Desogestrel

Source: Wikipedia, the free encyclopedia.

Desogestrel
Clinical data
Trade namesCerazette, Lovima, Hana, others
Other namesDSG; ORG-2969; 3-Deketo-11-methylene-17α-ethynyl-18-methyl-19-nortestosterone; 11-Methylene-17α-ethynyl-18-methylestr-4-en-17β-ol
AHFS/Drugs.comMultum Consumer Information
MedlinePlusa601050
License data
Routes of
administration		By mouth[1]
Drug classProgestogen
ATC code
Legal status
Legal status
5β-reductase, cytochrome P450 enzymes, others)[14]
Metabolites• Etonogestrel[14][1][11]
• Others[13][14][11]
Elimination half-lifeDesogestrel: 1.5 hours[13]
Etonogestrel: 21–38 hrs[13][15]
ExcretionUrine: 50%[13]
Feces: 35%[13]
Identifiers
  • (8S,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-11-methylidene-1,2,3,6,7,8,9,10,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-ol
JSmol)
Melting point109 to 110 °C (228 to 230 °F)
  • CC[C@]12CC(=C)[C@H]3[C@H]([C@@H]1CC[C@]2(C#C)O)CCC4=CCCC[C@H]34
  • InChI=1S/C22H30O/c1-4-21-14-15(3)20-17-9-7-6-8-16(17)10-11-18(20)19(21)12-13-22(21,23)5-2/h2,8,17-20,23H,3-4,6-7,9-14H2,1H3/t17-,18-,19-,20+,21-,22-/m0/s1 checkY
  • Key:RPLCPCMSCLEKRS-BPIQYHPVSA-N checkY
  (verify)

Desogestrel is a

symptoms in women.[1] The medication is available and used alone or in combination with an estrogen.[1][14] It is taken by mouth.[1]

hormonal activity.[14] The medication is a prodrug of etonogestrel (3-ketodesogestrel) in the body.[1][14]

Desogestrel was discovered in 1972 and was introduced for medical use in Europe in 1981.[16][13][17] It became available in the United States in 1992.[18][19][20] Desogestrel is sometimes referred to as a "third-generation" progestin.[21] Along with norethisterone, it is one of the only progestins that is widely available as a progestogen-only "mini pill" for birth control.[22][23] Desogestrel is marketed widely throughout the world.[24] It is available as a generic medication.[25] In 2020, the version with ethinylestradiol was the 120th most commonly prescribed medication in the United States, with more than 5 million prescriptions.[26][27]

Medical uses

Desogestrel is a hormone blocker,

spermogenesis and has been shown to have potential as a male contraceptive.[30][31]

Desogestrel and norethisterone are the only progestins that are widely used as a progestogen-only "mini pill".[22][23] It is also the only newer-generation progestin with reduced androgenic activity that is used in such formulations.[22][23]

Available forms

See also: Ethinylestradiol/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.[32] These formulations are all indicated specifically for contraceptive purposes.[32]

Contraindications

Contraindications of desogestrel include:[4]

Desogestrel is not indicated for use in pregnancy.[4] It is not contraindicated during lactation and breastfeeding.[33]

Side effects

See also:
Progestin § Side effects

Common

hormone-dependent tumors (e.g., liver tumors, breast cancer), and melasma.[4]

Overdose

No serious harmful effects have been reported with

safety studies, dosages of up to 750 μg/day desogestrel in women showed no adverse effects on laboratory and various other parameters and produced no reported subjective side effects.[13] There is no antidote to desogestrel overdose and treatment should be based on symptoms.[4]

Interactions

ciclosporine) or decreased levels (e.g., lamotrigine).[4]

Pharmacology

Pharmacodynamics

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

Desogestrel is a

hormonal activity.[34][1][14]

Relative affinities (%) of desogestrel and metabolites
Compound PRTooltip Progesterone receptor ARTooltip Androgen receptor ERTooltip Estrogen receptor GRTooltip Glucocorticoid receptor MRTooltip Mineralocorticoid receptor SHBGTooltip Sex hormone-binding globulin
CBG
Tooltip Corticosteroid binding globulin
Desogestrel 1 0 0 0 0 0 0
Etonogestrel (3-keto-DSG) 150 20 0 14 0 15 0
3α-Hydroxydesogestrel 5 0 0 ? ? ? ?
3β-Hydroxydesogestrel 13 3 2 ? ? ? ?
5α-Dihydroetonogestrel 9 17 0 ? ? ? ?
3α-Hydroxy-5α-dihydroetonogestrel 0 0 0 ? ? ? ?
3β-Hydroxy-5α-dihydroetonogestrel 1 0 1 ? ? ? ?
Notes: Values are percentages (%). Reference
CBGTooltip Corticosteroid-binding globulin. Sources: [35][34]

Progestogenic activity

Desogestrel is a

affinity for the PR itself (about 1% of that of promegestone).[1][14][36] Hence, etonogestrel is exclusively responsible for the effects of desogestrel.[11] Etonogestrel has about 150% of the affinity of promegestone and 300% of the affinity of progesterone for the PR.[14] 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][14] However, some studies in combination with oral estradiol have suggested that higher doses may be necessary.[37] 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).[34] 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.[34]

Due to its progestogenic activity, desogestrel has potent functional

antigonadotropic effects, which are similarly due to its progestogenic activity.[14][34] 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.[14]

Aside from its progestogenic activity, desogestrel also has some off-target hormonal activity at other steroid hormone receptors (see below).[13][34] However, these activities are relatively weak, and desogestrel is said to be one of the most selective and pure progestogens used in oral contraceptives.[13]

Antigonadotropic effects

Desogestrel has

antigonadotropic effects via its progestogenic activity, similarly to other progestogens.[14][34] It has been found to reduce testosterone levels by 15% in women at a dosage of 125 μg/day.[14] 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.[14] 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.[38] LH levels were suppressed maximally by desogestrel within 3 days, whereas 14 days were necessary for maximal suppression of FSH and testosterone levels.[38] 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.[38] 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.[38] Upon cessation of treatment, levels of LH, FSH, and testosterone all recovered to baseline values within 4 weeks.[38]

Androgenic activity

Etonogestrel has about 20% of the affinity of

sebum production, hirsutism, and slight virilization of female fetuses.[40][41][42][43]

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.[14] Desogestrel may slightly reduce ethinylestradiol-induced increases in SHBG levels.[14] 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.[14] 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]

Glucocorticoid activity

Desogestrel has no affinity for the

venous thromboembolism and atherosclerosis.[34] 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.[34]

Glucocorticoid activity of selected steroids in vitro
Steroid Class TRTooltip Thrombin receptor (↑)a GRTooltip glucocorticoid receptor (%)b
Dexamethasone Corticosteroid ++ 100
Ethinylestradiol Estrogen – 0
Etonogestrel Progestin + 14
Gestodene Progestin + 27
Levonorgestrel Progestin – 1
Medroxyprogesterone acetate Progestin + 29
Norethisterone Progestin – 0
Norgestimate Progestin – 1
Progesterone Progestogen + 10
Footnotes: a =
RBATooltip Relative binding affinity (%) for the glucocorticoid receptor (GR). Strength: – = No effect. + = Pronounced effect. ++ = Strong effect. Sources: [45]

Other activities

Desogestrel and etonogestrel have no affinity for the estrogen receptor, and hence have no estrogenic activity.[14][1][13] 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.[14]

Desogestrel and etonogestrel have no affinity for the

antimineralocorticoid activity.[14][34]

Desogestrel and etonogestrel show some albeit weak

IC50Tooltip half-maximal inhibitory concentration = 5 μM) in vitro.[14][34]

Desogestrel stimulates the

progesterone receptor membrane component-1 (PGRMC1).[46][47] Certain other progestins act similarly in this assay, whereas progesterone acts neutrally.[46][47] It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies.[48]

Pharmacokinetics

The

corticosteroid-binding globulin.[14]

Desogestrel is a

elimination half-life of about 21 to 38 hours, reflecting the nature of desogestrel as a prodrug.[13][1][15] Desogestrel and etonogestrel are eliminated exclusively as metabolites 50% in urine and 35% in feces.[13][11]

Chemistry

See also: List of progestogens

Desogestrel, also known as 3-deketo-11-methylene-17α-ethynyl-18-methyl-19-nortestosterone or as 11-methylene-17α-ethynyl-18-methylestr-4-en-17β-ol, is a

19-nortestosterone family of progestins.[14][51][52] Desogestrel is the C3 deketo analogue of etonogestrel and the C3 deketo and C11 methylene analogue of levonorgestrel.[14][53]

Synthesis

A chemical synthesis of desogestrel has been published.[54]

History

Desogestrel was synthesized in 1972 by

Organon International in the Netherlands and was first described in the literature in 1975.[16][55][56][57] It was developed following the discovery that C11 substitutions enhance the biological activity of norethisterone.[13] Desogestrel was introduced for medical use in 1981 under the brand names Marvelon and Desogen in the Netherlands.[13][17][14] Along with gestodene and norgestimate, it is sometimes referred to as a "third-generation" progestin based on the time of its introduction to the market.[21] It was the first of the three "third-generation" progestins to be introduced.[13] Although desogestrel was introduced in 1981 and was widely used in Europe from this time, it was not introduced in the United States until 1992.[18][19][20]

Society and culture

Generic names

Desogestrel is the

INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, DCITTooltip Denominazione Comune Italiana, and JANTooltip Japanese Accepted Name.[49][50][24] While under development, it was known as ORG-2969.[49][50][24]

Brand names

Desogestrel is marketed under a variety of brand names throughout the world including Alenvona, Apri, Azalia, Azurette, Bekyree, Caziant, Cerazette,[4] Cerelle, Cesia, Cyclessa, Cyred, Denise, Desogen, Desirett, Diamilla, Emoquette, Enskyce, Feanolla, Gedarel, Gracial, Hana,[5] Isibloom, Juleber, Kalliga, Kariva, Laurina, Lovima, Marvelon,[2] Mercilon,[3] Mircette, Mirvala, Novynette, Ortho-Cept, Pimtrea, Reclipsen, Regulon, Simliya, Solia, Velivet, Viorele, and Volnea among others.[50][24][58][59]

Availability

See also: List of progestogens available in the United States

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, Asia, and elsewhere.[24][60] 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.[33][60]

In the UK, in July 2021, some Desogestrel pills were made available to purchase over the counter,[61] without requiring a prescription from a doctor beforehand. Pharmacists use a suitability questionnaire to determine if the medication is going to be suitable for the person, and if it is then they can purchase it from a pharmacy or online (all online purchases require the suitability questionnaire completed before the medication is sent to the customer).

Controversy

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.[62] 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.[63] 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.[63] 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.[62] 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.[64]

Research

Desogestrel has been studied extensively as an

oligozoospermia in almost all men.[65]

References

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Further reading