PCOS patients have been published, however, without the analysis in different phenotypes. The aim of the present study was to investigate the relationships between serum androgens concentration, insulin resistance and distribution of fat mass using DXA method in various PCOS phenotypes according to the Rotterdam criteria. We examined 146 women: 34 (38%) had PCOS phenotype A, 20 (23%) phenotype B, 20 (23%) phenotype C and 15 (16%) phenotype D (with mean age of each phenotype 25 years), and 57 control subjects (mean age of 25.5 years). Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Serum concentrations of testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEA-S) were assessed and free androgen index (FAI) was calculated. In phenotypes A, B and C, we observed higher FAI in comparison to the control group (all p < 0.01). Serum concentrations of androstenedione and DHEA-S were higher in phenotypes A and C in comparison to the control group (all p < 0.01). However, only in phenotype A we found higher visceral adipose tissue (VAT) mass and android/gynoid ratio (A/G ratio) in comparison to the control group (all p < 0.01). In phenotype A, we observed connection of VAT with FAI (r = 0.58, p < 0.01). Accordingly, A/G ratio was related with FAI in all phenotypes (all p < 0.05). Additionally, in phenotype C, A/G ratio was related to serum concentrations of DHEA-S and androstenedione (r = 0.46, p = 0.03; r = 0.53, p = 0.01, respectively). We also found connections of HOMA-IR with VAT and A/G ratio in all phenotypes (all p < 0.05). Women with phenotype A had higher amount of VAT and A/G ratio in comparison to the control group. Serum concentration of androgens and insulin resistance are connected with VAT and A/G ratio in normoandrogenic and hyperandrogenic PCOS phenotypes.

Inflammation Triggered by Saturated Fat Ingestion Is Linked to Insulin Resistance and Hyperandrogenism in Polycystic Ovary Syndrome.

Inflammation and insulin resistance are often present in polycystic ovary syndrome (PCOS). We determined the effect of saturated fat ingestion on mononuclear cell (MNC) nuclear factor-κB (NFκB) activation; NFκB, inhibitory-κBα (IκBα), and tumor necrosis factor-α (TNFα) gene expression; and circulating C-reactive protein (CRP) in women with PCOS. Cross-sectional study. Academic medical center. Twenty reproductive-age women with PCOS (10 lean, 10 with obesity) and 20 ovulatory controls (10 lean, 10 with obesity). Activated NFκB, NFκB heterodimer subunits, IκBα and TNFα messenger ribonucleic acid content and NFκB p65 and IκBα protein content were quantified in mononuclear cells (MNC), and CRP was measured in plasma from blood drawn fasting and 2, 3, and 5 h after saturated fat ingestion. Insulin sensitivity was derived from oral glucose tolerance testing (ISOGTT). Androgen secretion was assessed from blood drawn fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration. In response to saturated fat ingestion, women with PCOS regardless of weight class exhibited lipid-induced increases in activated NFκB, NFκB, and TNFα gene expression and plasma CRP and decreases in IκBα protein compared with lean control subjects. Both PCOS groups exhibited lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects. Lipid-stimulated NFκB activation was negatively correlated with ISOGTT, and positively correlated with HCG-stimulated androgen secretion. In PCOS, increases in NFκB activation and circulating CRP and decreases in IκBα protein following saturated fat ingestion are independent of obesity. Circulating MNC and excess adipose tissue are separate and distinct contributors to inflammation in this disorder.

Altered circadian clock as a novel therapeutic target for constant darkness-induced insulin resistance and hyperandrogenism of polycystic ovary syndrome

The mechanisms underlying metabolic and reproductive dysfunction caused by arrhythmic circadian clock and their involvement in polycystic ovary syndrome (PCOS) are not understood. Here, we addressed this issue using rats with constant light or darkness exposure for 8 weeks and human leukocytes and serum of PCOS and non-PCOS patients. Additionally, we utilized HepG2 cells and KGN cells to verify the molecular mechanisms. The arrhythmic expressions of circadian clock genes due to constant darkness induced the metabolic and reproductive hallmarks of PCOS in rats. After exposure to constant darkness, decreased brain and muscle ARNT-like protein 1 (BMAL1) promoted insulin resistance via glucose transporter 4 (GLUT4), and decreased period (PER) 1 and PER2 promoted androgen excess via insulin-like growth factor-binding protein 4 (IGFBP4) and sex hormone binding globulin (SHBG) in the liver. Hyperinsulinemia and hyperandrogenism shared a bidirectional link promoting aberrant expression of circadian genes and inducing apoptosis of ovarian granulosa cells. Notably, the altered expressions of circadian clock genes in darkness-treated rats matched those of PCOS patients. Furthermore, melatonin treatment relieved the hyperinsulinemia and hyperandrogenism of darkness-treated rats via BMAL1, PER1, and PER2. Restoring normal light/dark exposure for 2 weeks reversed these conditions via BMAL1. In conclusion, our findings elucidated the critical function of circadian clock genes, especially BMAL1, PER1, and PER2 in PCOS, which might aid the development of feasible preventive and therapeutic strategies for PCOS in women with biorhythm disorder.

Hyperandrogenism and Metabolic Syndrome Are Associated With Changes in Serum-Derived microRNAs in Women With Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) remains one of the most common endocrine disorder in premenopausal women with an unfavorable metabolic risk profile. Here, we investigate whether biochemical hyperandrogenism, represented by elevated serum free testosterone, resulted in an aberrant circulating microRNA (miRNAs) expression profile and whether miRNAs can identify those PCOS women with metabolic syndrome (MetS). Accordingly, we measured serum levels of miRNAs as well as biochemical markers related to MetS in a case-control study of 42 PCOS patients and 20 Controls. Patients were diagnosed based on the Rotterdam consensus criteria and stratified based on serum free testosterone levels (≥0.034 nmol/l) into either a normoandrogenic (n = 23) or hyperandrogenic (n = 19) PCOS group. Overall, hyperandrogenic PCOS women were more insulin resistant compared to normoandrogenic PCOS women and had a higher prevalence of MetS. A total of 750 different miRNAs were analyzed using TaqMan Low-Density Arrays. Altered levels of seven miRNAs (miR-485-3p, -1290, -21-3p, -139-3p, -361-5p, -572, and -143-3p) were observed in PCOS patients when compared with healthy Controls. Stratification of PCOS women revealed that 20 miRNAs were differentially expressed between the three groups. Elevated serum free testosterone levels, adjusted for age and BMI, were significantly associated with five miRNAs (miR-1290, -20a-5p, -139-3p, -433-3p, and -361-5p). Using binary logistic regression and receiver operating characteristic curves (ROC), a combination panel of three miRNAs (miR-361-5p, -1225-3p, and -34-3p) could correctly identify all of the MetS cases within the PCOS group. This study is the first to report comprehensive miRNA profiling in different subgroups of PCOS women with respect to MetS and suggests that circulating miRNAs might be useful as diagnostic biomarkers of MetS for a different subset of PCOS.

Elevated Serum Mannose Levels as a Marker of Polycystic Ovary Syndrome.

Background: Recent reports have highlighted the role of monosaccharide biosynthesis in the pathogenesis of polycystic ovary syndrome (PCOS), suggesting that these processes may serve as a biomarker in PCOS. Mannose is the main monosaccharide for protein glycosylation in mammals; however, the correlation between mannose and PCOS remains largely unknown.Materials and Methods: A total of 132 Chinese Han women were recruited at Shengjing Hospital of China Medical University. Mannose levels were measured in serum samples collected from 71 patients with PCOS (29 lean, 42 obese) and 61 control subjects (28 lean, 33 obese). Receiver operating characteristics (ROC) curves were prepared to compare the diagnostic performance of mannose and hormonal parameters, individually or in combination. Multivariate logistic regression analysis was used to assess whether serum mannose levels were associated with PCOS after adjusting for other co-variables.Results: We showed that serum mannose levels were significantly increased in PCOS patients compared with control subjects regardless of obese status, and hyperandrogenic PCOS patients had higher serum mannose levels than normo-androgenic PCOS and control subjects. In addition, serum mannose levels were significantly correlated with serum androgen levels. Mannose had an area under the curve (AUC) of 73% at a cutoff value of 225.79 ng/mL with a sensitivity of 66.2% and specificity of 73.8% for predicting PCOS. There were no differences between mannose, total testosterone, free testosterone, or dehydroepiandrosterone sulfate in the reliability of predicting PCOS using the method outlined by Hanley and McNeil. Combining mannose and total testosterone resulted in a higher AUC of 83.3%, and had moderate sensitivity (78.9%) and specificity (77%) for predicting PCOS. The positive and negative predictive values were 80% and 75.8%, respectively. Multivariate logistic regression revealed that higher serum mannose levels were strongly associated with an increased risk of PCOS (P = 0.016; odds ratio, 5.623; 95% confidence interval, 1.371–23.070).Conclusion: Taken together, substantially elevated serum mannose levels are significantly associated with PCOS, highlighting the importance of further research into the role of mannose in the pathogenesis of PCOS.

Association of Perforin and Granzyme-B Levels with Hyperandrogenism in Polycystic Ovary Syndrome: A Case-Control Study

Polycystic ovary syndrome (PCOS) is shown to be associated with hyperandrogenemia and has some features such as cytotoxic T-cells activation and release of perforin and granzyme-B. Present work was aimed to investigate the relation of perforin and granzyme-B to androgenic state in PCOS. Forty three PCOS and 40 control women were recruited. After recording demographic data, sex hormone status and cardiovascular disease (CVD) risk factors were evaluated. Perforin and granzyme-B levels were measured using sandwich ELISA kits. Sex hormone binding globulin (SHBG) levels were lower in patients. Luteinizing hormone (LH), free testosterone (FT), dehydroepiandrosterone sulfate (DHEA-S), free androgen index (FAI), perforin and granzyme-B values were higher in PCOS group. Perforin and granzyme-B were positively correlated with FT and FAI and with each other in PCOS group. In patients, granzyme-B and perforin were related with FT and FAI, respectively. The results of present study together with evidences about the release of pro-inflammatory cytokines in insulin resistance, CVD and PCOS suggest that perforin/granzyme-B may be involved in interactions of sex hormones system in PCOS patients.

Oxidative Stress in Response to Saturated Fat Ingestion Is Linked to Insulin Resistance and Hyperandrogenism in Polycystic Ovary Syndrome.

Oxidative stress and insulin resistance are often present in polycystic ovary syndrome (PCOS). We determined the effect of saturated fat ingestion on leukocytic reactive oxygen species (ROS) generation, p47phox expression, and circulating thiobarbituric acid-reactive substances (TBARS) in women with PCOS. Cross-sectional study. Academic medical center. Twenty women of reproductive age with PCOS (10 lean, 10 with obesity) and 19 ovulatory control subjects (10 lean, 9 with obesity). ROS generation and p47phox mRNA and protein content were quantified in leukocytes, and TBARS was measured in plasma from blood drawn while the subjects were fasting and 2, 3, and 5 hours after saturated fat ingestion. Insulin sensitivity was derived from an oral glucose tolerance test (ISOGTT). Androgen secretion was assessed from blood drawn while the subjects were fasting and 24, 48, and 72 hours after human chorionic gonadotropin (HCG) administration. Regardless of weight class, women with PCOS exhibited lipid-induced increases in leukocytic ROS generation and p47phox mRNA and protein content as well as plasma TBARS compared with lean control subjects. Both PCOS groups exhibited lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects. The ROS generation, p47phox, and TBARS responses were negatively correlated with ISOGTT and positively correlated with HCG-stimulated androgen secretion. In PCOS, increases in ROS generation, p47phox gene expression, and circulating TBARS in response to saturated fat ingestion are independent of obesity. Circulating mononuclear cells and excess adipose tissue are separate and distinct contributors to oxidative stress in this disorder.

Steroid Mass Spectrometry for the Diagnosis of PCOS

The most appropriate steroids to measure for the diagnosis of hyperandrogenism in polycystic ovary syndrome (PCOS) are still open to debate but should preferably be measured using a high-quality method such as liquid chromatography tandem mass spectrometry (LC-MS/MS). Measurement of testosterone is recommended in all of the current clinical guidelines but other steroids, such as androstenedione and dehydroepiandrosterone sulfate (DHEAS), have also been shown to be useful in diagnosing PCOS and may give additional information on metabolic risk. The 11-oxygenated steroids, and in particular 11KT derived mainly from the adrenal gland, are also increasing in prominence and have been shown to be the dominant androgens in this condition. Polycystic ovary syndrome is a complex syndrome and it is not surprising that each of the clinical phenotypes are associated with different patterns of steroid hormones; it is likely that steroid profiling with LC-MS/MS may be better at identifying hyperandrogensim in each of these phenotypes. Research into PCOS has been hampered by the small sample size of clinical studies previously undertaken and larger studies, preferably using LC-MS/MS profiling of steroids, are needed

The contribution of hyperinsulinemia to the hyperandrogenism of polycystic ovary syndrome

Background: Polycystic Ovary Syndrome (PCOS) is a very common endocrine disorder of young women.Aim: The proper treatment of PCOS requires a thorough understanding of the underlying cause of disease. In this article, we review the extent to which hyperinsulinemia contributes to the development of PCOS.Setting: The goal of this review was to assess the current literature on the contribution of hyperinsulinemia to the hyperandrogenism of polycystic ovary syndrome in hopes of promoting future research and advancements in clinical treatments for women with PCOS focusing on this major contributing factor, hyperinsulinemia.Method: A review of published peer-reviewed literature was conducted by searching the keywords.Results: Excessive insulin causes both the overproduction of testosterone and decreased sex hormone binding globulin (SHBG) levels seen in PCOS, both of which collaborate in creating an increased testosterone effect.Conclusion: The majority of research and evidence shows that the hyperandrogenism of PCOS is likely caused by hyperinsulinemia. Yet the conventional treatment of hyperandrogenic symptoms in women with PCOS is not directed towards correcting this underlying hyperinsulinemia. Further research is needed to assess how the treatment of the hyperinsulinemia through lifestyle would compare to the current treatment of hyperandrogenemia through testosterone-lowering drugs.

Delayed endometrial decidualisation in polycystic ovary syndrome; the role of AR-MAGEA11

Polycystic ovary syndrome (PCOS) is a common gynaecological disorder, with a prevalence of up to 12% of women of reproductive age, and is in part characterised by elevated circulating androgens and aberrant expression of androgen receptor (AR) in the endometrium. A high percentage of PCOS patients suffer from infertility, a condition that appears to be linked to mistimed and incomplete decidualisation critically affecting events surrounding embryo implantation. The aim of this study was to examine the involvement of MAGEA11, and the genome-wide role of AR in PCOS. We determined that elevated androgen levels on PCOS cells had an impact on the delayed and incomplete decidual transformation of endometrial cells. The AR co-regulator MAGEA11, a known enhancer of AR function, was constitutively overexpressed throughout the menstrual cycle of PCOS patients, co-localised in the nucleus of PCOS stromal tissue and cells and formed a molecular complex with AR. Genome-wide AR analysis in PCOS stromal cells revealed that AR targets included genes involved in cell death and apoptosis, as well as genes commonly dysregulated in endometrial cancer. Enhanced MAGEA11 and AR-mediated transcriptional regulation may impact on a correct endometrial decidualisation response, subsequently affecting endometrial receptivity in these infertile women.Key messagesMAGEA11 and AR are overexpressed in hyperandrogenic PCOS patients.MAGEA11-AR overexpression in PCOS correlates with delayed decidualisation.AR and MAGEA11 associate in a molecular complex.AR directly regulates a unique set of genes controlling gene differentiation.

Relation of NT-probnp levels and cardiovascular disease risk factors in lean women with polycystic ovary syndrome

Women with polycystic ovary syndrome (PCOS) often have cardiovascular disease (CVD) risk factors. N-terminal fragment of brain natriuretic peptide (Nt-probnp) is used as a diagnostic and prognostic marker for CVD. The aim of this study was to evaluate whether Nt-probnp is increased in lean PCOS patients. A total of 110 lean (BMI < 25 kg/m2) PCOS patients and 80 age and BMI matched healthy lean controls were included in this study. Serum Homeostatic Model Assessment-Insulin Resistance (HOMA-IR), Matsuda insulin sensitivity index (ISI), Nt-probnp, C-reactive protein (CRP), androgen and lipid levels were measured. Serum Nt-probnp levels were significantly higher in the PCOS group. Hyperandrogenic PCOS patients had higher Nt-probnp levels. There were significant correlations between serum Nt-probnp and total testosterone, total cholesterol, HOMA and Matsuda levels. Linear regression analysis showed that Matsuda ISI and fasting insulin levels significantly affected the Nt-probnp levels (R2 of the model = 0.763; p<.0001).IMPACT STATEMENTWhat is already known on this subject? Many risk factors for cardiovascular disease (CVD) including insulin resistance, dyslipidaemia, hypertension and hyperandrogenism may be found in young women with polycystic ovary syndrome (PCOS), although evidence for CVD in lean women with PCOS is limited. N-terminal fragment of brain natriuretic peptide (NT-probnp) is a high predictive marker regarding of CVD, especially in patients without overt CVD. There have been contradictory results regarding Nt-probnp levels in PCOS patients and there have not been any effective studies regarding the relation between CVD risk factors and Nt-probnp levels for lean PCOS patients.What the results of this study add? This study found increased Nt-probnp levels in lean PCOS patients, which may indicate a positive correlation with risk for CVD. Strong relations were also found between Nt-probnp levels and increased insulin resistance, dyslipidaemia, decreased insulin sensitivity and hyperandrogenism. Lean PCOS patients have increased risk factors for CVD, and these risk factors are correlated with Nt-probnp levels. Nt-probnp is more affected by increased fasting insulin and decreased insulin sensitivity.What the implications are of these findings for clinical practice and/or further research? Lean PCOS patients should be evaluated for CVD. Further prospective controlled studies are needed in order to predict the long-term risk of developing CVD in lean PCOS patients.

Therapeutic Effects of Gentiopicroside on Hyperandrogenism in Polycystic Ovary Syndrome via Rho/Rho-Associated Protein Kinase Signaling

Therapeutic Effects of Gentiopicroside on Hyperandrogenism in Polycystic Ovary Syndrome via Rho/Rho-Associated Protein Kinase Signaling