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 ageneric medication.[23]
Dienogest is used primarily inbirth control pills in combination withethinylestradiol under the brand name Valette.[24][7][25] It is also available in a quadriphasic birth control pill combined with estradiol valerate, marketed as Natazia in the United States and Qlaira in some European countries and Russia.[26][27][28]
Dienogest is approved as a standalone medication under several brand names (Visanne, others) in many countries such as European nations, Israel, Australia, Japan, Singapore, and Malaysia for the treatment ofendometriosis.[29][10][30] It has been found to be equally effective asgonadotropin-releasing hormone agonists (GnRH agonists), such asleuprorelin (brand name Lupron), in the treatment of endometriosis.[29]
Birth control pills containing dienogest and estradiol valerate are approved in the United States for the treatment ofmenorrhagia (heavy menstrual bleeding).[12]
Dienogest is used in combination with estradiol valerate in the treatment ofmenopausalsymptoms in certain countries such as Germany and the Netherlands.[8][11]
Birth control pills containingestradiol valerate/dienogest are associated with a significantly increased risk ofvenous thromboembolism.[35] However, they are associated with a significantly lower risk of venous thromboembolism than birth control pills containingethinylestradiol and a progestin.[35]
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 onlipid metabolism,liver enzymes, thecoagulatory system, orthyroidmetabolism.[11]
Dienogest ismetabolized mainly by thecytochrome P450enzymeCYP3A4,[3][10] and for this reason,inhibitors andinducers of CYP3A4 can alter the amount of exposure to dienogest when administered concomitantly with it.[10] (For a list of CYP3A4 inhibitors and inducers, seehere.) The strong CYP3A4 inhibitorsketoconazole anderythromycin have been found to increase exposure to dienogest by up to 3-fold, whereas the strong CYP3A4 inducerrifampicin (rifampin) was found to decreasesteady-state andarea-under-curve concentrations of dienogest by 50% and 80%, respectively.[10]
Dienogest has been described as "special" progestogen, possessing low or moderateantigonadotropic efficacy but strong or very strongendometrial 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 themenstrual 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 withestradiol or anestradiol ester like estradiol valerate as birth control pills was unsatisfactory due to a high incidence ofirregular menstrual bleeding.[2] This is a property that ethinylestradiol does not share with estradiol, because of its resistance tometabolism 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 preventbreakthrough bleeding, and is uniquely able to treatheavy menstrual bleeding.[2] The absence ofwithdrawal bleeding, otherwise known as "silent menstruation", also may occur.[2] Dienogest has antiovulatory potency that is similar to that of17α-hydroxyprogesterone derivatives likecyproterone acetate but endometrial potency that is much stronger and similar to that ofgonane19-nortestosterone progestins likelevonorgestrel.[36]
Unlike other progestogens, except in the case of its strong effects in the uterus, dienogest has been described as lackingantiestrogenic effects, and does not antagonize beneficial effects of estradiol, for instance in themetabolic andvascular systems.[2]
The minimum effective dose of oral dienogest required to inhibitovulation is 1 mg/day.[2][1] The inhibition of ovulation by dienogest occurs mainly via a direct peripheral action in theovary of inhibitingfolliculogenesis as opposed to a central action of inhibitinggonadotropin secretion.[2][1] Oral therapy with 2 mg/day dienogest in cyclical premenopausal women reduced serum progesterone levels toanovulatory levels, but circulating levels ofluteinizing hormone andfollicle-stimulating hormone were not considerably affected.[2] At this dosage, estradiol levels are reduced to earlyfollicular phase levels of about 30 to 50 pg/mL.[2] Such levels are insufficient for reactivation of endometrioses, but are sufficient to avoidmenopausal-like symptoms such ashot flashes andbone loss.[2] This is in contrast togonadotropin-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 thebreasts asnorethisterone acetate, and may likewise increase the risk ofbreast cancer when combined with an estrogen in postmenopausal women, although this has yet to be confirmed in clinical studies.[2]
Testosterone levels with 2, 5, or 10 mg/day dienogest, 10 mg/day oralcyproterone acetate, orplacebo in healthy young men.[37]
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/daycyproterone 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 rapidlyabsorbed withoral administration and has highbioavailability 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 correspondingarea-under-the-curve levels were 306, 577, 1153, and 2293 ng/mL, respectively.[7] Dienogest reachessteady-state concentrations within 6 days of continuous administration, and does not accumulate in the body.[7][3] Theplasma protein binding of dienogest is 90%, with a relatively high free fraction of 10%.[7] It is exclusively bound toalbumin, with no binding to SHBG orcorticosteroid-binding globulin.[2][7][3] The lack of affinity of dienogest for SHBG is in contrast to most other 19-nortestosterone progestins.[2] Thevolume of distribution of dienogest is relatively low at 40 L.[7]
In terms ofstructure–activity relationships, the C17α cyanomethyl group of dienogest is responsible for its unique antiandrogenic instead of androgenic activity relative to other 19-nortestosterone progestins.[3] A loss of ability to activate the AR is also seen with other testosterone derivatives with extended-length C17α substitutions such astopterone (propyltestosterone) (compare to the AASethyltestosterone andmethyltestosterone) andallylestrenol (compare to the AASethylestrenol).[50][51] 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.[52] On the other hand, the C9(10) double bond of dienogest appears to inhibitmetabolism via5α-reductase and/or5β-reductase, which is the major metabolic route for other 19-nortestosterone progestins likenorethisterone,norgestrel, andetonogestrel, and this may serve to improve themetabolic stability andpotency of dienogest.[53][54]
Dienogest was synthesized in 1979 inJena,Germany under the leadership of Kurt Ponsold, was initially referred to asSTS-557.[17][18] It was found that its potency was 10 times that oflevonorgestrel.[55] The first product on the market to contain dienogest was a combined birth control pill (with ethinylestradiol), Valette, introduced in 1995 and made byJenapharm.[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]
Dienogest is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANTooltip British Approved Name, andJANTooltip Japanese Accepted Name, whilediénogest is itsDCFTooltip Dénomination Commune Française.[47][13] It is also known by its synonymsdienogestril andcyanomethyldienolone as well as by its numerous former developmental code names includingBAY 86-5258,M-18575,MJR-35,SH-660,SH-T00660AA,STS-557, andZK-37659.[47][13]
Dienogest is marketed in combination withestradiol valerate as abirth control pill primarily under the brand names Natazia and Qlaira and in combination withethinylestradiol 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 inmenopausal 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 ofendometriosis primarily under the brand name Visanne, but is also available under the brand names Alondra, Dinagest, Disven, Visabelle, and Visannette in various countries.[13]
Known availability of dienogest in countries throughout the world (as of August 2018). Alone is dienogest as a standalone medication. EV is estradiol valerate and EE is ethinylestradiol.
Dienogest is available both alone and in combination with ethinylestradiol and estradiol valerate widely throughout the world, including but not limited to Canada, Europe, Latin America, and Southeast Asia.[13][56] It is available specifically as a standalone medication in Canada, Europe, Latin America, Russia, Australia, South Africa, Georgia (country), Israel, Japan, South Korea, Hong Kong, and Thailand.[13][56] It is notably not available as a standalone medication in the United States or the United Kingdom.[13][56]
^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.PMID25069386.S2CID37627607.
^Stanczyk FZ, Bretsky (22 May 2013)."Biosynthesis, Transport, and Metabolism of Steroid Hormones". In Falcone T, Hurd WW (eds.).Clinical Reproductive Medicine and Surgery: A Practical Guide. Springer Science & Business Media. pp. 300–.ISBN978-1-4614-6837-0.Dienogest is a 19-nortestosterone derivative that is approved in the European Union for the treatment of endometriosis. It is not available in the United States as a separate drug. It is only available in the oral contraceptive Natazia (Bayer Pharmaceuticals, Montville, NJ, USA) (estradiol valerate/dienogest), which is a newer four-phasic pack that contains dienogest.
^abcMicks EA, Jensen JT (January 2013). "Treatment of heavy menstrual bleeding with the estradiol valerate and dienogest oral contraceptive pill".Advances in Therapy.30 (1):1–13.doi:10.1007/s12325-012-0071-3.PMID23239397.S2CID31125733.
^abMenzenbach B, Hübner M, Ponsold K (1984). "Untersuchungen zur Bromierung/Dehydrobromierung von 17-Cyanmethyl-17-hydroxy-östr-5(10)-en-3-on".Journal für Praktische Chemie.326 (6):893–898.doi:10.1002/prac.19843260606.
^abKaufmann G, Dautzenberg H, Henkel H, Müller G, Schäfer T, Undeutsch B, Oettel M (August 1999). "Nitrile hydratase from Rhodococcus erythropolis: metabolization of steroidal compounds with a nitrile group".Steroids.64 (8):535–540.doi:10.1016/S0039-128X(99)00028-8.PMID10493599.S2CID21769309.
^Whalen KL, Rose R (October 2011). "Estradiol valerate/dienogest: a novel oral contraceptive".The Annals of Pharmacotherapy.45 (10):1256–1261.doi:10.1345/aph.1Q216.PMID21917554.S2CID33366375.
^abAndres M, Lopes LA, Baracat EC, Podgaec S (September 2015). "Dienogest in the treatment of endometriosis: systematic review".Archives of Gynecology and Obstetrics.292 (3):523–529.doi:10.1007/s00404-015-3681-6.PMID25749349.S2CID22168242.
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^abWiegratz I, Kuhl H (September 2006). "Metabolic and clinical effects of progestogens".The European Journal of Contraception & Reproductive Health Care.11 (3):153–161.doi:10.1080/13625180600772741.PMID17056444.S2CID27088428.
^Knuth UA, Hano R, Nieschlag E (November 1984). "Effect of flutamide or cyproterone acetate on pituitary and testicular hormones in normal men".The Journal of Clinical Endocrinology and Metabolism.59 (5):963–969.doi:10.1210/jcem-59-5-963.PMID6237116.
^Jacobi GH, Altwein JE, Kurth KH, Basting R, Hohenfellner R (June 1980). "Treatment of advanced prostatic cancer with parenteral cyproterone acetate: a phase III randomised trial".British Journal of Urology.52 (3):208–215.doi:10.1111/j.1464-410x.1980.tb02961.x.PMID7000222.
^Sander S, Nissen-Meyer R, Aakvaag A (1978). "On gestagen treatment of advanced prostatic carcinoma".Scandinavian Journal of Urology and Nephrology.12 (2):119–121.doi:10.3109/00365597809179977.PMID694436.
^Kjeld JM, Puah CM, Kaufman B, Loizou S, Vlotides J, Gwee HM, et al. (November 1979). "Effects of norgestrel and ethinyloestradiol ingestion on serum levels of sex hormones and gonadotrophins in men".Clinical Endocrinology.11 (5):497–504.doi:10.1111/j.1365-2265.1979.tb03102.x.PMID519881.S2CID5836155.
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^Misro MM, Chaki SP, Kaushik MC, Nandan D (June 2009). "Trials for development of once-a-month injectable, hormonal male contraceptive using dienogest plus testosterone undecanoate: dose standardization, efficacy and reversibility studies in rats".Contraception.79 (6):488–497.doi:10.1016/j.contraception.2009.01.003.PMID19442786.
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Whalen KL, Rose R (October 2011). "Estradiol valerate/dienogest: a novel oral contraceptive".The Annals of Pharmacotherapy.45 (10):1256–1261.doi:10.1345/aph.1Q216.PMID21917554.S2CID33366375.
Micks EA, Jensen JT (January 2013). "Treatment of heavy menstrual bleeding with the estradiol valerate and dienogest oral contraceptive pill".Advances in Therapy.30 (1):1–13.doi:10.1007/s12325-012-0071-3.PMID23239397.S2CID31125733.
Bizzarri 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.PMID25069386.S2CID37627607.
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