Desogestrel

Desogestrel is a hormone blocker, progesterone receptors agonist, and antiandrogen. It is used in conjunction with estrogens and testosterones. Medications containing desogestrel and estrogen are used to treat endometriosis and as a component of menopausal hormone therapy. While commonly used as a female contraceptive, desogestrel suppresses spermogenesis and has been shown to have potential as a male contraceptive. Desogestrel and norethisterone are the only progestins that are widely used as a progestogen-only "mini pill". These formulations are all indicated specifically for contraceptive purposes. ==Contraindications==

Contraindications of desogestrel include: ==Side effects==

Common side effects of desogestrel may include menstrual irregularities, amenorrhea, headaches, nausea, breast tenderness, and mood changes (e.g., depression), as well as weight gain, acne, and hirsutism. However, it has also been reported to not adversely affect weight. In addition, acne and hirsutism are negligible when combined with ethinylestradiol, and this combination can actually be used to treat such symptoms. Desogestrel can also cause changes in total, , and cholesterol. Uncommon side effects of desogestrel may include vaginal infection, contact lens intolerance, vomiting, hair loss, dysmenorrhea, ovarian cysts, and fatigue, while rare side effects include rash, urticaria, and erythema nodosum. Breast discharge, ectopic pregnancies, and aggravation of angioedema may also occur with desogestrel. Serious side effects of combined oral contraceptives containing desogestrel may include venous thromboembolism, arterial thromboembolism, hormone-dependent tumors (e.g., liver tumors, breast cancer), and melasma. ==Overdose==

No serious harmful effects have been reported with overdose of desogestrel. Symptoms may include nausea, vomiting, and, in young girls, slight vaginal bleeding. In 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. There is no antidote to desogestrel overdose and treatment should be based on symptoms. == Interactions ==

Inducers of liver enzymes can increase the metabolism of desogestrel and etonogestrel and reduce their circulating levels. This may result in contraceptive failure. Examples of liver enzyme inducers include barbiturates (e.g., phenobarbital), bosentan, carbamazepine, efavirenz, phenytoin, primidone, rifampicin, and possibly also felbamate, griseofulvin, oxcarbazepine, rifabutin, St. John's Wort, and topiramate. Many antivirals for HIV/AIDS and HCV, such as boceprevir, nelfinavir, nevirapine, ritonavir, and telaprevir, may increase or decrease levels of desogestrel and etonogestrel. CYP3A4 inhibitors including strong inhibitors like clarithromycin, itraconazole, and ketoconazole and moderate inhibitors like diltiazem, erythromycin, and fluconazole may increase levels of desogestrel and etonogestrel. Hormonal contraceptives may interfere with the metabolism of other drugs, resulting in increased levels (e.g., ciclosporine) or decreased levels (e.g., lamotrigine). ==Pharmacology==

Pharmacodynamics (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. 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 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. LH levels were suppressed maximally by desogestrel within 3 days, whereas 14 days were necessary for maximal suppression of FSH and testosterone levels. Conversely, its selectivity for the PR over the AR is similar to other newer 19-nortestosterone progestins like gestodene and norgestimate. 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. Hence, desogestrel and etonogestrel have weak glucocorticoid activity. Certain other progestins act similarly in this assay, whereas progesterone acts neutrally. Pharmacokinetics The bioavailability of desogestrel has been found to range from 40 to 100%, with an average of 76%. Desogestrel and etonogestrel are eliminated exclusively as metabolites 50% in urine and 35% in feces. ==Chemistry==

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 synthetic estrane steroid and a derivative of testosterone. Desogestrel is the C3 deketo analogue of etonogestrel and the C3 deketo and C11 methylene analogue of levonorgestrel. Synthesis A chemical synthesis of desogestrel has been published. Synthetic problems with the existing state of the art led to a novel synthesis recently being proposed. The protection of 11-alpha-hydroxy-estra-4-ene-3,17-dione [6615-00-5] (1) with 2 equivalents of ethylene glycol gave (2). Oxidation of the alcohol in the presence of phenyl dichlorophosphate, DMSO and TEA gives [54048-32-7] (3). Organometallic addition of methyllithium to the ketone gives (4). Iodination with molecular iodine in the presence of Iodobenzene diacetate [3240-34-4] under an irradiation of ultraviolet light gives the 18-halogenated product (5). Treatment with thionyl chloride gives the exomethylene olefinic product (6). Organometallic addition of methyl lithium gave PC11014529 (7). Deprotection of both ketal groups in HCl acid gave 13b-Ethyl-11-methylenegon-4-ene-3,17-dione, PC13025342 (8). Treatment with 1 equivalent of ethane-1,2-dithiol gave [54024-18-9] (9). Organometallic addition of the acetylene was the next step (10). Cleavage of the thioketal in the presence of sodium metal in liquid ammonia completed the synthesis of desogestrel (11). ==History==

Desogestrel was synthesized in 1972 by Organon International in the Netherlands and was first described in the literature in 1975. It was developed following the discovery that C11 substitutions enhance the biological activity of norethisterone. ==Society and culture==

Generic names Desogestrel is the generic name of the drug and its , , , , , and . While under development, it was known as ORG-2969. Isibloom, Juleber, Kalliga, Kariva, Laurina, Lovima, Marvelon, Availability 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. 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. 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. 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. 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. ==Research==

Desogestrel has been studied extensively as an antigonadotropin for use in combination with testosterone as a hormonal contraceptive in men. Such combinations have been found to be effective in producing reversible azoospermia in most men and reversible azoospermia or severe oligozoospermia in almost all men. == References ==