Letrozole (Femara) for Fertility

Letrozole, also known by its brand name Femara, is an oral medication used to stimulate egg development and ovulation in female patients undergoing fertility treatment.  It has been prescribed by fertility doctors since the early 2000s.  Many clinics now prescribe Letrozole in place of Clomiphene Citrate (Clomid), which has been the standard first-line fertility drug for over 50 years. 

Reproductive endocrinologists and fertility specialists have started prescribing Letrozole for fertility in place of Clomid because it has fewer side effects, a lower risk of multiple pregnancies and recent research suggests it may result in higher ovulation and pregnancy rates.  Letrozole can also be used to improve fertility and induce ovulation for patients who don’t respond to Clomid and are considered “Clomid resistant.”

In this article, we will cover the basics of what Letrozole is, how it improves fertility, who should take it, how it’s used in conjunction with treatments and different protocols.

Fast Facts

• Letrozole is in a class of drugs called aromatase inhibitors.
• Femara is approved by the U.S. Food and Drug Administration to treat certain types of breast cancer.  In the early 2000s, fertility doctors started prescribing Femara off-label to increase egg development and ovulation in female patients.
• Several studies have shown that Letrozole may be more effective in treating infertility and increasing pregnancy rates for women suffering from Polycystic Ovarian Syndrome (PCOS) .
• Letrozole may be prescribed in conjunction with timed intercourse, IUI, and IVF cycles.  
• Letrozole has commonly been shown to induce ovulation in approximately 70% of women who otherwise do not ovulate.
• Letrozole has commonly been shown to lead to pregnancy and live births in approximately 25% of menstrual cycles in women normally don’t ovulate and thus have little to no chance of conceiving otherwise.
• Common side effects of Letrozole include headaches, fatigue, and dizziness.  Unlike Clomid, Letrozole doesn’t cause mood swings or affect the endometrial lining or cervical mucus .

What is Letrozole (Femara)

Letrozole is an aromatase inhibitor (lowers estrogen production) that can be used to induce ovulation in patients with irregular ovulation patterns or those who suffer from anovulation. It can also help to increase egg production in women who ovulate normally but have unexplained infertility. When taking Letrozole, some women produce and release multiple eggs. 

The impact of Letrozole on fertility has been widely studied.  Recently, researchers have focused on letrozole’s ability to treat infertility in PCOS patients. 

How does Letrozole Help Improve Fertility?

Letrozole helps to improve fertility in two main ways, (1) inducing ovulation and (2) increasing the number of eggs released each cycle.  

Letrozole to Induce and Increase Ovulation

Letrozole encourages the ovaries to ovulate by producing more natural stimulation.  Letrozole improves ovulation by blocking estrogen production, which causes the body to release higher than normal levels of follicle-stimulating hormone (FSH).  The additional levels of FSH stimulate ovarian follicle(s) to develop and mature in the ovary.  For women who don’t ovulate regularly or who have Polycystic Ovarian Syndrome (PCOS), the increased amounts of FSH can help to produce mature follicle(s) and egg(s), so ovulation can occur.   

For women without ovulatory issues, Letrozole can cause them to develop multiple mature follicles, which release more than one eggs for ovulation.  

Research has shown that Letrozole can also be beneficial to induce ovulation for women who have previously failed with Clomid or are considered “Clomid Resistant.”  In one study, Letrozole significantly helped to improve ovulation rates and live birth rates for women who have failed to ovulate with Clomid . 

Letrozole for (Multiple) Egg Development 

Letrozole can increase the number of eggs released each cycle by increasing the number of follicles that develop.  In a normal ovulatory cycle, one follicle develops, and one egg is released.  In a Letrozole medicated cycle, the amount of FSH a woman produces increases which may cause multiple follicles to develop and multiple eggs to be released, especially for women who ovulate regularly.  The release of multiple eggs gives a better chance for fertilization to occur.  Medicated cycles that result in the development of multiple follicles and eggs are referred to as controlled ovarian stimulation cycles.  

Mechanism of Function for Fertility

Aromatase is an enzyme that is responsible for a vital step in the production of estrogen.  Femara (Letrozole) is an aromatase inhibitor.  By inhibiting the function of aromatase, Letrozole suppresses the production of estrogen.  When there is less estrogen, the pituitary gland produces additional levels of follicle-stimulating hormone (FSH) and Luteinizing Hormone (LH).  The increased production of FSH and LH causes improved development, maturation, and ovulation of one or more egg.

Who Should Take Letrozole

If you experience any of the following, you may be a candidate for Letrozole:

1. Your periods are very irregular, or you don’t experience periods at all. 
2. You have been diagnosed with PCOS.
3. If your periods are regular but your progesterone levels are low. 
4. You are experiencing unexplained infertility.
5. You are undergoing fertility treatment. 
6. If you are male with infertility due to low testosterone. 

Letrozole for PCOS Patients

Polycystic Ovarian Syndrome (PCOS) is the most common cause of anovulatory infertility .  90–95% of anovulatory women seeking treatment for infertility have PCOS .  As such, it makes sense that a large portion of Letrozole research is conducted on patients with Polycystic Ovarian Syndrome. 

Clomid has historically been used as the first-line fertility treatment for PCOS patients with ovulatory issues.  However, recent research suggests that Letrozole may produce similar, if not better, results for inducing ovulation and producing live births for PCOS patients.

The National Institute of Health published a study in 2014 that measured the effectiveness of both Letrozole and Clomid to treat infertility for PCOS patients.  During the study, 374 women received Letrozole treatment, and 376 women received Clomiphene treatment for five days starting on day three of their cycle for up to 5 cycles.  Of the 374 women treated with Letrozole, 103 (27.5%) had a live birth.  Of the 376 women treated with Clomiphene, only 72 (19.1%) of the women had a live birth . 

Researchers from the study above also measured how Letrozole and Clomid affect ovulation rates for PCOS patients.  Not only was the live birth rate higher for the Letrozole group, but so was their cumulative ovulation rate.  The women in the Letrozole group had a cumulative ovulation rate of 61.7% (834 times in 1352 cycles). The women in the clomiphene group ovulated 48.3% of the time (688 times in 1425 cycles).  

Although Letrozole can cause women to produce multiple eggs, the result is not as common in women with PCOS or other ovulatory disorders.  For patients with PCOS, Letrozole can provide a slightly different benefit, mono-ovulation.  Patients with PCOS are commonly hyper-responsive to gonadotropin drugs. Ovarian hyperstimulation occurs when a woman’s ovaries swell and leak fluid into the body.  Research published by the American Society for Reproductive Medicine (ASRM) indicates that Letrozole is more likely to produce single ovulation than Gonadtropin drugs or Clomid .  Letrozole can cause PCOS patients to develop and ovulate an egg while keeping them at a lower risk for hyper-stimulation, which could be caused by other fertility medications.  

Letrozole for Unexplained Infertility

Recent studies have shown that Letrozole can be beneficial in treating unexplained infertility .  In one study, researchers measured the effects of Clomiphene and Letrozole treatment on improving pregnancy rate, miscarriage rate, incidence rate of adverse events, and the number of dominant follicles for patients with unexplained infertility.  The results of the study showed that women treated with Letrozole displayed a significantly higher rate of clinical pregnancy as compared to those treated with Clomiphene.  There was no statistical difference between the groups for the other fertility outcomes.  Researchers concluded that Letrozole is at least as effective as Clomiphene for treating women with unexplained infertility .  

Researchers compared the efficacy of Letrozole and Clomiphene treatment on 271 women with unexplained infertility in a randomized control trial.  More than double the percentage of women treated with Letrozole achieved pregnancy (23.07%) compared to the group treated with Clomiphene (10.7%) . 

In addition to the higher pregnancy rate, the group treated with Letrozole also saw a statistically significant improvement in endometrial receptivity when measured by endometrial thickness and other indicators.  Researchers concluded that Letrozole has a beneficial effect on the endometrium, which may improve implantation and pregnancy rates in women with unexplained infertility .  

Letrozole and Fertility Treatments

Letrozole is synonymous with the term ovulation Induction and can be used in conjunction with several different fertility treatments.  Many fertility doctors have shifted to prescribing Letrozole in conjunction with the following treatments: 

• Timed Intercourse
• Intrauterine Insemination (IUI) 
• In Vitro Fertilization (IVF)

Timed Intercourse with Letrozole 

Timed intercourse is the simplest fertility treatment available.  Letrozole is used during timed intercourse cycles to stimulate egg production and to induce ovulation. 

During a timed intercourse cycle, doctors use ultrasound and blood work monitoring (or even a home ovulation predictor kit) to monitor follicular development and egg growth.  By monitoring egg development and hormone levels, physicians are able to identify the window of time in which the woman is ovulating (when fertilization is most likely to occur.) This allows couples to engage in sexual intercourse at the time, which gives them the best chance of getting pregnant.  

Research has shown that Letrozole treatment may be more effective than Clomid for patients with unexplained infertility who are undergoing timed intercourse treatment.  In one study, patients treated with Letrozole showed statistically significant improvement in both endometrial thickness and follicular response when compared to the Clomid group.  The Letrozole group also had a significantly higher clinical pregnancy rate when compared to the Clomid group at 15.0% and 11.8%, respectively.  

Women whose infertility is caused by an ovulatory disorder are commonly prescribed Letrozole along with timed intercourse treatment.

Intrauterine Insemination (IUI)

IUI treatment is usually recommended to couples who haven’t been able to get pregnant after multiple timed intercourse cycles or for couples where the male partner may have sperm motility issues.  Similar to a timed intercourse cycle, Letrozole may be prescribed alongside IUI treatment to stimulate egg growth and to help time ovulation properly with the insemination.

During IUI treatment, sperm is collected, concentrated, and deposited into a woman’s uterus. IUI treatment aims to increase the number of sperm that reach the uterus and then the fallopian tubes to increase the chance that successful fertilization will occur.  Letrozole is used to increase the number of eggs available for fertilization and to improve ovulation.  When more eggs are produced, there are more targets available for the sperm to shoot at.  

As previously discussed, Letrozole can improve endometrial receptivity by increasing endometrial thickness and blood flow .  In one study, researchers measured the effects of endometrial thickness on pregnancy outcomes after IUI.  The results of the study showed a strong positive association between endometrial thickness and pregnancy outcome.  Letrozole’s ability to improve the condition of the endometrium may explain why some researchers have observed higher pregnancy rates in patients treated with Letrozole undergoing IUI treatment than patients treated with Clomid.  

Gonadotropin medications may also be used with an IUI cycle, although Letrozole is a much more affordable option.  Researchers have found that Letrozole treatment can help to achieve multi follicular development at a significantly lower cost than gonadotropins .  Multifollicular development is useful with IUI treatment because it can result in more eggs being ovulated.  As mentioned above, more eggs mean more targets for the sperm to fertilize.  

In Vitro Fertilization (IVF)

In Vitro Fertilization is the most effective fertility treatment. It involves a multi-week/month process in which eggs are removed from a female’s ovaries, fertilized with sperm in a petri dish, grown inside a lab for several days (usually 3-5), and then transferred into the female’s uterus to develop for the remainder of gestation.

IVF is used in conjunction with a multitude of medication protocols, including Letrozole treatment.  Fertility doctors may prescribe Letrozole along with IVF or mini-IVF treatment to stimulate ovulation and increase egg production.  

Letrozole is especially useful to induce ovulation in patients who are sensitive to gonadotropin medications or who at a higher risk of hyperstimulation who are planning to undergo IVF treatment.  Other times, fertility doctors may prescribe Letrozole along with gonadotropins to patients undergoing IVF treatment. 

In one study, researchers measured the effects of combining Letrozole and gonadotropin treatment.  Researchers treated patients with just gonadotropins or gonadotropins and Letrozole.  The results of the study showed that when Letrozole is used along with gonadotropins, it decreases the amount of gonadotropins needed without having a negative effect on pregnancy rates .  

Letrozole Protocols and Dosing

Letrozole is commonly found as a 2.5-milligram oral tablet.  Fertility doctors dictate when patients should begin taking Femara based on when their period begins. Generally, letrozole is taken over a period of five consecutive days.  The medication is usually started on day 2, 3, 4, or 5 of the female’s cycle and continued until day 6, 7, 8 or 9 (depending on when it was started).

If you are undergoing a timed intercourse cycle, your Femara start date will indicate when you should have sex to increase your chances of getting pregnant.  During a normal 28 day cycle, women ovulate or release an egg on day 14.  This begins the start of her luteal phase, which is when she can get pregnant.  In a Femara (Letrozole) medicated cycle, women ovulate approximately 7-10 days after they begin taking medication.  Fertility doctors will start monitoring the patient’s follicle growth after 5-7 days to gauge when she will start ovulating.  

If a woman started Femara treatment on day 3 of her cycle, she would likely ovulate between days 10-13.  If a woman started Femara treatment on day 5 of her cycle, she would likely ovulate between days 12-15.  Since eggs only last for around 12-48 hours after ovulation before they can no longer be fertilized, it is extremely important to understand the timing of the female partner’s cycle.  To ensure sperm have ample time to reach the egg, couples should have sex 2-3 days before ovulation occurs.  

If a patient is undergoing IUI or IVF treatment, her ovulation timing just as important for determining when treatment should be performed.   

In Conclusion

Letrozole is a useful fertility medication that is becoming more and more popular.  Letrozole may produce similar results to other oral fertility medications like Clomid (Clomiphene) with fewer side effects.  It can be used in conjunction with several different fertility treatments, and it is a much more affordable option than injectable medications like gonadotropins.  

As with all medications, be sure to consult with your doctor to see if Letrozole treatment can help to improve your fertility.