What is PCOS and how does it manifest?
Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder affecting reproductive aged women (1). An estimated 5-20% of women are thought to be affected by PCOS depending on the diagnostic criteria used (1). PCOS is characterised by functional hyperandrogenism with irregular or absent ovulation that can not be explained by other conditions (1). The new 2023 international evidence based guidelines for the diagnosis and management of PCOS states that PCOS should be diagnosed through the revised Rotterdam criteria which requires the presence of any two of the following criteria: i) clinical or biochemical hyperandrogenism, ii) ovulatory dysfunction and iii) polycystic ovaries on ultrasound or elevated anti-mullerian hormone (AMH) levels (2). The pathophysiology of PCOS involves the interaction of multiple different factors that are not yet fully understood. Factors include excessive androgen secretion (3), neuroendocrine factors such as increased LH pulse frequency/amplitude and increased LH/FSH ratios (3), hypothalamic pituitary adrenal axis dysfunction, insulin resistance and excess adiposity (3). Twin studies have suggested a 70% chance of genetic heritability and new research is investigating the role of the foetal developmental origins of PCOS involving in utero exposure to excess androgens (3)(1). The role of the intestinal microbiome in the development of PCOS is also being explored (3). In addition environmental toxin exposure is thought to play a role in the development of PCOS (4). These factors combined allow the expression of different PCOS phenotypes which have different clinical and biochemical manifestations (5)(6).
PCOS is the most common cause of anovulatory infertility (7). Infertility associated with PCOS is related to ovulation and implantation disorders caused by low-grade inflammation of the ovaries and endometrium, which in turn is caused by the underlying hormonal and metabolic factors underpinning PCOS (8). This article will discuss the three main underlying factors that contribute to sub fertility in women with PCOS, namely hormonal factors, insulin resistance and obesity.
Hormonal factors influencing fertility
The main underlying hormonal factors involved in PCOS is hyperandrogenism (9)(1). Elevated androgens can have both ovarian and adrenal origins (9)(10). The main androgenic hormones associated with PCOS are total and free testosterone, androstenedione and DHEA (10). Clinically, elevated androgens present as hirituism, acne and alopecia (10). Excess androgens interfere with normal folliculogenesis by encouraging the growth of primordial follicles and antral follicles in the ovary (10). As a response, the hypothalamus promotes a rise in GnRH which elevates the levels of lutenising hormone (LH) (10). Altered cortisol metabolism can also contribute to excess androgens through altered enzyme activity favouring cortisol balance through the overproduction of androgens (14). Elevated androgens cause theca cells in the ovaries to undergo hyperplasia as a result of increased LH stimulation, which also causes a build-up of follicular fluid that form cystic structures within the ovaries (10). The cystic structures represent follicles that have been arrested mostly in the pre-antral and antral stages, giving them the appearance of polycystic ovaries on ultrasound (10). This process largely inhibits the development of a dominant follicle selected for ovulation leading to chronic oligo-ovulation, anovulation and menstrual irregularities (11). The pro-inflammatory state and immunological response associated with hyerandrogenism can also interfere with implantation of pregnancy (8) and is associated with increased miscarriage and biochemical pregnancy loss (13).
Infrequent or absent ovulation is associated with chronic and unopposed oestrogen and progesterone deficiency. This leads to overstimulation of the endometrial lining, spontaneous inter menstrual bleeding, heavy menstrual bleeding and endometrial hyperplasia (10). Excess oestrogen can itself interfere with the negative feedback loop between the ovaries and hypothalamus, further suppressing ovulation (12). Irregular ovulation, elevated LH levels and spontaneous menstrual bleeding make ovulation detection and family planning significantly more difficult in women with PCOS. Careful monitoring of fertility biomarkers and sound education in the menstrual cycle are necessary in order to improve conception rates with irregular ovulation (12).
Insulin Resistance and infertility
Insulin resistance is common in women with PCOS affecting 65-70% of women (7) (15). 30-40% of PCOS women also have impaired glucose tolerance and an increased likelihood of developing metabolic syndrome and type 2 diabetes (7). Intrinsic insulin resistance is found in most cases of PCOS, even with a lean PCOS phenotype, however increased adiposity, especially around the abdomen increases the severity of insulin resistance (3). Insulin resistance promotes excessive androgen secretion from the ovary while also decreasing sex hormone binding globulin in the liver. This results in higher circulating levels of free testosterone (3) which stimulates fat accumulation (1). Insulin dependant fat accumulation can lead to an increased BMI but can also manifest as an increase in liver fat and muscle mitochondrial dysfunction in lean PCOS (3).
Insulin resistance and compensatory hyperinsulinemia is a driving mechanism behind hyperandrogenism, leading to irregular or absent ovulation. Infrequent ovulation greatly affects conception rates by reducing the opportunity for fertilisation. Insulin resistance can independently affect fertility even in non PCOS women (16). Insulin resistance may increase the risk of infertility by activating oxidative stress, interfering with energy metabolism, affecting oocyte development and quality, embryo quality, endometrial receptivity and embryo implantation (17). Impaired glucose tolerance can interfere with the normal differentiation and maturation of endometrial glandular tissue (17). This process is dependant on the GLUT4 factor leading to potential glucose deficiency in the endometrial cells (17). Glucose or energy deficiency within the endometrial cells could affect the normal growth of the endometrium, reduce endometrial receptivity and interfere with implantation (17). Insulin resistance is also shown to reduce assisted reproductive technology outcomes in sub fertile populations and is associated with increased miscarriage risk and other adverse pregnancy outcomes (17).
Obesity and infertility
Reproductive function in women with PCOS is strongly associated with bodyweight and metabolic function (18). While not all women with PCOS present with elevated BMI, obesity is a common manifestation in women with PCOS. Insulin resistance and obesity have a bi-directional relationship. While insulin resistance can cause weight gain in many women with PCOS, it is also true that increased adiposity worsens insulin resistance (18). Insulin resistance and subsequent elevated testosterone levels leads to abdominal fat accumulation and increased liver fat (18). Insulin resistance can increase cravings for sugary foods, reduce feelings of satiety and pre-dispose women to binge eating behaviour (18). Women with PCOS have reduced secretion of the gastrointestinal satiety peptides compared with non PCOS women of similar BMI (18). PCOS is also associated with dysregulation of ghrelin hormone in the digestive tract, leading to increased hunger and appetite (18). Dysregulation of appetite and hunger signalling hormones may offer additional explanation as to why many women with PCOS have a tendency towards obesity (18).
PCOS women with obesity are shown to have significantly lower sex hormone binding globulin levels and higher rates of anovulation compared to normal weight PCOS controls (18). While the underlying mechanisms of PCOS and infertility remain the same, obesity likely aggravates both hyperandrogenism and insulin resistance leading to a more severe PCOS presentation (18). Obesity is shown to worsen both natural and assisted fertility outcomes irrespective of a PCOS diagnosis (18). Morbidly obese women with PCOS have greater requirements for IVF, however are shown to have lower pregnancy and live birth rates compares to normal weight PCOS patients (18).
In addition to the underlying hormonal dysregulation common to PCOS, in obese presentations the adipose tissue acts as its own endocrine organ (19). Adipose tissue releases a number of bioactive molecules called adipokines that interact the molecular pathways of insulin resistance, inflammation, coagulation, oocyte differentiation and maturation and endometrial implantation (19). In addition, adipose tissue creates its own oestrogen hormone which interferes with the negative feedback loop to the hypothalamus thereby also impacting ovulation (20).
In conclusion, hyperandrogenism, insulin resistance and increased adiposity can greatly influence fertility in women with PCOS. These factors influence fertility primarily by reducing the frequency of ovulation thereby reducing the chance of conception. PCOS also interferes with fertility by affecting oocyte development and quality, embryo quality, endometrial receptivity and embryo implantation. Management of the PCOS patient attempting to conceive involves lifestyle modification, weight management and ovulation induction or IVF if appropriate. Fertility management for PCOS should be individualised and tailored to the unique needs and goals of the patient. Read more about infertility management for the PCOS patient here.
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