Oncofertility Publications

Asch A. Cancer Treatment and Research. 2010; 156: 181-6. PMID: 20811833.

Abstract

Folliculogenesis is a coordinated process, and the genes that regulate development are difficult to investigate in vivo. In vitro culture systems permit the assessment of individual follicles during development, thereby enabling gene expression patterns to be monitored during follicle development. Mouse multilayered secondary follicles (150-180 microm in diameter) were cultured in three-dimensional matrices of varying physical properties for up to 8 days. During this period of follicle growth in vitro, antrum formation and steroid production were monitored, and mRNA was isolated. The expression levels of genes (Star, Cyp11a1, Cyp17a1, Hsd3b1, Cyp19a1, Fshr, Lhcgr, Aqp7, Aqp8, Aqp9, and Hif1a) were measured and correlated to follicle developmental status. Follicles that developed an antrum and produced appropriate levels of estrogen and progesterone had unchanging expression of Star, Aqp7, Aqp8, and Hif1a and a 34-fold increase in Cyp19a1 expression at Day 8 of culture and had elevated Lhcgr at Days 6 and 8 of culture. Follicles that were healthy but did not form an antrum or produce appropriate levels of steroids, however, demonstrated increasing levels of Star, Aqp7, Aqp8, and Hif1a and a 15-fold increase in Cyp19a1 at Day 8 of culture, and Lhcgr levels were not elevated until Day 8 of culture. To our knowledge, this study provides the first temporal analysis of gene expression using individual culture in alginate hydrogels that correlates growth and steroidogenesis during follicle development and identifies expression patterns in healthy follicles and in developmentally disadvantaged follicles.

Erin R. West-Farrell, Min Xu, Monica A. Gomberg, Yee Hoong Chow, Teresa K. Woodruff, and Lonnie D. Shea; BIOLOGY OF REPRODUCTION 80, 432–439 (2009)

Abstract

The number of young cancer survivors is increasing owing to advances in cancer therapeutics, but many face infertility as a result of their treatment. Technologies that already exist for cancer patients concerned about their future fertility include sperm banking for men and hormonal intervention followed by in vitro fertilization and embryo cryopreservation for women. However, logistical barriers to timely patient referral and coordination of care between specialties can limit patient access to all the available options. Moreover, there are few alternatives for young women and girls who cannot delay their cancer treatment, or who are unable to undergo hormonal intervention. The Oncofertility Consortium is a network of researchers, physicians and scholars who are advancing fertility preservation options for young cancer patients. Research into the societal, ethical, and legal implications is also an important part of the work performed by the Oncofertility Consortium, which is providing new perspectives on patient decision-making about how to access these emerging reproductive technologies. Experts in the fields of oncology, reproductive medicine, the social sciences, law, education, and the humanities are working together to develop next-generation reproductive interventions and promote communication between scholars, clinicians, patients, and the public to ensure that young cancer patients are equipped with the most appropriate information and options for having a family in the future.

Woodruff, T. K. Nat. Rev. Clin. Oncol. 7, 466–475. 2010.

Faurot M, Woodruff TK. Cancer Treatment and Research. 2010; 156; 321-44. PMID: 20811845.

Abstract

The creation of the pool of follicles available for selection and ovulation is a multi-faceted, tightly regulated process that spans the period from embryonic development through to the first reproductive cycle of the organism. In mice, this development can occur in mere weeks, but in humans, it is sustained for years. Embryonic germ cell development involves the migration of primordial germs cells to the genital ridge, and the mitotic division of germ cell nuclei without complete cytokinesis to form a multi-nucleated syncytia, or germ cell nest. Through combined actions of germ cell apoptosis and somatic cell migration, the germ cell nuclei are packaged, with surrounding granulosa cells, into primordial follicles to form the initial follicle pool. Though often dismissed as quiescent and possibly uninteresting, this initial follicle pool is actually quite dynamic. In a very strictly controlled mechanism, a large portion of the initial primordial follicles formed is lost by atresia before cycling even begins. Remaining follicles can undergo alternate fates of continued dormancy or selection leading to follicular growth and differentiation. Together, the processes involved in the fate decisions of atresia, sustained dormancy, or activation carve out the follicle pool of puberty, the pool of available oocytes from which all future reproductive cycles of the female can choose. The formation of the initial and pubertal follicle pools can be predictably affected by exogenous treatment with hormones or molecules such as activin, demonstrating the ways the ovary controls the quality and quantity of germ cells maintained. Here, we review the biological processes involved in the formation of the initial follicle pool and the follicle pool of puberty, address the alternate models for regulating germ cell number and outline how the ovary quality-controls the germ cells produced.

Candace Tingen, Alison Kim, and Teresa K. Woodruff; Molecular Human Reproduction Vol. 15 No. 12 795-803 Dec 15, 2009

Abstract

Dicer is the ribonuclease III for synthesis of mature functional microRNAs (miRNAs), which play an important role in regulating cell development. In the mouse ovary, the Dicer1 protein was expressed in both oocyte and granulosa cells of the follicle. In the present study, the role of miRNAs in mouse ovarian development was explored by using Dicer1 conditional knockout (cKO) mouse ovarian tissue (Amhr2 Cre/-; Dicer flox/flox), in which Dicer1 is deleted specifically in follicular granulosa cells. The morphology and gene expression profile of cKO and wild type (WT) mouse ovaries at various stages of development (day 4, day 8, 8 weeks and 8 months) were examined. Comparative analysis of the follicle number indicated that conditional inactivation of Dicer1 in the follicular granulosa cells led to an increased primordial follicle pool endowment, accelerated early follicle recruitment and more degenerate follicles in the cKO ovaries. In addition, significant differences were noted in the expression of some follicle development-related genes between cKO and WT mouse ovaries, such as Amh, Inhba, Cyp17a1, Cyp19a1, Zps, Gdf9 and Bmp15, suggesting the function of miRNAs in regulating gene expression is time- and gene-dependent. With the Dicer1 inactivation, mmu-mir-503, a miRNA that is more abundant in mouse ovary than in other tissues, was down-regulated significantly. Meanwhile, the expression of mmu-mir-503 decreased notably with follicle development in the gonadotropin-primed mouse ovary. Up-regulation of mmu-mir-503 in primary cultured granulosa cells resulted in the decreased expression of both the target gene and non-target gene at the transcriptional level, which involve genes related to granulosa cell proliferation and luteinization. In conclusion, Dicer1 plays important roles in follicular cell development through the differential regulation of gene expression.

Lei Lei, Shiying Jin, Gabriel Gonzalez, Richard R. Behringer, Teresa K. Woodruff; Mol Cell Endocrinol Epub ahead of print Sep 30 2009

Scott-Trainer, J. Cancer Treatment and Research. 2010; 156: 469-70. PMID: 20811857.

Abstract

Regulation of ovarian follicle development depends on endocrine- and paracrine-acting hormones, the 3-dimensional architecture of the follicle, and the physical rigidity of the surrounding tissue. These 3 forces are integrated throughout the life cycle of the follicle to ensure appropriate hormone secretion, differentiation of the somatic cells, and maturation of the oocyte. The process of in-follicle maturation provides a new tool for understanding ovarian follicle development under the influence of these factors.

Teresa K. Woodruff and Lonnie D. Shea; Reprod Sci. Vol 14 No 8 Suppl 6-10 Dec 2007

Abstract

The mechanisms and physiology of reproductive function have fascinated scientists throughout time. Recent cellular and molecular level structural studies have provided unprecedented insights into reproductive systems and signaling networks. This ‘cutting edge’ editorial provides a recent example in each of these areas, namely, the anatomical integrity of the follicle, the molecular structure of activin with its binding partners and the molecular regulation of inhibin. These three examples of structure informing function help explain reproductive health and may provide solutions to reproductive disease.

Thomas F. Lerch, Min Xu, Theodore S. Jardetzky, Kelly E. Mayo, Ishwar Radhakrishnan, Ralph Kazer, Lonnie D. Shea, and Teresa K. Woodruff; Molecular Cell Endocrinol 267 1-5 2006

Abstract

OBJECTIVE:
To articulate the need for a new approach to primary ovarian insufficiency. The condition, also known as premature menopause or premature ovarian failure, is defined by the presence of menopausal-level serum gonadotropins in association with irregular menses in adolescent girls or women younger than 40 years. It can be iatrogenic as related to cancer therapy or may arise spontaneously, either alone or as part of a host of ultrarare syndromes. In a large percentage of spontaneous cases no pathogenic mechanism can be identified.

DESIGN:
Literature review and consensus building at a multidisciplinary scientific workshop.

CONCLUSION(S):
There are major gaps in knowledge regarding the etiologic mechanisms, psychosocial effects, natural history, and medical and psychosocial management of primary ovarian insufficiency. An international research consortium and disease registry formed under the guidance of an umbrella organization would provide a pathway to comprehensively increase basic and clinical knowledge about the condition. Such a consortium and patient registry also would provide clinical samples and clinical data with a goal toward defining the specific pathogenic mechanisms. An international collaborative approach that combines the structure of a patient registry with the principles of integrative care and community-based participatory research is needed to advance the field of primary ovarian insufficiency.

Amber R. Cooper, MD, Valerie L. Baker, MD, Evelina W. Sterling, PhD, Mary E. Ryan, MLS, Teresa K. Woodruff, PhD, and Lawrence M. Nelson, MD. Fertility and Sterility, 2010.

Trainer, J.; The American Brain Cancer Foundation Fertility Preservation March 24, 2009

Abstract

Oocytes grown in vitro are of low quality and yield few live births, thus limiting the ability to store or bank the ova of women wishing to preserve their fertility. We applied tissue engineering principles to the culture of immature mouse follicles by designing an alginate hydrogel matrix to maintain the oocyte’s 3- dimensional (3D) architecture and cell-cell interactions in vitro. A 3D culture mimics the in vivo follicle environment, and hydrogel-encapsulated follicles develop mature oocytes within the capacity for fertilization similar to that of oocytes matured in vivo. Embryos derived from cultured oocytes fertilized in vitro and transferred to pseudopregnant female mice were viable, and both male and female offspring were fertile. Our results demonstrate that alginate hydrogel-based 3D in vitro culture of follicles permits normal growth and development of follicles and oocytes. This system creates new opportunities for discovery in follicle biology and establishes a core technology for human egg banks for preservation of fertility.

Min Xu, Pamela K. Kreeger, Lonnie D. Shea, and Teresa K. Woodruff; Tissue Engineering Vol 10 2739-46 Oct 13 2006

Silber S J., Woodruff T K., Shea D L. Cancer Treatment and Research. 2010; 156: 41-54. PMID: 20811824.

Leilah E. Backhus, MD, MS and Laurie Zoloth, PhD

Chaudhry, A S. Cancer Treatment and Research. 2010; 156: 287-94. PMID: 20811842.

Abstract

PURPOSE:
Oncofertility, an emerging discipline at the intersection of cancer and fertility, strives to give cancer patients options when they are confronting potential infertility as a consequence of cancer treatment. Fertility preservation decisions must be made before treatment begins, adding stress to the decision-making process.

METHODS:
Healthcare providers need to be aware of the intricacies involved in oncofertility decision making, and the often tight time line that patients face when making these decisions. Cancer patient’s perspectives may also change, as the dual burden of a cancer diagnosis and potential infertility can cause great flux in emotions.

RESULTS:
A provider-facing decision tree was created to enhance patient decision-making capacities and outline the multiple potential intervention points.

CONCLUSIONS:
Decision trees, which highlight the important decision points during which providers can approach patients, can be a useful tool to help providers in counseling patients on fertility preservation.

Shauna L. Gardino, Jacqueline S. Jeruss, Teresa K. Woodruff. J Assit Reprod Genet, 2010.

Diagnosis codes to use in billing for fertility preservation. (Hint: these patients are not infertile.)

Abstract

Oncofertility is one of the 9 NIH Roadmap Initiatives, federal grants intended to explore previously intractable questions, and it describes a new field that exists in the liminal space between cancer treatment and its sequelae, IVF clinics and their yearning, and basic research in cell growth, biomaterials, and reproductive science and its tempting promises. Cancer diagnoses, which were once thought universally fatal, now often entail management of a chronic disease. Yet the therapies are rigorous, must start immediately, and in many cases result in premature failure of the body’s reproductive ability. In women, this loss is especially poignant; unlike the routine storage of sperm, which is done in men and boys facing similar treatment decisions, freezing oocytes in anticipation of fertility loss is not possible in most cases, and creating an embryo within days of diagnosis raises significant moral, social and medical challenges. Oncofertility is the study of how to harvest ovarian tissue in women facing cancer to preserve their gametes for future use with IVF, thus allowing the decisions about childbearing to be deferred and reproductive choices to be preserved. The research endeavor uses the capacity of the ovarian follicle to produce eggs in vitro. Developing the human follicle to ovulate successfully outside the body is scientifically difficult and ethically challenging. Infertility is linked to long-standing religious and moral traditions, and is intertwined with deeply contentious social narratives about women, families, illness and birth. Is the research morally permissible? Perhaps imperative if understood as a repair from iatrogenic harms? How are considerations of justice central to the work? How will vulnerable subjects be protected? What are the moral implications of the work for women, children and families? What are the implications for society if women could store ovarian tissue as a way of stopping the biological clock? What are the moral possibilities and challenges if eggs can be produced in large quantities from a stored ovarian tissue?

Zoloth, Laurie, Backhus, Leilah and Woodruff, Teresa(2008)’Waiting to be Born: The Ethical Implications of the
Generation of “NUBorn” and “NUAge” Mice from Pre-Pubertal Ovarian Tissue’,The American Journal of Bioethics,8:6,21 — 29.

Hirshfeld-Cytron J. Cancer Treatment and Research. 2010; 156: 467-8. PMID: 20811856.

Abstract

OBJECTIVE:
To evaluate predictors of undergoing fertility preservation treatment (FPT) in women with breast cancer.

DESIGN:
Secondary analysis of a clinical database.

SETTING:
Three academic fertility preservation centers.

PATIENT(S):
One hundred eight patients with breast cancer undergoing FPT and 77 patients with breast cancer not undergoing FPT from 2005 to 2010.

INTERVENTION(S):
None.

MAIN OUTCOME MEASURE(S):
Patients’ demographic and medical information.

RESULT(S):
Women who had FPT were older, wealthier, and had lower cancer stage compared with women who did not have FPT. The rate of the administration of neoadjuvant chemotherapy (NAC) was significantly lower in women who underwent FPT. After adjusting for age, body mass index (BMI), income, cancer stage, and center, a negative correlation persisted between NAC and FPT (odds ratio 0.091, 95% confidence interval 0.009-0.904). When we stratified the women by center, women at center 1 had a significantly lower FPT rate, lower parity, higher BMI, more advanced cancer stage, and lower income compared with centers 2 and 3. The rates of NAC were significantly higher in center 1.

CONCLUSION(S):
Although age, BMI, income, cancer stage, center, and NAC seem to be associated with undergoing FPT, NAC is the only modifiable variable. Because NAC restricts the time available for FPT, oncologists may consider offering adjuvant chemotherapy, except in cases in which NAC clearly improves survival, in women who are interested in FPT.

Kim J, Oktay K, Gracia C, Lee S, Morse C, Mersereau JE. Fertil Steril. 2012 Jan 3.

Abstract

PURPOSE:
The knowledge that cancer treatment may impair fertility in pediatric populations is an emerging aspect of quality of life in this population. However, decision making and use of fertility preservation (FP) among adolescent cancer patients and their families has not been well studied. This review summarizes the available published data on aspects of decision making and FP in adolescent cancer patients.

METHODS:
An electronic search was performed to identify peer-reviewed studies published between 1999 and 2009 using key Medical Subject Heading terms and inclusion criteria. Inclusion criteria limited eligible studies to those that focused on adolescent decision making in cancer treatment or FP, fertility concerns in pediatric oncology, capacity for decision making, and health decision making in pediatrics. Studies that did not meet at least one of these criteria were excluded.

RESULTS:
A total of 29 articles were reviewed and summarized. Three categories of results were seen: a focus on adolescent decision making in oncology, decision making in chronic illness, and decision making in cancer-related infertility and preservation.

CONCLUSION:
Most of the studies showed that adolescents have a strong desire to participate in decisions related to their cancer treatment and many have concerns regarding their future fertility, although barriers often prevented these discussions. More research is needed to explore the role of teenagers and parents in decisions about fertility in relation to cancer treatment.

Quinn GP, Murphy D, Knapp C, Stearsman DK, Bradley-Klug KL, Sawczyn K, Clayman ML. J Adolesc Health. 2011 Oct;49(4):337-46. Epub 2011 Mar 15. PMID: 21939862

Summary

Kathleen M. Galvin and Marla L. Clayman address a range of family factors and related ethical issues that affect decision-making when a female child or adolescent is faced with fertility threatening cancer treatments. Following the presentation of a framework through which to examine the role of children in decision-making, several child –and family- oriented complications related to both ethics and family communication are explored.

Galvin K M., Clayman M L. Cancer Treatment and Research. 2010; 156: 429-45. PMID: 20811853.