Adverse effects of progestin-primed ovarian stimulation: combination of clinical study and single-cell analysis

Handa, Mika; Takiuchi, Tsuyoshi; Kawaguchi, Sumika; Hon, Chung Chau; Moody, Jonathan; Okazaki, Yasushi; Ozaki, Kokoro; Horie, Masafumi; Ohara, Yasuhiro; Doshida, Masakazu; Takeuchi, Takumi; Matsubayashi, Hidehiko; Saji, Fumie; Miyake, Tatsuya; Ishikawa, Tomomoto; Ando, Yoshinari; Komukai, Sho; Kitamura, Tetsuhisa; Shin, Jay W.; Kimura, Tadashi

doi:https://doi.org/10.1016/j.rbmo.2025.104833

Adverse effects of progestin-primed ovarian stimulation: combination of clinical study and single-cell analysis

Handa, Mika; Takiuchi, Tsuyoshi; Kawaguchi, Sumika et al.

Reproductive BioMedicine Online, 2025, 51(2), 104833

Number of Access:35（2025-10-19 17:34 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/102651

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Title	Adverse effects of progestin-primed ovarian stimulation: combination of clinical study and single-cell analysis
Creator	researchmap permalink mikahanda mikahanda CreatorName Handa, Mika
	NRID 1000040733358 1000040733358 researchmap permalink Takiuchi-gyne Takiuchi-gyne Scopus Author ID 51764431400 51764431400 CreatorName Takiuchi, Tsuyoshi
	CreatorName Kawaguchi, Sumika
	NRID 1000020775671 1000020775671 CreatorName Hon, Chung Chau
	CreatorName Moody, Jonathan
	NRID 1000080280733 1000080280733 CreatorName Okazaki, Yasushi
	NRID 1000010754765 1000010754765 CreatorName Ozaki, Kokoro
	CreatorName Horie, Masafumi
	CreatorName Ohara, Yasuhiro
	CreatorName Doshida, Masakazu
	CreatorName Takeuchi, Takumi
	CreatorName Matsubayashi, Hidehiko
	NRID 1000040600987 1000040600987 researchmap permalink fumi_s fumi_s Scopus Author ID 59768704100 59768704100 CreatorName Saji, Fumie
	NRID 1000000814766 1000000814766 researchmap permalink a-1 a-1 Scopus Author ID 57188931396 57188931396 CreatorName Miyake, Tatsuya
	NRID 1000000432576 1000000432576 CreatorName Ishikawa, Tomomoto
	CreatorName Ando, Yoshinari
	NRID 1000070794543 1000070794543 ORCID 0000-0002-4329-2520 0000-0002-4329-2520 researchmap permalink sho.komukai sho.komukai Scopus Author ID 57200127087 57200127087 CreatorName Komukai, Sho
	NRID 1000030639810 1000030639810 ORCID 0000-0003-0107-0580 0000-0003-0107-0580 researchmap permalink Kitamura_T Kitamura_T Scopus Author ID 22234282700 22234282700 CreatorName Kitamura, Tetsuhisa
	CreatorName Shin, Jay W.
	NRID 1000090240845 1000090240845 CreatorName Kimura, Tadashi
Subject	Inverse probability weighting
	Mitochondrial DNA
	Mural granulosa cell
	Progestin-primed ovarian stimulation
	Single-cell RNA sequencing
Description	Handa M., Takiuchi T., Kawaguchi S., et al. Adverse effects of progestin-primed ovarian stimulation: combination of clinical study and single-cell analysis. Reproductive BioMedicine Online 51, 104833 (2025); https://doi.org/10.1016/j.rbmo.2025.104833.
Abstract	Research question: Does progestin-primed ovarian stimulation (PPOS) have a negative effect on reproductive outcomes compared with a gonadotrophin-releasing hormone (GnRH) antagonist protocol? Design: This retrospective cohort study included 907 patients aged <40 years with normal ovarian reserves undergoing either PPOS (n = 299) or a GnRH-antagonist protocol (n = 608) in their first IVF cycle between 2018 and 2020. An additional genetic analysis, single-cell RNA sequencing (scRNA-seq), was performed on the mural granulosa cells (mGC) of metaphase II oocyte follicles retrieved from 16 patients, with the above inclusion criteria, undergoing PPOS (n = 8) or a GnRH-antagonist protocol (n = 8) between 2021 and 2022. Inverse probability of treatment weighting (IPTW) was performed on the clinical data. Predetermined primary outcomes were the premature LH surge rate and the live birth rate of the first frozen embryo transfer cycle for the first and second IPTW analyses, respectively. Results: The premature LH surge rate was lower in the PPOS group compared with the GnRH-antagonist group (3.1% versus 20.1%, OR 0.13, 95% CI 0.07–0.23; P < 0.001) in the first IPTW analysis. The good-quality cleavage embryo rate was lower in the PPOS group compared with the GnRH-antagonist group (37.2% versus 49.1%; P < 0.001). The live birth rate was lower in the PPOS group compared with the GnRH-antagonist group (31.5% versus 42.3%, OR 0.63, 95% CI 0.46–0.86; P = 0.004) in the second IPTW analysis. The scRNA-seq analysis demonstrated higher expression of 12 mitochondrial DNA (mtDNA) genes in the PPOS group compared with the GnRH-antagonist group. Conclusion: PPOS suppressed the premature LH surge rate but was associated with a lower live birth rate compared with the GnRH-antagonist protocol. The elevated expression of mtDNA genes in mGC may also indicate a decline in oocyte quality with PPOS.
Publisher	Elsevier Ltd
Source Title	Reproductive BioMedicine Online
Volume (Issue)	51(2)
Page	104833
Date of Issued	2025-07-24
Language	English
Handle URL	https://hdl.handle.net/11094/102651
PISSN	14726483
eISSN	14726491
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1016/j.rbmo.2025.104833
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Reproductive BioMedicine Online. 2025, 51(2), p. 104833
DC.title	Adverse effects of progestin-primed ovarian stimulation: combination of clinical study and single-cell analysis
DC.creator	Handa, Mika
	Takiuchi, Tsuyoshi
	Kawaguchi, Sumika
	Hon, Chung Chau
	Moody, Jonathan
	Okazaki, Yasushi
	Ozaki, Kokoro
	Horie, Masafumi
	Ohara, Yasuhiro
	Doshida, Masakazu
	Takeuchi, Takumi
	Matsubayashi, Hidehiko
	Saji, Fumie
	Miyake, Tatsuya
	Ishikawa, Tomomoto
	Ando, Yoshinari
	Komukai, Sho
	Kitamura, Tetsuhisa
	Shin, Jay W.
	Kimura, Tadashi
DC.publisher	Elsevier Ltd
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-07-24
DC.identifier	https://doi.org/10.1016/j.rbmo.2025.104833
DC.subject	Inverse probability weighting
	Mitochondrial DNA
	Mural granulosa cell
	Progestin-primed ovarian stimulation
	Single-cell RNA sequencing
DC.description	Handa M., Takiuchi T., Kawaguchi S., et al. Adverse effects of progestin-primed ovarian stimulation: combination of clinical study and single-cell analysis. Reproductive BioMedicine Online 51, 104833 (2025); https://doi.org/10.1016/j.rbmo.2025.104833.
DCTERMS.abstract	Research question: Does progestin-primed ovarian stimulation (PPOS) have a negative effect on reproductive outcomes compared with a gonadotrophin-releasing hormone (GnRH) antagonist protocol? Design: This retrospective cohort study included 907 patients aged <40 years with normal ovarian reserves undergoing either PPOS (n = 299) or a GnRH-antagonist protocol (n = 608) in their first IVF cycle between 2018 and 2020. An additional genetic analysis, single-cell RNA sequencing (scRNA-seq), was performed on the mural granulosa cells (mGC) of metaphase II oocyte follicles retrieved from 16 patients, with the above inclusion criteria, undergoing PPOS (n = 8) or a GnRH-antagonist protocol (n = 8) between 2021 and 2022. Inverse probability of treatment weighting (IPTW) was performed on the clinical data. Predetermined primary outcomes were the premature LH surge rate and the live birth rate of the first frozen embryo transfer cycle for the first and second IPTW analyses, respectively. Results: The premature LH surge rate was lower in the PPOS group compared with the GnRH-antagonist group (3.1% versus 20.1%, OR 0.13, 95% CI 0.07–0.23; P < 0.001) in the first IPTW analysis. The good-quality cleavage embryo rate was lower in the PPOS group compared with the GnRH-antagonist group (37.2% versus 49.1%; P < 0.001). The live birth rate was lower in the PPOS group compared with the GnRH-antagonist group (31.5% versus 42.3%, OR 0.63, 95% CI 0.46–0.86; P = 0.004) in the second IPTW analysis. The scRNA-seq analysis demonstrated higher expression of 12 mitochondrial DNA (mtDNA) genes in the PPOS group compared with the GnRH-antagonist group. Conclusion: PPOS suppressed the premature LH surge rate but was associated with a lower live birth rate compared with the GnRH-antagonist protocol. The elevated expression of mtDNA genes in mGC may also indicate a decline in oocyte quality with PPOS.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	102651
citation_title	Adverse effects of progestin-primed ovarian stimulation: combination of clinical study and single-cell analysis
citation_author	Handa, Mika
	Takiuchi, Tsuyoshi
	Kawaguchi, Sumika
	Hon, Chung Chau
	Moody, Jonathan
	Okazaki, Yasushi
	Ozaki, Kokoro
	Horie, Masafumi
	Ohara, Yasuhiro
	Doshida, Masakazu
	Takeuchi, Takumi
	Matsubayashi, Hidehiko
	Saji, Fumie
	Miyake, Tatsuya
	Ishikawa, Tomomoto
	Ando, Yoshinari
	Komukai, Sho
	Kitamura, Tetsuhisa
	Shin, Jay W.
	Kimura, Tadashi
citation_publisher	Elsevier Ltd
citation_language	English
citation_date	2025-07-24
citation_journal_title	Reproductive BioMedicine Online
citation_volume	51
citation_issue	2
citation_firstpage	104833
citation_doi	https://doi.org/10.1016/j.rbmo.2025.104833
citation_public_url	https://hdl.handle.net/11094/102651

Adverse effects of progestin-primed ovarian stimulation: combination of clinical study and single-cell analysis

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