Clomid vs Letrozole for Fertility

When getting pregnant isn’t as straightforward as your junior high sex-ed class suggested, two medications often lead the conversation: Clomid (clomiphene citrate) and Letrozole (Femara).

Clomid has been the most commonly prescribed oral fertility drug for more than 50 years. It remains a first-line treatment for many women with infertility, especially those with ovulatory disorders such as polycystic ovary syndrome (PCOS) or unexplained infertility.

Femara (Letrozole) was originally approved by the FDA as a breast cancer treatment. But since 2001, it has been prescribed off-label for ovulatory infertility. Its use in fertility care has grown rapidly, and today it is considered a strong alternative to Clomid.

With both medications widely used, research has focused heavily on comparing their effectiveness and outcomes. In this article, we’ll review the evidence on Clomid vs. Letrozole and examine which option is emerging as the preferred first-line fertility treatment in today’s clinics.

Fast Facts

• Mechanism: Both Clomiphene (Clomid) and Letrozole (Femara) lower estrogen levels. This signals the body to produce more FSH and LH, the hormones that stimulate follicle development and trigger ovulation.

• Effectiveness: Both medications significantly increase the chances of ovulation and pregnancy, especially for women with ovulatory disorders.

• Treatment Options: Clomid and Letrozole can be used with timed intercourse cycles, intrauterine insemination (IUI), in vitro fertilization (IVF), or mini-IVF.

• Research Findings: Most studies suggest that Letrozole is slightly more effective than Clomid at inducing ovulation and supporting pregnancy.

• Side Effects: Even when Clomid works as well as Letrozole, Letrozole is often preferred because it typically causes fewer side effects and carries lower risks.

• Clomid Resistance: Letrozole is frequently prescribed for patients who do not respond to Clomid, or who are considered “Clomid resistant.”

• Male Fertility: Both medications are also used to treat certain forms of male infertility related to low testosterone.

What are Clomid (Clomiphene Citrate) and Letrozole (Femara) 

Clomid and Letrozole are oral medications that stimulate the ovaries to develop and release high-quality eggs.

They work by lowering estrogen levels, which the hypothalamus interprets as a signal to increase production of FSH and LH. These hormones, especially FSH, stimulate follicle growth, egg development, and ovulation (the release of the egg).

In short, both medications improve fertility in two key ways:

1. Increasing the number of mature, high-quality eggs developed each cycle

2. Inducing ovulation

How Clomid and Letrozole Work 

As mentioned, Clomid and Letrozole both exert their primary effect by “reducing” estrogen levels.  Exactly how these medications go about “lowering” estrogen levels is the primary driver of their differences. While this may be a little sciency for some, it’s pretty cool. If it’s too much, feel free to skip to the next section.

Clomid Mechanism of Function

Clomid is a selective estrogen receptor modulator meaning it blocks estrogen receptors in the brain. By blocking estrogen receptors, the brain is tricked into believing there are low levels of estrogen which again, triggers the pituitary to make more FSH and LH. . 

Clomiphene can take up to two weeks to clear out of the body (which is significantly longer than Letrozole).  Clomiphene’s significant half-time for clearance causes a prolonged blocking of estrogen receptors and increased FSH/LH production for a significant length of time after the medication is stopped.  

Clomid’s prolonged effects on FSH and estrogen production can cause more multiple follicle growth cycles when compared to natural and Letrozole cycles.  

Letrozole Mechanism of Function

Letrozole is a nonsteroidal aromatase inhibitor, meaning it blocks the conversion of androgens into estrogen. As a result, Letrozole directly lowers estrogen levels in the body. . 

With less circulating estrogen, the brain senses the lower levels and responds by increasing production of FSH and LH.

Clomid vs. Letrozole for Inducing Ovulation

Ovulatory disorders are one of the most common causes of infertility.  They affect about 30-40% of infertile women.  Polycystic Ovarian Syndrome (PCOS) is the most common cause of anovulatory infertility and also the most common diagnosis of infertility in general.

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

In 2014, the National Institute of Health (NIH) published a study that measured the effectiveness of Letrozole and Clomid to treat PCOS patients’ infertility. 

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.

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) . Other studies have shown similar results.

The research, however, is not entirely one-sided. A 2020 study of anovulatory women with PCOS also compared Letrozole and Clomid for ovulation induction. Ovulation rates were similar—86.7% for Letrozole and 85.2% for Clomid.

Despite this, researchers concluded that Letrozole was the better option because it was associated with higher pregnancy rates, shorter time to conception, and a lower risk of multiple pregnancies due to more frequent mono-follicular growth.

Clomid Resistance

Clomid successfully induces ovulation in many patients, but it is not effective for everyone. If ovulation does not occur, a doctor may increase the dosage. When higher doses still fail, the patient is considered Clomid resistant.

There are several reasons why Clomid resistance may occur. Women with a body mass index (BMI) over 25 have a reduced likelihood of responding to the medication. In addition, those with hyperprolactinemia—elevated prolactin levels in the blood—may also fail to respond effectively to Clomid. Women with PCOS are the most common to experience Clomid resistance, especially those who are diagnosed with insulin resistance or with hyperandrogenic levels.  

Research has shown that Letrozole can help to induce ovulation for some women who have previously failed with Clomid or are considered “Clomid Resistant.” 

In one study, Letrozole significantly improved ovulation rates and live birth rates for women who failed to ovulate with Clomid treatment.

Clomid vs. Letrozole Pregnancy & Live Birth Rates – PCOS

In the 2014 NIH study mentioned above, Letrozole was more effective at inducing ovulation for patients with Polycystic Ovarian Syndrome (PCOS). 

In that same study, researchers also measured Clomid and Letrozole’s effect on live birth rates. 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%) had a live birth.  .

In another study, researchers compared the effects of Letrozole and Clomiphene as first-line ovulation induction drugs to treat infertile PCOS women. 

They split 103 infertile women with PCOS into Clomiphene and Letrozole treatment groups. The patients treated with Letrozole experienced a pregnancy rate nearly three times that of the Clomiphene group.

The pregnancy rates were 21.56% for the Letrozole group and 7.84% for the Clomiphene group .  

Clomid vs. Letrozole Pregnancy & Live Birth Rates – Unexplained Infertility

Both Clomid and Letrozole can help women with unexplained infertility achieve pregnancy. However, there is no clear consensus on which is more effective.

Studies have produced conflicting results, with some supporting Clomid and others favoring Letrozole. Overall, most research shows that the two medications yield statistically similar pregnancy and live birth rates in this group of patients.

Following the 2014 National Institutes of Health (NIH) study showing that Letrozole outperformed Clomiphene for women with PCOS, the NIH also examined their effectiveness in treating unexplained infertility.

One trial, published in the New England Journal of Medicine (2015), compared the two drugs in women undergoing timed intrauterine inseminations (IUI) for up to four menstrual cycles. The results showed pregnancy in 35% of women taking Clomiphene and 28% of women taking Letrozole.

While pregnancy rates differed, live birth outcomes were similar: 23% of women in the Clomiphene group achieved live births compared with 19% in the Letrozole group.

Although the Letrozole group showed slightly lower results, the difference was not statistically significant. Researchers concluded that Clomiphene is at least as effective as Letrozole for treating unexplained infertility.  

Another study also compared Clomiphene and Letrozole in women with unexplained infertility. The randomized controlled trial found that Letrozole may improve implantation and pregnancy outcomes.

In this study, 23.1% of women treated with Letrozole conceived, compared with 10.7% in the Clomiphene group. . . 

In addition to higher pregnancy rates, women treated with Letrozole also demonstrated a statistically significant improvement in endometrial receptivity.

Researchers concluded that Letrozole has a more favorable effect on the uterine lining compared to Clomiphene, which may help explain its potential to improve implantation and pregnancy outcomes in women with unexplained infertility.

A 2019 systematic review and meta-analysis evaluated data from eight randomized controlled trials comparing Letrozole and Clomiphene in unexplained infertility.

The analysis found that 24% of patients treated with Letrozole and 23% of those treated with Clomiphene achieved pregnancy. There was no significant difference between the two groups in either pregnancy rates or live birth rates.

Researchers concluded that there is no significant statistical difference in the effectiveness of Clomid or Letrozole to improve clinical outcomes for patients with unexplained infertility.

Differences in Side Effects That Impact Fertility

One of the main reasons fertility specialists increasingly prescribe Letrozole is its lower risk of side effects compared to Clomiphene.

Clomiphene can lead to a thinner endometrial lining and a higher likelihood of multiple pregnancies in some patients.

These differences are thought to stem from the distinct mechanisms of action for each medication and the length of time they remain active in the body.

Endometrial Thinning

Some women develop a thin uterine lining (endometrium) during Clomid treatment cycles. A thin lining makes embryo implantation more difficult, reducing the chances of pregnancy.

Researchers believe this effect is due to Clomid’s prolonged action on estrogen receptors in the uterus. In a natural cycle, estrogen stimulates the endometrium to thicken. But because Clomid blocks estrogen receptors not only in the brain but also in the uterus, the endometrium may fail to develop correctly.

Since Letrozole also lowers estrogen, it might seem logical that it would have the same effect. However, studies show that patients treated with Letrozole generally have thicker endometrial linings compared to those treated with Clomiphene.

This is likely due to the fact that Letrozole is cleared more quickly from the body, allowing the uterine lining enough time to thicken. 

Multiple Pregnancies

Both Letrozole and Clomid can cause multiple eggs to be ovulated, but research indicates that Letrozole results in more mono-follicular cycles. . Mono-follicular cycles lead to singular pregnancies (rather than twins and triplets) and are thus much safer for both mom and baby.

Letrozole has a much shorter half-life than Clomid. During a Letrozole cycle, as the dominant follicle grows, it produces increasing amounts of estrogen. This estrogen is not blocked by Letrozole’s temporary aromatase-inhibiting effect, which leads to suppression of FSH.

As a result, the smaller developing follicles stop growing. In most women, this process allows a single dominant follicle to mature, leading to mono-ovulation rather than multiple ovulations.

In a Clomid cycle, FSH production is not suppressed by the rising levels of estrogen as the estrogen receptors remain blocked due to the two-week “half-life” of Clomid. These consistently high levels of FSH during a Clomid cycle often cause multiple follicles to reach maturity and ovulate.

Cost Comparison

Clomid and Letrozole are generally covered by insurance at similar rates and are comparably priced when paid out of pocket. According to GoodRx, Letrozole can cost as little as $20.50, while Clomiphene can be found for around $23.00.

Clomid vs. Letrozole: The Takeaway

Clomid and Letrozole are both well-established fertility medications. They reliably induce ovulation and increase egg production at a fraction of the cost of injectable gonadotropins. Both can also be used alongside a variety of fertility treatments to improve the chances of getting pregnant.

While research findings are mixed, Letrozole generally appears more effective at inducing ovulation and improving pregnancy rates, particularly in women with PCOS. Many fertility specialists also prefer Letrozole because it is associated with fewer side effects.

As always, decisions about fertility treatment should be made with the guidance of a doctor. Scheduling a consultation with one of our fertility specialists can help determine which medication is best suited to your individual needs and family-building goals.