{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T02:29:53Z","timestamp":1793413793401,"version":"4.5.0"},"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T00:00:00Z","timestamp":1736985600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018736","name":"Kaken Pharmaceutical","doi-asserted-by":"publisher","award":["23K08867"],"award-info":[{"award-number":["23K08867"]}],"id":[{"id":"10.13039\/100018736","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The judicious selection of ovulation inhibitors in ovarian stimulation protocols is crucial for the success of assisted reproductive technology (ART). Herein, we investigate the dose-dependent effects of chlormadinone acetate (CMA) and cetrorelix, two distinct ovulation inhibitors, on oocyte maturation in patients with normal ovarian reserve, using univariable and multivariable Poisson regression analyses. Patients undergoing progestin-primed ovarian stimulation (PPOS) with CMA (<jats:italic>n<\/jats:italic> = 299) or gonadotropin-releasing hormone antagonist (GnRH-ant) with cetrorelix (<jats:italic>n<\/jats:italic> = 605) during their initial <jats:italic>in vitro<\/jats:italic> fertilization cycle were enrolled at our center from March 2018 to October 2020 (<jats:italic>N<\/jats:italic> = 904). The primary and secondary outcomes were the oocyte maturation and fertilization rates, respectively. After adjusting for several covariates including age, anti-M\u00fcllerian hormone levels, total gonadotropin dose, and type of trigger, we calculated the dose-dependent adjusted relative risk (aRR) and 95% confidence interval (CI) for 1 mg of CMA or 0.25 mg of cetrorelix. In the PPOS group, the median age was 34.0 years, and the median total CMA dosage was 22 mg (interquartile range [IQR]: 18.0\u201332.0). In the GnRH-ant group, the median age was 35.0 years, and the median total cetrorelix dosage was 0.5 mg (IQR 0.5\u20130.5). The aRR of the maturation rate was 1.003 (95% CI: 0.999\u20131.007) with PPOS (<jats:italic>p<\/jats:italic> = 0.194) and 1.009 (95% CI: 0.962\u20131.059) with GnRH-ant (<jats:italic>p<\/jats:italic> = 0.717). The aRR of the fertilization rate was 1.002 (95% CI: 0.985\u20131.020) with PPOS (<jats:italic>p<\/jats:italic> = 0.783) and 1.022 (95% CI: 0.839\u20131.246) with GnRH-ant (<jats:italic>p<\/jats:italic> = 0.829). Collectively, these findings indicate that within the applied dosages, ovulation inhibitors do not significantly impact oocyte maturation or fertilization rates in patients with normal ovarian reserve. These valuable insights can be applied when designing ART protocols and may guide clinicians in optimizing infertility treatments.<\/jats:p>","DOI":"10.1371\/journal.pone.0317103","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T18:46:43Z","timestamp":1737053203000},"page":"e0317103","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Investigating dosage effects of ovulation inhibitors on oocyte maturation in assisted reproductive technology: A retrospective study among patients with normal ovarian reserve"],"prefix":"10.1371","volume":"20","author":[{"given":"Mika","family":"Handa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0605-5219","authenticated-orcid":true,"given":"Tsuyoshi","family":"Takiuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumika","family":"Kawaguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Ohara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakazu","family":"Doshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takumi","family":"Takeuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6527-434X","authenticated-orcid":true,"given":"Hidehiko","family":"Matsubayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomomoto","family":"Ishikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4329-2520","authenticated-orcid":true,"given":"Sho","family":"Komukai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuhisa","family":"Kitamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadashi","family":"Kimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,1,16]]},"reference":[{"key":"pone.0317103.ref001","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.clinbiochem.2018.03.012","article-title":"Fertility and infertility: definition and epidemiology","volume":"62","author":"M Vander Borght","year":"2018","journal-title":"Clin Biochem"},{"key":"pone.0317103.ref002","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/S0015-0282(16)54067-9","article-title":"Psychosocial distress and infertility: men and women respond differently","volume":"55","author":"J Wright","year":"1991","journal-title":"Fertil Steril"},{"key":"pone.0317103.ref003","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.fertnstert.2023.01.013","article-title":"Global fertility care with assisted reproductive technology","volume":"120","author":"GD Adamson","year":"2023","journal-title":"Fertil Steril"},{"key":"pone.0317103.ref004","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/S0002-9378(15)32963-X","article-title":"In vitro fertilization and cleavage of human ovarian eggs","volume":"55","author":"MF Menkin","year":"1948","journal-title":"Am J Obstet Gynecol"},{"key":"pone.0317103.ref005","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1016\/S0140-6736(84)92840-X","article-title":"Induction of ovulation for in-vitro fertilisation using Buserelin and gonadotropins","volume":"2","author":"RN Porter","year":"1984","journal-title":"Lancet"},{"key":"pone.0317103.ref006","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0015-0282(16)54803-1","article-title":"Flexible protocol for administration of human follicle-stimulating hormone with gonadotropin-releasing hormone antagonist","volume":"57","author":"S Byrd","year":"1992","journal-title":"Fertil Steril"},{"key":"pone.0317103.ref007","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1093\/humupd\/dmaa040","article-title":"Progestins for pituitary suppression during ovarian stimulation for ART: a comprehensive and systematic review including meta-analyses","volume":"27","author":"B Ata","year":"2021","journal-title":"Hum Reprod Update"},{"key":"pone.0317103.ref008","first-page":"CD013827","article-title":"Progestogens for prevention of luteinising hormone (LH) surge in women undergoing controlled ovarian hyperstimulation as part of an assisted reproductive technology (ART) cycle","volume":"11","author":"D Glujovsky","year":"2023","journal-title":"Cochrane Database Syst Rev"},{"key":"pone.0317103.ref009","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.ando.2010.02.021","article-title":"Human ovarian follicular development: from activation of resting follicles to preovulatory maturation","volume":"71","author":"A. Gougeon","year":"2010","journal-title":"Ann Endocrinol (Paris)."},{"key":"pone.0317103.ref010","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1111\/1471-0528.14622","article-title":"The pregnancy outcome of progestin-primed ovarian stimulation using 4 versus 10 mg of medroxyprogesterone acetate per day in infertile women undergoing in vitro fertilisation: a randomised controlled trial","volume":"124","author":"J Dong","year":"2017","journal-title":"BJOG"},{"key":"pone.0317103.ref011","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/S0015-0282(97)81407-0","article-title":"Comparison of different doses of gonadotropin-releasing hormone antagonist cetrorelix during controlled ovarian hyperstimulation","volume":"67","author":"C Albano","year":"1997","journal-title":"Fertil Steril"},{"key":"pone.0317103.ref012","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1093\/humrep\/der092","article-title":"ESHRE consensus on the definition of \u2019poor response\u2019 to ovarian stimulation for in vitro fertilization: the Bologna criteria.","volume":"26","author":"AP Ferraretti","year":"2011","journal-title":"Hum Reprod"},{"key":"pone.0317103.ref013","first-page":"214","article-title":"Correlation between anti-M\u00fcllerian hormone, age, and number of oocytes: A retrospective study in a Brazilian in vitro fertilization center","volume":"26","author":"IF Kozlowski","year":"2022","journal-title":"JBRA Assist Reprod"},{"key":"pone.0317103.ref014","doi-asserted-by":"crossref","first-page":"19750","DOI":"10.1038\/s41598-020-76543-y","article-title":"AMH has no role in predicting oocyte quality in women with advanced age undergoing IVF\/ICSI cycles","volume":"10","author":"X Dai","year":"2020","journal-title":"Sci Rep"},{"key":"pone.0317103.ref015","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.fertnstert.2020.07.008","article-title":"Ovarian follicular waves during the menstrual cycle: physiologic insights into novel approaches for ovarian stimulation","volume":"114","author":"A Baerwald","year":"2020","journal-title":"Fertil Steril"},{"key":"pone.0317103.ref016","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.1093\/humrep\/13.9.2392","article-title":"Single and multiple dose pharmacokinetics and pharmacodynamics of the gonadotrophin-releasing hormone antagonist cetrorelix in healthy female volunteers","volume":"13","author":"IJ Duijkers","year":"1998","journal-title":"Hum Reprod"},{"key":"pone.0317103.ref017","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1093\/humrep\/14.2.288","article-title":"A comparison of three gonadotrophin-releasing hormone analogues in an in-vitro fertilization programme: a prospective randomized study","volume":"14","author":"T Dada","year":"1999","journal-title":"Hum Reprod"},{"key":"pone.0317103.ref018","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1093\/biolre\/ioab236","article-title":"The two-step process of ovarian follicular growth and maturation in mammals can be compared to a fruit ripening where quality depends on the second step","volume":"106","author":"MA Sirard","year":"2022","journal-title":"Biol Reprod"},{"key":"pone.0317103.ref019","first-page":"1292","article-title":"The follicle-stimulating hormone (FSH) threshold\/window concept examined by different interventions with exogenous FSH during the follicular phase of the normal menstrual cycle: duration, rather than magnitude, of FSH increase affects follicle development","volume":"83","author":"I Schipper","year":"1998","journal-title":"J Clin Endocrinol Metab"},{"key":"pone.0317103.ref020","doi-asserted-by":"crossref","first-page":"114","DOI":"10.3389\/fendo.2017.00114","article-title":"Efficacy of follicle-stimulating hormone (FSH) alone, FSH + luteinizing hormone, human menopausal gonadotropin or FSH + human chorionic gonadotropin on assisted reproductive technology outcomes in the \"Personalized\" medicine era: A meta-analysis","volume":"8","author":"D Santi","year":"2017","journal-title":"Front Endocrinol (Lausanne)."},{"key":"pone.0317103.ref021","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/s12958-021-00768-3","article-title":"Comparative effectiveness of recombinant human follicle-stimulating hormone alfa (r-hFSH-alfa) versus highly purified urinary human menopausal gonadotropin (hMG HP) in assisted reproductive technology (ART) treatments: a non-interventional study in Germany","volume":"19","author":"KF B\u00fchler","year":"2021","journal-title":"Reprod Biol Endocrinol"},{"key":"pone.0317103.ref022","first-page":"238","article-title":"Human Menopausal Gonadotropin versus Recombinant FSH in Polycystic Ovary Syndrome Patients Undergoing In Vitro Fertilization.","volume":"6","author":"A Figen Turkcapar","year":"2013","journal-title":"Int J Fertil Steril"},{"key":"pone.0317103.ref023","first-page":"2019","article-title":"Required amount of rFSH, HP-hMG and HP-FSH to reach a live birth: a systematic review and meta-analysis","author":"EM Bordewijk","year":"2019","journal-title":"Hum Reprod Open"},{"key":"pone.0317103.ref024","doi-asserted-by":"crossref","first-page":"232","DOI":"10.5653\/cerm.2017.44.4.232","article-title":"Reduction of the cetrorelix dose in a multiple-dose antagonist protocol and its impact on pregnancy rate and affordability: A randomized controlled multicenter study","volume":"44","author":"AS Dawood","year":"2017","journal-title":"Clin Exp Reprod Med"},{"key":"pone.0317103.ref025","first-page":"1557","article-title":"Effect of flexible half-dose gonadotropin-releasing hormone antagonist protocol on in vitro fertilization outcome in predicted normal responder: A study protocol for a multicentered, randomized, non-inferiority, parallel controlled trial.","volume":"24","author":"YJ Ma","year":"2023","journal-title":"Drug Des Devel Ther"},{"key":"pone.0317103.ref026","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1007\/s00404-013-2806-z","article-title":"Effect of a low dose of gonadotropin releasing hormone antagonist on in vitro fertilization outcomes","volume":"288","author":"OS Kerimo\u011flu","year":"2013","journal-title":"Arch Gynecol Obstet"},{"key":"pone.0317103.ref027","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/S1028-4559(09)60250-3","article-title":"Preliminary report on the effect of a lower dose of gonadotropin-releasing hormone antagonist (cetrorelix) on ovarian hyperstimulation in lower-weight Asian women","volume":"45","author":"YL Chang","year":"2006","journal-title":"Taiwan J Obstet Gynecol"},{"key":"pone.0317103.ref028","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1093\/humrep\/dez132","article-title":"Predicting suboptimal oocyte yield following GnRH agonist trigger by measuring serum LH at the start of ovarian stimulation","volume":"34","author":"B Popovic-Todorovic","year":"2019","journal-title":"Hum Reprod"},{"key":"pone.0317103.ref029","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.fertnstert.2015.03.022","article-title":"Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization","volume":"104","author":"Y Kuang","year":"2015","journal-title":"Fertil Steril"},{"key":"pone.0317103.ref030","doi-asserted-by":"crossref","first-page":"e12483","DOI":"10.1002\/rmb2.12483","article-title":"Guidelines for reproductive medicine in Japan.","volume":"21","author":"M Yamada","year":"2022","journal-title":"Reprod Med Biol"},{"key":"pone.0317103.ref031","doi-asserted-by":"crossref","first-page":"644456","DOI":"10.3389\/fendo.2021.644456","article-title":"Comparison of cumulative live birth rates between GnRH-A and PPOS in low-prognosis patients according to POSEIDON criteria: A cohort study","volume":"12","author":"S Zhang","year":"2021","journal-title":"Front Endocrinol (Lausanne)."},{"key":"pone.0317103.ref032","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/j.fertnstert.2022.06.012","article-title":"Comparison of the cumulative live birth rates after 1 in vitro fertilization cycle in women using gonadotropin-releasing hormone antagonist protocol vs. progestin-primed ovarian stimulation: a propensity score-matched study","volume":"118","author":"H Chen","year":"2022","journal-title":"Fertil Steril"},{"key":"pone.0317103.ref033","doi-asserted-by":"crossref","first-page":"1117513","DOI":"10.3389\/fendo.2023.1117513","article-title":"Comparison of cumulative live birth rates between progestin-primed ovarian stimulation protocol and gonadotropin-releasing hormone antagonist protocol in different populations","volume":"14","author":"R Zhou","year":"2023","journal-title":"Front Endocrinol (Lausanne)."},{"key":"pone.0317103.ref034","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1210\/clinem\/dgad397","article-title":"Comparison of cumulative live birth rates between progestin and GnRH analogues in preimplantation genetic testing cycles","volume":"109","author":"R Zhou","year":"2023","journal-title":"J Clin Endocrinol Metab"},{"key":"pone.0317103.ref035","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.fertnstert.2016.10.030","article-title":"Use of Utrogestan during controlled ovarian hyperstimulation in normally ovulating women undergoing in vitro fertilization or intracytoplasmic sperm injection treatments in combination with a \"freeze all\" strategy: a randomized controlled dose-finding study of 100 mg versus 200 mg","volume":"107","author":"X Zhu","year":"2017","journal-title":"Fertil Steril"},{"key":"pone.0317103.ref036","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3109\/09513599609027986","article-title":"In situ hybridization study of messenger RNA for estrogen receptor and immunohistochemical detection of estrogen and progesterone receptors in the human ovary","volume":"10","author":"A Revelli","year":"1996","journal-title":"Gynecol Endocrinol"},{"key":"pone.0317103.ref037","doi-asserted-by":"crossref","first-page":"2092","DOI":"10.1093\/humrep\/deq125","article-title":"Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles","volume":"25","author":"E Bosch","year":"2010","journal-title":"Hum Reprod"},{"key":"pone.0317103.ref038","doi-asserted-by":"crossref","first-page":"990971","DOI":"10.3389\/fendo.2023.990971","article-title":"Effects of trigger-day progesterone in the preimplantation genetic testing cycle on the embryo quality and pregnancy outcomes of the subsequent first frozen-thawed blastocyst transfer","volume":"14","author":"J Li","year":"2023","journal-title":"Front Endocrinol (Lausanne)."},{"key":"pone.0317103.ref039","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/s10815-022-02682-y","article-title":"Delayed blastocyst development is influenced by the level of progesterone on the day of trigger","volume":"40","author":"R Villanacci","year":"2023","journal-title":"J Assist Reprod Genet"},{"key":"pone.0317103.ref040","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1093\/humrep\/deab160","article-title":"Is a freeze-all policy the optimal solution to circumvent the effect of late follicular elevated progesterone? A multicentric matched-control retrospective study analysing cumulative live birth rate in 942 non-elective freeze-all cycles","volume":"36","author":"A Racca","year":"2021","journal-title":"Hum Reprod"},{"key":"pone.0317103.ref041","doi-asserted-by":"crossref","first-page":"e0176482","DOI":"10.1371\/journal.pone.0176482","article-title":"Top quality blastocyst formation rates in relation to progesterone levels on the day of oocyte maturation in GnRH antagonist IVF\/ICSI cycles.","volume":"12","author":"VS Vanni","year":"2017","journal-title":"PLOS ONE"},{"key":"pone.0317103.ref042","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1093\/humrep\/dez238","article-title":"Do we need to measure progesterone in oocyte donation cycles? A retrospective analysis evaluating cumulative live birth rates and embryo quality","volume":"35","author":"A Racca","year":"2020","journal-title":"Hum Reprod"},{"key":"pone.0317103.ref043","first-page":"e91","article-title":"High progesterone levels on the day of HCG administration do not affect the embryo quality and the reproductive outcomes of frozen embryo transfers","volume":"169","author":"D Baldini","year":"2018","journal-title":"Clin Ter"},{"key":"pone.0317103.ref044","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.fertnstert.2020.06.016","article-title":"Luteinizing hormone-independent rise of progesterone as the physiological trigger of the ovulatory gonadotropins surge in the human","volume":"114","author":"DI Dozortsev","year":"2020","journal-title":"Fertil Steril"},{"key":"pone.0317103.ref045","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1093\/humrep\/dex367","article-title":"New application of dydrogesterone as a part of a progestin-primed ovarian stimulation protocol for IVF: a randomized controlled trial including 516 first IVF\/ICSI cycles","volume":"33","author":"S Yu","year":"2018","journal-title":"Hum Reprod"},{"key":"pone.0317103.ref046","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1080\/10543406.2011.559673","article-title":"Dose as instrumental variable in exposure-safety analysis using count models","volume":"22","author":"J. Wang","year":"2012","journal-title":"J Biopharm Stat"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0317103","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T18:47:00Z","timestamp":1737053220000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0317103"}},"subtitle":[],"editor":[{"given":"Simone","family":"Garzon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,1,16]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1,16]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0317103","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,16]]}}}