The pharmacokinetics and pharmacodynamics of 150 micrograms desogestrel (DG) or 150 micrograms 3-keto-desogestrel (KDG) in combination with 30 micrograms ethinylestradiol (EE) were compared in a cross-over study. While the EE levels as well as the area under the curve (AUC) of KDG did not differ, significantly higher peak levels of KDG were observed after intake of the KDG-containing formulation. As compared to the control cycle, LH and FSH were not reduced on day 3 of the first treatment cycle (3/I), but markedly suppressed on day 21 of the third cycle (21/III), the effects being more pronounced with the DG-containing pill. The serum levels of testosterone, free testosterone, androstenedione, androstanediol glucuronide, and dehydroepiandrosterone sulfate (DHEA-S) were significantly reduced already on day 3/I, while sex hormone-binding globulin (SHBG) was unchanged and corticosteroid-binding globulin (CBG) was increased. Thereafter, both SHBG and CBG rose markedly. The progressive decrease in DHEA-S correlated best with free testosterone and androstanediol glucuronide. The results indicate that the peak level of KDG is more important for the biological effectiveness than the AUC of KDG which 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.