- Email: [email protected]
Ovarian tissue cryopreservation and retransplantation – what do patients think about it?
ARTICLE IN PRESS Reproductive BioMedicine Online (2016) ■■, ■■–■■
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Ovarian tissue cryopreservation and retransplantation – what do patients think about it?
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Laura Lotz 1, Amina Maktabi 1, Inge Hoffmann, Sebastian Findeklee, Matthias W Beckmann, Ralf Dittrich *
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Department of Obstetrics and Gynecology, Erlangen University Hospital, Friedrich Alexander University of Erlangen– Nuremberg, Erlangen, Germany * Corresponding author.
E-mail address: [email protected] (R Dittrich). 1 These authors have contributed equally to this paper. Ralf Dittrich completed his dissertation on the influence of gonadotropins in the development of malignant germ cell tumours in 1989 at the University Hospital Erlangen, Germany. Since 1994, he has been director of the reproductive biology and gynaecological endocrinology laboratories at the same hospital. In 2006 he obtained his habilitation (adjunct professor) and in 2009 the professorship in Experimental Reproductive Medicine, both at the University of Erlangen-Nuremberg. His main research topic is cryopreservation of ovarian tissue and gametes (others being gynaecological endocrinology, the function of the uterus in mammalian reproduction and antioxidative properties of steroids and food compounds).
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Cryopreservation of ovarian tissue has been successfully applied clinically, with over 60 live births to date. The aim of the present study was to perform a survey of patients who have had ovarian tissue cryopreserved in the Department of Obstetrics and Gynecology, Erlangen University Hospital, in order to obtain information about: why patients opt for fertility preservation; their current fertility; pregnancy attempts and outcomes; and their intended plans for the cryopreserved ovarian tissue. In total, 147 women took part in the survey (average age 25.0 ± 7.0 years; response rate 48%; mean follow-up period 6 years). Sixty-six reported regular menstrual cycles; 48 were amenorrhoeic. Sixty-two women had tried to conceive; 33 reported pregnancies. Twenty-five had delivered healthy children after conceiving naturally; eight 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. Cryopreservation of ovarian tissue is an effective option and is very important for women diagnosed with cancer. Analyses of the clinical outcomes in these patients are essential in order to identify those patients capable of benefiting most from the procedure and in order to improve the technique.
Abstract
© 2015 Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd.
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KEYWORDS: cancer, cryobank, fertility preservation, ovarian tissue cryopreservation, ovarian tissue transplantation, survey
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http://dx.doi.org/10.1016/j.rbmo.2015.12.012 1472-6483/© 2015 Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd.
Please cite this article in press as: Laura Lotz, et al., Ovarian tissue cryopreservation and retransplantation – what do patients think about it?, Reproductive BioMedicine Online (2016), doi: 10.1016/j.rbmo.2015.12.012
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L Lotz et al.
Introduction
Materials and methods
Increasing survival rates among cancer patients and increasing awareness of the importance of quality of life after chemotherapy and radiotherapy have focused attention on the preservation of fertility after cancer treatment. Due to the considerable advances that have been made in reproductive medicine, patients can now be offered measures that make it possible for women who have been affected by cancer to have children after recovering from the disease (Anderson et al., 2015). A number of strategies for fertility preservation have been developed in recent years. Fertility-preserving measures have to be customized to match the patient’s individual clinical situation. Aspects that need to be taken into account include the time available before the start of oncological therapy, the patient’s age, her relationship status, potential ovarian involvement in the cancer and the gonadotoxic measures that are planned (De Vos et al., 2014). Research on the cryopreservation of ovarian tissue as a method of fertility preservation has now been continuing for more than a decade, and considerable successes have recently been achieved (Gamzatova et al., 2014). The removal of ovarian tissue is a simple procedure. Ovarian tissue can be obtained using minimally invasive techniques during laparoscopy, with unilateral ovariectomy or partial ovariectomy. Ovarian tissue can be cryopreserved independently of the menstrual phase and the procedure therefore does not lead to any delays in oncological therapy. In centres that offer cryopreservation of ovarian tissue, the procedure can be performed 1 day after the patient’s first visit. After the tissue has been removed, it can be processed immediately or transferred in special transportation containers to a centre specializing in the cryopreservation of ovarian tissue, with an associated cryobank (Dittrich et al., 2012). Donnez et al. reported the first live birth after autotransplantation of human ovarian tissue in 2004 (Donnez et al., 2004). In Germany, the first live birth after retransplantation of cryopreserved ovarian tissue was reported in 2012 (Muller et al., 2012). To date, 60 live births have been reported worldwide following transplantation of cryopreserved ovarian tissue (Dittrich et al., 2015; Donnez and Dolmans, 2015; Donnez et al., 2013; Macklon et al., 2014b). In the near future, it is expected that more and more patients who have been cured of cancer will be wishing to undergo reimplantation of ovarian tissue. Due to a lack of follow-up data, little information is available regarding the benefits of ovarian tissue cryopreservation in relation to reproductive outcomes. The aim of the present study was therefore to conduct a survey of patients who have undergone ovarian tissue cryopreservation in the Department of Obstetrics and Gynecology at Erlangen University Hospital, in order to obtain information about why they opted for fertility preservation, about their current fertility, pregnancy attempts and outcomes and about their intended plans for the cryopreserved ovarian tissue. Analyses of the clinical outcomes in these patients are essential for identifying those patients most capable of benefiting from the procedure and for improving the technique and its efficacy.
Study population and ovarian tissue freezing
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The database of Erlangen University Hospital was used for the group of patients examined. It includes all patients since 1998 for whom ovarian tissue was harvested and frozen for purposes of fertility preservation. The collection and cryobanking of ovarian tissue were performed in accordance with the standard procedure used at the centre. For each patient, one strip of cortex was used to analyse the tissue histology and follicular density and to assess for the presence of malignant cells. Ovarian tissue removal was carried out in an external hospital in 57 patients (17 in Dresden University Hospital, 11 in Regensburg University Hospital, 11 in Amberg Hospital, seven in Nuremberg Hospital, six in Darmstadt Hospital, three in Karlsruhe Hospital, one in Ansbach Hospital and one in Hamburg University Hospital). Cryopreservation and storage of the ovarian tissue took place at Erlangen University Hospital in all cases. All patients (n = 306) for whom ovarian tissue was cryopreserved in the department in Erlangen and who had completed at least 1 year of follow-up were asked to participate in the survey.
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Data collection and survey Medical data on the indications for cryopreservation of ovarian tissue were obtained from the patients’ medical files. A questionnaire was developed to enquire in particular into the patients’ personal situation, both before the removal of ovarian tissue and at the time of the survey. Selected questions were aimed at obtaining information about why the patients opted for fertility preservation, about their current fertility status and family planning, and about their current wishes in relation to their cryopreserved ovarian tissue. Finally, the questionnaire also covered the following topics: the medical diagnosis established and fertility-threatening treatment received, menstrual cycle changes and use of contraception, attempts to conceive and intended plan for cryopreserved ovarian tissue. All of the questions had multiple-choice answers available, but a free-text option for adding explanatory notes was provided for each. Up-to-date postal addresses for the entire group were retrieved from the central hospital registry.
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Ethical approval Approval was obtained from the local university ethics committee on 19 March 2013 (reference no. 48_13 B). The study was conducted with informed consent from the patients, or if they were under the age of 18 with consent from their parents or legal guardians.
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Patients’ characteristics at the time of ovarian tissue removal Of a total of 306 patients, 147 women (48%) agreed to take part in the survey and 26 (8%) declined to participate; 34 (11%)
Please cite this article in press as: Laura Lotz, et al., Ovarian tissue cryopreservation and retransplantation – what do patients think about it?, Reproductive BioMedicine Online (2016), doi: 10.1016/j.rbmo.2015.12.012
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ARTICLE IN PRESS Survey of ovarian tissue cryopreservation
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Figure 1
Age at survey
The age distributions at the time of ovarian tissue cryopreservation and at the time of the survey.
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had died in the meantime, and it was not possible to contact 99 (32%). At the time of ovarian tissue cryopreservation, the patients who responded to the survey had a mean age of 25.0 ± 7.0 years (range 7–43 years). Ninety-six percent of the patients undergoing ovarian cryopreservation were under 35 and 19% were under the age of 18 (Figure 1). Eighty-eight percent of the patients (n = 130) were nulliparous at the time of ovarian tissue cryopreservation, and 12% (n = 17) had already been pregnant. Eight of these patients had given birth to one child, and one woman had given birth to two children. Ten patients had a history of miscarriage. The Results section below refers only to the 147 participating patients. The women who took part in the survey did not differ statistically from nonparticipants with regard to age (25.3 ± 6.5 years), parity (89% were nulliparous), or the indication for ovarian tissue cryopreservation – the major indications were also haematological malignancy (36%, n = 57) and breast cancer (24%, n = 39).
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Statistical evaluation
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The data collected and qualitative responses to the survey were entered into the Microsoft Excel program to facilitate analysis. Descriptive statistics were computed to describe the demographic data, the indications for ovarian tissue cryopreservation, fertility before and after cryopreservation, menstrual cycle changes and the intended use of the cryopreserved tissue.
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Results
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Removal of ovarian tissue
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The ovarian tissue was removed laparoscopically in 137 patients. In 10 patients, it was harvested during laparotomy con-
ducted for a different indication. Approximately half of one ovary (n = 93) or approximately half of both ovaries (n = 54) was removed. The ovarian tissue removal was uneventful in all cases. No perioperative or postoperative complications such as severe bleeding, nerve injury, thromboembolism, or cardiorespiratory distress occurred. The fertility preservation procedures did not lead to postponement of the start of chemotherapy for any of the patients.
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Indications for ovarian tissue cryopreservation
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The indications for ovarian cryopreservation varied and included malignant and benign conditions. In all, 136 of the patients (93%) underwent the procedure for conditions involving malignancy. The two most common types of malignancy were haematological malignancy (45%, n = 61) and breast cancer (27%, n = 37). Among the haematological malignancies, Hodgkin’s lymphoma (n = 40), non-Hodgkin’s lymphoma (n = 7) and leukaemia (acute leukaemia, n = 7; chronic myeloid leukaemia, n = 7) represented 29%, 5% and 10%, respectively, of all the malignant conditions. Other malignant conditions included ovarian tumours (germ cell tumour, n = 11; ovarian cancer, n = 4; borderline tumour, n = 3), cervical cancer (n = 6), sarcoma (n = 6), mesothelioma (n = 3), sinus carcinoma (n = 2), vulvar carcinoma (n = 1), rectal cancer (n = 1) and gastric carcinoma (n = 1). Eleven (7%) patients underwent ovarian tissue cryopreservation for benign disease, as they were at high risk for primary ovarian insufficiency. Four of the 11 had vasculitis, three had dermoid cysts of the ovary, one had amyloidosis and one had haemophagocytic lymphohistiocytosis. The remaining two patients had ovarian tissue cryopreserved as a prophylactic measure in relation to Turner’s syndrome (Figure 2).
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Please cite this article in press as: Laura Lotz, et al., Ovarian tissue cryopreservation and retransplantation – what do patients think about it?, Reproductive BioMedicine Online (2016), doi: 10.1016/j.rbmo.2015.12.012
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ARTICLE IN PRESS 4
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Figure 2
Indications for ovarian tissue cryopreservation.
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Fertility preservation methods additional to ovarian cryopreservation
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Fifty-four patients (37%) in the study population also received injections of gonadotrophin-releasing hormone (GnRH) analogue during gonadotoxic treatment for fertility preservation. Twelve patients (8%) also underwent ovarian stimulation and oocyte retrieval before ovarian tissue harvesting for purposes of oocyte and embryo cryopreservation. Seven of them also received GnRH analogue injections. No complications occurred during these procedures.
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Patients’ characteristics at the time of the survey
Table 1 Menstrual cycles before ovarian tissue cryopreservation (OTC) and at the time of the survey. Menstrual cycle (n = 147) Regular Hormonal contraception Hormonal therapy Irregular Absent Hysterectomy Adnexectomy Ovarian failure Ongoing antihormonal therapy
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At the time of the survey, the patients’ mean age was 31 years; 21.8% were aged 25 or younger, and 10.2% were under the age of 20 (Figure 1). The mean follow-up period was 6 years; the longest follow-up period was 16 years and the shortest was 1 year. At the time of the survey, 66 women (45%) had regular menstrual cycles. Twenty-one (14%) were taking oral contraceptives and four (3%) were receiving hormone replacement therapy. Eight (5%) of the 147 patients reported irregular menstrual periods, and 48 patients (33%) were amenorrhoeic (Table 1).
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Family planning
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Among the women who responded to the survey, 113 (77%) had never been pregnant at the time of the survey and the number of childless women was 119 (81%). Thirty-nine (27%) stated that the reason for childlessness was that it was too early for them to have children yet. Twenty-nine (20%) mentioned their partner as the reason for infertility – either they did not have one (n = 16), or not the right one (n = 9), or the partner did not wish to have any children (n = 4). Fears about pregnancy-related risks after surviving cancer were men-
tioned by 23 women (16%) as the reason for previous childlessness. Two women gave career considerations as the reason for childlessness, while six women stated that they did not wish to have children. By contrast, 29 women (20%) reported that they had tried to become pregnant but had been unsuccessful up to the time of the survey.
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Pregnancy attempts and outcomes In total, 62 women (42%) tried to conceive during the followup period. At the time of the survey, 18 patients (12%) had made use of fertility treatment; seven women underwent IVF, two received intracytoplasmic sperm (ICSI) injection and one received intrauterine insemination. Five patients underwent autotransplantation of cryopreserved ovarian tissue. Three patients opted for oocyte donation. Thirty-three (22%) reported pregnancies and delivered healthy children, with or without a history of miscarriage. The pregnancies were natural in 25 cases (17%), while eight patients (5%) were achieved after assisted reproduction treatment (three with oocyte donation, two with IVF, two with autotransplantation of the cryopreserved ovarian tissue, and one after intrauterine
Please cite this article in press as: Laura Lotz, et al., Ovarian tissue cryopreservation and retransplantation – what do patients think about it?, Reproductive BioMedicine Online (2016), doi: 10.1016/j.rbmo.2015.12.012
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insemination). Among the patients who had natural pregnancies, 14 patients had additionally been treated with GnRH analogues during the gonadotoxic therapy.
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Reimplantation of ovarian tissue and patients’ views about it
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At the time of the survey, five of the patients who responded (3%) had already had ovarian tissue retransplantation. The autotransplantation procedures used, outcomes and live births were recently detailed in a review article (Dittrich et al., 2015). Eighty-two (56%) women had considered the idea of ovarian tissue retransplantation and would choose this option in case of difficulty in conceiving naturally. Eleven of the 82 (13%) women had obtained advice about undergoing ovarian tissue autotransplantation. By contrast, 22 patients (15%) had no specific plans with regard to their cryopreserved ovarian tissue, and ovarian tissue retransplantation was no longer an option for 43 women (29%). Eighteen of the latter had given birth to the children they wanted and therefore considered their family as being complete; six women had undergone fertility examinations with unremarkable findings; eight patients had decided not to have children after all; and 11 women gave various other reasons. Twenty-seven (18%) of them had already had their ovarian tissue removed from the tissue bank. Although at the time of the survey some of the patients had already decided against retransplantation and in favour of destruction of their ovarian tissue, none of the 147 women who responded to the questionnaire regretted having chosen to have ovarian tissue cryopreserved; they would all make the same choice again in a similar situation. Furthermore, 82% of the women interviewed expressed a continuing interest in having the tissue stored for possible future use.
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Discussion
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Almost all adults hope to become parents and plan to have children at some point in their lives. In patients who are facing a diagnosis of cancer and the treatment required for it, the additional prospect of infertility may have an adverse effect on their well-being and on their relationship with their partner (Nilsson et al., 2014). The potential influence of the oncological treatment on their fertility can therefore have traumatic effects. It has been shown that fertility-associated psychological disturbances often occur among these women in particular (Greil et al., 2011). However, to relieve psychological stress and uncertainty, it may be sufficient to provide the patients with information about the potential effects of the treatment on their fertility (Quinn and Vadaparampil, 2009). Choosing a fertility-preserving measure and having the prospect of later pregnancy after recovering from the illness and treatment can create a strong motivation to regain health. Preserving fertility through the cryopreservation of ovarian tissue is an increasingly successful clinical option that is giving hope to many women. Young women who still have a good reserve of ovarian follicles are obviously able to benefit most from cryopreservation and subsequent transplantation. The
5 mean age of the patients included in the present study at time of ovarian tissue cryopreservation was 25 years, a figure similar to that in other centres (Anderson et al., 2008; Imbert et al., 2014; Macklon et al., 2014a). A maximum age limit of approximately 35–37 years is recommended in our own department for the cryopreservation of ovarian tissue, although a few older patients were included during the initial years of cryobanking. The two main indications for ovarian tissue cryopreservation, as recorded by other ovarian tissue banks, are haematological malignancy (45%, n = 61) and breast cancer (27%, n = 37). Imbert et al. (Imbert et al., 2014) reported that within 5 years of oncological treatment, 90% of women have low concentrations of anti-Müllerian hormone (AMH; 0.5 ng/ml) and around 30% experience premature ovarian failure (folliclestimulating hormone 40 IU/l). In a study by Dillon et al. (2013), it was found that AMH concentrations returned to pretreatment baseline concentrations in only 9% of the women included. However the process of AMH changes during and after chemotherapy is dynamic, and caution should be exercised in interpreting individual AMH assessment in this context (Hamy et al., 2014). Spontaneous recovery of ovarian function after chemotherapy is not unusual. In a study by Schmidt et al., 112 of 143 (78%) women who had been treated for a malignant disease and had one ovary cryopreserved for fertility preservation recovered with intact ovarian function and conceived naturally after cryopreservation (Schmidt et al., 2013). In the present survey, 45% of the women reported a regular menstrual cycle and 17% of the patients became pregnant naturally. However, it was not possible to assess the symptoms of impaired ovarian function in the overall study cohort, as some women (17%) in the study were receiving hormonal therapy, masking their menstrual cycle, and amenorrhoea alone was used as a marker for ovarian function. Five of the patients who responded to the questionnaire had had their ovarian tissue retransplanted at the time of the survey. Although the usage rate of 3.4% appears low, these women would not have been able to have their own children if the ovarian tissue had not been banked. In a survey in Denmark, 13 of 201 women (6%) underwent autotransplantation (Macklon et al., 2014a), a figure corresponding to the percentage of men who make use of cryopreserved semen after cancer treatment (Magelssen et al., 2005). When a woman is diagnosed with cancer, a considerable time may elapse between the cryopreservation of ovarian tissue and the completion of treatment, with recovery then followed later by an actual request for autotransplantation. Twenty-two percent of the women who responded to the questionnaire were under the age of 25 at the time of the survey, and 27% indicated that they currently felt too young to have children. The infertility rate might therefore increase when the younger members of the cohort attempt to start families. Future long-term follow-up studies may therefore show that a higher percentage of women decide to make use of the cryopreserved tissue. Ovarian tissue retransplantation was no longer regarded as being an option in 29% of the patients, and 18% of them had already had their ovarian tissue removed from the tissue bank. The most common reason for this was that their planned family was completed. These data are in accordance with the findings of a report by Macklon et al. (Macklon et al., 2014a) in which 16 of 95 women (17%) with cryopreserved ovarian
Please cite this article in press as: Laura Lotz, et al., Ovarian tissue cryopreservation and retransplantation – what do patients think about it?, Reproductive BioMedicine Online (2016), doi: 10.1016/j.rbmo.2015.12.012
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tissue requested disposal of the tissue after an initial period of at least 5 years. On the other hand, 82% of the women interviewed expressed a continuing interest in having the tissue stored for possible future use. Even women who had already had children born naturally wanted their tissue to be stored further, although ovarian tissue cryopreservation is not reimbursed under public health insurance in Germany. As most of these patients have undergone chemotherapy or radiotherapy, they are at risk of early menopause, which is a further argument in favour of keeping the tissue for possible later use. Cryopreservation of ovarian tissue for women with cancer involves a risk that malignant cell clones may be cryopreserved at the same time, potentially inducing a relapse following retransplantation. The extent of the risk of reintroducing malignancy in specific situations depends on the type and stage of the cancer involved and on the quantity of malignant cells transferred (Bastings et al., 2013). Dolmans et al. reported positive findings for malignant cells at light microscopy evaluation of ovarian tissue samples in 1.3% of cases (five of 391) in their study population, for all types of cancer (Dolmans et al., 2013a). The records in our own database show no residual malignant disease at microscopic evaluation relative to any type of cancer. However, histological analysis may not be sensitive enough to detect infiltration with small numbers of cells, and malignant cells may be overlooked. To exclude micrometastases in some specific diseases, more sensitive methods such as polymerase chain reaction (PCR) and xenografting are therefore essential; however, the real potential of such malignant cells is unknown. In patients with leukaemia or ovarian tumours, the risk of reintroducing malignant disease via the transplanted tissue nevertheless appears to be high, and autotransplantation may therefore involve some risk (Dolmans et al., 2013b). The women who are affected by these types of cancer are aware of the risk and at present have to look for other options, such as oocyte donation. In the near future, however, it will become possible to use alternatives such as in-vitro maturation systems or transplantation of isolated follicles for the cryopreserved tissue to enable them to achieve pregnancy. With the substantial increase in rates of survival after cancer in recent years, there is now a greater awareness of the importance of the patients’ long-term quality of life. It is our responsibility to inform patients about new options in fertility treatment and the relatively good pregnancy outcomes that are possible with cryopreserved ovarian tissue. Female infertility is one of the most devastating long-term side effects of anticancer therapy. This may explain why none of the women who responded to the questionnaire regretted having chosen ovarian tissue cryopreservation, irrespective of whether or not they still had intact ovarian function, had conceived without transplantation, or had already disposed of the ovarian tissue. In conclusion, fertility preservation is of great importance to many young women and men diagnosed with cancer. Cryopreservation of ovarian tissue is a safe, simple, swift and effective option for preserving fertility in young patients facing or undergoing gonadotoxic therapy. Although many patients in the present study retained ovarian function and were able to conceive naturally, none of them regretted choosing ovarian tissue cryopreservation. There is a need for tailored prognostic and predictive models to be developed in order to op-
timize the patients’ chances of achieving pregnancy on an individualized basis, with or without the use of cryopreserved ovarian tissue. Further research is therefore needed in order to allow identification of young girls and women who are capable of benefiting most from having ovarian tissue cryostored.
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Acknowledgement The research for this study was performed by A. Maktabi in fulfilment of the requirements for the M.D. degree at Friedrich Alexander University, Erlangen–Nuremberg, Germany. The research was supported by grants from the Wilhelm Sander- Q3 Stiftung (reference no. 2008.086.1 and 2012.127.1), Munich, Germany, and the German Research Association (Deutsche Forschungsgemeinschaft; DI 1525/4-1).
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2013. Restoration of ovarian activity and pregnancy after transplantation of cryopreserved ovarian tissue: a review of 60 cases of reimplantation. Fertil. Steril. 99, 1503– 1513. Gamzatova, Z., Komlichenko, E., Kostareva, A., Galagudza, M., Ulrikh, E., Zubareva, T., Sheveleva, T., Nezhentseva, E., Kalinina, E., 2014. Autotransplantation of cryopreserved ovarian tissue – effective method of fertility preservation in cancer patients. Gynecol. Endocrinol. 30 (Suppl. 1), 43–47. Greil, A.L., McQuillan, J., Shreffler, K.M., Johnson, K.M., SlausonBlevins, K.S., 2011. Race-ethnicity and medical services for infertility: stratified reproduction in a population-based sample of U.S. women. J. Health Soc. Behav. 52, 493–509. Hamy, A.S., Porcher, R., Cuvier, C., Giacchetti, S., Schlageter, M.H., Coussieu, C., Gronier, H., Feugeas, J.P., Adoui, N., Lacorte, J.M., Poirot, C., Habdous, M., Espie, M., 2014. Ovarian reserve in breast cancer: assessment with anti-Mullerian hormone. Reprod. Biomed. Online 29, 573–580. Imbert, R., Moffa, F., Tsepelidis, S., Simon, P., Delbaere, A., Devreker, F., Dechene, J., Ferster, A., Veys, I., Fastrez, M., Englert, Y., Demeestere, I., 2014. Safety and usefulness of cryopreservation of ovarian tissue to preserve fertility: a 12-year retrospective analysis. Hum. Reprod. 29, 1931–1940. Macklon, K.T., Ernst, E., Andersen, A.N., Andersen, C.Y., 2014a. Cryobanking of human ovarian tissue: do women still want their tissue stored beyond 5 years? Reprod. Biomed. Online 29, 452– 456. Macklon, K.T., Jensen, A.K., Loft, A., Ernst, E., Andersen, C.Y., 2014b. Treatment history and outcome of 24 deliveries worldwide after autotransplantation of cryopreserved ovarian tissue, including two
7 new Danish deliveries years after autotransplantation. J. Assist. Reprod. Genet. 31, 1557–1564. Magelssen, H., Haugen, T.B., von During, V., Melve, K.K., Sandstad, B., Fossa, S.D., 2005. Twenty years experience with semen cryopreservation in testicular cancer patients: who needs it? Eur. Urol. 48, 779–785. Muller, A., Keller, K., Wacker, J., Dittrich, R., Keck, G., Montag, M., Van der Ven, H., Wachter, D., Beckmann, M.W., Distler, W., 2012. Retransplantation of cryopreserved ovarian tissue: the first live birth in Germany. Dtsch. Arztebl. Int. 109, 8–13. Nilsson, J., Jervaeus, A., Lampic, C., Eriksson, L.E., Widmark, C., Armuand, G.M., Malmros, J., Marshall Heyman, M., Wettergren, L., 2014. “Will I be able to have a baby?” Results from online focus group discussions with childhood cancer survivors in Sweden. Hum. Reprod. 29, 2704–2711. Quinn, G.P., Vadaparampil, S.T., 2009. Fertility preservation and adolescent/young adult cancer patients: physician communication challenges. J. Adolesc. Health 44, 394–400. Schmidt, K.T., Nyboe Andersen, A., Greve, T., Ernst, E., Loft, A., Yding Andersen, C., 2013. Fertility in cancer patients after cryopreservation of one ovary. Reprod. Biomed. Online 26, 272– 279.
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Declaration: The authors report no financial or commercial conflicts of interest.
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Received 6 September 2015; refereed 19 December 2015; accepted 22 December 2015.
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w w w. s c i e n c e d i r e c t . c o m w w w. r b m o n l i n e . c o m
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Ovarian tissue cryopreservation and retransplantation – what do patients think about it?
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Laura Lotz 1, Amina Maktabi 1, Inge Hoffmann, Sebastian Findeklee, Matthias W Beckmann, Ralf Dittrich *
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Department of Obstetrics and Gynecology, Erlangen University Hospital, Friedrich Alexander University of Erlangen– Nuremberg, Erlangen, Germany * Corresponding author.
E-mail address: [email protected] (R Dittrich). 1 These authors have contributed equally to this paper. Ralf Dittrich completed his dissertation on the influence of gonadotropins in the development of malignant germ cell tumours in 1989 at the University Hospital Erlangen, Germany. Since 1994, he has been director of the reproductive biology and gynaecological endocrinology laboratories at the same hospital. In 2006 he obtained his habilitation (adjunct professor) and in 2009 the professorship in Experimental Reproductive Medicine, both at the University of Erlangen-Nuremberg. His main research topic is cryopreservation of ovarian tissue and gametes (others being gynaecological endocrinology, the function of the uterus in mammalian reproduction and antioxidative properties of steroids and food compounds).
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Cryopreservation of ovarian tissue has been successfully applied clinically, with over 60 live births to date. The aim of the present study was to perform a survey of patients who have had ovarian tissue cryopreserved in the Department of Obstetrics and Gynecology, Erlangen University Hospital, in order to obtain information about: why patients opt for fertility preservation; their current fertility; pregnancy attempts and outcomes; and their intended plans for the cryopreserved ovarian tissue. In total, 147 women took part in the survey (average age 25.0 ± 7.0 years; response rate 48%; mean follow-up period 6 years). Sixty-six reported regular menstrual cycles; 48 were amenorrhoeic. Sixty-two women had tried to conceive; 33 reported pregnancies. Twenty-five had delivered healthy children after conceiving naturally; eight 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. Cryopreservation of ovarian tissue is an effective option and is very important for women diagnosed with cancer. Analyses of the clinical outcomes in these patients are essential in order to identify those patients capable of benefiting most from the procedure and in order to improve the technique.
Abstract
© 2015 Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd.
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KEYWORDS: cancer, cryobank, fertility preservation, ovarian tissue cryopreservation, ovarian tissue transplantation, survey
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http://dx.doi.org/10.1016/j.rbmo.2015.12.012 1472-6483/© 2015 Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd.
Please cite this article in press as: Laura Lotz, et al., Ovarian tissue cryopreservation and retransplantation – what do patients think about it?, Reproductive BioMedicine Online (2016), doi: 10.1016/j.rbmo.2015.12.012
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L Lotz et al.
Introduction
Materials and methods
Increasing survival rates among cancer patients and increasing awareness of the importance of quality of life after chemotherapy and radiotherapy have focused attention on the preservation of fertility after cancer treatment. Due to the considerable advances that have been made in reproductive medicine, patients can now be offered measures that make it possible for women who have been affected by cancer to have children after recovering from the disease (Anderson et al., 2015). A number of strategies for fertility preservation have been developed in recent years. Fertility-preserving measures have to be customized to match the patient’s individual clinical situation. Aspects that need to be taken into account include the time available before the start of oncological therapy, the patient’s age, her relationship status, potential ovarian involvement in the cancer and the gonadotoxic measures that are planned (De Vos et al., 2014). Research on the cryopreservation of ovarian tissue as a method of fertility preservation has now been continuing for more than a decade, and considerable successes have recently been achieved (Gamzatova et al., 2014). The removal of ovarian tissue is a simple procedure. Ovarian tissue can be obtained using minimally invasive techniques during laparoscopy, with unilateral ovariectomy or partial ovariectomy. Ovarian tissue can be cryopreserved independently of the menstrual phase and the procedure therefore does not lead to any delays in oncological therapy. In centres that offer cryopreservation of ovarian tissue, the procedure can be performed 1 day after the patient’s first visit. After the tissue has been removed, it can be processed immediately or transferred in special transportation containers to a centre specializing in the cryopreservation of ovarian tissue, with an associated cryobank (Dittrich et al., 2012). Donnez et al. reported the first live birth after autotransplantation of human ovarian tissue in 2004 (Donnez et al., 2004). In Germany, the first live birth after retransplantation of cryopreserved ovarian tissue was reported in 2012 (Muller et al., 2012). To date, 60 live births have been reported worldwide following transplantation of cryopreserved ovarian tissue (Dittrich et al., 2015; Donnez and Dolmans, 2015; Donnez et al., 2013; Macklon et al., 2014b). In the near future, it is expected that more and more patients who have been cured of cancer will be wishing to undergo reimplantation of ovarian tissue. Due to a lack of follow-up data, little information is available regarding the benefits of ovarian tissue cryopreservation in relation to reproductive outcomes. The aim of the present study was therefore to conduct a survey of patients who have undergone ovarian tissue cryopreservation in the Department of Obstetrics and Gynecology at Erlangen University Hospital, in order to obtain information about why they opted for fertility preservation, about their current fertility, pregnancy attempts and outcomes and about their intended plans for the cryopreserved ovarian tissue. Analyses of the clinical outcomes in these patients are essential for identifying those patients most capable of benefiting from the procedure and for improving the technique and its efficacy.
Study population and ovarian tissue freezing
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The database of Erlangen University Hospital was used for the group of patients examined. It includes all patients since 1998 for whom ovarian tissue was harvested and frozen for purposes of fertility preservation. The collection and cryobanking of ovarian tissue were performed in accordance with the standard procedure used at the centre. For each patient, one strip of cortex was used to analyse the tissue histology and follicular density and to assess for the presence of malignant cells. Ovarian tissue removal was carried out in an external hospital in 57 patients (17 in Dresden University Hospital, 11 in Regensburg University Hospital, 11 in Amberg Hospital, seven in Nuremberg Hospital, six in Darmstadt Hospital, three in Karlsruhe Hospital, one in Ansbach Hospital and one in Hamburg University Hospital). Cryopreservation and storage of the ovarian tissue took place at Erlangen University Hospital in all cases. All patients (n = 306) for whom ovarian tissue was cryopreserved in the department in Erlangen and who had completed at least 1 year of follow-up were asked to participate in the survey.
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126
Data collection and survey Medical data on the indications for cryopreservation of ovarian tissue were obtained from the patients’ medical files. A questionnaire was developed to enquire in particular into the patients’ personal situation, both before the removal of ovarian tissue and at the time of the survey. Selected questions were aimed at obtaining information about why the patients opted for fertility preservation, about their current fertility status and family planning, and about their current wishes in relation to their cryopreserved ovarian tissue. Finally, the questionnaire also covered the following topics: the medical diagnosis established and fertility-threatening treatment received, menstrual cycle changes and use of contraception, attempts to conceive and intended plan for cryopreserved ovarian tissue. All of the questions had multiple-choice answers available, but a free-text option for adding explanatory notes was provided for each. Up-to-date postal addresses for the entire group were retrieved from the central hospital registry.
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Ethical approval Approval was obtained from the local university ethics committee on 19 March 2013 (reference no. 48_13 B). The study was conducted with informed consent from the patients, or if they were under the age of 18 with consent from their parents or legal guardians.
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Patients’ characteristics at the time of ovarian tissue removal Of a total of 306 patients, 147 women (48%) agreed to take part in the survey and 26 (8%) declined to participate; 34 (11%)
Please cite this article in press as: Laura Lotz, et al., Ovarian tissue cryopreservation and retransplantation – what do patients think about it?, Reproductive BioMedicine Online (2016), doi: 10.1016/j.rbmo.2015.12.012
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Figure 1
Age at survey
The age distributions at the time of ovarian tissue cryopreservation and at the time of the survey.
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had died in the meantime, and it was not possible to contact 99 (32%). At the time of ovarian tissue cryopreservation, the patients who responded to the survey had a mean age of 25.0 ± 7.0 years (range 7–43 years). Ninety-six percent of the patients undergoing ovarian cryopreservation were under 35 and 19% were under the age of 18 (Figure 1). Eighty-eight percent of the patients (n = 130) were nulliparous at the time of ovarian tissue cryopreservation, and 12% (n = 17) had already been pregnant. Eight of these patients had given birth to one child, and one woman had given birth to two children. Ten patients had a history of miscarriage. The Results section below refers only to the 147 participating patients. The women who took part in the survey did not differ statistically from nonparticipants with regard to age (25.3 ± 6.5 years), parity (89% were nulliparous), or the indication for ovarian tissue cryopreservation – the major indications were also haematological malignancy (36%, n = 57) and breast cancer (24%, n = 39).
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Statistical evaluation
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The data collected and qualitative responses to the survey were entered into the Microsoft Excel program to facilitate analysis. Descriptive statistics were computed to describe the demographic data, the indications for ovarian tissue cryopreservation, fertility before and after cryopreservation, menstrual cycle changes and the intended use of the cryopreserved tissue.
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Results
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Removal of ovarian tissue
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The ovarian tissue was removed laparoscopically in 137 patients. In 10 patients, it was harvested during laparotomy con-
ducted for a different indication. Approximately half of one ovary (n = 93) or approximately half of both ovaries (n = 54) was removed. The ovarian tissue removal was uneventful in all cases. No perioperative or postoperative complications such as severe bleeding, nerve injury, thromboembolism, or cardiorespiratory distress occurred. The fertility preservation procedures did not lead to postponement of the start of chemotherapy for any of the patients.
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Indications for ovarian tissue cryopreservation
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The indications for ovarian cryopreservation varied and included malignant and benign conditions. In all, 136 of the patients (93%) underwent the procedure for conditions involving malignancy. The two most common types of malignancy were haematological malignancy (45%, n = 61) and breast cancer (27%, n = 37). Among the haematological malignancies, Hodgkin’s lymphoma (n = 40), non-Hodgkin’s lymphoma (n = 7) and leukaemia (acute leukaemia, n = 7; chronic myeloid leukaemia, n = 7) represented 29%, 5% and 10%, respectively, of all the malignant conditions. Other malignant conditions included ovarian tumours (germ cell tumour, n = 11; ovarian cancer, n = 4; borderline tumour, n = 3), cervical cancer (n = 6), sarcoma (n = 6), mesothelioma (n = 3), sinus carcinoma (n = 2), vulvar carcinoma (n = 1), rectal cancer (n = 1) and gastric carcinoma (n = 1). Eleven (7%) patients underwent ovarian tissue cryopreservation for benign disease, as they were at high risk for primary ovarian insufficiency. Four of the 11 had vasculitis, three had dermoid cysts of the ovary, one had amyloidosis and one had haemophagocytic lymphohistiocytosis. The remaining two patients had ovarian tissue cryopreserved as a prophylactic measure in relation to Turner’s syndrome (Figure 2).
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leukaemia breat cancer other malignancies 7
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Figure 2
Indications for ovarian tissue cryopreservation.
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Fertility preservation methods additional to ovarian cryopreservation
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Fifty-four patients (37%) in the study population also received injections of gonadotrophin-releasing hormone (GnRH) analogue during gonadotoxic treatment for fertility preservation. Twelve patients (8%) also underwent ovarian stimulation and oocyte retrieval before ovarian tissue harvesting for purposes of oocyte and embryo cryopreservation. Seven of them also received GnRH analogue injections. No complications occurred during these procedures.
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Patients’ characteristics at the time of the survey
Table 1 Menstrual cycles before ovarian tissue cryopreservation (OTC) and at the time of the survey. Menstrual cycle (n = 147) Regular Hormonal contraception Hormonal therapy Irregular Absent Hysterectomy Adnexectomy Ovarian failure Ongoing antihormonal therapy
Before OTC
At the time of the survey
85 49 0 7 6 0 0 0 0
66 21 4 8 48 3 8 8 13
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At the time of the survey, the patients’ mean age was 31 years; 21.8% were aged 25 or younger, and 10.2% were under the age of 20 (Figure 1). The mean follow-up period was 6 years; the longest follow-up period was 16 years and the shortest was 1 year. At the time of the survey, 66 women (45%) had regular menstrual cycles. Twenty-one (14%) were taking oral contraceptives and four (3%) were receiving hormone replacement therapy. Eight (5%) of the 147 patients reported irregular menstrual periods, and 48 patients (33%) were amenorrhoeic (Table 1).
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270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285
Among the women who responded to the survey, 113 (77%) had never been pregnant at the time of the survey and the number of childless women was 119 (81%). Thirty-nine (27%) stated that the reason for childlessness was that it was too early for them to have children yet. Twenty-nine (20%) mentioned their partner as the reason for infertility – either they did not have one (n = 16), or not the right one (n = 9), or the partner did not wish to have any children (n = 4). Fears about pregnancy-related risks after surviving cancer were men-
tioned by 23 women (16%) as the reason for previous childlessness. Two women gave career considerations as the reason for childlessness, while six women stated that they did not wish to have children. By contrast, 29 women (20%) reported that they had tried to become pregnant but had been unsuccessful up to the time of the survey.
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Pregnancy attempts and outcomes In total, 62 women (42%) tried to conceive during the followup period. At the time of the survey, 18 patients (12%) had made use of fertility treatment; seven women underwent IVF, two received intracytoplasmic sperm (ICSI) injection and one received intrauterine insemination. Five patients underwent autotransplantation of cryopreserved ovarian tissue. Three patients opted for oocyte donation. Thirty-three (22%) reported pregnancies and delivered healthy children, with or without a history of miscarriage. The pregnancies were natural in 25 cases (17%), while eight patients (5%) were achieved after assisted reproduction treatment (three with oocyte donation, two with IVF, two with autotransplantation of the cryopreserved ovarian tissue, and one after intrauterine
Please cite this article in press as: Laura Lotz, et al., Ovarian tissue cryopreservation and retransplantation – what do patients think about it?, Reproductive BioMedicine Online (2016), doi: 10.1016/j.rbmo.2015.12.012
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insemination). Among the patients who had natural pregnancies, 14 patients had additionally been treated with GnRH analogues during the gonadotoxic therapy.
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Reimplantation of ovarian tissue and patients’ views about it
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At the time of the survey, five of the patients who responded (3%) had already had ovarian tissue retransplantation. The autotransplantation procedures used, outcomes and live births were recently detailed in a review article (Dittrich et al., 2015). Eighty-two (56%) women had considered the idea of ovarian tissue retransplantation and would choose this option in case of difficulty in conceiving naturally. Eleven of the 82 (13%) women had obtained advice about undergoing ovarian tissue autotransplantation. By contrast, 22 patients (15%) had no specific plans with regard to their cryopreserved ovarian tissue, and ovarian tissue retransplantation was no longer an option for 43 women (29%). Eighteen of the latter had given birth to the children they wanted and therefore considered their family as being complete; six women had undergone fertility examinations with unremarkable findings; eight patients had decided not to have children after all; and 11 women gave various other reasons. Twenty-seven (18%) of them had already had their ovarian tissue removed from the tissue bank. Although at the time of the survey some of the patients had already decided against retransplantation and in favour of destruction of their ovarian tissue, none of the 147 women who responded to the questionnaire regretted having chosen to have ovarian tissue cryopreserved; they would all make the same choice again in a similar situation. Furthermore, 82% of the women interviewed expressed a continuing interest in having the tissue stored for possible future use.
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Discussion
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Almost all adults hope to become parents and plan to have children at some point in their lives. In patients who are facing a diagnosis of cancer and the treatment required for it, the additional prospect of infertility may have an adverse effect on their well-being and on their relationship with their partner (Nilsson et al., 2014). The potential influence of the oncological treatment on their fertility can therefore have traumatic effects. It has been shown that fertility-associated psychological disturbances often occur among these women in particular (Greil et al., 2011). However, to relieve psychological stress and uncertainty, it may be sufficient to provide the patients with information about the potential effects of the treatment on their fertility (Quinn and Vadaparampil, 2009). Choosing a fertility-preserving measure and having the prospect of later pregnancy after recovering from the illness and treatment can create a strong motivation to regain health. Preserving fertility through the cryopreservation of ovarian tissue is an increasingly successful clinical option that is giving hope to many women. Young women who still have a good reserve of ovarian follicles are obviously able to benefit most from cryopreservation and subsequent transplantation. The
5 mean age of the patients included in the present study at time of ovarian tissue cryopreservation was 25 years, a figure similar to that in other centres (Anderson et al., 2008; Imbert et al., 2014; Macklon et al., 2014a). A maximum age limit of approximately 35–37 years is recommended in our own department for the cryopreservation of ovarian tissue, although a few older patients were included during the initial years of cryobanking. The two main indications for ovarian tissue cryopreservation, as recorded by other ovarian tissue banks, are haematological malignancy (45%, n = 61) and breast cancer (27%, n = 37). Imbert et al. (Imbert et al., 2014) reported that within 5 years of oncological treatment, 90% of women have low concentrations of anti-Müllerian hormone (AMH; 0.5 ng/ml) and around 30% experience premature ovarian failure (folliclestimulating hormone 40 IU/l). In a study by Dillon et al. (2013), it was found that AMH concentrations returned to pretreatment baseline concentrations in only 9% of the women included. However the process of AMH changes during and after chemotherapy is dynamic, and caution should be exercised in interpreting individual AMH assessment in this context (Hamy et al., 2014). Spontaneous recovery of ovarian function after chemotherapy is not unusual. In a study by Schmidt et al., 112 of 143 (78%) women who had been treated for a malignant disease and had one ovary cryopreserved for fertility preservation recovered with intact ovarian function and conceived naturally after cryopreservation (Schmidt et al., 2013). In the present survey, 45% of the women reported a regular menstrual cycle and 17% of the patients became pregnant naturally. However, it was not possible to assess the symptoms of impaired ovarian function in the overall study cohort, as some women (17%) in the study were receiving hormonal therapy, masking their menstrual cycle, and amenorrhoea alone was used as a marker for ovarian function. Five of the patients who responded to the questionnaire had had their ovarian tissue retransplanted at the time of the survey. Although the usage rate of 3.4% appears low, these women would not have been able to have their own children if the ovarian tissue had not been banked. In a survey in Denmark, 13 of 201 women (6%) underwent autotransplantation (Macklon et al., 2014a), a figure corresponding to the percentage of men who make use of cryopreserved semen after cancer treatment (Magelssen et al., 2005). When a woman is diagnosed with cancer, a considerable time may elapse between the cryopreservation of ovarian tissue and the completion of treatment, with recovery then followed later by an actual request for autotransplantation. Twenty-two percent of the women who responded to the questionnaire were under the age of 25 at the time of the survey, and 27% indicated that they currently felt too young to have children. The infertility rate might therefore increase when the younger members of the cohort attempt to start families. Future long-term follow-up studies may therefore show that a higher percentage of women decide to make use of the cryopreserved tissue. Ovarian tissue retransplantation was no longer regarded as being an option in 29% of the patients, and 18% of them had already had their ovarian tissue removed from the tissue bank. The most common reason for this was that their planned family was completed. These data are in accordance with the findings of a report by Macklon et al. (Macklon et al., 2014a) in which 16 of 95 women (17%) with cryopreserved ovarian
Please cite this article in press as: Laura Lotz, et al., Ovarian tissue cryopreservation and retransplantation – what do patients think about it?, Reproductive BioMedicine Online (2016), doi: 10.1016/j.rbmo.2015.12.012
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tissue requested disposal of the tissue after an initial period of at least 5 years. On the other hand, 82% of the women interviewed expressed a continuing interest in having the tissue stored for possible future use. Even women who had already had children born naturally wanted their tissue to be stored further, although ovarian tissue cryopreservation is not reimbursed under public health insurance in Germany. As most of these patients have undergone chemotherapy or radiotherapy, they are at risk of early menopause, which is a further argument in favour of keeping the tissue for possible later use. Cryopreservation of ovarian tissue for women with cancer involves a risk that malignant cell clones may be cryopreserved at the same time, potentially inducing a relapse following retransplantation. The extent of the risk of reintroducing malignancy in specific situations depends on the type and stage of the cancer involved and on the quantity of malignant cells transferred (Bastings et al., 2013). Dolmans et al. reported positive findings for malignant cells at light microscopy evaluation of ovarian tissue samples in 1.3% of cases (five of 391) in their study population, for all types of cancer (Dolmans et al., 2013a). The records in our own database show no residual malignant disease at microscopic evaluation relative to any type of cancer. However, histological analysis may not be sensitive enough to detect infiltration with small numbers of cells, and malignant cells may be overlooked. To exclude micrometastases in some specific diseases, more sensitive methods such as polymerase chain reaction (PCR) and xenografting are therefore essential; however, the real potential of such malignant cells is unknown. In patients with leukaemia or ovarian tumours, the risk of reintroducing malignant disease via the transplanted tissue nevertheless appears to be high, and autotransplantation may therefore involve some risk (Dolmans et al., 2013b). The women who are affected by these types of cancer are aware of the risk and at present have to look for other options, such as oocyte donation. In the near future, however, it will become possible to use alternatives such as in-vitro maturation systems or transplantation of isolated follicles for the cryopreserved tissue to enable them to achieve pregnancy. With the substantial increase in rates of survival after cancer in recent years, there is now a greater awareness of the importance of the patients’ long-term quality of life. It is our responsibility to inform patients about new options in fertility treatment and the relatively good pregnancy outcomes that are possible with cryopreserved ovarian tissue. Female infertility is one of the most devastating long-term side effects of anticancer therapy. This may explain why none of the women who responded to the questionnaire regretted having chosen ovarian tissue cryopreservation, irrespective of whether or not they still had intact ovarian function, had conceived without transplantation, or had already disposed of the ovarian tissue. In conclusion, fertility preservation is of great importance to many young women and men diagnosed with cancer. Cryopreservation of ovarian tissue is a safe, simple, swift and effective option for preserving fertility in young patients facing or undergoing gonadotoxic therapy. Although many patients in the present study retained ovarian function and were able to conceive naturally, none of them regretted choosing ovarian tissue cryopreservation. There is a need for tailored prognostic and predictive models to be developed in order to op-
timize the patients’ chances of achieving pregnancy on an individualized basis, with or without the use of cryopreserved ovarian tissue. Further research is therefore needed in order to allow identification of young girls and women who are capable of benefiting most from having ovarian tissue cryostored.
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Acknowledgement The research for this study was performed by A. Maktabi in fulfilment of the requirements for the M.D. degree at Friedrich Alexander University, Erlangen–Nuremberg, Germany. The research was supported by grants from the Wilhelm Sander- Q3 Stiftung (reference no. 2008.086.1 and 2012.127.1), Munich, Germany, and the German Research Association (Deutsche Forschungsgemeinschaft; DI 1525/4-1).
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ARTICLE IN PRESS Survey of ovarian tissue cryopreservation 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585
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7 new Danish deliveries years after autotransplantation. J. Assist. Reprod. Genet. 31, 1557–1564. Magelssen, H., Haugen, T.B., von During, V., Melve, K.K., Sandstad, B., Fossa, S.D., 2005. Twenty years experience with semen cryopreservation in testicular cancer patients: who needs it? Eur. Urol. 48, 779–785. Muller, A., Keller, K., Wacker, J., Dittrich, R., Keck, G., Montag, M., Van der Ven, H., Wachter, D., Beckmann, M.W., Distler, W., 2012. Retransplantation of cryopreserved ovarian tissue: the first live birth in Germany. Dtsch. Arztebl. Int. 109, 8–13. Nilsson, J., Jervaeus, A., Lampic, C., Eriksson, L.E., Widmark, C., Armuand, G.M., Malmros, J., Marshall Heyman, M., Wettergren, L., 2014. “Will I be able to have a baby?” Results from online focus group discussions with childhood cancer survivors in Sweden. Hum. Reprod. 29, 2704–2711. Quinn, G.P., Vadaparampil, S.T., 2009. Fertility preservation and adolescent/young adult cancer patients: physician communication challenges. J. Adolesc. Health 44, 394–400. Schmidt, K.T., Nyboe Andersen, A., Greve, T., Ernst, E., Loft, A., Yding Andersen, C., 2013. Fertility in cancer patients after cryopreservation of one ovary. Reprod. Biomed. Online 26, 272– 279.
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Declaration: The authors report no financial or commercial conflicts of interest.
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Received 6 September 2015; refereed 19 December 2015; accepted 22 December 2015.
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Please cite this article in press as: Laura Lotz, et al., Ovarian tissue cryopreservation and retransplantation – what do patients think about it?, Reproductive BioMedicine Online (2016), doi: 10.1016/j.rbmo.2015.12.012
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