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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.

During a cross-over study with young female volunteers, the effects of a combination of 30 micrograms ethinylestradiol (EE) and 150 micrograms desogestrel (DG) or 3-keto-desogestrel (KDG) upon lipid metabolism were investigated on day 3 of the first cycle (day 3/I) and on day 21 of the third cycle of treatment (day 21/III). As compared to the control cycle, total cholesterol (CH), low-density lipoprotein CH (LDL-CH), and the apolipoproteins A-II and B were reduced already on day 3/I, the effects being more pronounced with the DG-containing formulation. On day 21/III of treatment with EE/DG, the levels of total CH, LDL-CH and apolipoprotein B did not differ from controls, while apolipoprotein A-II was significantly increased. The effects of EE/KDG were similar, except that on LDL-CH which was still reduced on day 21/III. The serum concentrations of total triglycerides (TG), very low-density lipoprotein CH (VLDL-CH), VLDL-TG, LD-TG, high-density lipoprotein CH (HDL-CH), HDL-TG, and apolipoprotein A-I were not significantly affected on day 3/I, but elevated on day 21/III. As during treatment with EE/KDG the peak level of KDG was higher than with EE/DG, the results indicate a more pronounced antagonistic effect of EE/KDG on some EE-induced changes on lipoproteins during the first days of intake. These short-term changes possibly reflect a rapid enhancement of hepatic uptake of remnants and LDL by EE. During long-term treatment, the other effects of EE, e.g. the stimulation of hepatic synthesis of TG, VLDL, and HDL and the inhibition of hepatic lipoprotein lipase, become apparent.

The serum concentrations of ethinylestradiol (EE) and 3-keto-desogestrel (KDG) were compared during treatment with a combination of 20 micrograms EE + 150 micrograms DG (20EE/DG) or of 30 micrograms EE + 150 micrograms DG (30EE/DG). During intake of both preparations, the peak levels and the areas under the curve (AUC) of EE increased significantly by approximately 100% between days 1 and 10. In the steady state, the maximal EE levels were 75 +/- 34 pg/ml (20EE/DG) and 136 +/- 55 pg/ml (30EE/DG), and the AUC were 464 +/- 236 pg.h/ml and 840 +/- 492 pg.h/ml. The KDG levels, which were identical with both preparations, increased between days 1 and 21 by approximately 300% up to values of 4.5 +/- 1.6 ng/ml. There were large interindividual variations in the AUC of EE and KDG and no correlation between the levels of EE and KDG. On day 21 of intake of 30EE/DG, the serum concentrations of sex-hormone- and corticosteroid-binding globulin were higher by 16% and 12%, respectively than with 20EE/DG. Although the morning peak levels of cortisol did not differ, the decrease which occurred thereafter, according to the circadian rhythm, was slower with 30EE/DG. There was no relationship between the serum concentrations of EE and/or KDG and the occurrence of irregular bleedings, which was similar during treatment with both preparations. As most of the women who bled had bleedings both with 20EE/DG and 30EE/DG, an influence of predisposition can be assumed.(ABSTRACT TRUNCATED AT 250 WORDS)