Pharmacokinetic and pharmacodynamic investigations with monthly injectable contraceptive preparations

Eight normally menstruating women received Cycloprovera (25 mg medroxyprogesterone acetate with 5 mg estradiol cypionate) and seven other volunteers received HRP-102 (50 mg norethisterone enanthate with 5 mg estradiol valerate) injections at 30-day intervals for three consecutive months. The peripheral plasma levels of estradiol (E2), progesterone (PROG), medroxyprogesterone acetate (MPA) and norethisterone (NET) were measured in the luteal phase of a pretreatment cycle, during the third treatment month and during a subsequent recovery period of 60 days. Blood samples were drawn three times a week (Mondays, Wednesdays and Fridays) and endometrial biopsies were taken on day 20 to 26 of the pretreatment cycle, 20 to 24 days after the last injection and 20 to 24 days after the first normal menstrual-like bleeding during the recovery period. The (geometric) mean maximum level of MPA was 2.9 (2.4-3.7) nmol/1 and that of NET 10.1 (6.4-15.8) nmol/l. Thirty days after the last injection, the MPA level was 0.72 (0.46-1.1) nmol/l and that of NET 1.7 (1.2-2.3) nmol/l. The maximum level of exogenous E2 was 890 (700-1130) pmol/l after Cycloprovera and 1570 (870-2820) pmol/l after HRP-102 administration. Forty-nine and 41 days, respectively, after the last injection, a broad (endogenous) E2 peak was observed in all subjects, which was not followed by an ovulatory rise in PROG levels. The first ovulatory rise in PROG occurred between 71 and 90 days after the last Cycloprovera and 59 to 87 days after the last HRP-102 injection. One subject in each of the two groups failed to ovulate during the 90-day post injection period. Dating and morphometric analysis of the endometrial biopsy specimens obtained 20 to 24 days after the last injection revealed that the suppressive effect of Cycloprovera was stronger than that of HRP-102. Each injection of both formulations was followed by a bleeding-free period of approximately two weeks. The percentage of days with bleeding and spotting was 24% for Cycloprovera and 29% for HRP-102. It is concluded, that both monthly injectables inhibit follicle maturation for some 30 days and ovulation and corpus luteum formation for some 60 days, providing thus a considerable margin of safety in terms of the expected duration of contraceptive protection.