Oncofertility Publications

Abstract

INTRODUCTION:
Recent improvements in cancer detection, treatment, and technology have increased survivorship rates. These same life-saving treatments, however, can lead to infertility or sterility. Oncofertility, an emerging field at the intersection of cancer and oncology, centers on providing cancer patients with the potential to preserve their biological fertility.

METHODS:
We examine the history of how men and women have been treated for infertility and analyze contemporary studies of how women without cancer respond to infertility.

RESULTS:
Both female and male cancer patients and survivors value their fertility, although there is conflicting evidence on the degree to which women and men value fertility. Some studies have found that women and men value their fertility equally while others found that women value their fertility more than men. Gendered norms around fertility and parenthood seem to be changing, which may minimize these discrepancies. DISCUSSIONS/

CONCLUSIONS:
Although oncofertility is a nascent field, infertility is a historically relevant medical condition that is characterized by gendered narratives and norms. An analysis of the historical evolution of the understanding and treatment of infertility leads insight into modern conceptualizations of infertility both generally and in the case of cancer. Understanding these historical and current gendered influences helps to define the current context in which cancer patients are confronting potential infertility. IMPLICATIONS FOR CANCER SURVIVORS: The insight gained from this analysis can be used to inform clinical practice, offering guidance to healthcare providers approaching cancer patients about potential infertility, regardless of gender.

Shauna Gardino, Sarah Rodriguez, & Lisa Campo-Engelstein. Journal of Cancer Survivalship, 2010 Dec 31. [Epub ahead of print]

“Fertility preservation treatments can be expensive; cost and the lack of insurance coverage are often the major reasons given by oncologists for why they do not provide information on fertility preservation options to their patients. One method of ensuring people in their reproductive years or children who are diagnosed with cancer have access to and insurance coverage for FPT is to legally treat them as a distinct group from people diagnosed with infertility.”

Basco D, Campo-Engelstein L, and Rodriguez, S. Journal of Law, Medicine, and Ethics.

Abstract

In this report, we investigate the fibrin-alginate interpenetrating network (FA-IPN) to provide dynamic cell-responsive mechanical properties, which we apply to the in vitro growth of ovarian follicles. The mechanical properties and polymerization rate of the gels were investigated by rheology, and the fiber structure was imaged by electron microscopy. Using a mouse model, two-layered secondary follicles were encapsulated in FA-IPNs, and growth, morphology, hormone production, fibrin degradation rate and the numbers of competent eggs were assessed. The initial mechanics of the FA-IPN are determined by the composite material, and subsequent degradation of fibrin by the encapsulated cells would produce a material with mechanical properties due to the alginate alone. The rate of meiotically competent oocytes produced by culture in FA-IPN was 82%, which was significantly greater than in alginate alone. This increase in oocyte quality is an important step in identifying 3D culture systems that can provide a fundamental tool to investigate follicle maturation, and may be applied to promote the growth of human follicles, which can be used to provide reproductive options for women facing a cancer diagnosis.

Ariella Shikanov, Min Xu, Teresa K. Woodruff, Lonnie D. Shea; Biomaterials Vol. 29 5476-85 Oct 30, 2009

Abstract

BACKGROUND:
In vitro follicle growth is a promising fertility preservation strategy in which ovarian follicles are cultured to produce mature and fertilization-competent oocytes. However, in primates, there has been limited success with in vitro follicle growth starting from primordial and primary follicles because adequate isolation methods and culture strategies have not been established. Understanding how to use primordial follicles for fertility preservation has significant implications because these follicles are the most abundant in the ovary, are found in all females and are fairly resistant to cryopreservation and chemotherapeutics.

METHODS:
In the primate ovary, primordial follicles are concentrated near the collagen-rich ovarian cortex. To obtain these follicles, we separated the ovarian cortex prior to enzymatic digestion and enriched the primordial follicle concentration by using a novel double filtration system. To test the hypothesis that a rigid physical environment, as found in vivo, is optimal for survival, primordial follicles were cultured in different concentrations of alginate for up to 6 days. Follicle survival and morphology were monitored throughout the culture.

RESULTS:
We found that primate ovarian tissue can be maintained for up to 24 h at 4°C without compromising tissue or follicle health. Hundreds of intact and viable primordial follicles were isolated from each ovary independent of animal age. Follicle survival and morphology were more optimal when follicles were cultured in 2% alginate compared with 0.5% alginate.

CONCLUSIONS:
By mimicking the rigid ovarian environment through the use of biomaterials, we have established conditions that support primordial follicle culture. These results lay the foundations for studying the basic biology of primordial follicles in a controlled environment and for using primordial follicles for fertility preservation methods.

Hornick JE, Duncan FE, Shea LD, Woodruff TK. Hum Reprod. 2012 Mar 28. PMID: 22456922.

Zoloth, L. Cancer Treatment and Research. 2010; 156: 307-17. PMID: 20811844.

Silber S J. Cancer Treatment and Research. 2010; 156: 471-80. PMID: 20811858.

Letters of Medical Necessity and Appeal to use for Fertility Preservation Procedure Billing to Insurance (Hint: Never use “infertilty” as a diagnosis code!)

Letters of Medical Necessity and Appeal to use for Fertility Preservation Procedure Billing to Insurance (Hint: Never use “infertility” as a diagnosis code!)

Laurie Zoloth, Leilah Backhus, Teresa K. Woodruff, Alyssa Henning, Michal Raucher. The American Journal of Bioethics, 8(6): W3-W5, 2008.

Abstract

OPINION STATEMENT:
Breast cancer effects nearly 200,000 American women each year, with 9% of these women still in their childbearing years. For this subset of future survivors, the issue of fertility may be a significant quality-of-life concern. Both the causes and treatments for infertility in young breast cancer patients must be thoroughly understood by the multidisciplinary team caring for these women in order for the caregivers to be effective advocates for their patients. Radiation, cytotoxic chemotherapy, and hormonal therapy all effect ovarian function to greater or lesser degrees, with the incidence of permanent post-treatment amenorrhea following systemic treatment for breast cancer in women age 50 or younger estimated as between 33% and 76%. The science of fertility preservation continues to experience significant advances in terms of the success of oocyte, embryo, and ovarian tissue preservation, and it is crucial that physicians and patients are aware of the available fertility preservation options. The optimal time to address the possibility of treatment-related infertility and strategies to combat this with younger patients is prior to treatment, rather than after cancer therapy has begun, and a full knowledge of the available technologies is a prerequisite for an informed discussion. Causes of ovarian suppression and options for treatment, including consideration of preimplantation genetic diagnosis and alternative parenting approaches are also discussed to assist the clinician caring for young patients with cancer.

Hulvat MC, Jeruss JS. Curr Treat Options Oncol. 2009 Dec;10(5-6):308-17. Review.

Abstract

OBJECTIVE:
To investigate the effect of slow cryopreservation on the morphology and function of primate primordial follicles within ovarian tissue slices.

DESIGN:
Fresh monkey ovarian tissue was frozen by slow cryopreservation and thawed for analysis of morphologic and functional parameters.

SETTING:
University-affiliated laboratory.

ANIMALS:
Rhesus monkey ovarian tissue.

INTERVENTION(S):
None.

MAIN OUTCOME MEASURE(S):
Histologic analysis, follicle counting, assessment of protein abundance and localization.

RESULT(S):
After freezing and thawing, 89% of the primordial follicles maintained their laminar-based architecture, with sizes close to those of fresh fixed follicles. Molecular markers of early follicle health (activin subunits and the phosphorylated form of the signaling protein Smad2 [pSmad2]) were present in fresh and frozen-thawed primordial follicles. Stroma cells, but not follicles, had a higher level of TUNEL staining. Granulosa cells within the follicles of frozen-thawed ovarian tissue cultured for 48 hours had the capacity to proliferate and sustained expression of the activin subunits and nuclear pSmad2.

CONCLUSION(S):
This study provides evidence that markers of early follicle growth and development are preserved after slow cryopreservation and thaw, with little effect on follicle morphology and function.

Shiying Jin, PhD, Lei Lei, PhD, Lonnie D. Shea, PhD, Mary B. Zelinski, PhD, Richard L. Stouffer, PhD, and Teresa K. Woodruff, PhD. Fertility and Sterility, 2010.

The United States annually spends over  $200 billion on cancer treatment and research. Over the past several decades, tremendous progress has been made in combating this disease.  The five-year survival rate for cancer has increased from thirty-five percent in 1950-1954 to sixty-seven percent in 1996-2004.  Moreover, over the last forty years, survival rates for childhood cancer have risen from twenty percent to eighty-one percent. However, the very success of new and improved therapies has created a host of problems that were not previously considered.  One of the results of the increased rate of post-cancer survival is the commensurate desire of former cancer patients to return to healthy lives, which for many includes having children.’  Unfortunately, for many this desire is difficult to fulfill, because the medication that succeeded in battling cancer is also quite often toxic to the reproductive organs.  Thus, many people are able to live longer lives, yet feel that their lives are incomplete because they became infertile. Whereas in the past fertility was not even part of the discussion when deciding on the proper treatment, now it is a top concern of many newly diagnosed cancer patients…

Gregory Dolin, MD, JD; Dorothy E. Roberts, JD; Lina M. Rodriguez, Teresa K. Woodruff, PhD.  49 Santa Clara L. Rev. 2009

Dolin G, Roberts D E., Rodriguez L M., Woodruff T K. Cancer Treatment and Research. 2010; 156: 111-34. PMID: 20811829.

McLeod, C. Cancer Treatment and Research. 2010; 156: 187-94. PMID: 20811834.

Abstract

Kristin, a 38-year-old female with breast cancer, was scheduled to begin treatment a week after receiving her diagnosis. Although she was in a four-year-long relationship, she had never thought about having kids. Kristin was told that embryo banking (IVF) was the best option for fertility preservation, and she had to decide immediately if she wanted biological children in order to start an egg-retrieval cycle. Because no other options were provided and she was uncertain about freezing embryos with her partner, she ended up foregoing fertility preservation prior to the treatments that ultimately left her infertile. Ethan, a 19-year-old male, was in the hospital for four days awaiting surgery to remove a pelvic sarcoma. The surgery required removal of his testes rendering him infertile. During those four days, no one talked to him or his family about sperm banking, even though it could have been accomplished in a matter of minutes.

Jona K, Gerber A. Cancer Treatment and Research. 2010; 156: 345-61. PMID: 20811846.

Abstract

Cryopreservation of oocytes and embryos is commonly used to preserve fertility. However, women undergoing cancer treatment may not have the time or may not be good candidates for these options. Ovarian cortical tissue cryopreservation and subsequent tissue transplant has been proven successful yet inefficient in preserving larger secondary follicles, and is not recommended as a fertility preservation option for women with certain cancers. We evaluated cryopreservation of individual follicles as an alternative option in rodents, nonhuman primates, and human primates. Under optimal conditions, cryopreserved mouse secondary follicles were able to reestablish granulosa cell-oocyte interactions, which are essential for subsequent follicle growth. Individual secondary follicles survived cryopreservation, were able to be cultured in a three-dimensional alginate hydrogel matrix to the antral stage, and the enclosed oocytes were competent for fertilization. Using a vital imaging technique (pol-scope) employed in many fertility centers, we were able to bioassay the thawed, cultured follicles for the presence of transzonal connections between the somatic and germ cells. Perturbations in these linkages were shown to be reversed when follicles were cryopreserved under optimal freezing conditions. We applied the optimized cryopreservation protocol to isolated rhesus monkey and human secondary follicles, and using the birefringent bioassay, we were able to show good correlation between early follicle growth and healthy somatic cell-oocyte connections. Our results suggest that ovarian follicles can be cryopreserved, thawed, and analyzed noninvasively, making follicle preservation an additional option for young cancer patients.

Susan L. Barrett, Lonnie D. Shea, Teresa K. Woodruff. Biology of Reproduction, 2010.

Abstract:

Cancer treatments can be detrimental to fertility; recent literature has focused on the efforts of fertility preservation for this patient population. It should be recognized, however, that several nonmalignant medical conditions and therapeutic interventions could be similarly hazardous to fertility. Some of these nonmalignant diseases and their treatments that can adversely impact the reproductive axis are gastrointestinal diseases, rheumatologic disorders, nonmalignant hematologic conditions, neurologic disorders, renal disorders, gynecologic conditions, and metabolic diseases. Their negative effects on reproductive function are only now being appreciated and include impaired ovarian function, endocrine function, or sexual function and inability to carry a pregnancy to term. Complications and comorbidities associated with certain diseases may limit the success of established fertility preservation options. Recent advances in fertility preservation techniques may provide these patients with new options for childbearing. Here, we review several fertility-threatening conditions and treatments, describe current established and experimental fertility preservation options, and present three initiatives that may help minimize the adverse reproductive effects of these medical conditions and treatments by raising awareness of the issues and options: (1) increase awareness among practitioners about the reproductive consequences of specific diseases and treatments, (2) facilitate referral of patients to fertility-sparing or restorative programs, and (3) provide patient education about the risk of infertility at the time of diagnosis before initiation of treatment.

Hirshfeld-Cytron J, Gracia C, Woodruff T K. Nonmalignant Diseases and Treatments Associated with Primary Ovarian Failure: An Expanded Role for Fertility Preservation. J Womens Health (Larchmt). 2011 Aug 9. PMID: 21827325

Abstract

The in vitro culture of immature ovarian follicles is used to examine the factors that regulate follicle development and may ultimately provide options for reproductive infertility. The objective of this study was to develop a three-dimensional in vitro culture system for the growth and development of individual granulosa cell-oocyte complexes. An alginate hydrogel was used to encapsulate immature mouse granulosa cell-oocyte complexes (GOCs) that were subsequently maintained in a serum-free in vitro culture. An overall incorporation efficiency of 50% was achieved. The complexes were assessed by transmission electron microscopy for changes in ultrastructure during in vitro growth. The architecture of the follicular complex was maintained during the encapsulation and the subsequent culture. The granulosa cells proliferated, and the oocytes also grew in volume and obtained the structural characteristics of mature oocytes including cortical granule formation, a well-developed zona pellucida with microvilli, normal mitochondria, and lattice-like structures in the cytoplasm. Oocytes retrieved and matured were able to resume meiosis, a necessary step for proper development. Thus, this system represents a new in vitro methodology for growth of individual granulosa cell-oocyte complexes.

Stephanie A. Pangas, Hahhad Saudye, Lonnie D. Shea, and Teresa K. Woodruff; Tissue Engineering Vol. 9 No. 5 1013-1021 2003

Cohn, F. Cancer Treatment and Research. 2010; 156: 249-58. PMID: 20811839.

Summary

Advances in medical technology provide regular opportunities to explore theological reflection and magisterial teaching at the border of science and conscience. This article reflects on one such advance involving fertility preservation for cancer patients. The authors argue that ovarian tissue transplantation (OTT) poses intriguing questions for Catholic teaching and theologians about reproductive technology.

Lauritzen P and Vicini A, S.J. Theological Studies. 2011 (72); 116-30.

Leilah E. Backhus, MD, MS, Laxmi A. Kondapalli, MD, MS, R. Jeffrey Chang, MD, Christos Coutifaris, MD, PhD, Ralph Kazer, MD, and Teresa K. Woodruff, PhD

Acknowledgements:

AUTHORED BY: Ataman, LaurenSmith, Brigid MartzWoodruff, Teresa K
DOI: doi:10.18131/g3-dams-1z38
GRANTS & FUNDING: This work was supported by the Center for Reproductive Health After Disease (P50HD076188) from the National Institutes of Health National Center for Translational Research in Reproduction and Infertility (NCTRI).

Source Link:

https://digitalhub.northwestern.edu/files/1b68450e-37e2-4dbe-8630-3ffc812c3040

Co-editors Clarisa Gracia and Teresa K. Woodruff

Forward by Roger A. Lobo, MD

Part I: Fertility Risks for Cancer Patients

1. Gonadotoxicity of Cancer Therapies in Pediatric and Reproductive-Age Females by Jennifer Levine
2. Gonadotoxicity of Cancer Therapies in Pediatric and Reproductive-Age Males by Jill P. Ginsberg

Part II: Options for Preserving Fertility

1. Fertility Preservation in Males by Robert Brannigan
2. Embryo and Oocyte Banking by Lynn M. Westphal and Jamie A.M. Massie
3. Ovarian Tissue Cryopreservation and Transplantation by Laxmi Kondapalli, MD, MS
4. The Role of In Vitro Maturation in Fertility Preservation by Peter S. Uzelac, Greg L. Christiansen, and Steven T. Nakajima
5. Mitigating the Risk: The Role of Ovarian Transposition and Medical Suppression by Jaime M. Knopman and Nicole Noyes

Part III: Care of the Oncofertility Patient

1. The Birds and the Bees and the Bank: Talking With Families About Future Fertility Amidst a Cancer Diagnosis by Gwendolyn P. Quinn, Caprice A. Knapp, and Devin Murphy
2. Addressing the Three Most Frequently Asked Questions of a Bioethicist in an Oncofertility Setting by Lisa Campo-Engelstein
3. Pregnancy in Cancer Survivors and Patients by Eileen Wang
4. Communication Between Oncofertility Providers and Patients by Jennifer Mersereau

Part IV: Oncofertility in Clinical Practice

1. Setting up an Oncofertility Program by H. Irene Su, Lindsay Ray, and R. Jeffery Chang
2. Patient Navigation and Coordination of Care for the Oncofertility Patient: A Practical Guide by Kristin Smith, Brenda Efymow, and Clarisa Gracia
3. Preparing an Interdisciplinary Workforce in Oncofertility – A suggested educational and research training program by Christos Coutifaris

Part V: Clinical Cases in Oncofertility and Resources

1. Clinical Cases in Oncofertility by Clarisa Gracia

Appendices – Oncofertility Resources for the Clinician by Kate E. Waimey

1. Appendix A. Sample IRB Protocol: Ovarian Tissue Freezing For Fertility Preservation In Women Facing a Fertility Threatening Medical Diagnosis Or Treatment Regimen
2. Appendix B. Sample Consent Form: Ovarian Tissue Freezing For Fertility Preservation In Adult Women Facing A Fertility Threatening Medical Diagnosis Or Treatment Regimen
3. Appendix C. Sample IRB Protocol: Oocyte Banking For Fertility Preservation In Women Facing A Fertility Threatening Medical Diagnosis Or Treatment Regimen
4. Appendix D. Sample Consent Form: Oocyte Banking For Fertility Preservation In Women Facing A Fertility Threatening Medical Diagnosis Or Treatment Regimen
5. Appendix E. Letter Template: Provider Letter of Medical Necessity for Fertility Preservation Procedures
6. Appendix F. Letter Template: Patient Letter of Appeal for Fertility Preservation Procedures Template
7. Appendix G. Updating or Establishing Your FDA Registration