{"paper_id":"bdae6a73-7dde-4dc0-97aa-249d00775d98","body_text":"LETTER\nLetter to the Editor in Response to ‘ ‘Effect\nof Polymorphisms in CYP2C9 and CYP2C19\non the Disposition, Safety and Metabolism\nof Progesterone Administrated Orally or Vaginally’ ’\nAaron Lazorwitz . Christina L. Aquilante . Jeanelle Sheeder .\nStephanie Teal\nReceived: October 8, 2019 / Published online: December 24, 2019\n/C211The Author(s) 2019\nKeywords: Etonogestrel; Pharmacogenomics;\nProgesterone; Women’s health\nFirst available online on September 3, 2019 in\nAdvances in Therapy , Zubiaur et al. [1] suggested\nthat the CYP2C19 phenotype may help explain\nsome of the variability in serum progesterone\nconcentrations when taken orally or vaginally\nand stated that there are ‘‘no other pharmaco-\ngenetic studies of progesterone’’ with which to\ncompare their results. In fact, our published\npharmacogenomics study of etonogestrel\nmetabolism is an important comparator [ 2].\nEtonogestrel, a progestin found in some forms\nof contraception including the continuous-re-\nlease subdermal implant, is metabolized in very\nsimilar processes to progesterone [ 3]. Clinical\ndata also support that the etonogestrel\ncontraceptive implant and other progestins\n(e.g., dienogest) have similar pharmacological\nproperties as progesterone, further supporting\ncommon metabolic and pharmacodynamic\npathways between these steroid hormones\n[4, 5]. Like Zubiaur and colleagues, we utilized a\ncandidate gene approach for our investigation,\nincluding genetic variants in CYP2C19,\nCYP2C9, and three other metabolizing enzyme\ngenes ( CYP3A4, CYP3A5, CYP3A7 ). However,\nunlike Zubiaur et al. [ 1], we did not find that\nvariants in CYP2C19 were associated with dif-\nferences in serum etonogestrel concentrations\namong our 350 contraceptive implant users [2].\nAlternatively, we found that a variant in\nCYP3A7 (the *1C variant) was significantly\nassociated with 23% lower etonogestrel con-\ncentrations than the respective wild-type geno-\ntype [2]. We also found that body mass index\nwas significantly associated with serum etono-\ngestrel concentrations and should be accounted\nfor in pharmacokinetic investigations with\nsimilar steroid hormones [ 2].\nWe agree with Zubiaur and colleagues that\ngenome wide association studies are needed to\nfurther explore the pharmacogenomics of ster-\noid hormones, particularly in light of the find-\nings by Zhang et al. [ 6] regarding the limited\nrole that CYP3A4 appears to have in the meta-\nbolism of steroid hormones. However, given the\ndisparate findings regarding CYP2C19 variants\nbetween our studies, additional research is\nEnhanced Digital Features To view enhanced digital\nfeatures for this article go to https://doi.org/10.6084/\nm9.figshare.11347016.\nA. Lazorwitz (&) /C1J. Sheeder /C1S. Teal\nDivision of Family Planning, Department of\nObstetrics and Gynecology, University of Colorado\nAnschutz Medical Campus, Aurora, CO, USA\ne-mail: Aaron.lazorwitz@ucdenver.edu\nC. L. Aquilante\nDepartment of Pharmaceutical Sciences, Skaggs\nSchool of Pharmacy and Pharmaceutical Sciences,\nUniversity of Colorado Anschutz Medical Campus,\nAurora, CO, USA\nAdv Ther (2020) 37:963–964\nhttps://doi.org/10.1007/s12325-019-01195-y\n\nwarranted to determine how much this specific\nCYP isoenzyme and variants within its gene\ntruly influence progesterone and progestin\nmetabolism.\nACKNOWLEDGEMENTS\nFunding. Our work cited in this article was\nprimarily supported by the Society of Family\nPlanning Research Fund [Grant Number\nSFPRF17-3] and was also supported by NIH/\nNCATS Colorado CTSA Grant Number UL1\nTR001082. No funding or sponsorship was\nreceived for publication of this article.\nAuthorship. All named authors meet the\nInternational Committee of Medical Journal\nEditors (ICMJE) criteria for authorship for this\narticle, take responsibility for the integrity of\nthe work as a whole, and have given their\napproval for this version to be published.\nDisclosures. Stephanie Teal has served on\nscientific advisory boards of Allergan and Bayer\nHealthcare, and serves on a data monitoring\nboard for a study funded by Merck and Co.\nStephanie Teal and Aaron Lazorwitz receive\nresearch funding from Merck and Co. for an\ninvestigator initiated study on drug–drug\ninteractions with the etonogestrel contraceptive\nimplant. The University of Colorado Depart-\nment of Obstetrics and Gynecology has received\nresearch funding from Bayer, Agile Therapeu-\ntics, Sebela, Merck and Co, and Medicines 360.\nJeanelle Sheeder and Christina Aquilante have\nnothing to disclose.\nCompliance with Ethics Guidelines. This\narticle is based on previously conducted studies\nand does not contain any studies with human\nparticipants or animals performed by any of the\nauthors.\nPeer Review. Please note, contrary to the\njournal’s standard single-blind peer review pro-\ncess, as a commentary this article underwent\nreview by a member of the journal’s Editorial\nBoard.\nOpen Access. This article is licensed under a\nCreative Commons Attribution-NonCommer-\ncial 4.0 International License, which permits\nany non-commercial use, sharing, adaptation,\ndistribution and reproduction in any medium\nor format, as long as you give appropriate credit\nto the original author(s) and the source, provide\na link to the Creative Commons licence, and\nindicate if changes were made. The images or\nother third party material in this article are\nincluded in the article’s Creative Commons\nlicence, unless indicated otherwise in a credit\nline to the material. If material is not included\nin the article’s Creative Commons licence and\nyour intended use is not permitted by statutory\nregulation or exceeds the permitted use, you\nwill need to obtain permission directly from the\ncopyright holder. To view a copy of this licence,\nvisit http://creativecommons.org/licenses/by-\nnc/4.0/.\nREFERENCES\n1. Zubiaur P, Ochoa D, Galvez MA, et al. Effect of\npolymorphisms in CYP2C9 and CYP2C19 on the\ndisposition, safety and metabolism of progesterone\nadministrated orally or vaginally. Adv Ther. 2019;36:\n2744–55.\n2. Lazorwitz A, Aquilante CL, Oreschak K, Sheeder J,\nGuiahi M, Teal S. Influence of genetic variants on\nsteady-state etonogestrel concentrations among con-\ntraceptive implant users. Obstet Gynecol.\n2019;133(4):783–94.\n3. Hatcher RA, Trussell J, Stewart F, et al. Contraceptive\ntechnology. New York: Ardent Media; 2011.\n4. Carvalho N, Margatho D, Cursino K, Benetti-Pinto\nCL, Bahamondes L. Control of endometriosis-associ-\nated pain with etonogestrel-releasing contraceptive\nimplant and 52 mg levonorgestrel-releasing intrauter-\nine system: randomized clinical trial. Fertil Steril.\n2018;110(6):1129–36.\n5. Lagana AS, Vitale SG, Granese R, et al. Clinical\ndynamics of dienogest for the treatment of\nendometriosis: from bench to bedside. Expert Opin\nDrug Metab Toxicol. 2017;13(6):593–6.\n6. Zhang N, Shon J, Kim MJ, et al. Role of CYP3A in oral\ncontraceptives clearance. Clin Transl Sci. 2018;11(3):\n251–60.\n964 Adv Ther (2020) 37:963–964","source_license":"CC0","license_restricted":false}