Clomid® vs. Letrozole: Which Is Better for Infertility?

Oct 18, 23 ● 5 min

Originally published 02/08/2023. Updated for accuracy and relevancy on 10/18/2023

Clomid® (clomiphene citrate) and Femara® (letrozole) are two common drugs prescribed for couples facing infertility. While some prescribing clinicians have a preference of one over the other, you may be wanting to do your homework to learn about your options. Let’s dive in.

Ovulation Induction Medications: How Do They Work?

Clomid® has been the most widely used drug treatment for fertility. It became popular over the last 40 years to help women get pregnant because it’s easy to use, low cost, and has relatively minimal side effects. Clomid® is a nonsteroidal triphenylethylene derivative estrogen agonist-antagonist (woo, that’s a mouthful!). Essentially, it induces ovulation by making your body believe that estrogen levels are low and helps your body prepare and release an egg to be fertilized. While success rate can depend on multiple factors, approximately 80% of women who take clomiphene will ovulate, and 30-40% of women who take clomiphene will become pregnant (this assumes three cycles of medication). [1]

Letrozole is used off-label for ovulation induction, and is especially common for patients trying to get pregnant with polycystic ovarian syndrome (PCOS). [2] It has the same goal as Clomid® (ovulation induction), but takes a different path to get there. Letrozole was initially used to treat breast cancer by reducing the level of estrogen in the body. Doctors and researchers saw that this stimulated the development of ovarian follicles and started prescribing it (off-label) for women with infertility.

Importance of Ovulation

Ovulation is important for pregnancy because it is the process by which the female reproductive system releases an egg from the ovary. Without an egg, there is no chance of a pregnancy. Ovulation occurs about once a month, usually around day 14 of a normal 28-day menstrual cycle. When an egg is released, it travels through the fallopian tube, where it may be fertilized by sperm if sexual intercourse has occurred.

Knowing if and when you ovulate is important for pregnancy because it is the time you are most likely to get pregnant, otherwise known as the “fertile window.” To increase the chances of pregnancy, it is critical to have regular, predictable ovulation (which you can track with ovulation tests) and to have sexual intercourse around that time.

Letrozole and Clomid® Dosage

Both Clomid® and letrozole are small oral tablets you take on a daily basis.

Clomid®: The typical starting dose is 50 mg daily for five days. If you don’t successfully get pregnant after a few cycles, your healthcare provider may increase the dosage to 150 mg for subsequent cycles. [3]
Letrozole: The typical dose is 2.5 mg daily during cycle days 3 to 7. If that doesn’t work within a few cycles, some clinicians may increase the dose to 5 mg daily, with a max of 7.5 mg. [3]

Letrozole and Clomid® Price

Generic options for both range from $5-$35 and may or may not be covered by your insurance. Contact your pharmacy to find out how much it charges.

Safety and Side Effects of Ovulation Induction Medications

One study published in JAMA compared the experiences of 750 women randomly assigned to take Clomid® or letrozole. They found [4]:

More people taking Clomid® experienced hot flashes: 33% compared to 20.3% for Letrozole
More people taking Letrozole had fatigue: 21.7% vs 14.9% for Clomid®
More people taking Letrozole experienced dizziness: 12.3% vs. 7.6% for Clomid®

Additionally, side effects can include ovarian hyperstimulation syndrome, cancer, congenital abnormalities (clomiphene only), bone density loss (letrozole only), or multiple pregnancies.

While you may experience some side effects, both Clomid® and letrozole are generally considered to be safe, effective drugs.

What Is More Effective, Clomid® or Letrozole?

Both Clomid® and letrozole have been shown to increase the chances of pregnancy. However, a look at multiple studies show that letrozole may be slightly more effective [4-7]:

Live birth rate	Clomid®	Letrozole
RS Legro, GS Brzyski, et all	19.1%	27.5%
SA Amer, J Smith , et all	19.4%	24.4%
JJ Yland, YH Chiu, et all	29.0%	32.0%
N Lefevre	21.4%	31.4%

Letrozole Off Label Use

Letrozole is not FDA approved for infertility – but that’s okay. "Off-label" means the FDA has not evaluated if a drug is safe and effective for treating that condition. Instead, the FDA evaluated whether the drug is safe and effective for some other use. [2]

In this case, Letrozole is FDA approved for the treatment of estrogen-sensitive breast cancer in postmenopausal people. But because it can stimulate ovulation in some cases, it has gained widespread off-label use as a treatment for infertility. [2] In fact, many healthcare professionals think letrozole should be used as the first line fertility treatment for women with PCOS. [3]

If you are struggling to get pregnant, we highly recommend talking to a healthcare professional. There are options out there, and a provider can help you find the best path. We wish you all the best!

Sources:

Roy Homburg, Clomiphene citrate—end of an era? a mini-review, Human Reproduction, Volume 20, Issue 8, August 2005, Pages 2043–2051, https://doi.org/10.1093/humrep/dei042
Understanding Unapproved Use of Approved Drugs "Off Label". February 2018. https://www.fda.gov/patients/learn-about-expanded-access-and-other-treatment-options/understanding-unapproved-use-approved-drugs-label
Sharma M, Balasundaram P. Ovulation Induction Techniques. [Updated 2023 Jun 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK574564/
Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome [published correction appears in N Engl J Med. 2014 Oct 9;317(15):1465]. N Engl J Med. 2014;371(2):119-129. doi:10.1056/NEJMoa1313517
Amer SA, Smith J, Mahran A, Fox P, Fakis A. Double-blind randomized controlled trial of letrozole versus clomiphene citrate in subfertile women with polycystic ovarian syndrome. Hum Reprod. 2017;32(8):1631-1638. doi:10.1093/humrep/dex227
Yland JJ, Chiu YH, Rinaudo P, Hsu J, Hernán MA, Hernández-Díaz S. Emulating a target trial of the comparative effectiveness of clomiphene citrate and letrozole for ovulation induction. Hum Reprod. 2022;37(4):793-805. doi:10.1093/humrep/deac005
LeFevre N. Aromatase Inhibitors Such as Letrozole (Femara) vs. Clomiphene (Clomid) for Subfertile Women with PCOS. Am Fam Physician. 2019;99(9):545-546.

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Halle Tecco, MBA, MPH, Natalist Founder

Professional Experience

Halle Tecco is the Founder of Natalist. She is an Adjunct Professor at Columbia Business School, the host of The Heart of Healthcare Podcast, a Co-Founder of Cofertility, and a... Read More