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Ovarian cryopreservation with transposition of a contralateral ovary: a combined approach for fertility preservation in women receiving pelvic radiation
Ovarian cryopreservation with transposition of a contralateral ovary: a combined approach for fertility preservation in women receiving pelvic radiation J. Ryan Martin, M.D.,a Pinar Kodaman, M.D., PhD.,a Kutluk Oktay, M.D.,b and Hugh S. Taylor, M.D.a a
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut; and b Weill Medical College, Cornell University, New York, New York
Objective: To describe a technique of fertility preservation by ovarian transposition combined with ovarian cryopreservation in the setting of oncologic pelvic radiation for a reproductive age woman. Design: Case report. Setting: IVF center at a tertiary care hospital. Patient(s): Thirty-year-old nulligravid women who previously underwent lumbar spinal cord tumor debulking requested fertility preservation before pelvic radiation. Intervention(s): Laparoscopic ovarian transposition with cryopreservation of the contralateral ovary. Main Outcome Measure(s): New technique in fertility preservation. Result(s): Laparoscopic surgery was used to evaluate, select, and remove a single ovary that then underwent cryopreservation. Transposition of the remaining ovary was subsequently successfully performed, placing it of out of the pelvis. Conclusion(s): The combination of ovarian cryopreservation and ovarian transposition may maximize future fertility options for women facing pelvic irradiation. This combined approach should be included among the options offered to reproductive age women before pelvic radiation. (Fertil Steril威 2007;87:189.e5–7. ©2007 by American Society for Reproductive Medicine.) Key Words: Cancer, fertility preservation, ovarian cryopreservation, transposition
Many reproductive age women who are found to have pelvic malignancies face not only oncologic surgery but also possible subsequent infertility because of pelvic irradiation therapy and chemotherapy. Because of advanced treatment and increased survival rates of reproductive age women with cancer, fertility preservation has become an important concern of treating physicians. Embryo cryopreservation has been a successful option for oncologic patients who have time before treatment to accommodate an IVF cycle. Although ovarian transposition has been practiced for many years, ovarian cryopreservation represents a new potential means of fertility preservation. Ovarian transposition is a common method of avoiding irradiation damage. This is a simple procedure that can be performed laparoscopically and is beneficial not only for preservation of fertility but also for preventing premature menopause (1). Currently, embryo cryopreservation is the preferred method of future fertility preservation because of its high post-thaw survival and delivery rates. Analysis of current literature on embryo cryopreservation quotes 50%– 80% thaw survival depending on embryo stage, 3%–15% implantation rates, and 15%–25% pregnancy rates per embryo (2). However, this is not Received January 14, 2006; revised and accepted April 11, 2006. Reprint requests: Hugh S. Taylor, M.D., Department of Obstetrics, Gynecology and Reproductive Sciences, 333 Cedar Street, New Haven, Connecticut 06520 (FAX: 203-785-7819; E-mail: [email protected]).
0015-0282/07/$32.00 doi:10.1016/j.fertnstert.2006.04.051
a practical option for a child, a single woman who does not wish to use a sperm donor or a woman without the luxury of time before radiation as IVF embryo cryopreservation takes approximately 2 months. Because of recent advances, ovarian cryopreservation is a potential experimental option for these women. After being thawed, ovarian tissue can be reimplanted and stimulated with gonadotropins for IVF. We report a case of combining ovarian transposition and ovarian cryopreservation to retain future fertility of a young woman awaiting pelvic irradiation therapy. REPORT OF THE TECHNIQUE A 30-year-old gravida 0 who recently underwent a second lumbar spine tumor debulking for recurrent ependymomas now required pelvic irradiation. She was diagnosed with recurrent grade 1 ependymomas in her thecal sac at L3–L4 of her spinal cord. She presented for fertility preservation and was initially offered embryo cryopreservation followed by ovarian transposition. However, because of time constraints, the patient declined embryo cryopreservation. She was then offered and accepted ovarian cryopreservation with simultaneous transposition. At the time of laparoscopy, the patient’s pelvic anatomy was normal with the exception of 3 superficial endometriotic implants measuring approximately 5 mm on the left ovary and fallopian tube. Her right ovary was normal and con-
Fertility and Sterility姞 Vol. 87, No. 1, January 2007 189.e5 Copyright ©2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
tained a corpus luteum. The right ovary was chosen for cryopreservation because of the evidence of recent ovulation, indicating its functionality. The ovary was then removed laparoscopically via bipolar cautery and sharp dissection of the infundibulopelvic ligament and utero-ovarian ligament. The ovary was placed in an endo-pouch and put in a sterile specimen container containing alpha minimal essential media. The container was placed on ice inside an insulated container and was taken to the Weill Medical College of Cornell University Medical Center, New York, New York, for cryopreservation. Cryopreservation was performed as previously reported by Oktay and Buyuk (3). The left tube and ovary were then mobilized by transecting the utero-ovarian ligament and mesovarium with bipolar cautery and sharp dissection. The ovary and tube were then mobilized out of the pelvis without tension. The ovary was then intracorporally sutured to the fascia superior to the pelvic brim providing approximately 5– 6 cm from the upcoming irradiation field. Metallic clips were then applied to the borders of the ovary allowing radiologic visualization. The proximity and alignment of the tube and ovary were retained, allowing the potential for natural ovum pickup. The patient tolerated the procedure well, and postoperatively she reported only minimal discomfort. She was then placed on oral contraceptives to prevent pregnancy and to retain maximal number of primordial follicles, thus minimizing irradiation damage. Her fist cycle of radiation occurred 4 weeks later. DISCUSSION Every year, hundreds of thousands of women and children are exposed to potentially sterilizing chemotherapy and radical surgery and radiation for treatment of cancer as well as benign conditions (4, 5). We present an example of a patient who presented with the desire for preserved fertility in the setting of upcoming pelvic irradiation therapy. We were able to combine common ovarian transposition with ovarian cryopreservation maximizing her chances for future fertility. Chemotherapy and pelvic radiation are well-known causes of premature ovarian failure. Chemotherapeutic agents are cytotoxic and have shown various deleterious effects on ovaries including decreased follicle number, absent follicles, and even fibrosis (6). Surgical transposition of ovaries at least 3 cm from the upper border of the radiation field has been shown to preserve ovarian function (7). Tulandi and Al-Took (8) reported a laparoscopic translocation whereby the utero-ovarian ligaments were divided, but the ovaries remained attached to the distal portion of the fallopian tubes. That patient achieved spontaneous pregnancy likely because of ovary and tube proximity, allowing for natural ovum pickup. According to Tulandi and Al-Took (8), laparoscopic ovarian transposition in women ⬍40 is associated with continued ovarian function in 88.6% of cases. This technique allows for optimal ovarian function in the setting of pelvic irradiation. 189.e6 Martin et al.
Currently, embryo cryopreservation is the optimal method to preserve future fertility because there are reasonable postthaw survival, implantation, and delivery rates (9). However, many patients begin their cancer treatment immediately or do not have an established partner to create embryos to be frozen. For these patients, cryopreservation of ovarian tissue is a promising new method for retaining future fertility. Human ovarian tissue cryopreservation was first documented in 1996 by Hovatta et al. (10) and 1997 by Oktay et al. (11), but was not applied to orthotopic transplantation until 2000 by Oktay and Sonmezer (12). The aim of cryopreservation technology is to first store and then reimplant thawed ovarian tissue in order to retain fertility and hormonal function. Cellular damage and destruction of primordial follicles are decreasing with improved cryopreservation and thawing techniques. Initially, Baird et al. (13) showed a large loss of post-thaw primordial follicles. However, because of improved freeze and thaw techniques, Imhof et al. (14) found an intact primordial follicle rate of 80% by light microscopy after freeze-thaw cycles. In addition, Bath et al. (15) removed ovarian cortical biopsies from a patient for potential reimplantation after requiring radiation. Cryopreservation and reimplantion of total ovaries, rather than ovarian biopsies, allow for greater follicular survival because of a larger number of primordial follicles (14). In 2000, Oktay and Sonmezer (12) showed the resumption of ovarian endocrine function afer cryopreservation and reimplantation. Thus far, there is limited success in humans with only one normal embryo development after heterotopic ovarian transplant (16) and two possible live births from an orthotopically transplanted ovary (17, 18). Reproductive age women with pelvic tumors face not only cancer but also potential infertility because of pelvic irradiation therapy. With improved techniques for freezing and thawing ovarian tissue, ovarian cryopreservation is a new way to preserve fertility. For those women whose circumstances prevent embryo cryopreservation, combining ovarian transposition with ovarian cryopreservation is a potential treatment to optimize future fertility treatment options. REFERENCES 1. Bisharah M, Tulandi T. Laparoscopic preservation of ovarian function: an underused procedure. Am J Obstet Gynecol 2002;188:367–70. 2. Kattera S, Chen C. A modified embryo cryopreservation method increases post thaw survival with concomitant increase in implantation. Fertil Steril 2005;84:1498 –1504. 3. Oktay K, Buyuk E. The technique of ovarian transplantation: laboratory and clinical insights. In: Tucker M, ed. A color atlas for human assisted reproduction. Philadelphia: Lippincott 2003:229 – 40. 4. Oktay KH, Yih M. Preliminary experience with orthotopic and heterotopic transplantation of ovarian cortical strips. Semin Reprod Med 2002;20:63– 4. 5. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics. CA Cancer J Clin 2003;53:5–26. 6. Falcone T, Bedaiwy A. Fertility preservation and pregnancy outcome after malignancy. Curr Opin Obstet Gynecol 2005;17:21– 6. 7. Bidzinski M, Lemieszczuk B, Zielinski J. Evaluation of hormonal function and features of ultrasound picture of transposed ovary in
Ovarian cryopreservation with transposition
Vol. 87, No. 1, January 2007
8. 9. 10.
11.
12. 13.
cervical cancer patients after surgery and pelvic irradiation. Eur J Obstet Gynecol 1993;14:77– 80. Tulandi T, Al-Took S. Laparoscopic ovarian suspension before irradiation. Fertil Steril 1998;70:382–3. Sonmezer M, Shamonki MI, Oktay K. Ovarian tissue cryopreservation: benefits and risks. Cell Tissue Res 2005;322:125–32. Hovatta O, Silye R, Krausz T, Abir R, Margara R, Trew G, et al. Cryopreservation of human ovarian tissue using dimethylsulphoxide and propanediol-sucrose cryoprotectants. Hum Reprod 1996;11:1268 – 72. Oktay K, Nugent D, Newton H, Salha O, Chatterjee P, Gosden RG. Isolation and characterization of primordial follicles from fresh and cryopreserved human ovarian tissue. Fertil Steril 1997;67:481– 6. Oktay K, Karlikaya G. Ovarian function after transplantation of frozen, banked autologous ovarian tissue. N Engl J Med 2000;342:1919. Baird DT. Long term ovarian function in sheep after ovariectomy and transplantation of autografts stored at ⫺196 celsius. Endocrinology 1999;140:462–71.
Fertility and Sterility姞
14. Imhof M, Hofstetter G, Bergmeister H, Rudas M, Kain R, Lipovac M, Huber J. Cryopreservation of a whole ovary as a strategy for restoring ovarian function. J Assist Reprod Genet 2004;21:459 – 65. 15. Bath LE, Tydeman G, Critchley HOD, Anderson RA, Baird DT, Wallace WHB. Spontaneous conception in a young woman who had ovarian tissue cryopreserved before chemotherapy and radiotherapy for a Ewing’s sarcoma of the pelvis: case report. Hum Reprod 2004;19: 2569 –72. 16. Oktay K, Buyuk E, Veeck L, Zaninovic N, Xu K, Takeuchi T, et al. Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet 2004;363:837– 40. 17. Donnez J, Dolmans MM, Demylle D, Jadoul P, Picard C, Squifflet J, et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet 2004;364:1405–10. 18. Meirow D, Levron J, Eldar-Geva T, Hardan I, Fridman E, Zalel Y, et al. Pregnancy after transplantation of cryopreserved ovarian tissue in a patient with ovarian failure after chemotherapy. N Engl J Med 2005;353:318 –21.
189.e7
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut; and b Weill Medical College, Cornell University, New York, New York
Objective: To describe a technique of fertility preservation by ovarian transposition combined with ovarian cryopreservation in the setting of oncologic pelvic radiation for a reproductive age woman. Design: Case report. Setting: IVF center at a tertiary care hospital. Patient(s): Thirty-year-old nulligravid women who previously underwent lumbar spinal cord tumor debulking requested fertility preservation before pelvic radiation. Intervention(s): Laparoscopic ovarian transposition with cryopreservation of the contralateral ovary. Main Outcome Measure(s): New technique in fertility preservation. Result(s): Laparoscopic surgery was used to evaluate, select, and remove a single ovary that then underwent cryopreservation. Transposition of the remaining ovary was subsequently successfully performed, placing it of out of the pelvis. Conclusion(s): The combination of ovarian cryopreservation and ovarian transposition may maximize future fertility options for women facing pelvic irradiation. This combined approach should be included among the options offered to reproductive age women before pelvic radiation. (Fertil Steril威 2007;87:189.e5–7. ©2007 by American Society for Reproductive Medicine.) Key Words: Cancer, fertility preservation, ovarian cryopreservation, transposition
Many reproductive age women who are found to have pelvic malignancies face not only oncologic surgery but also possible subsequent infertility because of pelvic irradiation therapy and chemotherapy. Because of advanced treatment and increased survival rates of reproductive age women with cancer, fertility preservation has become an important concern of treating physicians. Embryo cryopreservation has been a successful option for oncologic patients who have time before treatment to accommodate an IVF cycle. Although ovarian transposition has been practiced for many years, ovarian cryopreservation represents a new potential means of fertility preservation. Ovarian transposition is a common method of avoiding irradiation damage. This is a simple procedure that can be performed laparoscopically and is beneficial not only for preservation of fertility but also for preventing premature menopause (1). Currently, embryo cryopreservation is the preferred method of future fertility preservation because of its high post-thaw survival and delivery rates. Analysis of current literature on embryo cryopreservation quotes 50%– 80% thaw survival depending on embryo stage, 3%–15% implantation rates, and 15%–25% pregnancy rates per embryo (2). However, this is not Received January 14, 2006; revised and accepted April 11, 2006. Reprint requests: Hugh S. Taylor, M.D., Department of Obstetrics, Gynecology and Reproductive Sciences, 333 Cedar Street, New Haven, Connecticut 06520 (FAX: 203-785-7819; E-mail: [email protected]).
0015-0282/07/$32.00 doi:10.1016/j.fertnstert.2006.04.051
a practical option for a child, a single woman who does not wish to use a sperm donor or a woman without the luxury of time before radiation as IVF embryo cryopreservation takes approximately 2 months. Because of recent advances, ovarian cryopreservation is a potential experimental option for these women. After being thawed, ovarian tissue can be reimplanted and stimulated with gonadotropins for IVF. We report a case of combining ovarian transposition and ovarian cryopreservation to retain future fertility of a young woman awaiting pelvic irradiation therapy. REPORT OF THE TECHNIQUE A 30-year-old gravida 0 who recently underwent a second lumbar spine tumor debulking for recurrent ependymomas now required pelvic irradiation. She was diagnosed with recurrent grade 1 ependymomas in her thecal sac at L3–L4 of her spinal cord. She presented for fertility preservation and was initially offered embryo cryopreservation followed by ovarian transposition. However, because of time constraints, the patient declined embryo cryopreservation. She was then offered and accepted ovarian cryopreservation with simultaneous transposition. At the time of laparoscopy, the patient’s pelvic anatomy was normal with the exception of 3 superficial endometriotic implants measuring approximately 5 mm on the left ovary and fallopian tube. Her right ovary was normal and con-
Fertility and Sterility姞 Vol. 87, No. 1, January 2007 189.e5 Copyright ©2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
tained a corpus luteum. The right ovary was chosen for cryopreservation because of the evidence of recent ovulation, indicating its functionality. The ovary was then removed laparoscopically via bipolar cautery and sharp dissection of the infundibulopelvic ligament and utero-ovarian ligament. The ovary was placed in an endo-pouch and put in a sterile specimen container containing alpha minimal essential media. The container was placed on ice inside an insulated container and was taken to the Weill Medical College of Cornell University Medical Center, New York, New York, for cryopreservation. Cryopreservation was performed as previously reported by Oktay and Buyuk (3). The left tube and ovary were then mobilized by transecting the utero-ovarian ligament and mesovarium with bipolar cautery and sharp dissection. The ovary and tube were then mobilized out of the pelvis without tension. The ovary was then intracorporally sutured to the fascia superior to the pelvic brim providing approximately 5– 6 cm from the upcoming irradiation field. Metallic clips were then applied to the borders of the ovary allowing radiologic visualization. The proximity and alignment of the tube and ovary were retained, allowing the potential for natural ovum pickup. The patient tolerated the procedure well, and postoperatively she reported only minimal discomfort. She was then placed on oral contraceptives to prevent pregnancy and to retain maximal number of primordial follicles, thus minimizing irradiation damage. Her fist cycle of radiation occurred 4 weeks later. DISCUSSION Every year, hundreds of thousands of women and children are exposed to potentially sterilizing chemotherapy and radical surgery and radiation for treatment of cancer as well as benign conditions (4, 5). We present an example of a patient who presented with the desire for preserved fertility in the setting of upcoming pelvic irradiation therapy. We were able to combine common ovarian transposition with ovarian cryopreservation maximizing her chances for future fertility. Chemotherapy and pelvic radiation are well-known causes of premature ovarian failure. Chemotherapeutic agents are cytotoxic and have shown various deleterious effects on ovaries including decreased follicle number, absent follicles, and even fibrosis (6). Surgical transposition of ovaries at least 3 cm from the upper border of the radiation field has been shown to preserve ovarian function (7). Tulandi and Al-Took (8) reported a laparoscopic translocation whereby the utero-ovarian ligaments were divided, but the ovaries remained attached to the distal portion of the fallopian tubes. That patient achieved spontaneous pregnancy likely because of ovary and tube proximity, allowing for natural ovum pickup. According to Tulandi and Al-Took (8), laparoscopic ovarian transposition in women ⬍40 is associated with continued ovarian function in 88.6% of cases. This technique allows for optimal ovarian function in the setting of pelvic irradiation. 189.e6 Martin et al.
Currently, embryo cryopreservation is the optimal method to preserve future fertility because there are reasonable postthaw survival, implantation, and delivery rates (9). However, many patients begin their cancer treatment immediately or do not have an established partner to create embryos to be frozen. For these patients, cryopreservation of ovarian tissue is a promising new method for retaining future fertility. Human ovarian tissue cryopreservation was first documented in 1996 by Hovatta et al. (10) and 1997 by Oktay et al. (11), but was not applied to orthotopic transplantation until 2000 by Oktay and Sonmezer (12). The aim of cryopreservation technology is to first store and then reimplant thawed ovarian tissue in order to retain fertility and hormonal function. Cellular damage and destruction of primordial follicles are decreasing with improved cryopreservation and thawing techniques. Initially, Baird et al. (13) showed a large loss of post-thaw primordial follicles. However, because of improved freeze and thaw techniques, Imhof et al. (14) found an intact primordial follicle rate of 80% by light microscopy after freeze-thaw cycles. In addition, Bath et al. (15) removed ovarian cortical biopsies from a patient for potential reimplantation after requiring radiation. Cryopreservation and reimplantion of total ovaries, rather than ovarian biopsies, allow for greater follicular survival because of a larger number of primordial follicles (14). In 2000, Oktay and Sonmezer (12) showed the resumption of ovarian endocrine function afer cryopreservation and reimplantation. Thus far, there is limited success in humans with only one normal embryo development after heterotopic ovarian transplant (16) and two possible live births from an orthotopically transplanted ovary (17, 18). Reproductive age women with pelvic tumors face not only cancer but also potential infertility because of pelvic irradiation therapy. With improved techniques for freezing and thawing ovarian tissue, ovarian cryopreservation is a new way to preserve fertility. For those women whose circumstances prevent embryo cryopreservation, combining ovarian transposition with ovarian cryopreservation is a potential treatment to optimize future fertility treatment options. REFERENCES 1. Bisharah M, Tulandi T. Laparoscopic preservation of ovarian function: an underused procedure. Am J Obstet Gynecol 2002;188:367–70. 2. Kattera S, Chen C. A modified embryo cryopreservation method increases post thaw survival with concomitant increase in implantation. Fertil Steril 2005;84:1498 –1504. 3. Oktay K, Buyuk E. The technique of ovarian transplantation: laboratory and clinical insights. In: Tucker M, ed. A color atlas for human assisted reproduction. Philadelphia: Lippincott 2003:229 – 40. 4. Oktay KH, Yih M. Preliminary experience with orthotopic and heterotopic transplantation of ovarian cortical strips. Semin Reprod Med 2002;20:63– 4. 5. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics. CA Cancer J Clin 2003;53:5–26. 6. Falcone T, Bedaiwy A. Fertility preservation and pregnancy outcome after malignancy. Curr Opin Obstet Gynecol 2005;17:21– 6. 7. Bidzinski M, Lemieszczuk B, Zielinski J. Evaluation of hormonal function and features of ultrasound picture of transposed ovary in
Ovarian cryopreservation with transposition
Vol. 87, No. 1, January 2007
8. 9. 10.
11.
12. 13.
cervical cancer patients after surgery and pelvic irradiation. Eur J Obstet Gynecol 1993;14:77– 80. Tulandi T, Al-Took S. Laparoscopic ovarian suspension before irradiation. Fertil Steril 1998;70:382–3. Sonmezer M, Shamonki MI, Oktay K. Ovarian tissue cryopreservation: benefits and risks. Cell Tissue Res 2005;322:125–32. Hovatta O, Silye R, Krausz T, Abir R, Margara R, Trew G, et al. Cryopreservation of human ovarian tissue using dimethylsulphoxide and propanediol-sucrose cryoprotectants. Hum Reprod 1996;11:1268 – 72. Oktay K, Nugent D, Newton H, Salha O, Chatterjee P, Gosden RG. Isolation and characterization of primordial follicles from fresh and cryopreserved human ovarian tissue. Fertil Steril 1997;67:481– 6. Oktay K, Karlikaya G. Ovarian function after transplantation of frozen, banked autologous ovarian tissue. N Engl J Med 2000;342:1919. Baird DT. Long term ovarian function in sheep after ovariectomy and transplantation of autografts stored at ⫺196 celsius. Endocrinology 1999;140:462–71.
Fertility and Sterility姞
14. Imhof M, Hofstetter G, Bergmeister H, Rudas M, Kain R, Lipovac M, Huber J. Cryopreservation of a whole ovary as a strategy for restoring ovarian function. J Assist Reprod Genet 2004;21:459 – 65. 15. Bath LE, Tydeman G, Critchley HOD, Anderson RA, Baird DT, Wallace WHB. Spontaneous conception in a young woman who had ovarian tissue cryopreserved before chemotherapy and radiotherapy for a Ewing’s sarcoma of the pelvis: case report. Hum Reprod 2004;19: 2569 –72. 16. Oktay K, Buyuk E, Veeck L, Zaninovic N, Xu K, Takeuchi T, et al. Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet 2004;363:837– 40. 17. Donnez J, Dolmans MM, Demylle D, Jadoul P, Picard C, Squifflet J, et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet 2004;364:1405–10. 18. Meirow D, Levron J, Eldar-Geva T, Hardan I, Fridman E, Zalel Y, et al. Pregnancy after transplantation of cryopreserved ovarian tissue in a patient with ovarian failure after chemotherapy. N Engl J Med 2005;353:318 –21.
189.e7