Origins Of Polycystic Ovary Syndrome Research Articles

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. Discrete gestational AMH administration to pregnant mice induces hypergonadotropic hyperandrogenic, PCOS-like female offspring with high circulating AMH levels that persist over three generations, suggesting epigenetic contributions to PCOS through developmental programming. Moreover, adult-onset, selective hyperactivation of hypothalamic neurons expressing gonadotropin-releasing hormone (GnRH) induces hypergonadotropic hyperandrogenism and PCOS-like traits in female mice. Both gestational and adult AMH inductions of PCOS-like traits are prevented by GnRH antagonist coadministration, implicating luteinizing hormone-dependent ovarian theca cell testosterone (T) action, mediated through the AR in AMH-induced pathogenesis. Interestingly, gestational or peripubertal exogenous T or dihydrotestosterone induction of PCOS-like traits in female mice, rats, sheep, and monkeys fails to elicit ovarian AMH hypersecretion; thus, AMH excess per se may lead to a distinct pathogenic contribution to hyperandrogenic PCOS origins.

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. In turn, fat storage is counterbalanced by reduced insulin sensitivity and preferential accumulation of highly lipolytic intra-abdominal fat in vivo. This metabolic adaptation in PCOS balances energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction; its accompanying oligo-anovulation allowed PCOS women from antiquity sufficient time and strength for childrearing of fewer offspring with a greater likelihood of childhood survival. Heritable PCOS characteristics are affected by today's contemporary environment through epigenetic events that predispose women to lipotoxicity, with excess weight gain and pregnancy complications, calling for an emphasis on preventive healthcare to optimize the long-term, endocrine-metabolic health of PCOS women in today's obesogenic environment.

Chronic androgen excess in female mice does not impact luteinizing hormone pulse frequency or putative GABAergic inputs to GnRH neurons.

Polycystic ovary syndrome (PCOS) is associated with androgen excess and, frequently, hyperactive pulsatile luteinizing hormone (LH) secretion. Although the origins of PCOS are unclear, evidence from pre‐clinical models implicates androgen signalling in the brain in the development of PCOS pathophysiology. Chronic exposure of female mice to dihydrotestosterone (DHT) from 3 weeks of age drives both reproductive and metabolic impairments that are ameliorated by selective androgen receptor (AR) loss from the brain. This suggests centrally driven mechanisms in hyperandrogen‐mediated PCOS‐like pathophysiology that remain to be defined. Acute prenatal DHT exposure can also model the hyperandrogenism of PCOS, and this is accompanied by increased LH pulse frequency and increased GABAergic innervation of gonadotrophin‐releasing hormone (GnRH) neurons. We aimed to determine the impact of chronic exposure of female mice to DHT, which models the hyperandrogenism of PCOS, on pulsatile LH secretion and putative GABAergic input to GnRH neurons. To do this, GnRH‐green fluorescent protein (GFP) female mice received either DHT or blank capsules for 90 days from postnatal day 21 (n = 6 or 7 per group). Serial tail‐tip blood sampling was used to measure LH dynamics and perfusion‐fixed brains were collected and immunolabelled for vesicular GABA transporter (VGAT) to assess putative GABAergic terminals associated with GFP‐labelled GnRH neurons. As expected, chronic DHT resulted in acyclicity and significantly increased body weight. However, no differences in LH pulse frequency or the density of VGAT appositions to GnRH neurons were identified between ovary‐intact DHT‐treated females and controls. Chronic DHT exposure significantly increased the number of AR expressing cells in the hypothalamus, whereas oestrogen receptor α‐expressing neuron number was unchanged. Therefore, although chronic DHT exposure from 3 weeks of age increases AR expressing neurons in the brain, the GnRH neuronal network changes and hyperactive LH secretion associated with prenatal androgen excess are not evident. These findings suggest that unique central mechanisms are involved in the reproductive impairments driven by exposure to androgen excess at different developmental stages.

Diagnosis, causal factors and associated diseases of PCOS: A Mini-review

Polycystic ovary syndrome (PCOS) is a hormonal imbalance disorder, occurring commonly in women of reproductive age, which leads to infertility. Around 12-18% of women of reproductive age are affected by PCOS and up to 21% of women are at high risk. Although, the origin of PCOS is unknown and can’t be pinpointed; its onset is indisputably associated with several factors including genetics, lifestyles, hormonal, etc. Changes during the adolescent period have important indications to understand the health risks associated with this syndrome. Women with PCOS usually suffer from chronic anovulation and hyper-androgenism, which are the main noticeable indicators associated with PCOS and it results in pregnancy problems. Therefore, PCOS poses a great deal to women in their reproductive stage, which demands deep understanding and proper strategies that can be implemented to women with PCOS, to nurse the body back to fertility. PCOS being a syndrome comprising many symptoms, its treatment and management is mainly based on dealing the associated symptoms individually. In this review article, important causing factors, diagnostic criteria, and pathophysiology of PCOS along with important findings from recent studies are being discussed and highlighted.

In utero exposure to maternal stressful life events and risk of polycystic ovary syndrome in the offspring: The Raine Study

BackgroundPCOS is the most common endocrine disorder in reproductive age women. The origins of PCOS are unknown but experimental and limited human evidence suggests that greater prenatal exposure to androgens may predispose to PCOS. Experimental evidence suggests that maternal stressors may affect reproductive function in the offspring via changes in prenatal androgen exposure. In this present study, we aim to investigate whether maternal stressful life events during pregnancy are associated with polycystic ovary morphology (PCOM) or polycystic ovary syndrome (PCOS) in adolescent offspring. MethodIn a large population-based pregnancy cohort study (The Raine Study) continuously followed from prenatal life through to adolescence we examined the association between maternal stressful life events during pregnancy in both early and late gestation, and subsequent circulating concentrations of ovarian and adrenal androgens, PCOM and PCOS in the normal menstrual cycle of offspring age 14–16 years. Maternal stressful life events were prospectively recorded during pregnancy at 18 and 34 weeks using a 10-point questionnaire. Female offspring (n = 223) completed a questionnaire about their menstrual cycles, underwent a clinical examination for hirsutism (Ferriman-Gallwey score) and transabdominal pelvic ultrasound examination to determine ovarian morphology according to standardized criteria for classification of PCOM. Plasma samples were obtained at day 2–6 of the normal menstrual cycle for measurement of androgens. PCOM was defined according to the international consensus definition, 2003 and the evidence-based guideline for the assessment and management of PCOS, 2018. PCOS was diagnosed according to Rotterdam criteria and National Institute of Health (NIH) criteria. Multivariate linear and logistic regression analyses were used to examine the associations between maternal stressful life event exposure and ovarian morphology (PCOM), circulating ovarian and adrenal androgens (clinical and biochemical hyperandrogenism (hirsutism)) and presence of PCOS. ResultsOf 223 recruited adolescent girls, 78 (35.9%) and 68 (31.3%) had PCOM by the 2003 and 2018 criteria respectively, while 66 (29.6%) and 37 (16.6%) had PCOS, using Rotterdam and NIH criteria, respectively. Most girls (141/223, 63.2%) were exposed to at least one stressful life event in early gestation and around half (121/223, 54.3%) were exposed to at least one stressful life event in late gestation. Maternal stressful life events in early gestation were associated with a statistically significant lower prevalence of PCOM when applying the 2003 criteria [adjusted odds ratio [aOR] and 95% confidence intervals (CI): 0.74 (95% CI: 0.55; 0.99)], and a similar association was detected when applying the 2018 PCOM criteria (aOR, 0.69, 95% CI: 0.50; 0.95)]. Maternal stressful life events in early gestation were also associated with lower circulating concentrations of testosterone (β = −0.05, 95% CI: −0.09; −0.004) and androstenedione (β = −0.05, 95% CI: −0.10; −0.002) in the offspring. No similar effects for PCOM or circulating androgens were detected in late gestation. No statistically significant associations between maternal stressful life events in early or late gestation with PCOS (neither Rotterdam nor NIH criteria) in adolescence were detected. The prospective collection of maternal stressful life events during both early and late gestation and direct measurement of PCOM, PCOS and circulating androgens in adolescence and key co-variates implies minimal possibility of recall, information bias and selection bias. ConclusionMaternal exposure to stressful life events in early gestation is associated with significantly reduced circulating ovarian and adrenal androgen concentrations in adolescence (testosterone and androstenedione), and an indication of fewer cases of polycystic ovary morphology (PCOM) defined by the 2003 international consensus definition and by the 2018 international evidence-based guideline, but has no effect on polycystic ovary syndrome (PCOS), diagnosed using either Rotterdam or NIH criteria.

Polycystic Ovary Syndrome: A Brain Disorder Characterized by Eating Problems Originating during Puberty and Adolescence.

Polycystic ovary syndrome (PCOS) is an endocrine condition associated with reproductive and psychiatric disorders, and with obesity. Eating disorders, such as bulimia and recurrent dieting, are also linked to PCOS. They can lead to the epigenetic dysregulation of the hypothalamic–pituitary–gonadal (HPG) axis, thereby impacting on ovarian folliculogenesis. We postulate that PCOS is induced by psychological distress and episodes of overeating and/or dieting during puberty and adolescence, when body dissatisfaction and emotional distress are often present. We propose that upregulated activation of the central HPG axis during this period can be epigenetically altered by psychological stressors and by bulimia/recurrent dieting, which are common during adolescence and which can lead to PCOS. This hypothesis is based on events that occur during a largely neglected stage of female reproductive development. To date, most research into the origins of PCOS has focused on the prenatal induction of this disorder, particularly in utero androgenization and the role of anti-Müllerian hormone. Establishing causality in our peripubertal model requires prospective cohort studies from infancy. Mechanistic studies should consider the role of the gut microbiota in addition to the epigenetic regulation of (neuro) hormones. Finally, clinicians should consider the importance of underlying chronic psychological distress and eating disorders in PCOS.

The Mechanism of Androgen Actions in PCOS Etiology.

Polycystic ovary syndrome (PCOS) is the most common endocrine condition in reproductive-age women. By comprising reproductive, endocrine, metabolic and psychological features—the cause of PCOS is still unknown. Consequently, there is no cure, and management is persistently suboptimal as it depends on the ad hoc management of symptoms only. Recently it has been revealed that androgens have an important role in regulating female fertility. Androgen actions are facilitated via the androgen receptor (AR) and transgenic Ar knockout mouse models have established that AR-mediated androgen actions have a part in regulating female fertility and ovarian function. Considerable evidence from human and animal studies currently reinforces the hypothesis that androgens in excess, working via the AR, play a key role in the origins of polycystic ovary syndrome (PCOS). Identifying and confirming the locations of AR-mediated actions and the molecular mechanisms involved in the development of PCOS is critical to provide the knowledge required for the future development of innovative, mechanism-based interventions for the treatment of PCOS. This review summarises fundamental scientific discoveries that have improved our knowledge of androgen actions in PCOS etiology and how this may form the future development of effective methods to reduce symptoms in patients with PCOS.

Androgens and ovarian function: translation from basic discovery research to clinical impact.

In the last decade, it has been revealed that androgens play a direct and important role in regulating female reproductive function. Androgens mediate their actions via the androgen receptor (AR), and global and cell-specific Ar-knockout mouse models have confirmed that AR-mediated androgen actions play a role in regulating female fertility and follicle health, development and ovulation. This knowledge, along with the clinical data reporting a beneficial effect of androgens or androgen-modulating agents in augmenting in vitro fertilization (IVF) stimulation in women termed poor responders, has supported the adoption of this concept in many IVF clinics worldwide. On the other hand, substantial evidence from human and animal studies now supports the hypothesis that androgens in excess, acting via the AR, play a key role in the origins of polycystic ovary syndrome (PCOS). The identification of the target sites of these AR actions and the molecular mechanisms involved in underpinning the development of PCOS is essential to provide the knowledge required for the future development of novel, mechanism-based therapies for the treatment of PCOS. This review will summarize the basic scientific discoveries that have enhanced our knowledge of the roles of androgens in female reproductive function, discuss the impact these findings have had in the clinic and how a greater understanding of the role androgens play in female physiology may shape the future development of effective strategies to improve IVF outcomes in poor responders and the amelioration of symptoms in patients with PCOS.

Evolutionary origins of polycystic ovary syndrome: An environmental mismatch disorder.

Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder and has important evolutionary implications for female reproduction and health. PCOS presents an interesting paradox, as it results in significant anovulation and potential sub-fecundity in industrialized populations, yet it has a surprisingly high prevalence and has a high heritability. In this review, we discuss an overview of PCOS, current diagnostic criteria, associated hormonal pathways and a review of proposed evolutionary hypotheses for the disorder. With a multifactorial etiology that includes ovarian function, metabolism, insulin signaling and multiple genetic risk alleles, PCOS is a complex disorder. We propose that PCOS is a mismatch between previously neutral genetic variants that evolved in physically active subsistence settings that have the potential to become harmful in sedentary industrialized environments. Sedentary obesogenic environments did not exist in ancestral times and exacerbate many of these pathways, resulting in the high prevalence and severity of PCOS today. Overall, the negative impacts of PCOS on reproductive success would likely have been minimal during most of human evolution and unlikely to generate strong selection. Future research and preventative measures should focus on these gene-environment interactions as a form of evolutionary mismatch, particularly in populations that are disproportionately affected by obesity and metabolic disorders.Lay SummaryThe most severe form of polycystic ovary syndrome (PCOS) is likely a result of interactions between genetic predispositions for PCOS and modern obesogenic environments. PCOS would likely have been less severe ancestrally and the fitness reducing effects of PCOS seen today are likely a novel product of sedentary, urban environments.

Ovarian and Extra-Ovarian Mediators in the Development of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder affecting women of reproductive age. The origin of PCOS is still not clear and appears to be a function of gene x environment interactions. This review addresses the current knowledge of the genetic and developmental contributions to the etiology of PCOS, the ovarian and extra-ovarian mediators of PCOS and the gaps and key challenges that need to be addressed in the diagnosis, treatment and prevention of PCOS.

Reproductive and metabolic features during puberty in sons of women with polycystic ovary syndrome.

ContextIntrauterine life may be implicated in the origin of polycystic ovary syndrome (PCOS) modifying the endocrine and metabolic functions of children born to PCOS mothers independently of the genetic inheritance and gender. The aim of the present study was to evaluate the reproductive and metabolic functions in sons of women with PCOS during puberty.MethodsSixty-nine PCOS sons (PCOSs) and 84 control sons of 7–18 years old matched by the Tanner stage score were studied. A complete physical examination was conducted including anthropometric measurements (weight, height, waist, hip and body mass index). An oral glucose tolerance test was performed and circulating concentrations of luteinizing hormone, follicle-stimulating hormone (FSH), sex hormone-binding globulin, testosterone, androstenedione (A4), 17α-hydroxyprogesterone (17-OHP) and AMH were determined in the fasting sample.ResultsWaist-to-hip ratio, FSH and androstenedione levels were significantly higher in the PCOSs group compared to control boys during the Tanner stage II–III. In Tanner stages II–III and IV–V, PCOSs showed significantly higher total cholesterol and LDL levels. Propensity score analysis showed that higher LDL levels were attributable to the PCOSs condition and not to other metabolic factors. AMH levels were comparable during all stages. The rest of the parameters were comparable between both groups.ConclusionsSons of women with PCOS show increased total cholesterol and LDL levels during puberty, which may represent latent insulin resistance. Thus, this is a group that should be followed and studied looking for further features of insulin resistance and cardiovascular risk markers. Reproductive markers, on the other hand, are very similar to controls.

Системное хроническое воспаление и митохондриальная дисфункция в генезе синдрома поликистозных яичников

Системное хроническое воспаление и митохондриальная дисфункция в генезе синдрома поликистозных яичников

Developmental origins of polycystic ovary syndrome (PCOS), a case control study comparing birth weight in women with PCOS and control group

Evidence from various epidemiological studies and experimental animal studies has linked adverse intrauterine circumstances with health problems in adult life. This field of investigation is known as Developmental Origins of Health and Disease (DOHaD). Studies investigating the relation between developing polycystic ovary syndrome (PCOS) in adulthood and birth weight have yielded inconsistent results: PCOS is described more often in women with low birth weight and high birth weight, while other studies have failed to establish any relation. In this retrospective case–control study, we evaluated whether women diagnosed with PCOS had lower birth weight compared to women with a regular menstrual cycle (controls). Binary logistic regression models were used to analyze the data and correct for known confounders. About 65 women with PCOS and 96 controls were recruited for this purpose. The average birth weight of PCOS women (3357 g) did not differ from the average birth weight of controls (3409 g). Mean age at menarche differed significantly between groups, 13.7 years and 12.8 years (p = 0.006), respectively, for PCOS women and controls. In conclusion, we could not confirm the effect of adverse intrauterine conditions, reflected in birth weight, on developing PCOS.

Epigenetic background of the most common non-oncologic gynecological diseases

Epigenetic effects influence the function of genes regulating the main physiological mechanisms. Some of these environmental factors may reduce or inhibit the function of these genes. The environmental effects on gene function may result in a change of the DNA structure leading to non-heritable phenotype changes. Epigenetic factors play an important etiological role in the development of numerous diseases in obstetrics and gynecology. Uterine fibroids probably have a complex etiological background including epigenetic mechanisms. The multifactorial aetiology of endometriosis suggests key roles for immunological and hormonal factors in the development of the diseases. These mechanisms are influenced by epigenetic factors, which may serve as therapeutic targets in the future. The possible in utero origin of polycystic ovary syndrome determines the main directions of research concerning epigenetic factors in the etiological background, with the hope of eventual prevention and/or treatment in the preconceptional period as well as during pregnancy care.

Maternal Ovarian Androgen Production at the Time of Term Delivery

A growing body of literature suggests that the intrauterine environment may be important in the long-term health of offspring. Particular attention has been paid to elevated maternal serum androgens which have been implicated in the origins of polycystic ovary syndrome (PCOS) through so-called fetal programming. Previous work has characterized maternal serum androgen patterns during gestation however direct evidence as to the origins of maternal serum androgens during human pregnancy is lacking.

Early origins of polycystic ovary syndrome

The clinical manifestations of polycystic ovary syndrome(PCOS) often emerge during childhood and are related with early life events.Fetal androgen excess may contribute to the etiology of PCOS.Otherwise,fetal growth restriction can confer a setpoint of maximal adipose tissue expansion and may lead to a state of insulin resistance which may finally contribute to the pathophysiology of PCOS.Two hypothesis,the prenatal androgen hypothesis and the adipose tissue expandability hypothesis,have been advanced,and have explained the prenatal origins of PCOS.This paper discusses the relationship between the PCOS and the two hypotheses to demonstrate the PCOS as a fetal origins of adult disease. Key words: Polycystic ovary syndrome; Prenatal androgen; Adipose tissue expandability; Insulin resistance

Animal Models and the Developmental Origins of Polycystic Ovary Syndrome: Increasing Evidence for the Role of Androgens in Programming Reproductive and Metabolic Dysfunction

Polycystic ovary syndrome (PCOS) has been recognized as an important endocrine disorder for more than 70 yr, and its prevalence in the modern population is estimated to be between 5 and 10% of women of reproductive age (1). It is by far the most common cause of oligoor anovulation and accounts for more than 75% of cases of anovulatory infertility (2, 3). It is also the leading cause of hirsutism, androgenetic alopecia, and persistent acne, all of which are distressing and debilitating disorders in women. In the last 30 yr, increasing emphasis has been placed on metabolic dysfunction in women with PCOS. Insulin resistance and compensatory hyperinsulinemia are central to the metabolic abnormalities of PCOS (3, 4), and the syndrome is estimated to carry a 2to 4-fold increase in the risk of developing type 2 diabetes mellitus (5). The increasing pandemic of obesity threatens to make that figure an underestimate; obesity has a preferentially adverse effect on metabolic function in women with PCOS compared with similarly obese women without PCOS. Cardiovascular risk factors are also significantly increased in PCOS, although it remains unclear whether the incidence of cardiovascular events is similarly increased (5). Despite the plethora of clinical and experimental data regarding this very common endocrine disorder, our knowledge of the etiology of the syndrome is, at best, incomplete. There is strong evidence for a genetic cause (6–9), but environmental factors, particularly the effect of diet, clearly play an important part in the presentation and severity of PCOS if not in the origin of the disorder itself (10). One important strategy for better understanding the etiology of PCOS has been the use of animal models. In general, the main principle underlying studies in animals has been that many of the characteristic features of PCOS arise as a result of exposure to excess androgen, the biochemical hallmark of PCOS. The observation that androgen treatment of immature rats results in abnormal antral follicle development and disrupted ovulation was made in the mid-1970s (11). Since then, there have been many studies of the effects of excess androgen on ovarian function in rodents (12–15). The relevance of rodent models in understanding the ovarian disorders in PCOS is limited, however, by the fact that ovarian development (and the nature of ovulatory cycles) in rodents differs markedly from that in women. Rats and mice are poly-ovulators and women mono-ovulators. Another important aspect of rodent models is the effect of timing of androgen exposure on reproductive phenotype. Tyndall and colleagues (16) have recently shown that whereas testosterone treatment has minimal effect on adult ovarian function if given in late postnatal life, treatment in both fetal and postnatal life causes streak ovaries in rats. Over the last 15 yr, studies of larger species as models for PCOS have been explored and have given significant insight into the genesis of PCOS, particularly the notion that the syndrome has its origins during intrauterine development (17). Here the studies of Abbott and colleagues (17–19) in the rhesus monkey and of Padmanabhan and co-workers (20–24) in the sheep have proved particularly informative with regard to understanding the role of androgens in development of both reproductive and meta-

Fibrillin-3 in the fetal ovary: can it contribute to polycystic ovary syndrome?

Evaluation of: Hatzirodos N, Bayne RA, Irving-Rodgers HF et al. Linkage of regulators of TGF-β activity in the fetal ovary to polycystic ovary syndrome. FASEB J. 25(7), 2256–2265 (2011).Polycystic ovary syndrome (PCOS), a prevalent hyperandrogenic and anovulatory infertility and metabolic syndrome in reproductive-aged women, is heritable but its etiology is unknown. An allele within an intron of fibrillin-3, a TGF-β pathway regulator, is reliably associated with PCOS, and the epigenome of an early gestation monkey model for PCOS implicates altered TGF-β signaling. In the recent article by Hatzirodos et al., and in contrast to prior findings in mature human ovaries, prominent and transient fibrillin-3 expression is found in human and bovine fetal ovarian stroma during early gestation. Such developmentally constrained ovarian expression of a gene associated with PCOS phenotype has considerable implications for fetal origins of PCOS in women. Further study is needed, however, to determine whether differential expression of fetal ovarian fibrillin-3 results in polycystic ovary morphology, and whether differential fetal expression of fibrillin-3 in non-ovarian tissues enables PCOS-like dysfunction.

Early Origins of Polycystic Ovary Syndrome: Hypotheses May Change without Notice

Polycystic ovary syndrome (PCOS) is an evolving concept, as illustrated by its consecutive definitions. In 2004, the definition of PCOS in women changed from the classic National Institutes of Health (NIH) definition (clinical and/or biochemical androgen excess plus oligoovulation, with exclusion of specific etiologies such as hyperprolactinemia and 21-hydroxylase deficiency) (1) to the more inclusive Rotterdam definition (any two of the following three criteria, after similar exclusions: clinical and/or biochemical androgen excess, oligoor anovulation, and polycystic morphology on ultrasound) (2). In 2009, the Androgen Excess Society launched a new definition that considers PCOS primarily as a disorder of clinical and/or biochemical androgen excess, plus either chronic oligoovulation and/or polycystic ovaries, still with exclusion of specific etiologies (3). The core of the consecutive PCOS populations, however, changed little over the past decades because it continues to consist of women with hyperinsulinemic androgen excess (4–6). This core still constitutes the majority of PCOS women diagnosed by the latest definition, which, just as the earlier definitions, remains to be validated in adolescent girls (3). A better insight into the (epi-)genetics, early origins, and natural history of hyperinsulinemic androgen excess may sharpen the perspective of PCOS prevention and is therefore a priority in the current research agenda for PCOS.

Epigenetic abnormality: A possible mechanism underlying the fetal origin of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is one of the most common, yet heterogeneous and complex, endocrine disorders in women of reproductive age. Although the aetiology of PCOS remains uncertain, emerging evidence has indicated that exposure of the female fetus to the hyperandrogenism milieu in utero may result in PCOS phenotype after birth. Such a phenomenon has been formulated as the fetal origin of PCOS, which intends to give a possible explanation for PCOS aetiology. Given that the epigenetic modifications are usually involved in the development and inheritance of many adult diseases with fetal origin, we propose a hypothesis here referred to as "epigenetic abnormality underlying the fetal origin of PCOS". It states that in utero hyperandrogenism exposure may disturb the epigenetic reprogramming in fetal reproductive tissue, thereby resulting in postnatal POCS phenotype in women of reproductive age. Meanwhile, the incomplete erasure of such epigenetic abnormality in germ cells after fertilization may promote the transgenerational inherence of POCS. Thus, this epigenetic abnormality hypothesis has established a novel mechanism for PCOS development and inheritance. If verified, our hypothesis would open new avenues for the possible intervention at the critical period of prenatal life to prevent PCOS development and inheritance in adult women. Moreover, analysis of the epigenetic phenotypes and identification of specific epigenetic changes may help develop new tools for monitoring fetal development under an in utero hyperandrogenism environment.