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Hello Everyone,

Here we are with the latest installment of The Infertility Blog, which will discuss the differences between Clomid and Letrozole.

This one is a little medical, but I think I can get everyone through it just fine. I’ll start by saying both do the same thing, they both stimulate ovulation, but each does it in it’s own way. Both are pills, both can work great in women who are anovulatory, both work only fairly well for regularly menstruating infertile women. Let’s go over Clomid first. The generic name of Clomid is clomiphene citrate. It also goes by Serophene. Clomid is a drug that has been around since the 60’s.

In the lab it was discovered that this compound blocks estrogen. This does not sound like a good fertility drug if it’s blocking estrogen. In fact the developers thought that since it blocks estrogen , it may be a good contraceptive. Well it had the opposite effect. Why? After swallowing Clomid, it gets taken through the blood stream to all parts of the body, including the brain. The brain is important because that is where all of the control of ovulation starts. Normal ovulation can not happen without signals from the brain and pituitary gland. When Clomid, the “anti-estrogen”, gets to the brain, things start happening. More about this in a moment, first a bit about how estrogen works.

Estrogen, like all hormones, exerts its influence by landing on a receptor. A receptor is a protein either on the surface or inside the cell that recognizes a hormone and binds to the hormone. It is the receptor/hormone combination that then causes the cell to do what the hormone says to do. For example, after estrogen binds to the estrogen receptor the combined hormone/receptor can get the cervical cells make mucus for example. It’s very much like a lock and key. The estrogen is a key that only works in the estrogen lock (the estrogen receptor). Other hormones, like progesterone and testosterone, float around and then only bind with their receptors. Like a key, different hormones have slightly different shapes, and the receptors will only connect with a hormone if the hormone has the right shape.

OK, back to Clomid and the brain. When Clomid gets to the brain, because the Clomid molecule has a similar shape as the estrogen molecule, Clomid binds to the estrogen receptor. But because the shape of the Clomid molecule is not exactly the same as the estrogen molecule , the estrogen receptor Clomid combination is faulty, and can not signal the cell to do anything. Elsewhere in the body, the cervical cells will not make mucus. for example. The Clomid takes up all of the available places on the receptor so that the estrogen has nowhere to land, thus the actions of estrogen are blocked.

No estrogen, that is what the brain thinks. The brain says, “Hey, what happened, who turned off the estrogen?” So the brain tries to make more. Estrogen only comes from the ovary, with a few small exceptions, so the only way for the body to get estrogen is to stimulate the ovaries to start ovulating. This is accomplished by the brain stimulating the pituitary gland to put out bursts of FSH, which then travels through the blood stream to the ovaries and gets ovulation going. For most women, this estrogen block is not 100%. Its enough of a block to get ovulation going, but usually the Clomid can spare complete havoc the endometrium (uterine lining) and cervical mucus. In some women, but a small percentage, there is complete havoc; the cervical mucus completely dries up (overcome by insemination) and the uterine lining becomes too thin (can not be overcome). This is why some doctors give estrogen and Clomid at the same time.

It is believed that the Clomid will get the ovulation started and the given estrogen will counteract the Clomid in the uterus and cervix. I have not had much success with this method. I have found that if the Clomid creates havoc, adding estrogen does not help. Clomid works wonders for women who have irregular cycles, Clomid allow for more frequent, predictable ovulation, and this ups the odds of conception. Women with PCO are excellent candidates for Clomid because they have irregular cycles, which could be anywhere from every 35 days to every 6 months to never. Women who have irregular cycles but are not exactly PCO also have excellent results with Clomid. Women who do not get their periods due to exercise, eating disorders or other types of women with “hypothalamic amenorrhea” usually do not respond to Clomid.

This is because their brains do not respond to the Clomid because the brain knows that if there is severe stress or no food coming in, it’s not a good time to get pregnant, so even clomid will not work. We ask women to take Clomid (and letrozol) early in the cycle because we want to give the boost in FSH early so that maybe we can coax the ovary to make more than one egg that month. FSH rises from Clomid, and it’s the FSH that really does all of the work to initiate ovulation. In women who get periods every 4 months, it really does not matter if Clomid is given days 5, 10 20 or 30. We would prefer if you were not pregnant when taking Clomid (although it happens and probably not a problem), that’s why we wither give Provera to bring on a period or do a pregnancy test before you start. So that’s a little about Clomid. It works by blocking estrogen from it’s receptor. More to come next time.

Thanks for reading and please read disclaimer 5/17/06.Dr. Licciardi


  • Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in women. Fertil Steril. 2003;80(5):1302.
  • Hughes E, Collins J, Vandekerckhove P. Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev 2000; CD000057.