Interventional procedure overview of removal, preservation and reimplantation of ovarian tissue to restore fertility after gonadotoxic treatment

Abir R, Ben-Aharon I, Garor R et al. (2016) Cryopreservation of in vitro matured oocytes in addition to ovarian tissue freezing for fertility preservation in paediatric female cancer patients before and after cancer therapy. Human Reproduction 31: 750–62

Case series

n=42

Ovarian tissue was successfully collected from 79% of patients.

Although more oocytes were collected and matured from chemotherapy-naive paediatric patients, ovarian tissue and immature oocytes were also retrieved from young girls in whom cancer therapy has already been initiated.

Small case series, including immature oocyte collection as well as ovarian tissue collection.

Abir R, Aviram A, Feinmesser M et al. (2014) Ovarian minimal residual disease in chronic myeloid leukaemia. Reproductive Biomedicine Online 28: 255–60

Case report

n=1

Despite the lack of positive pathological and immunohistochemical evidence, PCR and 2-step nested PCR revealed that the ovary was contaminated by malignant minimal residual chronic myeloid leukaemia.

Case report of cryopreserved-thawed ovarian tissue contaminated with residual malignancy.

Amorim CA, Leonel ECR, Afifi Y et al. (2019) Cryostorage and retransplantation of ovarian tissue as an infertility treatment. Best Practice & Research. Clinical Endocrinology & Metabolism 33: 89–102

Review

OTC has been successfully applied worldwide to preserve fertility in cancer patients and women with different types of benign conditions that have a negative impact on their fertility.

Proper assessment of the risk of ovarian failure, existing ovarian reserve and patient choice have to be taken into account for the amount of the ovarian tissue needs to be retrieved.

Other systematic reviews have been included.

Andersen CY, Rosendahl M, Byskov AG et al. (2008) Two successful pregnancies following autotransplantation of frozen/thawed ovarian tissue. Human Reproduction 23: 2266–72

Case series

n=6

In all cases, the tissue restored menstrual cyclicity 14 to 20 weeks following transplantation. Four of the 6 women conceived following assisted reproduction: 2 women each, based on the orthotopic transplanted tissue, delivered 1 healthy child, 1 woman miscarried in gestational week 7; and the other had a positive hCG test but no clinical pregnancy. The remaining 2 women did not become pregnant.

Small case series.

Anderson RA, Wallace WHB, Baird DT (2008) Ovarian cryopreservation for fertility preservation: indications and outcomes. Reproduction 136: 681–9

Case series

n=36

Of the 36 women, 11 have died and 5 have had spontaneous pregnancies. So far, none have requested reimplantation of their stored ovarian tissue.

Small case series, with no reimplantation procedures.

Anderson RA, Wallace WHB, Telfer EE (2017) Ovarian tissue cryopreservation for fertility preservation: Clinical and research perspectives.

Human Reproduction Open 2017: 1–9

Review

Ovarian tissue cryopreservation is becoming established as a valuable approach to the preservation of fertility in women. Its application in prepubertal girls may be of particular value, as it offers the only approach in this patient group. More accurate data are needed on the likelihood of successful childbirth after this procedure and the factors that underpin successful application of this approach.

Other systematic reviews have been included.

Bach AS, Macklon KT, Kristensen SG (2020) Futures and fears in the freezer: Danish women's experiences with ovarian tissue cryopreservation and transplantation. Reproductive Biomedicine Online 41: 555–65

Case series

n=42

OTC was associated with positive experiences linked to the production of future-oriented hope and reproductive possibilities. It also generated a range of worries, particularly regarding hormone-sensitive cancers and the risk of re-transplanting malignant cells.

Small case series, exploring patient experiences and reflections on the procedure.

Bahroudi Z, Zarnaghi MR, Izadpanah M et al. (2022) Review of ovarian tissue cryopreservation techniques for fertility preservation. Journal of Gynecology Obstetrics and Human Reproduction 51: 102290

Review

This review of articles related to cryopreservation of ovarian tissue showed that recovery of endocrine function and the live birth rate following re-implantation had been steadily increasing.

Other systematic reviews have been included.

Beckmann MW, Dittrich R, Lotz L et al. (2017) Operative techniques and complications of extraction and transplantation of ovarian tissue: the Erlangen experience. Archives of Gynecology and Obstetrics 295: 1033–39

Case series

n=38 (399 women had ovarian tissue extracted)

There were no surgical complications within 28 days of tissue extraction. There were 10 pregnancies and 9 live births after transplantation in 7 different women; 26 of the 38 women developed hormonal activity, confirmed by a menstrual cycle or raised serum oestradiol level.

Small case series.

Bedaiwy MA, El-Nashar SA, El Saman AM et al. (2008) Reproductive outcome after transplantation of ovarian tissue: a systematic review. Human Reproduction 23: 2709–17

Systematic review

n=46 (25 reports)

Transplantation of ovarian tissue can re-establish ovarian function after premature ovarian failure; however, the efficacy of OTT using cryopreserved tissues is not yet equivalent to that of fresh grafts. A controlled multicentre trial with sufficient follow-up would provide valid evidence of the potential benefit of this procedure.

More recent systematic reviews are included.

Biasin E, Salvagno F, Berger M et al. (2015) Ovarian tissue cryopreservation in girls undergoing haematopoietic stem cell transplant: experience of a single centre. Bone Marrow Transplantation 50: 1206–11

Case series

n=47

93% (26/28) of evaluable patients developed hypergonadotropic hypogonadism at a median 23 months after haematopoietic stem cell transplant. One patient had autologous orthotopic transplantation that resulted in 1 live birth. Results show a very high rate of iatrogenic hypergonadotropic hypogonadism, highlighting the need for fertility preservation in these patients.

Small case series, included in the systematic review by Ni Dhonnabhain et al. (2022).

Bystrova O, Lapina E, Kalugina A et al. (2019) Heterotopic transplantation of cryopreserved ovarian tissue in cancer patients: a case series. Gynecological Endocrinology 35: 1043-1049

Case series

n=10

Follow up: 36 months

Frozen-thawed grafts were implanted subcutaneously in the forearm (n=2), the abdominal wall (n=11) and the peritoneal lining (n=3). Although the peritoneal site gave better results, graft longevity averaged the same at around 3 years.

Small case series, assessing serum hormones and follicle growth in heterotopic sites.

Calagna G, Della Corte L, Giampaolino P et al. (2020) Endometriosis and strategies of fertility preservation: a systematic review of the literature. European Journal of Obstetrics, Gynecology, and Reproductive Biology 254: 218–25

Systematic review

3 articles on OTC

After ovarian tissue transplantation, 1 pregnancy with IVF and 1 case of endocrine function or ovulation recovery were described.

Review focuses on fertility preservation strategies for people with endometriosis.

Choi YJ, Hong YH, Kim S et al. (2022) The experience of fertility preservation in a single tertiary center in Korea. Frontiers in Endocrinology 13: 845051

Case series

n=26 (OTC)

One woman had the cryopreserved ovarian tissue retransplanted and successfully generated embryos.

Small case series.

Christianson MS, Lukish DA, McCarter R Jr et al. (2021) Ovarian tissue cryopreservation in young females with cancer and its impact on ovarian follicle density. Journal of Pediatric Surgery 56: 2354–59

Case series

n=6

Following cryopreservation, on average the ovarian tissue retained 89% of the follicle density of paired fresh samples (95% CI 83% to 95%). Follicle density in young females with cancer is significantly reduced after OTC. However, the degree of reduction may be less than that reported in adult women.

Small case series, assessing follicle density in cryopreserved ovarian tissue.

Cioffi R, Cervini L, Taccagni G et al. (2022) A prospective, observational study of chemotherapy-induced ovarian damage on follicular reserve and maturation. Archives of Gynecology and Obstetrics 306: 1723–29

Case series

n=79

OTC appears to be feasible even after the start of chemotherapeutic treatment, since in treated patients, the main ovarian reserve indicators were not significantly reduced compared to untreated patients.

Study focuses on feasibility of OTC after chemotherapy has started.

Cordeiro Mitchell CN, Whiting-Collings LJ et al. (2020) Understanding patients' knowledge and feelings regarding their cryopreserved ovarian tissue: a qualitative interviewing study. Journal of Adolescent and Young Adult Oncology 9: 502–7

Case series

n=8

Most patients desired future fertility. Although half of the interviewees understood the OTC procedure, only 2 knew that the tissue can be used for future fertility and only 1 was aware of the benefits for vasomotor symptoms. Five patients expressed positive emotions regarding OTC; 1 felt angry that the decision was made by her parents and 2 were concerned that OTC might not have been a good choice. However, most expressed a desire to better understand OTC and most wished for more education about it.

Small case series, focusing on patients' knowledge and feelings about the procedure.

Corkum KS, Rhee DS, Wafford QE et al. (2019) Fertility and hormone preservation and restoration for female children and adolescents receiving gonadotoxic cancer treatments: A systematic review. Journal of Pediatric Surgery 54: 2200–9

Systematic review

91 studies

n=1,019 (OTC)

Eighteen patients had auto-transplantation of thawed ovarian cortical tissue that was harvested before the age of 21 years resulting in 10 live births.

A more recent systematic review is included.

Delattre S, Segers I, Van Moer E et al. (2020) Combining fertility preservation procedures to spread the eggs across different baskets: a feasibility study. Human Reproduction 35: 2524–36

Cohort study

n=207

19 patients requested warming of their cryopreserved material because of ovarian insufficiency. Of those, eight (42%) patients had a livebirth, of whom 3 were after OTC combined with in vitro maturation of oocytes retrieved from ovarian tissue 'ex vivo'. Combining different fertility preservation procedures is likely to enhance the reproductive fitness of patients having gonadotoxic treatment

A range of different procedures were used in the study.

Diaz AA, Kubo H, Handa N et al. (2022) A systematic review of ovarian tissue transplantation outcomes by ovarian tissue processing size for cryopreservation. Frontiers in Endocrinology 13: 918899

Systematic review

103 studies

OTT was done in 92 patients that had ovarian tissue cryopreserved into strips (n=51), squares (n=37), and fragments (n=4). The pregnancy rate was 81%, 46%, 67% in the strips, squares, fragment groups, respectively. The live birth rate was 56%,18%, 67% in the strips, squares, fragment groups, respectively. The mean time from OTT to ovarian hormone restoration was 3.9 months, 3.6 months, and 3 months in the strips, squares, and fragments groups, respectively.

Review focuses on outcomes according to size of processed ovarian tissue.

Diaz-Garcia C, Domingo J, Garcia-Velasco JA et al. (2018) Oocyte vitrification versus ovarian cortex transplantation in fertility preservation for adult women undergoing gonadotoxic treatments: a prospective cohort study. Fertility and Sterility 109: 478-485e2

Cohort study

n=1,824 (44 OTT)

Although we observed a trend toward higher live birth rate after oocyte vitrification, OTT is a very effective method to preserve fertility, allows for natural pregnancy, and restores ovarian function. In clinical scenarios where oocyte vitrification is not feasible, OTT remains the fertility preservation technique of choice and should no longer be considered experimental.

Study is included in the systematic review by Ni Dhonnabhain et al. (2022).

Dittrich R, Hackl J, Lotz L et al. (2015) Pregnancies and live births after 20 transplantations of cryopreserved ovarian tissue in a single center. Fertility and Sterility 103: 462–8

Case series

n=20

Ovarian activity resumed in all patients except 1. Seven patients conceived, with 1 miscarriage and 4 ongoing pregnancies. Four patients delivered healthy babies.

Small case series, included in the systematic review by Ni Dhonnabhain et al. (2022).

Dolmans MM, Iwahara Y, Donnez J et al. (2016) Evaluation of minimal disseminated disease in cryopreserved ovarian tissue from bone and soft tissue sarcoma patients. Human Reproduction 31: 2292–302

Case series

n=48

Minimal disseminated disease was not detected in frozen-thawed ovarian tissue from 26 patients by any of the sensitive methods applied.

Small study, assessing the presence of malignant cells in cryopreserved ovarian tissue.

Dolmans MM, Jadoul P, Gilliaux S et al. (2013) A review of 15 years of ovarian tissue bank activities. Journal of Assisted Reproduction and Genetics 30: 305–14

Case series

n=11 OTT (476 OTC)

At histology, malignant cells were found in ovarian tissue from leukaemia patients (n=3) and non-Hodgkin's lymphoma patients (n=2). Eleven patients had autotransplantation, resulting in 5 live births and 1 ongoing pregnancy.

Small case series, included in the systematic review by Ni Dhonnabhain et al. (2022).

Donnez J, Dolmans MM (2015) Ovarian cortex transplantation: 60 reported live births brings the success and worldwide expansion of the technique towards routine clinical practice. Journal of Assisted Reproduction and Genetics 32: 1167-70

Review

n=60

The mean duration of ovarian function after transplantation is about 5 years in case of high follicular density which is age dependent. So far, 60 live births have been reported either in peer reviewed journals or in abstracts of congress. All of them but 2 were obtained when the slow freezing technique was applied.

More recent studies are included.

Donnez J, Dolmans MM, Pellicer A et al. (2013) Restoration of ovarian activity and pregnancy after transplantation of cryopreserved ovarian tissue: a review of 60 cases of reimplantation. Fertility and Sterility 99: 1503–13

Case series

n=60

Among the 60 patients, 11 conceived and 6 of those had already delivered 12 healthy babies.

Small case series, included in the systematic review by Ni Dhonnabhain et al. (2022).

Dueholm Hjorth IM, Kristensen SG et al. (2020) Reproductive outcomes after in vitro fertilization treatment in a cohort of Danish women transplanted with cryopreserved ovarian tissue. Fertility and Sterility 114: 379–87

Cohort study

n=28

Eleven women achieved 15 pregnancies, of which 60% were lost during the first or second trimester, resulting in 5 of 28 women having 1 or more live births, and 7 healthy children being born.

Small case series, included in the systematic review by Ni Dhonnabhain et al. (2022).

Fabbri R, Vicenti R, Magnani V et al. (2022) Ovarian tissue cryopreservation and transplantation: 20 years experience in Bologna University. Frontiers in Endocrinology 13: 1035109

Cohort study

n=24 (30 transplants)

To date, out of 1,026 total women, 812 (79%) had their tissue stored. Sixty-eight (7%) patients died from their primary disease. Twenty four (2%) women had 33 OTTs. Restoration of menstruation was observed in 15 out of 17 menopausal women. Six pregnancies were achieved, 2 ended in abortion and 4 in the birth of healthy babies.

Larger studies are included.

Fajau-Prevot C, Le Gac YT, Chevreau C et al. (2017) Ovarian mucinous cystadenoma after ovarian graft. Obstetrics and Gynecology 129: 1035–6

Case report

n=1

During a caesarean delivery in a woman who had OTT, a cyst was removed from the ovarian graft. On pathologic evaluation, it was determined to be a mucinous cystadenoma.

Case report of cancer recurrence after OTT, also described in the systematic review by Khattak et al. (2022).

Findeklee S, Radosa JC, Takacs Z et al. (2019) Fertility preservation in female cancer patients: current knowledge and future perspectives. Minerva Ginecologica 71: 298–305

Review

11 studies on OTC

OTC has been developed as standard in fertility preserving treatment in recent years.

Approximately 100 children have been born, with some pregnancies still in progress.

More recent systematic reviews are included.

Fleury A, Pirrello O, Maugard C et al. (2018) Breast cancer and ovarian tissue cryopreservation: Review of the literature. Journal of Gynecology Obstetrics and Human Reproduction 47: 351–7

Review

8 articles

Sixteen cases of ovarian transplants among patients treated for breast cancer were published with 14 pregnancies, 11 births and 3 failures. Two cases of breast recurrences were published after ovarian grafting. However, the evidence on this technique is limited, with a first transplant published in 2004 and only a low number of cases.

Review focuses on patients with breast cancer.

Fortin A, Azais H, Uzan C et al. (2019) Laparoscopic ovarian tissue harvesting and orthotopic ovarian cortex grafting for fertility preservation: less is more. Fertility and Sterility 111: 408–10

Case series

n=34

Laparoscopic ovarian tissue harvesting and orthotopic ovarian cortex grafting restored ovarian endocrine activity in 88% of cases. Ten patients had become pregnant (29%), and the same number gave birth to at least 1 child.

Small case series.

Gook D, Hale L, Polyakov A et al. (2021) Experience with transplantation of human cryopreserved ovarian tissue to a sub-peritoneal abdominal site. Human Reproduction 36: 2473–83

Cohort study

n=17

Live births have resulted from oocytes aspirated from follicles within cryopreserved ovarian tissue transplanted in a sub-peritoneal abdominal site with similar outcomes observed in terms of number of mature oocytes recovered and embryo development from tissue transplanted to sub-peritoneal abdominal, ovarian, and pelvic sites.

Small study, focusing on grafting of ovarian tissue to sub-peritoneal abdominal sites.

Hoekman EJ, Louwe LA, Rooijers M et al. (2020) Ovarian tissue cryopreservation: Low usage rates and high live-birth rate after transplantation. Acta obstetricia et gynecologica Scandinavica 99: 213–21

Cohort study

n=69

The usage rate of autotransplantation was 9% (7/69).

Six babies were born to 4 women, giving a live-birth rate of 57% (4/7).

Small study, included in the systematic review by Ni Dhonnabhain et al. (2022).

Hornshoj VG, Dueholm M, Mamsen LS et al. (2021) Hormonal response in patients transplanted with cryopreserved ovarian tissue is independent of whether freezing was performed in childhood or adulthood. Journal of Assisted Reproduction and Genetics 38: 3039– 45

Cohort study

n=29

Ovarian tissue that was excised from girls at a time close to puberty, after which it was frozen and transplanted in adulthood, interacts with pituitary tissue in a similar manner to ovarian tissue that is frozen from adult women. Follicles located in the ovarian tissue from young girls are equally sensitive to gonadotropin stimulation as follicles from adult women when exposed to postmenopausal levels of gonadotropins.

Small study, assessing hormone response in transplanted ovarian tissue.

Hulsbosch S, Koskas M, Tomassetti C et al. (2018) A real-life analysis of reproductive outcome after fertility preservation in female cancer patients. Gynecologic and Obstetric Investigation 83: 156–63

Case series

n=66 (OTC)

Of the 66 patients who had OTC, 18 attempted pregnancy. One patient who had a transplantation of her cryopreserved ovarian tissue tried to conceive without success.

Small study, included in the systematic review by Ni Dhonnabhain et al. (2022).

Imbert R, Moffa F, Tsepelidis S et al. (2014) Safety and usefulness of cryopreservation of ovarian tissue to preserve fertility: a 12-year retrospective analysis. Human Reproduction 29: 1931–40

Cohort study

n=8 OTT (225 OTC)

Of the 8 patients who had OTT, 3 have become pregnant.

Small study, included in the systematic review by Ni Dhonnabhain et al. (2022).

Jadoul P, Guilmain A, Squifflet J et al. (2017) Efficacy of ovarian tissue cryopreservation for fertility preservation: lessons learned from 545 cases. Human Reproduction 32: 1046–54

Cohort study

n=21 OTT (545 OTC)

Of the 21 patients who had autotransplantation (4%), 7 delivered a healthy baby, yielding a post-transplantation live birth rate of 33%.

Of 451 patients who were sent a questionnaire, 143 agreed to respond (32%). Of 92 evaluable patients, 32% were menopausal and 69% showed persistent ovarian function. Of 52 women who attempted to conceive naturally, 37 were successful (71%). Among 140 patients who answered the questionnaire, 96% were satisfied with the procedure and only 1 major complication (intra-abdominal haemorrhage) was reported.

Small study, included in the systematic review by Ni Dhonnabhain et al. (2022).

Janse F, Donnez J, Anckaert E et al. (2011) Limited value of ovarian function markers following orthotopic transplantation of ovarian tissue after gonadotoxic treatment. The Journal of Clinical Endocrinology and Metabolism 96: 1136–44

Cohort study

n=10

On average, first menses took place after 4.7 months. Duration of graft functioning varied from 2 to more than 60 months. There were 2 spontaneous pregnancies.

Larger and more recent studies are included.

Jensen AK, Kristensen SG, Macklon KT et al. (2015) Outcomes of transplantations of cryopreserved ovarian tissue to 41 women in Denmark. Human Reproduction 30: 2838–45

Cohort study

n=41

Among 32 women with a pregnancy-wish, 10 (31%) had a child (14 children in total); this included 1 woman with a third trimester ongoing pregnancy. In addition, 2 legal abortions and 1 second trimester miscarriage occurred. A total of 24 clinical pregnancies were established in the 32 women with a pregnancy-wish. The tissue remained functional for close to 10 years in some cases and lasted only a short period in others. Three relapses occurred but were unlikely to be due to the transplanted tissue.

Small study, included in the systematic review by Ni Dhonnabhain et al. (2022).

Jensen AK, Macklon KT, Fedder J et al. (2017) 86 successful births and 9 ongoing pregnancies worldwide in women transplanted with frozen-thawed ovarian tissue: focus on birth and perinatal outcome in 40 of these children. Journal of Assisted Reproduction and Genetics 34: 325–36

Review and case series (n=7)

Worldwide, approximately 95 children have been born or will be born in the near future from OTC.

Information on the perinatal outcome was found on 40 children. The mean gestational age was 39 weeks and the mean birth weight was 3,168 g of the singleton pregnancies, which is within internationally recognised normal standards. Furthermore, half the singletons resulted from natural conception and all twins resulted from in vitro fertilisation treatment.

Included in systematic review by Gellert et al. (2018)

Jensen AK, Rechnitzer C, Macklon KT et al. (2017) Cryopreservation of ovarian tissue for fertility preservation in a large cohort of young girls: focus on pubertal development. Human Reproduction 32: 154–64

Cohort study

n=176 OTC

OTC should be recommended to all young girls, who present a high risk of developing ovarian insufficiency and/or infertility following high dose chemotherapy and/or irradiation.

None of the patients had OTT.

Karavani G, Schachter-Safrai N, Chill HH et al. (2018) Single-incision laparoscopic surgery for ovarian tissue cryopreservation. Journal of Minimally Invasive Gynecology 25: 474–79

Case series

n=231 (OTC)

Procedure duration and overall complication rates were similar between single-incision and standard multiport laparoscopic surgery. Number of ampules extracted from the preserved tissue was somewhat higher in the single-incision group (14.7 compared with 10.6 in the multiport group, p<0.01).

Study focuses on single-incision laparoscopic technique for removing ovarian tissue.

Kristensen SG, Wakimoto Y, Colmorn LB et al. (2021) Use of cryopreserved ovarian tissue in the Danish fertility preservation cohort. Fertility and Sterility 116: 1098–1106

Cohort study

n=117 OTT (1,186 OTC)

Stratified age analysis indicated that women aged 30 or above at OTC were more likely to return for OTT than women aged 18 to 29 years at OTC; mean storage times were 3.7 and 3.6 years, respectively. Only 4% of the girls aged less than 18 years at OTC had undergone OTT.

Study focuses on the use of cryopreserved tissue rather than outcomes of the procedure.

Leflon M, Rives-Feraille A, Letailleur M et al. (2022) Experience, and gynaecological and reproductive health follow-up of young adult women who have undergone ovarian tissue cryopreservation. Reproductive BioMedicine Online 45: 913–22

Cohort study

n=9 OTT (87 OTC)

More than 70% of women who planned a pregnancy after the end of treatment succeeded, with a natural pregnancy rate close to 53%. Of the 9 patients (8%) who had OTT for fertility restoration, 6 became pregnant and delivered at least once.

Larger studies are included.

Liebenthron J, Montag M, Reinsberg J et al. (2019) Overnight ovarian tissue transportation for centralized cryobanking: a feasible option. Reproductive Biomedicine Online 38: 740–49

Cohort study

n=30

A subgroup of 30 women who had a single orthotopic transplantation with a complete follow-up after transplantation until the end of study, a premature ovarian insufficiency after gonadotoxic therapy as well as the absence of pelvic radiation, was analysed. In this group, transplantations into a peritoneal pocket accounted for 90%. Transplants were still active at 1 year and above after transplantation in 93%. Pregnancy and delivery rates were 47% and 43%, respectively, with 1 ongoing pregnancy at the end of the study.

Larger studies are included.

Lotz L, Dietl A, Hoffmann I et al. (2022) Endometriosis in women undergoing ovarian tissue transplantation due to premature menopause after gonadotoxic treatment or spontaneous premature ovarian failure.

Acta obstetricia et gynecologica Scandinavica 101: 771–78

Case series

n=17

The mean age of the patients was 29.5 years (range 14 to 39) at the time of ovarian tissue harvest and 34.6 years (range 28 to 40) at transplantation. The pregnancy rate in the study population was 41%, with a live birth rate of 35%. Of the 7 pregnancies, 3 occurred after spontaneous conception.

Small study, focusing on people with endometriosis.

Lotz L, Maktabi A, Hoffmann I et al. (2016) Ovarian tissue cryopreservation and retransplantation--what do patients think about it? Reproductive Biomedicine Online 32: 394–400

Cohort study

n=5 OTT (147 OTC)

Sixty-two women had tried to conceive; 33 reported pregnancies. Twenty-five had delivered healthy children after conceiving naturally; 8 had conceived with assisted reproduction. Five patients had had their ovarian tissue retransplanted. Although many patients continued to have ovarian function, none of them regretted choosing cryopreservation of ovarian tissue.

Larger studies are included.

Lotz L, Barbosa PR, Knorr C et al. (2020) The safety and satisfaction of ovarian tissue cryopreservation in prepubertal and adolescent girls. Reproductive Biomedicine Online 40: 547–54

Cohort study

n=1 OTT (53 OTC)

Ovarian tissue retrieval was without complications in 52 patients. In 23 (54%) of the 43 women who were post-menarchal at OTC, transient amenorrhoea occurred. At survey, 15 women reported a regular menstrual cycle, 25 used oral contraceptives, 9 women reported hormone replacement therapy due to primary ovary insufficiency and 4 had amenorrhoea. Two patients reported the birth of a healthy child after IVF, while 51 patients are still childless, mostly due to their young age (mean 21 years). To date, 1 patient has had transplantation of the ovarian tissue. Forty-nine of the interviewees would again decide on OTC, while 3 argued against it based on cost; 1 woman was unsure.

Larger studies are included.

Marin L, Bedoschi G, Kawahara T et al. (2020) History, evolution and current state of ovarian tissue auto-transplantation with cryopreserved tissue: a successful translational research journey from 1999 to 2020. Reproductive Sciences 27: 955–62

Review

Ovarian transplantation with cryopreserved tissue has gone through remarkable evolution in the last 20 years. The first live birth is likely to be the 1 reported by Meirow et al. in 2005. The technique has evolved to reach a level where most recent live birth rates are exceeding 35% and the procedure is no longer considered experimental by many.

Other systematic reviews are included.

Meirow D, Ra'anani H, Shapira M et al. (2016) Transplantations of frozen-thawed ovarian tissue demonstrate high reproductive performance and the need to revise restrictive criteria. Fertility and Sterility 106: 467–74

Cohort study

n=20

After transplantation, the endocrine recovery rate was 93%. Fourteen patients had IVF treatments with a fertilisation rate of 58%. Sixteen pregnancies were achieved (10 after IVF, 6 spontaneous), resulting in 10 live births, 2 (twins) after harvesting from the mother at the age of 37. Two pregnancies are currently ongoing. After transplantation, 53% of patients conceived, and 32% delivered at least once. One patient conceived 4 times. Chemotherapy exposure before harvesting was not associated with inferior outcomes. All patients, including 2 leukaemia survivors, remained cancer free.

Small study, included in the systematic review by Ni Dhonnabhain et al. (2022).

Meng L, Kawamura K, Yoshioka N et al. (2022) Learning curve of surgeons performing laparoscopic ovarian tissue transplantation in women with premature ovarian insufficiency: a statistical process control analysis. Journal of Minimally Invasive Gynecology 29: 559–66

Case series

n=100

The laparoscopic ovarian tissue transplantation surgery was generally safe given that the postoperative complications were infrequent (2%). Although the performance of all 3 surgeons was acceptable, only surgeon A attained the level of competency after 66 cases. The transplantation method may not be the key factor for reducing surgery time in this surgery. An efficient ovarian tissue transplantation team is more important in reducing the surgery time than the surgeon's surgical technique alone.

Case series, assessing the learning curve of the procedure.

Oktay K, Marin L, Bedoschi G et al. (2022) Ovarian transplantation with robotic surgery and a neovascularizing human extracellular matrix scaffold: a case series in comparison to meta-analytic data. Fertility and Sterility 117: 181–92

Case series

n=7

Robot-assisted autologous cryopreserved ovarian tissue transplantation was done using a neovascularising extracellular matrix scaffold. Ovarian function returned after 14 weeks.

One recipient did not attempt to conceive, 2 needed a surrogate, and 4 delivered 6 healthy children.

Small case series, focusing on a new technique.

Oktay K, Oktem O (2010) Ovarian cryopreservation and transplantation for fertility preservation for medical indications: report of an ongoing experience. Fertility and Sterility 93: 762–8

cohort study

n=3 OTT (59 OTC)

No complications occurred and no histologic evidence of cancer was found in the harvested tissue. One woman with a heterotopic transplant conceived spontaneously and delivered. Of the 3 transplants, 1 ceased function after 9 months and 2 are still functioning at up to 7 years follow up.

Small study, included in the systematic review by Ni Dhonnabhain et al. (2022).

Pacheco F, Oktay K (2017) Current success and efficiency of autologous ovarian transplantation: a meta-analysis. Reproductive Sciences 24: 1111–20

Systematic review

19 reports

The cumulative clinical and live birth and ongoing pregnancy rates were 58% and 38%, respectively, and the endocrine restoration rate was 64%.

Given these recent data, ovarian tissue cryopreservation should be considered as a viable option for fertility preservation.

More recent systematic reviews are included.

Poirot C, Fortin A Lacorte JM et al. (2019) Impact of cancer chemotherapy before ovarian cortex cryopreservation on ovarian tissue transplantation. Human Reproduction 34: 1083– 94

Cohort study

n=31

At 1 year after OTT, the cumulative incidence of ovarian function recovery was 83% (93% in patients exposed to chemotherapy and 67% in others, p=0.14). Graft survival at 2 years after OTT was 77%. The cumulative incidence of pregnancy (Kaplan-Meier) at 3 years after OTT was 36% overall and 49% in case of previous chemotherapy, with no difference related to previous chemotherapy exposure. In total there were 13 pregnancies and 8 births in 7 patients.

Small study, included in the systematic review by Ni Dhonnabhain et al. (2022).

Poirot C, Brugieres L, Yakouben K et al. (2019) Ovarian tissue cryopreservation for fertility preservation in 418 girls and adolescents up to 15 years of age facing highly gonadotoxic treatment. Twenty years of experience at a single center. Acta obstetricia et gynecologica Scandinavica 98: 630–37

Cohort study

n=3 OTT (418 OTC)

Of the 418 patients who had OTC, 3 had OTT, 1 for puberty induction and the 2 others for restoring fertility. So far, no pregnancies have been achieved. Eighty-four patients who had OTC died.

Larger or more recent studies are included.

Poirot C, Fortin A, Dhedin N et al. (2019) Post-transplant outcome of ovarian tissue cryopreserved after chemotherapy in hematologic malignancies. Haematologica 104: e360-e363

Cohort study

n=25

Follow up: median 32 months

The cumulative incidence of ovarian function recovery at one year was 92% (95% CI 77% to 99%) with a median time to recovery of 4.6 months (range 2.2 to 7.6). The cumulative incidence of pregnancy was 52% (95% CI 31 to 77%) at 3 years and 60% (95% CI 37 to 83%) at 5 years, with no significant difference between post and per-chemotherapy groups. In the whole cohort, 11 patients became pregnant at least once (41% of all patients and 46% of patients who recovered ovarian function) and gave birth to at least 1 healthy child (n=8) or had an ongoing pregnancy (n=3).

Larger or more recent studies are included.

Pretalli JB, Frontczak Franck S, et al. (2019) Development of ovarian tissue autograft to restore ovarian function: protocol for a French multicenter cohort study. JMIR Research Protocols 30: e12944

Cohort study

n=25

11 women succeeded in becoming pregnant (pregnancy rate=44%, delivery rate=40%). Among these, 6 women conceived twice, and 1 pregnancy led to a miscarriage.

Small study, included in the systematic review by Ni Dhonnabhain et al. (2022).

Rodriguez-Wallberg KA, Marklund A, Lundberg F et al. (2019) A prospective study of women and girls undergoing fertility preservation due to oncologic and non-oncologic indications in Sweden-Trends in patients' choices and benefit of the chosen methods after long-term follow up. Acta obstetricia et gynecologica Scandinavica 98: 604–15

Cohort study

n=335 (OTC)

Utilisation rate was 5%.

Pregnancy rate was 25% and live birth rate was 7%.

Only a small proportion of patients had OTT.

Rodriguez-Wallberg KA, Tanbo T et al. (2016) Ovarian tissue cryopreservation and transplantation among alternatives for fertility preservation in the Nordic countries - compilation of 20 years of multicenter experience. Acta obstetricia et gynecologica Scandinavica 95: 1015–26

Case series

n=46

17 healthy children have been born and several additional pregnancies are currently ongoing. Overall, ovarian tissue cryopreservation was reported to be safe.

More recent or larger studies are included.

Rosendahl M, Andersen MT, Ralfkiaer E et al. (2010) Evidence of residual disease in cryopreserved ovarian cortex from female patients with leukemia. Fertility and Sterility 94: 2186–90

Case series

n=26 (OTC)

Histology and immunohistochemistry did not reveal malignant cell infiltration in the ovarian cortex of any of the patients. In 6 of the 8 patients (75%) with chromosomal abnormalities in the malignant cells, PCR showed evidence of leukemic cells in the ovarian tissue.

Small case series, assessing the presence of malignant cells in harvested ovarian tissue.

Rosendahl M, Greve T, Andersen CY (2013) The safety of transplanting cryopreserved ovarian tissue in cancer patients: a review of the literature. Journal of Assisted Reproduction and Genetics 30: 11–24

Systematic review

42 studies

Ovarian tissue from 422 patients has been subject to testing for malignant cells by imaging, histology, immunohistochemistry, molecular biology, animal- or clinical transplantation. In 31 (7%) the applied test raised suspicion of malignant cell infiltration.

Transplantation of frozen and thawed ovarian tissue may potentially re-introduce the malignancy. For most conditions, however, the risk is very low and is presumably related to the stage of disease at the time of OTC.

More recent systematic reviews are included.

Rosendahl M, Schmidt KT et al. (2011) Cryopreservation of ovarian tissue for a decade in Denmark: a view of the technique. Reproductive Biomedicine Online 22: 162–71

Case series

n=12 (18 transplants)

All women resumed ovarian function and 3 healthy babies were born to 2 women.

Larger or more recent studies are included.

Ruan X, Cheng J, Korell M et al. (2020) Ovarian tissue cryopreservation and transplantation prevents iatrogenic premature ovarian insufficiency: first 10 cases in China. Climacteric: the journal of the International Menopause Society 23: 574-580

Case series

n=10

The average age at OTC was 33.7 years; the time from OTC to OTT was 15 months. The average time from OTT to restoration of ovarian function was 3.4 months. One year after OTT, all ovaries were still functioning normally. In the first case, the function now remains preserved for more than 3 years. So far, the woman who wishes to conceive has no pregnancy.

Small study, included in the systematic review by Ni Dhonnabhain et al. (2022).

Ruan X, Cheng J, Du J et al. (2022) Analysis of fertility preservation by ovarian tissue cryopreservation in pediatric children in China. Frontiers in Endocrinology 13: 930786

Cohort study

n=49 children

OTC is the only method to preserve the fertility of prepubertal girls, and it is safe and effective. Chemotherapy before OTC is not a contraindication to OTC.

Small study assessing the effect of chemotherapy before OTC.

Sanchez M, Novella-Maestre E, Teruel J et al. (2008) The Valencia Programme for Fertility Preservation. Clinical & Translational Oncology 10: 433–8

Cohort study

n=4 OTT (200 OTC)

Of the 4 patients who had OTT, 2 had ovarian function resumption, in 1 case a month after the implant and in the other 5.5 months after.

More recent or larger studies are included.

Schifflers S, Delbecque K, Galant C et al. (2018) Microscopic infiltration of cryopreserved ovarian tissue in 2 patients with Ewing sarcoma. Journal of Pediatric Hematology/Oncology 40: e167-e170

case reports

n=2

Reports of 2 female patients with Ewing sarcoma and microscopic ovarian infiltration. In both cases, the initial workup found no metastasis. However, the examination of cryopreserved ovarian tissues revealed the presence of tumour cells. These reports underline that, in patients with Ewing sarcoma, retransplantation of cryopreserved ovarian tissue is not harmless and could lead to cancer relapse.

Malignant cells in the ovarian graft is reported in the systematic review by Khattak et al. (2022)

Schmidt KT, Rosendahl M, Ernst E et al. (2011) Autotransplantation of cryopreserved ovarian tissue in 12 women with chemotherapy-induced premature ovarian failure: the Danish experience. Fertility and Sterility 95: 695–701

Cohort study

n=12

All 12 women regained ovarian function between 8 and 26 weeks (mean 19 weeks) after transplantation. There were 6 pregnancies: 2 biochemical, 1 clinical that miscarried in week 7, and 2 resulting in the delivery of 2 healthy infants born at term to 2 women. One of these women subsequently conceived spontaneously and delivered another healthy infant. The life span of the transplanted tissue has been between 6 months and still functioning after 54 months.

Small study, included in the systematic review by Ni Dhonnabhain et al. (2022).

Shapira M, Dolmans MM, Silber S et al. (2020) Evaluation of ovarian tissue transplantation: results from three clinical centers. Fertility and Sterility 114: 388–97

Cohort study

n=60 (70 transplants)

Menses returned in 94% of patients. Fifty pregnancies and 44 deliveries were attained, with 50% of women achieving at least 1 pregnancy and 42% at least 1 delivery. Twelve patients had more than 1 transplant and had their endocrine activity restored. Repeated transplantations yielded 5 live births in 3 patients, 2 of whom had already given birth after the first transplantation. Preharvesting chemotherapy was not associated with inferior outcomes. Of 7 patients whose pelvis was exposed to radiation before OTT, 4 conceived and delivered.

Small study, included in the systematic review by Ni Dhonnabhain et al. (2022).

Sheshpari S, Shahnazi M, Mobarak H et al. (2019) Ovarian function and reproductive outcome after ovarian tissue transplantation: a systematic review. Journal of Translational Medicine 17: 396

Systematic review

n=210 OTT (693 OTC)

25 articles

In general, 70% of patients who OTT had ovarian and endocrine function restoration as well as follicular growth. Pregnancy was reported with 52% of the patients. The available evidence suggests that ovarian tissue transplantation is a useful and an applied approach to restore hormonal function, endocrine balance and eventually fertility outcomes in patients that are predisposed to lose their fertility, diagnosed with premature ovarian failure, as well as women undergoing cancer treatments.

More recent systematic reviews are included.

Silber SJ, Goldsmith S, Castleman L et al. (2022) In-vitro maturation and transplantation of cryopreserved ovary tissue: understanding ovarian longevity. Reproductive Biomedicine Online 44: 504–14

Cohort study

n=17 OTT

(119 OTC)

Every woman had a return of ovarian function 5 months after transplant, similar to previous observations. As observed before, anti-Mullerian hormone concentration rose as follicle-stimulating hormone fell 4 months later. The grafts continued to work up to 8 years. Of the 17, 13 (76%) became pregnant with intercourse at least once, resulting in 19 healthy live births, including 6 live births from 3 women who had had leukaemia.

Larger studies are included.

An earlier publication from this author is included in the systematic review by Ni Dhonnabhain et al. (2022).

Stern CJ, Gook D, Hale LG et al. (2014) Delivery of twins following heterotopic grafting of frozen-thawed ovarian tissue. Human Reproduction 29: 1828

Case report

n=1

At caesarean, there was macroscopic evidence of tumour involving the diaphragm and a peritoneal deposit at the left pelvic brim, in a patient who had OTT. There was no evidence of tumour in the graft sites. All macroscopic tumour was resected and histology confirmed granulosa cell tumour. The possibility that tumour recurrence resulted from the grafted tissue cannot be excluded.

Case report of cancer recurrence after OTT, also described in the systematic review by Khattak et al. (2022).

Takae S, Furuta S, Iwahataa H et al. (2022) Cryopreservation of paediatric ovarian tissue with an updated version of the Edinburgh criteria for appropriate patient selection. Reproductive Biomedicine Online 44: 667–76

Cohort study

n=31 OTC

Two out of 31 had complications after surgery (infection and drug allergy) and 1 patient with leukaemia (3%) had minimum residual disease on the extracted ovarian tissue. Of the 14 patients who completed treatment, 12 (86%) had primary ovarian insufficiency more than a year after treatment. Two out of 31 (6.5%) died because of recurrence of their underlying disease (median 28 months, range 0 to 60 months).

None of the patients had OTT.

Tanbo T, Greggains G, Storeng R et al. (2015) Autotransplantation of cryopreserved ovarian tissue after treatment for malignant disease - the first Norwegian results.

Acta obstetricia et gynecologica Scandinavica 94: 937–41

Cohort study

n=2 OTT (164 OTC)

Of the 164 patients who had OTC between 2004 and 2014, 15 patients died during the observation period. Six patients requested OTT, which was done in 2 women. Both patients conceived, 1 spontaneously and 1 after assisted reproduction because of a concomitant male factor. The pregnancies were uneventful and they each gave birth to a healthy child.

Small study, included in the systematic review by Ni Dhonnabhain et al. (2022).

Van der Ven H, Liebenthron J, Beckmann M et al. (2016) Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates. Human Reproduction 31: 2031–41

Cohort study

n=74 (95 transplants)

The average age of all transplanted 74 women was 31 years at the time of cryopreservation and 35 at the time of transplantation. Twenty-one pregnancies and 17 deliveries were recorded.

Persistent tissue activity 12 months after transplantation suggests that the pregnancy and delivery rates may increase further in the future. As transplantation into the peritoneum results in a high success rate, this approach may be an alternative to transplantation into the ovary. However, in order to establish the best transplantation site, a randomised study is needed.

Study is included in the systematic review by Ni Dhonnabhain et al. (2022).

Vatel M, Torre A, Paillusson B et al. (2021) Efficacy of assisted reproductive technology after ovarian tissue transplantation in a cohort of 11 patients with or without associated infertility factors. Journal of Assisted Reproduction and Genetics 38: 503–11

Cohort study

n=11

Nine pregnancies and 4 live births occurred after spontaneous conception in 5 patients without an infertility factor, none in the infertility group.

This study confirms that IVF treatment in women with grafted frozen-thawed ovarian tissue is associated with poor outcomes. However, the chances of natural conception are high in women without an infertility factor. Patients with an infertility factor, without the possibility of spontaneous pregnancy, should be informed of poor reproductive outcomes after OTT followed by assisted reproductive techniques.

Larger studies are included.