Oncofertility Publications

Abstract

The ovarian follicle is the functional unit of the ovary that secretes sex hormones and supports oocyte maturation. in vitro follicle techniques provide a tool to model follicle development in order to investigate basic biology, and are further being developed as a technique to preserve fertility in the clinic1-4. Our in vitro culture system employs hydrogels in order to mimic the native ovarian environment by maintaining the 3D follicular architecture, cell-cell interactions and paracrine signaling that direct follicle development 5. Previously, follicles were successfully cultured in alginate, an inert algae-derived polysaccharide that undergoes gelation with calcium ions6-8. Alginate hydrogels formed at a concentration of 0.25% w/v were the most permissive for follicle culture, and retained the highest developmental competence 9. Alginate hydrogels are not degradable, thus an increase in the follicle diameter results in a compressive force on the follicle that can impact follicle growth10. We subsequently developed a culture system based on a fibrin-alginate interpenetrating network (FA-IPN), in which a mixture of fibrin and alginate are gelled simultaneously. This combination provides a dynamic mechanical environment because both components contribute to matrix rigidity initially; however, proteases secreted by the growing follicle degrade fibrin in the matrix leaving only alginate to provide support. With the IPN, the alginate content can be reduced below 0.25%, which is not possible with alginate alone 5. Thus, as the follicle expands, it will experience a reduced compressive force due to the reduced solids content. Herein, we describe an encapsulation method and an in vitro culture system for ovarian follicles within a FA-IPN. The dynamic mechanical environment mimics the natural ovarian environment in which small follicles reside in a rigid cortex and move to a more permissive medulla as they increase in size11. The degradable component may be particularly critical for clinical translation in order to support the greater than 106-fold increase in volume that human follicles normally undergo in vivo.

Shikanov A., Xu M., Woodruff T.K., Shea L.D. (). A Method for Ovarian Follicle Encapsulation and Culture in a Proteolytically Degradable 3 Dimensional System. JoVE. http://www.jove.com/details.php?id=2695&access=ugoti9et

Abstract

OBJECTIVE: To develop an in vitro strategy to support the growth of early-stage follicles and produce mature oocytes competent for fertilization.

DESIGN: Whole ovaries from 8-day-old mice were cultured for 4 days, and then secondary follicles were isolated and cultured for 12 days in a three-dimensional alginate or fibrin-alginate (FA) hydrogel matrix.

SETTING: University-affiliated laboratory.

ANIMALS: Mice.

INTERVENTION(S): None.

MAIN OUTCOME MEASURES: Histologic evaluation of follicle development, steroid hormone production, and rates of oocyte maturation, oocyte fertilization, and embryo formation.

RESULT(S): Culture of 8-day-old mouse ovaries for 4 days resulted in transition of the follicle population from primordial and primary follicles to secondary follicles, similar to that seen in a 12-day-old ovary. Isolated secondary follicles cultured for 12 days showed larger increases in oocyte diameter and more frequent antrum formation and theca cell differentiation in the FA-hydrogel matrix compared with the alginate matrix. Steroid hormone secretion patterns were consistent with the changes in follicle morphology and cell differentiation observed in the cultured follicles. Compared with oocytes from alginate follicle cultures, a greater number of oocytes retrieved from the FA-based follicle cultures progressed to metaphase I, reached metaphase II, and could be fertilized and cleaved to two-cell embryos. The organ culture plus FA-hydrogel follicle culture strategy produced a very high rate of oocyte progression to metaphase II (88 +/- 8.7% [mean +/- SEM]) and formation of two-cell embryos (54 +/- 4%).

CONCLUSION(S): A strategy combining whole ovary culture of early-stage follicles and subsequent FA hydrogel in vitro follicle culture produced a high percentage of oocytes competent for fertilization; this might provide new options for fertility preservation in women and prepubertal girls facing fertility-threatening diseases or treatments.

Shi Ying Jin, Lei Lei, Ariella Shikanov, Lonnie D. Shea, and Teresa K. Woodruff; Fert. Ster. ePub ahead of print. 2010

Shnorhavorian M. Cancer Treatment and Research. 2010; 156: 485. PMID: 20811860.

Abstract:

Resource wealth or absence defines access to many fields of science and medicine; the emerging field of oncofertility is one prime example of this resource and access dilemma. At the intersection of life and death, where life-limiting and life-producing events cross paths, the implicit contradictions of cancer and fertility have left men and women with limited choices, until recently. As the field of oncofertility expands, it was realized that many intellectual and practice based resource issues have equal or greater impact on access to care as insurance and reimbursement. Indeed, the contrasting emotions and expectations of practitioners and patients, together with a continued paucity of scientific knowledge about fertility in the cancer setting and the lack of clinical assessment of reproductive outcomes for adolescents and young adults, represent some of the boundary conditions to increase access to oncofertility. When these barriers are scaled up to the global setting, the need for advocacy and leadership from multiple organizations and individuals becomes urgent. To better understand this uniquely defined resource landscape, we conducted an analysis of the strengths, weaknesses, opportunities, and threats (SWOT) faced by global oncofertility a SWOT analysis to better understand the current state of the field and to create multimodal interventions that may provide a roadmap for the future of this discipline.

Acknowledgments:

AUTHORED BY: Woodruff, Teresa KCampo-Engelstein, LisaAlmeida-Santos, Teresa
DOI: doi:10.18131/g3-8379-g677
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/7f794595-230e-48a0-aee1-d92f567d09a7

Gardino S L., Russel A E., Woodruff T K. Cancer Treatment and Research. 2010; 156: 153-70. PMID: 20811831.

Abstract

Increases in the number of adult cancer survivors and other issues have forced the oncology community to examine, evaluate, and alter the cancer care paradigm. Pediatric oncologists are grappling with the task of transitioning a growing population of adult survivors of childhood cancer to adult medicine, while oncologists caring for adult cancer survivors are seeking models of follow-up care that are acceptable to patients and providers. Workforce and access-to-care issues suggest that primary care providers will see more cancer survivors in their practices across time, although it is unclear how prepared they are for this task. Translational research is needed to develop evidence-based clinical care and survivorship care plans. A broad picture of the evolving field of adult cancer survivorship is presented. The recent focus on young adult survivors of childhood cancer, an overview of translational research needed to inform the physical and psychosocial care of cancer survivors, and the roles of primary and specialty care providers managing this population is examined. Finally, an overview of evolving treatment summary and care plan initiatives is presented.

Jacobs LA, Palmer SC, Schwartz LA, DeMichele A, Mao JJ, Carver J, Gracia C, Hill-Kayser CE, Metz JM, Hampshire MK, Vachani C, Pucci D, Meadows AT. CA Cancer J Clin. 2009 Nov-Dec;59(6):391-410.

Abstract

BACKGROUND:
Ovarian tissue cryopreservation is an emerging fertility preservation option, and culturing follicles isolated from this tissue to obtain mature gametes may ultimately be the best solution for patients for whom transplantation is contraindicated. It is unclear, however, how patient-specific variables (including age, weight and menstrual cycle stage) impact follicle growth and quality during three-dimensional culture.

METHODS:
We used a mouse model to systematically determine how these variables impact in vitro follicle growth. We characterized metabolic and hormonal profiles of mice at specific ages, weights and cycle stages and secondary follicles from these cohorts were isolated and cultured. We then assessed follicle survival, growth and function, as well as meiotic competence and spindle morphology of the resulting oocytes.

RESULTS:
We found that older mice and mice with increased body weight had higher serum cholesterol, abnormal glucose tolerance and lower levels of circulating Anti-Müllerian hormone compared with younger and leaner controls. Secondary follicles isolated from different cohorts and grown in vitro had indistinguishable growth trajectories. However, the follicles isolated from older and heavier mice and those in diestrus had altered hormone profiles. These follicles contained oocytes with reduced meiotic competence and produced oocytes with greater spindle defects.

CONCLUSIONS:
These results suggest that the original physical environment of the follicle within the ovary can impact its function when isolated and cultured. These findings are valuable as we begin to use in vitro follicle growth technology for a heterogeneous fertility preservation patient population.

Hirshfeld-Cytron JE, Duncan FE, Xu M, Jozefik JK, Shea LD, Woodruff TK. Hum Reprod. 2011 Sep;26(9):2473-85. Epub 2011 Jun 13. PMID: 21669966

Gardino S L., Sfekas A, Dranove D. Cancer Treatment and Research. 2010; 156: 363-70. PMID 20811847.

Abstract

BACKGROUND:
In late reproductive-aged breast cancer survivors, there is a need for real-time biomarkers of postchemotherapy ovarian function. The objective was to determine whether antimullerian hormone (AMH) and inhibin B are such biomarkers. The authors tested whether AMH and inhibin B were impacted by breast cancer treatment by comparing cancer survivors to age-matched control women and determined the association between these hormones and postchemotherapy menstrual pattern.

METHODS:
Breast cancer patients (n = 127) with American Joint Committee on Cancer stage I to III disease who were premenopausal at diagnosis were enrolled postchemotherapy and observed. The primary endpoint was chemotherapy-related amenorrhea (CRA) (> or = 12 months of amenorrhea after chemotherapy). Matched pair analyses compared AMH, inhibin B, and follicle-stimulating hormone (FSH) levels between cancer and age-matched control subjects. Associations between hormones, CRA status, and change in CRA status over time were assessed.

RESULTS:
The median age of the patients at chemotherapy was 43.2 years (range, 26.7-57.8 years). At enrollment, median follow-up since chemotherapy was 2.1 years, and 55% of subjects had CRA. Compared with age-matched controls, cancer subjects had significantly lower AMH (P = .004) and inhibin B (P < .001) and higher FSH (P < .001). AMH (P = .002) and inhibin B (P = .001) were found to be significantly associated with risk of CRA, even after controlling for FSH. AMH was significantly lower (P = .03) and FSH was significantly higher (P = .04) in menstruating subjects who developed subsequent CRA.

CONCLUSIONS:
AMH and inhibin B are 2 additional measures of postchemotherapy ovarian function in late reproductive-aged breast cancer survivors. With further research and validation, these hormones may supplement limited current tools for assessing and predicting postchemotherapy ovarian function.

Su HI, Sammel MD, Green J, Velders L, Stankiewicz C, Matro J, Freeman EW, Gracia CR, Demichele A. Cancer. 2009 Nov 13.

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

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

Abstract:

Turner syndrome (TS) is the most common sex chromosome disorder. A hallmark clinical feature of TS is early ovarian failure, which severely decreases a womans chances of achieving natural pregnancy. Ovarian tissue cryopreservation, an experimental fertility preservation process, may provide women with TS another reproductive option. This study explored the attitudes of the Turner syndrome community regarding possible issues surrounding fertility preservation.

Acknowledgments:

AUTHORED BY: Gaber, Rikki
DOI: doi:10.18131/g3-81vk-1m98
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/28201f5d-8f20-4d1c-add3-409ca6f061a5

Abstract:

Fertility preservation attitudes and perceptions have been widely studied among male and female cancer survivors as well as oncologists and reproductive specialists. Currently there is little information available on the perceptions and attitudes of partners on fertility preservation and cancer. The object of this study is to investigate attitudes and perceptions towards fertility preservation among cancer survivor partners, as well as evaluate partner influence and additional factors that impact FP decision-making.

Acknowledgments:

AUTHORED BY: Frome, KendraGoetsch, Allison LouiseWicklund, Catherine AHutten Selkirk, Christina GWoodruff, Teresa K
DOI: doi:10.18131/g3-rwwc-g486
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/11306426-f23a-4db9-bb68-b49f43362d41

Abstract

Purpose:
To investigate attitudes and perceptions towards fertility preservation (FP) among cancer survivor partners, as well as evaluate partner influence and additional factors that impact decision-making in pursuing FP.

Methods:
Partners (n = 50) of cancer survivors and fighters were recruited to take an online survey through nine cancer support organizations. Cancer survivors and fighters were invited to share the link with their partner. Survey question themes included attitudes towards FP, partner perceptions of the level of influence they have on the patient’s decision to pursue FP, and partner perspectives of the different factors that play a role in their decision to engage in FP.

Results:
Almost all (98%) of partners thought FP was an acceptable family building option. Seventy-seven percent of partners were present at the time of the patient’s treatment options discussion, and 66% of partners said that they received information about the patient’s FP options. Half of partners (52%) felt they received enough FP information and the majority of partners (66%) were interested in learning more about FP. Eighty-three percent of partners said that the patient discussed the option of FP with them before making a decision. When asked what factors would play a role in the decision to pursue or not to pursue FP, partners said that desire for future children (86%) and safety of FP timing with cancer (81%) were the most influential factors.

Conclusion:
Partners play an active role in the FP decision-making process. Our findings support the involvement and participation of partners in the FP discussions.

Kendra Frome, BS, Allison Goetsch , MS, Cathy Wicklund , MS, Christina G Hutten Selkirk , MS, and Teresa K Woodruff , PhD

Zoloth, L and Henning A A. Cancer Treatment and Research. 2010; 156: 261-78. PMID: 20811840.

Shulman L P., Dungan J S. Cancer Treatment and Research. 2010; 156: 69-85. PMID: 20811826.

Acknowledgments:

AUTHORED BY: Ataman, LaurenSmith, Brigid MartzWoodruff, Teresa K
DOI: doi:10.18131/g3-a6hd-t246
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/1aaa14ed-50b0-4c3c-a249-d088b8424a1d

Quinn GP. Challenges Conducting Qualitative Psychosocial Research for Adolescent and Young Adult Patients and Survivors. (2011) Journal of Adolescent and Young Adult Oncology 1, 2, 71-76.

Gardino S L., Emanuel L L. Cancer Treatment and Research. 2010; 156: 447-58. PMID: 20811854.

Kondapalli L A., Hong F, Gracia C R. Cancer Treatment and Research. 2010; 156: 55-67. PMID 20811825

Abstract:

In generating a communication strategy for The Oncofertility Consortium, we used three general guiding principles; presented here as tactics that may have value in other areas of our field. First, technology implementation and delivery is a collaboration between people, ideas, the message and infrastructure. Secondly, methods and tactics should match the need. Third, creation of a robust, interdisciplinary intellectual environment depends upon establishment of a common language between scientists, clinicians,scholars, patients and practitioners. While the needs and expectations of the medical enterprise (patient and provider), research enterprise and community-facing activities vary greatly, the tactics and methods below were integrated into a seamless product that provides value to the field. Investments of intellectual time and tangible dollars in this kind of work is paramount to increasing the pace, quality and reach of the work. If we,as a field, limit our research to publications in Biology of Reproduction, we will only reach a limited audience. If we wish to ensure translations of our work and ideas to the clinical setting, and if we wish to engage the public in the work that is supported by taxpayer dollars, new tactics are required. The following is a short description of the ways in which these concepts were put into practice in the development of the Oncofertility Consortium and the National Physicians Cooperative (NPC), the scientists and the practitioners providing fertility options to young cancer patients, respectively. The purpose of this editorial is to provide food for thought on how other reproductive science endeavors can be catalyzed by integrating technology into their work.

Acknowledgments:

AUTHORED BY: Woodruff, Teresa K
DOI: doi:10.18131/g3-7pr4-r416
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/50abe4ff-81d9-40ab-bafd-24d68b1d9c40