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Clomiphene vs Letrozole


Today we're going to be talking about some medicines that many of you are familiar with. They are Clomid and Letrozole. I'm going to be talking about the mechanisms of actions of both of those, but first you should know that 40% of infertility is due to ovulation dysfunction, a disorder of ovulation. Many of those are polycystic ovarian syndrome patients. Clomid has been around since the early 1970-s, and the newcomer Letrozole has been around and in use since the late 1990-s.

Should you use one or the other? Well, your doctor is the best one to make that decision for you based upon your age, your height, your weight, your ovarian reserve and other factors. So, let him or her make that decision for you, but I'm going to talk a little bit about Clomid first, then Letrozole. I'm going to go over the mechanisms of action.


Clomid is prescribed usually in the dosage of 1-2 tablets a day.  Then you would use an ovulation prediction kit or have an ultrasound, whatever your doctor decides, and you'd time your relations.

So, let's talk about Clomid. Clomid is an oral medication. It's inexpensive. It's readily available, and it has very few side effects. Probably one in five women might have some side effects in terms of its anti-estrogen ability, meaning some hot flashes or night sweats, or vaginal dryness for the first couple of days. Then those symptoms might flip completely as the estrogen rises and doubles over normal. Clomid will cause ovulation for 70-80% of women, and 30-40% of those women will actually conceive.


Letrozole is also an oral medication. It's less available and certainly more expensive. So, why would one take Letrozole over Clomid? The chance of having twins is 0.9%, less than 1%, whereas the chance for twins with Clomid is 7-8%. I have even had a couple of triplet pregnancies on Clomid. I'm not trying to scare you, but it is possible. 

Drugs Mechanism

Now, a little bit about the mechanism. This is something that you can use in your next cocktail party and amaze your friends. So, Clomid or Clomiphene, actually, blocks estrogen receptors at the hypothalamus and at the pituitary. Estrogen is made by the granulosa cells. Estrogen feeds back to the pituitary and to the hypothalamus, the area that controls the pituitary. But it's blocked out by Clomid. So, even though the estrogen level might be normal, the brain is sensing low estrogen. It sends out a signal increasing the follicle stimulating hormone. Follicle-stimulating hormone will then come down and increase the number of granulosa cells or even cause one of these lessor follicles to develop the possibility for twins. So, you'll stop taking the Clomid, and then we would anticipate ovulation some days thereafter. You might use an ovulation prediction kit, or you might even use a shot of the ovulation trigger HCG to cause that egg to release.

So, now I would like to tell you about the mechanism of Letrozole. It is an oral medication taken for five cycle days. Luteinizing hormone and other hormones produce androgens like testosterone and androgens in the cells outside of the follicles. Curiously, these androgens have to get across the granulosa cells to be converted into estrogens. We use that step as the basis for this particular drug’s mechanism.

So, testosterone is converted through the granulosa cells to the biologically most potent estrogen called estradiol. So, Letrozole works on these steps. Letrozole is a so-called aromatase enzyme inhibitor. Now, aromatase is the enzyme found throughout the body that converts androgens and estrogens. So, we take advantage of that fact, and what happens is that we don't get the normal amount of estrogen feeding back to the pituitary, because we've shut that down, and we're getting a smaller amount of estrogen feeding back, and so, the brain perceives too little estrogen. Much like the Clomid mechanism, when there's too little estrogen, there's more in the way of follicle stimulating hormone. Here, this will come down, and stimulate these cells, but we, typically, don't get a second follicle emerging. So, the twin rate is about 1% or less.

Clomiphene vs Letrozole

So, that is the mechanism of Letrozole. It works on the granulosa cells, not in the brain and pituitary and the way Clomid does.

Another couple things we talked about Clomid being an anti-estrogen and that means that it has an anti-estrogenic effect on the lining to the uterus and on cervical mucus. Sometimes that can act against conception, Letrozole does not do that, and locally there's sufficient estrogen with Letrozole to have a thick and more hospitable lining.

One other important difference is that if you were to take a tablet of Clomid right now, then it could still be found in your body 5-6 six weeks from today. If you were to take Letrozole, however, it would be completely out of your bloodstream in days, and it's completely out of your body by the time that the embryo makes its way into the uterus.

So, these medications are not associated with an increased risk in birth defects. Letrozole has about half the rate as Clomid, but Clomid is still within the normal background population in terms of birth defects.

So, the ultimate decision about whether to use Clomid or Letrozole is up to your doctor, he or she will know what's best for you. Oftentimes, in a Clomid or Letrozole there will be performed other tests in that same month. A very common test is a post-coital test. A post-coital test looks at the interaction between the sperm and the cervical mucus.

Some years ago as I first started practice and we did a post-coital test. First thing, in the afternoon, it was a one o'clock appointment, and this was the absolute best post-coital test we'd ever seen. Just seeing 1 or 2 or 3 sperm is considered acceptable, but we saw literally millions, in fact hundreds of millions of sperm in that droplet.

We could not believe our eyes, and I took my senior partner side. I said: “Have you ever seen a post-coital test like this?” He said: “I really haven't.” He said: “This is amazing.” And so, I went back to ask the patient. I said: “Now, you're supposed to have had intercourse.” 12 hours ago was that. She owes: “Well, not quite that long. I said: “Well, what would you estimate? 8 hours, 10 hours are not quite that long.” “Well, 4 hours, 6 hours are not quite long.” I said: “Well, let me ask how long ago it was.” And she looks at her watch, and she says: “About 10 minutes.” And she says: “I thought it was supposed to be 10 minutes.” I said: “No, 10-12 hours.” She goes well: “That's why my husband drove his van today, and we had lunch in the van, and then after lunch a little afternoon delight.”

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