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) (IC50 = 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.
It is an inactive prodrug of etonogestrel with essentially no affinity for the PR itself (about 1% of that of promegestone). Hence, etonogestrel is exclusively responsible for the effects of desogestrel. Etonogestrel has about 150% of the affinity of promegestone and 300% of the affinity of progesterone for the PR. Desogestrel (via etonogestrel) is a very potent progestogen and inhibits ovulation at very low doses, in the low microgram range. The effective minimum dosage for inhibition of ovulation is 60 μg/day desogestrel (alone, not in combination with an estrogen). However, some studies in combination with oral estradiol have suggested that higher doses may be necessary. Desogestrel and etonogestrel are among the most potent progestogens available, along with gestodene and levonorgestrel (which have effective ovulation-inhibiting dosages 40 μg/day and 60 μg/day, respectively). Oral desogestrel is clinically on the order of 5,000 times more potent than oral micronized progesterone (which has an effective ovulation-inhibiting dosage of more than 300 mg/day) in humans.Due to its progestogenic activity, desogestrel has potent functional antiestrogenic effects in certain tissues. It dose-dependently antagonizes the effects of ethinylestradiol on the vaginal epithelium, cervical mucus, and endometrium, with marked progestogenic effects occurring at a dosage of 60 μg/day. There is a rise in body temperature in some women at 30 μg/day and in all women at 60 μg/day. Desogestrel also has antigonadotropic effects, which are similarly due to its progestogenic activity.