Developmental programming: Testosterone excess masculinizes female pancreatic transcriptome and function in sheep.

Hyperandrogenic disorders, such as polycystic ovary syndrome, are often associated with metabolic disruptions such as insulin resistance and hyperinsulinemia. Studies in sheep, a precocial model of translational relevance, provide evidence that in utero exposure to excess testosterone during days 30-90 of gestation (the sexually dimorphic window where males naturally experience elevated androgens) programs insulin resistance and hyperinsulinemia in female offspring. Extending earlier findings that adverse effects of testosterone excess are evident in fetal day 90 pancreas, the end of testosterone treatment, the present study provides evidence that transcriptomic and phenotypic effects of in utero testosterone excess on female pancreas persist after cessation of treatment, suggesting lasting organizational changes, and induce a male-like phenotype in female pancreas. These findings demonstrate that the female pancreas is susceptible to programmed masculinization during the sexually dimorphic window of fetal development and shed light on underlying connections between hyperandrogenism and metabolic homeostasis.

Serum Expression of miR-23a-3p and miR-424-5p Indicate Specific Polycystic Ovary Syndrome Phenotypes: A Pilot Study.

MicroRNAs (miRNAs) are single-stranded, non-coding RNAs that regulate mRNA expression on a post-transcriptional level. Observational studies suggest an association of serum miRNAs and polycystic ovary syndrome (PCOS), a common heterogeneous endocrinopathy characterized by hyperandrogenism (HA), oligo- or amenorrhea (OM) and polycystic ovaries. It is not known whether these miRNA profiles also differ between PCOS phenotypes. In this pilot study, we compared serum expression profiles between the four PCOS phenotypes (A-D) and analyzed them both in PCOS (all phenotypes) and in phenotypes with HA by quantitative-real-time PCR (qRT-PCR). The serum expression of miR-23a-3p was upregulated in phenotype B (n = 10) and discriminated it from phenotypes A (n = 11), C (n = 11) and D (n = 11, AUC = 0.837; 95%CI, 0.706-0.968; p = 0.006). The expression of miR-424-5p was downregulated in phenotype C (n = 11) and discriminated it from phenotypes A, B and D (AUC = 0.801; 95%CI, 0.591-1.000; p = 0.007). MiR-93-5p expression was downregulated in women with PCOS (all phenotypes, n = 42) compared to controls (n = 8; p = 0.042). Phenotypes with HA (A, B, C; n = 32) did not show differences in the analyzed expression pattern. Our data provide new insights into phenotype-specific miRNA alterations in the serum of women with PCOS. Understanding the differential hormonal and miRNA profiles across PCOS phenotypes is important to improve the pathophysiological understanding of PCOS heterogeneity.

miRNA expression in PCOS: unveiling a paradigm shift toward biomarker discovery.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder that affects a substantial percentage of women, estimated at around 9-21%. This condition can lead to anovulatory infertility in women of childbearing age and is often accompanied by various metabolic disturbances, including hyperandrogenism, insulin resistance, obesity, type-2 diabetes, and elevated cholesterol levels. The development of PCOS is influenced by a combination of epigenetic alterations, genetic mutations, and changes in the expression of non-coding RNAs, particularly microRNAs (miRNAs). MicroRNAs, commonly referred to as non-coding RNAs, are approximately 22 nucleotides in length and primarily function in post-transcriptional gene regulation, facilitating mRNA degradation and repressing translation. Their dynamic expression in different cells and tissues contributes to the regulation of various biological and cellular pathways. As a result, they have become pivotal biomarkers for various diseases, including PCOS, demonstrating intricate associations with diverse health conditions. The aberrant expression of miRNAs has been detected in the serum of women with PCOS, with overexpression and dysregulation of these miRNAs playing a central role in the atypical expression of endocrine hormones linked to PCOS. This review takes a comprehensive approach to explore the upregulation and downregulation of various miRNAs present in ovarian follicular cells, granulosa cells, and theca cells of women diagnosed with PCOS. Furthermore, it discusses the potential for a theragnostic approach using miRNAs to better understand and manage PCOS.

Fructose intake from sugar-sweetened beverages is associated with a greater risk of hyperandrogenism in women: UK Biobank cohort study.

OBJECTIVE: To assess the association between fructose consumption and serum sex hormone-binding globulin (SHBG), (free) testosterone, and risk of hyperandrogenism in a population-based cohort. DESIGN: An observational and genetic association study in participants of the UK Biobank (n = 136 384 and n = 383 392, respectively). METHODS: We assessed the relationship of (1) the intake of different sources of fructose (ie, total, fruit, fruit juice, and sugar-sweetened beverages [SSBs]) and (2) rs2304681 (a missense variant in the gene encoding ketohexokinase, used as an instrument of impaired fructose metabolism), with SHBG, total and free testosterone levels, and risk of hyperandrogenism (free androgen index >4.5). RESULTS: The intake of total fructose and fructose from fruit was associated with higher serum SHBG and lower free testosterone in men and women and lower risk of hyperandrogenism in women. In contrast, fructose intake from SSB (≥10 g/day) was associated with lower SHBG in men and women and with higher free testosterone levels and risk of hyperandrogenism in women (odds ratio [OR]: 1.018; 95% confidence interval [CI]: 1.010; 1.026). Carriers of the rs2304681 A allele were characterized by higher circulating SHBG (both men and women), lower serum free testosterone (women), and a lower risk of biochemical hyperandrogenism (OR: 0.997, 95% CI: 0.955; 0.999; women) and acne vulgaris (OR: 0.975, 95% CI: 0.952; 0.999; men and women combined). CONCLUSIONS: The consumption of ≥10 g/day fructose from SSB, corresponding to ≥200 mL serving, is associated with a 2% higher risk of hyperandrogenism in women. These observational data are supported by our genetic data.

Combination of metformin with liraglutide in treating HAIR-AN syndrome in children: A case report and literature review. / 二甲双胍联合利拉鲁肽治疗儿童HAIR-AN综合征1ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

Hyperandrogenism-insulin resistance-acanthosis nigricans (HAIR-AN) syndrome is a special and rare subtype of polycystic ovarian syndrome. It can lead to hyperandrogenism (HA), insulin resistance (IR), and acanthosis nigricans (AN) accompanied by acne, hirutism, irregular menstruation, and other androgen excess symptoms. A case of pediatric HAIR-AN syndrome with severe AN was admitted to the Department of Endocrinology, China-Japan Friendship Hospital. The patient's clinical manifestations, laboratory data, imaging features, and gene sequencing were analyzed, and the patient was diagnosed with pediatric HAIR-AN syndrome. Obesity, IR, hyperglycemia, menstrual disorder, and AN were significantly improved after treating with metformin and liraglutide. HAIR-AN syndrome occurs in various forms. When the patient appears unexplained acanthosis nigricans and menstrual disorders, the disease should be considered possible. Early diagnosis and symptomatic supportive treatment can improve the quality of life.

CircEpha5 regulates the synthesis and secretion of androgen in mouse preantral follicles by targeting miR-758-5p.

Circular RNAs are involved in the pathogenesis of various diseases, although its expression pattern and role in polycystic ovary syndrome (PCOS), characterised by hyperandrogenism, are not very clear. This article assessed the circRNAs expression profile in the ovaries of PCOS mice by circRNAs high-throughput sequencing and explored the role of circEpha5 in hyperandrogenism. The results showed that the overexpression of circEpha5 in mouse preantral follicles could increase the expression of Cyp17a1, an androgen synthesis-related gene, which resulted in a higher serum level of testosterone. Dual-luciferase reporter gene studies identified miR-758-5p as a direct target of circEpha5. Consequently, miR-758-5p expression was downregulated upon circEpha5 overexpression. Ectopically expressed miR-758-5p reversed the stimulation effects of circEpha5 on steroidogenesis-related gene expression and testosterone release. Therefore, circEpha5 could sponge miR-758-5p to regulate the expression of Cyp17a1, thereby promoting the synthesis and secretion of androgen in the preantral follicles. This work is contributed to the understanding of the pathogenesis of hyperandrogenemia and lays the foundation for the development of therapeutic targets of PCOS hyperandrogenism.

IMPACT STATEMENTWhat is already known on this subject? PCOS is a complex endocrine and metabolic disorders with hyperandrogenism as the main clinical manifestation. There are a variety of abnormal expression circRNAs in PCOS, however, the relationship between circEpha5 and hyperandrogenism has yet to be fully elucidated.What do the results of this study add? We first found that expression levels of serum circEpha5 were significantly higher in PCOS than in a normal group. Using mouse preantral follicle culture model and the letrozole-induced PCOS mouse model, the mechanism of CircEpha5 regulating androgen secretion was studied.What the implications are of these findings for clinical practice and/or further research? It was revealed that CircEpha5 can absorb miR-758-5p in the sponge to regulate the expression of Cyp17a1, thereby promoting the synthesis and secretion of androgen in preantral follicles, which may become a key target for the screening and treatment of PCOS hyperandrogenism.

Single-Cell RNA-Seq Identifies Pathways and Genes Contributing to the Hyperandrogenemia Associated with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by hyperandrogenemia of ovarian thecal cell origin, resulting in anovulation/oligo-ovulation and infertility. Our previous studies established that ovarian theca cells isolated and propagated from ovaries of normal ovulatory women and women with PCOS have distinctive molecular and cellular signatures that underlie the increased androgen biosynthesis in PCOS. To evaluate differences between gene expression in single-cells from passaged cultures of theca cells from ovaries of normal ovulatory women and women with PCOS, we performed single-cell RNA sequencing (scRNA-seq). Results from these studies revealed differentially expressed pathways and genes involved in the acquisition of cholesterol, the precursor of steroid hormones, and steroidogenesis. Bulk RNA-seq and microarray studies confirmed the theca cell differential gene expression profiles. The expression profiles appear to be directed largely by increased levels or activity of the transcription factors SREBF1, which regulates genes involved in cholesterol acquisition (LDLR, LIPA, NPC1, CYP11A1, FDX1, and FDXR), and GATA6, which regulates expression of genes encoding steroidogenic enzymes (CYP17A1) in concert with other differentially expressed transcription factors (SP1, NR5A2). This study provides insights into the molecular mechanisms underlying the hyperandrogenemia associated with PCOS and highlights potential targets for molecular diagnosis and therapeutic intervention.

Deletion of Androgen Receptor in LepRb Cells Improves Estrous Cycles in Prenatally Androgenized Mice.

Androgens are steroid hormones crucial for sexual differentiation of the brain and reproductive function. In excess, however, androgens may decrease fertility as observed in polycystic ovary syndrome, a common endocrine disorder characterized by oligo/anovulation and/or polycystic ovaries. Hyperandrogenism may also disrupt energy homeostasis, inducing higher central adiposity, insulin resistance, and glucose intolerance, which may exacerbate reproductive dysfunction. Androgens bind to androgen receptors (ARs), which are expressed in many reproductive and metabolic tissues, including brain sites that regulate the hypothalamo-pituitary-gonadal axis and energy homeostasis. The neuronal populations affected by androgen excess, however, have not been defined. We and others have shown that, in mice, AR is highly expressed in leptin receptor (LepRb) neurons, particularly in the arcuate (ARH) and the ventral premammillary nuclei (PMv). Here, we assessed if LepRb neurons, which are critical in the central regulation of energy homeostasis and exert permissive actions on puberty and fertility, have a role in the pathogenesis of female hyperandrogenism. Prenatally androgenized (PNA) mice lacking AR in LepRb cells (LepRbΔAR) show no changes in body mass, body composition, glucose homeostasis, or sexual maturation. They do show, however, a remarkable improvement of estrous cycles combined with normalization of ovary morphology compared to PNA controls. Our findings indicate that the prenatal androgenization effects on adult reproductive physiology (ie, anestrus and anovulation) are mediated by a subpopulation of LepRb neurons directly sensitive to androgens. They also suggest that the effects of hyperandrogenism on sexual maturation and reproductive function in adult females are controlled by distinct neural circuits.

Polycystic ovary syndrome and iron overload: biochemical link and underlying mechanisms with potential novel therapeutic avenues.

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder in women with components of significant genetic predisposition and possibly multiple, but not yet clearly defined, triggers. This disorder shares several clinical features with hemochromatosis, a genetically defined inheritable disorder of iron overload, which includes insulin resistance, increased adiposity, diabetes, fatty liver, infertility, and hyperandrogenism. A notable difference between the two disorders, however, is that the clinical symptoms in PCOS appear at much younger age whereas they become evident in hemochromatosis at a much later age. Nonetheless, noticeable accumulation of excess iron in the body is a common finding in both disorders even at adolescence. Hepcidin, the iron-regulatory hormone secreted by the liver, is reduced in both disorders and consequently increases intestinal iron absorption. Recent studies have shown that gut bacteria play a critical role in the control of iron absorption in the intestine. As dysbiosis is a common finding between PCOS and hemochromatosis, changes in bacterial composition in the gut may represent another cause for iron overload in both diseases via increased iron absorption. This raises the possibility that strategies to prevent accumulation of excess iron with iron chelators and/or probiotics may have therapeutic potential in the management of polycystic ovary syndrome.

Loci on chromosome 12q13.2 encompassing ERBB3, PA2G4 and RAB5B are associated with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia of ovarian theca cell origin. We report significant association of androgen production with 15 single nucleotide variants (SNVs) identified by exome sequencing of theca cells from women with PCOS and normal ovulatory women. Ten SNVs are located within a 150 kbp region on 12q13.2 which encompasses loci identified in PCOS genome-wide association studies (GWAS) and contains PCOS candidate genes ERBB3 and RAB5B. The region also contains PA2G4 which encodes a transcriptional corepressor of androgen receptor and androgen receptor-regulated genes. PA2G4 has not previously been recognized as related to PCOS in published GWAS studies. Two of the SNVs are predicted to have functional consequences (ERBB3 missense SNV, PA2G4 promoter SNV). PA2G4 interacts with the ERBB3 cytoplasmic domain containing the missense variant, suggesting a potential signaling pathway disruption that could lead to the PCOS ovarian phenotype. Single cell RNA sequencing of theca cells showed significantly less expression of PA2G4 after forskolin treatment in PCOS cells compared to normal cells (padj = 3.82E-30) and in cells heterozygous for the PA2G4 promoter SNV compared to those without the SNV (padj = 2.16E-11). This is consistent with a functional effect of the PA2G4 promoter SNV. No individual SNV was significantly associated with PCOS in an independent family cohort, but a haplotype with minor alleles of three SNVs was found preferentially in women with PCOS. These findings suggest a functional role for 12q13.2 variants in PCOS and implicate variants in ERBB3 and PA2G4 in the pathophysiology of PCOS.

History of Polycystic Ovary Syndrome, Premature Adrenarche, and Hyperandrogenism in Pediatric Endocrinology.

Descriptions of probable PCOS can be found in ancient Roman writings and in Renaissance art. Attention to domesticated animal reproduction led ancient observers to understand the role of the testes in male phenotypes, proven experimentally by testicular transplantation (in chickens) in 1849. Testosterone was isolated and its structure determined in the 1930s, but the multiple pathways of androgen synthesis have only been delineated recently. Adrenarche as an event separate from puberty was described in 1937, but the mechanism(s) triggering its onset remains unclear, although most work points to intraadrenal events. The identification of 11-ketotestosterone as the principal adrenal androgen is very recent (2018). Definitions of PCOS have evolved with the elucidation of its complex biology. PCOS is now recognized as a complex disorder characterized by irregular menses and hyperandrogenism often associated with infertility; its prevalence may be as high as 20% of reproductive age women. Work in the 1980s associated premature exaggerated adrenarche with PCOS, linking the adrenal to an "ovarian" syndrome. Obesity has long been noted in many patients with PCOS, and associated insulin resistance was noted in the 1980s, possibly associated with fetal developmental events such as low birth weight, but the mechanistic link between carbohydrate metabolism and hyperandrogenism remains unclear, despite intensive investigation. Genome-wide association studies have identified apparently associated genes, but mechanistic links are apparent for only some of these. Adrenarche, PCOS, and adrenal and ovarian hyperandrogenism remain very active areas of clinical and basic research.

The influence of ESR1 polymorphisms on selected hormonal, metabolic and mineral balance markers in women with hyperandrogenism.

Hyperandrogenism is the most common endocrine disorder in women, characterized by an imbalance in normal estrogen and androgen levels in the blood. Androgens influence bone mineral density, body mass composition, muscle mass, mental state, and the regulation of sexual function.. The aim of the study was to assess the effect of estrogen receptor α gene (ESR1) polymorphisms on selected markers of bone metabolism and hormonal parameters in women with hyperandrogenism. The study group included 80 young women with hyperandrogenism who underwent measurements of bone mineral density (BMD), and determination of hormonal and metabolic parameters. Enzyme immunoassays were used to measure leptin, sRANKL (soluble receptor activator of nuclear factor-kB ligand), osteoprotegerin and 25-OH vitamin D total levels. An analysis of ESR1 gene polymorphisms was performed using the real-time PCR method. A relationship was demonstrated between the concentration of free estradiol (FEI) and the concentration of 17-OH-progesterone, and the ESR1 gene polymorphisms: rs3020314 (p = 0.031, p = 0.026 respectively) and rs1884051 (p = 0.033, p = 0.026 respectively). In conclusion, the ESR gene polymorphisms may be associated with hormonal disturbances in the concentration of estrogens and androgens, in hyperandrogenism in young women which may indirectly affect bone mineral density. However, no statistically significant relationships between the studied polymorphisms and the selected parameters of mineral metabolism have been demonstrated..

A brief insight into the etiology, genetics, and immunology of polycystic ovarian syndrome (PCOS).

Polycystic ovarian syndrome (PCOS) is a prevailing endocrine and metabolic disorder occurring in about 6-20% of females in reproductive age. Most symptoms of PCOS arise early during puberty. Since PCOS involves a combination of signs and symptoms, thus it is considered as a heterogeneous disorderliness. The most accepted diagnostic criteria is Rotterdam criteria which involves two of the latter three features: (a) hyperandrogenism, (b) oligo- or an-ovulation, and (c) polycystic ovaries. The persistent hormonal imbalance leads to multiple small antral follicles formation and irregular menstrual cycle, ultimately causing infertility among females. Insulin resistance, cardiovascular diseases, abdominal obesity, psychological disorders, infertility, and cancer are also related to PCOS. These pathophysiologies associated with PCOS are interrelated with each other. Hyperandrogenism causes insulin resistance and hyperglycemia, leading to ROS formation, oxidative stress, and abdominal adiposity. In consequence, inflammation, ROS production, insulin resistance, and hyperandrogenemia also increase. Elevation of AGEs in the body either produced endogenously or consumed from diet exaggerates PCOS symptoms and is also related to ovarian dysfunction. This review summarizes how AGE formation, inflammation, and oxidative stress are significantly essential in PCOS progression. Alterations during prenatal development like exposure to excess AMH, androgens, or toxins (bisphenol-A, endocrine disruptors, etc.) may also be the etiologic mechanism behind PCOS. Although the etiology of this disorder is unclear, environmental and genetic factors are primarily involved. Physical inactivity, as well as unhealthy eating habits, has a vital role in the progression of PCOS. This review outlines a collection of specific genes phenotypically linked with PCOS. Furthermore, beneficial effect of metformin in maintaining endocrine abnormalities and ovarian function is also mentioned. Kisspeptin is a protein which helps in onset of puberty and increases GnRH pulsatile release during ovulation as well as role of KNDy neurons in GnRH pulsatile signal required for reproduction are also elaborated. This review also focuses on the immunology related to PCOS involving chronic low-grade inflammation, and how the alterations within the follicular microenvironment are intricated in the development of infertility in PCOS patients. How PCOS develops following antiepileptic and psychiatric medication is also expanded in this review. Initiation of antiandrogen treatment in early age (≤ 25 years) might be helpful in spontaneous conception in PCOS women. The role of BMP (bone morphogenetic proteins) in folliculogenesis and their expression in oocytes and granulosa cells are also explained. GDF8 and SERPINE1 expression in PCOS is given in detail.

Increased Prevalence of Elevated DHEAS in PCOS Women with Non-Classic (B or C) Phenotypes: A Retrospective Analysis in Patients Aged 20 to 29 Years.

It is well known that a subgroup of women with PCOS present an excessive adrenal androgen production, generally associated with ovarian hyperandrogenism. In the past, it has been impossible to correlate adrenal hyperandrogenism to any clinical or hormonal pattern of PCOS. However, adrenal androgens are strictly dependent on age and their blood values reduce by 40% in patients moving from their twenties to thirties. Due to this, serum DHEAS values are strongly influenced by the age distribution of studied populations. To avoid this bias, in this study we retrospectively analyzed the clinical and hormonal data of PCOS women in their twenties (age between 20 and 29 years). Data of 648 young hyperandrogenic women with PCOS were evaluated. Serum DHEAS was increased in a third (33%) of studied patients and was associated with higher values of testosterone (T) and androstenedione (A). In each phenotype, patients with high DHEAS had higher values of T and A than patients with normal DHEAS of the same phenotype. Therefore, a DHEAS increase is generally part of a generalized higher androgen production in a subgroup of PCOS patients, independently of the finding of anovulatory or ovulatory cycles or of polycystic or normal ovaries. However, our study showed some important differences between PCOS phenotypes. A lower prevalence of increased DHEAS in A phenotype PCOS patients who generally have the highest androgen levels, versus non-classic (B or C) PCOS phenotypes, was observed. It was also found that patients with A phenotype PCOS present significantly lower BMI and serum insulin than patients with normal DHEAS of the same phenotype while, in patients with the B or C phenotype, the opposite occurs. We conclude that adrenal hyperandrogenism is more common in patients with non-classic (B and C) phenotypes of PCOS and is generally part of a generalized higher production of androgens in a subgroup of PCOS patients. However, other factors may increase the adrenal androgen production and influence the clinical expression of the syndrome. More studies in large, selected for age, populations of PCOS women with different phenotypes are needed.

Comparison of Reproductive Function Between Normal and Hyperandrogenemia Conditions in Female Mice With Deletion of Hepatic Androgen Receptor.

Obesity, altered glucose homeostasis, hyperinsulinism, and reproductive dysfunction develops in female humans and mammals with hyperandrogenism. We previously reported that low dose dihydrotestosterone (DHT) administration results in metabolic and reproductive dysfunction in the absence of obesity in female mice, and conditional knock-out of the androgen receptor (Ar) in the liver (LivARKO) protects female mice from DHT-induced glucose intolerance and hyperinsulinemia. Since altered metabolic function will regulate reproduction, and liver plays a pivotal role in the reversible regulation of reproductive function, we sought to determine the reproductive phenotype of LivARKO mice under normal and hyperandrogenemic conditions. Using Cre/Lox technology, we deleted the Ar in the liver, and we observed LivARKO female mice have normal puberty timing, cyclicity and reproductive function. After DHT treatment, like control mice, LivARKO experience altered estrous cycling, reduced numbers of corpus lutea, and infertility. Liver Ar is not involved in hyperandrogenemia-induced reproductive dysfunction. The reproductive dysfunction in the DHT-treated LivARKO lean females with normal glucose homeostasis indicates that androgen-induced reproductive dysfunction is independent from metabolic dysfunction.

Androgen signaling in adipose tissue, but less likely skeletal muscle, mediates development of metabolic traits in a PCOS mouse model.

Polycystic ovary syndrome (PCOS) is a common, multifactorial disorder characterized by endocrine, reproductive, and metabolic dysfunction. As the etiology of PCOS is unknown, there is no cure and symptom-oriented treatments are suboptimal. Hyperandrogenism is a key diagnostic trait, and evidence suggests that androgen receptor (AR)-mediated actions are critical to PCOS pathogenesis. However, the key AR target sites involved remain to be fully defined. Adipocyte and muscle dysfunction are proposed as important sites involved in the manifestation of PCOS traits. We investigated the role of AR signaling in white adipose tissue (WAT), brown adipose tissue (BAT), and skeletal muscle in the development of PCOS in a hyperandrogenic PCOS mouse model. As expected, dihydrotestosterone (DHT) exposure induced key reproductive and metabolic PCOS traits in wild-type (WT) females. Transplantation of AR-insensitive (AR-/-) WAT or BAT from AR knockout females (ARKO) into DHT-treated WT mice ameliorated some metabolic PCOS features, including increased body weight, adiposity, and adipocyte hypertrophy, but not reproductive PCOS traits. In contrast, DHT-treated ARKO female mice transplanted with AR-responsive (AR+/+) WAT or BAT continued to resist developing PCOS traits. DHT-treated skeletal muscle-specific AR knockout females (SkMARKO) displayed a comparable phenotype with that of DHT-treated WT females, with full development of PCOS traits. Taken together, these findings infer that both WAT and BAT, but less likely skeletal muscle, are key sites of AR-mediated actions involved in the experimental pathogenesis of metabolic PCOS traits. These data further support targeting adipocyte AR-driven pathways in future research aimed at developing novel therapeutic interventions for PCOS.NEW & NOTEWORTHY Hyperandrogenism is a key feature in the pathogenesis of polycystic ovary syndrome (PCOS); however, the tissue sites of androgen receptor (AR) signaling are unclear. In this study, AR signaling in white and brown adipose tissue, but less likely in skeletal muscle, was found to be involved in the development of metabolic PCOS traits, highlighting the importance of androgen actions in adipose tissue and obesity in the manifestation of metabolic disturbances.

DNA methylation in polycystic ovary syndrome: Emerging evidence and challenges.

Polycystic ovary syndrome (PCOS) is a disease related to reproductive endocrine abnormalities in women of reproductive age, often accompanied by metabolic diseases such as hyperandrogenemia, insulin resistance and dyslipidemia. However, the etiology and mechanism of PCOS are still unclear. In recent years, more and more studies have found that epigenetic factors play an important role in PCOS. DNA methylation is the most widely studied epigenetic modification. At present, changes of DNA methylation have been found in serum, ovarian, hypothalamus, skeletal muscle, adipose tissue of PCOS patients, and these changes are closely related to insulin resistance, lipid metabolism and follicular development of PCOS. Although the current research on DNA methylation in PCOS is not in-depth, it indicated up a good direction for future research on the etiology and mechanism of PCOS. This review discussed the relationship between DNA methylation and PCOS. It is expected to help accelerate the application of DNA methylation in the diagnosis and treatment of PCOS.

Anti-Müllerian Hormone in Pathogenesis, Diagnostic and Treatment of PCOS.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-aged women. It is characterized by chronic anovulation, hyperandrogenism, and the presence of polycystic ovary in ultrasound examination. PCOS is specified by an increased number of follicles at all growing stages, mainly seen in the preantral and small antral follicles and an increased serum level of Anti-Müllerian Hormone (AMH). Because of the strong correlation between circulating AMH levels and antral follicle count on ultrasound, Anti-Müllerian Hormone has been proposed as an alternative marker of ovulatory dysfunction in PCOS. However, the results from the current literature are not homogeneous, and the specific threshold of AMH in PCOS and PCOM is, therefore, very challenging. This review aims to update the current knowledge about AMH, the pathophysiology of AMH in the pathogenesis of PCOS, and the role of Anti-Müllerian Hormone in the treatment of this syndrome.

MeCP2 duplication causes hyperandrogenism by upregulating LHCGR and downregulating RORα.

Duplication of MECP2 (methyl-CpG-binding protein 2) gene causes a serious neurological and developmental disorder called MECP2 duplication syndrome (MDS), which is usually found in males. A previous clinical study reported that MDS patient has precocious puberty with hyperandrogenism, suggesting increased MeCP2 may cause male hyperandrogenism. Here we use an MDS mouse model and confirm that MECP2 duplication significantly upregulates androgen levels. We show for the first time that MeCP2 is highly expressed in the Leydig cells of testis, where androgen is synthesized. Mechanistically, MECP2 duplication increases androgen synthesis and decreases androgen to estrogen conversion through either the upregulation of luteinizing hormone receptor (LHCGR) in testis, as a result of MeCP2 binds to G-quadruplex structure of Lhcgr promoter and recruits the transcription activator CREB1 or the downregulation of the expression of aromatase in testis by binding the CpG island of Rorα, an upstream regulator of aromatase. Taken together, we demonstrate that MeCP2 plays an important role in androgen synthesis, supporting a novel non-CNS function of MeCP2 in the process of sex hormone synthesis.

Polymorphisms of Vitamin D Receptor and the Effect on Metabolic and Endocrine Abnormalities in Polycystic Ovary Syndrome: A Review.

Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine disorder in women of reproductive age. Vitamin D and its receptor are thought to play an important role in PCOS susceptibility, although the impact of vitamin D receptor (VDR) polymorphisms on the hormonal and metabolic profile is still controversial. A literature search in PubMed and Embase was performed up to September 2020 for case-control studies in women suffering from PCOS, with outcome related to VDR polymorphisms effect on metabolic/endocrine disturbances. We have found 16 eligible studies including 2566 women with PCOS and 2430 controls. ApaI polymorphism seemed to be associated with hyperandrogenism in both Asian and Caucasian population. FokI variant was correlated with metabolic/endocrine parameters especially in Asian population, while a relation between Cdx2 genotypes and insulin sensitivity was observed in both ethnicities. VDR polymorphisms have an important role in PCOS development and related hormonal and metabolic abnormalities. Few case-control studies analysed the interaction between VDR variants and metabolic/endocrine parameters with the majority of the articles focused on the Asian region. Further research on various ethnic populations with larger sample size are still needed for a definitive conclusion, in order to allow early diagnosis and prevention of PCOS comorbidities.