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
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.
If a woman is not seeking to get pregnant, PCOS is often treated with hormonal contraceptives. The goal in treatment is to decrease hyperandrogenism and to address the negative effects of PCOS on the endometrium of the uterus.
Typically, hormonal contraceptives contain a low dose of estrogen and progesterone, and are taken for 3 weeks, with one week off for a "withdrawal bleed". The estrogen and progesterone act to restore normal negative feedback regulation and lower LH secretion. This is often sufficient to reduce hyperandrogenism and its associated symptoms.
Hormonal contraceptives are also useful for preventing uterine
problems. In untreated PCOS, the endometrium experiences unopposed
estrogen: that is, high levels of estrogen with no
progesterone, because the cycle doesn't advances to the luteal
phase. Recall that estrogen stimulates endometrial
proliferation, while high levels of progesterone (as occur
during the luteal phase) will stop proliferation and promote
endometrial secretion. Long stretches of unopposed
estrogen will promote too much endometrial proliferation,
causing the woman to have menorrhagia (excessive
menstrual bleeding). Increased stimulation of endometrial
proliferation (as occurs in PCOS) also increases a woman's risk
for the development of endometrial
If the woman is seeking to get pregnant, the first line of therapy is treatment with clomiphene. Clomiphene is a selective estrogen receptor modulator (SERM), which means that it binds to the estrogen receptor, and acts as either an agonist or an antagonist depending on the tissue. In the hypothalamus and anterior pituitary, clomiphene acts as an estrogen antagonist. It prevents the negative feedback effect of estrogen, thus allowing FSH secretion to increase so that follicle development can be stimulated.
The aromatase inhibitors letrozole and anastrozole are approved for the treatment of breast cancer in post-menopausal women. These drugs are not approved for ovulation induction, but in off-label use have been found to be an effective treatment. These drugs prevent the conversion of androgens to estrogens. Just as clomiphene does, aromatase inhibitors work to induce ovulation by limiting estrogenís negative feedback inhibition of gonadotropin secretion. The difference is that they do so by preventing estrogen formation, rather than antagonizing the estrogen receptor.
A potential advantage of aromatase inhibitors over clomiphene
is that they have a shorter half-life, allowing normal estrogen
action later in the cycle. In the mid-follicular phase, negative
feedback from estrogen limits gonadotropin secretion so that
only a single follicle becomes dominant. Thus, ovulation
induction with aromatase inhibitors should have less risk than
clomiphene for inducing multiple ovulations. As well, the
shorter half-life allows more estrogen stimulation of
endometrial development during the proliferative phase in the
uterus. A study published in the New England Journal of
Medicine in 2014 found that ovulation induction with letrozole
resulted in more live births compared to clomiphene (27.5% vs.
19.1%). More studies are needed to compare aromatase
inhibitors with clomiphene.
This treatment approach addresses the problem of insulin resistance. Studies have shown that early interventions to improve insulin sensitivity can help prevent or slow the development of type 2 diabetes mellitus. Interestingly, increasing insulin sensitivity also seems to help improve ovarian function. Weight loss improves insulin sensitivity, and can also restore normal ovulatory cycles in some women with PCOS. Metformin is an insulin sensitizing drug that is sometimes used to treat PCOS. Studies show that in women who are insulin resistant, metformin is apparently safe and effective in lowering insulin and androgen levels, and may increase ovulation. However metformin is not recommended as a first-line therapy for ovulation induction.
In some women, clomiphene and other treatments are not successful at inducing ovulation. In this case, exogenous FSH is needed to stimulate follicle development. The first treatment developed was menotropin, a mixture of gonadotropins purified from the urine of menopausal women. (Can you think why this would be a particularly rich source of FSH and LH?) Although menotropin contains LH, it is really the FSH that is important for stimulating ovulation in women with PCOS. Urofollitropin is FSH purified from menopausal urine. More recently, purified recombinant FSH (follitropin) has been produced.
Treatment with gonadotropins is more expensive, and involves more risk. One problem is that high levels of FSH may induce multiple ovulations and cause higher order pregnancies (i.e. twins or triplets) which are risky for the mother and the developing fetuses. Another problem is ovarian hyperstimulation syndrome, a dangerous condition that arises when the ovary is stimulated so that multiple follicles mature. During ovarian hyperstimulation syndrome there is an increase in vascular permeability that leads to edema, nausea, and abdominal pain. If severe, it can result in clotting abnormalities, respiratory distress, and renal failure. Because of the risk of ovarian hyperstimulation, a woman treated with gonadotropins needs to be carefully monitored with transvaginal ultrasound (to monitor the number of developing follicles) and for excessive increases in estrogen secretion.
Ovarian surgery is another approach that can be used in women
for whom clomiphene treatment is unsuccessful. There are
different techniques, but they all involve inducing damage to
ovarian tissue. The hypothesis is that a small amount of damage
to the ovary works to break the cycle of excessive androgen
production and abnormal negative feedback. While there are risks
involved with surgery, an advantage is that there is no risk of
ovarian hyperstimulation syndrome or multiple pregnancy.
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)
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