which has potent functional antiandrogenic effects mainly due to increased SHBG levels, the androgenic activity of desogestrel is said to be essentially without any clinical relevance. Indeed, combined oral contraceptives containing ethinylestradiol and desogestrel have been found to significantly decrease free concentrations of testosterone and to possess overall antiandrogenic effects, significantly reducing symptoms of acne and hirsutism in women with hyperandrogenism. Glucocorticoid activity Desogestrel has no affinity for the glucocorticoid receptor, but etonogestrel has about 14% of the affinity of dexamethasone for this receptor. Hence, desogestrel and etonogestrel have weak glucocorticoid activity. At typical clinical dosages, the glucocorticoid activity of desogestrel is said to be negligible or very weak and hence not clinically relevant. However, it may nonetheless possibly influence vascular function, with some upregulation of the thrombin receptor observed with etonogestrel in vascular smooth muscle cells in vitro. This could, in theory, increase coagulation and contribute to an increased risk of venous thromboembolism and atherosclerosis. The affinity of etonogestrel for the glucocorticoid receptor is a product of its C11 methylene substitution, as substitutions at the C11 position are a common feature of corticosteroids and as levonorgestrel, which is etonogestrel without the C11 methylene group (17α-ethynyl-18-methyl-19-nortestosterone), has only 1% of the affinity of dexamethasone for the receptor and hence is considered to have negligible glucocorticoid activity. Other activities Desogestrel and etonogestrel have no affinity for the estrogen receptor, and hence have no estrogenic activity. However, the metabolite 3β-hydroxydesogestrel has weak affinity for the estrogen receptor (about 2% of that of estradiol), although the significance of this is uncertain. Desogestrel and etonogestrel have no affinity for the mineralocorticoid receptor, and hence have no mineralocorticoid or antimineralocorticoid activity. Desogestrel and etonogestrel show some albeit weak inhibition of 5α-reductase (5.7% inhibition at 0.1 μM, 34.9% inhibition at 1 μM) and cytochrome P450 enzymes (e.g., CYP3A4) ( = 5 μM) in vitro. Desogestrel stimulates the proliferation of MCF-7 breast cancer cells in vitro, an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1). Certain other progestins act similarly in this assay, whereas progesterone acts neutrally. It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies. Pharmacokinetics The bioavailability of desogestrel has been found to range from 40 to 100%, with an average of 76%. This significant interindividual variability is comparable to that