Dydrogesterone as an Option in the Medical Treatment of Endometriosis: A Brief Comment

Dydrogesterone as an Option in the Medical Treatment of Endometriosis: A Brief Comment D i d r o g e s t e r o n ac o m oo p ç ã on ot r a t a m e n t oc l í n i c od a endometriose: Um breve comentário Bruno Ramalho de Carvalho 1 1 Bruno Ramalho – R e p r o d u ç ã oH u m a n a ,B r a s í l i a ,D F ,B r a z i l Rev Bras Ginecol Obstet 2022;44(8):802 –803. Address for correspondence Bruno Ramalho de Carvalho, MD, MSc, Bruno Ramalho – Reprodução Humana, SGAS 614, Conjunto C, Sala 177, 70200-740, Edifício Vitrium, Asa Sul, Brasília, Distrito Federal, Brazil (e-mail: [email protected]). Dear Editor, Endometriosis-related pain and morbidity are assumed to cause substantial impact on quality of life. Due to its chronic - ity, the disease is expected to be clinically managed in a long- term individualized plan, considering easy access, cost-effec - tiveness, acceptance, and adherence, regardless of surgical interventions, when (and if) they are necessary. A better health-related quality of life is the main goal of the endometriosis treatment. It may be reached, individual- ly, by relieving chronic pelvic pain, either acyclic, dysmenor- rhea or dyspareunia, reducing the use of analgesics, and eventually protecting fertilit y. The opt imized treatment of the disease often combines hormonal and surgical approaches, but the current literature 1 shows an inclination towards the use of medical strategies as first choices, ulti- mately postponing, or even avoiding, the need for surgery. Aiming to inhibit the growth of endometriotic lesions, medical alternatives like selective progesterone receptor modulators, antiangiogenic factors and immunomodulators have been studied in recent years. 2 As a matter of fact, estrogens combined with progestagens or progestagens alone still seem to be the most used agents to suppress ovarian function and disease activity, 2 but there is a lack of comparative information to determine a best choice among the available molecules. Despite the different potencies to suppress the hypothalamic -pituitary-ovarian axis, progesta- gens in general may be similarly effective to control endo- metriosis. Individualization of the treatment is, then, expected to be the less expensive, with minimal adverse effects and maximal adherence. 3,4 Dydrogesterone is a retroprogesterone characterized by high selectivity for progesterone receptors and potent pro- gestagenic activity. According to the medical lea flet, it may be prescribed in two regimens in the treatment of endome- triosis, namely: a cyclical regimen, from the 5th to the 25th days of the menstrual cycle, and a continuous one, both with daily doses ranging from 10 mg to 30 mg. 5 However, knowl- edge on the comparative ef ficacy of the two protocols is also scarce, and the recently published ORCHIDEA Study1 brought interesting data to light. As the primary outcome, a signi ficant decrease in the intensity of chronic pelvic pain was observed among women receiving dydrogesterone in the daily doses of 20 mg or 30 mg. By assessing women experience after treatment cycle 6, it was also observed a reduction in the number of days of analgesics use, and the severity of dysmenorrhea, as much as improvements in sexual well-being.1 In other words, the study pointed to a comparable gain in quality of life between the two daily doses, whether in cyclical or continuous regimens, at least for the first 6 months. 4 Regarding adverse events, the ORCHIDEA Study 1 found mild uterine bleeding as the most frequent one (1.1%), as it is expected for other progestagen-only treatment regimens, especially in the continuous model. However, despite being related to a better control of uterine bleeding, vaginal discharge and irritation, and coital well-being, than other progestagens, adverse events like headache, dizziness, ab- dominal pain, flatulence, and nausea may be more frequent with dydrogesterone, 6 and this must be better evaluated in future well-designed studies. received April 27, 2022 accepted after revision May 2, 2022 published online July 15, 2022 DOI https://doi.org/ 10.1055/s-0042-1751075. ISSN 0100-7203. © 2022. Federação Brasileira de Ginecologia e Obstetrícia. All rights reserved. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Revinter Publicações Ltda., Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil Letter to the Editor THIEME 802 Article published online: 2022-07-15 The earlier results of the application of dydrogesterone in women with endometriosis were published more than four decades ago, 7 but such a use has been notedly explored with more interest in the lastfifteen years. The study by Trivedi et al. (2007)8 was the first to convincingly demonstrate significant improvements in pelvic pain, dysmenorrhea and dyspareunia, and a 74% rate of satisfaction in the postlaparoscopic follow-up at 3 to 6 months. A recently published meta-analysis 9 of 19 studies (1,709 women) confronted different regimens of dydrogesterone to gonadotropin-releasing hormone (GnRH) agonists, aroma- tase inhibitors or anti-progestagens against endometriosis. Despite the suggestion that dydrogesterone is the most effective among them for dysmenorrhea, little could be obtained regarding de finite conclusions, since the available studies are generally small, non-randomized and heteroge- neous. Of note, a special view on the ef ficacy of dydrogester- one to treat sexual dysfunction in women with endometriosis is expected from large cohorts with long term follow ups, since the preliminary data are encourag- ing. 10 Following the same reasoning, the ability of dydro- gesterone to prevent the increase in size of ovarian endometriomas must be reassured by robust studies. 11 It is true that the absence of clinically relevant activity on estrogen, glucocorticoid, mineralocorticoid, or androgenic receptors may be a positive characteristic of dydrogesterone in currently recommended daily doses versus other proges- tagens. In addition to favoring the lower occurrence of adverse events, that pharmacological pro file may be safer for women in childbearing age, in the absence of contracep- tion. 6,12 Moreover, the good oral bioavailability and the theoretical lower risk of developing breast or endometrial cancer compared to other progestagens 6 are aspects to be considered for a first clinical treatment choice. However, it should be argued that any progestagen may be initially considered suf ficient against the symptoms of en- dometriosis. Then, what is expected from science is to fill the gaps by the confrontation of different progestins commonly used for treating endometriosis, such as the contemporary dienogest,13 or the molecules from previous generations. The information available to date is still insuf ficient to establish the clinical superiority of one molecule over the others. The ORCHIDEA Study 1 reported that dydrogesterone may relieve endometriosis-related chronic pelvic pain for at least 6 months of use in the regimen of preference. As aforementioned, the best progestagen for the treatment of endometriosis will be the one that is affordable, efficient, and well-accepted by each woman. Therefore, dydrogesterone is as welcome as any other progestagen in the search for the best individualized approach. Conflict of Interests The author has no con flict of interests to declare. References 1 Sukhikh GT, Adamyan LV, Dubrovina SO, Baranov II, Bezhenar VF, Kozachenko AV, et al. Prolonged cyclical and continuous regi- mens of dydrogesterone are effective for reducing chronic pelvic pain in women with endometriosis: results of the ORCHIDEA study. Fertil Steril. 2021;116(06):1568 –1577. Doi: 10.1016/j. fertnstert.2021.07.1194 2 Rafique S, Decherney AH. Medical management of endometri- osis. Clin Obstet Gynecol. 2017;60(03):485 –496. Doi: 10.1097/ GRF.0000000000000292 3 Falcone T, Flyckt R. Clinical management of endometriosis. Obstet Gynecol. 2018;131(03):557 –571. Doi: 10.1097/ AOG.0000000000002469 4 Eaton JL. Round-the-clock or start-and-stop: Does the regimen matter when dydrogesterone is used to treat chronic pelvic pain due to endometriosis? Fertil Steril. 2021;116(06):1578 –1579. Doi: 10.1016/j.fertnstert.2021.10.018 5 Duphaston® [Internet]. São PauloAbbott Laboratórios do Bra- sil2021 [cited 2022 Apr 7]. Available from: https://dam.abbott. com/pt-br/documents/pdfs/nossas-bulas/D/BU-29-DUPHAS- TON-bula-profissional-FINAL.pdf 6 Ott J, Egarter C, Aguilera A. Dydrogesterone after 60 years: a glance at the safety pro file. Gynecol Endocrinol. 2022;38(04): 279–287. Doi: 10.1080/09513590.2021.2016692 7 Johnston WI. Dydrogesterone and endometriosis. Br J Obstet Gynaecol. 1976;83(01):77 –80. Doi: 10.1111/j.1471-0528.1976. tb00734.x 8 Trivedi P, Selvaraj K, Mahapatra PD, Srivastava S, Malik S. Effective post-laparoscopic treatment of endometriosis with dydrogester- one. Gynecol Endocrinol. 2007;23(Suppl 1):73 –76 9 Peng C, Huang Y, Zhou Y. Dydrogesterone in the treatment of endometriosis: evidence mapping and meta-analysis. Arch Gynecol Obstet. 2021;304(01):231–252. Doi: 10.1007/s00404-020-05900-z 10 Yalçın Bahat P, Yücel B, Yuksel Ozgor B, Kadiro ğ ulları P, Topbas Selçuki NF, Çakmak K, et al. The effect of dydrogesterone on sexual function in endometriosis. J Obstet Gynaecol. 2021;1-4:1 –4. Doi: 10.1080/01443615.2021.1958765 11 Kitawaki J, Koga K, Kanzo T, Momoeda M. An assessment of the efficacy and safety of dydrogesterone in women with ovarian endometrioma: An open-label multicenter clinical study. Reprod Med Biol. 2021;20(03):345 –351. Doi: 10.1002/rmb2.12391 12 Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, et al. Classi fication and pharmacology of proges- tins. Maturitas. 2008;61(1-2):171 –180. Doi: 10.1016/j.maturi- tas.2008.11.013 13 Andres MdeP , Lopes LA, Baracat EC, Podgaec S. Dienogest in the treatment of endometriosis: systematic review. Arch Gynecol Obstet. 2015;292(03):523–529. Doi: 10.1007/s00404-015-3681-6 Rev Bras Ginecol Obstet Vol. 44 No. 8/2022 © 2022. Federação Bras ileira de Ginecologia e Obstetrícia. All rights reserved. Dydrogesterone as an Option in the Medical Treatment of Endometriosis Carvalho 803