First pregnancies, live birth, and in vitro fertilization outcomes after transplantation of frozen-banked ovarian tissue with a human extracellular matrix scaffold using robot-assisted minimally invasive surgery

Abstract

Background Ovarian tissue cryopreservation is an experimental fertility preservation method and the transplantation techniques are still evolving. Objective We attempted to improve the technique with the utility of a human decellularized extracellular tissue matrix scaffold, robot-assisted minimally invasive surgery and peri-operative pharmacological support. Study design We prospectively studied 2 subjects with Hemophagocytic Lymphohistiocytosis (P-A) and Non-Hodgkin Lymphoma (P-B) who underwent ovarian tissue cryopreservation at the age of 23, before receiving preconditioning chemotherapy for hematopoietic stem cell transplantation. Both experienced ovarian failure post-chemotherapy and we transplanted ovarian cortical tissues to the contralateral menopausal ovary 7 and 12 years later, using a human extra cellular tissue matrix scaffold and robotic-assistance. The extra cellular tissue matrix scaffold-tissue compatibility was shown in pre-clinical studies. Patients also received estrogen supplementation and baby aspirin preoperatively to aid in the revascularization process. Results Ovarian follicle development was observed approximately ten (P-A) and eight (P-B) weeks after ovarian tissue transplantation. Following eight and seven cycles of in vitro fertilization, nine and ten day-3 embryos were cryopreserved (P-A and P-B, respectively). While the baseline FSH (range: 3.6–15.4 mIU/mL) levels near-normalized by seven months and remained steady post ovarian transplantation in P-A, P-B showed improved but elevated FSH levels throughout (range: 21–31 mIU/mL). Highest follicle yield was achieved 14 (8 follicles; P-A) and 11 months (6 follicles; P-B) post intervention. P-A experienced a chemical pregnancy after the third frozen embryo transfer attempt. She then conceived following her first fresh in vitro fertiliza tion-embryo transfer and the pregnancy is currently ongoing. P-B conceived after the first frozen embryo transfer attempt and delivered a healthy boy at term. Conclusions We reported the first pregnancies after the minimally-invasive transplantation of previously cryopreserved ovarian tissue with an extra-cellular tissue matrix scaffold. This approach seems to be associated with steady ovarian function after a follow up of up to 2 years.

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

“…An overview of the perinatal outcome of children conceived in women who have had frozen-thawed ovarian tissue transplanted available from peer-reviewed papers, including nine new Danish cases, is given in Tables 2 [13,, 3, and 4. Table 2 provides detailed information on the deliveries from published peer-reviewed journals including information on the woman (diagnosis, age at cryopreservation and signs of menopause before transplantation, time from transplantation Oktay et al [13] S F N A 1 Meirow et al [14] SF NA* 4 (+2) The Nordic countries [15] and this publication SF (Sweden VF) 14 7(+2)** FertiPROTEKT network [16] SF 54*** 11 Dunlop et al [17] S F N A 1…”

Ovarian regeneration: The potential for stem cell contribution in the postnatal ovary to sustained endocrine function

“…There are clinical case reports citing restoration of fertility in humans via ovarian tissue transplantation in which patients elected to have tissue removed and cryopreserved for grafting at a later date, or transplanted directly into a heterotrophic site (Oktay, 2001; Oktay et al, 2004). Multiple clinics have now reported restoration of ovarian function following ovarian tissue grafting, including a rise in serum estradiol concentrations and reduction in circulating FSH levels, occurring on average between 3.5 and 6.5 months post transplantation (Donnez et al, 2004, 2010, 2011; Macklon et al, 2014; Suzuki et al, 2015; Rodriguez-Wallberg et al, 2015; Oktay et al, 2016). Notably, in many instances the ovarian tissue grafts continue to function for several years following engraftment (Anderson et al, 2012).…”

“…She received a portion of her twins’ ovarian cortex, and later reestablished menstruation and conceived a child naturally (Silber et al, 2005). Currently, ovarian cryopreservation and tissue vitrification are at the forefront of ovarian repair strategies after an expected premature ovarian failure (Silber, 2012; Suzuki et al, 2015; Oktay et al, 2016) but are not employed to extend ovarian endocrine function in women.…”

Fertility Preservation in Women with Turner Syndrome: A Comprehensive Review and Practical Guidelines

“…The first successful ovarian transplantation with cryopreserved and thawed tissue was reported in 2000 by Oktay and Karlikaya 36 resulting in restoration of hormonal function in a previously menopausal woman. The subsequent decade witnessed pregnancies resulting from these procedures with the current total of reported pregnancies standing above 40 37 . It is important to appreciate that thus far, all these pregnancies with the exception of a recent case report 38 , resulted from use of ovarian tissue that was harvested from and subsequently transferred back to adult women choosing ovarian tissue cryopreservation as a fertility preserving strategy in the setting of medical diagnoses such as cancer or other medical conditions.…”