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Clomiphene Citrate & Letrozole

Note: Clomiphene citrate production has been discontinued as of early 2017. Patients may find it difficult to obtain as pharmacy supplies are exhausted worldwide.

Clomiphene citrate is a first-line treatment for polycystic ovary syndrome (PCOS) and infertility. It bears structural similarity to estradiol and works by competitively inhibiting estrogen receptors at the hypothalamus and pituitary. The result is a compensatory increase in follicle stimulating hormone (FSH) concentrations aimed at increasing ovarian folliculogenesis. Current indications for treatment with clomiphene citrate include PCOS, oligomenorrhea, unexplained infertility and less common uses such as luteal phase defect and in vitro fertilization.

Side effects of clomiphene citrate may include hot flushes, bloating, breast discomfort, nausea, mood changes and headache. Visual symptoms are rare but should prompt immediate discontinuation of the medication. Women with liver disease or pre-existing ovarian cysts that could be malignant should not take clomiphene citrate. It has a long half-life and is detectable up to 30 days after administration.

Letrozole (FemaraTM) is endorsed by the Canadian Fertility and Andrology Society (CFAS) as an alternative to clomiphene citrate for fertility treatment. It blocks the final step in estrogen synthesis by competitively inhibiting the aromatase enzyme. Letrozole reduces estrogen production in all tissues where aromatase is present. The resulting increase in FSH, aimed at restoring estrogen concentrations, thereby increases ovarian folliculogenesis. It is administered orally, and its half-life is about 48 hours.

Side effects of letrozole include bone pain, hot flushes, back pain, nausea and dyspnea but are usually only experienced after long-term use.

A recent, large randomized controlled trial compared letrozole to clomiphene citrate for women with PCOS. It demonstrated a higher live birth rate (27.5% vs. 19.1) and a higher cumulative ovulation rate (61.7% vs. 48.3%) with letrozole than with clomiphene. There was no statistical difference in congenital anomalies, pregnancy loss or twins (Legro et. al., NEJM, 2014).

Letrozole and clomiphene citrate are typically administered for a 5-day course beginning on day 3 or day 5 of the menstrual cycle. Menses can be spontaneous or induced by a progestogen (e.g. Provera 10mg PO x 10 days or Prometrium 200mg PO x 10 days). We advise patients to start testing for the LH surge using ovulation predictor kits (OPKs) around day 10. Intercourse should occur approximately every other day beginning from day 10 until day 20. Serum progesterone measurement in the mid-luteal phase (day 21-23) can confirm ovulation (> 10 nmol/L). The starting dose for clomiphene citrate is 50mg (1 tablet) and can be increased to 100mg and 150mg for anovulation as needed. The equivalent doses of letrozole are considered to be 2.5mg (1 tablet), 5mg and 7.5mg. Patients who do not ovulate on 150mg of clomiphene citrate or 7.5mg of letrozole are considered resistant to the medication.

The multiple pregnancy rate for both clomiphene citrate and letrozole are similar at 5%.

In 2005, Novartis issued a warning about the use of letrozole in premenopausal women due to the risk of birth defects. This was based on a small study that was never formally published. Since that time there have been much larger groups of patients studied and no increase in fetal malformations has been reported. In 2017, the CFAS issued a statement supporting the use of letrozole for fertility treatment.

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