Clomid Vs Letrozole: What’s the Difference?

In a perfect world, deciding to become pregnant should be easy, but in reality, getting pregnant doesn’t always go as planned. If you are contemplating or undergoing fertility treatments, you may be prescribed fertility drugs as a part of that process. Over the past 40 years, the most commonly prescribed drug prescribed for reproductive treatments has been Clomid (Clomiphene Citrate). However, there is a new player now, as more fertility doctors and clinics are prescribing Letrozole (brand name Femara) in conjunction with fertility treatments. And while the two drugs are similar, there is enough information and research on them available to help us understand their differences. Here are some things that are helpful to know:

• Both Clomid and Letrozole decrease or block estrogen, which increases FSH (follicle stimulating hormone) and LH (luteinizing hormone) levels to drive egg development and ovulation. Both of these drugs significantly increase your chances of ovulating, and ultimately becoming pregnant, especially if you are having an ovulation disorder.
• Both of these medications may be used for women undergoing reproductive treatments, such as IVF, IUI, DI and timed intercourse cycles.
• There is a great deal of research on these drugs, and most of it concludes that Letrozole may be slightly more effective than Clomid in stimulating ovulation and attaining pregnancy. Scientists have also found that all things being equal, Letrozole tends to come with fewer side effects, because of the shorter half life, and risks associated with its use.
• For women who have tried Clomid without success, and who are considered to be resistant to the effects of Clomid, Letrozole is still an option.

Differences in How These Drugs Work

While both of these drugs have the effect of lowering estrogen levels, how they do this is the key to why they are different. Clomid works by blocking estrogen receptors in your brain, which makes it believe that estrogen levels in your body are low. This causes your pituitary gland to produce FSH (follicle stimulating hormone) and LH (luteinizing hormone), which helps your ovaries release an egg for fertilization.

Letrozole is an off-label drug developed to reduce estrogen levels in women with breast cancer. Off-label means that the drug was developed to treat one condition, but may safely be used for another purpose. Letrozole is a nonsteroidal aromatase inhibitor. That’s a mouthful, but what it means is that it works by actually blocking estrogen synthesis. Where Clomid makes your brain believe that estrogen is low as a way to trigger ovulation, Letrozole truly lowers estrogen levels to trigger ovulation. Like Clomid, the lower estrogen levels also boost production of FSH and LH, triggering ovulation.

If Both of These Drugs Stimulate Ovulation, Why Choose One Over the Other?

While Clomid has been the drug of choice for years, there are some instances where Letrozole may be the better option. Research to date has found that Letrozole is only slightly more effective in producing ovulation. However, research published by the U.S. National Institute of Health in 2014 discovered that for women with PCOS (polycystic ovarian syndrome) the ovulation rate and rate of live births was significantly higher in the participants who took Letrozole. More recently, a 2020 study determined that the rate of ovulation for women with PCOS was similar whether they took Clomid or Letrozole. However, the researchers also concluded that Letrozole was a better choice because it resulted in higher pregnancy rates, a shorter time to become pregnant and more single-follicular growth, decreasing the chance of multiple pregnancies (twins, triplets, etc.). Because Letrozole has a shorter half-life to detox from your body, your endometrial lining is able to grow thicker more quickly to support a healthy pregnancy.

In treating women with unexplained fertility, there are a number of studies on the efficacy of the two drugs, but there is no clear consensus. While some studies report that Letrozole results in a higher pregnancy rate, the live birth rate for both drugs is similar.

The difference in choosing one drug over the other may lie in side effects that may actually affect fertility. One of the reasons that Letrozole is gaining popularity is that it’s cleared out of your body much faster than Clomid. The faster half-life of Letrozole (the time it takes for half of the drug to clear out of your body) means that your body goes back to doing what it normally does quicker. Research shows that women taking Letrozole have a thicker endometrial lining, making it easier for an embryo to implant, compared to women who took Clomid. Some participants on Clomid experienced thinning of their uterine lining, likely due to longer estrogen suppression associated with Clomid.

While both Clomid and Letrozole can result in more than one egg being released during ovulation, research studies have concluded that Letrozole is associated with more single-follicle cycles. Again, this finding is likely due to the faster half-life of Letrozole, compared to that of Clomid. During a cycle on Letrozole, generally one dominant follicle grows and secretes more estrogen that can’t be blocked by the effects of Letrozole, so the single follicle develops, instead of multiples.

Both of these fertility drugs may produce side effects that don’t affect your fertility, but they can be uncomfortable nonetheless. They include changes in your mood, nausea and vomiting, headaches, bloating, dry skin, breast tenderness, dizziness, hot flashes, night sweats and fatigue. A study published in the Journal of the American Medical Association reported that the incidence of some of these side effects were different between Clomid and Letrozole. The researchers found that women taking Clomid experienced more hot flashes (33%), compared to those taking Letrozole (20.3%). However, those taking Letrozole experienced more fatigue (21.7% vs 14.9% for Clomid) and more dizziness (12.3% vs 7.6% for Clomid).

While women who are undergoing assisted reproductive treatments understand that discomfort may occur when taking these fertility medications, it’s important to know that acupuncture can help minimize many of these side effects. In addition, research has documented that adding acupuncture to your fertility treatments can actually improve your chances of success. That’s because acupuncture has been found to increase circulation of blood and nutrients to your ovaries and uterus, it prepares your uterus to enhance implantation and can help reduce discomfort associated with assisted fertility procedures. In addition, a great deal of research supports the use of acupuncture to reduce stress; and let’s face it, undergoing fertility treatments can be really stressful!

The bottom line is that both Clomid and Letrozole are effective and safe medications for fertility. They both work to trigger ovulation, they increase egg production, can be used to increase the rate of pregnancy with a variety of fertility treatments, and are relatively affordable. The research is conflicting on whether one drug is decidedly more effective than the other, however Letrozole seems to be associated with slightly higher ovulation and pregnancy rates. The faster half-life of Letrozole is also associated with fewer side-effects that may actually affect your fertility. And finally, acupuncture can be a great adjunct to your fertility treatments, both in reducing side effects of fertility drugs and in boosting the effectiveness of the treatments. If you’d like more information about your fertility and acupuncture, please contact my clinic.

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