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Good Day to All,

Now a bit more about Letrozol (also known as Femara). Letrozol and Clomid have the same end result: ovulation, but they go about it in a much different way. Letrozol acts by decreasing the body’s ability to make estrogen, whereas with Clomid estrogen is produced but its actions are blocked.

Letrozol is an aromatase inhibitor. Aromatase is the enzyme that makes estrogen. Now there are many steps to making estrogen, but aromatase is the last and most important step. Aromatase takes testosterone and slightly changes it to become estrogen. Yes, women have some testosterone, but men have more. To me it’s amazing that testosterone and estrogen, two hormones that are so different, are just one step away from each other. Nevertheless, that’s the case and the system somehow works.

As Letrazol inhibits the formation of estrogen, estrogen levels fall. And this helps women become pregnant? Crazy as it sounds that answer is yes, and this happens in a way similar to the workings of Clomid. Once again, the brain sees no estrogen (this time because there really is very little). The brain reacts, and puts out more FSH to stimulate the ovary to make estrogen, which the ovary can only do my making a follicle, that just so happens to contain an egg. Just as with the Clomid, the follicle grows, the egg matures and ovulation usually comes next.

How can you get pregnant if you are taking a drug that is blocking (Clomid) or eliminating (Letrozol) estrogen? You do not need estrogen to ovulate. Estrogen is a buy-product of the growing follicle. The reason estrogen is made by the follicle is so that the lining of the uterus (the endometirum) can grow. And yes you need the endometrium, but for most women only a small amount of estrogen is needed to get a good lining. Plus, the aromatase inhibitors do not make the estrogen go to zero, and Clomid does no completely block estrogen. These drugs may cause the endometrium to see much less estrogen than usual but enough gets through for adequate growth.

In addition, Letrazol and Clomid are only taken for 5 days, usually until day 7-9. This leaves 5-6 days for the follicle to grow a bit more and produce more estrogen, all while the drugs are leaving the body.

There are some differences in the negative effects between Clomid and Letrozol. Clomid has a long half life meaning it stays in the body for days after the last dose. Its half life is 5-7 days, so blood levels go up and up each day the pill is taken and significant amounts are present around ovulation. Therefore conditions around the time of ovulation can be effected by the Clomid i.e. the cervical mucus can be too thick and the lining of the uterus can be too thin. The half life of Letrozol is shorter.

The good news is that for most women these drugs work quite well. We do not know why some women have more side effects than others. Subtle genetic differences between women lead to very subtle differences in the shapes of one or more of the proteins involved in binding.

Letrozol also has fewer mental side effects. Common Clomid side effects include headaches, hot flashes, depression, seeing spots, jitteriness, trouble sleeping, and there are a few others. Letrozol does not cause as many of these symptoms.

If Letrozol seems to be better for the mucus, lining of the uterus, and has fewer side effects, why don’t we use it as our first line of therapy over Clomid? This requires a little more discussion which will come in the next entry.

Thanks for reading and don’t forget the disclaimer 5.17.06.

Dr. Licciardi


  • Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J, Librach C, Greenblatt E, Casper RF. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril. 2006 Jun;85(6):1761-5.
  • Fisher SA, Reid RL, Van Vugt DA, Casper RF. A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women. Fertil Steril. 2002 Aug;78(2):280-5.
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