Current and Emerging Concepts of Polycystic Ovary Syndrome – Manual from M.P. PCOS Society(Part 1)

The most prevalent reproductive endocrine condition affecting women of reproductive age is called polycystic ovary syndrome, or PCOS. Hyperandrogenism, irregular ovulation, and polycystic ovarian shape are the hallmarks of PCOS. Despite the fact that PCOS has been recognized for more than a century, there is ongoing debate over its diagnosis, origin, clinical characteristics, and course of therapy. The first scientific study of (PCOS) was conducted in 1935 by Stein and Leventhal, although Vallisneri provided the first account of PCOS in 1721, marking the historical evolution of the syndrome. The first scientific PCOS diagnostic criteria were proposed in 1990 at an NIH-sponsored conference. The syndrome is most often known as Polycystic Ovary Syndrome (PCOS), and the NIH 2012 criteria are now the mainstream diagnostic standards used, i.e., Rotterdam 2003 criteria with phenotypic classification. The last guideline on PCOS, i.e., the international evidence-based policy (2018), amended in 2023, is acceptable to all groups working on PCOS. AMH may be the most effective biomarker currently identified for PCOS. Complex and heterogeneous, PCOS is influenced by environmental and epigenetic factors in addition to genetic vulnerability. This chapter on PCOS aims to provide an introductory note along with the historical evolution of PCOS. 

Polycystic Ovary Syndrome (PCOS) affects women of reproductive age worldwide, showing varied prevalence rates depending on the diagnostic criteria utilized. It is also thought to be influenced by race and ethnicity. Ethnic and geographical variations in its prevalence and presentation highlight the multifactorial nature of the syndrome. The economic burden of PCOS extends beyond healthcare costs to encompass its impact on Quality of Life (QoL) and is associated with significantly higher risks of obesity, dyslipidemia, Impaired Glucose Tolerance (IGT), and long-term complications such as diabetes, cardiovascular disease, etc. Recognizing PCOS as a global health priority necessitates multifaceted approaches to improve awareness, diagnosis, and management worldwide. This chapter presents the current knowledge on the epidemiological aspects of PCOS and its prevalence based on the different diagnostic criteria–American Society for Reproductive Medicine (ASRM) (Rotterdam 2003), National Institutes of Health (NIH) 1990, European Society of Human Reproduction (ESHRE), and Androgen Excess and PCOS (AE-PCOS) Society 2006 – estimated in different populations. The evidence-based data regarding the relationship between PCOS provides valuable insights, and race and ethnicity are also discussed. Finally, this chapter provides an overview of the economic burden of PCOS as well as ethnic and geographic variations in the prevalence of PCOS, drawing insights from key research findings. 

Though PCOS is a common endocrine disorder, there are controversies related to diagnosis and management. Hyperandrogenism with anovulation has always been indicative of PCOS. Though these symptoms are common in women with PCOS, neither is regarded as an absolute criterion for the diagnosis. With the introduction of ultrasound criteria, there has been an extension to the spectrum of PCOS. To date, there is no clear-cut definition of clinical and biochemical hyperandrogenemia questioning their role in the diagnosis. Subjective assessment of hirsutism and polycystic ovarian morphology again questions the reliability of these modalities. Diagnosis of PCOS in adolescence and perimenopause is again a challenge. In this review, we detail the controversies related to the diagnosis and elaborate on other novel modalities that can assist in the diagnosis.

The generally accepted Rotterdam criteria for diagnosing PCOS should include two of the following criteria: chronic anovulation, Hyperandrogenism (HA) (clinical/biologic), and polycystic ovaries on ultrasound, leading to four types of clinical presentations. It is a challenge to use the adult reproductive phase criteria for diagnosing PCOS in the non-reproductive phase of life. Recently, there has been a consensus on the diagnostic criteria for PCOS in adolescence. In adolescence, hormonal fluctuations and irregular menstrual cycles can mimic PCOS symptoms, necessitating careful evaluation to distinguish physiological changes from pathological ones. Conversely, menopausal transitions can obscure PCOS diagnosis due to overlapping symptoms such as menstrual irregularities and hormonal imbalances. Pregnancy introduces additional complexities, as hormonal changes and gestational conditions may mimic or obscure PCOS symptoms, requiring nuanced diagnostic approaches. Moreover, PCOS often coexists with other metabolic and reproductive disorders, such as thyroid dysfunction and endometriosis, further complicating diagnosis and management. This chapter describes the differential diagnosis strategies for the accurate identification of PCOS in these intricate scenarios.

Clinical presentation of PCOS varies among individuals. A patient with Polycystic Ovary Syndrome (PCOS) may present to the gynecologist with menstrual irregularities, mainly oligo-amenorrhea, by means of detected polycystic morphology on ultrasonography. A patient might also seek a dermatologist for hyperandrogenic manifestations, such as acne, hirsutism, androgenic alopecia, and acanthosis nigricans, or a fertility clinic with complains of infertility. Patients may arrive at the obesity clinic with metabolic abnormalities. Understanding the clinical features at presentation is crucial for understanding the disease and conducting a thorough assessment of the patient. Therefore, in this chapter, we will learn in detail about the assessment of all the clinical features of PCOS in detail. Since PCOS is the diagnosis of exclusion, clinical features differentiating PCOS from other conditions with overlapping symptoms like non-classical congenital adrenal hyperplasia, hypo-hyperthyroidism, hyperprolactinemia, Cushing syndrome, acromegaly, and ovarian and adrenal neoplasm will also be discussed.

Dermatological issues like hirsutism, acne, androgenetic alopecia, and acanthosis nigricans frequently coexist, significantly impacting patients' well-being. Understanding the underlying pathophysiological mechanisms is crucial for early detection and effective management. Key contributors to dermatological manifestations in PCOS include hyperandrogenism, insulin resistance, and chronic inflammation, mediated by immunological pathways, genetic predispositions, and hormonal imbalances. Hirsutism results from androgen excess and increased 5α-reductase activity. Adult acne, influenced by androgens and follicular hyperkeratinization, worsens with chronic inflammation. Androgenetic alopecia involves complex mechanisms like Wnt signaling alterations and chronic scalp inflammation. Acanthosis nigricans, indicative of insulin resistance, highlights metabolic dysfunction in PCOS. Insulin-like growth factor receptor abnormalities and hyperinsulinemia drive its pathogenesis. This chapter draws the landscape of the interplay between endocrinology and dermatology in PCOS.

Accumulating data indicates that the pathophysiology of PCOS may involve modified developmental and epigenetic programming brought on by hormonal dysregulation of the mother's uterine environment. In addition, there is a higher chance of PCOS-related metabolic and reproductive problems for both male and female relatives of PCOS-affected individuals. This review aims to provide an overview of the main research findings in the field of epigenetics and its influence on the manifestation of this disorder in women. The major focus will be DNA methylation studies, the role of miRNAs, and the transgenerational inheritance of PCOS.

PCOS has historically been diagnosed clinically, often supported by laboratory parameters. However, the role of ultrasound has evolved over time. While initially used to identify features consistent with PCOS, its interpretation has become more complex. The presence of a “string of pearls” appearance on ultrasound has contributed to the perception of PCOS, but this may not always accurately reflect the condition. Advancements in ultrasound technology, particularly with higher frequency probes and endovaginal imaging, have improved the visualization of ovarian structures. However, there is inconsistency in how ultrasound findings are interpreted by clinicians and understood by patients. The presence of multifollicular ovaries, often observed on ultrasound, is frequently associated with PCOS, yet the significance of this finding in relation to the different PCOS phenotypes remains uncertain. 

Hyperandrogenism in PCOS contributed from ovary and adrenal glands clinically manifests as hirsutism, acne, and alopecia. In PCOS, LH hypersecretion over FSH occurs due to increased frequency of pulsatile secretion of gonadotropin-releasing hormone. In contrast to an associated deficiency in FSH, excess LH promotes ovarian androgen production, or FSH resistance harms follicular development. In PCOS women, LH:FSH ratio alteration leads to ovarian theca cell proliferation, which leads to elevated steroidogenesis and, eventually, hyperandrogenism. There are 5 types of androgen in women: Dehydroepiandrosterone Sulfate (DHEAS), Androstenedione (A4), Testosterone (T), Dehydroepiandrosterone (DHEA), and Dihydrotestosterone (DHT). Among these androgens, testosterone and DHT are more active than others. Androgen is also secreted from the adrenal gland in small amounts. By the enzyme aromatase, testosterone converts to estradiol, both of which coordinate the function of reproductive function in women. Excess of androgen from the ovary causes ovarian follicular changes, leading to anovulation and menstrual irregularities. Not only the development but the progression of PCOS is also influenced by hyperandrogenism. Complications of PCOS, such as type 2 diabetes, hypertension, and obesity, also occur by hyperandrogenism, increasing insulin resistance. Thus, it is important to address this hyperandrogenism clinically to stop the progression and complications of PCOS.

 In addition to reproductive abnormalities, metabolic imbalances, especially insulin resistance, characterize the core of PCOS pathology that, in turn, heightens the existing hormonal dysregulation and possibly culminates in long-term complications like type 2 diabetes and cardiovascular disorders. Insulin resistance is seen in most people with PCOS. Insulin resistance in PCOS is due to post-receptor signaling defects and is selective with attenuated metabolic and normal mitogenic pathways. It is also probably tissue-selective. Insulin resistance alters the hypothalamic pituitary ovarian axis and increases LH production greater than FSH. LH increases androgen production from thecal cells of the ovary. Insulin resistance increases the risk of impaired glucose tolerance, type 2 diabetes mellitus, obesity, cardiovascular disease, and dyslipidemia. So, strategies for decreasing insulin resistance are important. Lifestyle intervention and insulin sensitizers are in use in clinical practice for improving insulin sensitivity. Further research is needed to develop newer therapeutics for insulin resistance.

The pathogenesis of Polycystic Ovary Syndrome (PCOS) is mostly dependent on adipocyte malfunction, which contributes to the syndrome's diverse metabolic and reproductive symptoms. The main cells of adipose tissue, called adipocytes, are not just passive energy stores; they are also active endocrine organs that secrete a variety of adipokines, hormones, and inflammatory mediators that regulate metabolism. Adipose tissue inflammation, insulin resistance, and dysregulated adipokine production are all signs of adipocyte dysfunction in PCOS, which exacerbates the metabolic abnormalities that are typical of the condition. 

Hypothalamic-Pituitary-Ovarian (HPO) axis dysfunction lies central to the pathophysiology of this condition. The cyclicity of the HPO axis is maintained by rigorous feedback mechanisms–both positive and negative. In PCOS, altered hypothalamic kisspeptin signaling culminates in increased LH secretion, leading to increased androgen output from the ovarian theca cells and impaired FSH secretion, leading to aberrant folliculogenesis. A number of factors may be responsible for this hypothalamic-pituitary-ovarian disarray, like Anti-Mullerian Hormone (AMH), insulin, Insulin-like Growth Factor- 1 and 2 (IGF-1 & IGF-2), leptin, galanin, etc. Also, various neurotransmitters like opioid signaling, GABAergic, and glutamatergic transmission may act in tandem with the causation of this endocrine disorder. Still, many questions remain unanswered for which extensive research is being undertaken. 

PCOS is proposed to be an orchestration of gene-gene and geneenvironment interactions. The syndrome is highly inherited, and the risk increases by up to 40% in families with a history of PCOS. Familial clustering of PCOS symptoms is now well documented, pointing to the genetic contribution to the condition. Research currently available indicates that PCOS is a complex illness influenced by a number of variables, including environment, lifestyle, diet, genetics, and epigenetics. Nevertheless, it is currently unknown how much of each component contributes to the total phenotype. Currently, no single gene or related genes have been unanimously regarded as a significant cause of PCOS. Several genes have been linked to PCOS, and mutations or polymorphisms in these genes have a role in disease development. Until now, accurate genetic variations in PCOS have not been documented. Single-gene mutations, on the other hand, cause the phenotypic manifestations of PCOS. This chapter discusses the several genetic aspects linked to PCOS through gonadotropin regulation, gonadotrophin activity, ovarian and adrenal steroidogenesis, steroid hormone activities, energy homeostasis, insulin action, insulin secretion, and chronic inflammation.

Accumulating data indicates that the pathophysiology of PCOS may involve modified developmental and epigenetic programming brought on by hormonal dysregulation of the mother's uterine environment. In addition, there is a higher chance of PCOS-related metabolic and reproductive problems for both male and female relatives of PCOS-affected individuals. This Chapter aims to provide an overview of the main research findings in the field of epigenetics and its influence on the manifestation of this disorder in women. The major focus will be DNA methylation studies, the role of miRNAs, and the transgenerational inheritance of PCOS.

Polycystic Ovary Syndrome (PCOS) stands out as one of the most common endocrine and metabolic disorders, showcasing a range of clinical symptoms like polycystic ovaries, heightened androgen production, irregular menstrual cycles, ovulation irregularities, infertility, and pregnancy complications. Furthermore, it has been linked to chronic low-grade inflammation. The development of PCOS involves multiple factors, and among them, Oxidative Stress (OS) and low-grade chronic inflammation play a crucial role. These two factors have a profound influence on the normal functioning of reproductive organs, particularly in terms of follicular development and the pathogenesis of PCOS. The abnormal function of Reactive Oxygen Species (ROS) and inflammatory markers directly affects the progression of PCOS and its impact on reproductive health. Patients with PCOS exhibit notably higher levels of oxidative stress markers and inflammatory markers compared to healthy individuals, suggesting a relationship between elevated oxidative stress and the progression of PCOS. This chapter provides an overview of significant oxidative markers and inflammatory molecules associated with PCOS, particularly in the context of coexisting conditions such as obesity, insulin resistance, and hyperandrogenism. Additionally, the potential implications of oxidative stress on immune function are briefly addressed.

The U.S. Environmental Protection Agency (EPA) defines EDC as “an exogenous agent that interferes with synthesis, secretion, transport, metabolism, binding action, or elimination of natural blood-borne hormones that are present in the body and are responsible for homeostasis, reproduction, and developmental process”. The global production of EDCs increased 23.5 fold between 1947 and 2007. In 2012 alone, around 9.5 trillion pounds of pesticides, chemicals, drugs, and plastics were produced. The most common contaminants are BPA(bisphenol-A), pesticides, and CPF (chlorpyrifos). Substantial evidence from in vitro and animal studies incriminates many of these endocrine disruptors in the induction of reproductive and metabolic aberrations resembling PCOS characteristics. This chapter describes the differential diagnosis strategies for the accurate identification of PCOS in these intricate scenarios. 

Recent research shows a possible causative relationship of PCOS pathogenies with gut and vaginal dysbiosis. Reduction in (α) diversity and modification in beta (β) diversity and relative abundance of taxa of gut and vaginal microbiome is well known among PCOS women. Gut dysbiosis results in leaky gut and endotoxemia, which lead to chronic inflammation, insulin resistance, and hyperandrogenism with metabolic and reproductive PCOS phenotype. Altered microbial metabolites such as Short-Chain Fatty Acids (SCFA), Branch-Chain Amino Acids (BCAA), and Bile Acids (BA) contribute to the pathogenesis of PCOS. The gut-brain axis is also contributed mainly through the modification of gut peptide hormones. The interplay between gut dysbiosis and Hyperandrogenism (HA) is bidirectional. The understanding of this link between microbial dysbiosis has opened new therapeutic opportunities in PCOS.