Letrozole vs. Clomid: How They Differ

Quick comparison

What they do

Both medicines are used in ovulation induction, which means prompting the ovaries to release an egg in a woman who is not ovulating regularly. Clomiphene's FDA label states it is indicated for the treatment of ovulatory dysfunction in women desiring pregnancy, and that impediments to pregnancy must be excluded or adequately treated before starting. It names PCOS among the conditions where patients are most likely to respond.

Letrozole is an aromatase inhibitor. Its FDA-approved indications, on the Femara label, are breast cancer in postmenopausal women. MedlinePlus likewise describes it as a breast cancer medicine and does not list ovulation induction. Doctors may still prescribe an approved drug for another use, which is called off-label, and the American Society for Reproductive Medicine (ASRM) lists aromatase inhibitors among the oral treatments it evaluated for couples with unexplained infertility.

Both are oral tablets. The clomiphene label says that once ovulation has been established, each course should start on or about the 5th day of the cycle.

What the PPCOS II trial found

The best-known head-to-head comparison is a 2014 trial in the New England Journal of Medicine, run by the NICHD Reproductive Medicine Network. It randomly assigned 750 women with PCOS, aged 18 to 40, to letrozole or clomiphene for up to five treatment cycles. All had at least one patent fallopian tube and a normal uterine cavity, and their male partners had a sperm concentration of at least 14 million per milliliter.

The primary outcome was live birth during treatment. More women had a live birth on letrozole than on clomiphene, and ovulation was more frequent with letrozole. The trial found no significant differences between the two medicines in overall congenital anomalies, pregnancy loss or twin pregnancy.

Read these numbers with care. They come from women with PCOS who met strict entry criteria and had their cycles closely tracked, and they describe a group, not a prediction for any one person. The trial does not show how either medicine performs in women who ovulate regularly or have other causes of infertility. ASRM's guideline for unexplained infertility, which covers aromatase inhibitors and clomiphene alongside intrauterine insemination, concludes that the treatment of unexplained infertility is by necessity empiric.

Side effects

Clomiphene: the label reports adverse events in more than 1% of 8,029 patients in clinical studies, including ovarian enlargement (13.6%), vasomotor flushes (10.4%), abdominal or pelvic discomfort and bloating (5.5%), nausea and vomiting (2.2%), breast discomfort (2.1%), visual symptoms (1.5%), headache (1.3%), and abnormal uterine bleeding (1.3%). Visual symptoms such as blurring, spots, or flashes can occur and increase with total dose or duration of therapy. The label says they are usually reversible but can be prolonged, and it advises stopping treatment if they occur. It also warns about ovarian hyperstimulation syndrome (OHSS), which can progress rapidly. Among reported pregnancies in the trials, 7.98% were multiple, 6.9% of them twins.

Letrozole: in the PPCOS II trial, clomiphene was associated with more hot flushes, and letrozole with more fatigue and dizziness. Rates of other adverse events were similar. The trial reported four major congenital anomalies on letrozole and one on clomiphene, a difference that was not significant. The Femara label contraindicates letrozole in pregnancy and says post-marketing reports linked use during pregnancy to spontaneous abortions and congenital birth defects, which is why a pregnancy test comes first.

MedlinePlus tells people taking clomiphene to call a doctor right away for blurred vision, visual spots or flashes, or double vision, and for stomach or lower stomach pain, stomach swelling, weight gain, or shortness of breath. Clomiphene increases the chance of a multiple pregnancy.

Who should not use them

The clomiphene label lists contraindications that include pregnancy, abnormal uterine bleeding of undetermined origin, ovarian cysts or enlargement not due to PCOS, uncontrolled thyroid or adrenal dysfunction, an intracranial lesion such as a pituitary tumor, and hypersensitivity to the drug. Letrozole is contraindicated in pregnancy and in people with a known hypersensitivity.

These are reasons a clinician reviews your history and results before prescribing anything, rather than a checklist to self-assess.

Monitoring

Ovulation induction is not a set-and-forget medicine. The clomiphene label calls for a pelvic examination before the first and each later course, and says a basal body temperature graph or other tests can help determine whether ovulation occurred, with properly timed intercourse being important. In the PPCOS II trial, visits were scheduled to determine ovulation and pregnancy. ASRM's committee opinion on clomiphene describes its indications, use, monitoring, and side effects.

The clomiphene label also says long-term cyclic therapy is not recommended beyond a total of about six cycles. If ovarian enlargement occurs, further therapy should wait until the ovaries return to their pretreatment size.

How medication works in Gala Fertility

At Gala Fertility, medication is prescribed only if your clinician decides it is right for you, after your results are reviewed and explained to you both on one video visit. It is prescribed one month at a time, for up to six cycles, and shipped to your door from a licensed US pharmacy, with a check-in after every cycle. Some medications may be prescribed off-label, for a use other than the one the FDA approved. If a medication is prescribed off-label, your clinician explains what that means. Gala Fertility is for male-female couples, both 18 or older, and is not available in New York, New Jersey, or Rhode Island. IUI, IVF, and other in-person care after a referral are separate and not included.

Learn more about fertility medication, fertility testing for couples, or trying to conceive. When you are ready, start your fertility intake together.

This article is general education, not medical advice. Talk to a clinician about your own treatment.

Sources

1. Legro RS, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014.
2. Practice Committee of ASRM. Use of clomiphene citrate in infertile women: a committee opinion. Fertil Steril. 2013.
3. Practice Committee of ASRM. Evidence-based treatments for couples with unexplained infertility: a guideline. Fertil Steril. 2020.
4. ANI Pharmaceuticals / NLM DailyMed. Clomiphene citrate tablets prescribing information.
5. Novartis / NLM DailyMed. Femara (letrozole) tablets prescribing information.
6. MedlinePlus. Clomiphene: drug information. National Library of Medicine.
7. MedlinePlus. Letrozole: drug information. National Library of Medicine.

This article is for general information and is not medical advice. Talk to a licensed provider about your own health.