Pathophysiology of polycystic ovary syndrome revisited: Current understanding and perspectives regarding future research

Abstract

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-age women and has lifelong effects on health.

Methods: In this review, I discuss the pathophysiology of PCOS. First, I summarize our current understanding of the etiology and pathology of PCOS, then, discuss details of two representative environmental factors involved in the pathogenesis of PCOS. Finally, I present perspectives regarding the directions of future research.

Main findings: The pathophysiology of PCOS is heterogeneous and shaped by the interaction of reproductive dysfunction and metabolic disorders. Hyperandrogenism and insulin resistance exacerbate one another during the development of PCOS, which is also affected by dysfunction of the hypothalamus-pituitary-ovarian axis. PCOS is a highly heritable disorder, and exposure to certain environmental factors causes individuals with predisposing genetic factors to develop PCOS. The environmental factors that drive the development of PCOS pathophysiology make a larger contribution than the genetic factors, and may include the intrauterine environment during the prenatal period, the follicular microenvironment, and lifestyle after birth.

Conclusion: On the basis of this current understanding, three areas are proposed to be subjects for future research, with the ultimate goals of developing therapeutic and preventive strategies and providing appropriate lifelong management, including preconception care.

Keywords: delayed effects of prenatal exposure; endoplasmic reticulum stress (ER stress); follicular microenvironment; gastrointestinal microbiome; polycystic ovary syndrome (PCOS).

FIGURE 1

Diagnostic criteria. (A) 2003 Rotterdam criteria. Phenotype A, featuring all three characteristics of hyperandrogenism (HA), ovulatory dysfunction (OD), and polycystic ovarian morphology (PCOM); phenotype B, featuring HA and OD but not PCOM; phenotype C, featuring HA and PCOM but not OD; and phenotype D, featuring OD and PCOM but not HA. (B) Comparison of the phenotypes defined using the 2003 Rotterdam criteria and the other diagnostic criteria. Polycystic ovary syndrome (PCOS) diagnosed using the 1990 National Institutes of Health (NIH) criteria corresponds to phenotypes A or B, while a diagnosis made using the 2006 androgen excess & PCOS (AE‐PCOS) criteria corresponds to phenotypes A, B, or C. PCOS diagnosed using the 2007 Japan Society of Obstetrics and Gynecology (JSOG) criteria may correspond to components of phenotype A or D. FSH, follicle‐stimulating hormone; LH, luteinizing hormone

FIGURE 2

Pathophysiology of polycystic ovary syndrome (PCOS). Hyperandrogenism is a key feature and has a synergistic effect with insulin resistance to induce the development of PCOS. Individual contributions of hyperandrogenism and insulin resistance differ from patient to patient, which accounts for the heterogenous nature of PCOS and its presentation. Hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology (PCOM) are the characteristics defined in the 2003 Rotterdam criteria. Hyperandrogenism, ovulatory dysfunction, aberrant gonadotropin‐releasing hormone (GnRH) pulsation and the resulting abnormal gonadotropin secretion, and insulin resistance comprise the vicious cycle that underpins the pathophysiology of PCOS. The abnormalities in the ovarian function of women with PCOS include the hypersecretion of androgens and ovulatory dysfunction, which causes PCOM. The hypersecretion of androgens is caused by intrinsic dysfunction of theca cells and/or the hypothalamus‐pituitary‐ovarian axis, while hyperandrogenism causes abnormal GnRH pulsation and gonadotropin secretion through the aberrant negative or positive feedback of progesterone and estrogen. The abnormal gonadotropin secretion in patients with PCOS is characterized by a high luteinizing hormone (LH)/follicle‐stimulating hormone (FSH) ratio, which induces ovarian dysfunction, including the hypersecretion of androgens. In addition, the high concentration of anti‐Müllerian hormone (AMH), which is secreted by the pre−/small antral follicles that accumulate in the ovaries of women with PCOS, further exacerbates the ovarian dysfunction by having deleterious effects on the follicular microenvironment and/or GnRH pulsation. Hyperandrogenism is further aggravated by hyperinsulinemia, which develops secondary to insulin resistance. Hyperinsulinemia causes an increase in androgen secretion by theca cells and an inhibition of the production of sex hormone‐binding globulin (SHBG) in the liver, thereby increasing the circulating concentration of bioactive free testosterone. Insulin resistance develops in tissues such as liver and muscle, and is associated with visceral adiposity and adipocyte dysfunction, which are exacerbated by hyperandrogenism

FIGURE 3

Endoplasmic reticulum stress (ER stress) develops in the follicles and forms a key component of the pathophysiology of polycystic ovary syndrome (PCOS). Local hyperandrogenism in the follicular microenvironment activates ER stress in PCOS. ER stress contributes to the pathophysiology of PCOS by affecting the function of granulosa cells (GCs) in a number of ways. ER stress stimulates the production of transforming growth factor‐β1 (TGF‐β1), a profibrotic growth factor, in GCs and accelerates interstitial fibrosis in the ovary. ER stress mediates the testosterone‐induced apoptosis of granulosa cells by inducing expression of the proapoptotic factor death receptor 5 (DR5) and is associated with follicular growth arrest at the antral follicle stage. ER stress also mediates the effects of testosterone to induce the expression of receptor for advanced glycation end products (RAGE) in GCs, which results in the accumulation of advanced glycation end products (AGEs), thereby affecting various cellular processes. ER stress also activates the aryl hydrocarbon receptor (AHR), a representative receptor for endocrine‐disrupting chemicals (EDCs), and its downstream signaling in GCs, which may alter steroid metabolism in these cells. Furthermore, ER stress induces the expression of multiple genes that are associated with cumulus oocyte‐complex (COC) expansion in GCs via notch signaling

FIGURE 4

Temporal relationship between alterations in the gut microbiome and the development of polycystic ovary syndrome (PCOS)‐like phenotypes in prenatally androgenized (PNA) mice. PNA mice were generated by injecting dihydrotestosterone (DHT) into pregnant dams. The gut microbiomes of PNA and control mice were analyzed when they were prepubertal (4 weeks of age); at puberty (6 weeks); and during their adolescence (8 weeks), young adulthood (12 weeks), and adulthood (16 weeks). Then, the temporal relationship between the alterations in the gut microbiome and the development of the PCOS‐like phenotype was evaluated. The reproductive phenotype of PCOS, involving changes in estrous cyclicity, ovarian histology, and serum testosterone concentration, became apparent at puberty in the PNA offspring. This was followed by the appearance of the metabolic characteristics of PCOS in young adulthood, featuring differences in body mass, the size of visceral adipocytes, insulin tolerance, and fasting blood glucose (FBG) concentration. By contrast, alterations to the gut microbiome of female PNA offspring were apparent as early as before puberty and were present throughout the study

FIGURE 5

Summary and future directions. Three principal characteristics of the pathophysiology of polycystic ovary syndrome (PCOS) have been identified to date: an interaction between reproductive dysfunction and metabolic disorders, high familial aggregation and heritability, and a substantial contribution of environmental factors. On the basis of this current understanding, the following three areas represent targets for future research. (1) To identify the factors that induce the development and progression of PCOS after birth and elucidate the underlying mechanisms. (2) To elucidate the mechanisms underlying the high heritability of PCOS. (3) To identify biomarkers that could be used to identify individuals at high risk of developing PCOS during their early life. Future research should aim to develop therapeutic and preventive strategies, with the ultimate goal of achieving appropriate lifelong management, including preconception care