Hum. Reprod. Advance Access published online on August 9, 2008
Human Reproduction, doi:10.1093/humrep/den301
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Reproductive outcome after transplantation of ovarian tissue: a systematic review
1 Department of Gynecology and Obstetrics and Gynecology, the Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA 2 University Hospitals of Cleveland, Cleveland, OH, USA 3 Department of Obstetrics and Gynecology, Assiut University, Egypt 4 Research Institute GROW, Maastricht University and Academisch ziekenhuis, Maastricht, The Netherlands
5 Correspondence address. E-mail: falcont{at}ccf.org
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Abstract |
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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.
Key words: systematic review/ovarian transplantation/ovarian function/pregnancy/cancer
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Introduction |
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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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Materials and Methods |
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Search strategy and identification of studies
A systematic search on the MEDLINE, EMBASE, Cochrane Systematic Reviews, CENTRAL, Web of Science and Scopus databases from inception until June 2007 was performed. In this search, we used terms referring to ‘ovarian tissue transplantation’ and ‘reproductive outcomes’. No language restriction was applied. Two reviewers (M.A.B. and S.A.E.) independently reviewed the identified reports. Disagreements in study inclusion were resolved by consensus and agreement in the selection of the studies was evaluated using kappa statistics. In addition, both reviewers independently reviewed the bibliographies of the retrieved articles and the recent reviews for additional studies. The search was conducted to include published peer reviewed studies on the reproductive outcomes after OTT in humans including re-establishment of ovarian function (ROF) evidenced by ovarian follicular growth or menstruation, and pregnancy.
Outcomes
The primary outcome for this review was the ROF after OTT as defined by evidence of follicular growth or the return of menstruation with the ‘time to ROF’ as the primary end-point for this outcome. Secondary outcomes included short-term (<12 months) and long-term (>12 months) maintenance of OVF and the occurrence of pregnancy after the OTT procedure. Subgroup analyses were planned a priori and performed based on study characteristics (study design and the number of participants in each study), patients’ characteristics [etiology of OTT, age at POF, age at OTT, baseline follicle-stimulating hormone (FSH)], procedure-specific variables (fresh versus frozen, autologous versus heterologous and orthotopic versus heterotopic) and the amount of the transplanted tissues (whole ovary, whole or most of the cortex and cortical strips). We also reported on the pregnancy outcome in the subgroup of women who sought pregnancy including those who underwent in vitro fertilization (IVF).
Data extraction
A standardized data extraction sheet was developed and two reviewers (M.A.B. and S.A.E.) independently extracted the individual data from each included report. Disagreements were resolved by consensus. The methodological characteristics of the included studies including study design, number of participants and procedure-specific characteristics of OTT were reported. The baseline demographic and clinical individual patient-level data in the sheet included age at the time of OTT, indication for OTT, wish for pregnancy, medical and surgical history, documented occurrence of POF, the baseline FSH level and the age of the patient at POF, and previous chemotherapy or radiotherapy. The procedural-specific data included the technique and the approach used for OTT along with the amount of transplanted tissues. The duration of the follow-up was recorded in all patients. Authors were contacted to verify unclear information in a few instances (Silber and Gosden, 2007).
Statistical analysis
Count and percentages along with their exact binomial 95% confidence intervals (95% CIs) were reported for categorical data (Newcombe, 1998). Mean and standard deviation (SD) were used for continuous variables with normal distribution whereas median and inter-quartile range (25th percentile and the 75th percentile) were used for skewed data. Kaplan–Meier method was used to estimate the cumulative rate for the primary and secondary outcomes and their corresponding 95% CI (Kaplan and Meier, 1958).
Cox proportional hazard models were used to identify predictors of various outcomes after OTT and to explore sources of heterogeneity. For each outcome, univariate analyses were presented for clinical and procedural variables with potential impact on the outcome. A global (multivariate) analysis was then performed including selected unrelated co-variants along with a variable representing the included studies. Potential predictors were considered for inclusion in the global analysis if they had a P-value of <0.20 in the univariate analysis (Robins and Greenland, 1986). If zero events occurred in a subgroup, a correction of one event was added to each subgroup to make the calculation of hazard ratios defined. Sensitivity analyses were performed to evaluate the effect of this correction on variables included in the global analyses (Higgins and Green, 2008). Statistical analyses in this study were performed using RevMan software version 4.2.8 (The Cochrane Collaboration, Oxford, UK) and JMP version 6.0 (SAS Institute Inc., Cary, NC, USA).
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Results |
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Study identifications
Out of 744 reports identified in the search, 25 reports met the inclusion criteria of the review (Fig. 1). All identified studies were observational studies including 3 cohort studies, 1 case series and 21 case reports. The total agreement in the selection of studies between the two reviewers was 95% with kappa of 0.9 (95% CI 0.8, 1.0). Out of these 25 reports, four reports included further technical and follow-up data about the same cases included in other studies by the same research groups (Leporrier et al., 1987
; Von Theobald et al., 1987; Oktay et al., 2001b, 2003; Tryde Schmidt et al., 2004; Schmidt et al., 2005; Rosendahl et al., 2006). Finally, the review included 21 unique reports including 46 women who underwent transplantation of ovarian tissues from 1985 through 2007 (Table I).
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Clinical characteristics of the included studies
Individual patient data was available for all 46 patients included. The median age was 36 years (IQR 28–41 years, and range from 15–49 years). OTT was performed to treat already diagnosed POF in 27 women, to avoid the development of POF in 16 women, to treat infertility in 2 women and in 1 woman evidence of return of OVF was documented after accidental entrapment of some ovarian tissues in the abdominal wall after laparoscopic oophorectomy for a benign indication. To date, only 3 out of 46 women had one or more whole ovaries freshly transplanted (no cryopreservation was performed) with or without microvascular attachment of their pedicle (Leporrier et al., 1987
; Hilders et al., 2004; Mhatre et al., 2005). In two of these three women, the patients’ own ovaries were transplanted to their upper limb to avoid the effect of pelvic radiation as a treatment of Hodgkin lymphoma in one patient and uterine cervical cancer in the other (Leporrier et al., 1987; Hilders et al., 2004). In the remaining patient, the transplant was performed to re-establish OVF in a patient with ovarian dysgenesis (Turner’s syndrome). In that patient, a complete ovary with its vascular pedicle was removed form a HLA-matched donor (her 26-year-old sister) and transplanted into the pelvis with the ovarian vascular pedicle attached to the inferior epigastric vessels (Mhatre et al., 2005). In all three women, no documentations of ovarian failure by FSH elevation before ovarian transplant were reported. Nevertheless, OVF was reported in all three patients after transplant (Leporrier et al., 1987; Hilders et al., 2004; Mhatre et al., 2005). However, long-term OVF beyond 1 year and up to 18 years was only reported by Leporrier and colleagues (Leporrier et al., 2002a).
Re-establishment of OVF (primary outcome)
For the evaluation of the primary outcome (ROF), 27 out of the total identified 46 cases underwent OTT to re-establish their OVF after diagnosis of POF. Four of these women did not have documented FSH levels at the time of OTT and were excluded (Oktay and Karlikaya, 2000; Hilders et al., 2004; Mhatre et al., 2005). Thus, only 23 patients who had pre-OTT FSH >30 IU/l were included in this analysis. Data needed for evaluation of the primary outcome were complete in all 23 patients (Table II). The return of OVF was based on the return of follicular growth and menstruation in 19 cases (18 spontaneous and 1 withdrawal bleeding), and detection of follicular growth in the remaining four cases (all had hysterectomies). The time needed to re-establish OVF ranged from 60 to 244 days with a median time to return of OVF of 120 days with all patients [100% (95% CI 91, 100)] showing at least some evidence of OVF at 244 days using Kaplan–Meier Plot (Fig. 2).
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To explore heterogeneity, we compared the risk ratios for the return of OVF between different subgroups depending on patient and procedure characteristics. For procedure-related variables, fresh and heterologous OTT increased the likelihood of return of OVF [HR of 2.42 (95% CI 0.97, 6.04, P = 0.058) and 9.30 (95% CI 2.45, 45.10, P = 0.001), respectively]. In addition, larger sized grafts were more likely to reestablish OVF [HR of 4.67 (1.40, 15.04, P = 0.012)]. In the global (multivariate) analysis, fresh grafts had an increased likelihood for ROF after OTT compared with cryopreserved grafts with an adjusted HR of 2.44 (95% CI 0.92, 6.49, P = 0.073).
Recurrent ovarian failure
Data needed for evaluation of the time to recurrent ovarian failure were complete for all 23 patients; however, the median follow-up time after ROF was only 210 days (range 30–845 days). At 6 months after the procedure, 4 out of 23 women had recurrence of ovarian failure with a cumulative recurrent failure rate of 22% (95%, 4–44%) (Fig. 3). This early recurrent failure was evidenced by increased FSH (>30 IU/l), reduced estrogen production and the failure of detection of follicular growth, despite induction with high doses of FSH in all four patients. Long-term evaluation of OVF was not possible due to the insufficient length of follow-up in the published reports. Follow-up of OVF beyond 12 months was only available for eight cases (38%) (Oktay et al., 2001b; Schmidt et al., 2005; Rosendahl et al., 2006; Silber and Gosden, 2007). In these eight patients, the re-established OVF was documented till the end of the follow-up.
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Women who had recurrent ovarian failure were significantly older at OTT with a median age of 37.5 years (range 35–47; IQR 35.5, 44.8) compared with 33 years (range 24, 44; IQR 27, 36) in those who did not have recurrent ovarian failure [HR of 1.18 (95% CI 1.01, 1.14, P = 0.035)]. The median age at which the patient was diagnosed with POF prior to transplant was 36.5 years (range 30, 47) compared with 28 years (range 13, 44) in those who did not have recurrent ovarian failure after [HR of 1.15 (95% CI 1.02, 1.30), P = 0.022]. In addition, all four women who had recurrent failure had cryopreserved autologous, grafts which consisted of smaller cortical strips. The four women did re-establish their OVF after 90 days. In the global (multivariate) analysis, fresh grafts had a decreased likelihood for recurrent ovarian failure after OTT compared with cryopreserved grafts with adjusted HR of 0.47 (95% CI 0.18, 1.12, P = 0.090) (Global chi-square estimate for this multivariate model was 10.13 with three degrees of freedom and P = 0.018).
Pregnancy rate after ovarian transplant
For the evaluation of pregnancy after ovarian transplant, out of the identified 46 cases included in the review, 21 women were excluded from this part of the analysis as they had hysterectomy or were reported by the authors that they did not seek pregnancy (Marconi et al., 1997; Callejo et al., 2001; Hilders et al., 2004; Kim et al., 2004; Kiran et al., 2004; Sanchez et al., 2007). Thus, 25 women with intact uteri were included in the final analysis for pregnancy after OTT. These women included 20 women with evidence of POF before OTT (FSH >30 IU/l) (Radford et al., 2001; Donnez et al., 2004; Oktay et al., 2004; Meirow et al., 2005; Schmidt et al., 2005; Wolner-Hanssen et al., 2005; Demeestere et al., 2006; Donnez et al., 2006; Oktay, 2006; Rosendahl et al., 2006; Silber and Gosden, 2007), two women with endometriosis who underwent OTT for preservation of ovarian tissue from an ovary that was not possible to conserve (Donnez et al., 2005), two young women with Turner’s syndrome who underwent heterologous fresh orthotopic OTT using partial cortex in one and the whole ovary in the other (Mhatre et al., 2005), and the last patient who underwent chemotherapy for Hodgkin’s but did not have evidence of ovarian failure at the time of OTT (Leporrier et al., 1987). In these 25 women, a total of 11 pregnancies in nine women were reported. However, one of these women became pregnant spontaneously twice after heterotopic OTT in the suprapubic area of the abdominal wall without performing IVF and was censored from the analysis at the time of her first pregnancy (Oktay, 2006).
Thus, the final analysis included a total of nine pregnancies in eight women in five reports (Donnez et al., 2004; Meirow et al., 2005; Demeestere et al., 2006; Rosendahl et al., 2006; Silber and Gosden, 2007). The 12 month cumulative pregnancy rate was 37% (95% CI 19–60%) (Fig. 4). In those eight women; the first pregnancy was achieved after a median duration of 9 months after OTT (range 5.6–16 months). In one woman, a second pregnancy was achieved 25.5 months after OTT and in the eighth menstrual cycle after delivery (Silber and Gosden, 2007). In four out of those eight women, autologous OTT using cryopreserved ovarian tissues was performed (Donnez et al., 2004; Meirow et al., 2005; Demeestere et al., 2006; Rosendahl et al., 2006), whereas in the remaining four women, heterologous OTT using fresh ovarian tissue from their monozygotic twins discordant for ovarian failure was performed (Silber and Gosden, 2007). To date, no pregnancies have been reported after the three published cases of whole intact fresh human ovary transplantation. Although all three had intact uteri, none has yet pursued pregnancy (Leporrier et al., 1987; Hilders et al., 2004; Mhatre et al., 2005). To explore potential heterogeneity in the pregnancy outcome among the included studies, we performed a stratified analysis based on study and patient characteristics. In the global analysis, only lower OTT FSH level was a significant predictor of pregnancy after OTT with adjusted HR of 1.06 (95% CI 1.01, 1.13, P = 0.011) (The global chi-square for this multivariate model was 9.37 with four degrees of freedom and P = 0.052.) (Table III).
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Pregnancies were achieved spontaneously in five women (six pregnancies), whereas in the remaining three women, pregnancies were achieved through IVF (natural cycle IVF in two and antagonist IVF protocol in one). The diagnosis of pregnancy was biochemical in one patient (Rosendahl et al., 2006
), whereas in the other seven women, clinical pregnancy was diagnosed based on the detection of gestational sac and embryonic pole by ultrasound assessment (Donnez et al., 2004; Meirow et al., 2005; Demeestere et al., 2006; Silber and Gosden, 2007) (Table IV).
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Discussion |
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An important finding of this study is that regardless of the technique used or the approach of OTT, some degree of OVF was restored in all patients. This supports the short-term efficacy of the procedure in humans. Another significant finding is that the efficacy of OTT using cryopreserved tissues is not yet equivalent to that of fresh grafts. This warrants for further improvements in cryopreservation protocols and surgical techniques to optimize the outcome.
OVF after cryopreserved compared with fresh ovarian transplant
The increased likelihood of return of OVF in fresh grafts compared with cryopreserved grafts can be explained by the relatively larger cortical tissue size in fresh grafts resulting in transplantation of a larger cohort of viable follicles compared with the cryopreserved grafts (Silber and Gosden, 2007). Given the fact that previous animal studies suggested that cryopreservation of ovarian tissues does not substantially change the reproductive outcome after OTT, this observation could not be explained solely by the possible negative effects of the cryopreservation protocol (Aubard et al., 1999; Baird et al., 1999; Candy et al., 2000). However, further improvement in the cryopreservation techniques is still required to optimize the outcome after OTT of cryopreserved ovarian tissues in humans (Torrents et al., 2003; Bedaiwy et al., 2006; Bedaiwy and Falcone, 2007). Delayed ROF >90 days was significantly associated with a higher likelihood for early recurrent ovarian failure. This is most likely the result of the warm ischemic insult after OTT. Consequently, ovarian transplants with a vascular pedicle are currently being explored to ensure immediate graft revascularization, possible reduction in ovarian failure recurrence and prolongation of graft survival (Martinez-Madrid et al., 2004; Bedaiwy et al., 2006; Jadoul et al., 2007). The site of OTT—whether orthotopic or heterotopic—did not seem to affect the return of OVF or recurrent ovarian failure. Additionally, the age at OTT of the patient also did not affect the likelihood of return of OVF; however, older women at OTT were more likely to have recurrent ovarian failure.
To date, there is insufficient evidence to support the long-term efficacy of OTT after fresh and cryopreserved OTT. For whole ovarian transplant, the first case, reported by Leporrier in 1987, was reported to still have evidence of OVF in 2002 (Leporrier et al., 1987, 2002b). However, this patient has her other ovary in place and was reported to have follicular growth in her pelvic ovary 6 months after OTT. In patients with evidence of POF at the time of OTT, only eight had follow-up >12 months and for studies reporting on cryopreserved OTT, only four women had >12 months follow-up after the ROF (Oktay et al., 2001b; Tryde Schmidt et al., 2004; Rosendahl et al., 2006). Despite the fact that at the end of the follow-up period, each of these four cases who underwent cryopreserved OTT had evidence of OVF, the overall recurrent ovarian failure was documented in >20% of the cases.
Pregnancy after cryopreserved compared with fresh ovarian transplant
Pregnancy is an important reproductive outcome after OTT, and for some groups of women, it represents one of the main goals of the technique. To date, 25 women who had OTT sought pregnancy and a total of nine pregnancies from the transplanted ovarian tissues in eight women were documented. To date, three women gave birth to three full-term babies and four women still have ongoing pregnancies. Two deliveries were after autotransplantation of cryopreserved-thawed ovarian tissue (Donnez et al., 2004; Meirow et al., 2005) and the third was after heterologous transplantation of fresh cortical tissue between twins discordant for POF (Silber et al., 2005). An interesting finding is the comparable likelihood of pregnancy after cryopreserved and fresh OTT. This finding supports previous results from animal studies suggesting similar reproductive outcomes using cryopreserved and fresh grafts (Aubard et al., 1999; Baird et al., 1999; Candy et al., 2000).
One important concern is the source of oocytes in pregnancies after OTT. The source of oocytes was verified in the case of heterotopic OTT when fertilization and chemical pregnanacy resulted from an oocyte aspirated from the heterotopic transplanted ovarian tissue (Rosendahl et al., 2006). Despite the high likelihood of ovarian failure in young women undergoing chemotherapy and radiotherapy for treatment of cancer, spontaneous restoration of OVF after documented POF was documented in two published reports. In the first, spontaneous pregnancy was reported in a young woman 6 years after receiving combined chemotherapy and radiation for treatment for Ewing’s sarcoma without receiving any ovarian transplants (Bath et al., 2004) and in the second report, pregnancy occurred in a young woman 2.5 years after chemotherapy for Hodgkin’s lymphoma (Oktay, 2006). Nevertheless, the possibility of pregnancy after treatment of cancer is by itself an important step that provides hope for patients with cancer.
Limitations
This systematic review was limited by the constraints of the published data and small number of patients and limited follow-up, as well as by the fact that data are either case reports or small case series. Publication bias is an important threat to the validity of the review, especially with the inclusion of case reports. In addition, almost all the available reports are from experts, and wider scale use of this technique is expected to result in less favorable outcomes. Thus, caution is recommended in the interpretation of the success rates of the procedure in wider scale. Another important limitation is the heterogeneity in the methods and surgical approach of the operation as well as the various indications. To limit the effect of heterogeneity on the primary outcome, we only included patients with robust evidence of ovarian failure before the procedure to decrease the heterogeneity at baseline. The absence of a control group in these studies is another important limitation.
In conclusion, transplantation of ovarian tissue can re-establish OVF after POF; however, evidence is not sufficient to evaluate the long-term efficacy and longevity of ovarian grafts. Future research should be directed toward optimization of the technology utilized in cryopreservation of ovarian tissue and in the standardization of the laboratory and surgical technology used (Torrents et al., 2003) as well as the use of vascularized grafts to minimize ischemic damage (Bedaiwy et al., 2006). After optimization of the technique, the next step would be to conduct a multicenter controlled clinical trial with sufficient follow-up (5 years) to systematically evaluate the efficacy of this procedure before wide clinical utilization. The sample needed for such a study is expected to be small, given the previously reported high efficacy of ovarian transplantation. The suggested primary end-point would be the rate of recurrent ovarian failure and pregnancy after OTT. Stratification based on the type of cancer, the chemotherapy regimen used and other relevant patient and procedural characteristics is recommended.
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Acknowledgement |
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The Authors would like to thank Dr David Starks from the Department of Gynecology and Obstetrics and Gynecology, University Hospitals of Cleveland, Cleveland, OH, USA, for his assistance.
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Footnotes |
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The first two authors participated equally in this work. 
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Submitted on February 3, 2008; resubmitted on May 31, 2008; accepted on June 6, 2008.
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