Oncofertility Publications

Nieman CL, Kinahan KE, Yount SE, Rosenbloom SK, Yost KJ, Hahn EA, Volpe T, Dilley KJ, Zoloth L, Woodruff TK. Cancer Treat Res. 2007;138:201-17. Review. No abstract available. PMID: 18080667

Abstract

OBJECTIVE:
To characterize the early experience of a clinical program designed to provide strategies for fertility preservation to female cancer patients about to undergo chemotherapy or radiation therapy.

DESIGN:
Retrospective chart review; case-control study.

SETTING:
Academic medical center.

PATIENT(S):
Sixty-five female cancer patients and 57 age-matched infertility patients.

INTERVENTION:
Enrollment in a program for fertility preservation.

MAIN OUTCOME MEASURE(S):
Choice of active participation, fertility preservation option selection, clinical outcomes of patients undergoing oocyte retrieval, attitudes regarding embryo disposition.

RESULT(S):
Of 65 patients referred to the program, 18 declined to undergo embryo, oocyte, or tissue cryopreservation. Six were found not to be eligible for medical reasons. Of the remaining 41 patients, 35 chose to cryopreserve embryos, four chose to cryopreserve oocytes, and two chose to undergo ovarian tissue freezing. Fewer oocytes were recovered from the embryo cryopreservation group when compared with an age-matched control group, but the mean number of zygotes generated was similar. Attitudes regarding embryo disposition were different between the two groups. No serious clinical sequelae resulted from participation.

CONCLUSION(S):
Fertility preservation techniques employing available technology may provide safe and practical options to female cancer patients facing chemotherapy or radiation therapy. A significant number of otherwise appropriate participants decline active management. Cancer patients display different attitudes regarding embryo disposition when compared with infertility patients without cancer.

Susan C. Klock, John X. Zhang, and Ralph R. Kazer; Fertility and Sterility, In Press 2009

Abstract

Ovarian cryopreservation before chemotherapy and autotransplantation post-treatment can restore fertility to women with premature ovarian failure. Although the majority of primordial follicles survive the cryopreservation cycle, the follicular pool is reduced after transplantation due to ischemic death. Therefore, we engineered a biomaterial-based system to promote angiogenesis in a mouse model of ovarian transplantation. To mimic the clinical situation of sterility, a bilateral ovariectomy was performed 2 weeks before transplantation, during which time serum levels of follicular stimulating hormone rose to menopausal levels. Before transplantation, vitrified/thawed ovarian tissue from 12-day-old C57Bl/6J pups was encapsulated in fibrin modified with heparin-binding peptide (HBP), heparin, and loaded with 0.5 μg vascular endothelial growth factor (VEGF). The group transplanted with fibrin-HBP-VEGF had twice as many surviving primordial follicles and an increased number of blood vessels relative to the no biomaterial control. Transplanted tissue was viable and supported natural conception that led to live and healthy offspring. The timeline of live births with VEGF delivery suggested that primary follicles survived transplantation, and provided the gametes for the first litter. Thus, VEGF delivery from fibrin supported integration of the transplant with the host, promoted angiogenesis, and enhanced engraftment and function of the tissue.

Shikanov A, Zhang Z, Xu M, Smith RM, Rajan A, Woodruff TK, Shea LD. Tissue Eng Part A. 2011 Dec;17(23-24):3095-104. Epub 2011 Sep 21. PMID: 21740332

Zoloth, L. Cancer Treatment and Research. 2010; 156: 487-9. PMID: 20811861.

Campo-Engelstein, Lisa. Cancer Treatment and Research. 2010; 156: 381-8. PMID 20811849.

Xu M, Pavone ME, Woodruff T. Nature Medicine. 2011 Dec 6;17(12):1562-3. PMID: 22146461

Fertility impairment and loss due to cancer or its treatment is a significant survivorship consideration for many pediatric, adolescent, and young adult cancer survivors. Chemotherapeutics, radiation, and surgery can impact the future fertility of men, women, and children with cancer. The field of oncofertility, founded to ensure the reproductive future of cancer survivors, gained momentum with 5 years of funding through a 2007 National Institutes of Health Roadmap Grant for Biomedical Research. This report from working group meetings at the fifth annual Oncofertility Consortium Conference speaks to the present state of oncofertility research and clinical care, existing gaps, and future directions for the field. This summary from conference participants and leaders in the field addresses the science, clinical specialties, and academic scholarship that can guide the field as the Roadmap Grant funding comes to a close.

KE Waimey, FE Duncan, H Su, K Smith, H Wallach, K Jona, C Coutifaris, CR. Gracia, LD Shea, RE Brannigan, R Chang, M Zelinski, R Stouffer, R Taylor, and TK Woodruff. JOURNAL OF ADOLESCENT AND YOUNG ADULT ONCOLOGY. Volume 2, Number 1, 2013.

Barrett S L., Woodruff T K. Cancer Treatment and Research. 2010; 156: 25-39. PMID: 20811823.

Abstract

Ovarian tissue transplantation is an experimental procedure that can be used to treat both infertility and premature menopause. Working within the current legal framework in the USA, I examine whether ovarian tissue should be legally treated like gametes or organs in the case of ovarian tissue transplantation between two women. One option is to base classification upon its intended use: ovarian tissue used to treat infertility would be classified like gametes, and ovarian tissue used to treat premature menopause would be classified like organs. In the end, however, I argue that this approach will not work because it engenders too many legal, cultural and logistical concerns and that, at least for the near future, we should treat ovarian tissue like gametes.

Campo-Engelstein, L. Journal of Medical Ethics. 37(3): 166-70, 2011 Jan 18. [Epub ahead of print] PMID: 21245477

Knapp C A., Quinn G P. Cancer Treatment and Research. 2010; 156: 391-401. PMID: 20811850.

Abstract

PURPOSE:
Young adult cancer survivors are often unaware of their fertility status and uninformed regarding their fertility and fertility preservation options. This qualitative research study explores the fertility and parenthood concerns of reproductive-age female cancer survivors and how they make parenthood decisions.

METHODS:
Population- and clinic-based recruitment methods were used to identify a diverse group of survivors between the ages of 18 and 34 years. Our final sample size included 22 participants who attended one of seven focus groups. We used cross-case, inductive analysis to identify themes.

RESULTS:
The following main themes were identified: (1) A hopeful but worried approach to fertility and parenthood, (2) Frustration with a lack of choice or control over fertility, (3) Young survivors want information about their fertility, (4) Young survivors want better continuity of care in survivorship, (5) Cancer diagnosis and related fertility problems introduce relationship challenges, and (6) Decisions about parenthood are complicated.

CONCLUSIONS:
The diverse group of young cancer survivors in this study identified several common needs and concerns regarding fertility andparenthood. This study illustrates that young survivors could benefit from improved information regarding their fertility and parenthood options throughout survivorship, better coordination of medical care, and support navigating many emotional and practical issues that arise when considering their reproductive and parenthood options.

Gorman JR, Bailey S, Pierce JP, Su HI .J Cancer Surviv. 2011 Dec 17. PMID: 22179785

Abstract

Synthetic hydrogels with tunable properties are appealing for regenerative medicine. A critical limitation in hydrogel design at low solids concentration is the formation of defects, which increase gelation times and swelling, and reduce elasticity. Here, we report that trifunctional cross-linking peptides applied to 4-arm poly-(ethylene glycol) (PEG) hydrogels decreased swelling and gelation time relative to bi-functional crosslinkers. In contrast to bi-functional peptides, the third cross-linking site on the peptide created a branch point if an intramolecular cross-link formed, which prevented non-functional “dangling-ends” in the hydrogel network and enhanced the number of elastically active cross-links. The improved network formation enabled mouse ovarian follicle encapsulation and maturation in vitro. Hydrogels with bi-functional crosslinkers resulted in cellular dehydration, likely due to osmosis during the prolonged gelation. For trifunctional crosslinkers, the hydrogels supported a 17-fold volumetric expansion of the tissue during culture, with expansion dependent on the ability of the follicle to rearrange its microenvironment, which is controlled through the sensitivity of the cross-linking peptide to the proteolytic activity of plasmin. The improved network design enabled ovarian follicle culture in a completely synthetic system, and can advance fertility preservation technology for women facing premature infertility from anticancer therapies.

Shikanov A, Smoith R M., Xu M, Woodruff T K., Shea L D. Biomaterials. 2011. April; 32(10): 2524-31.

Abstract

The availability of viable oocytes is the limiting factor in the development of new reproductive techniques. Many attempts have been made to grow immature oocytes in vitro during recent decades. Recently, a modified alginate-based three-dimensional culture system was designed to support the growth and maturation of multilayered secondary follicles. This system was able to produce oocytes that successfully completed meiosis, fertilization, and development to the blastocyst stage. Subsequent attempts to culture two-layered secondary follicles were unsuccessful under the original conditions. Herein, we investigated the effect of alginate consistency on two-layered follicle growth and oocyte developmental competence by encapsulating follicles into alginate scaffolds of various concentrations. Although there were no significant differences in survival rates, 0.25% and 0.5% alginate supported more rapid growth of follicles and antrum formation compared with 1.5% and 1.0% alginate after 8 days of culture. Alginate scaffold concentration also affected the proliferation and differentiation of somatic cells (theca and granulosa cells), measured in terms of morphological changes, steroid profiles (androstenedione, estradiol, and progesterone), and specific molecular markers (Fshr, Lhcgr, and Gja1). Theca cell proliferation and steroid production were hindered in follicles cultured in 1.5% alginate. In vitro fertilization and embryo culture revealed that oocytes obtained from 0.25% alginate retained the highest developmental competence. Overall, the present study showed that the alginate scaffold consistency affects folliculogenesis and oocyte development in vitro and that the alginate culture system can and should be tailored to maximally support follicle growth depending on the size and stage of the follicles selected for culture.

Min Xu, Erin West, Lonnie D. Shea, and Teresa K. Woodruff; Biology of Reproduction Vol 75 916-923 Sep 6 2006

Abstract

PURPOSE:
Survival to reproductive age among men with cancer has steadily increased and yet cancer therapy and cancer itself may carry the risk of infertility. Since 2006, we have used a formalized fertility preservation program with expedited fertility care at our institution. We assessed the impact of this program by comparing the frequency of sperm cryopreservation and patient characteristics before and after its implementation.

MATERIALS AND METHODS:
Men 18 to 55 years old diagnosed with cancer at our institution from 2002 to 2010 were included in our study. We retrospectively reviewed patient charts to identify those who were offered and subsequently used fertility preservation services before and afterprogram formalization.

RESULTS:
From 2002 to 2010 at our institution 4,818 men 18 to 55 years old were diagnosed with cancer, of whom 411 were offered fertilitypreservation consultation and 249 underwent sperm cryopreservation. Since program implementation, the annual number of men receiving fertilitypreservation consultation and undergoing sperm cryopreservation increased by 2.4 and 2.7-fold, respectively, while the total number diagnosed with cancer remained fairly constant. Upon substratifying patients into the more conventional reproductive age range of 18 to 40 years 23.4% of all men with cancer in this group were offered consultation before formalization vs 43.3% after formalization (p <0.05). The overall sperm use and discard rates were 8.4% and 14.8%, respectively.

CONCLUSIONS:
A formalized institutional fertility preservation program significantly increased the overall number and percent of male patientswith cancer who received fertility preservation consultation and pursued sperm cryopreservation. These increases were seen in men with all types of cancer and across all demographics assessed at our institution.

Sheth KR, Sharma V, Helfand BT, Cashy J, Smith K, Hedges JC, Kohler TS, Woodruff TK, Brannigan RE, J Urol. 2012 Jan 18

Abstract

BACKGROUND:
Ovarian tissue cryopreservation is the only option for preserving fertility in prepubertal girls and cancer patients requiring immediate treatment. Following ovarian tissue cryopreservation, fertility can be restored after tissue transplant or in vitro follicle maturation.

METHODS:
Macaque (n= 4) ovarian cortex was cryopreserved using slow-rate freezing (slow freezing) or vitrification. Tissues were fixed for histology or phosphohistone H3 (PPH3) analysis, cultured with bromodeoxyuridine (BrdU) or used for three-dimensional secondary follicle culture. Follicular diameter and steroid hormones were measured weekly.

RESULTS:
Slow freezing induced frequent cryo-injuries while vitrification consistently maintained morphology of the stroma and secondary follicles. PPH3 was similar in fresh and vitrified, but sparse in slow-frozen tissues. BrdU uptake appeared diminished following both methods compared with that in fresh follicles. In vitro follicle survival and growth were greater in fresh than in cryopreserved follicles. Antrum formation appeared similar after vitrification compared with the fresh, but was reduced following slow freezing. Steroid production was delayed or diminished following both methods compared with fresh samples.

CONCLUSIONS:
Secondary follicle morphology was improved after vitrification relative to slow freezing. Following vitrification, stroma was consistently more compact with intact cells typical to that of fresh tissue. BrdU uptake demonstrated follicle viability post-thaw/warming. For the first time, although not to the extent of fresh follicles, macaque follicles from cryopreserved tissue can survive, grow, form an antrum and produce steroid hormones, indicating some functional preservation. The combination of successful ovarian tissue cryopreservation with in vitro maturation of follicles will offer a major advancement to the field of fertility preservation.

Ting AY, Yeoman RR, Lawson MS, Zelinski MB. Hum Reprod. 2011 Sep;26(9):2461-72. Epub 2011 Jun 24. PMID: 21705370

In August of 1944, John Rock and Miriam Menkin were the first researchers to fertilize a human egg outside of the body. This experiment proved that in vitro fertilization was possible in humans. Despite the absence of any pregnancies resulting from the embryos in their experiments, Rock and Menkin made their mark in the history of embryology, demonstrating the ability to manipulate embryos as well as providing an important look into the very earliest stages of human life.

Menkin, M F., Rock, J. Science. 1944, August 4; 100 (2588): 105-7. PMID: 17788930

Abstract

BACKGROUND:
Young female adult and adolescent cancer patients facing life-preserving but fertility-threatening chemo- or radiation-therapy are increasingly seeking options to protect their reproductive potential. Ovarian tissue cryopreservation with transplantation is a promising technique to safeguard fertility in cancer patients. However, this method may risk re-introduction of the original cancer to the survivor of the disease. Thus, developing a method for in vitro growth of immature follicles may provide a method for fertility restoration in the future.

METHODS:
Human secondary follicles were isolated from ovarian tissues obtained from cancer patients and grown in vitro within a bio-engineered culture system for 30 days.

RESULTS:
Human ovarian follicles became steroidogenically active, and developed from the early secondary to antral stage in vitro. The follicles contained healthy, growing oocytes that were connected by transzonal projections between the somatic cells and oocyte.

CONCLUSIONS:
Our data support the notion that human follicle development can be achieved in vitro in a bio-engineered culture system. More studies are required to investigate whether the fully sized oocytes obtained from in vitro grown follicle are competent to resume meiosis and be fertilized.

Min Xu, Susan L. Barrett, Erin West-Farrell, Laxmi A. Kondapalli,, Sarah E. Kiesewetter, Lonnie D. Shea, and Teresa K. Woodruff; Human Reproduction Vol.24, No.10 2531-40 Oct. 24, 2009

Female cancer patients who seek fertility preservation but cannot undergo ovarian stimulation and embryo preservation may consider: 1) retrieval of immature oocytes followed by in vitro maturation (IVM); 2) ovarian tissue cryopreservation followed by transplantation or in vitro follicle culture (IVFC). Conventional IVM is carried out during the follicular phase of menstrual cycle. There is limited evidence demonstrating that immature oocyte retrieved during the luteal phase can mature in vitro and be fertilized to produce viable embryos. While in vitro follicle culture is successful in rodents, its application in nonhuman primates has made limited progress. The objective of this study was to investigate the competence of immature luteal-phase oocytes from baboon and to determine the effect of FSH on baboon preantral follicle culture and oocyte maturation in vitro. Oocytes from small antral follicle COCs with multiple cumulus layers (42%) were more likely to resume meiosis and progress to MII than oocytes with a single layer of cumulus cells, or less (23% vs. 3%, respectively). Twenty-four percent of mature oocytes were successfully fertilized by ICSI, and 25% of these developed to morula stage embryos. Preantral follicles were encapsulated in fibrin-alginate-matrigel (FAM) matrices, and cultured to small antral stage in a FSH-independent manner. FSH negatively impacted follicle health by disrupting the integrity of oocyte and cumulus cells contact. Follicles grown in the absence of FSH produced MII oocytes with normal spindle structure. In conclusions, baboon luteal-phase COCs and oocytes from cultured preantral follicles can be matured in vitro. Oocyte meiotic competence correlated positively with the number of cumulus cell layers. This study clarifies the parameters of the follicle culture system in nonhuman primates and provides foundational data for future clinical development as a fertility preservation option for women with cancer.

Xu M, Fazleabas AT, Shikanov A, Jackson E, Barrett SL, Hirshefeld-Cytron J, Kiesewetter SE, Shea LD, Woodruff TK.

Redig A J., Brannigan R, Stryker S J., Woodruff T K. Cancer. 2011, Jan 1; 117(1): 4-10.