PCOS (Polycystic Ovary Syndrome)

Women’s body has a unique constitution. When we talk about women’s health, it is about the ever-changing body dynamics that are unique to her and involve detailed and individual studies of prevention, screening, diagnosis, and treatment of disorders.

Polycystic ovary syndrome (PCOS) is extremely prevalent and probably constitutes the most frequently encountered endocrinopathy in women during their reproductive age. The ovaries may develop numerous small collections of fluid (follicles) compared with normal controls with premature growth arrest of antral follicles at 5 to 8 mm and fail to regularly release eggs.

Follicular Development during Each Menstrual Cycle

Primary care providers do not commonly appreciate that the syndrome is associated with significant morbidity in terms of both reproductive and nonreproductive events. Having the disorder may significantly impact the quality of life of women during their reproductive years, and it contributes to morbidity and even mortality by the time of menopause.

PCOS start developing from the early pubertal years. The female hypothalamic–pituitary–ovarian (HPO) axis is a meticulously synchronized and tightly regulated network is ultimately responsible for reproductive competence and survival of the species. The HPO axis responds to internal signals (i.e., hormonal and neuronal) and external factors (i.e., environment influences). Beginning during gestation, these factors impact future generations through epigenetic factors affecting the brain and the developing germ cells.

Polycystic ovary syndrome (PCOS), a disorder primarily characterized as the signs and symptoms of androgen excess and ovulatory dysfunction, disrupts HPO axis function. Depending on diagnostic criteria, this disorder affects ∼6% to 20% of reproductive-aged women.

PCOS Phenotypes

Typical clinical features include:

  • Hirsutism (condition in which a woman develops excessive hair growth),
  • Other cutaneous signs of PCOS include severe cystic acne and male pattern baldness due to androgen excess
  • Irregular menses, chronic anovulation, and infertility.
  • The persistent hyperandrogenism (excess production and circulation of male sex hormone testosterone) in females and its effects on the body is associated with impaired hypothalamic-pituitary feedback, Luteinizing hormone (LH) hypersecretion, premature granulosa cell luteinization, abnormal ova maturation, and premature arrest of activated primary follicles.

By the time the diagnosis is established, PCOS presents as a phenotype reflecting a self-perpetuating vicious cycle involving neuroendocrine, metabolic, and ovarian dysfunction. Over the years, numerous hypotheses have been proposed regarding the proximate physiologic origins for PCOS. PCOS reflects the interactions among multiple proteins and genes influenced by epigenetic and environmental factors. Specific sections of this article deconstruct the factors contributing to the development of PCOS in humans and preclinical models. Clinical and biochemical hyperandrogenism are major features of PCOS.

Reasons of PCOS

  • Insulin Resistance (IR), Hyperinsulinemia, and the β-Cell: Studies have shown Up to 70 percent of women with PCOS have insulin resistance, meaning that their cells can’t use insulin properly. Insulin is the hormone primarily responsible for glucose homeostasis and lipogenesis. In addition to its effects on carbohydrate, fat, and protein metabolism, insulin functions as a mitogenic hormone that helps the body use sugar from foods for energy. When cells can’t use insulin properly, the body’s demand for insulin increases. The pancreas makes more insulin to compensate.

The phenotype of female patients with insulin receptor gene mutations includes insulin resistance (IR), compensatory hyperinsulinemia, and hyperandrogenism. Although IR and hyperinsulinemia are commonly detected in women with PCOS, insulin receptor gene mutations are extremely rare among women with PCOS. The compensatory hyperinsulinemia associated with IR provokes excessive ovarian/adrenal androgen secretion and decreases hepatic SHBG synthesis with the net result of increasing circulating testosterone concentrations which interferes with the development of the follicles (the sacs in the ovaries where eggs develop) and prevents normal ovulation.

Women with PCOS have intrinsic IR independent of the extent of obesity and magnitude of androgen concentrations. Even lean women with PCOS manifest IR; increasing body mass index (BMI) exacerbates IR. Normal-weight adolescent girls with PCOS have peripheral IR, increased liver fat, and muscle mitochondrial dysfunction compared with normal-weight girls.

  • Chronic low-grade inflammation has emerged as a key contributor to the pathogenesis of Polycystic Ovary Syndrome (PCOS). A dietary trigger such as glucose is capable of inciting oxidative stress and an inflammatory response from mononuclear cells (MNC) of women with PCOS, and this phenomenon is independent of obesity. This is important because MNC-derived macrophages are the primary source of cytokine production in excess adipose tissue, and also promote adipocyte cytokine production in a paracrine fashion.
  • Neuroendocrine Factors: Increased LH pulse frequency, LH pulse amplitude, and increased LH/FSH ratios are described in women with PCOS. The initial features of PCOS emerge during the early pubertal years, concomitant with reactivation of the hypothalamic GnRH pulse generator, increased gonadotropin secretion, and subsequent increased ovarian estrogen production.

Hypothalamic neurons in the arcuate nucleus secrete kisspeptin, neurokinin B, and dynorphin. These neurons, labeled as the KNDy neurons, are the leading contenders for the hypothalamic GnRH pulse generator because of the colocalization of these three peptides and their roles in episodic GnRH secretion .Rather than initiating puberty, the GnRH pulse generator and GnRH neurons represent downstream nodes modulated by other hormones and neurosecretory factors. In other words, activation of excitatory inputs and inactivation of inhibitory inputs moderated by multiple influences regulate the output of the GnRH pulse generator to govern the timing of puberty. This process culminates in increased GnRH and gonadotropin secretion.

  • Valproate and HPO Axis Function: Women treated with VPA can develop PCOS-like symptoms. Valproic acid (VPA), a branched short-chain fatty acid derived from valeric acid, is used to treat epilepsy, bipolar disorders, and prevent migraine headaches.

VPA increases GABA levels by interfering with GABA degradation pathways. GnRH neurons express both GABAA and GABAB receptors, implicating GABA signalling in the regulation of GnRH secretion. Signalling through the GABAA receptor can elicit an excitatory effect on GnRH neurons. Lean women with PCOS had significantly higher CSF GABA concentrations compared with eumenorrheic lean control women; the women with PCOS also demonstrated increased LH pulse amplitude and LH pulse frequency on frequent blood sampling. These clinical observations suggest that GABA signaling could influence the neuroendocrine changes associated with PCOS such as LH pulse frequency.

  • Obesity, the Adipocyte, and Nutrient Excess: Overweight and obesity are common among adolescent girls and adult women with PCOS. In response to nutrient excess, adipocytes can enlarge (hypertrophy) or form new adipocytes (hyperplasia). According to the adipose tissue expandability hypothesis, adipocyte hypertrophy establishes a microenvironment characterized by hypoxia, proinflammatory cytokine secretion, free fatty acid “spillover,” macrophage invasion, and IR. IR decreases suppression of adipocyte lipolysis, resulting in increased serum free fatty acids and triglycerides, ultimately leading to increased hepatic de novo lipogenesis and hyperlipidemia. Another consequence is increased fat storage in skeletal muscle, liver, and pancreas because the adipose tissue capacity to store lipid is exceeded. In the liver, ectopic fat storage is labelled hepatic steatosis, which can develop into non-alcoholic fatty liver disease

White adipose tissue has several distinct locations, that is, visceral and subcutaneous. Partitioning of fat among different storage sites influences metabolic consequences: increased abdominal fat is associated with greater risk for dysglycemia and cardiovascular disease. Investigation of normal-weight women with PCOS showed increased total abdominal fat mass due to preferential deposition of intra-abdominal fat with an increased population of small subcutaneous abdominal adipocytes.

Emerging pilot data in adolescent girls with PCOS showed that reduction of visceral fat improved menstrual irregularity.

Mismatches between prenatal and postnatal weights have led to the advance of the developmental origins of the disease hypothesis. The longitudinal prospective population-based study (Northern Finland Birth Cohort Study) found that women with PCOS had lower birth weights, experienced adiposity rebounds at younger ages, and had higher subsequent BMI values .These findings are consistent with the concept that a mismatch between prenatal weight and postnatal weight gain is associated with increased risk for PCOS, ectopic fat storage, and hepatic steatosis.

The Process of Menses or Periods

With reactivation of the Gonadotrophin-releasing hormone (GnRH) pulse generator, increased gonadotropin secretion stimulates ovarian estrogen hormone secretion and hence, follicular development. Estrogen promotes uterine growth and endometrial proliferation; endometrial estrogen exposure eventually culminates in vaginal withdrawal bleeding and menarche (the first period) or menses or periods.  Studies have suggested the median age of girls at menarche in girls between 11. 98% of girls by the age 15 years will have experienced menarche.

Contemporary understanding is that it takes 3 to 4 years post menarche for adult menstrual cyclicity to mature. By the third year after menarche, 10 or more menses occur annually in 90% of adolescent girls Approximately 41% of girls have achieved ovulatory cycles by the fourth gynaecologic year. Importantly, ovulation may occur despite irregular menses.

Systematic review of menstrual patterns during the first gynaecologic year concluded that menstrual and ovulatory patterns are diverse during this time period. In 22 studies involving >2000 adolescents, frequent menstrual bleeding (<21 days) occurred in 23% and prolonged menstrual bleeding (>30 to 45 days) occurred in at least 33%. A pilot study entailing serial hormone concentrations and ultrasound studies in ovulatory postmenarcheal girls revealed lower steroid (estrogen and progesterone) concentrations, slower dominant follicle growth rate, and longer follicular phases compared with adult women; these data suggest that coordinated development of all components of the HPO axis may take up to 5 years post menarche.

PCOS Management

It is observed that Weight /fat and insulin resistance comes out a major cause. “Meta form” drug is a standard protocol (in spite US FDA has raised alarm against it —but permitted use till alternate is found)—and the original use of the drug was to manage diabetes type 2.

Healthy lifestyle interventions must be incorporated in the management plan of all adolescents with PCOS because a large proportion of these adolescents are overweight/obese or are at risk for gaining excessive weight. Lifestyle interventions comprise multiple components, including healthy diets, physical activity, decreased sedentary behaviors, and behavioral strategies.

The interventions should also include the family, as parents’ involvement and their readiness to change affect adolescent outcomes. Engagement and adherence to lifestyle interventions can be improved by the management of psychological factors such as anxiety, body image concerns, and disordered eating, which are common in adolescents. Two systematic reviews of lifestyle interventions in women with PCOS show improvements in weight, hyperandrogenism, and IR. Lifestyle interventions in adolescents with PCOS have shown additional improvements in quality of life.

  • Diet: Studies have revealed that a low-carbohydrate diet (20 to 40 g/d) and a hypocaloric diet (<40 g of fat per day) during 12 weeks improved weight and menstrual irregularities with no difference between the diets. Similarly, both low–glycaemic load and low-fat diets during 6 months improved weight with no difference between diets. A low-energy diet compared with a healthy diet for 6 months was associated with weight loss, more regular menses, and decreased hirsutism. Nutrition education in addition to exercise training and behavioral therapy for 12 months resulted in weight loss, as well as improvement of menstrual irregularities and androgen levels in adolescents with obesity and PCOS. Prevention of weight gain and effective weight management is important in adolescent PCOS, as obesity exacerbates metabolic and psychological comorbidities of PCOS. Additionally, weight-loss strategies up to 7% of body weight have resulted in improving menstrual irregularity and testosterone levels. There are limited data for the use of weight loss medications in adolescents
  • Physical activity of longer duration, frequency, and intensity results in better maintenance of health. Importantly, moderate to vigorous physical activity for at least 60 minutes per day is associated with better physical and psychosocial health in children and adolescents. Sixty minutes of moderate to vigorous physical activity at least 3 times a week should be encouraged for the prevention of weight gain and maintenance of health in PCOS. Exercise interventions can also improve cardiometabolic risk factors in women with PCOS . Alternative exercise activities such as yoga for 12 weeks can also improve PCOS symptoms during adolescence .
  • Limiting sedentary behaviors such as watching television and the use of tablets, computers, and/or mobile phones to 2 h/d is advised for adolescents and relates to better health

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