{"paper_id":"94db86b8-5756-412e-85c6-e609be0904e0","body_text":"Mini Review\nVolume 13 Issue 2 - November 2018\nDOI: 10.19080/JGWH.2018.13.555860\nJ Gynecol Women’s Health\nCopyright © All rights are reserved by Raisa Noor Khan\nJ Gynecol Women’s Health 13(2): JGWH.MS.ID.555860 (2018) 001\nJournal of\nGynecology and Women’s Health\nISSN 2474-7602\nDienogest-The Millennium Molecule!!\nShilpa Venkatesh, Pravin Singarayar and Raisa Noor Khan*\nDepartment of Obstetrics & Gynecology, St. Johns Medical College & teaching hospital, India\nSubmission: December 26, 2017 ; Published: November 29, 2018\n*Corresponding author: Raisa Noor Khan, Department of Obstetrics & Gynecology, St Johns Medical College & teaching hospital, India\nIntroduction\nDienogest (DNG) is a fourth-generation progestin, being \nextensively used in a wide variety of clinical settings in gynecology. \nIn order to write this comprehensive review, a literature search \nwas performed to identify systematic reviews and randomized \ntrials involving DNG. Databases searched included MEDLINE, \nPUBMED, Embassy and the Cochrane library. The term ‘dienogest’ \nwas associated with the following search terms: ‘endometriosis’ , \n‘contraception’ , ‘hormone replacement therapy’ , ‘safety’ , ‘efficacy’\nPharmacology\nDienogest (DNG) is a 19-nortestosterone derivative (a \nC-19 progestogen) with a cyanomethyl instead of an ethinyl \ngroup at the C-17 position. Properties derived from its C-19 \nderivative structure include its short plasma half-life, of about \n10h (which means the drug is not accumulated), and its high oral \nbioavailability, of more than 90%. DNG also has some properties  \n \ntypical of other progesterone derivatives, including a lack of effect \non the metabolic and cardiovascular systems, and considerable \nantiandrogenic activity [1,2]. DNG has no antiestrogenic activity, \nwhich is explained in its role in the treatment of endometriosis [3]. \nIt is exclusively protein bound (albumin-90%, free-10%). The lack \nof DNG binding to sex hormone binding globulin means it does not \ndisplace testosterone, resulting in the androgenic effects observed \nwith other progestins. It is metabolized by hydroxylation and \nconjugation, predominantly in the liver [4]. DNG is available in the \ndose of 2mg/day (Figure1) (Table 1).\nTable 1: Properties of Dienogest.\nAttributed to Its C19  \nDerivative Structure\nTypical of Other Progesterone \n Derivatives\nShort plasma half-life High  \nendometrial efficacy High oral \nbioavailability\nLack of CVS and metabolic  \neffects Anti-androgenic activity\nAbbreviations: DNG: Dienogest; HRT: Hormone Replacement Therapy; LA: Leuprolide Acetate; VAS: Visual Analog Scale\nFigure 1: Structure of Dienogest.\n\n\nHow to cite this article: Shilpa V, Pravin S, Raisa N K. Dienogest-The Millennium Molecule!!. J Gynecol Women’s Health. 2018: 13(2): 555860. \nDOI: 10.19080/JGWH.2018.13.555860.002\nJournal of Gynecology and Women’s Health\nAdverse effects\nIn a safety cohort of 727 women [5], the most frequently \nreported adverse effect with DNG was headache (9%), acne \n(5.1%), nausea (4.2%), weight gain (3.6%). Changes in menstrual \nbleeding patterns were also common in these trials. After 9-12 \nmonths of use, bleeding was regularized in 22%, but 28% reported \namenorrhea, oligomenorrhoea in 24% and polymorphous in 2.7%.\nClinical settings in which dienogest is currently used\na. Endometriosis\nb. In contraception\nc. Hormone replacement therapy (HRT)\nDienogest in Endometriosis\nMechanism of action:  DNG reduces endometriotic lesions \nthrough a number of biological mechanisms. It is associated with \nrelatively moderate inhibition of gonadotrophin secretion, leading \nto a modest reduction in the endogenous production of estradiol5. \nWhen given continuously, dienogest induces a hypoestrogenic, \nhypergestagenic local endocrine environment, causing a \ndecidualization of endometrial tissue followed by atrophy of the \nendometriotic lesions. In exploratory models of endometriosis, \ndialogist also demonstrates antiproliferative, anti-inflammatory, \nand anti-angiogenic effects [6-9].\nDienogest versus GnRh agonists\nPain relief: A large RCT9 (N=252) was carried out, in which \n124 women were randomised to receive DNG and 128 women \nreceived leuprolide acetate (LA). The VAS (Visual analog scale) \nscore was selected as the primary efficacy variable in this study \nbecause the VAS is an appropriate and well-established tool for \nthe measurement of pelvic pain associated with endometriosis \n[10]. Absolute reductions in VAS score from baseline to week \n24 were 47.5mm with DNG and 46.0mm with LA. This finding \nwas of high clinical relevance, as pelvic pain is one of the most \nimportant symptoms of endometriosis and because agents in the \nGnRh agonist class are widely considered a reference standard \ntreatment for improving these symptoms [11].\nHypoestrogenic effects: It is a known fact that GnRH agonists \nproduce hypogonadotrophic hypogonadism. An interesting \nhypothesis was proposed by Barbieri [12], way back in 1992. It \nstated that, ‘a concentration of estradiol that will partially prevent \nbone loss may not stimulate endometrial growth’ . DNG maintains \nestrogen levels within the therapeutic window for endometriosis, \nthat is 30-50pg/ml. Hence, the incidence of hypoestrogenic effects \nis less with DNG when compared to LA9.\nBone Mineral Density (BMD) reduction:  GnRH agonists \ncause significant loss in trabecular and cortical bone, particularly \nlumbar spine and femoral neck. This may even exceed 1% per \nmonth [13]. On the other hand, DNG showed no change in the \nmean lumbar BMD during the treatment period9, demonstrating \nminimal changes in bone turnover/bone resorption markers.\nDienogest versus other progestins (norethindrone ac -\netate)\nDienogest as the first-choice progestin for the medical \ntherapy of symptomatic endometriosis does not confer additional \nbenefits compared with norethindrone acetate in terms of pain \nrelief, health-related quality of life, or sexual functioning [14]. \nEffectiveness of either of the progestins is greatly affected by \neconomic aspects.\nFertility considerations with DNG use based on the current \nevidence, dienogest causes complete inhibition of ovulation at a \ndaily dose of 2mg [15,16]. However, dienogest monotherapy was \nnot developed as a contraceptive, and women taking dienogest \nas a treatment for endometriosis are advised to use non-\nhormonal methods of contraception [17]. The ovarian activity \nresumes rapidly (range 1-43 days) after cessation of dienogest \n[15]. Successful pregnancy has been reported in women with \nendometriosis following the cessation of dienogest treatment 2mg \ndaily for duration of up to 1 year [18,19].\nLong term safety profile of DNG in endometriosis: Two large \ntrials have been performed in Europe and Japan, to investigate \nthe role of DNG in the long-term treatment of endometriosis. The \nEuropean trial offered DNG for an overall treatment period of 65 \nweeks [19]. The intensity of pain showed significant, sustained \nimprovement during this long-term study. In addition, during the \n24-week treatment free period following the long term study, visual \nanalog scores increased only moderately, suggesting that DNG \ninduces a beneficial effect that may persist even after treatment \ncessation. The results of the European study were supported by a \n52 week, non-randomized trial of DNG conducted in Japan on 135 \nwomen with confirmed endometriosis [20]. Patient satisfaction \nwith DNG at the end of treatment was high, with 88.9% of women \nresponding that they were ‘’certainly willing” or “would prefer” to \nuse DNG again.\nDienogest as A Contraceptive\nEstradiol valerate/dienogest (E2V/DNG) is a 4-phasic oral \ncontraceptive approved for the prevention of pregnancy. The \n4-phasic design allows for acceptable cycle control and in efficacy \ntrials of estradiol valerate/dienogest in women aged 18-35 years, \nthe Pearl Index ranged from 0.40 to 1.64, a range comparable to \nthat of other combination oral contraceptives [21].\nIn most combination oral contraceptives, the estrogen \ncomponent is responsible for providing cycle control and \nstabilizing the endometrium for an acceptable bleeding pattern. \nE2V, unlike ethinyl estradiol, did not provide an adequate level of \nendometrial stability, as evidenced by breakthrough bleeding rates \nin preliminary studies [22]. Hence, E2V.containing combination \noral contraceptives did not reach the market until this novel \ncombination of E2V and DNG was evaluated . \nThis combination integrates an estrogen step-down and \na progestin step-up approach in a quadri-phasic regimen \n(Figure 2). The American College of Obstetrics and Gynecology \n\n003\nJournal of Gynecology and Women’s Health How to cite this article: Shilpa V, Pravin S, Raisa N K. Dienogest-The Millennium Molecule!!. J Gynecol Women’s Health. 2018: 13(2): 555860. \nDOI: 10.19080/JGWH.2018.13.555860.\nrecommends that patients with anovulatory or ovulatory bleeding \nbe treated with a combination oral contraceptive if they require \ncontraception [23,24]. E2V/DNG is an appropriate first choice in \nheavy menstrual bleeding, for most premenopausal women who \nhave a need for contraception, do not have contraindications to \nestrogen therapy, and do not desire LNG-IUD insertion. Use of \nE2V/DNG for six months has led to significant reduction in heavy \nmenstrual bleeding with an average 65% reduction in mean blood \nloss [23].\nFigure 2: Daily doses of E2V and DNG in the quadriphonic regimen.\nDienogest in HRT\nA combination of 2mg estradiol valerate with 2mg dienogest \n(E2V/DNG) is the first continuous combined postmenopausal \nHormone Replacement Therapy (HRT) preparation to contain \na progestogen with substantial anti-androgenic activity. A study \nof its clinical efficacy and safety in a comparative study versus a \ncombination of 2mg estradiol with 1mg norethisterone acetate \n(E2/NETA) has shown both preparations to be highly effective \nin achieving a rapid response in women with postmenopausal \nsymptoms [25]. E2V/DNG is a novel HRT preparation that has a \nhighly favorable bleeding profile.\nConclusion\nDienogest is a novel drug in the treatment of endometriosis, \nwith an efficacy comparable to GnRh agonists. It is orally \nadministered (unlike GnRh agonists) and more reasonably priced. \nIts role in contraception and HRT seems promising.\nReferences\n1. Herkert O, Kuhl H, Sandow J, Busse R, Schini-Kerth VB (2001) Sex \nsteroids used in hormonal treatment increase vascular procoagulant \nactivity by inducing thrombin receptor (PAR-1) expression: role of the \nglucocorticoid receptor. Circulation 104(23): 2826-2831.\n2. Köhler G, Faustmann TA, Gerlinger C, Seitz C, Mueck AO (2010) A dose \nranging study to determine the efficacy and safety of 1, 2 and 4 mg of \ndienogest daily for endometriosis. Int J Gynecol Obstet 108(1): 21-25.\n3. Ruan X, Seeger H, Mueck A O (2012) The pharmacology of dienogest. \nMaturitas 71(4): 337-344.\n4. Teichmann A(2003) Pharmacology of estradiol valerate/dienogest. \nClimacteric. 6 suppl 2: 17-23.\n5. Strowitzki T , Faustmann T , Gerlinger C, Seitz C (2010) Dienogest in \nthe treatment of endometriosis associated pelvic pain: a 12 week \nrandomised, double-blind, placebo-controlled study. Eur J Obstet \nGynecol Reprod Biol 151(2): 193-198.\n6. Sasagawa S, Shimizu Y, Kami H, Takeuchi T , Mita S, et al. (2008) \nDienogest is a selective progesterone receptor agonist in transactivation \nanalysis with potent oral endometrial activity due to its efficient \npharmacokinetic profile. Steroids 73(2): 222-231.\n7. Sasagawa S, Shimizu Y, Nagaoka T , Tokado H, Imada K, et al. (2008) \nDienogest, a selective progestin, reduces plasma estradiol level through \ninduction of apoptosis of granulosa cells in the ovarian dominant \nfollicle without follicle-stimulating hormone suppression in monkeys. J \nEndocrinol invest. 31(7): 636-641.\n8. Katayama H, Katayama T , Uematsu K, Hiratsuka M, Kiyomura M, et \nal. (2010) Effect of dienogest administration on angiogenesis and \nhemodynamics in a rat endometrial autograft model. Hum Reprod. \n25(11): 2851-2858.\n9. Strowitzki T , Marr J, Gerlinger C, Faustmann T , Seitz C (2010) Dienogest \nis as effective as leuprolide acetate in treating the painful symptoms of \nendometriosis: a 24 week, randomized, multicentre, open-label trial. \nHum Reprod 25(3): 633-641.\n10. Fauconnier A, Dallongeville E, Huchon C, Ville Y, Falissard B (2009) \nMeasurement of acute pelvic pain intensity in gynecology; a comparison \nof five methods. Obstet Gynecol 113(2pt 1): 260-269.\n11. Schlaff WD, Carson SA, Luciano A, Ross D, Bergqvist A (2006) A \nsubcutaneous injection of depot medroxyprogesterone acetate \ncompared with leuprolide acetate in the treatment of endometriosis-\nassociated pain. Fertil Steril 85(2): 314-325.\n12. Barbieri R L (1992) Hormone treatment of endometriosis: the estrogen \nthreshold hypothesis. Am J Obstet Gynecol 166(2): 740-745.\n13. Pickersgill A (1998) GnRH agonists and add-back therapy: Is there a \nperfect combination? Br J Obstet Gynecol 105(5): 475-485.\n14. Vercellini P , Bracco B, Mosconi P , Roberto A, Alberico D, et al. (2016) \nNorethindrone acetate or dienogest for the treatment of symptomatic \nendometriosis: a before and after study. Fertil Steril 105 (3) :734-743.\n15. Klipping C, Duijkers I, Faustmann TA, Klein SF, Schuett B (2010) \nPharmacodynamic study of four oral dosages of dienogest. Fertility and \nSterility 94(4): S181.\n16. Moore C, Carol W, Graser T , Mellinger U, Walter F (1999) Influence of \ndienogest on ovulation in young fertile women. Clin Drug Invest 18(4): \n271-278.\n17. Adolf E Schindler (2011) Dienogest in long-term treatment of \nendometriosis. Int J of Women’s Health 3: 175-184.\n\nHow to cite this article: Shilpa V, Pravin S, Raisa N K. Dienogest-The Millennium Molecule!!. J Gynecol Women’s Health. 2018: 13(2): 555860. \nDOI: 10.19080/JGWH.2018.13.555860.004\nJournal of Gynecology and Women’s Health\n18. Momoeda M, Taketani Y (2007) Randomized double-blind, multicentre, \nparallel-group dose-response study of dienogest in patients with \nendometriosis. Jpn Pharmacol Ther 35: 769-783.\n19. Petraglia F, Hornung D, Seitz C, Faustmann T , Gerlinger C, et al. (2011) \nReduced pelvic pain in women with endometriosis: efficacy of long \nterm dienogest treatment. Arch Gynecol Obstet 285(1): 167-173.\n20. Momoeda M, Harada T , Terakawa N, Aso T , Fukunaga M, et al. (2009) \nLong term treatment of dienogest for the treatment of endometriosis. J \nObstet Gynaecol Res 35(6): 1069-1076.\n21. Whalen KL, Rose R (2011) Estradiol Valerate/Dienogest: a novel oral \ncontraceptive. Ann Pharmacother 45(10): 1256-1261.\n22. Fruzzeti F, Bitzer J (2010) Review of clinical experience with estradiol \nin combined oral contraceptives. 81(1): 8-15.\n23. Rafie S, Borgelt L, Koepf ER, Temple-Cooper ME, Lehman KJ (2013) \nNovel oral contraceptive for heavy menstrual bleeding: estradiol \nvalerate and dienogest. Int J Women’s Health 5: 313-321.\n24. (2010) American College of Obstetricians and Gynecologists. ACOG \npractice bulletin: management of anovulatory bleeding. Int J Gynaecol \nObstet 72(3): 263-271.\n25. Von Schoultz B (2003) Clinical efficacy and safety of combined estradiol \nvalerate and dienogest: a new no-bleed treatment. 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