Inducing Ovulation in PCOS: Dr. Kimberley Thornton
Women with polycystic ovarian syndrome (PCOS) often suffer from infertility due to irregular ovulation. There are several medications which help induce ovulation as a first line treatment for infertility.
Polycystic ovarian syndrome (PCOS) is one of the most common gynecological disorders and is estimated to impact 6-15% of women. The Rotterdam criteria, which is used by most gynecologists to diagnose the disorder, characterizes women with PCOS as having 2 out of the following 3 criteria: (1) hyperandrogenism, (2) oligoamenorrhea or amenorrhea, and (3) polcystic ovaries on ultrasound. Hyperandrogenism can be diagnosed by clinical findings such as hirsutism (excessive hair growth on face or chest) and acne or through serum hormone measurements of testosterone and DHEAS. Oligoamenorrhea means a woman has infrequent menstrual cycles or some women with PCOS do not get their menstrual cycles at all which is called amenorrhea. Polycystic ovaries on ultrasound are defined as 12 or more follicles (small fluid pockets containing eggs) on at least one ovary or an ovarian volume greater than 10 cm3. PCOS is considered a diagnosis of exclusion, meaning all other possible disorders that could have similar presentations must be ruled out. To date, we do not know what causes PCOS and why it affects some women but not others.
Many women with PCOS suffer from infertility largely due to irregular ovulation or anovulation. All women are born with every egg they are ever going to have at birth. These eggs are stored in the ovary and are immature, meaning they do not have the ability to fertilize. When a woman gets her menstrual cycle each month, the pituitary in her brain releases hormones called FSH and LH that signal the ovary to start growing an egg. From the pool of eggs stored inside in the ovary, the female body releases a group of eggs in fluid filled pockets called follicles to the surface of the ovary. The female body then typically only releases enough hormones for one of those follicles to continue to grow or become the “lead follicle” and for the egg inside to mature and ovulate. As humans we are not designed to have 5 or 6 babies like puppies or kittens, so typically the ovary discards all the other follicles and potential eggs that it had started to grow that cycle. Either a pregnancy occurs or if it does not, this cycle starts all over again with the next menstrual cycle. In women with PCOS, the group of follicles is released to the surface of the ovary, but in a sense the follicles almost get “stuck” at that stage. The endocrinologic dysfunction prevents the “lead follicle” from growing and ovulation often occurs at irregular intervals or does not happen at all. A woman is only fertile the few days around the time of ovulation each cycle. Therefore, if ovulation is occurring infrequently this presents as less opportunities to be able to conceive and makes it difficult for most couples to time intercourse to maximize chances of conception. Given this, ovulation induction or the process of inducing ovulation to occur on a regular basis with medications is typically first line treatment for women with PCOS who are experiencing infertility.
Letrozole is considered the first line treatment for ovulation induction in women with PCOS. It is a pill medication that is taken once a day for 5 days shortly after a menstrual cycle begins (cycle day 2-5). Letrozole is an aromatase inhibitor, which means it blocks the enzyme aromatase which turns androgen hormones into estrogen. This temporarily lowers estrogen levels. Since the ovary and eggs produce estrogen, the pituitary senses this drop in estrogen level and secretes more FSH which stimulates the ovary to grow a lead follicle and can induce ovulation. We typically monitor a woman while she is on Letrozole and bring her in for a mid-cycle ultrasound to confirm that a lead follicle has grown. Letrozole has been shown to have higher ovulation rates and live birth rates compared to Clomid in women with PCOS and is why it is considered first line therapy. Hot flashes are a common side effect while taking this medication. Letrozole can induce more than one lead follicle to grow which can increase the risk of a twin pregnancy. Studies have shown a 3.4% risk of twins in women taking Letrozole.
Clomid is one of the oldest fertility medications on the market and was traditionally first line treatment for ovulation induction for PCOS prior Letrozole. It is also a pill medication taken once a day for five days shortly after a menstrual cycle begins (cycle day 2-5) like Letrozole. Clomid is a selective estrogen receptor modulator (SERM) that has both anti and pro estrogen activity at different tissues. It blocks estrogen receptors in the hypothalamus which essentially tricks the brain into thinking the body is not making enough estrogen. This causes the pituitary to secrete more FSH which in turn stimulates the ovary to grow a lead follicle similar to Letrozole. We also typically monitor a woman with a mid-cycle ultrasound to confirm a lead follicle has grown and to check the uterine lining with Clomid. Some women develop a thin uterine lining from Clomid since it has anti-estrogen properties in the uterus. A thin lining may require estrogen tablets or being switched to Letrozole for future cycles. Clomid commonly causes hot flashes and increases the risk of a twin pregnancy. Studies have shown a 7.4% risk of twins in women taking Clomid.
Gonadotropins are injectable medications that contain the hormones FSH and LH. They can be used to induce ovulation in women with PCOS, but have high rates of higher order multiples and ovarian hyperstimulation syndrome. Women with PCOS are very sensitive to gonadotropins and it is difficult to control how many eggs will grow with this treatment. Given this, these medications are typically only used in women who have not responded to both Clomid and Letrozole. Many times, a physician may recommend that a women go directly to IVF if they do not respond to Clomid and Letrozole to reduce the risk of higher order multiple gestations.
Metformin is an insulin sensitizing agent that has been used in the past to promote ovulation in women with PCOS. Metformin has been shown to be significantly less effective than Clomid and Letrozole at achieving a live birth. It is now only recommended for use in women with PCOS who have glucose intolerance.