Potential of anastrozole for release of endogenous FSH

Abstract

Objective: To evaluate the pharmacodynamic, pharmacokinetic, and safety profiles for the aromatase inhibitor anastrozole when administered to healthy premenopausal women. Design: A phase I, single-center study on the effects of single and multiple doses of anastrozole. Twenty-six subjects were enrolled. The first 20 subjects were randomized to a single dose of 5 mg, 10 mg, 15 mg, or 20 mg anastrozole, or to serve as untreated controls. Subjects 21–23 and 24–26 were assigned to receive five daily doses of 10 mg and 15 mg anastrozole, respectively. Materials and Methods: Treatment administration occurred on cycle day 2 for the single dose groups and cycle days 2–6 for the multi-dose groups. Pharmacodynamics were assessed from serial measurements of E2, FSH, LH, testosterone and androstenedione. Follicular development was monitored by ultrasound, and endometrial biopsies were performed during the luteal phase. Pharmacokinetics were assessed via measurements of anastrozole plasma concentrations. Safety was determined through the monitoring of adverse event reports, vital signs and routine blood analyses. Results: Suppression of estradiol levels was quickly seen in all anastrozole-treated patients. For the single-dose group, E2 levels reached their nadir approximately 3 – 6 hours following administration and decreased by an average of 39% from baseline. Mean reductions of 21%, 46%, 55% and 37%, were seen in the 5, 10, 15 and 20 mg dose groups. Levels for the control group were essentially unchanged. Estradiol typically returned to pre-treatment levels within 24 hours. Although the multi-dose groups saw similar rapid declines, the levels typically returned to baseline by the fifth day of treatment. FSH levels rose in the anastrozole treated patients, peaking approximately 24 hours post-treatment. At 24-hours FSH increased from baseline by 13%, 52%, 49% and 75% in the 5, 10, 15 and 20 mg dose groups. Levels were essentially unchanged from baseline levels in the control group. In the multi-dose treatment groups, FSH levels increased from baseline by an average 39% during cycle days 2 – 6, as compared to 9% in the control group. No treatment related effects were seen in LH, androstenedione, or testosterone levels. One patient in the 15 mg multi-dose group developed three mature follicles while all other patients developed a single dominant follicle. Endometrial maturation at the mid-luteal phase was not different among the groups. The pharmacokinetic profile was consistent with prior reports for anastrozole in healthy volunteers. The results were linear across the doses tested. The most frequently reported adverse events were headache, menstrual irregularities, and GI symptoms. Most events were mild and transient in nature. There were no serious AEs, nor clinically significant changes in vital signs, hematological or biochemical markers. Conclusion: Anastrozole was well tolerated at the doses tested. The results demonstrate the expected effects of aromatase inhibitors, which is suppression of endogenous estradiol with a resultant increase in FSH levels. The duration of action was consistent with the half-life of the drug and does not appear to affect overall menstrual function in normal volunteers. Potential clinical effects on follicular development cannot be assessed from these limited data. However, the effect of the study drug upon endocrine function and subsequent follicle recruitment in subjects with ovulatory dysfunction would be worthy of further investigation.