PCOS and Hormonal Health

How does PCOS affect hormonal health?

According to a 2023 study on the Metabolic and Biochemical Profile in Women with PCOS, PCOS was associated with elevated androgens, elevated LH/FSH ratio (luteinizing to follicle stimulating hormone ratio), higher TSH (thyroid stimulating hormone), increased estrogen and hyperprolactinemia.

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 Hormonal 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]

At the start of each menstrual cycle, this elevated level of GnRH triggers the pituitary gland to produce an elevated level of Luteinizing Hormone (LH), one of 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][4][5]

This overproduction of LH results in a higher ratio of LH to Follicle Stimulating Hormone (FSH), the other key hormone playing this role (know as a higher “LH/FSH ratio”).

This hormonal imbalance associated with PCOS can interfere with the follicular phase of the menstrual cycle, resulting in no one single dominant mature egg or ovum developing:[6][7]

Between day 6 and 14 of the menstrual cycle, FSH causes follicles, small sacs of fluid in your ovaries that contain a developing egg or oocyte, in one ovary to begin to mature;
Between day 10 and 14, a dominant follicle emerges that out-competes the other follicles for FSH;
This dominant follicle then secretes inhibin that reduces FSH production in effect “turning off” neighboring follicles;[8]
This mature follicle develops into a fully mature egg, within what is now known as a Graafian follicle² and reaches up to 2.5 cm in diameter;[10]
Instead, in individuals with PCOS, an elevated level of GnRH in individuals with PCOS can result in over-production of LH,[11] so that follicle development stalls at the antral phase (2-9 mm in diameter)[12] and no dominant follicle emerges;
In some individuals with PCOS these immature follicles can accumulate and remain as several small follicles often referred to as a “string of pearls”,[13] hence the naming of the condition as polycystic ovarian syndrome (PCOS).[14]

The hormonal imbalance can also interfere with the process of ovulation itself:[15][16]

In a typical cycle, the Graafian follicle moves towards the surface of the ovary and, at around day 14, the mature follicle produces sufficient estradiol to trigger an LH surge which kicks off the steps towards ovulation; and
In an individual with PCOS none of the small immature follicles is typically capable of growing to a size that would be sufficient to trigger this LH surge.[17]

Due to the increased numbers of preantral and small antral follicles, the cumulative production of Anti-Müllerian Hormone (AMH) from their granulosa cells increases.[18] AMH plays a crucial role in slowing the depletion of ovarian reserve as it inhibits the activation of immature follicles.[19]

As a result, PCOS is associated with anovulation and oligo-ovulation (sporadic ovulation).[20] In a regular menstrual cycle the LH surge at ovulation would cause the corpus luteum, the structure left once the mature egg is released, to produce more progesterone, a hormone needed to support the early stages of pregnancy including implantation.[21][22][23] As a result,individuals with PCOS often have a low level of progesterone.

An elevated LH level also leads to increased stimulation of theca cells, a type of cell within the ovary that plays an essential role in fertility.[24] 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,[25] to two androgens or sex hormones (androstenedione and testosterone).[26][27]

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,[28] and are converted to estradiol, a form of estrogen, a sex hormone responsible for triggering egg release and thickening the lining of the uterus.[29]

Some of these excess androgens are not converted and therefore lead to an androgen-rich environment within the ovary[30] and an elevated level of circulating androgens. As a result, PCOS is associated with hyperandrogenism (HA) or androgen excess (AE), an elevated level of 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).[31] 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.[32]

Insulin resistance can lead to an accumulation of fat in the liver (hepatic steatosis).[33] This buildup of liver fat triggers inflammatory factors and suppress the production of Sex Hormone-Binding Globulin (SHBG),[34] a hormone that transports androgens and estrogens in the blood and controls their access to tissues in the body.[35]

An elevated level of androgens in peripheral tissue such as adipose tissue (body fat) are converted to estrone, a different form of estrogen.[36] Insulin resistance and the corresponding depressed level of SHBG can compound the effect of this elevated estrogen level.[37] In some individuals with PCOS, the elevated level of estrogen to progesterone leads to a condition called estrogen dominance or unopposed estrogen, causing cell overgrowth in the lining of the uterus.[38]

The HPO axis is intimately intertwined with the system of hormones that connects the hypothalamus, the pituitary and the adrenal gland (the HPA-axis).[39] The pituitary gland (the “P” in the HPO and HPA axis) is a pea-sized gland at the base of the brain that plays a central role in regulating hormones that control vital functions in the body.[40] In addition to LH and FSH, this gland produces adrenocorticotropic hormone (ACTH).[41] The adrenal glands (the “A” in HPA axis) are small triangular organs at the top of the kidneys which, in response to ACTH, produce cortisol, a hormone that helps regulate your stress response.[42]

In individuals with PCOS the HPA axis is overactive due to a number of different mechanisms, including:

Elevated androgens can accelerate the breakdown of cortisol and cause the adrenal glands to produce more ACTH and stimulate the production of more cortisol to maintain a normal level;[43]
Hyperinsulinemia (high insulin) also activates ACTH;[44]
Hyperglycemia (high blood sugar) also activates ACTH and creates a vicious cycle as elevated cortisol raises blood sugar;[45]
Low-grade inflammation (due to a normal of mechanisms in individuals in PCOS) triggers the stress response in an effort to control this inflammation and, over time, inflammation can cause the body to become resistant to its anti-inflammatory effects;[46]
Visceral fat, particularly around the abdomen (central adiposity), has a higher concentration of cortisol receptors and 11β-HSD1 enzymes (enzymes that convert inactive glucocorticoids into active forms like cortisol)[47] and therefore regenerates cortisol locally;[48] and
The burden of disease associated with PCOS results in increased underlying stress and risk of developing mental health conditions.

Another hormone produced by the pituitary gland is prolactin, a hormone that plays a role in fertility and sexual function as well as stimulating breast milk production after birth.[49]

In roughly a third of individuals with PCOS, the prolactin level is elevated.[50] Elevated prolactin is also a contributory factor in infertility since they reduce the number of ovarian follicles and reduce the likelihood of ovulation (hence we typically don’t conceive during the post-partum period when breastfeeding).[51]

Another 13-14% of individuals with PCOS may experience low prolactin (hypoprolactinemia).[52] Low prolactin is a contributory factor in some of the symptoms of PCOS, including irregular periods, sexual dysfunction, hair and skin changes, fatigue and mood changes.[53] Low prolactin can also cause challenges with breastfeeding.[54]

The pituitary gland also produces thyroid-stimulating hormone (TSH), a hormone that regulates the activity of the thyroid gland.[55]

PCOS is linked to increased production of TSH but the level is typically within what is considered the normal range (euthyroid state).[56] A large study demonstrated that the TSH level is correlated with hyperandrogenism (high androgens).[57]

Individuals with PCOS have a higher risk of developing thyroid disorders, although hypothyroidism (low thyroid activity) is almost 3x as common as hyperthyroidism (high thyroid activity).[58]

Overall risk factors for hormonal health include:[59][60]

Tumors, adenomas (noncancerous tumors) or damage to endocrine glands;
Autoimmune conditions;
Stress;
Certain medications, including steroids; and
Exposure to certain chemicals known as endocrine disruptors through pollution, workplace exposure or through cosmetics, food or household products.[61]