{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:57:17Z","timestamp":1760237837302,"version":"build-2065373602"},"reference-count":50,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,6,3]],"date-time":"2022-06-03T00:00:00Z","timestamp":1654214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomedicines"],"abstract":"<jats:p>It is a challenge to obtain sufficient eggs during in vitro fertilization (IVF) in women with impending ovarian failure (IOF)\/diminished ovarian reserve (DOR). Although studies have suggested that more than one wave of follicle growth exists, the efficacy of controlled ovulation stimulation (COS) in both follicular and luteal phases of the same ovarian cycle (DuoStim) is not established in women with IOF\/DOR. We investigated the efficacy of DuoStim using the intraovarian injection of recombinant human follicle-stimulating hormone (rhFSH) during oocyte retrieval in women with DOR. For luteal-phase stimulation, intraovarian (Group A, N = 28) or superficial subcutaneous (Group B, N = 18) injection of 300 IU rhFSH immediately after oocyte retrieval was administered as the first dose, and intermittent superficial subcutaneous addition of gonadotropins was employed accordingly for further COS in both groups. In Group A, significantly lower Gn doses, a shorter duration of COS, a greater number of antral follicle counts, and an increased number of retrieved mature and total oocytes were noted. Compared with the clinical outcomes of luteal-phase COS, the average daily doses of rhFSH used in Group A were significantly lower. In summary, the novel approach using intraovarian rhFSH injection provides an efficient treatment regimen in women with IOF\/DOR.<\/jats:p>","DOI":"10.3390\/biomedicines10061312","type":"journal-article","created":{"date-parts":[[2022,6,3]],"date-time":"2022-06-03T10:33:01Z","timestamp":1654252381000},"page":"1312","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intraovarian Injection of Recombinant Human Follicle-Stimulating Hormone for Luteal-Phase Ovarian Stimulation during Oocyte Retrieval Is Effective in Women with Impending Ovarian Failure and Diminished Ovarian Reserve"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8082-1196","authenticated-orcid":false,"given":"Chao-Chin","family":"Hsu","sequence":"first","affiliation":[{"name":"Taiwan United Birth-Promoting Experts Fertility Clinic, Tainan 710, Taiwan"},{"name":"Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei 100, Taiwan"},{"name":"Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, Tainan 701, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei 100, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-Hsuan","family":"Lee","sequence":"additional","affiliation":[{"name":"Nepean Hospital, Penrith, NSW 2747, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2584-9380","authenticated-orcid":false,"given":"Yuan-Shuo","family":"Hsueh","sequence":"additional","affiliation":[{"name":"Department of Medical Science Industries, College of Health Sciences, Chang Jung Christian University, Tainan 711, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5606-3420","authenticated-orcid":false,"given":"Chih-Ying","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7866-5481","authenticated-orcid":false,"given":"Hui Hua","family":"Chang","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan"},{"name":"School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan"},{"name":"Department of Pharmacy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan"},{"name":"Department of Pharmacy, National Cheng Kung University Hospital, Dou-Liou Branch, Yunlin 640, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2824","DOI":"10.1016\/j.fertnstert.2010.04.067","article-title":"Anti-M\u00fcllerian hormone (AMH) defines, independent of age, low versus good live-birth chances in women with severely diminished ovarian reserve","volume":"94","author":"Gleicher","year":"2010","journal-title":"Fertil. Steril."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.fertnstert.2015.05.017","article-title":"Diminished ovarian reserve in the United States assisted reproductive technology population: Diagnostic trends among 181,536 cycles from the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System","volume":"104","author":"Devine","year":"2015","journal-title":"Fertil. Steril."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1007\/s10815-015-0595-y","article-title":"Diminished ovarian reserve, premature ovarian failure, poor ovarian responder\u2014A plea for universal definitions","volume":"32","author":"Cohen","year":"2015","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1093\/humrep\/dev029","article-title":"Surgical diminished ovarian reserve after endometrioma cystectomy versus idiopathic DOR: Comparison of in vitro fertilization outcome","volume":"30","author":"Roustan","year":"2015","journal-title":"Hum. Reprod."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1093\/humrep\/15.7.1452","article-title":"Elevated FSH concentrations in imminent ovarian failure are associated with higher FSH and LH pulse amplitude and response to GnRH","volume":"15","author":"Schoemaker","year":"2000","journal-title":"Hum. Reprod."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1007\/s10815-007-9181-2","article-title":"Different ovarian stimulation protocols for women with diminished ovarian reserve","volume":"24","author":"Loutradis","year":"2007","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1093\/humrep\/der092","article-title":"ESHRE consensus on the definition of \u2018poor response\u2019 to ovarian stimulation for in vitro fertilization: The Bologna criteria","volume":"26","author":"Ferraretti","year":"2011","journal-title":"Hum. Reprod."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/S0015-0282(03)00544-2","article-title":"A new model for ovarian follicular development during the human menstrual cycle","volume":"80","author":"Baerwald","year":"2003","journal-title":"Fertil. Steril."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.fertnstert.2013.09.007","article-title":"Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing in vitro fertilization\/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen-thawed embryo transfer cycles","volume":"101","author":"Kuang","year":"2014","journal-title":"Fertil. Steril."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1016\/j.fertnstert.2016.03.002","article-title":"Follicular versus luteal phase ovarian stimulation during the same menstrual cycle (DuoStim) in a reduced ovarian reserve population results in a similar euploid blastocyst formation rate: New insight in ovarian reserve exploitation","volume":"105","author":"Ubaldi","year":"2016","journal-title":"Fertil. Steril."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s10815-019-01638-z","article-title":"What is the true place of a double stimulation and double oocyte retrieval in the same cycle for patients diagnosed with poor ovarian reserve? A systematic review including a meta-analytical approach","volume":"37","author":"Sfakianoudis","year":"2020","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1080\/03009734.2020.1734694","article-title":"DuoStim\u2014A reproducible strategy to obtain more oocytes and competent embryos in a short time-frame aimed at fertility preservation and IVF purposes. A systematic review","volume":"125","author":"Vaiarelli","year":"2020","journal-title":"Ups. J. Med. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.1093\/humrep\/deaa203","article-title":"The euploid blastocysts obtained after luteal phase stimulation show the same clinical, obstetric and perinatal outcomes as follicular phase stimulation-derived ones: A multicenter study","volume":"35","author":"Vaiarelli","year":"2020","journal-title":"Hum. Reprod."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s10815-022-02409-z","article-title":"Second stimulation in the same ovarian cycle: An option to fully-personalize the treatment in poor prognosis patients undergoing PGT-A","volume":"39","author":"Vaiarelli","year":"2022","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1097\/GME.0000000000001746","article-title":"Resumed ovarian function and pregnancy in early menopausal women by whole dimension subcortical ovarian administration of platelet-rich plasma and gonadotropins","volume":"28","author":"Hsu","year":"2021","journal-title":"Menopause"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"50","DOI":"10.3389\/fendo.2020.00050","article-title":"Live birth in woman with premature ovarian insufficiency receiving ovarian administration of platelet-rich plasma (PRP) in combination with gonadotropin: A case report","volume":"11","author":"Hsu","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e716","DOI":"10.1210\/clinem\/dgab709","article-title":"Extended injection intervals of gonadotropins by intradermal administration in IVF treatment","volume":"107","author":"Hsu","year":"2022","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/1477-7827-9-112","article-title":"Ovarian sensitivity index is strongly related to circulating AMH and may be used to predict ovarian response to exogenous gonadotropins in IVF","volume":"9","author":"Biasoni","year":"2011","journal-title":"Reprod. Biol. Endocrinol. RB&E"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1093\/humrep\/der479","article-title":"Antral follicle responsiveness to follicle-stimulating hormone administration assessed by the Follicular Output RaTe (FORT) may predict in vitro fertilization-embryo transfer outcome","volume":"27","author":"Gallot","year":"2012","journal-title":"Hum. Reprod."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.rbmo.2019.01.007","article-title":"Dual stimulation using corifollitropin alfa in 54 Bologna criteria poor ovarian responders\u2014A case series","volume":"38","author":"Alsbjerg","year":"2019","journal-title":"Reprod. Biomed. Online"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1007\/s10815-012-9752-8","article-title":"Luteal phase GnRHa trigger in random start fertility preservation cycles","volume":"29","author":"Ozkaya","year":"2012","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1016\/j.fertnstert.2013.07.1992","article-title":"Effective method for emergency fertility preservation: Random-start controlled ovarian stimulation","volume":"100","author":"Cakmak","year":"2013","journal-title":"Fertil. Steril."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"317","DOI":"10.3389\/fendo.2018.00317","article-title":"Double stimulation in the same ovarian cycle (DuoStim) to maximize the number of oocytes retrieved from poor prognosis patients: A multicenter experience and swot analysis","volume":"9","author":"Vaiarelli","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/j.rbmo.2014.08.009","article-title":"Double stimulations during the follicular and luteal phases of poor responders in IVF\/ICSI programmes (Shanghai protocol)","volume":"29","author":"Kuang","year":"2014","journal-title":"Reprod. Biomed. Online"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3481","DOI":"10.1093\/humrep\/des318","article-title":"Live birth rates following natural cycle IVF in women with poor ovarian response according to the Bologna criteria","volume":"27","author":"Polyzos","year":"2012","journal-title":"Hum. Reprod."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s00404-013-2794-z","article-title":"Initiation of ovarian stimulation independent of the menstrual cycle: A case-control study","volume":"288","author":"Buendgen","year":"2013","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"557","DOI":"10.29252\/ijrm.14.9.557","article-title":"GnRH agonist trigger versus hCG trigger in GnRH antagonist in IVF\/ICSI cycles: A review article","volume":"14","author":"Alyasin","year":"2016","journal-title":"Int. J. Reprod. Biomed."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1093\/humrep\/deab259","article-title":"Why double ovarian stimulation in an in vitro fertilization cycle is potentially unsafe","volume":"37","author":"Tocci","year":"2022","journal-title":"Hum. Reprod."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1016\/S0149-2918(03)80222-9","article-title":"The impact of reducing dose frequency on health outcomes","volume":"25","author":"Richter","year":"2003","journal-title":"Clin. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Hsu, C.-C., Hsu, L., Hsueh, Y.-S., Lin, C.-Y., Chang, H.H., and Hsu, C.-T. (2021). Ovarian folliculogenesis and uterine endometrial receptivity after intermittent vaginal injection of recombinant human follicle-stimulating hormone in infertile women receiving in vitro fertilization and in immature female rats. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910769"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Hsu, C.C., Hsu, I., Lee, L.H., Hsu, R., Hsueh, Y.S., Lin, C.Y., and Chang, H.H. (2022). Ovarian follicular growth through intermittent vaginal gonadotropin administration in diminished ovarian reserve women. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14040869"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3109\/09513590.2015.1102879","article-title":"The use of ovarian reserve markers in IVF clinical practice: A national consensus","volume":"32","author":"Ferraretti","year":"2016","journal-title":"Gynecol. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1093\/humupd\/dmaa035","article-title":"Mild versus conventional ovarian stimulation for IVF in poor, normal and hyper-responders: A systematic review and meta-analysis","volume":"27","author":"Datta","year":"2021","journal-title":"Hum. Reprod. Update"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1089\/jayao.2017.0028","article-title":"Determination of follicular localization in human ovarian cortex for vitrification","volume":"7","author":"Haino","year":"2018","journal-title":"J. Adolesc. Young Adult Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1038\/s41467-020-14936-3","article-title":"Single-cell analysis of human ovarian cortex identifies distinct cell populations but no oogonial stem cells","volume":"11","author":"Wagner","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S0303-7207(00)00340-3","article-title":"Expression and actions of both the follicle stimulating hormone receptor and the luteinizing hormone receptor in normal ovarian surface epithelium and ovarian cancer","volume":"172","author":"Parrott","year":"2001","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1002\/ijc.20478","article-title":"Follicle stimulating hormone-induced growth promotion and gene expression profiles on ovarian surface epithelial cells","volume":"112","author":"Ji","year":"2004","journal-title":"Int. J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/1757-2215-6-20","article-title":"Stimulation of ovarian stem cells by follicle stimulating hormone and basic fibroblast growth factor during cortical tissue culture","volume":"6","author":"Parte","year":"2013","journal-title":"J. Ovarian Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3","DOI":"10.18632\/aging.100117","article-title":"Stem cells in aged mammalian ovaries","volume":"2","author":"Skutella","year":"2010","journal-title":"Aging"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/1757-2215-7-25","article-title":"Dynamics associated with spontaneous differentiation of ovarian stem cells in vitro","volume":"7","author":"Parte","year":"2014","journal-title":"J. Ovarian Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"R35","DOI":"10.1530\/REP-14-0220","article-title":"FSH-FSHR3-stem cells in ovary surface epithelium: Basis for adult ovarian biology, failure, aging, and cancer","volume":"149","author":"Bhartiya","year":"2015","journal-title":"Reproduction"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1210\/me.2008-0103","article-title":"Constitutively active protein kinase A qualitatively mimics the effects of follicle-stimulating hormone on granulosa cell differentiation","volume":"22","author":"Orwig","year":"2008","journal-title":"Mol. Endocrinol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1095\/biolreprod.112.099127","article-title":"Ovarian Kaleidoscope database: Ten years and beyond","volume":"86","author":"Hsueh","year":"2012","journal-title":"Biol. Reprod."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1093\/molehr\/gap036","article-title":"Purification of germline stem cells from adult mammalian ovaries: A step closer towards control of the female biological clock?","volume":"15","author":"Tilly","year":"2009","journal-title":"Mol. Hum. Reprod."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18632\/aging.100119","article-title":"Failure of the stem cell niche rather than loss of oocyte stem cells in the aging ovary","volume":"2","author":"Massasa","year":"2010","journal-title":"Aging"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"971","DOI":"10.18632\/aging.100105","article-title":"Aged mouse ovaries possess rare premeiotic germ cells that can generate oocytes following transplantation into a young host environment","volume":"1","author":"Niikura","year":"2009","journal-title":"Aging"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s12958-015-0080-6","article-title":"Controlled Ovarian Stimulation with recombinant-FSH plus recombinant-LH vs. human Menopausal Gonadotropin based on the number of retrieved oocytes: Results from a routine clinical practice in a real-life population","volume":"13","author":"Revelli","year":"2015","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_48","first-page":"Cd005070","article-title":"Recombinant luteinizing hormone (rLH) and recombinant follicle stimulating hormone (rFSH) for ovarian stimulation in IVF\/ICSI cycles","volume":"5","author":"Mochtar","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"hoz008","DOI":"10.1093\/hropen\/hoz008","article-title":"Required amount of rFSH, HP-hMG and HP-FSH to reach a live birth: A systematic review and meta-analysis","volume":"2019","author":"Bordewijk","year":"2019","journal-title":"Hum. Reprod. Open"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1002\/(SICI)1098-2795(199906)53:2<198::AID-MRD9>3.0.CO;2-K","article-title":"Homologous and heterologous ligands downregulate follicl\u00d6 stimulating hormone receptor mRNA in porcine granulosa cells","volume":"53","author":"Murphy","year":"1999","journal-title":"Mol. Reprod. Dev."}],"container-title":["Biomedicines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9059\/10\/6\/1312\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:24:17Z","timestamp":1760138657000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9059\/10\/6\/1312"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,3]]},"references-count":50,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["biomedicines10061312"],"URL":"https:\/\/doi.org\/10.3390\/biomedicines10061312","relation":{},"ISSN":["2227-9059"],"issn-type":[{"type":"electronic","value":"2227-9059"}],"subject":[],"published":{"date-parts":[[2022,6,3]]}}}