Transcriptomic changes in the pituitary of female mice with androgen excess through dihydrotestosterone (DHT) treatment

Androgen excess in women is associated with the development of PCOS and its abnormalities. The Hypothalamus Pituitary Ovarian axis signaling is altered with excessed androgens, leading to anovulation and infertility. Previous studies have shown that AR signaling in the pituitary alters gonadotrophin release. Hence, the present pioneering study was an approach to determine the transcriptomic changes responsible to the phenotype seen with DHT excess. RNA seq data showed that 583 genes were differentially regulated by DHT in pituitary, of which 344 were upregulated and 239 downregulated. Meanwhile, Transcriptional factor analysis showed that majority of the genes changed had Androgen responsive elements.

Mitochondria in Sex Hormone-Induced Disorder of Energy Metabolism in Males and Females

Androgens have a complex role in the regulation of insulin sensitivity in the pathogenesis of type 2 diabetes. In male subjects, a reduction in androgens increases the risk for insulin resistance, which is improved by androgen injections. However, in female subjects with polycystic ovary syndrome (PCOS), androgen excess becomes a risk factor for insulin resistance. The exact mechanism underlying the complex activities of androgens remains unknown. In this review, a hormone synergy-based view is proposed for understanding this complexity. Mitochondrial overactivation by substrate influx is a mechanism of insulin resistance in obesity. This concept may apply to the androgen-induced insulin resistance in PCOS. Androgens and estrogens both exhibit activities in the induction of mitochondrial oxidative phosphorylation. The two hormones may synergize in mitochondria to induce overproduction of ATP. ATP surplus in the pancreatic β-cells and α-cells causes excess secretion of insulin and glucagon, respectively, leading to peripheral insulin resistance in the early phase of type 2 diabetes. In the skeletal muscle and liver, the ATP surplus contributes to insulin resistance through suppression of AMPK and activation of mTOR. Consistent ATP surplus leads to mitochondrial dysfunction as a consequence of mitophagy inhibition, which provides a potential mechanism for mitochondrial dysfunction in β-cells and brown adipocytes in PCOS. The hormone synergy-based view provides a basis for the overactivation and dysfunction of mitochondria in PCOS-associated type 2 diabetes. The molecular mechanism for the synergy is discussed in this review with a focus on transcriptional regulation. This view suggests a unifying mechanism for the distinct metabolic roles of androgens in the control of insulin action in men with hypogonadism and women with PCOS.

Androgen excess increases food intake in a rat polycystic ovary syndrome model by down-regulating hypothalamus insulin and leptin signaling pathways preceding weight gain

Background Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic disorder characterized by high androgen levels. The aim of this study was to evaluate the effects of hyperandrogenism on the hypothalamus, and subsequently on the food intake and obesity in females. Methods A dihydroxy testosterone (DHT)-induced rat model was established to recapitulate the hyperandrogenism features of PCOS patients. Body weight and food intake of the rats were recorded. The food intake of DHT-induced rats was restricted by pair feeding to exclude possible effects of weight gain on the hypothalamus. The expression levels of relevant proteins and mRNAs in the hypothalamus, primary hypothalamic neurons exposed to DHT were analyzed by Western blotting and RT-PCR respectively. The leptin levels in serum and cerebrospinal fluid (CSF) were measured, and leptin was injected via the intracerebroventricular (ICV) route to test the leptin sensitivity of hypothalamus. Results The excessive pre-puberty androgen levels in the DHT-induced rats markedly elevated food intake prior to weight gain. Consistent with this, the expression of NPY and Agouti-related peptide (Agrp) mRNAs were up-regulated, which occurred prior to obesity and even with restricted food intake. In addition, the hypothalamic sensitivity to insulin and leptin was also impaired in the DHT-induced rats before obesity and with restricted food intake. DHT significantly reduced the leptin levels in the CSF, and ICV injection of leptin inhibited the DHT-induced increase in food intake. Conclusions Androgen excess increased food intake in rats and promoted obesity by down-regulating insulin and leptin signaling in the hypothalamus, most likely by suppressing leptin levels in the CSF.

Effect of the spatial–temporal specific theca cell Cyp17 overexpression on the reproductive phenotype of the novel TC17 mouse

Background In the ovarian follicle, the Theca Cells (TCs) have two main functions: preserving morphological integrity and, importantly, secreting steroid androgen hormones. TCs express the essential enzyme 17α-hydroxylase/17,20-desmolase (CYP17), which permits the conversion of pregnenolone and progesterone into androgens. Dysregulation of CYP17 enzyme activity due to an intrinsic ovarian defect is hypothesized to be a cause of hyperandrogenism in women. Androgen excess is observed in women with polycystic ovary syndrome (PCOS) resulting from excess endogenous androgen production, and in transgender males undergoing exogenous testosterone therapy after female sex assignment at birth. However, the molecular and morphological effects of Cyp17 overexpression and androgen excess on folliculogenesis is unknown. Methods In this work, seeking a comprehensive profiling of the local outcomes of the androgen excess in the ovary, we generated a transgenic mouse model (TC17) with doxycycline (Dox)-induced Cyp17 overexpression in a local and temporal manner. TC17 mice were obtained by a combination of the Tet-dependent expression system and the Cre/LoxP gene control system. Results Ovaries of Dox-treated TC17 mice overexpressed Cyp17 specifically in TCs, inducing high testosterone levels. Surprisingly, TC17 ovarian morphology resembled the human ovarian features of testosterone-treated transgender men (partially impaired folliculogenesis, hypertrophic or luteinized stromal cells, atretic follicles, and collapsed clusters). We additionally assessed TC17 fertility denoting a perturbation of the normal reproductive functions (e.g., low pregnancy rate and numbers of pups per litter). Finally, RNAseq analysis permitted us to identify dysregulated genes (Lhcgr, Fshr, Runx1) and pathways (Extra Cellular Matrix and Steroid Synthesis). Conclusions Our novel mouse model is a versatile tool to provide innovative insights into study the effects of Cyp17 overexpression and hyperandrogenism in the ovary.

“THE EFFECT OF CYPROTERONE ACETATE AND ETHINYLESTRADIOL COMBINATION ON HYPERANDROGENIC AND OTHER SYMPTOMS IN PCOS”

INTRODUCTION- Polycystic ovarian syndrome (PCOS) is a common, heterogeneous disorder affecting 5-15% of women of reproducing age group and characterized by hyperandrogenic skin symptoms, (acne, Hirsutism and female pattern alopecia,) irregular menstrual bleeding, obesity, dysmenorrhea infertility, and increased risk of metabolic syndrome and endometrial cancer. MATERIAL AND METHOD-The present study was conducted in a private gynecological Clinic Shivpuri, (M.P.). After taking Consent women suffering from PCOS (Fullled the clinical and USG criteria of PCOS(Rotterdam criteria )) along with androgenic symptoms like acne, hirsutism and androgenetic alopecia with or without other symptoms like menstrual irregularities and dysmenorrhea were included in the study.. All patients then received a combination of ethenyl Estradiol (0.035mg) + Cyproterone acetate (2mg). The Patients were followed in the third month, Sixth month, and at about 1 year for improvement in various complaints RESULT- According to presenting symptoms the most common presenting symptom was acne 72.72%, followed by menstrual irregularities 68.18%, hirsutism 50%, alopecia 27.27%, and dysmenorrhea in 27.27%. In acne patients, 37.5% of patients showed improvement after 3 cycles of CPA/EE, 75% showed at 6 months and in 93.75%, improvement was seen at 12 months. In the case of alopecia (83.33%) patient showed improvement after >6 cycles. Patients with hirsutism showed no improvement after 3 months of therapy but 54.54% of the patients showed a change in texture after 6 months of therapy and 72.72% after 9-12 months of therapy. Patients with dysmenorrhea reported a decrease in pain after therapy. The acceptance of the treatment was very good. In 86.36% of patients, good tolerance of drug was seen and in only 3 patients adverse effects (headache and nausea) of the drug were there. All the patients were having good to moderate satisfaction with the therapy. CONCLUSION- Since androgen excess is the prime defect in polycystic ovarian disease, its reduction is the main therapeutic target for most women. Our study found that combined hormonal contraceptives containing ethenyl Estradiol (0.035mg) + Cyproterone acetate (2mg) in a 21/7 regimen had a positive effect in the treatment of acne, hirsutism, menstrual irregularity, and dysmenorrhea in PCOS patients.

Ovarian steroid cell tumors, not otherwise specified: Analysis of nine cases with a literature review

Objective Ovarian steroid cell tumors (SCTs), not otherwise specified (NOS), are rare, with few large studies. The purpose of this study was to analyze the clinical features, prognosis, and treatment choices for SCT-NOS patients of different age groups. Methods This was a retrospective study. We identified nine SCT-NOS cases, confirmed by post-operative histopathological examination, and analyzed clinical features, surgical procedures, and follow up outcomes. We also reviewed cases reports of SCT-NOS. Results A total of nine cases were included. The age range was 9–68 years (mean, 41.89 ± 19.72 years). Clinical features included virilization, amenorrhea, abdominal pain, vaginal bleeding, isosexual precocious puberty, Cushing’s syndrome, and abnormal weight gain with elevated testosterone levels. The follow up interval ranged 5–53 months and no recurrence was observed. Conclusion Ovarian SCTs covered all age groups, with manifestations of androgen excess. Younger patients appeared to have a more favorable prognosis, which provided more opportunities for these patients to pursue treatment options that will preserve reproductive function.

Evaluation of Cardiovascular Disease Risk in Women having Poly Cystic Ovarian Syndrome

PCOS, also known as Stein-Leventhal syndrome, is a common endocrine disease characterized by two of the following three characteristics: Once the associated endocrinological and gynecological diseases have been ruled out, oligo-ovulation or anovulation, ii) clinical and/or biochemical indications of hyperandrogenism, or iii) polycystic ovaries should be considered. Cardiovascular disease (CVD) risk factors are common in women with polycystic ovarian syndrome (PCOS). The Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society established a panel to offer evidence-based evaluations of research examining the PCOS-CVD risk connection and to produce CVD prevention recommendations. The main pathophysiological abnormality in polycystic ovarian syndrome is a source of much debate (PCOS). Chronic anovulation in conjunction with androgen excess, hyperinsulinemia, and changes in gonadotropin production are now widely accepted as symptoms of this disease in women. Polycystic ovarian syndrome (PCOS) is linked to obesity and low-grade inflammation, and it may raise the risk of cardiovascular disease (CVD). This study examines the assessment of cardiovascular disease risk in women with PCOS.