What is PCOS?
Polycystic ovarian syndrome (PCOS) is a leading cause of oligomenorrhea (infrequent menses) and amenorrhea (lack of menses) in women. It is a complex condition consisting of metabolic, hypothalamic, pituitary, ovarian and adrenal interactions with both environmental and genetic factors playing a role in its development. It is characterized by anovulation, excess androgen production and insulin resistance. Follicle stimulating hormone (FSH) and luteinizing hormone (LH) are still produced by the pituitary, but the normal cycle of pulsed secretions is disrupted. Ovarian follicles develop and estrogen is produced, but the follicles never full mature and no ovulation occurs.
Pathophysiology of PCOS
As we mentioned above elevated androgen production and insulin resistance are common features of PCOS. First, we will discuss how elevated androgens affect ovulation and menstrual irregularities. Then, we will discuss how insulin resistance affects the menstrual cycle.
In women with PCOS there is altered hypothalamic-pituitary-ovarian activity. The pulsatile secretion of gonadotropin releasing hormone (GnRH) is altered leading to increased LH secretion by the pituitary. There are two cells in the ovary – theca cells and granulosa cells. LH preferentially stimulates the theca cells to produce androgens. Normally, these androgens would travel to the granulosa cells in the ovary to be converted to estrogen under FSH stimulation. However, the excess LH stimulation generates an imbalanced amount of androgens in comparison to estrogen. The estrogen never becomes elevated enough in the late follicular phase to stimulate an LH surge for ovulation. The hyperandrogenic state in the ovary as well as the lack of ovulation, increases the risk of follicles turning into cysts. Without ovulation, there is no corpus luteum formed producing higher levels of progesterone. This leads to estrogen excess in comparison to progesterone.
Elevated insulin leads to altered hypothalamic function, so FSH and LH are not secreted properly. More LH is secreted, which increases the activity of enzymes in the ovary responsible for producing androgens. Higher insulin levels also decreases production of sex hormone binding globulin (SHBG) in the liver. SHBG is a protein that can bind to sex hormones to inactivate them. The lower levels of SHBG increase the amount of free testosterone in the system, which is responsible for signs of androgen dominance like abnormal hair growth and acne. Elevated androgens in women can, in turn, also increase insulin levels.
PCOS Menstrual Cycle vs. Normal Menstrual Cycle
During the follicular phase (day 1-14) of normal menstrual cycle there is a higher amount of FSH that stimulates follicle development in the ovary. The mature follicle produces increasing estrogen, which will help to stimulate an LH surge. This surge around day 14 stimulates the release of an egg from a mature follicle (ovulation). The ruptured follicle then turns into the corpus luteum, which will produce higher amounts of progesterone during the luteal phase (day 14-28).
In PCOS, there are higher levels of LH. This prevents normal follicle development and there is no surge in LH mid cycle to stimulate ovulation. LH also stimulates androgen production in the ovary, which can also be converted to estrogen by an enzyme called aromatase. Without ovulation, there is no corpus luteum producing higher amounts of progesterone.
PCOS is a complex condition and is often a diagnosis of exclusion for women have oligo-ovulation once other disorders have been excluded. The set of diagnostic criteria used most commonly is the Rotterdam Criteria – PCOS can be diagnosed if it has 2 out of 3 features: oligo/anovulation (irregular or no ovulation), hyperandrogenism (elevated androgen hormones), and appearance of polycystic ovaries on ultrasound.
Other conditions that cause oligo- or anovulation must also be ruled out. These include pregnancy, thyroid disorders, ovarian failure, hyperprolactinemia, functional hypothalamic amenorrhea, and hyperandrogenism from a tumor or congenital adrenal hyperplasia. Blood testing measuring beta human chorionic gonadotropin (BHCG), FSH, LH, thyroid stimulating hormone (TSH), prolactin, total and free testosterone, dehydroepiandrosterone (DHEA) /dehydroepiandrosterone-sulfate (DHEA-S), and 17-hydroxyprogesterone (17-OHP) can be helpful in ruling out or diagnosing these other conditions.
Anti-Mullerian hormone (AMH) is often elevated in PCOS. This is not specific to PCOS, however, as it can also be elevated in women without the condition. An elevated AMH level in PCOS is indicative of a higher number of follicles arrested in the pre-antral and antral stages that fail to ovulate.
Although insulin resistance is not part of the diagnostic criteria for PCOS, it is highly prevalent in women with PCOS. In order to get a snapshot of a patient’s glycemic status, it can be helpful to at least get a fasting glucose, insulin and hemoglobin A1c.
Obesity and PCOS
There is a preconception that women with PCOS are overweight. While it is true that elevated BMI can increase your risk of/exacerbate PCOS, it is not a pre-requisite for having the condition.
Fat cells can produce their own hormones and cytokines. Having higher body fat, especially visceral adiposity, can therefore increase the risk of developing or exacerbate insulin resistance.
The two main androgenic hormones causing symptoms in PCOS patients are testosterone and androstenedione. There are other androgens in our bodies though like DHT, DHEA and DHEA-S. The adrenal glands produce all of the DHEA-S and about 80% of the DHEA in the body. They also produce about half of the androstenedione and about ¼ of the of the circulating testosterone. While insulin resistance and elevated insulin often drive the ovarian production of testosterone, it is the hypothalamus-pituitary-adrenal (HPA) axis that stimulates the production of DHEA/DHEA-S. These hormones can be converted to testosterone by peripheral tissues in the body. This process can occur independently from the ovaries and insulin resistance and is driven by stress. The pituitary gland secretes adrenocorticotropic hormone (ACTH) in response to stress. ACTH then stimulates the adrenal glands to produce cortisol, adrenaline, and noradrenaline. In addition to these stress hormones, ACTH stimulates the production of adrenal androgen hormones like DHEA/DHEA-S. Measuring not only testosterone, but also DHEA/DHEA-S can be helpful in identifying the underlying mechanism of hyperandrogenism.
Inflammation & PCOS
Chronic low-grade inflammation has emerged as another potential driver or exacerbating factor in PCOS. In PCOS patients, markers of inflammation and oxidative stress are highly correlated with circulating androgens. Inflammatory triggers can stimulate ovarian theca cell enzymes responsible for androgen production.
It is best to work with a doctor who can personalize a diet, lifestyle, and supplement/medication plan for your unique needs. Below are some examples of commonly used supplements that can be helpful as part of a holistic treatment plan for PCOS.