ASRM removes the experimental label from Ovarian Tissue Cryopreservation (OTC): pediatric research must continue

This article is a timely commentary on the recent American Society for Reproductive Medicine (ASRM) practice committee report on fertility preservation for patients undergoing gonadotoxic therapy, which removed the experimental label from ovarian tissue cryopreservation

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Authors:

Erin E. Rowell, M.D.a-d, Francesca E. Duncan, Ph.D.e, Monica M. Laronda, Ph.D.a-c

a Division of Pediatric Surgery, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL USA 
b Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL USA 
c Fertility & Hormone Preservation & Restoration Program, Stanley Manne Children’s Research Institute, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL USA 
d Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL USA  
eDepartment of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL USA 

Consider This:

The American Society for Reproductive Medicine (ASRM) recently released its practice committee report on fertility preservation for patients undergoing gonadotoxic therapy, which covered available options and programmatic requirements for fertility preservation (1). Of note, it states “Ovarian tissue banking is an acceptable fertility-preservation technique and is no longer considered experimental. Ovarian tissue banking is the only method to preserve fertility for prepubertal girls since ovarian stimulation and IVF are not options…” (1). The removal of this experimental label is based on overall evidence of safety of procuring ovarian tissue, cryopreserving the tissue, and transplanting thawed tissue orthotopically. This opinion is a critical advance for the field of Oncofertility and for the clinical practice of fertility preservation because cancer survivors around the world consider the option to have biological children a key quality of life measure (2,3). As pediatric fertility specialists and reproductive biology researchers, our team considers the discussion of fertility preservation options critical given that female gametes are a finite source  (4). Major professional societies including ASRM and the American Academy of Pediatrics (AAP) recommend that fertility preservation be considered prior to starting treatment for pediatric patients at risk for infertility (4). However, it is clear from the cohort of patients who have had successful live births that the success rate of this procedure is low and that the longevity of most grafts is limited. From a research perspective, we are just beginning to uncover methods to optimize ovarian tissue cryopreservation (OTC) procedures and to develop methods to maximize the potential of this tissue.  Research is especially important for pediatric and adolescent patients who do not have other fertility preservation options. However, there is a paucity of knowledge about the ovary and the quality of gametes obtained in the pre- and peri-pubertal population. In fact, there is only a single peer-reviewed case report and one report in the lay press of children born following transplantation of tissue cryopreserved when the mother was peripubertal and prepubertal, respectively (5,6). The pediatric population is thus vastly underrepresented in the clinical studies and data used to generate the ASRM guidelines. We fully endorse the ASRM guidelines for programmatic support of fertility preservation options and rapid access. We also urge the field to consider the following priorities in the setting of pediatric and adolescent OTC: (1) developing standardized surgical procurement techniques, (2) defining tissue processing methods to preserve pediatric ovarian tissue quality during removal and preparation for cryopreservation, (3) determining the rate of success for live births after transplant of ovarian tissue across ages, pubertal status, disease states, and treatments, (4) performing translational research on gamete quality and options for future fertility and hormone restoration. More research is required for developing standardized ovarian tissue procurement techniques.  Although OTC is the only fertility preservation option for prepubertal children with ovaries, there are currently no standard operative approaches for safely procuring the ovarian tissue from a pediatric or adolescent patient with minimal damage to the ovarian reserve (5). There are several points unique to this population which must be considered, including the presence of the ovarian reserve near the capsule of the ovary, the small body habitus of the patient, and the close proximity of the ovary to the other adnexal structures. It is also essential that any fertility preservation procedure not delay medical therapy for the patient’s primary indications. A recent study by our team demonstrates the importance of minimizing capsular disruption and heat effects to the ovarian tissue during surgical removal, as even distant exposure to an ultrasonic advanced energy device can alter folliculogenesis in our mini-pig model (6). We emphasize the importance of surgical technique in the removal of ovarian tissue and the corollary importance of preparing the tissue for freezing as central to the quality of the cryopreservation and ultimately to the success of the future use of the tissue for fertility restoration (7,8). More research is required for optimizing tissue processing techniques for pediatric and adolescent ovaries.  Our current protocols for ovarian tissue processing for OTC are based on procedures established in sheep which have been demonstrated as successful in restoring short-term fertility and hormone function in mostly adult patients (9–11). The procedure includes thinning the ovarian tissue while removing the medullary region, where growing follicles reside, and preserving the cortical region, where the primordial follicles exist in a more densely packed stroma. However, the prepubertal ovary is fundamentally different than the adult ovary in that the ovarian volume increases with age (12) and there does not appear to be a clearly delineated border between the cortex and medulla. Additionally, our experience with processing ovarian tissue from prepubertal patients has revealed that primordial follicles exist within tissue fragments of OTC processing media, which does not occur in media processed from adult patients and is thought to only contain the medullary region. More research is required to maximize the technique for processing in an effort to preserve the most primordial follicles that could restore both fertility and hormones in these pediatric patients once transplanted. Although the main objective in OTC is to preserve the ovarian cortex which contains the majority of primordial follicles or ovarian reserve, during the tissue processing, small antral follicles in the medulla are disrupted and cumulus oocyte complexes (COCs) are released into the media (13–15). In a process referred to as ex vivo in vitro maturation (ex vivo IVM), these COCs can be recovered and matured in vitro to obtain eggs arrested at metaphase of meiosis II (MII) which can be cryopreserved for future use. Our data and those of others demonstrate that ex vivo IVM is successful in producing mature MIIs in ~25-36% of the COCs collected from ovarian tissue processing, and live births have been reported from this egg source (13,15,16). Ex vivo IVM is performed clinically in a subset of sites around the globe but is not considered standard of care (13). The majority of the results have come from the adult population, and more research is required to determine how to mature prepubertal gametes into high quality eggs that could be a potential source for fertility preservation for patients with limited options. More research is required for transplantation of ovarian tissue that was preserved in prepubertal or adolescent patients.  As of 2017, over 130 live births have been reported from tissues cryopreserved from females who were an average of 30 years old at the time of cryopreservation (9,10). This procedure was successful in producing live births in 20 – 30% of cases (9,10). Hormone production was restored for up to 12 years with an average of 2-5 years (9,10). Within these reports, 18 patients were under 21 (9-20.3 years) years old when they cryopreserved their tissue and auto-transplantation of thawed tissue in each of these patients resulted in 10 live births for 9 mothers (10). The reported success rate for producing offspring from OTC followed by transplantation is low and the longevity of most grafts is limited. Moreover, these results do not account for all transplantations performed and thus may inflate the current rate of success. However, a female’s reproductive potential peaks in her late 20s and early 30s and is largely dictated by the quantity and quality of her gametes (17,18). There are approximately five times more abnormal non-growing follicles in prepubertal human ovaries than postpubertal ovaries (19) and fewer cultured primordial follicles from prepubertal patients grow to the secondary stage and some of these oocytes grown in situ lack a germinal vesicle (GV) membrane or nucleolus (19). Therefore, age-associated differences in folliculogenesis underlie the need for research into ovarian tissue transplantation of OTC tissue that was cryopreserved when the patient was prepubertal.  More research is required to determine the quality of eggs obtained through ovarian stimulation in adolescent and young adult patients.  The committee opinion points to fertility preservation options for those over 18 and those adolescent patients that are peripubertal and premenarchal to include ovarian stimulation and in vitro maturation (IVM) for oocyte or egg cryopreservation (1). However, by preserving gametes that may not otherwise have contributed to physiologic fertility and may be suboptimal due to their pubertal status, we are changing the landscape of reproduction in the pediatric patient population (17,18). Additionally, IVM rates are significantly lower in oocytes from prepubertal than from postpubertal patients. There is broad evidence from anthropologic, agricultural and epidemiologic data that altered egg quality during the pubertal transition may have significant effects on reproductive function and fertility (17). For example, higher incidences of egg aneuploidy are observed in humans in their teens and early 20s relative to late 20s and early 30s (18,20). A recent paper demonstrated that eggs harvested from patients under 20 years old following ovarian tissue stimulation, resulted in MII eggs with an increase in chromosome errors (18). Therefore, patients and families need to be appropriately counseled about the uncertainty of egg quality from adolescent and young adult patients and more research is required to determine which fertility preservation techniques, oocyte and egg cryopreservation versus OTC, may benefit this population in the future. Specialized research centers and collaborations are needed to support these research initiatives and develop informed standards and guidelines for ovarian fertility preservation and restoration.  Because of ASRM’s newly released statement that OTC is no longer considered experimental, we predict that, in the long term, there will be an increase in fertility preservation access and coverage for oncology patients across the country through new legislative action. We emphasize the need for specialized experts as part of comprehensive pediatric and adolescent fertility preservation team that are trained in educating patients and families on infertility risk, performing precise surgical tissue removal to preserve quality ovarian tissue, processing the tissue in a pediatric-centered way to maximize tissue for long term storage, and ultimately transplanting the ovarian tissue to restore fertility and hormone function. Our own program relies on the expertise of our clinical and basic research teams who review the current literature and guidelines reported in lay and scientific venues to allow patients and families to realize the benefit of research for improving methods and technologies that maximize the future potential for fertility and hormone restoration. We collect IRB-approved patient information pertinent for risk assessment and factors that could strongly influence or predict fertility and hormone function, and research specimens, including ovarian tissue biopsies and ovarian tissue processing media that includes medullary tissue and COCs, otherwise discarded during processing. We advocate for continuing research protocols that support transparent consent for and collection of research specimens from pediatric and adolescent patients to support the needed resources to advance this critical research and improve current methods. We encourage fertility preservation programs to support or collaborate with researchers to advance this cause. All of this research is necessary to inform improved care for the pediatric population.   

References:

1. ASRM Practice Committee. Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion. Fertil Steril 2019;112(6):1022–33.

2. Armuand GM, Wettergren L, Rodriguez-Wallberg KA, Lampic C. Desire for children, difficulties achieving a pregnancy, and infertility distress 3 to 7 years after cancer diagnosis. Support Care Cancer 2014;22(10):2805–12.

3. Canada AL, Schover LR. The psychosocial impact of interrupted childbearing in long‐term female cancer survivors. Psycho Oncol 2012;21(2):134–43.

4. Martinez F, Andersen C, Barri P, Brannigan R, Cobo A, Donnez J, et al. Update on fertility preservation from the Barcelona International Society for Fertility Preservation–ESHRE–ASRM 2015 expert meeting: indications, results and future perspectives. Fertil Steril 2017;108(3):407 415.e11.

5. Rowell EE, Corkum KS, Lautz TB, Laronda MM, Walz AL, Madonna M, et al. Laparoscopic unilateral oophorectomy for ovarian tissue cryopreservation in children. J Pediatr Surg 2018;54(Pediatr Blood Cancer 60 2012):543–9.

6. Rowell EE, Corkum KS, Even KA, Laronda MM. Ovarian Tissue Health After Laparoscopic Unilateral Oophorectomy: A Porcine Model for Establishing Optimized Fertility Preservation Techniques in Children. J Pediatr Surg 2020;

7. Anazodo A, Laws P, Logan S, Saunders C, Travaglia J, Gerstl B, et al. The Development of an International Oncofertility Competency Framework: A Model to Increase Oncofertility Implementation. Oncol 2019;theoncologist.2019-0043.

8. Lautz TB, Harris CJ, Laronda MM, Erickson L, Rowell EE. A Fertility Preservation Toolkit for Pediatric Surgeons Caring for Children with Cancer. Semin Pediatr Surg 2019;150861.

9. Pacheco F, Oktay K. Current Success and Efficiency of Autologous Ovarian Transplantation: A Meta-Analysis. Reprod Sci 2017;24(8):1111 1120.

10. Corkum KS, Rhee DS, Wafford EQ, Demeestere I, Dasgupta R, Baertschiger R, et al. Fertility and hormone preservation and restoration for female children and adolescents receiving gonadotoxic cancer treatments: A systematic review. J Pediatr Surg 2019;(Pediatr Blood Cancer 60 2012):ahead of print.

11. Gosden R, Baird D, Wade J, Webb R. Restoration of fertility to oophorectomized sheep by ovarian autografts stored at-196 C. Human Reproduction 1994;9(4):597 603.

12. Rosendahl M, Schmidt K, Ernst E, Rasmussen P, Loft A, Byskov A, et al. Cryopreservation of ovarian tissue for a decade in Denmark: a view of the technique. Reprod Biomed Online 2011;22(2):162 171.

13. Segers I, Mateizel I, Moer E, Smitz J, Tournaye H, Verheyen G, et al. In vitro maturation (IVM) of oocytes recovered from ovariectomy specimens in the laboratory: a promising “ex vivo” method of oocyte cryopreservation resulting in the first report of an ongoing pregnancy in Europe. J Assist Reprod Gen 2015;32(8):1221 1231.

14. Abir R, Ben-Aharon I, Garor R, Yaniv I, Ash S, Stemmer SM, et al. Cryopreservation of in vitro matured oocytes in addition to ovarian tissue freezing for fertility preservation in paediatric female cancer patients before and after cancer therapy. Hum Reprod 2016;31(4):750–62.

15. Yin H, Jiang H, Kristensen S, Andersen C. Vitrification of in vitro matured oocytes collected from surplus ovarian medulla tissue resulting from fertility preservation of ovarian cortex tissue. J Assist Reprod Gen 2016;33(6):741–6.

16. Fasano G, Moffa F, Dechène J, Englert Y, Demeestere I. Vitrification of in vitro matured oocytes collected from antral follicles at the time of ovarian tissue cryopreservation. Reprod Biol Endocrin 2011;9(1):150.

17. Duncan FE. Egg Quality during the Pubertal Transition—Is Youth All It’s Cracked Up to Be? Front Endocrinol 2017;8:226.

18. Gruhn JR, Zielinska AP, Shukla V, Blanshard R, Capalbo A, Cimadomo D, et al. Chromosome errors in human eggs shape natural fertility over reproductive life span. Science 2019;365(6460):1466–9.

19. Anderson R, McLaughlin M, Wallace W, Albertini D, Telfer E. The immature human ovary shows loss of abnormal follicles and increasing follicle developmental competence through childhood and adolescence. Hum Reprod 2013;29(1):97 106.

20. Franasiak JM, Forman EJ, Hong KH, Werner MD, Upham KM, Treff NR, et al. The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening. Fertil Steril 2014;101(3):656-663.e1.

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