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Clomiphene: Fertile or futile?

Clomiphene is the most commonly used drug to treat infertility.

Many women struggling to get pregnant will go to their OB/GYN and receive a prescription for this drug, otherwise known as Clomid. The woman takes the pill for five days at the beginning of her cycle and is often told to return to have blood work drawn a couple of weeks later. The patient is then told to call back if they get their menstrual cycle. Unfortunately, this medication is often used incorrectly and may cause more harm than good. Let’s discuss what clomiphene is, how it works, how to use it to get the most benefit and who benefits most.

Clomiphene is a pill that is an “anti-estrogen.” It is in the same family as the well-known breast cancer drug tamoxifen and, in theory, could be used to battle that terrible disease. It works by binding to receptors for the hormone estrogen and so the body thinks that estrogen is lacking.

Sound like menopause? Many women actually suffer from hot flashes while on clomiphene. The drug works because of a gland behind your nose known as the pituitary gland. The pituitary secretes a hormone called Follicle Stimulating Hormone-FSH, whose role it is to wake up the eggs in the ovaries and push them onward in the race to become a human being. As you may know, hundreds of eggs “wake up” each month and begin a 60-70 day journey to reach maturity.

In natural conditions, only one or rarely two eggs make it to ovulation each month and that’s why it’s rare to see more than one baby or twins born without some fertility drug involved. As the eggs wake up and develop they secrete estrogen into the bloodstream that reaches and binds to the estrogen receptors on the pituitary gland. This rise in estrogen signals eggs are indeed responding to the FSH and so the pituitary slows down it’s secretion of FSH. This is called “feed-back inhibition.” If the receptors are full of clomiphene, then estrogen can’t bring the message that “we are waking up”. The pituitary never knows eggs are responding with estrogen and the gland continues to push out more FSH. In other words, clomiphene “blinds” the pituitary and tricks it into secreting more FSH, which in turn, stimulates the egg production in the ovary.

If the positive effect of clomiphene is to push the ovaries harder, who does that help? It helps people who otherwise would not ovulate at all such as patients with a condition sometimes referred to as Polycystic Ovarian Syndrome-PCOS. It is estimated that 15% of all American women of fertile age do not ovulate regularly — but I will address this in another blog.

What about women who release an egg every month? These are women who have regular menstrual cycles and may actually feel themselves ovulate each month. Can clomiphene increase their odds of conceiving? The startling reality is if you give clomiphene to women who are likely to be ovulating regularly you actually LOWER their chances of getting pregnant. The reason clomiphene reduces the odds of conception lies in the negative impact of its anti-estrogen nature. Estrogen impacts tissues other than the pituitary. Most importantly, it is responsible for thickening the lining or endometrium of the uterus in anticipation of the embryo implanting. Estrogen also makes the cervical mucous thin and favorable for sperm transport and clomiphene can block that effect. This is a crucial issue because, as you may know, birth control pills largely work by creating cervical mucous that is hostile to sperm. Nevertheless, clomiphene is frequently prescribed to women who ovulate.

Clomiphene commonly leads to more eggs being released in a treatment cycle. In fact, 1 out of every 7 pregnancy assisted by clomiphene is twins or more. It is this fact, multiple egg release that drives the use of the drug. Perhaps by causing more eggs to be released we can raise the odds of fertility. I think it is a reasonable strategy as long as you monitor the effects of the drug. In my clinic, I always follow along with ultrasounds to measure the thickness of the lining. If it is too thin, we can treat that by supplementing estrogen after the five days of clomid are finished. Also, I often use a second drug to help with the actual release of the eggs which may be affected by clomiphene. It is also important to monitor after a clomiphene cycle because another major side effect is the creation of very large ovarian cysts that can cause issues.

In my opinion, clomiphene is used so widely because it is very inexpensive compared to the other fertility medicines and because it is relatively safe. Many people do, in fact, get pregnant and benefit. However, it can be a problem if clomiphene is used month after month without ultrasound surveillance and for long periods of time. Three or four months are all that is recommended, and, in fact, some studies point to a cancer risk with long-term use.

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