Aromatase Inhibitor Effects on Ovarian Function During the Follicular and Early Luteal Phase in Women

In clinical practice emergency contraception (EC) intends to suppress follicular development, ovulation, or the ability of a conceptus to implant. Exogenous steroids, estrogen and progestin, are used in various formulations to accomplish the suppression. Though EC are now available 'over-the-counter' in Canada and many countries around the world; the ovarian response is unpredictable and EC do not inhibit ovulation at the most critical times of the menstrual cycle. In 2002 approximately 120,000 of 450,000 pregnancies in Canada ended in elective pregnancy termination. In the US 49% of the 3.5 million annual pregnancies were unintended and 54% of the unintended pregnancies resulted in elective termination.

Current hormonal contraceptive regimens, pre and post coital, are based on the traditional theory of follicular development that states that a single group of antral follicles is recruited in the late luteal phase for growth. Recent documentation has show that human ovarian folliculogenesis occurs in a 2-3 wave like pattern during a menstrual cycle. Wave emergence has been documented to occur in the early luteal phase with the final wave being ovulatory. The new model of follicular wave dynamics is well established and supported by experimental evidence in the bovine and equine models.

Traditionally these hormonal medications are taken 72 to 120 hours after known or suspected barrier contraception failure or unprotected intercourse. The two standard steroidal EC methods are Plan BTM, containing of 0.75 mg levonorgestrel (LNG), and the Yuzpe method, containing 0.1 mg ethinyl estradiol (EE) and 0.5 mg LNG. Ovarian follicular development and ovulation in women have been studied after EC use; however, the mechanisms underlying follicular growth, regression, and ovulation during EC use remain poorly elucidated. The mechanism of action differs with each EC regimen as well as being dependent upon the relative timing between dosing, intercourse, and ovulation. Previous studies have shown that EC are most effective if used when the dominant follicle diameter is small (4 to 5 days prior to ovulation), however, during this time interval intercourse is less likely to result in pregnancy whether or not EC were administered.

All current emergency contraception (EC) options are guided by the traditional theory of follicular development. Based on the findings of an unpredictable response of the ovaries to EC treatment, the occurrence of ovulation after treatment with EC, and findings of follicle growth in a 2-3 wave pattern, we need to reconsider the phase of the menstrual cycle and the treatment given for emergency contraception.

Aromatase inhibitors (AI) prevent the enzymatic conversion of androgens to estrogens. This significantly lowers serum estrogen levels. AI have been administered around the time of menses for ovulation induction and ovulation was seen to follow 10 to 12 days later. The rationale for inducing atresia of dominant follicles stems from this observation. Acute estradiol deprivation should theoretically initiate atresia of all viable follicles in the cohort resulting in the emergence of a new follicle wave without an ovulation event occurring.