Reproductive Outcome After Transplantation of Ovarian Tissue
Reproductive Outcome After Transplantation of Ovarian Tissue
Background: Despite interest in ovarian tissue transplantation (OTT) as a promising procedure for fertility preservation, to date, no precise data are available about its effectiveness. We systematically reviewed reproductive function after OTT for fertility preservation in women at high risk of premature ovarian failure (POF).
Methods: We searched the MEDLINE, EMBASE, Cochrane Systematic Reviews, CENTRAL, Web of Science and Scopus databases for studies on the reproductive outcomes after OTT in humans up to June 2007. Women with follicle-stimulating hormone (FSH) >30 IU/l at the time of OTT were included in a meta-analysis of individual-patient data to evaluate the time to re-establishment of ovarian function (ROF). Secondary outcomes included short-term (<12 months) and long-term (>12 months) ovarian function (OVF) and pregnancy after OTT.
Results: We identified 25 reports including 46 unique cases. OTT was performed to treat POF in 27 women, to prevent POF in 15, to treat infertility in 2 and accidentally in 1. In 23 women with FSH >30 at the time of OTT, OVF was re-established with a median time to ROF of 120 days (range 60-244). Within 6 months after ROF, four women had recurrent ovarian failure. There are insufficient data to evaluate the long-term OVF (>12 months). Fresh grafts had an increased likelihood of return of OVF and a decreased likelihood for recurrent ovarian failure compared with cryopreserved grafts [HR of 2.44 (95% CI 0.92, 6.49) and 0.47 (95% CI 0.18, 1.12), respectively]. In 25 women who sought pregnancy, eight women had nine pregnancies at 12 months, giving a cumulative pregnancy rate of 37% (95% CI 19, 60).
Conclusions: Transplantation of ovarian tissue can re-establish OVF after POF; however, the efficacy of OTT using cryopreserved tissues is not yet equivalent to that of fresh grafts. A controlled multicenter trial with sufficient follow-up would provide valid evidence of the potential benefit of this procedure.
Ovarian tissue transplantation (OTT) is becoming an increasingly popular strategy for fertility preservation. The original indication was to restore fertility in cancer patients (autologous transplantation). Nevertheless, the spectrum has now expanded to incorporate OTT in twins discordant for premature ovarian failure (POF) and to restore ovarian function (OVP) in women with ovarian dysgenesis using ovarian tissue from matched donors, i.e. heterologous transplantation (Mhatre et al., 2005; Silber et al., 2005; Silber and Gosden, 2007). Another proposed indication, yet not pursued, is to prolong the reproductive life in otherwise healthy women (Silber and Gosden, 2007). Despite the experimental nature of the procedure, there is an increasing public awareness of its availability as a potential fertility preservation strategy for those at risk. The American Society of Reproductive Medicine (ASRM) practice committee categorized the use of ovarian tissue cryopreservation with subsequent transplantation as an experimental option for fertility preservation with the notion that it should be performed after approval of the local Institutional Review Boards (Lee et al., 2006). Despite sparse evidence of its clinical usefulness, ovarian tissue banking has been offered to patients as a clinical service for almost two decades by many clinical centers around the globe (Grischenko et al., 1987; Martin et al., 2007; Poirot et al., 2007; Weintraub et al., 2007). The three potential uses proposed for harvested ovarian tissue were in vitro maturation of primordial follicles, xenografting of ovarian tissue or subsequent ovarian transplantation. To date, only the latter has been successfully attempted in humans (Oktay and Karlikaya, 2000; Silber and Gosden, 2007).
Successful attempts of OTT have been reported using a variety of ovarian tissue sizes ranging from cortical strips to the transplantation of the whole ovary with or without its vascular pedicle (Oktay, 2001; Oktay et al., 2001a; Donnez et al., 2006). Although fresh transplantation was possible for all these variety of sizes, transplantation of previously frozen ovarian tissues was only reported using cortical strips in humans. Most of the reported ovarian tissue cryopreservation protocols were modifications of the original one reported by Gosden et al. (1994). In addition, wide varieties of alternative sites and surgical techniques have been reported. Orthotopic ovarian transplantation has been tried to the ovarian stump or to the periovarian region (Oktay and Karlikaya, 2000; Donnez et al., 2004; Meirow et al., 2005; Silber and Gosden, 2007). Alternatively, heterotopic ovarian transplantation has been performed to a variety of locations including the arm (Leporrier et al., 1987; Callejo et al., 2001), the forearm (Oktay et al., 2001b; Wolner-Hanssen et al., 2005), rectus abdominis muscle (Kim et al., 2004), the subcutaneous tissue of the abdominal wall (Oktay et al., 2004) and the suprapubic area (Oktay, 2006). A combined orthotopic and heterotopic approach has been utilized as well (Schmidt et al., 2005; Rosendahl et al., 2006). The orthotopic transplantation process has been accomplished via either laparoscopy (Donnez et al., 2004) or laparotomy (Meirow et al., 2005; Silber and Gosden, 2007).
Despite the relatively large number of reports on OTT approaches and techniques, to date, there are no precise data on the reproductive outcomes after OTT. This is in part due to the small numbers of patients and the wide range of indications, surgical techniques and duration of follow-up. The experimental nature as well as ethical concerns prevented the execution of larger well-designed studies to answer these important questions. We therefore performed a systematic review to summarize the reports on the reproductive outcomes after OTT for fertility preservation purposes, including prevention and reversal of POF.
Background: Despite interest in ovarian tissue transplantation (OTT) as a promising procedure for fertility preservation, to date, no precise data are available about its effectiveness. We systematically reviewed reproductive function after OTT for fertility preservation in women at high risk of premature ovarian failure (POF).
Methods: We searched the MEDLINE, EMBASE, Cochrane Systematic Reviews, CENTRAL, Web of Science and Scopus databases for studies on the reproductive outcomes after OTT in humans up to June 2007. Women with follicle-stimulating hormone (FSH) >30 IU/l at the time of OTT were included in a meta-analysis of individual-patient data to evaluate the time to re-establishment of ovarian function (ROF). Secondary outcomes included short-term (<12 months) and long-term (>12 months) ovarian function (OVF) and pregnancy after OTT.
Results: We identified 25 reports including 46 unique cases. OTT was performed to treat POF in 27 women, to prevent POF in 15, to treat infertility in 2 and accidentally in 1. In 23 women with FSH >30 at the time of OTT, OVF was re-established with a median time to ROF of 120 days (range 60-244). Within 6 months after ROF, four women had recurrent ovarian failure. There are insufficient data to evaluate the long-term OVF (>12 months). Fresh grafts had an increased likelihood of return of OVF and a decreased likelihood for recurrent ovarian failure compared with cryopreserved grafts [HR of 2.44 (95% CI 0.92, 6.49) and 0.47 (95% CI 0.18, 1.12), respectively]. In 25 women who sought pregnancy, eight women had nine pregnancies at 12 months, giving a cumulative pregnancy rate of 37% (95% CI 19, 60).
Conclusions: Transplantation of ovarian tissue can re-establish OVF after POF; however, the efficacy of OTT using cryopreserved tissues is not yet equivalent to that of fresh grafts. A controlled multicenter trial with sufficient follow-up would provide valid evidence of the potential benefit of this procedure.
Ovarian tissue transplantation (OTT) is becoming an increasingly popular strategy for fertility preservation. The original indication was to restore fertility in cancer patients (autologous transplantation). Nevertheless, the spectrum has now expanded to incorporate OTT in twins discordant for premature ovarian failure (POF) and to restore ovarian function (OVP) in women with ovarian dysgenesis using ovarian tissue from matched donors, i.e. heterologous transplantation (Mhatre et al., 2005; Silber et al., 2005; Silber and Gosden, 2007). Another proposed indication, yet not pursued, is to prolong the reproductive life in otherwise healthy women (Silber and Gosden, 2007). Despite the experimental nature of the procedure, there is an increasing public awareness of its availability as a potential fertility preservation strategy for those at risk. The American Society of Reproductive Medicine (ASRM) practice committee categorized the use of ovarian tissue cryopreservation with subsequent transplantation as an experimental option for fertility preservation with the notion that it should be performed after approval of the local Institutional Review Boards (Lee et al., 2006). Despite sparse evidence of its clinical usefulness, ovarian tissue banking has been offered to patients as a clinical service for almost two decades by many clinical centers around the globe (Grischenko et al., 1987; Martin et al., 2007; Poirot et al., 2007; Weintraub et al., 2007). The three potential uses proposed for harvested ovarian tissue were in vitro maturation of primordial follicles, xenografting of ovarian tissue or subsequent ovarian transplantation. To date, only the latter has been successfully attempted in humans (Oktay and Karlikaya, 2000; Silber and Gosden, 2007).
Successful attempts of OTT have been reported using a variety of ovarian tissue sizes ranging from cortical strips to the transplantation of the whole ovary with or without its vascular pedicle (Oktay, 2001; Oktay et al., 2001a; Donnez et al., 2006). Although fresh transplantation was possible for all these variety of sizes, transplantation of previously frozen ovarian tissues was only reported using cortical strips in humans. Most of the reported ovarian tissue cryopreservation protocols were modifications of the original one reported by Gosden et al. (1994). In addition, wide varieties of alternative sites and surgical techniques have been reported. Orthotopic ovarian transplantation has been tried to the ovarian stump or to the periovarian region (Oktay and Karlikaya, 2000; Donnez et al., 2004; Meirow et al., 2005; Silber and Gosden, 2007). Alternatively, heterotopic ovarian transplantation has been performed to a variety of locations including the arm (Leporrier et al., 1987; Callejo et al., 2001), the forearm (Oktay et al., 2001b; Wolner-Hanssen et al., 2005), rectus abdominis muscle (Kim et al., 2004), the subcutaneous tissue of the abdominal wall (Oktay et al., 2004) and the suprapubic area (Oktay, 2006). A combined orthotopic and heterotopic approach has been utilized as well (Schmidt et al., 2005; Rosendahl et al., 2006). The orthotopic transplantation process has been accomplished via either laparoscopy (Donnez et al., 2004) or laparotomy (Meirow et al., 2005; Silber and Gosden, 2007).
Despite the relatively large number of reports on OTT approaches and techniques, to date, there are no precise data on the reproductive outcomes after OTT. This is in part due to the small numbers of patients and the wide range of indications, surgical techniques and duration of follow-up. The experimental nature as well as ethical concerns prevented the execution of larger well-designed studies to answer these important questions. We therefore performed a systematic review to summarize the reports on the reproductive outcomes after OTT for fertility preservation purposes, including prevention and reversal of POF.
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