Recent diagnostic and therapeutic advances in oncology have led to greater survival rates in children and young adults with malignancies. However, in women, while cancer therapies improve long-term survival, such treatments often lead to premature ovarian failure and infertility related to early ovarian aging. As more young women survive cancer and lead productive lives, these concerns are becoming increasingly important. Nevertheless, it is difficult to predict if and when such problems will arise and what the severity and duration will be. Indeed, there are no early clinical signs of decreased ovarian dysfunction and even young women who maintain cyclic menses after therapy are at high risk of infertility, early menopause, and long-term health problems related to early ovarian failure. While it has recently been observed that hormone and ultrasound measures of ovarian reserve are impaired in long term survivors of cancer, it is not clear whether these measures reflect fertility potential and time to menopause in this population. We have intriguing preliminary data to suggest that childhood and young adult cancer survivors exposed to high risk cancer therapies in their mid 20's have hormone and ultrasound measures of ovarian reserve similar to naturally aging women in their mid 40's. The current proposal represents the first comprehensive and appropriately powered investigation of the acute and long-term reproductive consequences of cancer treatment in adolescent and young women. The proposed aims are 1) to assess acute changes in reproductive function during and after chemotherapy in cancer patients, 2) to assess the long-term reproductive function of women exposed to cancer therapies and make comparisons to similarly aged and late reproductive aged unexposed females and 3) assess for the presence of follicular and luteal dysfunction in cancer survivors by comparing daily urinary hormone metabolites over 2 menstrual cycles between subjects exposed to high dose alkylating agent therapy and 2 unexposed populations of females. The findings of this proposal will help confirm our preliminary findings, and will be critical in estimating the reproductive window in cancer survivors. In addition, this research will expand our knowledge of the effects of cancer therapy and will help to establish a method to predict the impact of chemotherapy prior to treatment. Ultimately, this data will be critical to determine if these measures are useful in predicting the timing and extent of ovarian dysfunction as well as fertility potential in this population and will have a major impact on the quality of life of girls and women who survive cancer.

Public Health Relevance

Recent diagnostic and therapeutic advances in oncology have led to greater survival rates in children and young adults with malignancies. However, while cancer therapies, especially alkylating agents, improve long- term survival, such treatments often lead to premature ovarian failure and reproductive dysfunction related to early ovarian aging. This proposal will assess the immediate and long-term changes in reproductive function in young females exposed to chemotherapy. The findings of this research will have a major impact on patient counseling and targeting fertility preservation efforts.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD062797-03
Application #
8301493
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Lamar, Charisee A
Project Start
2010-07-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$508,312
Indirect Cost
$166,907
Name
University of Pennsylvania
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Johnson, Lauren; Sammel, Mary D; Schanne, Allison et al. (2016) Female cancer survivors exposed to alkylating-agent chemotherapy have unique reproductive hormone profiles. Fertil Steril 106:1793-1799.e2
Chan, Jessica L; Johnson, Lauren N C; Efymow, Brenda L et al. (2015) Outcomes of ovarian stimulation after treatment with chemotherapy. J Assist Reprod Genet 32:1537-45
Kondapalli, Laxmi A; Dillon, Katherine E; Sammel, Mary D et al. (2014) Quality of life in female cancer survivors: is it related to ovarian reserve? Qual Life Res 23:585-92
Johnson, Lauren N C; Sammel, Mary D; Dillon, Katherine E et al. (2014) Antimüllerian hormone and antral follicle count are lower in female cancer survivors and healthy women taking hormonal contraception. Fertil Steril 102:774-781.e3
Johnson, Lauren N C; Dillon, Katherine E; Sammel, Mary D et al. (2013) Response to ovarian stimulation in patients facing gonadotoxic therapy. Reprod Biomed Online 26:337-44
Gracia, Clarisa R; Jeruss, Jacqueline S (2013) Lives in the balance: women with cancer and the right to fertility care. J Clin Oncol 31:668-9
Practice Committee of American Society for Reproductive Medicine (2013) Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion. Fertil Steril 100:1214-23
Dillon, Katherine E; Sammel, Mary D; Prewitt, Maureen et al. (2013) Pretreatment antimullerian hormone levels determine rate of posttherapy ovarian reserve recovery: acute changes in ovarian reserve during and after chemotherapy. Fertil Steril 99:477-83
Dillon, Katherine E; Sammel, Mary D; Ginsberg, Jill P et al. (2013) Pregnancy after cancer: results from a prospective cohort study of cancer survivors. Pediatr Blood Cancer 60:2001-6
Lamar, Charisee; Taymans, Susan; Rebar, Robert et al. (2013) Ovarian Reserve: Regulation and Implications for Women's Health. Proceedings of the 2012 NICHD-ASRM Conference. J Assist Reprod Genet 30:285-92

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