Polycystic ovary syndrome


Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. Its prevalence among women of reproductive age is estimated to be between 5-10%. PCOS is classified as a syndrome because it is a heterogeneous disorder: not all of the women with PCOS will express all of the symptoms associated with the disorder.

A diagnosis of PCOS is made if a woman has chronic problems with ovulation coupled with hyperandrogenism (excess secretion of androgens). Problems with ovulation will manifest themselves as amenorrhea (lack of menstruation) or oligomenorrhea (irregular menstruation). Hyperandrogenism may cause hirsutism, which is a masculine pattern of hair growth on the body, and acne, because androgens have an effect on the sebaceous glands of the skin that promotes acne. Androgens may also cause hair loss on the scalp.

PCOS gets its name from the changes seen in the ovary (although not all women with PCOS have polycystic ovaries). Polycystic ovaries are enlarged and contain multiple (greater than 10) immature follicles. The immature follicles show a relative hyperplasia of theca cells, and fewer granulosa cells. Development of these follicles is arrested well before the point of dominant follicle selection, so the LH surge doesn't occur, and therefore, neither does ovulation.

There are also metabolic disturbances associated with PCOS. Frequently, women with PCOS are found to be insulin resistant. Because insulin resistance is a decreased sensitivity to insulin, this means that more insulin is necessary to achieve the same effect. For this reason, individuals who are insulin resistant have higher levels of insulin secretion or hyperinsulinemia. Because women with PCOS are insulin resistant, they are at a greater risk for developing type 2 diabetes mellitus (T2DM).  Many women with PCOS are also overweight or obese, and this contributes to their insulin resistance and risk for T2DM.

Endocrine disturbances in PCOS

Normal follicle development begins when estrogen and progesterone levels drop due to degeneration of the corpus luteum. The release from negative feedback inhibition allows a small but steady increase in FSH and LH levels that stimulates the growth phase for a group of follicles. In the early follicular phase, granulosa cells respond to FSH only, while theca cells respond to LH. The hormonal interactions in the early follicular phase are shown in Figure 1.

The cause of PCOS is not at all clear, but one consistent observation is that there is an imbalance in gonadotropin production. LH secretion is elevated, while FSH secretion is the same, or even decreased. LH stimulates theca cell proliferation and secretion of androgens, but there is insufficient FSH to stimulate granulosa cells. Recall that production of estrogen by the ovary requires the activity of the enzyme aromatase that is expressed in granulosa cells. The result is high levels of androgens secreted from the ovary (hyperandrogenism), and a failure of follicle development to progress.

Figure 2 depicts how the endocrine disturbances in PCOS become part of a vicious cycle, where the abnormalities are reinforced. The androgens secreted from the ovary are converted to estrogen because certain body tissues (in particular, adipose tissue) express aromatase. This continuous level of estrogen causes abnormal feedback regulation of gonadotropin secretion, such that LH secretion continues to be high relative to FSH secretion. Hyperinsulinemia contributes to the problem because insulin stimulates ovarian androgen production.

Treatments for PCOS

Hormonal contraceptives


Aromatase inhibitors

Insulin sensitizers


Ovarian Surgery

For those who are interested, here is the reference for the study comparing letrozole to clomiphene for ovulation induction.

Legro, R.S. et al. (2014) Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome. New England Journal of Medicine 371: 119-129 (link)

URL:  http://www.nejm.org/doi/full/10.1056/NEJMoa1313517

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