Desogestrel

Desogestrel is available alone in the form of 75 μg oral tablets and at a dose of 150 μg in combination with 20 or 30 μg ethinylestradiol in oral tablets.[19] These formulations are all indicated specifically for contraceptive purposes.[19]

Etonogestrel (3-ketodesogestrel), the active form of desogestrel.

Desogestrel is a prodrug of etonogestrel (3-ketodesogestrel), and, via this active metabolite, it has progestogenic activity, antigonadotropic effects, very weak androgenic activity, very weak glucocorticoid activity, and no other hormonal activity.[23][1][5]

Desogestrel is a progestogen, or an agonist of the progesterone receptor (PR).[1] It is an inactive prodrug of etonogestrel with essentially no affinity for the PR itself (about 1% of that of promegestone).[1][5][25] Hence, etonogestrel is exclusively responsible for the effects of desogestrel.[2] Etonogestrel has about 150% of the affinity of promegestone and 300% of the affinity of progesterone for the PR.[5] Desogestrel (via etonogestrel) is a very potent progestogen and inhibits ovulation at very low doses, in the low microgram range.[1] The effective minimum dosage for inhibition of ovulation is 60 μg/day desogestrel (alone, not in combination with an estrogen).[1][5] However, some studies in combination with oral estradiol have suggested that higher doses may be necessary.[26] 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).[23] 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.[23]

Due to its progestogenic activity, desogestrel has potent functional antiestrogenic effects in certain tissues.[5][23] 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.[5] There is a rise in body temperature in some women at 30 μg/day and in all women at 60 μg/day.[5] Desogestrel also has antigonadotropic effects, which are similarly due to its progestogenic activity.[5][23] The contraceptive effects of desogestrel in women are mediated not only by prevention of ovulation via its antigonadotropic effects but also by its marked progestogenic and antiestrogenic effects on cervical mucus and the endometrium.[5]

Aside from its progestogenic activity, desogestrel also has some off-target hormonal activity at other steroid hormone receptors (see below).[4][23] However, these activities are relatively weak, and desogestrel is said to be one of the most selective and pure progestogens used in oral contraceptives.[4]

Desogestrel has antigonadotropic effects via its progestogenic activity, similarly to other progestogens.[5][23] It has been found to reduce testosterone levels by 15% in women at a dosage of 125 μg/day.[5] In addition, desogestrel has been extensively investigated as an antigonadotropin at dosages of 150 to 300 μg/day in combination with testosterone in male contraceptive regimens.[5] One study found that 150 μg/day and 300 μg/day desogestrel alone in healthy young men suppressed luteinizing hormone (LH) levels by about 35% and 42%, respectively; follicle-stimulating hormone (FSH) levels by about 47% and 55%, respectively; and testosterone levels by about 59% and 68%, respectively.[27] LH levels were suppressed maximally by desogestrel within 3 days, whereas 14 days were necessary for maximal suppression of FSH and testosterone levels.[27] A previous study by the same authors found that increasing the dosage of desogestrel from 300 μg/day to 450 μg/day resulted in no further suppression of gonadotropin concentrations.[27] The addition of a low dose of 50 or 100 mg/week intramuscular testosterone enanthate after 3 weeks increased testosterone levels and further suppressed LH and FSH levels, to the limits of assay detection (i.e., to undetectable or near-undetectable levels), in both the 150 μg/day and 300 μg/day desogestrel groups.[27] Upon cessation of treatment, levels of LH, FSH, and testosterone all recovered to baseline values within 4 weeks.[27]

Etonogestrel has about 20% of the affinity of metribolone and 50% of the affinity of levonorgestrel for the androgen receptor (AR) while desogestrel has no affinity for this receptor.[1][5] The 5α-reduced metabolite of etonogestrel, 5α-dihydroetonogestrel (3-keto-5α-dihydrodesogestrel), also has some affinity for the AR (about 17% of that of metribolone).[5] Desogestrel (via etonogestrel) has very low androgenic potency, about 1.9 to 7.4% of that of methyltestosterone in animal assays, and hence is considered to be a very weak androgen.[1][5][25] Although etonogestrel has about the same affinity for the AR as norethisterone, due to the relatively increased progestogenic potency and decreased androgenic activity of etonogestrel, the drug has markedly higher selectivity for the PR over the AR than older 19-nortestosterone progestins like norethisterone and levonorgestrel.[4][9][28] Conversely, its selectivity for the PR over the AR is similar to other newer 19-nortestosterone progestins like gestodene and norgestimate.[9][28] It has been estimated that 150 μg/day desogestrel has less than one-sixth of the androgenic effect of 1 mg/day norethisterone (these being common dosages of the drugs used in combined oral contraceptives).[28] Clinical studies with norethisterone even at very high dosages (e.g., 10 to 60 mg/day) have observed only mild androgenic effects in a minority of women including acne, increased sebum production, hirsutism, and slight virilization of female fetuses.[29][30][31][32]

In accordance with its very weak androgenic activity, desogestrel has minimal effects on lipid metabolism and the blood lipid profile, although there may still be some significant changes.[1] Desogestrel also reduces sex hormone-binding globulin (SHBG) levels by 50% when given to women alone, but when combined with 30 μg/day ethinylestradiol, which in contrast strongly activates SHBG production, there is a 200% increase in SHBG concentrations.[5] Desogestrel may slightly reduce ethinylestradiol-induced increases in SHBG levels.[5] However, at the dosages used in oral contraceptives and in combination with ethinylestradiol, 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.[5] 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.[1]

Desogestrel has no affinity for the glucocorticoid receptor, but etonogestrel has about 14% of the affinity of dexamethasone for this receptor.[5][23][33] Hence, desogestrel and etonogestrel have weak glucocorticoid activity.[5][23][33] At typical clinical dosages, the glucocorticoid activity of desogestrel is said to be negligible or very weak and hence not clinically relevant.[5][23][33] 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.[5][23][33] This could, in theory, increase coagulation and contribute to an increased risk of venous thromboembolism and atherosclerosis.[23] 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.[23]

Desogestrel and etonogestrel have no affinity for the estrogen receptor, and hence have no estrogenic activity.[5][1][4] 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.[5]

Desogestrel and etonogestrel have no affinity for the mineralocorticoid receptor, and hence have no mineralocorticoid or antimineralocorticoid activity.[5][23]

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.[5][23]

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).[35][36] Certain other progestins act similarly in this assay, whereas progesterone acts neutrally.[35][36] It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies.[37]

The bioavailability of desogestrel has been found to range from 40 to 100%, with an average of 76%.[5][2][3] This significant interindividual variability is comparable to that with norethisterone and levonorgestrel.[2] Peak concentrations of etonogestrel occur about 1.5 hours after a dose while concentrations of desogestrel are very low and have disappeared by 3 hours after a dose.[5] Steady-state levels of etonogestrel are achieved after about 8 to 10 days of daily administration.[1] Accumulation of etonogestrel is thought to be related to progressive inhibition of 5α-reductase and cytochrome P450 monooxygenases (e.g., CYP3A4).[5] The plasma protein binding of desogestrel is 99% and it is bound exclusively to albumin.[4] Etonogestrel is bound 95 to 98% to plasma proteins.[1][5] It is bound about 65 to 66% to albumin and 30 to 32% to SHBG, with 2 to 5% free in the circulation.[1][5] While desogestrel is not bound to SHBG, etonogestrel has relatively high affinity for this plasma protein of 3 to 15% of that of dihydrotestosterone, although this is considerably less than that of the related progestins levonorgestrel and gestodene.[5][2] Neither desogestrel nor etonogestrel are bound by corticosteroid-binding globulin.[5]

Desogestrel is a prodrug of etonogestrel (3-ketodesogestrel) and upon ingestion is rapidly and completely transformed into this metabolite in the intestines and liver.[5][1][2] Hydroxylation of the C3 position of desogestrel catalyzed by cytochrome P450-dependent enzymes, with 3α-hydroxydesogestrel and 3β-hydroxydesogetrel as intermediates, followed by oxidation of the C3 hydroxyl group, is responsible for the transformation.[4][5][2] A small percentage of desogestrel is metabolized into levonorgestrel, which involves the removal of the C11 methylene group.[1] Following further metabolism of etonogestrel, which occurs mainly by reduction of the Δ⁴-3-keto group (by 5α- and 5β-reductases) and hydroxylation (by monooxygenases), the major metabolite of desogestrel is 3α,5α-tetrahydroetonogestrel.[5] Desogestrel has a very short terminal half-life of about 1.5 hours while etonogestrel has a relatively long elimination half-life of about 21 to 38 hours, reflecting the nature of desogestrel as a prodrug.[4][1][6] Desogestrel and etonogestrel are eliminated exclusively as metabolites 50% in urine and 35% in feces.[4][2]

A chemical synthesis of desogestrel has been published.[43]

Desogestrel is the generic name of the drug and its INN, USAN, BAN, DCF, DCIT, and JAN.[38][39][15] While under development, it was known as ORG-2969.[38][39][15]

Desogestrel is marketed under a variety of brand names throughout the world including Alenvona, Apri, Azalia, Azurette, Caziant, Cerazette, Cerelle, Cesia, Cyclessa, Denise, Desogen, Desirett, Diamilla, Emoquette, Feanolla, Gedarel, Gracial, Kariva, Laurina, Linessa, Marvelon, Mercilon, Mircette, Mirvala, Novynette, Ortho-Cept, Reclipsen, Regulon, Solia, Velivet, and Viorele among others.[39][15]

Desogestrel is available widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, many other European countries, Australia, New Zealand, South Africa, Latin America, South, East, and Southeast Asia, and elsewhere in the world.[15][47] In the United States, it is available only in combination with ethinylestradiol as a combined oral contraceptive; it is not available alone and is not approved for any other indications in this country.[21][47]

In February 2007, the consumer advocacy group Public Citizen released a petition requesting that the Food and Drug Administration ban oral contraceptives containing desogestrel in the United States, citing studies going as far back as 1995 that suggest the risk of dangerous blood clots is doubled for women on such pills in comparison to other oral contraceptives.[48] In 2009, Public Citizen released a list of recommendations that included numerous alternative, second-generation birth control pills that women could take in place of oral contraceptives containing desogestrel.[49] Most of those second-generation medications have been on the market longer and have been shown to be as effective in preventing unwanted pregnancy, but with a lower risk of blood clots.[49] Medications cited specifically in the petition include Apri-28, Cyclessa, Desogen, Kariva, Mircette, Ortho-Cept, Reclipsen, Velivet, and some generic pills, all of which contain desogestrel in combination with ethinylestradiol.[48] Medications containing desogestrel as the only active ingredient (as opposed to being used in conjunction with ethinylestradiol, like in combined oral contraceptives) do not show an increased thrombosis risk and are therefore safer than second-generation birth-control pills in regards to thrombosis.[50]