Oncofertility Publications

Abstract

Scholars have shown that organ transplantation may transform ideas about one’s body, with recipients feeling that they are receiving not just a body part but also a part of the donor’s identity. This article focuses on a different way in which organ transplantation shapes recipient identity: the idea of becoming whole. We present the case studies of two women separated by a century (one in 1902 and the other in 2004) who sought ovarian transplantation, and examine how ovarian transplantation can engender a sense of wholeness on the individual, the familial, and the cultural levels, due to its ability to enable a recipient to naturally conceive and experience pregnancy.

Rodriguez S, Campo-Engelstein L. Conceiving Wholeness: Women, Motherhood, and Ovarian Transplantation, 1902-2004. Perspect Biol Med. 2011;54(3):409-16. PMID: 21857130

Abstract

OBJECTIVE:
To identify whether a health-related quality of life (HRQoL) instrument intended to capture reproductive concerns is sensitive and appropriate for adolescent patients with cancer.

METHODS:
Pilot testing was completed by administering a 10-item instrument designed to identify reproductive concerns of female adolescent patients with cancer aged 12-18. Parents were also asked to predict their daughters’ responses. Fourteen patients and parents participated. The main outcome measures were language, relevance, accuracy, sensitivity, and missing content regarding the HRQoL instrument. Two pediatric hospitals and 1 local support group for patients and survivors served as the setting for this study.

RESULTS:
The majority of parents provided inaccurate predictions of their daughters’ responses regarding their reproductive concerns. Overall, parents underestimated their daughters’ concerns because the majority of adolescents reported a strong desire for future parenthood whereas parents expected their daughters to be satisfied with survivorship.

CONCLUSIONS:
Adolescent patients with cancer have strong reproductive concerns; however, this may not be captured on current HRQoL instruments and may be further neglected due to parents’ unawareness. Discussions should be encouraged with adolescent patients before beginning treatment regarding their concerns and values about parenting in the future and cannot rely on parent-proxy reports.

Quinn GP, Knapp C, Murphy D, Sawczyn K, Sender L. Pediatrics. 2012 Apr;129(4):e930-6. Epub 2012 Mar 19. PMID: 22430446.

Lisa Campo-Engelstein. Journal of Clinical Oncology, Vol. 28, 2010.

Jungheim E S., Carson K R., Brown D. Cancer Treatment and Research. 2010; 156: 403-12. PMID: 20811851.

Abstract

Cancer therapy can be lifesaving but significantly diminish female reproductive potential. This review provides an overview of the deleterious effects of cancer treatments on reproductive function, the fertility preservation options currently available for young women, and the outcomes of pregnancy after cancer treatment. In addition, special considerations for women who are diagnosed with cancer during pregnancy are discussed. To optimize the continuum of care for the patient, new corridors of communication between obstetricians, gynecologists, and oncology specialists must be developed to ensure the best outcomes for the patient, both in terms of cancer treatment and fertility preservation.

Kong, BY, Skory RM, Woodruff TK. Clinical Obstetrics and Gynecology; Issue: Volume 54(4), December 2011, p 619–632.

This article explores how 70 younger women diagnosed with breast cancer draw on social support resources. The authors found that most respondents’ core support networks were their families, and social support came in several forms including emotional, tangible, and informational. However, the authors also found that many respondents relied on a distinct form of social support, experiential support, which has not been identified in current research. Experiential support is defined as a relationship with someone who has gone through a similar illness and can help provide firsthand information, insight, and even hope. The authors conclude that experiential support is an important area for future research on social support and health outcomes.

Snyder, KA, and Pearse, W. Journal of Psychosocial Oncology. 28:413-431,2010.

The stage at which follicle-enclosed cumulus-oocyte complexes achieve developmental competence in primates is unknown. Therefore, studies were designed to characterize the ability of oocytes in small antral follicles present during the menstrual cycle to spontaneously resume meiosis, fertilize, and support early embryo development. Ovaries were removed from adult rhesus monkeys (n = 12) during the early follicular phase (Days 3-4) of spontaneous cycles. Small antral follicles were divided into five groups according to their diameter; group I: <0.5 mm; group II: 0.5-0.99 mm; group III: 1.0-1.49 mm; group IV: 1.5-1.99 mm; and group V: 2.0-2.5 mm. The cumulus-oocyte complex from healthy small antral follicles (devoid of dark oocytes or granulosa cells) were extracted (n = 199) and cultured for 48 h under different conditions: in TALP (tyrode, albumin, lactate, pyruvate) medium alone, SAGE medium alone, or plus gonadotropins. At 48 h, oocyte meiotic status and diameter were measured after treatment of cumulus-oocyte complexes with hyaluronidase. Cumulus-oocyte complexes derived from follicles of 0.5- to 2-mm diameter contain oocytes that typically reinitiate meiosis in the absence or presence of gonadotropins and fertilize via in vitro fertilization or intracytoplasmic sperm injection. Moreover, the inseminated oocytes can reach the morula stage but arrest. Thus, the ability of these oocytes to complete maturation, as monitored from subsequent embryonic development after fertilization, is suboptimal. Further studies on primate IVM of oocytes from SAFs are warranted in order for them to be considered as an additional, novel source of gametes for fertility preservation in cancer patients. Peluffo MC, Barrett SL, Stouffer RL, Hennebold JD, Zelinski MB. Biol Reprod 83:525-532, 2010. PMID 20519694.

Abstract

BACKGROUND:
Female cancer patients are offered ‘banking’ of gametes before starting fertility-threatening cancer therapy. Transplants of fresh and frozen ovarian tissue between healthy fertile and infertile women have demonstrated the utility of the tissue banked for restoration of endocrine and fertility function. Additional methods, like follicle culture and isolated follicle transplantation, are in development. METHODS Specialist reproductive medicine scientists and clinicians with complementary expertise in ovarian tissue culture and transplantation presented relevant published literature in their field of expertise and also unpublished promising data for discussion. As the major aims were to identify the current gaps prohibiting advancement, to share technical experience and to orient new research, contributors were allowed to provide their opinioned expert views on future research. RESULTS Normal healthy children have been born in cancer survivors after orthotopic transplantation of their cryopreserved ovarian tissue. Longevity of the graft might be optimized by using new vitrification techniques and by promoting rapid revascularization of the graft. For the in vitro culture of follicles, a successive battery of culture methods including the use of defined media, growth factors and three-dimensional extracellular matrix support might overcome growth arrest of the follicles. Molecular methods and immunoassay can evaluate stage of maturation and guide adequate differentiation. Large animals, including non-human primates, are essential working models. CONCLUSIONS Experiments on ovarian tissue from non-human primate models and from consenting fertile and infertile patients benefit from a multidisciplinary approach. The new discipline of oncofertility requires professionalization, multidisciplinarity and mobilization of funding for basic and translational research.

J. Smitz, M.M. Dolmans, J. Donnez, J.E. Fortune, O. Hovatta, K. Jewgenow, H.M. Picton, C. Plancha, L.D. Shea, R.L. Stouffer, E.E. Telfer, T.K. Woodruff, and M.B. Zelinski. Human Reproduction Update, 2010.

J. Smitz,11,†, M.M. Dolmans, J. Donnez, J.E. Fortune, O. Hovatta, K. Jewgenow, H.M. Picton, C. Plancha, L.D. Shea, R.L. Stouffer, E.E. Telfer, T.K. Woodruff, and M.B. Zelinski. Human Reproduction Update, Vol.16, No.4 pp. 395–414, 2010.

Smith, R M., Woodruff T K., Shea L D. Cancer Treatment and Research. 2010; 156: 11-24. PMID 20811822.

Acknowledgements:

AUTHORED BY: Woodruff, Teresa K
DOI: doi:10.18131/g3-k3fd-5d89
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/10014f57-93aa-4fe1-bc0b-7444813e9b3a

Snyder K, Pearse W. J American Medical Association.2011;306 (2): 202-203. 

Jeruss J S. Cancer Treatment and Research. 2010; 156: 461-6. PMID: 20811855.

Summary

Lisa Campo-Engelstein and Kiran Sreenivas argue that in order for cancer patients to make informed choices about fertility preservation, they should be made aware of surrogacy as an option of having biological children and the challenges that accompany this choice. They examine the availability of surrogacy to cancer patients and provide an overview of both domestic and international surrogacy laws. Finally, they discuss surrogacy tourism as an option for cancer survivors and underscore the importance of fully informing cancer patients about surrogacy, including potential legal barriers in utilizing it, before they make fertility preservation decisions prior to cancer treatment.

Sreenivas K, Campo-Engelstein L. Cancer Treatment and Research. 2010; 156: 135-52. PMID: 20811830.

Abstract

BACKGROUND:
Extracellular activation of signal transduction pathways and their downstream target transcription factors (TFs) are critical regulators of cellular processes and tissue development. The intracellular signaling network is complex, and techniques that quantify the activities of numerous pathways and connect their activities to the resulting phenotype would identify the signals and mechanisms regulating tissue development. The ability to investigate tissue development should capture the dynamic pathway activity and requires an environment that supports cellular organization into structures that mimic in vivo phenotypes. Taken together, our objective was to develop cellular arrays for dynamic, large-scale quantification of TF activity as cells organized into spherical structures within 3D culture.

METHODOLOGY/PRINCIPAL FINDINGS:
TF-specific and normalization reporter constructs were delivered in parallel to a cellular array containing a well-established breast cancer cell line cultured in Matrigel. Bioluminescence imaging provided a rapid, non-invasive, and sensitive method to quantify luciferase levels, and was applied repeatedly on each sample to monitor dynamic activity. Arrays measuring 28 TFs identified up to 19 active, with 13 factors changing significantly over time. Stimulation of cells with β-estradiol or activin A resulted in differential TF activity profiles evolving from initial stimulation of the ligand. Many TFs changed as expected based on previous reports, yet arrays were able to replicate these results in a single experiment. Additionally, arrays identified TFs that had not previously been linked with activin A.

CONCLUSIONS/SIGNIFICANCE:
This system provides a method for large-scale, non-invasive, and dynamic quantification of signaling pathway activity as cells organize into structures. The arrays may find utility for investigating mechanisms regulating normal and abnormal tissue growth, biomaterial design, or as a platform for screening therapeutics.

Weiss MS, Peñalver Bernabé B, Bellis AD, Broadbelt LJ, Jeruss JS, Shea LD. PLoS One. 2010 Nov 17;5(11):e14026.PMID: 21103341

Synopsis

Breast cancer development involves a series of mutations in a heterogeneous group of proto-oncogenes/tumor suppressor genes that alter mammary cells to create a microenvironment permissive to tumorigenesis. Exposure to hormones during infertility treatment may have a mutagenic effect on normal mammary epithelial cells, high-risk breast lesions and early-stage breast cancers. Our goal was to understand the association between infertility treatment and normal and cancerous breast cell proliferation.

Cooley A, Matthews L, Zelivianski S, Hardy A, and Jeruss J.S. Human Reproduction, Vol.0, No.0 pp. 1–7, 2011.

Abstract

Hydrogel-encapsulating culture systems support the consistent growth of ovarian follicles from various species, such as mouse, non-human primate, and human; however, further innovations are required for the efficient production of quality oocytes from early-stage follicles. In this report, we investigated the coculture of mouse ovarian follicles with mouse embryonic fibroblasts (MEFs), commonly used as feeder cells to promote the undifferentiated growth of embryonic stem (ES) cells, as a means to provide the critical paracrine factors necessary for follicle survival and growth. Follicles were encapsulated within alginate hydrogels and cocultured with MEFs for 14 days. Coculture enabled the survival and growth of early secondary (average diameter of 90-100 μm) and primary (average diameter of 70-80 μm) follicles, which developed antral cavities and increased in diameter to 251-347 μm. After 14 days, follicle survival ranged from 70% for 100-μm follicles to 23% for 70-μm follicles. Without MEF coculture, all follicles degenerated within 6-10 days. Furthermore, 72%-80% of the oocytes from surviving follicles underwent germinal vesicle breakdown (GVBD), and the percentage of metaphase II (MII) eggs was 41%-69%. Medium conditioned by MEFs had similar effects on survival, growth, and meiotic competence, suggesting a unidirectional paracrine signaling mechanism. This advancement may facilitate the identification of critical factors responsible for promoting the growth of early-stage follicles and lead to novel strategies for fertility preservation.

Tagler D, Tu T, Smith RM, Anderson NR, Tingen CM, Woodruff TK, Shea LD. Tissue Eng Part A. 2012 Mar 2. PMID: 22296562.

Abstract

In vitro ovarian follicle cultures may provide fertility-preserving options to women facing premature infertility due to cancer therapies. An encapsulated three-dimensional (3-D) culture system utilizing biomaterials to maintain cell-cell communication and support follicle development to produce a mature oocyte has been developed for the mouse. We tested whether this encapsulated 3-D system would also support development of nonhuman primate preantral follicles, for which in vitro growth has not been reported. Three questions were investigated: Does the cycle stage at which the follicles are isolated affect follicle development? Does the rigidity of the hydrogel influence follicle survival and growth? Do follicles require luteinizing hormone (LH), in addition to follicle-stimulating hormone (FSH), for steroidogenesis? Secondary follicles were isolated from adult rhesus monkeys, encapsulated within alginate hydrogels, and cultured individually for </=30 days. Follicles isolated from the follicular phase of the menstrual cycle had a higher survival rate (P < 0.05) than those isolated from the luteal phase; however, this difference may also be attributed to differing sizes of follicles isolated during the different stages. Follicles survived and grew in two hydrogel conditions (0.5% and 0.25% alginate). Follicle diameters increased to a greater extent (P < 0.05) in the presence of FSH alone than in FSH plus LH. Regardless of gonadotropin treatment, follicles produced estradiol, androstenedione, and progesterone by 14-30 days in vitro. Thus, an alginate hydrogel maintains the 3-D structure of individual secondary macaque follicles, permits follicle growth, and supports steroidogenesis for </=30 days in vitro. This study documents the first use of the alginate system to maintain primate tissue architecture, and findings suggest that encapsulated 3-D culture will be successful in supporting the in vitro development of human follicles.

Min Xu, Erin R. West-Farrell, Richard L. Stouffer, Lonnie D. Shea, Teresa K. Woodruff, and Mary B. Zelinski; Biology of Reproduction(3):587-94 Sep.8, 2009

Abstract

In vitro ovarian follicle culture provides a tool to investigate folliculogenesis, and may one day provide women with fertility-preservation options. The application of tissue engineering principles to ovarian follicle maturation may enable the creation of controllable microenvironments that will coordinate the growth of the multiple cellular compartments within the follicle. Three-dimensional culture systems can preserve follicle architecture, thereby maintaining critical cell-cell and cell-matrix signaling lost in traditional two-dimensional attached follicle culture systems. Maintaining the follicular structure while manipulating the biochemical and mechanical environment will enable the development of controllable systems to investigate the fundamental biological principles underlying follicle maturation. This review describes recent advances in ovarian follicle culture, and highlights the tissue engineering principles that may be applied to follicle culture, with the ultimate objective of germline preservation for females facing premature infertility.

Erin R. West, Lonnie D. Shea, and Teresa K. Woodruff; Semin Reproduction Med. Vol 25 No 4 287-99 July 2007

Gracia C R., Gracia J J., Chen S. Cancer Treatment and Research. 2010; 156: 195-208. PMID: 20811835.

Abstract

The extracellular matrix (ECM) promotes and/or inhibits many cellular processes, including but not limited to proliferation, differentiation, and survival, which must occur for follicle growth and oocyte maturation. The ECM regulation of cellular processes in ovarian cells is being investigated in many animal models, including avian, rat, bovine, porcine, rabbit, sheep, human, and mouse. Granulosa cells are more frequently employed; however, the culture of intact follicles and ovaries has been developed and enables ECM functions in folliculogenesis to be studied. ECM components that have been examined are used individually (collagen, laminin, fibronectin) or collectively (Matrigel, isolated basal lamina, and ECM produced by cell lines) in both two- and three-dimensional model systems. In granulosa cell cultures, ECM affects morphology, aggregation and communication, survival, proliferation, and steroidogenesis; whereas follicle and ovary cultures demonstrate a regulation of folliculogenesis. This article describes the ECM functionality on ovarian cells throughout development, and highlights the potential of developing technologies to identify structure-function relationships in follicle maturation.

Courtney B. Berkholtz, Lonnie D. Shea, and Teresa K. Woodruff; Semin Reproducion Med Vol 24 No 4 262-9 Sep 2006