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From the first obscure reference until the 19th century, the maternal mortality rate from an ectopic pregnancy was nearly 100%. In the past 140 years, because of early detection and prompt surgical management, the mortality rate from an ectopic pregnancy declined from 72%-90% in 1880 to 0.48% from 2004 to 2008.1 Given this remarkable reduction in mortality, the 20th-century approach to ectopic pregnancy evolved from preserving the life of the mother to preserving fertility by utilizing conservative treatment with methotrexate and/or tubal surgery.
Why the reference to ectopic pregnancy? Advances in oncology have comparably affected our approach to cancer patients. The increase in survival rates following a cancer diagnosis has fostered revolutionary developments in fertility preservation to obviate the effect of gonadotoxic therapy. We have evolved from shielding and transposing ovaries to ovarian tissue cryopreservation2,3 with rapid implementation.
One of the leaders in the field of female fertility preservation is Kutluk Oktay, MD, of Yale University, New Haven, Conn. I posed the following salient questions to him on the state of fertility preservation as well as expectations for the future.
Q1. What medication/treatment is gonadotoxic that warrants a consultation for fertility preservation?
A: While new drugs for cancer treatment continue to be approved and require testing for gonadotoxicity, evidence is clear on the damaging effects of alkylating agents such as cyclophosphamide, ifosfamide, chlorambucil, and melphalan on primordial follicle reserve.4 A useful tool to determine the risk of alkylating agents affecting fertility is the Cyclophosphamide Equivalent Dose (CED) Calculator. Likewise, topoisomerase inhibitors, such as doxorubicin4 induce ovarian reserve damage by causing double-strand DNA breaks (DSBs) in oocytes.5-7 Contrary to common belief, chemotherapy exposure suppresses the mechanisms that can initiate follicle growth.6 When DSBs occur, some oocytes may be able to repair such damage, otherwise apoptosis is triggered, which results in irreversible ovarian reserve loss.7 Younger individuals have much higher repair capacity, the magnitude of damage can be hard to predict, and it is variable.8,9 So, prior exposure to gonadotoxic drugs does not preclude consideration of fertility preservation.10
In addition, pelvic radiation, in a dose-dependent manner, causes severe DSBs and triggers the same cell suicide mechanisms while also potentially damaging uterine function. Additional information can be found in the American Society of Clinical Oncology Fertility Preservation Guidelines.4
Q2. What are the current options for fertility preservation in patients who will be exposed to gonadotoxic medication/treatment?
A: The current fertility preservation options for female patients faced with gonadotoxic treatments are embryo, oocyte, and ovarian tissue cryopreservation (OTC). Selection of fertility preservation is typically contingent upon the timetable of treatment. Oocyte and embryo cryopreservation have been the standard of care. Recently, OTC had its experimental designation removed by American Society for Reproductive Medicine11 with the advantage of not requiring ovarian stimulation or sexual maturity; and it may to be performed while patients are receiving chemotherapy. If successful, OTC followed by orthotopic transplantation has the potential to restore natural ovarian function, thereby allowing spontaneous conception.10 Especially in young adults, ovarian reserve loss is fractional and can remain at reasonable levels after a few courses of chemotherapy. Ovarian stimulation is risky after the initiation of chemotherapy because of the severe DNA damage to oocytes of developing follicles and the associated poor response.7 Hence, ovarian stimulation should be initiated and completed before the initiation of chemotherapy.
Q3. How successful are the approved fertility preservation options in obtaining oocytes for future utilization by ART?
A: We have decades of experience with embryo cryopreservation and proven success rates that patients can check on the SART.org website for individual clinics. For oocyte cryopreservation, models are used to provide calculation estimates because the technique is less established.12 Although success rates are approaching those with fresh oocytes, they are still not equal.13 OTC followed by orthotopic tissue transplantation has the least outcomes data (approximately 200 reported livebirths to date with a 25% live birth rate per recipient worldwide10 since the first success was reported in 2000.2,14
With our robotic surgical approach to orthotopic and heterotopic ovarian tissue transplantation and the utility of neovascularizing agents, we have found that ovarian graft longevity is extended. Oocytes/embryos can be obtained and has resulted in one to two livebirths in all our recipients to date.10 Unfortunately, if any of the critical steps are not up to standards (freezing, thawing, or transplantation), success rates can dramatically decline. Therefore, providers and patients should seek centers with experience in all three stages of this procedure to maximize outcomes.
Q4. Are there concerns of increasing recurrence/mortality with fertility preservation given hormonal exposure?
A: Yes, this concern exists, at least in theory for estrogen-sensitive cancers, most commonly breast cancer. We developed ovarian stimulation protocols supplemented with anti-estrogen treatments (tamoxifen, an estrogen-receptor antagonist, and letrozole, an aromatase inhibitor) that appear equally effective and reduce estrogen exposure in any susceptible cancer.15,16 Even in estrogen receptor–negative tumors, high estrogen exposure may activate non–estrogen receptor–dependent pathways. In addition, even those tumors that are practically deemed estrogen receptor negative may still contain a small percentage of estrogen receptors, which may become active at high estrogen levels.
Therefore, when we approach women with estrogen-sensitive cancers, e.g., breast and endometrial, we do not alter our approach based on receptor status. One exception occurs in women with BRCA mutations, especially the BRCA1, as they have 25% lower serum anti-müllerian hormone (AMH) levels,8,17 yield fewer oocytes in response to ovarian stimulation,18,19 and have lower fertilization rates and embryo numbers20 compared with those without the mutations.
Q5. Are all reproductive centers capable of offering fertility preservation? If not, how does a patient find a center?
A: All IVF clinics offer embryo and, presumably, oocyte cryopreservation. Pregnancy outcomes vary based on the center’s experience. Globally, major differences exist in the availability and competency of OTC along with the subsequent transplantation approach. A limited number of centers have competency in all aspects of OTC, i.e., cryopreservation, thawing, and transplantation. In general, fertility preservation patients have a multitude of medical issues that necessitate management expertise and the bandwidth to coordinate with cancer health professionals. The reproductive centers offering fertility preservation should be prepared to respond immediately and accommodate patients about to undergo gonadotoxic treatment.
Q6. How should a patient be counseled before proceeding with fertility preservation?
A: The candidate should be counseled on the likelihood of damage from gonadotoxic therapy and all fertility preservation options, on the basis of the urgency of treatment and the woman’s long-term goals. For example, the desire for a large family may compel a patient to undergo multiple cycles of ovarian stimulation or a combination of oocyte/embryo cryopreservation with OTC. In patients who are undergoing embryo cryopreservation, I recommend preimplantation genetic testing for aneuploidies, although there are limitations to its application. Other novel pieces of information we are using in counseling are baseline AMH levels and BRCA mutation status for women with breast cancer. In an 8-year-long NIH-funded prospective longitudinal study we found that women with both baseline AMH < 2 ng/mL and BRCA mutations are at significantly higher risk of losing their ovarian reserve and developing amenorrhea.21 Because the oocytes of women with BRCA mutations are deficient in DNA repair as we have previously shown,19 they are more liable to death upon exposure to DNA-damaging cancer drugs such as cyclophosphamide and doxorubicin.22
Q7. What is the time limit for use of cryopreserved oocytes/tissue?
A: Under optimal storage conditions, cryopreserved oocytes/tissue can be utilized indefinitely without a negative effect on pregnancy outcomes.
Q8. What does the future hold for fertility preservation?
A: The future holds promise for both the medical and nonmedical (planned) utility of fertility preservation. With the former, we will see that the utility of OTC and orthotopic and heterotopic tissue transplantation increase as success rates improve. Improved neovascularizing agents will make the transplants last longer and enhance pregnancy outcomes.23,24 I see planned fertility preservation increasing, based on the experience gained from cancer patients and some preliminary experience with planned OTC, especially for healthy women who wish to consider delaying menopause.25,26
Because of attrition from apoptosis, approximately 2,000 oocytes are wasted per ovulation. Through calculation models, we predict that if an equivalent of one-third of a woman’s ovarian cortex can be cryopreserved (which may not significantly affect the age at natural menopause) before age 40 years, transplantation at perimenopause may provide sufficient primordial follicles to delay menopause for 5 years or longer.26 Because ovarian tissue can also be transplanted subcutaneously under local anesthesia, as we have shown,27,28 repeated heterotopic transplants can be performed in an office setting at reduced cost, invasiveness, and with enhanced effectiveness. We can expect increasing reports and progress on this planned use of OTC and transplantation in the future.
Dr. Oktay is professor of obstetrics & gynecology and reproductive sciences and director of the Laboratory of Molecular Reproduction and Fertility Preservation at Yale University, New Haven, Conn. Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
References
1. Lurie S. Eur J Obstet Gynecol Reprod Biol. 1992 Jan 9;43(1):1-7.
2. Oktay K and Karlikaya G. N Engl J Med. 2000 Jun 22;342(25):1919.
3. Sonmezer and Oktay K. Hum Reprod Update. 2004;10(3):251-66.
4. Oktay K et al. J Clin Oncol. 2018 Jul 1;36(19):1994-2001.
5. Goldfarb SB et al. Breast Cancer Res Treat. 2021;185:165-73.
6. Titus S et al. Sci Rep. 2021 Jan 11;11(1):407.
7. Soleimani R et al. Aging (Albany NY). 2011 Aug;3(8):782-93.
8. Titus S et al. Sci Transl Med. 2013 Feb 13;5(172):172ra21.
9. Oktay KH et al. Fertil Steril. 2022 Jan 5:S0015-0282(21)02293-7.
10. Oktay K et al. Fertil Steril. 2022;117(1):181-92.
11. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2019;112(6):1022–33.
12. Cil A et al. Fertil Steril. 2013 Aug;100(2):492-9.e3.
13. Goldman KN et al. Fertil Steril. 2013 Sep;100(3):712-7.
14. Marin L and Oktay K. Scientific history of ovarian tissue cryopreservation and transplantation. In: Oktay K (ed.), Principles and Practice of Ovarian Tissue Cryopreservation and Transplantation. Elsevier;2022:1-10.
15. Oktay K et al. J Clin Oncol. 2005 Jul 1;23(19):4347-53.
16. Kim JY et al. J Clin Endocrinol Metab. 2016 Apr;101(4):1364-71.
17. Turan V et al. J Clin Oncol. 2021;39:18.
18. Oktay K et al. J Clin Oncol. 2010 Jan 10;28(2):240-4.
19. Lin W et al. J Clin Endocrinol Metab. 2017;102(10):3839-47.
20. Turan V et al. Reprod Sci. 2018;(25):26-32.
21. Oktay K et al. Presence of BRCA mutations and a pre-chemotherapy AMH level of < 2ng/mL strongly predict risk of amenorrhea in women with breast cancer P-291. Presented at the American Society for Reproductive Medicine 78th annual meeting, Anaheim, Calif. Oct. 22-26, 2022.
22. Oktay KH et al. Fertil Steril. 2020;113(6):1251‐60.e1.
23. Soleimani R et al. PLoS One. 2011 Apr 29;6(4):e19475.
24. Marin L et al. Future aspects of ovarian cryopreservation and transplantation. In: Oktay K (ed.). Principles and Practice of Ovarian Tissue Cryopreservation and Transplantation. Elsevier; 2022;223-30.
25. Oktay KH et al. Trends Mol Med. 2021;27(8):753-61.
26. Oktay K and Marin L. Ovarian tissue cryopreservation for delaying childbearing and menopause. In: Oktay, K. (Ed.), Principles and Practice of Ovarian Tissue Cryopreservation and Transplantation. Elsevier;2022:195-204.
27. Oktay K et al. JAMA. 2001 Sep 26;286(12):1490-3.
28. Oktay K et al. Lancet. 2004 Mar 13;363(9412):837-40.
From the first obscure reference until the 19th century, the maternal mortality rate from an ectopic pregnancy was nearly 100%. In the past 140 years, because of early detection and prompt surgical management, the mortality rate from an ectopic pregnancy declined from 72%-90% in 1880 to 0.48% from 2004 to 2008.1 Given this remarkable reduction in mortality, the 20th-century approach to ectopic pregnancy evolved from preserving the life of the mother to preserving fertility by utilizing conservative treatment with methotrexate and/or tubal surgery.
Why the reference to ectopic pregnancy? Advances in oncology have comparably affected our approach to cancer patients. The increase in survival rates following a cancer diagnosis has fostered revolutionary developments in fertility preservation to obviate the effect of gonadotoxic therapy. We have evolved from shielding and transposing ovaries to ovarian tissue cryopreservation2,3 with rapid implementation.
One of the leaders in the field of female fertility preservation is Kutluk Oktay, MD, of Yale University, New Haven, Conn. I posed the following salient questions to him on the state of fertility preservation as well as expectations for the future.
Q1. What medication/treatment is gonadotoxic that warrants a consultation for fertility preservation?
A: While new drugs for cancer treatment continue to be approved and require testing for gonadotoxicity, evidence is clear on the damaging effects of alkylating agents such as cyclophosphamide, ifosfamide, chlorambucil, and melphalan on primordial follicle reserve.4 A useful tool to determine the risk of alkylating agents affecting fertility is the Cyclophosphamide Equivalent Dose (CED) Calculator. Likewise, topoisomerase inhibitors, such as doxorubicin4 induce ovarian reserve damage by causing double-strand DNA breaks (DSBs) in oocytes.5-7 Contrary to common belief, chemotherapy exposure suppresses the mechanisms that can initiate follicle growth.6 When DSBs occur, some oocytes may be able to repair such damage, otherwise apoptosis is triggered, which results in irreversible ovarian reserve loss.7 Younger individuals have much higher repair capacity, the magnitude of damage can be hard to predict, and it is variable.8,9 So, prior exposure to gonadotoxic drugs does not preclude consideration of fertility preservation.10
In addition, pelvic radiation, in a dose-dependent manner, causes severe DSBs and triggers the same cell suicide mechanisms while also potentially damaging uterine function. Additional information can be found in the American Society of Clinical Oncology Fertility Preservation Guidelines.4
Q2. What are the current options for fertility preservation in patients who will be exposed to gonadotoxic medication/treatment?
A: The current fertility preservation options for female patients faced with gonadotoxic treatments are embryo, oocyte, and ovarian tissue cryopreservation (OTC). Selection of fertility preservation is typically contingent upon the timetable of treatment. Oocyte and embryo cryopreservation have been the standard of care. Recently, OTC had its experimental designation removed by American Society for Reproductive Medicine11 with the advantage of not requiring ovarian stimulation or sexual maturity; and it may to be performed while patients are receiving chemotherapy. If successful, OTC followed by orthotopic transplantation has the potential to restore natural ovarian function, thereby allowing spontaneous conception.10 Especially in young adults, ovarian reserve loss is fractional and can remain at reasonable levels after a few courses of chemotherapy. Ovarian stimulation is risky after the initiation of chemotherapy because of the severe DNA damage to oocytes of developing follicles and the associated poor response.7 Hence, ovarian stimulation should be initiated and completed before the initiation of chemotherapy.
Q3. How successful are the approved fertility preservation options in obtaining oocytes for future utilization by ART?
A: We have decades of experience with embryo cryopreservation and proven success rates that patients can check on the SART.org website for individual clinics. For oocyte cryopreservation, models are used to provide calculation estimates because the technique is less established.12 Although success rates are approaching those with fresh oocytes, they are still not equal.13 OTC followed by orthotopic tissue transplantation has the least outcomes data (approximately 200 reported livebirths to date with a 25% live birth rate per recipient worldwide10 since the first success was reported in 2000.2,14
With our robotic surgical approach to orthotopic and heterotopic ovarian tissue transplantation and the utility of neovascularizing agents, we have found that ovarian graft longevity is extended. Oocytes/embryos can be obtained and has resulted in one to two livebirths in all our recipients to date.10 Unfortunately, if any of the critical steps are not up to standards (freezing, thawing, or transplantation), success rates can dramatically decline. Therefore, providers and patients should seek centers with experience in all three stages of this procedure to maximize outcomes.
Q4. Are there concerns of increasing recurrence/mortality with fertility preservation given hormonal exposure?
A: Yes, this concern exists, at least in theory for estrogen-sensitive cancers, most commonly breast cancer. We developed ovarian stimulation protocols supplemented with anti-estrogen treatments (tamoxifen, an estrogen-receptor antagonist, and letrozole, an aromatase inhibitor) that appear equally effective and reduce estrogen exposure in any susceptible cancer.15,16 Even in estrogen receptor–negative tumors, high estrogen exposure may activate non–estrogen receptor–dependent pathways. In addition, even those tumors that are practically deemed estrogen receptor negative may still contain a small percentage of estrogen receptors, which may become active at high estrogen levels.
Therefore, when we approach women with estrogen-sensitive cancers, e.g., breast and endometrial, we do not alter our approach based on receptor status. One exception occurs in women with BRCA mutations, especially the BRCA1, as they have 25% lower serum anti-müllerian hormone (AMH) levels,8,17 yield fewer oocytes in response to ovarian stimulation,18,19 and have lower fertilization rates and embryo numbers20 compared with those without the mutations.
Q5. Are all reproductive centers capable of offering fertility preservation? If not, how does a patient find a center?
A: All IVF clinics offer embryo and, presumably, oocyte cryopreservation. Pregnancy outcomes vary based on the center’s experience. Globally, major differences exist in the availability and competency of OTC along with the subsequent transplantation approach. A limited number of centers have competency in all aspects of OTC, i.e., cryopreservation, thawing, and transplantation. In general, fertility preservation patients have a multitude of medical issues that necessitate management expertise and the bandwidth to coordinate with cancer health professionals. The reproductive centers offering fertility preservation should be prepared to respond immediately and accommodate patients about to undergo gonadotoxic treatment.
Q6. How should a patient be counseled before proceeding with fertility preservation?
A: The candidate should be counseled on the likelihood of damage from gonadotoxic therapy and all fertility preservation options, on the basis of the urgency of treatment and the woman’s long-term goals. For example, the desire for a large family may compel a patient to undergo multiple cycles of ovarian stimulation or a combination of oocyte/embryo cryopreservation with OTC. In patients who are undergoing embryo cryopreservation, I recommend preimplantation genetic testing for aneuploidies, although there are limitations to its application. Other novel pieces of information we are using in counseling are baseline AMH levels and BRCA mutation status for women with breast cancer. In an 8-year-long NIH-funded prospective longitudinal study we found that women with both baseline AMH < 2 ng/mL and BRCA mutations are at significantly higher risk of losing their ovarian reserve and developing amenorrhea.21 Because the oocytes of women with BRCA mutations are deficient in DNA repair as we have previously shown,19 they are more liable to death upon exposure to DNA-damaging cancer drugs such as cyclophosphamide and doxorubicin.22
Q7. What is the time limit for use of cryopreserved oocytes/tissue?
A: Under optimal storage conditions, cryopreserved oocytes/tissue can be utilized indefinitely without a negative effect on pregnancy outcomes.
Q8. What does the future hold for fertility preservation?
A: The future holds promise for both the medical and nonmedical (planned) utility of fertility preservation. With the former, we will see that the utility of OTC and orthotopic and heterotopic tissue transplantation increase as success rates improve. Improved neovascularizing agents will make the transplants last longer and enhance pregnancy outcomes.23,24 I see planned fertility preservation increasing, based on the experience gained from cancer patients and some preliminary experience with planned OTC, especially for healthy women who wish to consider delaying menopause.25,26
Because of attrition from apoptosis, approximately 2,000 oocytes are wasted per ovulation. Through calculation models, we predict that if an equivalent of one-third of a woman’s ovarian cortex can be cryopreserved (which may not significantly affect the age at natural menopause) before age 40 years, transplantation at perimenopause may provide sufficient primordial follicles to delay menopause for 5 years or longer.26 Because ovarian tissue can also be transplanted subcutaneously under local anesthesia, as we have shown,27,28 repeated heterotopic transplants can be performed in an office setting at reduced cost, invasiveness, and with enhanced effectiveness. We can expect increasing reports and progress on this planned use of OTC and transplantation in the future.
Dr. Oktay is professor of obstetrics & gynecology and reproductive sciences and director of the Laboratory of Molecular Reproduction and Fertility Preservation at Yale University, New Haven, Conn. Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
References
1. Lurie S. Eur J Obstet Gynecol Reprod Biol. 1992 Jan 9;43(1):1-7.
2. Oktay K and Karlikaya G. N Engl J Med. 2000 Jun 22;342(25):1919.
3. Sonmezer and Oktay K. Hum Reprod Update. 2004;10(3):251-66.
4. Oktay K et al. J Clin Oncol. 2018 Jul 1;36(19):1994-2001.
5. Goldfarb SB et al. Breast Cancer Res Treat. 2021;185:165-73.
6. Titus S et al. Sci Rep. 2021 Jan 11;11(1):407.
7. Soleimani R et al. Aging (Albany NY). 2011 Aug;3(8):782-93.
8. Titus S et al. Sci Transl Med. 2013 Feb 13;5(172):172ra21.
9. Oktay KH et al. Fertil Steril. 2022 Jan 5:S0015-0282(21)02293-7.
10. Oktay K et al. Fertil Steril. 2022;117(1):181-92.
11. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2019;112(6):1022–33.
12. Cil A et al. Fertil Steril. 2013 Aug;100(2):492-9.e3.
13. Goldman KN et al. Fertil Steril. 2013 Sep;100(3):712-7.
14. Marin L and Oktay K. Scientific history of ovarian tissue cryopreservation and transplantation. In: Oktay K (ed.), Principles and Practice of Ovarian Tissue Cryopreservation and Transplantation. Elsevier;2022:1-10.
15. Oktay K et al. J Clin Oncol. 2005 Jul 1;23(19):4347-53.
16. Kim JY et al. J Clin Endocrinol Metab. 2016 Apr;101(4):1364-71.
17. Turan V et al. J Clin Oncol. 2021;39:18.
18. Oktay K et al. J Clin Oncol. 2010 Jan 10;28(2):240-4.
19. Lin W et al. J Clin Endocrinol Metab. 2017;102(10):3839-47.
20. Turan V et al. Reprod Sci. 2018;(25):26-32.
21. Oktay K et al. Presence of BRCA mutations and a pre-chemotherapy AMH level of < 2ng/mL strongly predict risk of amenorrhea in women with breast cancer P-291. Presented at the American Society for Reproductive Medicine 78th annual meeting, Anaheim, Calif. Oct. 22-26, 2022.
22. Oktay KH et al. Fertil Steril. 2020;113(6):1251‐60.e1.
23. Soleimani R et al. PLoS One. 2011 Apr 29;6(4):e19475.
24. Marin L et al. Future aspects of ovarian cryopreservation and transplantation. In: Oktay K (ed.). Principles and Practice of Ovarian Tissue Cryopreservation and Transplantation. Elsevier; 2022;223-30.
25. Oktay KH et al. Trends Mol Med. 2021;27(8):753-61.
26. Oktay K and Marin L. Ovarian tissue cryopreservation for delaying childbearing and menopause. In: Oktay, K. (Ed.), Principles and Practice of Ovarian Tissue Cryopreservation and Transplantation. Elsevier;2022:195-204.
27. Oktay K et al. JAMA. 2001 Sep 26;286(12):1490-3.
28. Oktay K et al. Lancet. 2004 Mar 13;363(9412):837-40.
From the first obscure reference until the 19th century, the maternal mortality rate from an ectopic pregnancy was nearly 100%. In the past 140 years, because of early detection and prompt surgical management, the mortality rate from an ectopic pregnancy declined from 72%-90% in 1880 to 0.48% from 2004 to 2008.1 Given this remarkable reduction in mortality, the 20th-century approach to ectopic pregnancy evolved from preserving the life of the mother to preserving fertility by utilizing conservative treatment with methotrexate and/or tubal surgery.
Why the reference to ectopic pregnancy? Advances in oncology have comparably affected our approach to cancer patients. The increase in survival rates following a cancer diagnosis has fostered revolutionary developments in fertility preservation to obviate the effect of gonadotoxic therapy. We have evolved from shielding and transposing ovaries to ovarian tissue cryopreservation2,3 with rapid implementation.
One of the leaders in the field of female fertility preservation is Kutluk Oktay, MD, of Yale University, New Haven, Conn. I posed the following salient questions to him on the state of fertility preservation as well as expectations for the future.
Q1. What medication/treatment is gonadotoxic that warrants a consultation for fertility preservation?
A: While new drugs for cancer treatment continue to be approved and require testing for gonadotoxicity, evidence is clear on the damaging effects of alkylating agents such as cyclophosphamide, ifosfamide, chlorambucil, and melphalan on primordial follicle reserve.4 A useful tool to determine the risk of alkylating agents affecting fertility is the Cyclophosphamide Equivalent Dose (CED) Calculator. Likewise, topoisomerase inhibitors, such as doxorubicin4 induce ovarian reserve damage by causing double-strand DNA breaks (DSBs) in oocytes.5-7 Contrary to common belief, chemotherapy exposure suppresses the mechanisms that can initiate follicle growth.6 When DSBs occur, some oocytes may be able to repair such damage, otherwise apoptosis is triggered, which results in irreversible ovarian reserve loss.7 Younger individuals have much higher repair capacity, the magnitude of damage can be hard to predict, and it is variable.8,9 So, prior exposure to gonadotoxic drugs does not preclude consideration of fertility preservation.10
In addition, pelvic radiation, in a dose-dependent manner, causes severe DSBs and triggers the same cell suicide mechanisms while also potentially damaging uterine function. Additional information can be found in the American Society of Clinical Oncology Fertility Preservation Guidelines.4
Q2. What are the current options for fertility preservation in patients who will be exposed to gonadotoxic medication/treatment?
A: The current fertility preservation options for female patients faced with gonadotoxic treatments are embryo, oocyte, and ovarian tissue cryopreservation (OTC). Selection of fertility preservation is typically contingent upon the timetable of treatment. Oocyte and embryo cryopreservation have been the standard of care. Recently, OTC had its experimental designation removed by American Society for Reproductive Medicine11 with the advantage of not requiring ovarian stimulation or sexual maturity; and it may to be performed while patients are receiving chemotherapy. If successful, OTC followed by orthotopic transplantation has the potential to restore natural ovarian function, thereby allowing spontaneous conception.10 Especially in young adults, ovarian reserve loss is fractional and can remain at reasonable levels after a few courses of chemotherapy. Ovarian stimulation is risky after the initiation of chemotherapy because of the severe DNA damage to oocytes of developing follicles and the associated poor response.7 Hence, ovarian stimulation should be initiated and completed before the initiation of chemotherapy.
Q3. How successful are the approved fertility preservation options in obtaining oocytes for future utilization by ART?
A: We have decades of experience with embryo cryopreservation and proven success rates that patients can check on the SART.org website for individual clinics. For oocyte cryopreservation, models are used to provide calculation estimates because the technique is less established.12 Although success rates are approaching those with fresh oocytes, they are still not equal.13 OTC followed by orthotopic tissue transplantation has the least outcomes data (approximately 200 reported livebirths to date with a 25% live birth rate per recipient worldwide10 since the first success was reported in 2000.2,14
With our robotic surgical approach to orthotopic and heterotopic ovarian tissue transplantation and the utility of neovascularizing agents, we have found that ovarian graft longevity is extended. Oocytes/embryos can be obtained and has resulted in one to two livebirths in all our recipients to date.10 Unfortunately, if any of the critical steps are not up to standards (freezing, thawing, or transplantation), success rates can dramatically decline. Therefore, providers and patients should seek centers with experience in all three stages of this procedure to maximize outcomes.
Q4. Are there concerns of increasing recurrence/mortality with fertility preservation given hormonal exposure?
A: Yes, this concern exists, at least in theory for estrogen-sensitive cancers, most commonly breast cancer. We developed ovarian stimulation protocols supplemented with anti-estrogen treatments (tamoxifen, an estrogen-receptor antagonist, and letrozole, an aromatase inhibitor) that appear equally effective and reduce estrogen exposure in any susceptible cancer.15,16 Even in estrogen receptor–negative tumors, high estrogen exposure may activate non–estrogen receptor–dependent pathways. In addition, even those tumors that are practically deemed estrogen receptor negative may still contain a small percentage of estrogen receptors, which may become active at high estrogen levels.
Therefore, when we approach women with estrogen-sensitive cancers, e.g., breast and endometrial, we do not alter our approach based on receptor status. One exception occurs in women with BRCA mutations, especially the BRCA1, as they have 25% lower serum anti-müllerian hormone (AMH) levels,8,17 yield fewer oocytes in response to ovarian stimulation,18,19 and have lower fertilization rates and embryo numbers20 compared with those without the mutations.
Q5. Are all reproductive centers capable of offering fertility preservation? If not, how does a patient find a center?
A: All IVF clinics offer embryo and, presumably, oocyte cryopreservation. Pregnancy outcomes vary based on the center’s experience. Globally, major differences exist in the availability and competency of OTC along with the subsequent transplantation approach. A limited number of centers have competency in all aspects of OTC, i.e., cryopreservation, thawing, and transplantation. In general, fertility preservation patients have a multitude of medical issues that necessitate management expertise and the bandwidth to coordinate with cancer health professionals. The reproductive centers offering fertility preservation should be prepared to respond immediately and accommodate patients about to undergo gonadotoxic treatment.
Q6. How should a patient be counseled before proceeding with fertility preservation?
A: The candidate should be counseled on the likelihood of damage from gonadotoxic therapy and all fertility preservation options, on the basis of the urgency of treatment and the woman’s long-term goals. For example, the desire for a large family may compel a patient to undergo multiple cycles of ovarian stimulation or a combination of oocyte/embryo cryopreservation with OTC. In patients who are undergoing embryo cryopreservation, I recommend preimplantation genetic testing for aneuploidies, although there are limitations to its application. Other novel pieces of information we are using in counseling are baseline AMH levels and BRCA mutation status for women with breast cancer. In an 8-year-long NIH-funded prospective longitudinal study we found that women with both baseline AMH < 2 ng/mL and BRCA mutations are at significantly higher risk of losing their ovarian reserve and developing amenorrhea.21 Because the oocytes of women with BRCA mutations are deficient in DNA repair as we have previously shown,19 they are more liable to death upon exposure to DNA-damaging cancer drugs such as cyclophosphamide and doxorubicin.22
Q7. What is the time limit for use of cryopreserved oocytes/tissue?
A: Under optimal storage conditions, cryopreserved oocytes/tissue can be utilized indefinitely without a negative effect on pregnancy outcomes.
Q8. What does the future hold for fertility preservation?
A: The future holds promise for both the medical and nonmedical (planned) utility of fertility preservation. With the former, we will see that the utility of OTC and orthotopic and heterotopic tissue transplantation increase as success rates improve. Improved neovascularizing agents will make the transplants last longer and enhance pregnancy outcomes.23,24 I see planned fertility preservation increasing, based on the experience gained from cancer patients and some preliminary experience with planned OTC, especially for healthy women who wish to consider delaying menopause.25,26
Because of attrition from apoptosis, approximately 2,000 oocytes are wasted per ovulation. Through calculation models, we predict that if an equivalent of one-third of a woman’s ovarian cortex can be cryopreserved (which may not significantly affect the age at natural menopause) before age 40 years, transplantation at perimenopause may provide sufficient primordial follicles to delay menopause for 5 years or longer.26 Because ovarian tissue can also be transplanted subcutaneously under local anesthesia, as we have shown,27,28 repeated heterotopic transplants can be performed in an office setting at reduced cost, invasiveness, and with enhanced effectiveness. We can expect increasing reports and progress on this planned use of OTC and transplantation in the future.
Dr. Oktay is professor of obstetrics & gynecology and reproductive sciences and director of the Laboratory of Molecular Reproduction and Fertility Preservation at Yale University, New Haven, Conn. Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
References
1. Lurie S. Eur J Obstet Gynecol Reprod Biol. 1992 Jan 9;43(1):1-7.
2. Oktay K and Karlikaya G. N Engl J Med. 2000 Jun 22;342(25):1919.
3. Sonmezer and Oktay K. Hum Reprod Update. 2004;10(3):251-66.
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