PCOS and Cardiometabolic Health

How does PCOS affect cardiometabolic health?

According to a 2019 study on Metabolic Disturbances in Non-Obese Women with PCOS, even those individuals with PCOS who are not overweight have increased risk of metabolic dysfunction and long-term health complications.

Polycystic ovarian syndrome (PCOS) is one of the most common, most profound and most overlooked health conditions affecting individuals assigned female at birth. It is a multi-system disorder which impacts hormonal, menstrual, reproductive/maternal, cardio-metabolic, oncological, mental/neurological, sexual and immune system health. In this article we explore the link between PCOS and Cardio-Metabolic Health.

At its core, PCOS is associated with abnormal functioning of the system of hormones that connects the hypothalamus, the pituitary and the ovaries (the HPO-axis).[1]

In individuals with PCOS, the activity level (pulse frequency) of one of the hormones produced in the hypothalamus, the Gonadotrophin Releasing Hormone (GnRH), is over-active.[2]

An elevated level of GnRH triggers an elevated level of Luteinizing Hormone (LH) in the pituitary, LH and Follicle Stimulating Hormone (FSH) being the two hormones responsible for stimulating growth of follicles, the part of the ovary that contains eggs, and synchronize the release of eggs from the ovaries;[3]
An elevated LH level leads to increased stimulation of theca cells, a type of cell within the ovary that plays an essential role in fertility;[4]
The increased stimulation of these theca cells increases the rate of conversion of cholesterol, a fat-like substance that is found in all cells in the body and needed to make hormones,[5] to two androgens or sex hormones (androstenedione and testosterone);[6][7]
A portion of these androgens then travel to neighboring granulosa cells, a type of cell within the ovary that is important for the production of reproductive hormones;[8]
Within granulosa cells, some of these androgens are converted to estrogen, a sex hormone responsible for triggering egg release and thickening the lining of the uterus;[9] and
Some of these excess androgens are not converted and therefore lead to an androgen-rich environment within the ovary[10] and elevated circulating androgens.

As a result, PCOS is associated with hyperandrogenism (HA) or androgen excess (AE), elevated androgens in individuals assigned female at birth.

Elevated androgens disrupt the way that adipose tissue metabolizes glucose. The adipose tissue produces less adiponectin, a hormone that helps with insulin sensitivity and inflammation, and more leptin, a hormone that causes you to feel hungry in efforts to maintain enough fat stores for long-term health. As a result, 65-70% of individuals with PCOS develop insulin resistance (IR).[11] In another study insulin resistance was shown to affect up to 95% of individuals with PCOS who are overweight and up to 75% of individuals who are lean.[12]

Initially, the pancreas compensates for insulin resistance by producing more insulin resulting in hyperinsulinemia.[13]

Eventually, the pancreas is no longer able to produce enough insulin to maintain a healthy level of blood sugar and the individual develops hyperglycemia, or high blood sugar.[14]

Uncontrolled high blood sugar eventually leads to prediabetes and/or type 2 diabetes; more than 50% of individuals with PCOS develop type 2 diabetes before the age of 40.[15]

Insulin resistance is also linked to Alzheimer’s disease with it sometimes referred to as “type 3 diabetes”;[16] individuals with PCOS may be at up to 2x the risk of developing dementia[17] with some mild cognitive impairment starting in mid-life.[18]

In parallel, insulin resistance in fat cells stimulates the release of fatty acids into the blood, stimulating the liver to produce and secrete very low-density lipoprotein (VLDL). The release of VLDL into the blood results in an increased level of lipids in the blood overall, hypertriglyceridemia. VLDL also stimulates the exchange of cholesteryl esters from both high-density lipoprotein (HDL) and low-density lipoprotein (LDL). The triglyceride (TG) enriched HDL then releases Apolipoprotein A-1 (ApoA-1) protein into the blood which is rapidly cleared from the blood, leaving HDL less available to play a role in removing cholesterol from the body. The TG-enriched HDL undergoes lipolysis and becomes smaller and more dense. There is a resulting low level of available HDL and a high level of small dense LDL, i.e., dyslipidemia or high cholesterol.[19]

In addition, insulin resistance can interfere with the process of creating new fatty acids within the liver so the even when insulin signaling is reduced the liver continues to produce fatty acids.[20] This results in increased production of free fatty acids and the accumulation of fat within the liver.[21] Individuals with PCOS therefore have increased risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD),[22] a spectrum of liver-related or hepatic diseases characterized by increased fat content within the liver (also known as MAFLD, NAFLD, NAFL and NASH).

Androgen excess, insulin resistance, hyperinsulinemia and hyperglycemia contribute to hypertension or high blood pressure through a number of mechanisms:[23]

Androgen excess may directly affect both the properties of the arterial walls and the process of plaque build up;[24]
Insulin resistance stimulates the sympathetic nervous system, increasing glucose metabolism in the brain’s arcuate nucleus, leading to increased heart rate and narrowed blood vessels;[25]
In individuals with insulin resistance, hyperinsulinemia may decrease the production of nitric oxide resulting in constriction of blood vessels;[26] and
Hyperinsulinemia and hyperglycemia promote reabsorption of sodium by the kidneys,[27] leading to increased salt in the blood, increased fluid retention and increased blood pressure;[28] and
Androgen excess and insulin resistance are believed to contribute to an elevated aldosterone level[29] (around 30% of individuals with PCOS have hyperaldosteronism)[30] resulting in salt and water retention and therefore increased blood pressure.[31]

Individuals with PCOS are therefore at increased risk of developing metabolic syndrome (MeTS), the incidence of hypertension (high blood pressure), hyperglycemia (high blood sugar), dyslipidemia (high cholesterol) and central adiposity (accumulation of fat around the waist);[32] the incidence of MeTS in individuals with PCOS is believed to be as high as 33%.[33]

These metabolic markers are also risk factors for cardiovascular disease (CVD), including:[34]

Aortic disease, weakening or other disruption to the aorta, the largest blood vessel that carries blood from the heart to the body;
Coronary heart disease, where the flow of oxygen-rich blood to the heart is reduced;
Peripheral arterial disease, where there is a blockage in arteries to the legs or arms; and
Stroke, a cardiovascular event where there is interference to the blood flow to the brain resulting in death of brain cells[35][36] or mini-stroke (transient ischaemic attack), where the blood flow is temporarily disrupted.

Individuals with PCOS are at 2x the risk of a cardiovascular event such as heart attack or stroke.[37]

Overall risk factors for cardio-metabolic health include:[38]

Insulin resistance;
Hypertension (high blood pressure);
Hyperglycemia (high blood sugar);
Dyslipidemia (high cholesterol);
Increasing age;
Family history of cardio-metabolic disease before the age of 55 in male relatives and/or 65 in female relatives;
Being from a high-risk ethnic background (aboriginal, South Asian or black);
Use of tabacco;
High alcohol consumption;
Central adiposity (measured by waist circumference);
High inflammation (measured by high sensitivity C-reactive protein level);
Lack of consumption of fruits and vegetables;
Sedentary lifestyle; and
Psychosocial stress, stress induced by situations of social threat including social evaluation, social exclusion and achievement situations claiming goal-directed performance.[39]