The Use of High Dose Letrozole in Ovulation Induction and Controlled Ovarian Hyperstimulation

Letrozole, an aromatase inhibitor, has been demonstrated to be effective as an ovulation induction and controlled ovarian hyperstimulation agent. However, dose administration has generally been limited to 5 days at 2.5 to 7.5 mg daily. We undertook a retrospective review of over 900 treatment cycles using letrozole in doses as high as 12.5 mg per day. Results indicate that such doses do indeed offer benefit to patients; in that there is increased follicular growth and a higher number of predicted ovulations with higher doses of the drug. However, increasing doses does not produce a detrimental effect upon endometrial thickness. High-dose letrozole may be of value in women who fail to respond adequately to lower doses. Furthermore, randomized trials are needed to determine whether high-dose letrozole might actually be optimal as a starting dose for certain treatment groups.

In women undergoing ovulation induction for the treatment of oligoanovulation, clomiphene citrate has long been the initial drug of choice for first-line therapy [1]. The drug works primarily by competitively inhibiting the binding of estradiol to its receptor in the hypothalamus, thereby releasing the hypothalamus from negative inhibition and allowing increased release of follicle stimulating hormone (FSH) from the pituitary gland. This increase in FSH release enhances follicular growth, increasing the chances of ovulation. The drug has also proven useful for producing multiple ovulation in couples with unexplained infertility, male factor infertility, and other disorders where controlled ovarian hyperstimulation has been deemed of value.

While approved for use in the United States for more than 40 years, clomiphene has some significant limitations. First, only 75–80% of anovulatory women respond to the medication with appropriate follicular growth [1]. Furthermore, side effects of the drug can be psychologically difficult to endure (hot flashes and mood swings) and detrimental to fertility (impaired endometrial development and abnormal cervical secretions). The drug has a lengthy half-life, and adverse effects may be cumulative over time [2].

A class of drugs known as aromatase inhibitors also has the potential to enhance FSH release, not by the inhibiting estradiol-receptor interaction, but rather by inhibition of estradiol synthesis. One such inhibitor, letrozole, was approved for use in 1997 for the treatment of breast cancer. By 2001, it had been used in anovulatory women with great success, and at present the drug is extremely popular among physicians and patients in the treatment of both ovulation dysfunction and for controlled ovarian hyperstimulation: the drug has a half-life of only 45 hours, and side effects, while similar to those of clomiphene, are far milder and less frequent [3].

The original choice of dosing with letrozole was extrapolated from several studies performed on postmenopausal women being treated for breast cancer [4, 5]. Data derived from these patients suggested substantial inhibition of estradiol formation with doses of 2.5–5 mg daily. However, the application of these data to short-term use of the drug in reproductive age women is highly questionable. Nevertheless, clinical investigation of the drug in infertile women has been generally limited to 5 days of treatment at doses of 2.5–7.5 mg daily.

For several years, we have, in women felt to be suboptimally responding to established doses of letrozole, administered doses of the drug up to 12.5 mg daily. This manuscript was designed to examine the following questions: (1) is there a role for the use of high doses (greater than 7.5 mg daily) of letrozole in the treatment of chronic anovulatory patients?; (2) is there a role for the use of high-dose letrozole in controlled ovarian hyperstimulation?; (3) what effect does higher-dose letrozole have upon endometrial development?

This study is a retrospective cohort analysis with data extracted from our electronic medical record (eIVF, Practice Highway, Dallas). All patients treated with letrozole and intrauterine insemination at the Wisconsin Fertility Institute (Middleton, WI USA), from January, 2007, to December, 2009, were included in the study. Ages ranged from 23 to 47 years. All patients were administered 5 days of a fixed dose of letrozole beginning day 3 of their cycle; if the patient was anovulatory, medroxyprogesterone was administered to induce menses. Ultrasonography was performed on cycle day 11, and follicular number, follicular size, and endometrial thickness and pattern were determined; follicles were measured in two perpendicular dimensions and the mean value recorded, while endometrial thickness was measured at the point of greatest thickness.

Predicted ovulation number was calculated based upon the size of follicles on day 11, with a 1.7 mm per day adjusted increase until the day of triggering ovulation with human chorionic gonadotropin (hGG) [6]. Each extrapolated follicle size was then assigned a probability of ovulation taken from previously published data [7]. Summation of these probabilities yielded a single predicted ovulation number per cycle.

Descriptive statistics were calculated for all variables in an univariate manner. Multivariate linear and logistic regression analysis were performed to determine the relative importance of each predictor variable and its covariates. Terms remained in the equation as significant if 𝑃