Tip of the iceberg: the hidden health consequences of polycystic ovary syndrome

Tip of the iceberg: the hidden health consequences of polycystic ovary syndrome

Written by Lauren Madden Doyle 1,2 , Michael W. O’Reilly 1,21. Department of Endocrinology, Beaumont Hospital2. Endocrinology Research Group, Department of Medicine, Royal College of Surgeons in Ireland (RCSI)

Lauren Madden Doyle

Michael W. O’Reilly

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age, with an estimated prevalence of 6-13% depending on diagnostic criteria applied. 1,2 The Rotterdam diagnostic criteria were introduced in 2003 and largely replaced the 1990 National Institutes of Health (NIH) criteria. As per Rotterdam, PCOS can be diagnosed on identification of two of the following three criteria: (i) oligo- or amenorrhoea, (ii) clinical and/or biochemical evidence of androgen excess or (iii) sonographic evidence of polycystic ovaries.

This was an expansion on the previous NIH criteria, which did not include ultrasound as a diagnostic factor for PCOS.

Typically, patients report a constellation of symptoms which include features of androgen excess such as hirsutism, acne or alopecia, as well as irregular or absent periods, subfertility and in many cases difficulty losing weight. Traditionally, the health impact of PCOS has focused on reproductive dysfunction, with much emphasis on anovulatory infertility and oligomenorrhoea. In recent years, focus has shifted to the overarching associated metabolic derangements and other long term health complications. 2,6 This transition in our understanding of PCOS as a chronic metabolic condition with lifelong health implications is important, and increasing awareness amongst healthcare professionals and the general public remains a challenge. Up to 50% of women with underlying PCOS remain undiagnosed, and the first international clinical practice consensus guideline was only published in 2018. 27

The role of androgen excess and insulin resistance

Before considering the excess metabolic morbidity and health complications of PCOS, a brief discussion of the underlying pathogenesis is warranted. Androgen excess is a cardinal pathological feature of PCOS, with both ovarian and adrenal phenotypes of androgen excess reported. The pathogenesis of androgen excess in PCOS reflects a complex interplay between insulin resistance and androgen metabolism, with hyperinsulinaemia driving androgen generation at the level of the ovary, adrenal and even adipose tissue. 22 Weak adrenal androgenic precursors including androstenedione (A4) and dehydroepiandrosterone (DHEA) may be activated in peripheral tissues into more potent androgens such as testosterone (T) and dihydrotestoterone (DHT), while T may also be produced and secreted directly by ovarian luteal cells.

Clinically, patients will present with classic symptoms of androgen excess, namely hirsutism, acne & frontotemporal alopecia. Generally these develop over a more protracted timeframe, and features of overt virilisation such as clitoromegaly or deepening of the voice, as observed in virilising ovarian or adrenal neoplasms, are notably absent. Cosmetic implications of androgen excess have traditionally been the focus of management in PCOS, however recent studies have linked biochemical hyperandrogenism with a direct impact on cardiovascular & metabolic health. Elevated serum T alongside low sex hormone binding globulin (SHBG) levels are closely linked with metabolic perturbations in PCOS9,10,. These include insulin resistance, impaired glucose tolerance (IGT), type 2 diabetes mellitus (T2DM), dyslipidaemia and non-alcoholic fatty liver disease (NAFLD). Rather than purely associative, we see emerging evidence that androgen excess is directly complicit in mediating some of the metabolic health complications in women with PCOS.

Insulin resistance, a strong risk factor for development of overt hyperglycaemia, has been linked with PCOS since early models of pathogenesis. Whilst not included in diagnostic criteria, up to 75% of women with PCOS demonstrate features of insulin resistance.3,4 This observation is independent of BMI, and in vivo data suggest an intrinsic defect of insulin signalling in skeletal muscle in PCOS. The direction of causality linking androgen excess and insulin resistance in PCOS is unclear, and the associations between these metabolic perturbations remains a key focus of research in this condition.

The concept of PCOS as a disorder of insulin resistance is not a new one, with metformin employed as a therapeutic agent for menstrual cycle regulation and to enhance rates of spontaneous pregnancy in those with PCOS for decades. Initially insulin resistance results in reduced peripheral glucose uptake at key sites such as muscle, with compensatory hyperinsulinaemia maintaining euglycaemia for many years. Ultimately, however, beta cell failure can lead to overt hyperglycaemia, a process that appears to be expedited by the presence of obesity and androgen excess. 2,4,5

PCOS & metabolic disease: type 2 diabetes and beyond

Two large meta-analyses have demonstrated the association between PCOS and both IGT and T2DM7. 8 These showed a three-fold increase in risk of IGT in women with a diagnosis of PCOS, with the highest risk demonstrated in patients of Asian ethnicity. Similarly, the risk of T2DM was also shown to be four-fold increased compared to the general population.

The implications of insulin resistance in PCOS extend far beyond an impact on glycaemic control. Similar to IGT and T2DM, a large UK-based population study derived from primary care records has demonstrated an increased risk of NAFLD in women with PCOS. This study of 63,000 women compared with 121,000 controls found that a diagnosis of PCOS conferred a 2.0-2.4 fold increase in the risk of NAFLD.

Significantly, this also linked circulating T levels with an increased risk of NAFLD, which highlights a potential independent role for hyperandrogenism as a potential pathogenic factor in the aetiology of PCOS-related fatty liver disease. 2,9,10

Traditionally, women during their reproductive years have been perceived as having low overall cardiovascular risk, particularly in comparison to their male counterparts. A diagnosis of PCOS however, appears to change this risk profile. Overall, while the absolute risk of major adverse cardiovascular events (MACEs) remains low, data has shown there is an increased risk of cardiovascular morbidity in the PCOS cohort. A recent retrospective cohort study of 176,000 women with PCOS in the UK CPRD dataset demonstrated a 26% increase in nonfatal myocardial infarction (MI), revascularisation & angina, when compared to age & weight adjusted controls.1, 11,12 Further analysis highlighted risk of progression was highest in those with increased BMI, T2DM & from regions of socioeconomic deprivation. While morbidity is increased, overall cardiovascular mortality and risk of cerebrovascular events is unchanged, likely due to the young age profile. Mechanistically, there are a number of potential drivers of this increased risk of cardiovascular events. At a biochemical level, insulin resistance appears to cause vasoconstriction due to reduced nitric oxide production, and leads to increased lipid trafficking and lipolysis, with patients at a subsequent increased risk of hypertension, dyslipidaemia and likely atherosclerosis. Patients with PCOS demonstrate significant derangements in lipid profiles, with reduced HDL cholesterol levels & increased triglycerides, while LDL-C levels remain unchanged.12

Anovulatory infertility and reproductive morbidity in PCOS

It is long established that women with PCOS experience anovulatory cycles which manifest as oligo- or amenorrhoea. The pathological basis of anovulation appears also to be multifactorial; increased follicle recruitment may be driven by an interplay between luteninising hormone (LH) secretion and insulin, while androgen excess may lead to subsequent arrest of follicular development and consequent failure of ovulation. Strategies to help with ovulation in PCOS primarily include weight loss through a combination of dietary and lifestyle modifications, and metformin. Both are employed in an effort to reduce peripheral insulin resistance and address hyperinsulinaemia, with a secondary knock-on effect on ovulation. Several studies have demonstrated the efficacy of metformin in restoring ovulation through its mechanism as an insulin sensitising agent. 23,24 Additional ovulation induction agents utilised to overcome anovulatory infertility include clomiphene and letrozole. Clomiphene is a selective oestrogen receptor modulator (SERM), which enhances follicular development via hypothalamic stimulation and FSH/LH production. Letrozole, an aromatase inhibitor, also enhances endogenous FSH levels and is used to induce ovulation in those desiring fertility. Reproductive outcomes may be better for letrozole compared to clomiphene, 25 and the former is recommended as first line therapy for ovulation induction in the 2018 clinical practice guideline; however larger scale randomised controlled trials are required to confirm this. 27

Antenatally, patients with PCOS have an increased risk of pregnancy related complications, largely due to its associations with metabolic risk factors. One retrospective study in Japan of 1,000,000 patients on a national database highlighted an increased risk of first trimester miscarriage in the context of a prior diagnosis of PCOS. This appeared to be reduced when metformin was used as an agent for ovulation induction. 17 Another metaanalysis also identified PCOS as an independent risk factor for multiple antenatal and neonatal complications including gestational diabetes mellitus (GDM), pregnancy induced hypertension (PIH) & pre-eclampsia (PET), preterm delivery, caesarean delivery, neonatal hypoglycaemia and neonatal death. 18

Mental Health & Quality of Life Indices in PCOS

Multiple studies have demonstrated an increased risk of depression and anxiety in patients with a diagnosis of PCOS. 2,16,19,20 This is likely multifactorial, with cosmetic manifestations such as hirsutism, increased BMI & poor body image playing a role, in addition to concerns regarding subfertility. However, even when controlling for these factors, PCOS has emerged as an independent risk factor for depression & anxiety. The role of hyperandrogenism & insulin resistance on cortical pathways may be a potential driver of this phenomenon. 19,20 It is not surprising given its multiple implications, that PCOS is also associated with reduced health related quality of life scores.

Emerging health issues in PCOS

The long-term health impacts of PCOS extend beyond the increased cardiometabolic risk profile. Women with PCOS have a significantly increased risk of endometrial cancer compared to the background female population. This is due to the unopposed proliferative effect of oestrogen on the endometrial lining caused by anovulatory cycles, with ectopic oestrogen production by increased adipose tissue also contributing in those with increased BMI. 2,6,14 Theoretically, this increased oestrogen exposure may also predispose to breast cancer, however meta-analyses have thus far failed to demonstrate a concrete link between PCOS & breast cancer. 14

PCOS also increases risk of obstructive sleep apnoea (OSA), independent of BMI. A recent observational cohort study of over 76,000 women with PCOS in the U.K. showed an increased risk of OSA across all ranges of BMI, with the highest risk observed in those with elevated BMI and documented anovulation or hirsutism. Insulin resistance, androgen excess and low luteal phase progesterone levels have all been postulated as potential mechanistic factors in the pathogenesis of OSA in PCOS. 15

There is increasing evidence of neurological sequelae of androgen exposure in PCOS. Idiopathic intracranial hypertension (IIH) shares similar demographic features to PCOS, largely affecting women of reproductive age with co-existent obesity. A recent study highlighted the presence of a convincing androgen excess phenotype in women with IIH, potentially implicating hyperandrogenism in its pathogenesis. 26 Whether this represents a severe variant of PCOS or a distinct clinical androgen excess phenotype remains unclear at this point. However its importance is clear not only a potential therapeutic target for IIH, but also in the identification of androgen excess as a driver of other co-morbidities in the PCOS population.

Conclusion

PCOS is a complex heterogeneous condition, with a spectrum of severity and multiple different phenotypes, and our understanding of the condition is continuing to expand. Our current perspective has evolved dramatically since the turn of the century, and it is now clearly defined as a complex chronic condition with far-reaching metabolic, reproductive and other multi-system complications. Current research in PCOS is targeted at identifying those at highest risk of metabolic manifestations, and further elucidating the relationship between insulin resistance & hyperandrogenism.

The diversity of clinical phenotypes of women with PCOS remains a diagnostic & therapeutic challenge. It has become increasingly clear it is a condition with expansive long term health consequences largely attributed to its metabolic risk. As a condition which affects an estimated 5% of the population, given its metabolic burden, it undoubtedly has far-reaching public health consequences.

PCOS has often been dismissed as a purely reproductive health problem, but the bulk of emerging evidence reframes it as a chronic systemic metabolic disorder. This shift in understanding is crucial.

Future horizons for PCOS are centred on establishing which patient cohort shoulders the burden of this metabolic risk, and identifying a targeted treatment for its pathogenesis.