The Subcutaneous Adipose Microenvironment as a Determinant of Body Fat Development in Polycystic Ovary Syndrome.

Context: Adipose steroid metabolism modifies body fat development in polycystic ovary syndrome (PCOS).

Objective: To determine whether subcutaneous (SC) abdominal adipose aldo-keto reductase 1C3 (AKR1C3; a marker of testosterone generation) is increased in normal-weight women with PCOS vs age- and body mass index (BMI)-matched normoandrogenic ovulatory women (controls) and is related to SC abdominal adipose activator protein-1 (AP-1; a marker of adipocyte differentiation) and/or androgen receptor (AR) protein expression in predicting fat accretion.

Design: Prospective cohort study.

Male infertility and obesity.

Purpose Of Review: The increasing rate of obesity is having an adverse impact on male reproduction.

Recent Findings: The negative effect of reactive oxygen species on male reproductive tissues and the age of onset of obesity are new areas of research on male infertility.

Summary: This review highlights how obesity impairs male reproduction through complex mechanisms, including metabolic syndrome, lipotoxicity, sexual dysfunction, hormonal and adipokine alterations as well as epigenetic changes, and how new management strategies may improve the reproductive health of men throughout life.

Anti-Müllerian Hormone: A Molecular Key to Unlocking Polycystic Ovary Syndrome?

Anti-Müllerian hormone (AMH) is an important component within androgen receptor (AR)-regulated pathways governing the hyperandrogenic origin of polycystic ovary syndrome (PCOS). In women with PCOS, granulosa cell AMH overexpression in developing ovarian follicles contributes to elevated circulating AMH levels beginning at birth and continuing in adolescent daughters of PCOS women. A 6 to 7% incidence among PCOS women of gene variants coding for AMH or its receptor, AMHR2, suggests genetic contributions to AMH-related pathogenesis.

An Evolutionary Model for the Ancient Origins of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy of reproductive-aged women, characterized by hyperandrogenism, oligo-anovulation and insulin resistance and closely linked with preferential abdominal fat accumulation. As an ancestral primate trait, PCOS was likely further selected in humans when scarcity of food in hunter-gatherers of the late Pleistocene additionally programmed for enhanced fat storage to meet the metabolic demands of reproduction in later life. As an evolutionary model for PCOS, healthy normal-weight women with hyperandrogenic PCOS have subcutaneous (SC) abdominal adipose stem cells that favor fat storage through exaggerated lipid accumulation during development to adipocytes in vitro.

Interplay of Cortisol, Testosterone, and Abdominal Fat Mass in Normal-weight Women With Polycystic Ovary Syndrome.

Context: Ovarian and adrenal steroidogenesis underlie endocrine-metabolic dysfunction in polycystic ovary syndrome (PCOS). Adipocytes express aldo-keto reductase 1C3 and type 1 11β-hydroxysteroid dehydrogenase, which modulate peripheral androgen and cortisol production.

Objectives: To compare serum adrenal steroids, including 11-oxygenated androgens (11-oxyandrogens), cortisol, and cortisone between normal-weight women with PCOS and body mass index- and age-matched ovulatory women with normal-androgenic profiles (controls), and assess whether adrenal steroids associate with abdominal adipose deposition.

Randomized clinical trial: effect of low-dose flutamide on abdominal adipogenic function in normal-weight women with polycystic ovary syndrome.

Objective: To examine whether low-dose flutamide administration to normal-weight women with polycystic ovary syndrome (PCOS) reduces abdominal fat deposition, attenuates accelerated lipid accumulation in newly formed adipocytes derived from subcutaneous (SC) abdominal adipose stem cells (ASCs), and/or alters glucose-lipid metabolism.

Design: A double-blind, placebo-controlled randomized clinical trial.

Setting: An academic medical center.

Experimentally Induced Hyperinsulinemia Fails to Induce Polycystic Ovary Syndrome-like Traits in Female Rhesus Macaques.

As in women with polycystic ovary syndrome (PCOS), hyperinsulinemia is associated with anovulation in PCOS-like female rhesus monkeys. Insulin sensitizers ameliorate hyperinsulinemia and stimulate ovulatory menstrual cycles in PCOS-like monkeys. To determine whether hyperinsulinemia (>694 pmol/L), alone, induces PCOS-like traits, five PCOS-like female rhesus monkeys with minimal PCOS-like traits, and four control females of similar mid-to-late reproductive years and body mass index, received daily subcutaneous injections of recombinant human insulin or diluent for 6−7 months.

Female Adult Acne and Androgen Excess: A Report From the Multidisciplinary Androgen Excess and PCOS Committee.

In endocrine and reproductive endocrine literature, adult female acne is considered as a possible clinical expression of hyperandrogenism, with most polycystic ovary syndrome (PCOS) guidelines considering acne as a condition of androgen excess. Adult female acne, however, in the dermatological literature is considered as an inflammatory skin disease and new guidelines on adult female acne have been produced by dermatological societies, with little perspective from any endocrine or reproductive endocrine points of view. An expert task force was appointed by the AE-PCOS society to determine the current state of knowledge and provide evidence-based recommendations that could be valid for all specialists taking care of female adult acne.

Polycystic ovary syndrome as a plausible evolutionary outcome of metabolic adaptation.

As a common endocrinopathy of reproductive-aged women, polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology. It is linked with insulin resistance through preferential abdominal fat accumulation that is worsened by obesity. Over the past two millennia, menstrual irregularity, male-type habitus and sub-infertility have been described in women and confirm that these clinical features of PCOS were common in antiquity.

Serum Testosterone to Androstenedione Ratio Predicts Metabolic Health in Normal-Weight Polycystic Ovary Syndrome Women.

Context: Increased aldo-keto reductase 1C3 (AKR1C3)-mediated conversion of androstenedione (A4) to testosterone (T) promotes lipid storage in subcutaneous (SC) abdominal adipose in overweight/obese polycystic ovary syndrome (PCOS) women.

Objective: This work examines whether an elevated serum T/A4 ratio, as a marker of enhanced AKR1C3 activity in SC abdominal adipose, predicts metabolic function in normal-weight PCOS women.

Methods: This prospective cohort study took place in an academic center and comprised 19 normal-weight PCOS women and 21 age- and body mass index-matched controls.

Passing on PCOS: new insights into its epigenetic transmission.

Polycystic ovary syndrome (PCOS) is a prevalent reproductive-metabolic disorder with poorly understood etiology. Mimouni et al. (2021) demonstrate global genomic DNA hypomethylation in women with PCOS and their daughters, and in F3 generation PCOS-like mice, together with substantial normalization of PCOS-like mice by methyl donor dietary supplementation.

Accelerated subcutaneous abdominal stem cell adipogenesis predicts insulin sensitivity in normal-weight women with polycystic ovary syndrome.

Objective: To examine whether subcutaneous (SC) abdominal adipose stem cell differentiation into adipocytes in vitro predicts insulin sensitivity (Si) in vivo in normal-weight women with polycystic ovary syndrome (PCOS) and controls.

Design: Prospective cohort study.

Setting: Academic medical center.

Dynamic changes in chromatin accessibility, altered adipogenic gene expression, and total versus de novo fatty acid synthesis in subcutaneous adipose stem cells of normal-weight polycystic ovary syndrome (PCOS) women during adipogenesis: evidence of cellular programming.

Background: Normal-weight polycystic ovary syndrome (PCOS) women exhibit adipose resistance in vivo accompanied by enhanced subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes with accelerated lipid accumulation per cell in vitro. The present study examines chromatin accessibility, RNA expression and fatty acid (FA) synthesis during SC abdominal ASC differentiation into adipocytes in vitro of normal-weight PCOS versus age- and body mass index-matched normoandrogenic ovulatory (control) women to study epigenetic/genetic characteristics as well as functional alterations of PCOS and control ASCs during adipogenesis.

Results: SC abdominal ASCs from PCOS women versus controls exhibited dynamic chromatin accessibility during adipogenesis, from significantly less chromatin accessibility at day 0 to greater chromatin accessibility by day 12, with enrichment of binding motifs for transcription factors (TFs) of the AP-1 subfamily at days 0, 3, and 12.

Loss of anti-Müllerian hormone (AMH) immunoactivity due to a homozygous AMH gene variant rs10417628 in a woman with classical polycystic ovary syndrome (PCOS).

Anti-Müllerian hormone (AMH) is produced by granulosa cells of pre-antral and small antral ovarian follicles. In polycystic ovary syndrome (PCOS), higher levels of serum AMH are usually encountered due to the ample presence of small antral follicles and a high AMH production per follicular unit which have led to the proposal of AMH as a serum diagnostic marker for PCOS or as a surrogate for polycystic ovarian morphology (PCOM). However, heterozygous coding mutations of the AMH gene with decreased in vitro bioactivity have been described in some women with PCOS.

Developmental Programming: Sheep Granulosa and Theca Cell-Specific Transcriptional Regulation by Prenatal Testosterone.

Prenatal testosterone (T)-treated sheep, similar to polycystic ovarian syndrome women, manifest reduced cyclicity, functional hyperandrogenism, and polycystic ovary (PCO) morphology. The PCO morphology results from increased follicular recruitment and persistence of antral follicles, a consequence of reduced follicular growth and atresia, and is driven by cell-specific gene expression changes that are poorly understood. Therefore, using RNA sequencing, cell-specific transcriptional changes were assessed in laser capture microdissection isolated antral follicular granulosa and theca cells from age 21 months control and prenatal T-treated (100 mg intramuscular twice weekly from gestational day 30 to 90; term: 147 days) sheep.

Endocrine-Metabolic Dysfunction in Polycystic Ovary Syndrome: an Evolutionary Perspective.

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology, with metabolic dysfunction from insulin resistance and abdominal fat accumulation worsened by obesity. As ancestral traits, these features could have favored abdominal fat deposition for energy use during starvation, but have evolved into different PCOS phenotypes with variable metabolic dysfunction. Adipose dysfunction in PCOS from hyperandrogenemia and hyperinsulinemia likely constrains subcutaneous (SC) fat storage, promoting lipotoxicity through ectopic lipid accumulation and oxidative stress, insulin resistance and inflammation in non-adipose tissue.

A primate perspective on oocytes and transgenerational PCOS.

'Androgenized' rodent models are widely used to explore the pathophysiology underlying human polycystic ovary syndrome (PCOS), including reproductive and metabolic dysfunction. Based on a recent study using a dihydrotestosterone (DHT)-treated murine model, it has been proposed that prenatal androgen excess alone can predispose to transgenerational transmission of PCOS. From RNA sequencing analysis of metaphase II (MII) oocytes of androgenized lineages, the authors speculated that oocyte factors, including up-regulation of cytotoxic granulosa-associated RNA binding protein-like 1 (TiaL1), are sufficient to promote disease transfer across generations.

Animal Models to Understand the Etiology and Pathophysiology of Polycystic Ovary Syndrome.

More than 1 out of 10 women worldwide are diagnosed with polycystic ovary syndrome (PCOS), the leading cause of female reproductive and metabolic dysfunction. Despite its high prevalence, PCOS and its accompanying morbidities are likely underdiagnosed, averaging > 2 years and 3 physicians before women are diagnosed. Although it has been intensively researched, the underlying cause(s) of PCOS have yet to be defined.

Naturally Occurring and Experimentally Induced Rhesus Macaque Models for Polycystic Ovary Syndrome: Translational Gateways to Clinical Application.

Indian rhesus macaque nonhuman primate models for polycystic ovary syndrome (PCOS) implicate both female hyperandrogenism and developmental molecular origins as core components of PCOS etiopathogenesis. Establishing and exploiting macaque models for translational impact into the clinic, however, has required multi-year, integrated basic-clinical science collaborations. Paradigm shifting insight has accrued from such concerted investment, leading to novel mechanistic understanding of PCOS, including hyperandrogenic fetal and peripubertal origins, epigenetic programming, altered neural function, defective oocytes and embryos, adipogenic constraint enhancing progression to insulin resistance, pancreatic decompensation and type 2 diabetes, together with placental compromise, all contributing to transgenerational transmission of traits likely to manifest in adult PCOS phenotypes.

In utero Androgen Excess: A Developmental Commonality Preceding Polycystic Ovary Syndrome?

In utero androgen excess reliably induces polycystic ovary syndrome (PCOS)-like reproductive and metabolic traits in female monkeys, sheep, rats, and mice. In humans, however, substantial technical and ethical constraints on fetal sampling have curtailed safe, pathogenic exploration during gestation. Evidence consistent with in utero origins for PCOS in humans has thus been slow to amass, but the balance now leans toward developmental fetal origins.

Mechanisms of intergenerational transmission of polycystic ovary syndrome.

Developmental origins of adult disease (DoHAD) refers to critical gestational ages during human fetal development and beyond when the endocrine metabolic status of the mother can permanently program the physiology and/or morphology of the fetus, modifying its susceptibility to disease after birth. The aim of this review is to address how DoHAD plays an important role in the phenotypic expression of polycystic ovary syndrome (PCOS), the most common endocrinopathy of women characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology. Clinical studies of PCOS women are integrated with findings from relevant animal models to show how intergenerational transmission of these central components of PCOS are programmed through an altered maternal endocrine-metabolic environment that adversely affects the female fetus and long-term offspring health.