PRODRUG VERSUS DRUG EFFECTS OF 150 MU-G DESOGESTREL OR 3-KETO-DESOGESTREL IN COMBINATION WITH 30 MU-G ETHINYLESTRADIOL ON HORMONAL PARAMETERS - RELEVANCE OF THE PEAK SERUM LEVEL OF 3-KETO-DESOGESTREL

The pharmacokinetics and pharmacodynamics of 150 mu g desogestrel(DG) or 150 mu g 3-keto-desogestrel (KDG) in combination with 30 mu g ethin ylestradiol (EE) were compared in a cross-over study. While the EE lev els as well as the area under the curve (AUG) of KDG did not differ, s ignificantly higher peak levels of KDG were observed after intake of t he KD G-containing formulation. As compared to the control cycle, LH a nd FSH were not reduced on day 3 of the first treatment cycle (3/I), b ut markedly suppressed on day 21 of the third cycle (21/III), the effe cts being more pronounced with the DG-containing pill. The serum level s of testosterone, free testosterone, androstenedione, androstanediol glucuronide, and dehydroepiandrosterone sulfate (DHEA-S) were signific antly reduced already on day 3/I, while sex hormone-binding globulin ( SHBG) was unchanged and corticosteroid-binding globulin (CBG) was incr eased. Thereafter, both SHBG and CBG rose markedly. The progressive de crease in DHEA-S correlated best with free testosterone and androstane diol glucuronide. The results indicate that the peak level of KDG is m ore important for the biological effectiveness than the AUC of KDG whi ch appears to antagonize the suppressive action of EE on gonadotropin release. The rapid decrease in the androgen levels seems to be due to a direct inhibitory action of the pill on ovarian and adrenal steroid biosynthesis.