Hyperandrogenism and menstrual imbalance are the best predictors of metformin response in PCOS patients

Background Moving from the correlation between insulin-resistance and PCOS, metformin has been administered in some PCOS women improving ovulatory and metabolic functions and decreasing androgen levels. Inconsistency and unpredictability of response to metformin limit its extensive use. Aim of this study was to identify reliable predictors of response to metformin therapy for weight loss and reduction in plasma androgen levels using ANNs (artificial neural networks). Methods One hundred eight consecutive women with PCOS (ESHRE/ASRM 2003 Rotterdam criteria) treated with metformin 1500 mg/day, at inclusion and every 6 months underwent to a complete clinical, endocrine/metabolic assessment and ultrasonographic evaluation. Therapy outcomes were BMI reduction (≥1 kg/m2) in overweight/obese and free-androgen-index (FAI) decrease (≥1%) in hyperandrogenemic women. Semantic connectivity maps (SCMs) were obtained through Auto-CM, a fourth generation ANN, to compare patients’ baseline clinical features to the treatment outcomes. Multivariate logistic regression analysis was used to assess the major predictor in drop-out patients and the associated risk. Results At 6 months 54 out of 103 (52,4%) obese patients showed BMI reduction and 45 out of 89 (50,6%) hyperandrogenemic women showed FAI decrease. The further response rates at 12 months were 30,6 and 47%, respectively. SCMs showed a clear polarization for both the outcomes with elevated accuracy. Treatment responsiveness resulted strictly related to oligo-amenorrhea and hyperandrogenemia at baseline. In addition, lower serum testosterone levels at baseline were found to be the major predictor of treatment discontinuation. Conclusions In women with PCOS, menstrual pattern imbalance and ovarian androgens excess are the best predictors of metformin response. They may pave the way for a rethinking of the criteria for evaluating hyperandrogenism in order to better define the large population included in the diagnosis of PCOS. Baseline plasma testosterone level can serve as a sensitive marker to predict treatment compliance.

Cysteine–Cysteine Motif Chemokine Receptor 5 Expression in Letrozole-Induced Polycystic Ovary Syndrome Mice

Polycystic ovary syndrome (PCOS), which affects 5–10% of women of reproductive age, is associated with reproductive and metabolic disorders, such as chronic anovulation, infertility, insulin resistance, and type 2 diabetes. However, the mechanism of PCOS is still unknown. Therefore, this study used a letrozole-exposed mouse model in which mice were orally fed letrozole for 20 weeks to investigate the effects of letrozole on the severity of reproductive and metabolic consequences and the expression of cysteine–cysteine motif chemokine receptor 5 (CCR5) in letrozole-induced PCOS mice. The letrozole-treated mice showed a disrupted estrous cycle and were arrested in the diestrus phase. Letrozole treatment also increased plasma testosterone levels, decreased estradiol levels, and caused multicystic follicle formation. Furthermore, histological analysis of the perigonadal white adipose tissue (pgWAT) showed no significant difference in the size and number of adipocytes between the letrozole-treated mice and the control group. Further, the letrozole-treated mice demonstrated glucose intolerance and insulin resistance during oral glucose and insulin tolerance testing. Additionally, the expression of CCR5 and cysteine-cysteine motif ligand 5 (CCL5) were significantly higher in the pgWAT of the letrozole-treated mice compared with the control group. CCR5 and CCL5 were also significantly correlated with the homeostasis model assessment of insulin resistance (HOMA-IR). Finally, the mechanisms of insulin resistance in PCOS may be caused by an increase in serine phosphorylation and a decrease in Akt phosphorylation.

Ovarian Hilus Cell Hyperplasia and Sertoli-Leydig Cell Tumor in a Patient with Postmenopausal Virilization: a Rare Case Report

Objective; We present a case report regarding a 71-year-old woman with postmenopausal virilization caused by ovarian hilus cell hyperplasia and Sertoli-Leydig cell tumor who was suffered from hair loss, clitoromegaly and hirsutism. Case Report; The patient’s plasma testosterone levels were high. In the MRI examination, a nodular formation of 20x26mm in size was observed in the right ovary. At the transvaginal ultrasound, a cystic mass of 28x28mm was seen in the right ovary. Then we performed a total laparoscopic hysterectomy and bilateral salpingo-oophorectomy. The final pathology showed a poorly differentiated Sertoli Leydig cell tumor at the right ovary and hilus cell hyperplasia at the left ovary. Sertoli-Leydig cell tumors, which are relatively less common, are extremely rare to be seen in the postmenopausal period. Conclusion; What distinguishes this case from others is that Sertoli-Leydig cell tumor and hilus cell hyperplasia may cause virilization symptoms together, in addition to its prevalence in advanced age.

Dose Dependent Degeneration of Leydig Cells Following Kisspeptin-10 Administration: An Ultrastructural Study

Background: The discovery of kisspeptin signaling as a key regulator of gonadotropin releasing hormone (GnRH) secretion from the hypothalamus enhanced our understanding of the neuroendocrine regulation of mammalian reproduction. Effects of central and peripheral administration of kisspeptin on plasma gonadotropins, testosterone and spermatogenesis are studied in detail. Objective: The present study was conducted to check the ultrastructure of Leydig cells in prepubertal male rats in response to the administration of a range of kisspeptin doses. Method: To this end, we administered a range of kisspeptin-10 doses (1µg, 1ηg and 10ρg) intraperitoneally, to prepubertal male Sprague-Dawley rats (PND 35) twice daily after every 12 hours. Control rats were injected with physiological saline in parallel. Results: At the end of the treatment, plasma concentrations of testosterone was measured by competitive binding radioimmunoassay and small pieces of rat testicular tissue were processed for electron microscopy to examine the ultrastructure of Leydig cells. Plasma testosterone concentration was reduced significantly at 1ηg (P<0.05) and 1μg (P<0.01) doses as compared to control. Distinct ultrastructural changes categorized as dilatation of cytoplasmic organelles, irregular shaped nuclei with nuclear membrane invaginations, reduced nuclear sizes, degeneration and vacuolation were observed in the kisspeptin-10 treated Leydig cells as compared to control. Quantification of the data showed reduced Leydig cell indices and hyperplasia of the interstitial cells. Conclusion: It is concluded that chronic intermittent administration of kisspeptin-10 has a dose dependent degenerative effect on the plasma testosterone levels and Leydig cells ultrastructure in prepubertal male rats.

Protective effect of propolis against aluminum chloride-induced reproductive toxicity in male rats

The aim of the present study was to investigate the toxic effects of aluminum chloride (AlCl3) on the reproductive organs, as well as, the protective effect of propolis against AlCl3-induced reproductive toxicity in male rats. Eighty adult male fertile Sprague Dawley albino rats were randomly divided into four groups of 20 each. Group 1: served as control group and received only distilled water. Group 2: received a daily ingestion of 80 mg/kg of AlCl3. Group 3: received a daily ingestion of 200 mg/kg of an ethanol extract of propolis. Group 4: received a daily ingestion of 80 mg/kg of AlCl3 in addition to 200 mg/kg of an ethanol extract of propolis. The duration of experiment was six weeks. At the end of the experiment, the testes, seminal vesicles, prostate glands and epididymides were dissected out, and weighed. Sperm characteristics were evaluated and plasma testosterone level was estimated. There were no significant changes between the control and the propolis-treated group. AlCl3-treated group showed a highly significant decrease in the index weights of testes and prostate glands, a highly significant lower sperm count, motility and viability, a highly significant increase in the number of abnormal sperms, as well as, a highly significant decrease in serum testosterone level (p < 0.001), compared to control. Rats of AlCl3+propolis-treated group showed a highly significant improvement in all previous alterations. In conclusion, propolis appeared to ameliorate AlCl3-induced reproductive toxicity in male rats.

Chronic Dietary Exposure of Roosters to a Glyphosate-Based Herbicide Increases Seminal Plasma Glyphosate and AMPA Concentrations, Alters Sperm Parameters, and Induces Metabolic Disorders in the Progeny

The effects of chronic dietary Roundup (RU) exposure on rooster sperm parameters, fertility, and offspring are unknown. We investigated the effects of chronic RU dietary exposure (46.8 mg kg−1 day−1 glyphosate) for 5 weeks in 32-week-old roosters (n = 5 RU-exposed and n = 5 control (CT)). Although the concentrations of glyphosate and its main metabolite AMPA (aminomethylphosphonic acid) increased in blood plasma and seminal fluid during exposure, no significant differences in testis weight and sperm concentrations were observed between RU and CT roosters. However, sperm motility was significantly reduced, associated with decreased calcium and ATP concentrations in RU spermatozoa. Plasma testosterone and oestradiol concentrations increased in RU roosters. These negative effects ceased 14 days after RU removal from the diet. Epigenetic analysis showed a global DNA hypomethylation in RU roosters. After artificial insemination of hens (n = 40) with sperm from CT or RU roosters, eggs were collected and artificially incubated. Embryo viability did not differ, but chicks from RU roosters (n = 118) had a higher food consumption, body weight and subcutaneous adipose tissue content. Chronic dietary RU exposure in roosters reduces sperm motility and increases plasma testosterone levels, growth performance, and fattening in offspring.

Alcohol-Induced Mitochondrial and NADPH Oxidase Mediated ROS Generation Alter Neuroendocrine Status: Role of Pterocarpus Santalinus

The association between oxidative stress and endocrine status with respect to the role of Pterocarpus santalinus (PSE) against alcohol-induced neurotoxicity in rats was investigated. Male albino rats were divided into, control, alcohol treated, alcohol + PSE treated, and PSE treated group. Twenty percent of ethanol (5g/kg body weight/day) was given with and without PSE (250 mg/kg body weight/day) for 60 days. Decreased plasma testosterone, estradiol, thyroid hormones (T3 and T4), and increased cortisol concentrations in alcohol treated rats were observed. Besides, elevated lipid peroxidation, protein carbonyls, NADPH oxidase (NOX), and cytochrome P-450 (CYP-450) activities, with mitochondrial dysfunction were noticed. Moreover, increased protein expression of the phosphorylated protein kinase C (p-PKC), phospholipase C (p-PLC), and NOX2 with decreased antioxidant status was also noticed in alcohol ingested rats. Administration of PSE to alcohol treated rats reduced oxidative stress by increasing antioxidant status, also modulated mitochondrial dysfunction and protein expression of p-PKC, p-PLC and NOX2. In conclusion, ROS generated via mitochondrial dysfunction causes activation of NOX activity through PLC and PKC dependent pathways leading to more ROS generation, which in turn alters the circulating hormonal levels. The phytocompounds present in PSE confer therapeutic efficacy by scavenging ROS and thereby offer protection.

Male White-shouldered Fairywrens (Malurus alboscapulatus) elevate testosterone when courting females but not during territorial challenges

Testosterone mediates suites of physical and behavioral traits across vertebrates, and circulation varies considerably across and within taxa. However, an understanding of the causal factors of variation in circulating testosterone has proven difficult despite decades of research. According to the challenge hypothesis, agonistic interactions between males immediately prior to the breeding season produce the highest levels of testosterone measured during this period. While many studies have provided support for this hypothesis, most species do not respond to male-male competition by elevating testosterone. As a result, a recent revision of the hypothesis (challenge hypothesis 2.0) places male-female interactions as the primary cause of rapid elevations in testosterone circulation in male vertebrates. Here, we offer a test of both iterations of the challenge hypothesis in a tropical bird species. We first illustrate that male White-shouldered Fairywrens (Malurus alboscapulatus) differ by subspecies in plasma testosterone concentrations. Then we use a social network approach to find that males of the subspecies with higher testosterone are characterized by greater social interaction scores, including more time aggregating to perform sexual displays. Next, we use a controlled experiment to test whether males respond to simulated territorial intrusion or courtship interaction contexts by elevating testosterone. Males sampled during courtship had greater plasma testosterone both relative to flushed controls and males sampled during simulated intrusion. Ultimately, our results are consistent with challenge hypothesis 2.0, as males rapidly elevated testosterone following interactions with females, but not during territorial challenges.

Role of the Renal Androgen Receptor in Ammonia Metabolism

Background: There are sex differences in renal ammonia metabolism and structure, many of which are mediated by testosterone. This study's goal was to determine the role of renal expression of testosterone's canonical receptor, androgen receptor (AR), in these sexual dimorphisms. Methods: We studied mice with kidney-specific AR deletion (KS-AR-KO) generated using Cre/loxP techniques; control mice were Cre-negative littermates (WT). Results: In male, but not female, mice, KS-AR-KO increased ammonia excretion, which eliminated sex differences. Although renal structural size typically parallel ammonia excretion, KS-AR-KO decreased kidney size, cortical proximal tubule volume density and cortical proximal tubule cell height in males; neither were altered in females and collecting duct volume density was unaltered in both sexes. Analysis of key protein involved in ammonia handling showed in male mice that KS-AR-KO increased both PEPCK and NKCC2 expression, and decreased NHE3 and NBCe1-A expression. In female mice, KS-AR-KO did not alter these parameters. These effects occurred even though KS-AR-KO did not alter plasma testosterone, food intake or serum Na+, K+, or HCO3- significantly in either sex. Conclusions: AR-dependent signaling pathways in male, but not female, kidney regulate PEPCK and NKCC2 expression and lead to the sexual differences in ammonia excretion. Opposing effects on NHE-3 and NBCe1-A expression likely limit the magnitude of ammonia excretion changes. Since AR is not present in the TAL, the effect of KS-AR-KO on NKCC2 expression is indirect. Finally, AR mediates the greater kidney size and PT volume density in male than in female mice.