Management of Primary Ovarian Insufficiency Symptoms in Survivors of Childhood and Adolescent Cancer

View More View Less
  • a Northwestern University, Chicago, Illinois; and Royal Hospital for Women, University of New South Wales, Kids Cancer Centre at Sydney Children's Hospital, Nelune Comprehensive Cancer Centre, Prince of Wales Cancer Centre, and School of Women's and Children's, University of New South Wales, Randwick, Australia.
Restricted access

Cancer treatments can damage the ovaries, causing primary ovarian insufficiency (POI), a condition associated with numerous sequelae that impact long-term quality of life. This article systematically reviews the literature on the prevalence, surveillance, and treatment of POI in survivors of pediatric and adolescent and young adult (AYA) cancers. A systematic review of the literature was conducted in January 2018 through a search of Medline, Embase, Web of Science, and SCOPUS, alongside the screening of relevant reference lists. An initial search identified 746 potentially relevant studies. A total of 36 studies were included in the final review. Studies were categorized into one of the following categories: incidence/prevalence of POI, measurement of ovarian reserve, and other. Depending on patient characteristics, cancer diagnosis, and treatment, the prevalence of POI ranged from 2.1% to 82.2%. Risk factors for POI included exposure to alkylating agents and abdominal/pelvic radiation. POI may be associated with a number of complications, including low bone mineral density and poor cardiovascular health. Radiotherapy and chemotherapy are known to cause gonadal damage in female survivors of pediatric and AYA cancers. Acute or chronic effects depend on the dose of treatment, age of the individual, radiotherapy field, and ovarian reserve of the individual. Some women experience short-term loss of reproductive function and then may resume menstrual cycles, months or even years later. Although protecting fertility through banking of mature eggs, embryos, and tissue samples has become standard of care, additional steps need to be taken to ensure that patients have adequate hormone levels to maintain whole-body health, including life expectancy, bone health, cardiovascular health, quality of life, sexual and genitourinary function, and neurologic function. Surveillance and management of each of these comorbidities is critically important to survivor health.

Correspondence: Teresa K. Woodruff, PhD, Northwestern University, 303 East Superior Street, Room 10-121, Chicago, IL 60411. Email: tkw@northwestern.edu
  • 1.

    Howlader N, Noone AM, Krapcho M, eds. SEER Cancer Statistics Review, 1975-2014, National Cancer Institute. Bethesda, MD. Available at: https://seer.cancer.gov/csr/1975_2014/, based on November 2016 SEER data submission, posted to the SEER web site, April 2017. Accessed August 2, 2018.

    • Search Google Scholar
    • Export Citation
  • 2.

    Jeruss J, Woodruff T. Preservation of fertility for cancer patients. N Engl J Med 2009;360:902911.

  • 3.

    De Vos M, Smitz J, Woodruff TK. Fertility preservation in women with cancer. Lancet 2014;384:13021310.

  • 4.

    Johnson EK, Finlayson C, Rowell EE. Fertility preservation for pediatric patients: current state and future possibilities. J Urol 2017;198:186194.

    • Search Google Scholar
    • Export Citation
  • 5.

    Woodruff TK. Reproductive endocrinology: fertility in female survivors of childhood cancer. Nat Rev Endocrinol 2013;9:571572.

  • 6.

    Woodruff TK. The Oncofertility Consortium—addressing fertility in young people with cancer. Nat Rev Clin Oncol 2010;7:466475.

  • 7.

    Woodruff TK. Preserving fertility during cancer treatment. Nat Med 2009;15:11241125.

  • 8.

    Sobota A, Ozakinci G. Fertility and parenthood issues in young female cancer patients—a systematic review. J Cancer Surviv 2014;8:707721.

    • Search Google Scholar
    • Export Citation
  • 9.

    De Vos M, Devroey P, Fauser BC. Primary ovarian insufficiency. Lancet 2010;376:911921.

  • 10.

    Pluye P, Gagnon MP, Griffiths F, Johnson-Lafleur J. A scoring system for appraising mixed methods research, and concomitantly appraising qualitative, quantitative and mixed methods primary studies in Mixed Studies Reviews. Int J Nurs Stud 2009;46:529546.

    • Search Google Scholar
    • Export Citation
  • 11.

    Livesey EA, Hindmarsh PC, Brook CG. Endocrine disorders following treatment of childhood brain tumours. Br J Cancer 1990;61:622625.

  • 12.

    Byrne J, Fears TR, Gail MH. Early menopause in long-term survivors of cancer during adolescence. Am J Obstet Gynecol 1992;166:788793.

  • 13.

    Mackie EJ, Radford M, Shalet SM. Gonadal function following chemotherapy for childhood Hodgkin's disease. Med Pediatr Oncol 1996;27:7478.

  • 14.

    Teinturier C, Hartmann O, Valteau-Couanet D. Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure. Bone Marrow Transplant 1998;22:989994.

    • Search Google Scholar
    • Export Citation
  • 15.

    Chiarelli AM, Marrett LD, Darlington G. Early menopause and infertility in females after treatment for childhood cancer diagnosed in 1964-1988 in Ontario, Canada. Am J Epidemiol 1999;150:245254.

    • Search Google Scholar
    • Export Citation
  • 16.

    Larsen EC, Muller J, Schmiegelow K. Reduced ovarian function in long-term survivors of radiation- and chemotherapy-treated childhood cancer. J Clin Endocrinol Metab 2003;88:53075314.

    • Search Google Scholar
    • Export Citation
  • 17.

    Sklar CA, Mertens AC, Mitby P. Premature menopause in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 2006;98:890896.

    • Search Google Scholar
    • Export Citation
  • 18.

    Mansky P, Arai A, Stratton P. Treatment late effects in long-term survivors of pediatric sarcoma. Pediatr Blood Cancer 2007;48:192199.

  • 19.

    Green DM, Sklar CA, Boice JD. Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study. J Clin Oncol 2009;27:23742381.

    • Search Google Scholar
    • Export Citation
  • 20.

    Thomas-Teinturier C, El Fayech C, Oberlin O. Age at menopause and its influencing factors in a cohort of survivors of childhood cancer: earlier but rarely premature. Hum Reprod 2013;28:488495.

    • Search Google Scholar
    • Export Citation
  • 21.

    Hudson MM, Ness KK, Gurney JG. Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 2013;309:23712381.

  • 22.

    Raciborska A, Bilska K, Filipp E. Ovarian function in female survivors after multimodal Ewing sarcoma therapy. Pediatr Blood Cancer 2015;62:341345.

    • Search Google Scholar
    • Export Citation
  • 23.

    DeWire M, Green DM, Sklar CA. Pubertal development and primary ovarian insufficiency in female survivors of embryonal brain tumors following risk-adapted craniospinal irradiation and adjuvant chemotherapy. Pediatr Blood Cancer 2015;62:329334.

    • Search Google Scholar
    • Export Citation
  • 24.

    Salih SM, Elsarrag SZ, Prange E. Evidence to incorporate inclusive reproductive health measures in guidelines for childhood and adolescent cancer survivors. J Pediatr Adolesc Gynecol 2015;28:95101.

    • Search Google Scholar
    • Export Citation
  • 25.

    Elchuri SV, Patterson BC, Brown M. Low anti-Müllerian hormone in pediatric cancer survivors in the early years after gonadotoxic therapy. J Pediatr Adolesc Gynecol 2016;29:393399.

    • Search Google Scholar
    • Export Citation
  • 26.

    Wilson CL, Chemaitilly W, Jones KE. Modifiable factors associated with aging phenotypes among adult survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 2016;34:25092515.

    • Search Google Scholar
    • Export Citation
  • 27.

    Chemaitilly W, Li Z, Krasin MJ. Premature ovarian insufficiency in childhood cancer survivors: a report from the St. Jude Lifetime Cohort. J Clin Endocrinol Metab 2017;102:22422250.

    • Search Google Scholar
    • Export Citation
  • 28.

    Bath LE, Wallace WHB, Shaw MP. Depletion of ovarian reserve in young women after treatment for cancer in childhood: detection by anti-Müllerian hormone, inhibin B and ovarian ultrasound. Hum Reprod 2003;18:23682374.

    • Search Google Scholar
    • Export Citation
  • 29.

    Lie Fong S, Laven JS, Hakvoort-Cammel FG. Assessment of ovarian reserve in adult childhood cancer survivors using anti-Müllerian hormone. Hum Reprod 2009;24:982990.

    • Search Google Scholar
    • Export Citation
  • 30.

    Brougham MF, Crofton PM, Johnson EJ. Anti-Mullerian hormone is a marker of gonadotoxicity in pre- and postpubertal girls treated for cancer: a prospective study. J Clin Endocrinol Metab 2012;97:20592067.

    • Search Google Scholar
    • Export Citation
  • 31.

    Nielsen SN, Andersen AN, Schmidt KT. A 10-year follow up of reproductive function in women treated for childhood cancer. Reprod Biomed Online 2013;27:192200.

    • Search Google Scholar
    • Export Citation
  • 32.

    Krawczuk-Rybak M, Leszczynska E, Poznanska M. Anti-Müllerian hormone as a sensitive marker of ovarian function in young cancer survivors. Int J Endocrinol 2013;2013:125080.

    • Search Google Scholar
    • Export Citation
  • 33.

    Krawczuk-Rybak M, Leszczynska E, Poznanska M. The progressive reduction in the ovarian reserve in young women after anticancer treatment. Horm Metab Res 2013;45:813819.

    • Search Google Scholar
    • Export Citation
  • 34.

    Charpentier AM, Chong AL, Gingras-Hill G. Anti-Müllerian hormone screening to assess ovarian reserve among female survivors of childhood cancer. J Cancer Surviv 2014;8:548554.

    • Search Google Scholar
    • Export Citation
  • 35.

    Lunsford AJ, Whelan K, McCormick K, McLaren JF. Antimullerian hormone as a measure of reproductive function in female childhood cancer survivors. Fertil Steril 2014;101:227231.

    • Search Google Scholar
    • Export Citation
  • 36.

    Thomas-Teinturier C, Allodji RS, Svetlova E. Ovarian reserve after treatment with alkylating agents during childhood. Hum Reprod 2015;30:14371446.

    • Search Google Scholar
    • Export Citation
  • 37.

    Wilson CL, Chemaitilly W, Jones KE. Modifiable factors associated with aging phenotypes among adult survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 2016;34:25092515.

    • Search Google Scholar
    • Export Citation
  • 38.

    Gurney JG, Kaste SC, Liu W. Bone mineral density among long-term survivors of childhood acute lymphoblastic leukemia: results from the St. Jude Lifetime Cohort study. Pediatr Blood Cancer 2014;61:12701276.

    • Search Google Scholar
    • Export Citation
  • 39.

    Mandel K, Atkinson S, Barr RD, Pencharz P. Skeletal morbidity in childhood acute lymphoblastic leukemia. J Clin Oncol 2004;22:12151221.

  • 40.

    Hesseling PB, Hough SF, Nel ED. Bone mineral density in long-term survivors of childhood cancer. Int J Cancer 1998;78:4447.

  • 41.

    Wilson CL, Dilley K, Ness KK. Fractures among long-term survivors of childhood cancer. Cancer 2012;118:59205928.

  • 42.

    Gurney JG, Kadan-Lottick NS, Packer RJ. Endocrine and cardiovascular late effects among adult survivors of childhood brain tumors. Cancer 2003;97:663673.

    • Search Google Scholar
    • Export Citation
  • 43.

    Ness KK, Krull KR, Jones KE. Physiologic frailty as a sign of accelerated aging among adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort study. J Clin Oncol 2013;31:44964503.

    • Search Google Scholar
    • Export Citation
  • 44.

    Tomioka A, Maru M, Kashimada K. Physical and social characteristics and support needs of adult female childhood cancer survivors who underwent hormone replacement therapy. Int J Clin Oncol 2017;22:786792.

    • Search Google Scholar
    • Export Citation
  • 45.

    Mostoufi-Moab S, Seidel K, Leisenring WM. Endocrine abnormalities in aging survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 2016;34:32403247.

    • Search Google Scholar
    • Export Citation
  • 46.

    Stuenkel CA, Davis SR, Gompel A. Treatment of symptoms of the menopause: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2015;100:39754011.

    • Search Google Scholar
    • Export Citation
  • 47.

    Britton LE. Unintended pregnancy: a systematic review of contraception use and counseling in women with cancer. Clin J Oncol Nurs 2017;21:189196.

    • Search Google Scholar
    • Export Citation
  • 48.

    Visser JA, Schipper I, Laven JS, Themmen AP. Anti-Müllerian hormone: an ovarian reserve marker in primary ovarian insufficiency. Nat Rev Endocrinol 2012;8:331341.

    • Search Google Scholar
    • Export Citation
  • 49.

    Iwase A, Nakamura T, Osuka S. Anti-Müllerian hormone as a marker of ovarian reserve: what have we learned, and what should we know? Reprod Med Biol 2016;15:127136.

    • Search Google Scholar
    • Export Citation
  • 50.

    Rocca WA, Grossardt BR, de Andrade M. Survival patterns after oophorectomy in premenopausal women: a population-based cohort study. Lancet Oncol 2006;7:821828.

    • Search Google Scholar
    • Export Citation
  • 51.

    Parker WH, Broder MS, Chang E. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the Nurses' Health Study. Obstet Gynecol 2009;113:10271037.

    • Search Google Scholar
    • Export Citation
  • 52.

    Jacoby VL, Grady D, Wactawski-Wende J. Oophorectomy vs ovarian conservation with hysterectomy: cardiovascular disease, hip fracture, and cancer in the Women's Health Initiative Observational Study. Arch Intern Med 2011;171:760768.

    • Search Google Scholar
    • Export Citation
  • 53.

    Ossewaarde ME, Bots ML, Verbeek AL. Age at menopause, cause-specific mortality and total life expectancy. Epidemiology 2005;16:556562.

  • 54.

    Amagai Y, Ishikawa S, Gotoh T. Age at menopause and mortality in Japan: the Jichi Medical School cohort study. J Epidemiol 2006;16:161166.

  • 55.

    Hong JS, Yi SW, Kang HC. Age at menopause and cause-specific mortality in South Korean women: Kangwha Cohort Study. Maturitas 2007;56:411419.

    • Search Google Scholar
    • Export Citation
  • 56.

    Wu X, Cai H, Kallianpur A. Impact of premature ovarian failure on mortality and morbidity among Chinese women. PLoS One 2014;9:e89597.

  • 57.

    Manson JE, Woodruff TK. Reproductive health as a marker of subsequent cardiovascular disease. JAMA Cardiol 2016;1:776777.

  • 58.

    Shuster LT, Rhodes DJ, Gostout BS. Premature menopause or early menopause: long-term health consequences. Maturitas 2010;65:161166.

  • 59.

    Rossouw JE, Prentice RL, Manson JE. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:14651477.

    • Search Google Scholar
    • Export Citation
  • 60.

    Reslan OM, Khalil RA. Vascular effects of estrogenic menopausal hormone therapy. Rev Recent Clin Trials 2012;7:4770.

  • 61.

    Yang XP, Reckelhoff JF. Estrogen, hormonal replacement therapy and cardiovascular disease. Curr Opin Nephrol Hypertens 2011;20:133138.

  • 62.

    Langdahl B, Ferrari S, Dempster DW. Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis. Ther Adv Musculoskelet Dis 2016;8:225235.

    • Search Google Scholar
    • Export Citation
  • 63.

    European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI Webber L, Davies M. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod 2016;31:926937.

    • Search Google Scholar
    • Export Citation
  • 64.

    Ratcliffe MA, Lanham SA, Reid DM, Dawson AA. Bone mineral density (BMD) in patients with lymphoma: the effects of chemotherapy, intermittent corticosteroids and premature menopause. Hematol Oncol 1992;10:181187.

    • Search Google Scholar
    • Export Citation
  • 65.

    Castañeda S, Carmona L, Carvajal I. Reduction of bone mass in women after bone marrow transplantation. Calcif Tissue Int 1997;60:343347.

  • 66.

    Popat VB, Calis KA, Vanderhoof VH. Bone mineral density in estrogen-deficient young women. J Clin Endocrinol Metab 2009;94:22772283.

  • 67.

    Christianson MS, Shen W. Osteoporosis prevention and management: nonpharmacologic and lifestyle options. Clin Obstet Gynecol 2013;56:703710.

    • Search Google Scholar
    • Export Citation
  • 68.

    Crofton PM, Evans N, Bath LE. Physiological versus standard sex steroid replacement in young women with premature ovarian failure: effects on bone mass acquisition and turnover. Clin Endocrinol (Oxf) 2010;73:707714.

    • Search Google Scholar
    • Export Citation
  • 69.

    Blatt J, Meacham LR. Keeping Your Bones Healthy After Childhood Cancer. Available at: http://www.survivorshipguidelines.org/pdf/healthlinks/English/bone_health_Eng.pdf. Accessed August 2, 2018.

    • Search Google Scholar
    • Export Citation
  • 70.

    U.S. Preventive Services Task Force. Screening for osteoporosis: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2011;154:356364.

    • Search Google Scholar
    • Export Citation
  • 71.

    Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. Children's Oncology Group website. Available at: www.survivorshipguidelines.org. Accessed August 2, 2018.

    • Search Google Scholar
    • Export Citation
  • 72.

    Muka T, Oliver-Williams C, Kunutsor S. Association of age at onset of menopause and time since onset of menopause with cardiovascular outcomes, intermediate vascular traits, and all-cause mortality. JAMA Cardiol 2016;1:767776.

    • Search Google Scholar
    • Export Citation
  • 73.

    Langrish JP, Mills NL, Bath LE. Cardiovascular effects of physiological and standard sex steroid replacement regimens in premature ovarian failure. Hypertension 2009;53:805811.

    • Search Google Scholar
    • Export Citation
  • 74.

    Cook ED, Iglehart EI, Baum G. Missing documentation in breast cancer survivors. Menopause 2017;24:13601364.

  • 75.

    Lindau ST, Abramsohn EM, Matthews AC. A manifesto on the preservation of sexual function in women and girls with cancer. Am J Obstet Gynecol 2015;213:166174.

    • Search Google Scholar
    • Export Citation
  • 76.

    Pereira N, Schattman GL. Fertility preservation and sexual health after cancer therapy. J Oncol Pract 2017;13:643651.

  • 77.

    Carter J, Stabile C, Seidel B. Vaginal and sexual health treatment strategies within a female sexual medicine program for cancer patients and survivors. J Cancer Surviv 2017;11:274283.

    • Search Google Scholar
    • Export Citation
  • 78.

    Rocca WA, Bower JH, Maraganore DM. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology 2007;69:10741083.

    • Search Google Scholar
    • Export Citation
  • 79.

    Rocca WA, Bower JH, Maraganore DM. Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology 2008;70:200209.

    • Search Google Scholar
    • Export Citation
  • 80.

    Vearncombe KJ, Rolfe M, Wright M. Predictors of cognitive decline after chemotherapy in breast cancer patients. J Int Neuropsychol Soc 2009;15:951962.

    • Search Google Scholar
    • Export Citation
  • 81.

    Scott EL, Zhang QG, Vadlamudi RK, Brann DW. Premature menopause and risk of neurological disease: basic mechanisms and clinical implications. Mol Cell Endocrinol 2014;389:26.

    • Search Google Scholar
    • Export Citation
  • 82.

    Cramer H, Rabsilber S, Lauche R. Yoga and meditation for menopausal symptoms in breast cancer survivors—a randomized controlled trial. Cancer 2015;121:21752184.

    • Search Google Scholar
    • Export Citation
  • 83.

    Moskowitz CS, Chou JF, Sklar CA. Radiation-associated breast cancer and gonadal hormone exposure: a report from the Childhood Cancer Survivor Study. Br J Cancer 2017;117:290299.

    • Search Google Scholar
    • Export Citation
  • 84.

    Hudson MM, Ness KK, Gurney JG. Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 2013;309:23712381.

  • 85.

    Mewes JC, Steuten LM, Duijts SF. Cost-effectiveness of cognitive behavioral therapy and physical exercise for alleviating treatment-induced menopausal symptoms in breast cancer patients. J Cancer Surviv 2015;9:126135.

    • Search Google Scholar
    • Export Citation
  • 86.

    Atema V, van Leeuwen M, Oldenburg HS. An internet-based cognitive behavioral therapy for treatment-induced menopausal symptoms in breast cancer survivors. Menopause 2017;24:762767.

    • Search Google Scholar
    • Export Citation
  • 87.

    Nekhlyudov L, Aziz NM, Lerro C, Virgo KS. Oncologists' and primary care physicians' awareness of late and long-term effects of chemotherapy: implications for care of the growing population of survivors. J Oncol Pract 2014;10:e2936.

    • Search Google Scholar
    • Export Citation
  • 88.

    Cohen PA, Brennan A, Marino JL. Managing menopausal symptoms after breast cancer—a multidisciplinary approach. Maturitas 2017;105:47.

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 592 380 24
PDF Downloads 409 291 31
EPUB Downloads 0 0 0