{"paper_id":"047f774a-eda4-4a29-97e0-1e8a3d86a96c","body_text":"Abstract\nLinzagolix is a novel, oral GnRH receptor antagonist developed for the treatment of endometriosis and uterine fibroids. We assessed high-dose linzagolix safety and bleeding pattern effects in healthy women using combined versus delayed hormonal add-back therapy (ABT). This was a single-center, open-label, parallel-group study in 32 premenopausal women, who were randomized to daily linzagolix (200 mg)/ABT for 10 weeks (“Combined-ABT”) or linzagolix (200 mg) for 4 weeks followed by linzagolix (200 mg)/ABT for 6 weeks (“Delayed-ABT”). Main outcome measures included bleeding records, trough estradiol (E2) concentrations and adverse events. Linzagolix alone promptly reduced bleeding, leading to amenorrhea in all women by week 5. When combined ABT was started (week 5), spotting (≤ 0.80 days/week/subject) and bleeding (≤ 0.53 days/week/subject) occurred; bleeding was markedly more frequent than after ABT start in the “Combined-ABT” group. In the “Combined-ABT” group, spotting (≤ 0.69 days/week/subject) and occasional bleeding (≤ 0.25 days/week/subject) occurred during the first half of treatment with a tendency to further decrease during the second half. Linzagolix alone rapidly reduced E2 reaching median week 4 levels of 4.1 pg/mL. Median E2 after combined linzagolix/ABT ranged between 35 and 42 pg/mL for the “Delayed-ABT” group (weeks 5–10) and between 24 and 32 pg/mL for the “Combined-ABT” group (weeks 1–10). Linzagolix was well tolerated. Most frequently reported adverse events were headache (32/156) and hot flushes (19/156). Hot flushes exclusively occurred in the “Delayed-ABT” group. In this study, treatment start with a combined linzagolix/ABT regimen resulted in better bleeding control, no hot flushes, and lower median E2 levels than a “Delayed-ABT” regimen. These results may help defining the linzagolix/ABT regimen to be adopted when treating sex-hormone-dependent diseases. Clinical Trial Registration Number—EudraCT Number: 2017-003822-34\nSimilar content being viewed by others\nReferences\nDonnez J, Dolmans MM. Uterine fibroid management: from the present to the future. Hum Reprod Update. 2016;22(6):665–86.\nBorah BJ, Nicholson WK, Bradley L, Stewart EA. The impact of uterine leiomyomas: a national survey of affected women. Am J Obstet Gynecol. 2013;209(4):319 e311–20.\nStewart EA. Clinical practice. Uterine fibroids. N Engl J Med. 2015;372(17):1646–55.\nWechter ME, Stewart EA, Myers ER, Kho RM, Wu JM. Leiomyoma-related hospitalization and surgery: prevalence and predicted growth based on population trends. 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J Fam Plann Reprod Health Care. 2008;34(1):27–34.\nAcknowledgments\nThe authors thank the clinical site Celerion, in particular, Rachel Andrews for her support and contributions to the study.\nFunding\nFunding for the study was provided by ObsEva and ObsEva contributed to the study design, research, and interpretation of data, and the writing, reviewing, and approving of the publication. ObsEva contracted the clinical conduct of the study to Celerion Ltd.\nAuthor information\nAuthors and Affiliations\nContributions\nAll authors met all 3 of the following conditions:\n1) Authors made substantial contributions to conception and design, and/or acquisition of data, and/or analysis and interpretation of data;\n2) Authors participated in drafting the article or revising it critically for important intellectual content; and\n3) Authors gave final approval of the version to be submitted and any revised version. In detail:\nStudy conception and design: OP\nAcquisition of data: DB\nAnalysis and interpretation of data: OP, DB, LM, JPG\nDrafting of manuscript: OP\nCritical revision: OP, DB, LM, JPG\nCorresponding author\nEthics declarations\nConflict of Interest\nOP, LM and JPG are employees of ObsEva; DB is an employee of Celerion Ltd.\nAdditional information\nPublisher's Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nElectronic Supplementary Material\nESM 1 (download DOCX )\n(DOCX 185 kb)\nRights and permissions\nAbout this article\nCite this article\nPohl, O., Marchand, L., Bell, D. et al. Effects of combined GnRH receptor antagonist linzagolix and hormonal add-back therapy on vaginal bleeding—delayed add-back onset does not improve bleeding pattern. Reprod. Sci. 27, 988–995 (2020). https://doi.org/10.1007/s43032-020-00172-z\nReceived:\nAccepted:\nPublished:\nVersion of record:\nIssue date:\nDOI: https://doi.org/10.1007/s43032-020-00172-z","source_license":"CC0","license_restricted":false}