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(brand names Serophene, Clomid)

(brand name Femara)

Both clomiphene citrate and letrozole are medications used to treat infertile women who have an ovulation problem. These medications work by helping your pituitary gland (located at the base of the brain) improve the stimulation of developing follicles (eggs) in the ovaries. Neither clomiphene citrate nor letrozole may help a woman become more fertile if she is already ovulating normally. For that reason, these medications are most often prescribed to those patients who have been found to have an abnormality with their cycle.

Clomiphene is often referred to as the "fertility pill". Letrozole is very similar to clomiphene in the way it works. However, letrozole is quickly cleared from the body. It only works for the cycle in which it is taken and is less likely to adversely affect the uterine lining and cervical mucous. With clomiphene, one may experience effects 6-8 weeks after stopping the medication. Both medications are prescribed for five days each cycle, usually beginning on day three and continuing through day seven. The usual initial dose for clomiphene is 50 mg, one tablet daily. The number of tablets can be increased to as many as four daily, if a lesser dosage does not result in ovulation. Rarely are more than two tablets required. Clomiphene should be repeated each cycle until pregnancy occurs, or your doctor discontinues it. The usual dosage of letrozole is 2.5 mg., one tablet each day.

Of all women treated with clomiphene, or letrozole, 60% to 80% will ovulate normally. However, only half of those patients who ovulate will become pregnant. It is not known why only half of the women who apparently ovulate with clomiphene or letrozole therapy become pregnant. It is suspected that factors other than inadequate ovulation may be contributing to the fertility problem. Therefore, if you are not pregnant after three or four cycles, additional testing such as hysterosalpingogram or laparoscopy may be necessary. If you have polycystic ovary syndrome, a trial of metformin (Glucophage) therapy may be advised.

Some 10% to 20% of women taking clomiphene or letrozole will experience side effects. By far, most of these are minor and temporary in nature. They include such things as hot flashes, blurred vision, nausea, bloating sensation, and headache. Serious side effects are rarely seen with either medication. There are two side effects associated with clomiphene or letrozole therapy that warrant specific discussion. The first is the possibility of multiple pregnancy. The frequency of twins occurring in women who conceive while taking clomiphene or letrozole has been reported to be as high as 10%. Triplets may occur as frequently as 1 in 400 births, and quadruplets in 1 in 800 births. Neither clomiphene nor letrozole is the "fertility drug" you may have heard in the news bulletins often associated with large numbers of infants, such as quintuplets. Newer studies suggest that long-term use of either clomiphene or letrozole for more than 12 cycles may place you at an increased risk of developing ovarian cancer. Secondly, clomiphene and letrozole have also been associated with the occasional development of ovarian cysts. These cysts are not true growths of the ovary and within a few weeks will resolve without treatment. However, on an extremely rare occasion, these cysts have been known to cause internal bleeding or twist, requiring surgery and removal of the involved ovary. However, I must again emphasize that such a complication is extremely rare.

Clomiphene or letrozole stimulated cycles are not unlike normal cycles in that there is only a 20-25% chance of conception occurring each cycle during the first three to four treatment cycles, even if the medication is working properly. (Results may be lower with unexplained infertility.) This means that at least four to six cycles of treatment are necessary before one has given either medication an adequate trial. Recent studies indicate that if a pregnancy occurs as a result of the clomiphene/letrozole treatment, there is no clinically significant increased risk of miscarriage or congenital birth defects when compared to other infertile couples who conceived without clomiphene/letrozole treatment. However, women with polycystic ovary syndrome may be at higher risk for miscarriage during a pregnancy conceived using either of these medications.

Letrozole Protocol (Femara) (usually taken CD3-7)

What is Letrozole?

The new aromatase inhibitor, Letrozole, reversibly, inhibits the enzyme responsible for estrogen biosynthesis. By decreasing the estrogen levels in the body it may release the hypothalamus and/or pituitary from the negative feed back of estrogen on the release of gonadotropins. This will result in an increase in endogenous FSH and LH, which stimulate the development of ovarian follicles. This is similar to the proposed mechanism of action of clomiphene citrate. However, Letrozole may have another peripheral mechanism of action directly in the ovaries. Letrozole is eliminated from the body in a few days after last administration (in contrast to CC which may last up to few months). Also, it does not have a direct antiestrogen action by itself as in CC. So there should be no unwanted peripheral antiestrogen effects on the endometrium, the cervix…etc.

The commercial name of Letrozole is Femara. It is available in 2.5 & 5 mg tablets. It is a drug that was developed to inhibit the estrogen production in postmenopausal women with breast cancer. We are not using it as a chemotherapy drug. It has been tested and tolerated very well when administered continuously for several months.

Who is a candidate for Letrozole?

Patients who meet one or more of the following criteria may be offered the option of trying Letrozole for induction of ovulation:

• Failure to ovulate on clomiphene citrate.

• Ovulation with clomiphene citrate but with very thin endometrium (less than 0.5 cm)

• Ovulation with clomiphene citrate with failure to achieve pregnancy after 6 cycles.

• Severe side effects with clomiphene citrate.

The classical alternative in the above-mentioned conditions would be FSH injections. This option will be discussed with the patient first. Considering the higher expenses and inconvenience of daily injections with possible severe hyperstimulation, Letrozole may be a safe and acceptable drug to try.

What are the possible side effects?

Usually mild in the form of headache, mild gastrointestinal upsets, hot flushes and easy fatigue.


Reproductive Biology Unit - Mt. Sinai Hospital, Toronto, Ontario, Canada

Infertility Journey