Can Clomid (clomiphene citrate) be effective for infertility if Letrozole (letrozole) is not?

From the Guidelines

Yes, it is possible for clomid to work if letrozole doesn’t work for infertility, as they have different mechanisms of action and some women may respond better to one medication than the other. The most recent and highest quality study, a systematic review and meta-analysis by Cohlen et al. 1, found that clomiphene citrate or tamoxifen are acceptable alternatives to low dose gonadotrophins for low multiple pregnancy and birth rates, although at a lower live birth rate than with gonadotrophins.

Key Points to Consider

• Clomiphene citrate and letrozole work through different mechanisms to induce ovulation, with clomiphene citrate blocking estrogen receptors and letrozole decreasing estrogen production 1.
• Some women may respond better to one medication than the other based on their specific hormonal profile and the cause of their infertility.
• Clomid is typically prescribed at 50-100 mg daily for 5 days, usually starting on day 3-5 of the menstrual cycle.
• If letrozole hasn't worked, trying Clomid for 3-6 cycles may be recommended before considering other fertility treatments.
• However, Clomid has a higher risk of multiple pregnancies and side effects like hot flashes, mood swings, and visual disturbances compared to letrozole, as noted in the study by Cantineau et al. 1.
• Regular monitoring with ultrasounds and hormone tests during treatment is crucial to assess follicle development and adjust dosing as needed, as emphasized by van Rumste et al. (2008) in their systematic review and meta-analysis 1.

Important Considerations for Treatment

• The study by Erdem et al. (2015) and Peeraer et al. (2015) found that gonadotrophins showed significantly higher live birth rates and comparable, relatively low multiple pregnancy rates compared to clomiphene citrate 1.
• The Cochrane systematic review concluded that there is no benefit in using Letrozole compared to clomiphene citrate based on moderate quality evidence 1.
• High-level evidence shows that when gonadotrophins are used in IUI, regimens with 75 IU or lower should be used as higher doses have similar pregnancy rates while increasing multiple pregnancy rates, as noted in the study by Cantineau et al. (2007) and confirmed by Erdem et al. (2015) and Peeraer et al. (2015) 1.

From the FDA Drug Label

Clomiphene citrate is indicated for the treatment of ovulatory dysfunction in women desiring pregnancy. Properly timed coitus in relationship to ovulation is important Clomiphene citrate therapy cannot be expected to substitute for specific treatment of other causes of ovulatory failure.

It is possible for Clomid to work if Letrozole doesn’t work for infertility, as Clomid is indicated for the treatment of ovulatory dysfunction in women desiring pregnancy and the drug label does not mention Letrozole as a factor that would affect Clomid's efficacy 2. However, the success of Clomid depends on various factors, including the patient's underlying condition and the presence of other impediments to pregnancy. Ovulatory dysfunction must be present, and other causes of infertility must be excluded or adequately treated before beginning Clomiphene citrate therapy.

• The patient should have adequate levels of endogenous estrogen.
• Primary Pituitary or Ovarian Failure should be ruled out, as Clomiphene citrate therapy cannot substitute for specific treatment of these conditions.
• Other impediments to pregnancy, such as thyroid disorders, adrenal disorders, hyperprolactinemia, and male factor infertility, should be excluded or adequately treated.

From the Research

Clomid and Letrozole for Infertility

• Clomid (clomiphene citrate) and letrozole are two medications used to treat infertility in women.
• According to a study published in The New England Journal of Medicine 3, letrozole was found to have a lower live birth rate compared to clomiphene citrate, but the difference was not significant.
• Another study published in The Cochrane Database of Systematic Reviews 4 found that gonadotropins (which can be used in conjunction with clomiphene citrate) probably result in more live births than continued clomiphene citrate in women with polycystic ovary syndrome (PCOS) who do not ovulate or conceive on clomiphene citrate or letrozole.

Comparison of Clomid and Letrozole

• A review of the physiology behind letrozole applications in infertility published in the Journal of Assisted Reproduction and Genetics 5 suggests that current protocols for using letrozole may not be optimal, and that clomiphene citrate may be a more effective option for some women.
• A study published in Fertility and Sterility 6 found that combining clomiphene citrate or letrozole with gonadotropins in IVF cycles can reduce the amount of gonadotropins used and decrease the incidence of ovarian hyperstimulation syndrome (OHSS).
• Another study published in the Yonsei Medical Journal 7 found that minimal stimulation using gonadotropin combined with clomiphene citrate or letrozole for intrauterine insemination (IUI) cycles resulted in comparable pregnancy rates, but with a lower incidence of OHSS in the letrozole group.

Possibility of Clomid Working if Letrozole Doesn't

• Based on the available evidence, it is possible for clomid to work if letrozole doesn't, as the two medications have different mechanisms of action and may be more or less effective for individual women 3, 4, 5, 6, 7.
• However, the effectiveness of clomid or letrozole for infertility treatment depends on various factors, including the underlying cause of infertility, the woman's age, and her overall health.