Infertility Treatments > Medical > Letrozole

    Letrozole is a one of a new class of medications known as non-steroidal aromatase inhibitors. This means that it inhibits the action of an enzyme in the body called aromatase. Aromatase is the enzyme that converts male hormones (specifically androstenedione) to female hormones (specifically estrone). Letrozole use results in a decrease in the levels of estrogen. This, in turn, results in the pituitary gland increasing its production of the hormone FSH (Follicle Stimulating Hormone) in an attempt to induce the ovary to increase its production of estrogen. This increase in FSH acts as a stimulant to the ovary to produce eggs and follicles. This is how letrozole works - it increases the production of FSH and FSH is the hormone that induces the ovary to produce follicles and eggs.

    Letrozole is a non-steroidal, highly selective and reversible aromatase inhibitor. Aromatase is the enzyme that converts male hormones (androstenedione and testosterone) to female hormones (estrone and estradiol). By inhibiting the action of aromatase, letrozole lowers the levels of estrogens. If estrogen levels are lowered in the beginning of the follicular phase (the first few days after the period), the pituitary compensates by increasing the production of FSH (follicle stimulating hormone). Increased levels of FSH result in increased stimulation to the ovaries. This is the same mechanism of action of clomiphene (clomid, serophene), the first-line fertility medications that have been used for over forty years.

Letrozole does have significant advantages over clomiphene. Clomiphene is associated with significant side effects, including hot flashes, vaginal dryness, headaches, and mood swings. Letrozole is essentially side-effect free. While clomiphene use results in ovulation in 80 – 90% of patients, pregnancy rates are much lower. This seems to be due to the fact that clomiphene results in depletion of estrogen receptors. Clomiphene has a half-life of up to two weeks, and depletion of estrogen receptors results in the side-effects of clomiphene, including the adverse metabolic effects such as decreased cervical mucus production and poor development of the lining of the uterus (endometrium). Letrozole has a half-life of about 40 hours, with minimal effects on the cervical mucus and lining of the uterus.

Letrozole is approved by the FDA exclusively for the treatment of post-menopausal women with breast cancer. Use of letrozole for ovulation induction is an off-label use. Many medications are used for off-label indications, but the use of letrozole for this indication came under fire based on a small Canadian study published by Biljan. This study was poorly controlled and involved very small numbers of patients and birth defects (3). However, its suggestion that use of letrozole was associated with an increased risk of birth defects resulted in the company that produces letrozole, Novartis Pharmaceutical, issuing a letter advising that letrozole not be used for ovulation induction.

Other studies have refuted the findings of Biljan’s study. Tulandi et al compared congenital malformations among 911 children conceived with either clomiphene or letrozole. They found a rate of 2.4% in the letrozole group vs 4.8% in the clomiphene group. (The rate of congenital anomalies among children conceived without intervention is about 3%). Furthermore, they found significantly fewer cardiac anomalies in the letrozole group. Mitwally et al reported on 394 pregnancies in women treated with fertility medications, including letrozole. They too found no increased risk of congenital malformations.

Letrozole has a half-life of forty hours. When used for ovulation induction, it is completely cleared from the maternal circulation by the time of conception. This makes it very difficult indeed to understand how the use of letrozole could result in congenital malformations. There is no question that this medication should not be used during pregnancy, but it is used for ovulation induction only following the onset of a normal menses.

The motivation to use letrozole is based on the chances of pregnancy with this medication. While most patients will ovulate with clomiphene (60-90%), pregnancy rates are disappointing (10-40%). Letrozole results in higher pregnancy rates than clomiphene, has less adverse effects on the cervical mucus and endometrium, and works extremely well when used in combination with gonadotropins (FSH/LH injections). Furthermore, the multiple pregnancy rate with letrozole seems to be lower than that encountered with any other form of ovulation induction. There is actually some evidence that letrozole may improve the development of the endometrium. Letrozole is more specific, better tolerated, and more potent than clomiphene.

In our practice, Letrozole has replaced clomiphene for the treatment of impaired fertility. When used alone it can restore normal ovulation to individuals with irregular or absent ovulation. When used in conjunction with injections of FSH, it dramatically decreases the amount of FSH needed to obtain excellent ovulation induction.

Letrozole has very few side effects but if you do note any changes or symptoms, please notify your physician.

The usual starting does of Letrozole is 2.5 or 5 mg a day for 5 days. Most conceptions with letrozole occur in the first three of four treatment cycles. Letrozole does not dramatically increase the incidence of multiple pregnancy, but twins can occur in up to 7% of individuals treated with this medication.
As noted above, there has been some concern about the use of Letrozole and the risk of fetal malformations. Letrozole absolutely should not be used during pregnancy, or if there is any chance a woman is pregnant. However, while it is "off-label", the use of Letrozole during the early follicular phase for ovulation induction seems to be perfectly safe. The half life of Letrozole is short (40 hours), and it is therefore completely cleared from the circulation by the time conception occurs.

I (we) understand that Letrozole, when used for the treatment of infertility, is being used for an “off-label” indication. We have been informed of the risks of this medication and hereby consent to its use. We have had the opportunity to ask questions and all questions have been answered to our satisfaction.

Name: _______________________ Signed: __________________________ Date: ___________

Name: _______________________ Signed: __________________________ Date: ___________

Witness: ______________________ Signed: _________________________ Date: ____________

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