This study assessed the pharmacodynamic effects of medroxyprogesterone acetate (MPA) and estradiol cypionate (E2C) (MPA/E2C) (Lunelle monthly contraceptive injection) through changes in serum progesterone concentrations. A total of 16 surgically sterile women with regular menstrual cycles were studied for one control cycle, three consecutive treatment months, and 3-5 months of follow-up. Serum progesterone levels and, consequently, ovulation were suppressed beyond the entire dosing interval, indicated by the absence of any luteal-like progesterone peaks. The first normal ovulatory cycle, based on progesterone concentrations of 4.7 ng/ml or higher, was noted in 11 women between days 63 and 112 after the third injection. Select MPA parameters were correlated with return of ovulation. The correlation coefficients were 0.757 and 0.492 for area under the curve and minimum concentration, respectively, indicating that return of ovulation is dependent, in part, on area under the curve and on the magnitude of the serum MPA trough level. Generally, the higher the minimum concentration levels, the longer the time to return of ovulation. This study concluded that the return of ovulation, as confirmed by serum progesterone concentrations of 4.7 ng/ml or higher, was observed as early as 63 days after the third and final monthly intramuscular injection of MPA/E2C. This indicates that consistent suppression of the hypothalamic-pituitary-ovarian axis is reversible after discontinuation of dosing.