Letrozole for Infertility Treatment

Background information

Letrozole is being used commonly as an infertility treatment. Letrozole is a recent addition to the drugs being used for fertility treatment. Fertility drugs are used often in infertility treatments. There are two situations in which fertility drugs may be useful. First, these drugs can be used to induce an egg to develop and be released in women who are not ovulating on their own. This is known as ovulation induction. Fertility drugs can also be used to increase the chances of pregnancy in women who are already ovulating. This is known as superovulation.

letrozole femara

Letrozole (Femara)

In many fertility centers, clomiphene citrate (Clomid, Serophene) has been the drug of first choice for either ovulation induction or superovulation for many years. In general, it has been a relatively effective medication. However, clomiphene citrate lasts for a long time in the body and may therefore have an adverse effect on the cervical mucus and uterine lining. Some groups of patients, such as women with PCOS – polycystic ovary syndrome, do not respond well to clomiphene citrate. The Pregnancy in Polycystic Ovary Syndrome (PPCOS I) study found that over 6 months time, 1 in 4 PCOS patients never had a single documented ovulation. The cumulative live birth rate was only 23% over the 6 months. One reason theorized for the lower pregnancy rate with clomid is an adverse effect on the uterine lining.

Another group of fertility drugs which are administered as injections are called gonadotropins (Gonal F, Follistim). The gonadotropins are very efficient at inducing ovulation and have higher pregnancy rates than clomiphene citrate. However, gonadotropins are much more expensive than clomiphene citrate and the injectable route is uncomfortable for patients to administer and inconvenient. The risk for multiple pregnancies is also much higher with gonadotropins.

Letrozole as a Fertility Treatment 

Letrozole is a medication that has been widely used in women with breast cancer. It is sold under the trade name Femara. Letrozole belongs to a class of medications known as aromatase inhibitors. Aromatase is an enzyme that is responsible for the production of estrogen in the body. Letrozole works by inhibiting aromatase thereby suppressing estrogen production. Clomiphene citrate, on the other hand, blocks estrogen receptors. In both cases, the result is that the pituitary gland produces more of the hormones needed to stimulate the ovaries. These hormones, FSH and LH, can cause the development of ovulation in women who are anovulatory or increase the number of eggs developing in the ovaries of women who already ovulate. As a result, several studies have now been published using letrozole as a fertility drug.

One of the earliest studies using letrozole as a fertility drug looked at 12 women with inadequate response to clomiphene citrate. Ovulation on letrozole occurred in 9 of 12 cycles and 3 patients conceived. A later study by the same investigators compared the effects of letrozole to those of clomiphene citrate. This time 19 women were studied. Ten women received clomiphene citrate and nine women received letrozole. This study was unable to demonstrate any difference in the number of women who ovulated, the number of eggs that developed in each woman, or the thickness of the uterine lining during treatment. However, a more recent study by a different group of investigators found that compared with clomiphene citrate, letrozole is associated with a thicker uterine lining and a lower miscarriage rate.

At the 2013 meeting of the American Society for Reproductive Medicine (ASRM), the results of the PPCOS II study were first presented. In this study, which has now been published, 750 PCOS women were randomized to receive either letrozole or Clomid for up to 5 treatment cycles.
The findings convincingly showed that for women with PCOS:
  • The ovulation rate was superior with letrozole (61.7%) than with Clomid (48.3%)
  • The cumulative live birth rate was higher with letrozole (27.5%) the with Clomid (19.5%)
  • The live birth benefit was higher in obese women (BMI ≥ 35)
  • letrozole was equal or superior to Clomid at all BMI groups
There was no difference in:
  • the risk for pregnancy loss (letrozole 31.8% vs Clomid 28.2%)
  • Multiple pregnancy rates (all twins) (letrozole 3.2% vs Clomid 7.4%)
  • The number of serious adverse events

Use of letrozole in women without PCOS

The majority of studies looking at the use of letrozole compared to Clomid in women who do not have PCOS have concluded either there is no difference between the two or that clomid is superior for this group of patients.

Letrozole and birth defects

A study presented at ASRM in 2005, in which researchers analyzed births that occurred after treatment with letrozole found seven serious birth defects in 150 babies, which is about 4.7%. This was compared to a database of 36,050 normal deliveries. The incidence of birth defects in the control babies was 1.8% This means that birth defects were 3 times more likely to occur with letrozole.

This prompted the manufacturer (Novartis) to review their safety database and found 13 reports of already pregnant women receiving the drug worldwide. Of those 13 women, two had children with birth defects (15.4%).Novartis sent a letter to fertility physicians stating: “Femara (letrozole) is contraindicated in women with premenopausal endocrine status, in pregnancy, and/or lactation due to the potential for maternal and fetal toxicity and fetal malformations”.

In response, 5 Canadian fertility centers reviewed their birth outcomes and incidence of birth defects in women who conceived with letrozole and compared them to Clomid. The Canadian study involved 911 newborns. The major birth defect rate in the letrozole group was 1.2% (6/514) and in the Clomid group was 3.0% (12/397).

In the United States, the labeling of letrozole already warned that it had been associated with birth defects. Novartis has never sought FDA approval to market letrozole as a fertility medication and was clearly concerned about their liability if given in pregnancy.

Letrozole is a medication that is metabolized rapidly in the body. It is not thought to have significant levels in the blood or tissues for a prolonged period of time.

In the PPCOS II study, each baby born was closely studied for birth defects at the time of birth with additional screening within 1 month of birth by trained pediatric personnel. There was no difference in the rate of birth defects between letrozole and Clomid.

Letrozole side effects

Letrozole works based on its ability reduce estrogen levels. Low estrogen levels of any cause can cause a woman to have symptoms. The data on side effects comes from women who have been using letrozole for an extended period of time in order to treat breast cancer. The treatment duration for letrozole is only five days. In our experience, we have seen side effects that are similar to those seen with clomiphene citrate:
  • Hot flashes
  • Headaches
  • Breast tenderness

Letrozole and pregnancy

Studies conducted so far have shown either no increased risk of miscarriage or a decrease in miscarriage risk. Letrozole is considered pregnancy Category D. Letrozole should not be given to women who are already pregnant. Studies in rats and mice have shown that letrozole increases the risk of fetal death and malformations. Since there are no studies in human beings, it should be assumed that a similar effect is possible.

Letrozole Fertility Treatment Protocols

Monitoring with ovulation predictor kits and having intercourse only.

1. Call the office on Day 1 of your period.
2. Day 2 or 3 – Office visit- Blood test and ultrasound.
3. Take the letrozole 2.5 mg tablet on days 5,6,7,8, and 9.
4. Start testing urine on the morning of day 10 or 11.
5. Look for the first definite color change. Do not continue to test after the color change.
6. Have intercourse the same day you see the color change and the next day.
7. Call the office when you see the color change. Schedule an appointment approximately one week later for a blood test to verify ovulation.

Monitoring with ovulation predictor kits and having an IUI – intrauterine insemination

1. Call the office on Day 1 of your period.
2. Day 2 or 3 – Office visit- Blood test and ultrasound.
3. Take the letrozole 2.5 mg on days 5,6,7,8, and 9.
4. Start testing urine on the morning of day 10 or 11.
5. Look for the first definite color change. Do not continue to test after the color change.
6. Call the office the same morning you see the color change. Have intercourse that night.
7. Schedule the intrauterine insemination for the next day (The day after the color change)
8. Schedule an appointment approximately one week later for a blood test to verify ovulation
9. Schedule an appointment approximately two weeks later for a pregnancy test

Monitoring in the office with intrauterine insemination or intercourse

1. Call the office on Day 1 of your period.
2. Day 2 or 3 – Office visit- Blood test and ultrasound.
3. Take the letrozole on days 5,6,7,8, and 9.
4. Day 10 or 11 – Office visit – Blood test and ultrasound. You will receive instructions that afternoon when to return for the next visit.
5. Only when instructed – Take the hCG trigger injection in the evening. Have intercourse that evening also.
6. Schedule the insemination for 2 (two) days after the hCG trigger . If you are not doing intrauterine insemination, have intercourse again on this day
7. 1 week after hCG trigger – Office visit – Blood test only (Progesterone level)
8. 2 weeks after hCG trigger – Office visit – Blood test only (Pregnancy test)