Dienogest was discovered in 1979 and was introduced for medical use in 1995.[17][18][19] Additional formulations of dienogest were approved between 2007 and 2010.[10][20] It is sometimes referred to as a "fourth-generation" progestin.[21][22] Dienogest is marketed widely throughout the world.[13] It is available as a generic medication.[23]
Birth control pills containing dienogest and estradiol valerate are approved in the United States for the treatment of menorrhagia (heavy menstrual bleeding).[12]
Birth control pills containing estradiol valerate/dienogest are associated with a significantly increased risk of venous thromboembolism.[35] However, they are associated with a significantly lower risk of venous thromboembolism than birth control pills containing ethinylestradiol and a progestin.[35]
Overdoseedit
In safety studies, dienogest has been assessed in women with endometriosis at high doses of as much as 20 mg/day for up to 24 weeks and produced no clinically relevant effects on lipid metabolism, liver enzymes, the coagulatory system, or thyroidmetabolism.[11]
Interactionsedit
Dienogest is metabolized mainly by the cytochrome P450enzymeCYP3A4,[3][10] and for this reason, inhibitors and inducers of CYP3A4 can alter the amount of exposure to dienogest when administered concomitantly with it.[10] (For a list of CYP3A4 inhibitors and inducers, see here.) The strong CYP3A4 inhibitors ketoconazole and erythromycin have been found to increase exposure to dienogest by up to 3-fold, whereas the strong CYP3A4 inducer rifampicin (rifampin) was found to decrease steady-state and area-under-curve concentrations of dienogest by 50% and 80%, respectively.[10]
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PRTooltip progesterone receptor, metribolone for the ARTooltip androgen receptor, estradiol for the ERTooltip estrogen receptor, dexamethasone for the GRTooltip glucocorticoid receptor, aldosterone for the MRTooltip mineralocorticoid receptor, DHTTooltip dihydrotestosterone for SHBGTooltip sex hormone-binding globulin, and cortisol for CBGTooltip Corticosteroid-binding globulin. Sources:[1]
Dienogest has been described as "special" progestogen, possessing low or moderate antigonadotropic efficacy but strong or very strong endometrial efficacy.[2][7] In relation to its endometrial activity, dienogest is said to be one of the strongest progestogens available.[2] The high endometrial activity of dienogest underlies its ability to stabilize the menstrual cycle when combined with either ethinylestradiol or estradiol valerate (which has lower relative effects on the uterus compared to ethinylestradiol) in birth control pills, and also its use in the treatment of endometriosis.[2] The combination of most other progestins with estradiol or an estradiol ester like estradiol valerate as birth control pills was unsatisfactory due to a high incidence of irregular menstrual bleeding.[2] This is a property that ethinylestradiol does not share with estradiol, because of its resistance to metabolism in the endometrium and hence its greater relative effects in this part of the body.[1] In contrast to other progestins, due to its high endometrial efficacy, the combination of dienogest with estradiol valerate in birth control pills is able to prevent breakthrough bleeding, and is uniquely able to treat heavy menstrual bleeding.[2] The absence of withdrawal bleeding, otherwise known as "silent menstruation", also may occur.[2] Dienogest has antiovulatory potency that is similar to that of 17α-hydroxyprogesterone derivatives like cyproterone acetate but endometrial potency that is much stronger and similar to that of gonane19-nortestosterone progestins like levonorgestrel.[36]
Unlike other progestogens, except in the case of its strong effects in the uterus, dienogest has been described as lacking antiestrogenic effects, and does not antagonize beneficial effects of estradiol, for instance in the metabolic and vascular systems.[2]
The minimum effective dose of oral dienogest required to inhibit ovulation is 1 mg/day.[2][1] The inhibition of ovulation by dienogest occurs mainly via a direct peripheral action in the ovary of inhibiting folliculogenesis as opposed to a central action of inhibiting gonadotropin secretion.[2][1] Oral therapy with 2 mg/day dienogest in cyclical premenopausal women reduced serum progesterone levels to anovulatory levels, but circulating levels of luteinizing hormone and follicle-stimulating hormone were not considerably affected.[2] At this dosage, estradiol levels are reduced to early follicular phase levels of about 30 to 50 pg/mL.[2] Such levels are insufficient for reactivation of endometrioses, but are sufficient to avoid menopausal-like symptoms such as hot flashes and bone loss.[2] This is in contrast to gonadotropin-releasing hormone analogues (GnRH analogues), which suppress estradiol levels to lower concentrations and readily induce menopausal-like symptoms.[2]
Dienogest appears to have similar effects in the breasts as norethisterone acetate, and may likewise increase the risk of breast cancer when combined with an estrogen in postmenopausal women, although this has yet to be confirmed in clinical studies.[2]
Antigonadotropic effectsedit
Dienogest has been found to suppress testosterone levels in men by 43% at 2 mg/day, 70% at 5 mg/day, and 81% at 10 mg/day.[37][38] The suppression of testosterone levels with 10 mg/day dienogest was comparable to that with 10 mg/day cyproterone acetate.[38][37] In general, progestogens are able to suppress testosterone levels in men by a maximum of about 70 to 80% at sufficiently high doses.[39][40][41][42][43]
Dienogest is rapidly absorbed with oral administration and has high bioavailability of approximately 90%.[3]Peak levels of dienogest occur within approximately 2 hours after an oral dose.[7] The pharmacokinetics of dienogest are linear; single oral doses of dienogest were found to result in maximal levels of 28 ng/mL with 1 mg, 54 ng/mL with 2 mg, 101 ng/mL with 4 mg, and 212 ng/mL with 8 mg.[7] The corresponding area-under-the-curve levels were 306, 577, 1153, and 2293 ng/mL, respectively.[7] Dienogest reaches steady-state concentrations within 6 days of continuous administration, and does not accumulate in the body.[7][3] The plasma protein binding of dienogest is 90%, with a relatively high free fraction of 10%.[7] It is exclusively bound to albumin, with no binding to SHBG or corticosteroid-binding globulin.[2][7][3] The lack of affinity of dienogest for SHBG is in contrast to most other 19-nortestosterone progestins.[2] The volume of distribution of dienogest is relatively low at 40 L.[7]
In terms of structure–activity relationships, the C17α cyanomethyl group of dienogest is responsible for its unique antiandrogenic instead of androgenic activity relative to other 19-nortestosterone progestins.[48] A loss of ability to activate the AR is also seen with other testosterone derivatives with extended-length C17α substitutions such as topterone (propyltestosterone) (compare to the AAS ethyltestosterone and methyltestosterone) and allylestrenol (compare to the AAS ethylestrenol).[51][52] Studies with steroids similar to dienogest (e.g., dienolone) have found that the introduction of a double bond between the C9 and C10 positions is associated with similar/almost unchanged affinity for the PR and AR.[53] On the other hand, the C9(10) double bond of dienogest appears to inhibit metabolism via 5α-reductase and/or 5β-reductase, which is the major metabolic route for other 19-nortestosterone progestins like norethisterone, norgestrel, and etonogestrel, and this may serve to improve the metabolic stability and potency of dienogest.[54][55]
Historyedit
Dienogest was synthesized in 1979 in Jena, Germany under the leadership of Kurt Ponsold, was initially referred to as STS-557.[17][18] It was found that its potency was 10 times that of levonorgestrel.[56] The first product on the market to contain dienogest was a combined birth control pill (with ethinylestradiol), Valette, introduced in 1995 and made by Jenapharm.[19] In 2007, dienogest was introduced as Dinagest in Japan for the treatment of endometriosis, and it was subsequently marketed for this indication as Visanne in Europe and Australia in December 2009 and April 2010, respectively.[10] Qlaira was introduced in Europe in 2009 and Natazia was introduced in the United States in 2010.[20]
Society and cultureedit
Generic namesedit
Dienogest is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, and JANTooltip Japanese Accepted Name, while diénogest is its DCFTooltip Dénomination Commune Française.[47][13] It is also known by its synonyms dienogestril and cyanomethyldienolone as well as by its numerous former developmental code names including BAY 86-5258, M-18575, MJR-35, SH-660, SH-T00660AA, STS-557, and ZK-37659.[47][13]
Brand namesedit
Dienogest is marketed in combination with estradiol valerate as a birth control pill primarily under the brand names Natazia and Qlaira and in combination with ethinylestradiol as a birth control pill primarily under the brand name Valette, although these combinations are marketed under numerous other brand names as well.[13] In the case of the dienogest and estradiol valerate birth control pill, these other brand names include Gianda and Klaira.[13] Dienogest is also marketed in combination with estradiol valerate for use in menopausal hormone therapy under a variety of brand names including Climodien, Climodiène, Estradiol Valeraat / Dienogest, Klimodien, lafamme, Lafleur, Mevaren, Valerix, and Velbienne.[13] Dienogest is marketed as a standalone medication for the treatment of endometriosis primarily under the brand name Visanne, but is also available under the brand names Alondra, Dinagest, Disven, Visabelle, and Visannette in various countries.[13]
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^ abBizzarri N, Remorgida V, Leone Roberti Maggiore U, Scala C, Tafi E, Ghirardi V, et al. (September 2014). "Dienogest in the treatment of endometriosis". Expert Opinion on Pharmacotherapy. 15 (13): 1889–1902. doi:10.1517/14656566.2014.943734. PMID 25069386. S2CID 37627607.
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Laganà AS, Vitale SG, Muscia V, Rossetti P, Buscema M, Triolo O, et al. (March 2017). "Endometrial preparation with Dienogest before hysteroscopic surgery: a systematic review". Archives of Gynecology and Obstetrics. 295 (3): 661–667. doi:10.1007/s00404-016-4244-1. PMID 27904953. S2CID 23557269.
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García Uranga-Romano J, Hernández-Valencia M, Zárate A, Basavilvazo-Rodríguez MA (2017). "[Dienogest usefulness in pelvic pain due to endometriosis. A meta-analysis of its effectiveness]". Revista Medica del Instituto Mexicano del Seguro Social (in Spanish). 55 (4): 452–455. PMID 28591499.
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Regidor PA, Schindler AE (October 2017). "Antiandrogenic and antimineralocorticoid health benefits of COC containing newer progestogens: dienogest and drospirenone". Oncotarget. 8 (47): 83334–83342. doi:10.18632/oncotarget.19833. PMC5669973. PMID 29137347.
External linksedit
"Dienogest". Drug Information Portal. U.S. National Library of Medicine.