Fresh and cryopreserved ovarian tissue transplantation for preserving reproductive and endocrine function: a systematic review and individual patient data meta-analysis
Authors: Khattak Hajra , Malhas Rosamund , Craciunas Laurentiu , Afifi Yousri , Amorim Christiani A , Fishel Simon , Silber Sherman , Gook Debra , Demeestere Isabelle , Bystrova Olga , Lisyanskaya Alla , Manikhas Georgy , Lotz Laura , Dittrich Ralf , Colmorn Lotte Berdiin , Macklon Kirsten Tryde , Hjorth Ina Marie Dueholm , Kristensen Stine Gry , Gallos Ioannis , Coomarasamy Arri 
Published: January 2022

Abstract

BACKGROUND
Ovarian tissue cryopreservation involves freezing and storing of surgically retrieved ovarian tissue in liquid or vapour nitrogen below –190°C. The tissue can be thawed and transplanted back with the aim of restoring fertility or ovarian endocrine function. The techniques for human ovarian tissue freezing and transplantation have evolved over the last 20 years, particularly in the context of fertility preservation in pre-pubertal cancer patients. Fresh ovarian tissue transplantation, using an autograft or donor tissue, is a more recent development; it has the potential to preserve fertility and hormonal function in women who have their ovaries removed for benign gynaecological conditions. The techniques of ovarian tissue cryopreservation and transplantation have progressed rapidly since inception; however, the evidence on the success of this intervention is largely based on case reports and case series.

OBJECTIVE AND RATIONALE
The aim of this study was to systematically review the current evidence by incorporating study-level and individual patient-level meta-analyses of women who received ovarian transplants, including frozen–thawed transplant, fresh or donor graft.

SEARCH METHODS
The review protocol was registered with PROSPERO (CRD42018115233). A comprehensive literature search was performed using MEDLINE, EMBASE, CINAHL and Cochrane Central Register of Controlled Trials from database inception to October 2020. Authors were also contacted for individual patient data if relevant outcomes were not reported in the published manuscripts. Meta-analysis was performed using inverse-variance weighting to calculate summary estimates using a fixed-effects model.

OUTCOMES
The review included 87 studies (735 women). Twenty studies reported on ≥5 cases of ovarian transplants and were included in the meta-analysis (568 women). Fertility outcomes included pregnancy, live birth and miscarriage rates, and endocrine outcomes included oestrogen, FSH and LH levels. The pooled rates were 37% (95% CI: 32–43%) for pregnancy, 28% (95% CI: 24–34%) for live birth and 37% (95% CI: 30–46%) for miscarriage following frozen ovarian tissue transplantation. Pooled mean for pre-transplant oestrogen was 101.6 pmol/l (95% CI: 47.9–155.3), which increased post-transplant to 522.4 pmol/l (95% CI: 315.4–729; mean difference: 228.24; 95% CI: 180.5–276). Pooled mean of pre-transplant FSH was 66.4 IU/l (95% CI: 52.8–84), which decreased post-transplant to 14.1 IU/l (95% CI: 10.9–17.3; mean difference 61.8; 95% CI: 57–66.6). The median time to return of FSH to a value &lt;25 IU/l was 19 weeks (interquartile range: 15–26 weeks; range: 0.4–208 weeks). The median duration of graft function was 2.5 years (interquartile range: 1.4–3.4 years; range: 0.7–5 years). The analysis demonstrated that ovarian tissue cryopreservation and transplantation could restore reproductive and hormonal functions in women. Further studies with larger samples of well-characterized populations are required to define the optimal retrieval, cryopreservation and transplantation processes.

WIDER IMPLICATIONS
Ovarian tissue cryopreservation and transplantation may not only be effective in restoring fertility but also the return of reproductive endocrine function. Although this technology was developed as a fertility preservation option, it may have the scope to be considered for endocrine function preservation.