Current and Emerging Concepts of Polycystic Ovary Syndrome–Manual from M.P. PCOS Society (Part 2)

The development of PCOS is associated with genetic and various lifestyle factors predisposing to obesity and/or insulin resistance. Lifestyle interventions are considered the first line of management for PCOS and its associated complications. A weight loss of 5-10% can significantly decrease central obesity, hyperinsulinemia, and metabolic complications in overweight/obese patients with improvement in reproductive health and hyperandrogenemia. Lifestyle interventions include a healthy, balanced diet, increased physical activity, and behavioral strategies. There has also been an increased interest in traditional, complementary, and integrated medicine (yoga, mindfulness meditation, etc.) for the management of PCOS. This chapter covers the role and recommendations for lifestyle interventions in the management of PCOS based on recent evidence-based guidelines, including the barriers to effective implementation and sustainability. 

Hormonal contraceptives, progestins, and metformin are some of the most often prescribed treatments for PCOS. Ovulation induction therapies, which may include medications like Letrozole, Clomiphene, or Gonadotropin therapy, are the mainstay of infertility treatment. Hormonal contraceptives and adjuvant anti-androgen therapy are frequently used to treat hirsutism. Women with Polycystic Ovarian Syndrome (PCOS) are frequently administered Oral Contraceptive Tablets (OCP), which target symptoms like irregular menstrual cycles and clinical hyperandrogenism while simultaneously offering contraception and endometrial protection. In essence, this chapter aims to furnish a comprehensive overview of contemporary research findings pertaining to the utilization of oral contraceptives in managing PCOS. This chapter sheds light on the evolving landscape of PCOS management and the potential avenues offered by oral contraceptive strategies.

Polycystic Ovary Syndrome (PCOS) stands out as a prevalent endocrine disorder marked by hirsutism, menstrual irregularities, and polycystic ovarian morphology, often accompanied by diverse metabolic abnormalities. Notably, more than half of those diagnosed with PCOS also present features of obesity or metabolic syndrome. Traditional therapeutic approaches for PCOS involve oral contraceptive drugs, antiandrogens, and insulin sensitizers. Recently, there has been a heightened interest in leveraging the positive impact of weight loss on PCOS and associated metabolic disorders, leading to increased exploration of anti-obesity drugs and antihyperglycemia medications known for their weight loss efficacy in PCOS management. Several approved obesity drugs, including orlistat, phentermine/topiramate, Glucagonlike peptide-1 (GLP-1) agonists, and sodium-glucose cotransporter-2 inhibitors, have exhibited favorable effects in individuals with PCOS. Notably, the combination of GLP-1 agonists and metformin emerges as a particularly promising option. This combined therapy demonstrates superior efficacy in weight reduction, normalization of serum androgens, and improvement of menstrual cycle abnormalities. The observed multifaceted benefits underscore the potential of this integrated approach to enhance overall therapeutic outcomes for individuals grappling with PCOS. Consequently, the exploration of anti-obesity and anti-hyperglycemia medications as integral components of the conventional PCOS treatment paradigm signifies a noteworthy avenue, holding promise for improved patient care and outcomes.

Anti-androgens function to ameliorate symptomatic manifestations associated with hyperandrogenism in PCOS, thereby addressing a cornerstone aspect of the condition's pathophysiology. Chemically, antiandrogens are classified into steroidal (such as spironolactone and cyproterone acetate) and nonsteroidal (including flutamide, nilutamide, and bicalutamide). Through their antagonistic action on androgen receptors or inhibition of androgen synthesis, antiandrogens mitigate hirsutism, acne, and alopecia, thereby improving the quality of life and psychological well-being of PCOS women. Additionally, studies have highlighted the profound implications of hyperandrogenism on crucial aspects of reproductive physiology, including ovulation dynamics, reduced pregnancy rates, risk of preterm delivery, and susceptibility to preeclampsia, culminating in diminished rates of live births. Consequently, there is a compelling rationale to consider that the incorporation of anti-androgen therapy may hold promise in augmenting fertility outcomes within this patient cohort.

Due to hyperandrogenism, dermatological manifestations are common in PCOS, which include acne, hirsutism, alopecia, hyperpigmentation, seborrhea, skin tags, and milia. These dermatological symptoms can significantly impact the quality of life and self-esteem of affected individuals. Therefore, effective management strategies are essential to address these concerns comprehensively. This chapter aims to provide a comprehensive overview of the management of dermatological symptoms associated with PCOS. It discusses the various treatment modalities that are reviewed, including topical agents, oral medications, cosmetic procedures, and laser therapy.

Metabolic disturbances, chronic low-grade inflammation, and oxidative stress serve as a pivotal nexus in the manifestation and progression of PCOS. In essence, nutritional supplements have shown promising results in the restoration of reproductive, metabolic, and psychological aberrations, in part in PCOS, by altering the above-mentioned key pathways associated with PCOS etiology. Besides, deficiencies in certain nutrients among PCOS women reinforce the notion that supplementation may address imbalances to improve clinical symptoms, thus offering a strategic approach towards comprehensive and personalized therapeutic interventions in relation to the severity of manifestations of this endocrinopathy among women. This chapter aims to elucidate empirical evidence supporting the application of prebiotics, probiotics, synbiotics, vitamin D, vitamin B12, and vitamin K in the context of PCOS intervention. 

Given that the pathophysiology of PCOS is rooted in insulin resistance, insulin-sensitizing agents have proven to be beneficial in improving metabolic abnormalities. Newer classes of antidiabetic agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists (GLP1RA), dipeptidyl peptidase IV (DPP IV) inhibitors, and sodium-glucose transport protein 2 (SGLT2) inhibitors, are being investigated for the treatment of PCOS. They have advantageous impacts on body weight, cardiovascular health, and antihyperglycemic effects and might be an intriguing therapeutic addition to the PCOS repertoire. Other drugs in the pipeline include statins and phosphodiesterase4 inhibitors (PDE4 inhibitors). The ongoing studies on the roles of clomiphene, aromatase inhibitors, and bromocriptine in reproductive function hold enormous promise and have shown potential as therapeutic strategies to be employed in the administration of PCOS-related reproductive complications.

Drug repurposing involves the study of finding new indications of already approved drugs. In PCOS, this approach has helped by taking advantage of diverse pharmacological uses of drugs to treat the intricate pathophysiology of the disease. Several medications having different indications, including metformin and statins, have demonstrated promising effectiveness in managing PCOS symptoms. These repurposed drugs target insulin resistance, hyperandrogenism, and dyslipidemia, providing an integrated approach to PCOS treatment and potentially improving metabolic and reproductive outcomes. Additionally, fecal microbiota transplantation emerges as a novel curative option in PCOS, focusing on the intricate link between gut microbiota and metabolic health. Alterations in the gut microbiota, termed dysbiosis, have shown a close relationship with the pathogenesis of PCOS. Thus, FMT, which involves the transfer of microbiota from a healthy donor to the patient's gut, aims to restore the gut flora alterations and improve the PCOS symptoms. Preliminary studies have shown that FMT potentially improves PCOS symptoms by perfecting metabolic, inflammatory, and hormonal profiles. Likewise, vaginal microbiota seems to have a crucial role in female reproductive health, and in relation to this, vaginal microbiota transplantation holds promise as an innovative strategy for managing PCOS. VMT has shown encouraging results in various gynecological diseases, such as bacterial vaginosis. This chapter, therefore, provides insights about the alternative treatments explored for the management of PCOS.

Bariatric surgical interventions have emerged as a promising therapeutic option for PCOS patients struggling with severe obesity. Bariatric surgery encompasses various procedures like gastric bypass, sleeve gastrectomy, and gastric banding aimed at promoting weight loss by altering the anatomy of the gastrointestinal tract. Beyond weight reduction, these surgeries exert profound metabolic effects, including improved insulin sensitivity and hormonal balance, which are pivotal in managing PCOS. However, bariatric surgery is not without risks and should be considered in the context of individual patient needs and medical history. Close monitoring and multidisciplinary care are essential post-surgery to ensure optimal outcomes and long-term success. This chapter provides an overview of bariatric surgical interventions as a promising avenue for managing PCOS in severely obese patients, addressing both weight-related issues and underlying metabolic dysregulation. Additionally, the potential implications of bariatric on reproductive aspects are briefly addressed. 

Insulin resistance is a common feature in Polycystic Ovary Syndrome (PCOS), affecting both obese and lean women, and is associated with an elevated risk of Cardiovascular Disease (CVD). The relationship between PCOS and CVD risk factors is multifaceted, involving dyslipidemia, hyperglycemia, obesity, and hypertension. Obesity exacerbates the metabolic disturbances in PCOS. Hypertension is more prevalent in women with PCOS, driven by factors like autonomic nervous system imbalance and decreased nitric oxide synthesis. Metabolic syndrome is notably more common in women with PCOS, with insulin resistance being a central factor. Subclinical CVD manifestations in PCOS include increased inflammatory and endothelial activation markers and impaired Flow-mediated Dilation (FMD). Early identification and management of these risk factors are crucial for preventing and mitigating CVD in women with PCOS. 

Polycystic Ovarian Syndrome (PCOS) is associated with a higher risk of metabolic complications, even among younger individuals. The metabolic complications include Impaired Glucose Tolerance (IGT), Type 2 Diabetes Mellitus (T2DM), obesity, and dyslipidemia. These are the traditional cardiovascular risk factors that have been proposed to predispose women with PCOS to increased cardiovascular morbidity, although the evidence remains insufficient at present to suggest direct causality. This chapter describes the risk of metabolic complications among women with PCOS.

 NAFLD (Non-Alcoholic Fatty Liver Disease) is emerging as an important cause of chronic liver disease worldwide. It ranges from end-stage liver disease to fatty infiltration. PCOS (Polycystic ovarian syndrome) is one of the most prevalent endocrine abnormalities seen in reproductive-age women, which causes significant morbidity. This article aims to provide the readers with a comprehensive overview of the two disease conditions and insights into the pathophysiology of NAFLD in PCOS with implications for therapeutic research and drug targets.

An association between PCOS and hormone-sensitive malignancies in women (endometrial, breast, and ovarian cancers) has been suggested. It is imperative to have robust evidence on this issue to develop preventive strategies for the same. The literature available to date suggests a definite association between endometrial cancer and PCOS with a 3-to-4-fold increased risk. There is enough literature to suggest that there is no clear association between breast cancer and PCOS. However, the data regarding the relationship between PCOS and ovarian cancer is controversial, and more studies are needed to establish a causal association. It is important to note that the association of PCOS with these gynecological cancers is further complicated by the confounding factors and the common treatment modalities that a woman receives for PCOS during her reproductive years for symptom alleviation.

Apart from the well-known presentations of anovulation, infertility, hirsutism, acne, and hyperandrogenism, women with PCOS are not only at risk for metabolic complications but may have comorbidities such as thyroid disorders and sleep disturbances, especially obstructive sleep apnea. The incidence of hypothyroidism, especially subclinical hypothyroidism, is common in PCOS, which may interfere with the treatment outcomes, especially for anovulation. Similarly, obstructive sleep apnea is also more common and may be responsible for the worsening of the associated metabolic disorders and interferes with treatment for inducing ovulation. Therefore, in the management of PCOS, one must be aware of the potential comorbidities, which must be identified in a timely manner and properly managed.

There are numerous choices available to aid couples in general and women with PCOS in particular in having children. There are two categories of treatment options: Assisted Reproductive Technologies (ART) (IVF/ICSI) and “All other possibilities”. The woman’s age and the man’s sperm quality determine where to start. Additionally, the evaluation of the best option is influenced by previous fertility treatments and their outcomes. Only in cases when the sperm quality is normal, the woman is under 36-37 years old, and the issue is anovulation, should one or more of “All other possibilities” be considered. When compared to age 30, the monthly fertility rate (ability to conceive) has already decreased to 1/3 by the time a woman is 37. Thus, even if all other parameters are normal, age is the most crucial factor affecting a woman’s capacity to conceive. At 36-37 years old, there is limited time for ovulation induction, and ART will double the likelihood of conception compared to becoming pregnant at home, even when all other factors are normal. Female fecundity, the capacity to have a child, will also be significantly influenced by genetic factors, smoking, and weight. The last two factors can be changed in spite of being difficult. Smoking and obesity will both reduce fecundity by at least 30%. When finances are a concern, “All other possibilities” are typically more affordable and more effective than no treatment at all.

PCOS is associated with multiple adverse effects during pregnancy, making these women a high-risk pregnancy. These adverse risks extend beyond pregnancy as well, potentially posing intergenerational risks to the children of affected women. These risks can be attributed to the biochemical features of PCOS, as well as other coexisting factors such as high BMI, insulin resistance, hypertension, thyroid disorders, type 2 diabetes, and prediabetes, which are commonly observed in women with PCOS. In order to provide a good pregnancy outcome, optimum antenatal care and surveillance is necessary.

The dysfunctional gonadotropin secretion and other features of PCOS like Insulin Resistance (IR), chronic inflammatory state, and hyperandrogenism have a significant impact on reproductive and gestational outcomes. Women with PCOS have reduced ability to conceive owing to poor oocyte quality, ovulatory dysfunction, implantation failure, and uterine abnormalities. Besides, if the conception stage is crossed, these subjects are at a graded risk of carrying the pregnancy to term and developing various issues like recurrent pregnancy loss, preterm labour, gestational diabetes, and hypertension. This chapter summarises the mechanistic insights into various pregnancy complications and management strategies among PCOS women. Having background knowledge of what and how will help us not only in preparing the optimal management of these women but also put physicians in a position to use preconception counseling as a tool in the armamentarium of prevention of complications of pregnancy and enhance clinical outcomes. 

Traditionally viewed through the lens that is primarily focused on its hormonal and metabolic disruptions, PCOS has increasingly drawn attention to its multifaceted nature, encompassing psychological, social, and emotional dimensions. While the etiology of PCOS remains complex and multifactorial, recent research has shed light on the intricate interplay between neuroendocrine dysregulation, psychological distress, and sociocultural factors in the pathogenesis and manifestation of this syndrome. Due to varied presentations and significant impact on the health of women, it becomes imperative to explore not only the medical aspects of PCOS but also the psychosocial facets that shape patients' experiences. This chapter delves into the intricate interplay between the medical and psychosocial dimensions of PCOS, shedding light on its far-reaching effects on women's lives.

As per the Diagnostic and Statistical Manual of Mental Disorders 5th edition text revision (DSM-5 TR), feeding and eating disorders “are characterized by a persistent disturbance of eating or eating related behavior that results in altered consumption or absorption of food and that significantly impairs physical health or psychosocial functioning.” A meta-analysis published recently concluded that women with PCOS had over three times the odds of being diagnosed with an ED (Eating disorder). There is considerable overlap in symptoms of Binge Eating Behavior (BEB) and PCOS like difficulty losing in weight, irregular menstrual cycles, infertility, and hirsutism. Hormonal and menstrual irregularities and hyperandrogenism have been linked to both PCOS and BEB. Insulin resistance, obesity, stress and serotonin have overlapping etiology for both. Gut microbiomes and reward system of the brain are implicated in the etiopathogenesis of PCOS and ED. High levels of body dissatisfaction are seen in women with PCOS and coping with these psychosocial factors can lead to disordered eating in women. There is an increased risk of developing PCOS at puberty and in adolescence due to high levels of estrogen. Binge Eating Behavior (BEB) is a common symptom of eating disorders including Bulimia Nervosa (BN), binge eating disorder (BED), and binge/purge subtype of anorexia nervosa (AN-BP). Treatment of Feeding and Eating Disorders (FEDs) remains challenging with evidence based intervention still lacking for certain disorders (AN in adults). Relapse and treatment non-responsiveness are high.

Aside from its physical symptoms, PCOS has a substantial influence on psychological well-being, frequently leading to increased anxiety, despair, and a lower overall quality of life. The multidimensional character of PCOS needs a comprehensive treatment strategy that addresses both the physiological and psychosocial aspects of the disorder. Psychological symptoms related to PCOS can be caused by a variety of factors, including hormone imbalances, metabolic problems, and the psychosocial stress of managing a chronic illness. The obvious signs of PCOS, such as weight gain, acne, and hirsutism, can increase body image difficulties and social anxiety, resulting in a vicious cycle of psychological discomfort. PCOS's intricacy and chronicity mean that women frequently endure continuous issues, needing therapies that provide longterm support and respite.

Artificial Intelligence (AI) has shown considerable potential in improving PCOS diagnosis and management. Key AI concepts such as machine learning, computer vision, deep learning, and natural language processing are discussed in the chapter. AI has proven invaluable in the prediction and diagnosis of PCOS, with studies showing high accuracy using AI-based models. Algorithms analyze ultrasound images, scleral images, and other clinical parameters, although the final diagnosis still requires an expert clinician. Machine learning algorithms, including Random Forest, have been beneficial in classifying PCOS and predicting sub-phenotypes. AI also aids in managing PCOS and its complications, analyzing endometrial immune cells, predicting complication risks, recommending diet interventions, and developing early detection systems. Large language models like Chat GPT and Google Bard play crucial roles, offering literature reviews, answering questions, generating patient education material, and facilitating personalized treatments. The future of AI in PCOS suggests a need for more collaboration between technology and clinical medicine researchers, converting clinical research into practical software, and adopting a multimodal AI approach. These advancements could significantly transform PCOS care and deepen our understanding of the disease.