Novel approaches to fertility restoration in women with premature ovarian insufficiency

Figures & data

Figure 1. Summary of emerging approaches that may provide new opportunities for women with premature ovarian insufficiency in the future.

Figure 2. The phosphoinositide 3-kinase (P13K) signaling pathway, highlighting points that have been manipulated in current in vitro activation protocols. FOXO3A, Forkhead box O protein-3A; mTOR, mammalian target of rapamycin; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PTEN, phosphatase and tensin homolog.

Figure 3. The Hippo signaling pathway.

Table 1. Summary of clinical research aimed at improving the fertility of women with premature ovarian insufficiency (POI).

Study	Intervention	Number of patients	Inclusion criteria	Intervention description	Control	Pregnancy (method)	Live birth
Edessy et al.^23	Autologous MSC transplant	10	Post menarche <40 yo FSH ≥20 mIU/ml	Autologous transplant of bone marrow-derived MSCs	N/A	1 (unclear)	1
Ding et al.^25	Autologous MSC transplant	14	POI, 18–39 yo Amenorrhea >1 year FSH ≥40 mIU/ml	Group 1 (n = 6): autologous transplant of umbilical cord-derived MSCs Group 2 (n = 8): autologous transplant of umbilical cord-derived MSCs + collagen	N/A	2 (natural, one from each group)	1
Herraiz et al.^29	Autologous MSC transplant	17	Poor responders according to ESHRE guidelines	Autologous transplant of bone marrow-derived MSCs	Contralateral ovary	3 (natural) 2 (IVF)	3
Sfakianoudis et al.^34	Infusion of platelet-rich plasma	30	POI, <40 yo Amenorrhea >1 year FSH ≥25 mIU/ml	Intraovarian infusion of platelet-rich plasma	N/A	3 (natural)	0
Hsu et al.^35	Infusion of platelet-rich plasma	1 (case report)	37 yo Amenorrheic with FSH 43.5 mIU/ml and AMH <0.02 ng/ml	Intraovarian infusion of platelet-rich plasma	N/A	1 (ICSI)	1
Kawamura et al.^6	In vitro activation	27	POI, <40 yo Amenorrhea >1 year FSH ≥40 mIU/ml	Ovarian cryopreservation + thaw, fragmentation, in vitro culture with bpV(HOpic) and 740YP	N/A	2 (ICSI)	1
Suzuki et al.^48	In vitro activation	10	POI, <40 yo Amenorrhea >4 months FSH ≥35 mIU/ml	Ovarian cryopreservation + thaw, fragmentation, in vitro culture with bpV(HOpic) and 740YP	N/A	1 (ICSI)	1
Zhai et al.^49	In vitro activation	14	POI, <40 yo Amenorrhea >1 year FSH ≥35 mIU/ml	Ovarian fragmentation, in vitro culture with bpV(HOpic) and 740YP	N/A	1 (IVF)	1
Lunding et al.^59	In vitro activation (without pharmacological intervention)	20	Indication for IVF/ICSI 25–39 yo Serum AMH <0.7 ng/ml	Ovarian biopsy, fragmentation, and auto-transplantation to a peritoneal pocket	Contralateral ovary	3 (natural) 9 (IVF/ICSI)	10
Fabregues et al.^60	In vitro activation (without pharmacological intervention)	1 (case report)	30 yo Amenorrheic with FSH 89.9 mIU/ml and AMH 0.02 ng/ml	Ovarian biopsy, fragmentation, and auto-transplantation to a peritoneal pocket	N/A	1 (IVF)	1

Note that some studies include women with poor ovarian reserve rather than POI. AMH, anti-Müllerian hormone; ESHRE, European Society of Human Reproduction and Embryology; FSH, follicle stimulating hormone; ICSI, intra-cytoplasmic sperm injection; IVF, in vitro fertilization; MSC, mesenchymal stem cell; N/A, not applicable; yo, years old.

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Sfakianoudis K, Simopoulou M, Grigoriadis S, et al. Reactivating ovarian function through autologous platelet-rich plasma intraovarian infusion: pilot data on premature ovarian insufficiency, perimenopausal, menopausal, and poor responder women. J Clin Med 2020;9:1809

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Suzuki N, Yoshioka N, Takae S, et al. Successful fertility preservation following ovarian tissue vitrification in patients with primary ovarian insufficiency. Hum Reprod 2015;30:608–15

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Zhai J, Yao G, Dong F, et al. In vitro activation of follicles and fresh tissue auto-transplantation in primary ovarian insufficiency patients. J Clin Endocrinol Metab 2016;101:4405–12

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Lunding SA, Pors SE, Kristensen SG, et al. Biopsying, fragmentation and autotransplantation of fresh ovarian cortical tissue in infertile women with diminished ovarian reserve. Hum Reprod 2019;34:1924–36

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Fabregues F, Ferreri J, Calafell JM, et al. Pregnancy after drug-free in vitro activation of follicles and fresh tissue autotransplantation in primary ovarian insufficiency patient: a case report and literature review. J Ovarian Res 2018;11:76

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