Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Late endocrine effects of childhood cancer

Key Points

  • Endocrine sequelae in survivors of childhood cancer depend on sex, age and pubertal stage at the time of cancer therapy, and on tumour location and therapeutic interventions

  • Each cancer therapy, including drugs and radiation, can result in a distinct profile of endocrinopathies; each cancer survivor should undergo endocrine monitoring targeted to the risks conferred by their cancer therapies

  • Obesity and metabolic disease are late endocrine effects that require screening, lifestyle management, treatment of other coexisting endocrinopathies and targeted pharmacological or surgical therapy to prevent early cardiovascular morbidity

  • Endocrine treatments should be used for standard indications in survivors of childhood cancer, supervised by an experienced endocrinologist

  • Health-care providers should remain vigilant to issues related to fertility and sexual dysfunction and refer patients to specialists for counselling and management as needed

  • Adult survivors of childhood and adolescent cancers require a purposeful and planned transition to a multidisciplinary adult care team with the capacity to guide long-term screening, prevention and therapeutic care interventions

Abstract

The cure rate for paediatric malignancies is increasing, and most patients who have cancer during childhood survive and enter adulthood. Surveillance for late endocrine effects after childhood cancer is required to ensure early diagnosis and treatment and to optimize physical, cognitive and psychosocial health. The degree of risk of endocrine deficiency is related to the child's sex and their age at the time the tumour is diagnosed, as well as to tumour location and characteristics and the therapies used (surgery, chemotherapy or radiation therapy). Potential endocrine problems can include growth hormone deficiency, hypothyroidism (primary or central), adrenocorticotropin deficiency, hyperprolactinaemia, precocious puberty, hypogonadism (primary or central), altered fertility and/or sexual function, low BMD, the metabolic syndrome and hypothalamic obesity. Optimal endocrine care for survivors of childhood cancer should be delivered in a multidisciplinary setting, providing continuity from acute cancer treatment to long-term follow-up of late endocrine effects throughout the lifespan. Endocrine therapies are important to improve long-term quality of life for survivors of childhood cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Survivors of childhood cancer are at increased risk of a range of late endocrine effects.

Similar content being viewed by others

References

  1. CureSearch Children's Oncology Group. Childhood cancer survivor statistics. CureSearch[online], (2015).

  2. Robison, L. L. & Hudson, M. M. Survivors of childhood and adolescent cancer: life-long risks and responsibilities. Nat. Rev. Cancer 14, 61–70 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Hudson, M. M. et al. Clinical ascertainment of health outcomes among adults treated for childhood cancer. J. Am. Med. Assoc. 309, 2371–2381 (2013).

    Article  CAS  Google Scholar 

  4. Bhatia, S. Cancer survivorship — pediatric issues. Hematology Am. Soc. Hematol. Educ. Program 507–515 (2005).

  5. Landier, W. & Bhatia, S. Cancer survivorship: a pediatric perspective. Oncologist 13, 1181–1192 (2008).

    Article  PubMed  Google Scholar 

  6. Nandagopal, R. et al. Endocrine late effects of childhood cancer therapy: a report from the Children's Oncology Group. Horm. Res. 69, 65–74 (2008).

    CAS  PubMed  Google Scholar 

  7. Leung, W. et al. A prospective cohort study of late sequelae of pediatric allogeneic hematopoietic stem cell transplantation. Medicine (Baltimore) 86, 215–224 (2007).

    Article  Google Scholar 

  8. Rutter, M. M. & Rose, S. R. Long-term endocrine sequelae of childhood cancer. Curr. Opin. Pediatr. 19, 480–487 (2007).

    Article  PubMed  Google Scholar 

  9. Chemaitilly, W. & Sklar, C. A. Endocrine complications in long-term survivors of childhood cancers. Endocr. Relat. Cancer. 17, R141–R159 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Patterson, B. C. et al. Endocrine health problems detected in 519 patients evaluated in a pediatric cancer survivor program. J. Clin. Endocrinol. Metab. 97, 810–818 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. Dickerman, J. D. The late effects of childhood cancer therapy. Pediatrics 119, 554–568 (2007).

    Article  PubMed  Google Scholar 

  12. Savage, L. J. & Murray, R. D. Late effects of cancer therapy on growth and GH. Int. Growth Monitor. 16, 2–7 (2006).

    Google Scholar 

  13. Schwartz, C. L., Hobbie, W. L., Constine, L. S. & Ruccione, K. S. (eds) in Survivors of Childhood and Adolescent Cancer: A Multidisciplinary Approach 3rd edn 1–13; 151–166; 253–281; 339–351; 369–384 (Springer-Verlag, 2015).

    Book  Google Scholar 

  14. Couto-Silva, A. C., Brauner, R. & Adan, L. F. Endocrine sequelae after radiotherapy in childhood and adolescence. Arq. Bras. Endocrinol. Metabol. 49, 825–832 (2005).

    Article  PubMed  Google Scholar 

  15. Van Dorp, W. Long-term endocrine side effects of childhood Hodgkin's lymphoma treatment: a review. Hum. Reprod. Update 18, 12–28 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Francis, G. L. et al. Management guidelines for children with thyroid nodules and differentiated thyroid cancer. Thyroid 25, 716–759 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Landier, W. et al. Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers. Children's Oncology Group [online], (2015).

  18. Tulandi, T. G. & Gosden, R. G. (eds) Preservation of Fertility (Taylor & Francis, 2004).

  19. Wallace, W. H., Anderson, R. A. & Irvine, D. S. Fertility preservation for young patients with cancer: who is at risk and what can be offered? Lancet Oncol. 6, 209–218 (2005).

    Article  PubMed  Google Scholar 

  20. Servitzoglou, M. et al. Dose-effect relationship of alkylating agents on testicular function in male survivors of childhood lymphoma. Pediatr. Hematol. Oncol. 32, 613–623 (2015).

    Article  CAS  PubMed  Google Scholar 

  21. Kobayashi, H. et al. Testicular morphological changes in children with acute lymphoblastic leukemia following chemotherapy. Acta Paediatr. Jpn 38, 640–643 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Molina, J. R., Barton, D. L. & Loprinzi, C. L. Chemotherapy-induced ovarian failure: manifestations and management. Drug Saf. 28, 401–416 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Committee on Adolescent Health Care. Primary ovarian insufficiency in adolescents and young women. Obstet. Gynecol. 124, 193–197 (2014).

  24. Levine, J. in Oncofertility Medical Practice: Clinical Issues and Implementation (eds Gracia, C. & Woodruff, T. K.) 3–14 (Springer, 2012).

  25. Lee, S. J. et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J. Clin. Oncol. 24, 2917–2931 (2006).

    Article  PubMed  Google Scholar 

  26. Haddy, T. B., Mosher, R. B., Nunez, S. B. & Reaman, G. H. Growth hormone deficiency after chemotherapy for acute lymphoblastic leukemia in children who have not received cranial radiation. Pediatr. Blood Cancer 46, 258–261 (2006).

    Article  PubMed  Google Scholar 

  27. Hogler, W. et al. Incidence of skeletal complications during treatment of childhood acute lymphoblastic leukemia: comparison of fracture risk with general practice research database. Pediatr. Blood Cancer 48, 21–27 (2007).

    Article  PubMed  Google Scholar 

  28. Thomas, I. H. et al. Bone mineral density in young adult survivors of acute lymphoblastic leukemia. Cancer 113, 3248–3256 (2008).

    Article  PubMed  Google Scholar 

  29. Muszynska-Roslan, K. et al. Little evidence of low bone mass in acute lymphoblastic leukemia survivors. J. Clin. Densitom. 15, 108–115 (2012).

    Article  PubMed  Google Scholar 

  30. Alikasifoglu, A. et al. Bone mineral density and serum bone turnover markers in survivors of childhood acute lymphoblastic leukemia: comparison of megadose methylprednisolone and conventional-dose prednisolone treatments. Am. J. Hematol. 80, 113–118 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Hochberg, J., El-Mallawany, N. K. & Cairo, M. S. Humoral and cellular immunotherapy in ALL in children, adolescents, and young adults. Clin. Lymphoma Myeloma Leuk. 14, S6–S13 (2014).

    Article  PubMed  Google Scholar 

  32. Torino, F. et al. Endocrine side-effects of anti-cancer drugs: mAbs and pituitary dysfunction: clinical evidence and pathogenic hypotheses. Eur. J. Endocrinol. 169, R153–R164 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Ishida, Y. et al. Late effects and quality of life of childhood cancer survivors: part 2. Impact of radiotherapy. Int. J. Hematol. 92, 95–104 (2010).

    Article  PubMed  Google Scholar 

  34. Chow, E. J. et al. Differential effects of radiotherapy on growth and endocrine function among acute leukemia survivors: a childhood cancer survivor study report. Pediatr. Blood Cancer 60, 110–115 (2013).

    Article  PubMed  Google Scholar 

  35. Rizzo, J. D. et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation. Biol. Blood Marrow Transplant. 12, 138–151 (2006).

    Article  PubMed  Google Scholar 

  36. Felicetti, F. et al. Endocrine late effects after total body irradiation in patients who received hematopoietic cell transplantation during childhood: a retrospective study from a single institution. J. Cancer Res. Clin. Oncol. 137, 1343–1348 (2011).

    Article  PubMed  Google Scholar 

  37. van Dijk, I. W. et al. Dose–effect relationships for adverse events after cranial radiation therapy in long-term childhood cancer survivors. Int. J. Radiat. Oncol. Biol. Phys. 85, 768–775 (2013).

    Article  PubMed  Google Scholar 

  38. Wessel, T. et al. Age at menarche in childhood cancer survivors: results of a nationwide survey in Germany. Horm. Res. Paediatr. 77, 108–114 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Shalitin, S. et al. Endocrine outcome in long-term survivors of childhood brain tumors. Horm. Res. Paediatr. 76, 113–122 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Rose, S. R., Danish, R. K., Kearney, N. S., Schreiber, R. E. & Hudson, M. M. ACTH deficiency in childhood cancer survivors. Pediatr. Blood Cancer 45, 808–813 (2005).

    Article  PubMed  Google Scholar 

  41. Patterson, B. C. et al. Adrenal function testing in pediatric cancer survivors. Pediatr. Blood Cancer 53, 1302–1307 (2009).

    Article  PubMed  Google Scholar 

  42. Haller, M. J. & Schatz, D. A. Endocrine complications of childhood cancer therapy: evaluation and management. Pediatr. Endocrinol. Rev. 4, 196–204 (2007).

    PubMed  Google Scholar 

  43. Byrne, J. et al. Fertility in women treated with cranial radiotherapy for childhood acute lymphoblastic leukemia. Pediatr. Blood Cancer 42, 589–597 (2004).

    Article  PubMed  Google Scholar 

  44. Rose, S. R., Lawson, S., Burns, K. & Merchant, T. E. in Survivors of Childhood and Adolescent Cancer: A Multidisciplinary Approach 3rd edn (eds Schwartz, C. L. et al.) 65–94 (Springer-Verlag, 2015).

    Book  Google Scholar 

  45. Vinchon, M. et al. Craniopharyngioma and hypothalamic obesity in children. Childs Nerv. Syst. 25, 347–352 (2009).

    Article  PubMed  Google Scholar 

  46. Lustig, R. H. et al. Risk factors for the development of obesity in children surviving brain tumors. J. Clin. Endocrinol. Metab. 88, 611–616 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Rose, S. R. Clinical utility of time-of-day normal ranges for TSH. J. Pediatr. 157, 662–667 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Patterson, B. C. et al. Growth hormone exposure as a risk factor for the development of subsequent neoplasms of the central nervous system: a report from the childhood cancer survivor study. J. Clin. Endocrinol. Metab. 99, 2030–2037 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Chow, E. J. et al. Risk of thyroid dysfunction and subsequent thyroid cancer among survivors of acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. Pediatr. Blood Cancer 53, 432–437 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Sklar, C. et al. Abnormalities of the thyroid in survivors of Hodgkin's disease: data from the Childhood Cancer Survivor Study. J. Clin. Endocrinol. Metab. 85, 3227–3232 (2000).

    CAS  PubMed  Google Scholar 

  51. Bhatti, P. et al. Risk of second primary thyroid cancer after radiotherapy for a childhood cancer in a large cohort study: an update from the childhood cancer survivor study. Radiat. Res. 174, 741–752 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Cooper, D. S. et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19, 1167–1214 (2009).

    Article  PubMed  Google Scholar 

  53. McMullen, T. et al. Hyperparathyroidism after irradiation for childhood malignancy. Int. J. Radiat. Oncol. Biol. Phys. 73, 1164–1168 (2009).

    Article  PubMed  Google Scholar 

  54. Wilson, S. D. et al. Primary hyperparathyroidism with a history of head and neck irradiation: the consequences of associated thyroid tumors. Surgery 150, 869–877 (2011).

    Article  PubMed  Google Scholar 

  55. Taylor, A. J. et al. Risk of thyroid cancer in survivors of childhood cancer: results from the British Childhood Cancer Survivor Study. Int. J. Cancer 125, 2400–2405 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Chen, S. H. et al. Surgical correction of postradiation spinal deformity. Chang Gung Med. J. 26, 160–169 (2003).

    PubMed  Google Scholar 

  57. Hovi, L. et al. Growth in children with poor-risk neuroblastoma after regimens with or without total body irradiation in preparation for autologous bone marrow transplantation. Bone Marrow Transplant. 24, 1131–1136 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Xu, W., Janss, A. & Moshang, T. Adult height and adult sitting height in childhood medulloblastoma survivors. J. Clin. Endocrinol. Metab. 88, 4677–4681 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Stava, C. J., Jimenez, C. & Vassilopoulou-Sellin, R. Endocrine sequelae of cancer and cancer treatments. J. Cancer Surviv. 1, 261–274 (2007).

    Article  PubMed  Google Scholar 

  60. Byrne, J. et al. Fertility of long-term male survivors of acute lymphoblastic leukemia diagnosed during childhood. Pediatr. Blood Cancer 42, 364–372 (2004).

    Article  PubMed  Google Scholar 

  61. Klose, M. et al. From isolated GH deficiency to multiple pituitary hormone deficiency: an evolving continuum — a KIMS analysis. Eur. J. Endocrinol. 161, S75–S83 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Green, D. M. et al. Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the childhood cancer survivor study. J. Clin. Oncol. 27, 2374–2381 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Vantyghem, M. C. et al. Management of endocrino-metabolic dysfunctions after allogeneic hematopoietic stem cell transplantation. Orphanet J. Rare Dis. 9, 162 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Perkins, J. L. et al. Long-term follow-up of children who underwent hematopoeitic cell transplant (HCT) for AML or ALL at less than 3 years of age. Pediatr. Blood Cancer 49, 958–963 (2007).

    Article  PubMed  Google Scholar 

  65. Lucchini, G. & Bader, P. Hematopoietic stem cell transplantation and immunotherapy for pediatric acute myeloid leukemia: an open challenge. Expert Rev. Hematol. 7, 291–300 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. Blijdorp, K. et al. Endocrine sequelae and metabolic syndrome in adult long-term survivors of childhood acute myeloid leukemia. Leuk. Res. 37, 367–371 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Leung, W. et al. A prospective cohort study of late sequelae of pediatric allogenic hematopoietic stem cell transplantation. Medicine 86, 215–224 (2007).

    Article  PubMed  Google Scholar 

  68. Mulder, R. L. et al. Prevalence and risk factors of radiation-induced growth hormone deficiency in childhood cancer survivors: a systematic review. Cancer Treat. Rev. 35, 616–632 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Vinchon, M., Baroncini, M., Leblond, P. & Delestret, I. Morbidity and tumor-related mortality among adult survivors of pediatric brain tumors: a review. Childs Nerv. Syst. 27, 697–704 (2011).

    Article  PubMed  Google Scholar 

  70. Hamre, H. et al. Gonadal function and parenthood 20 years after treatment for childhood lymphoma: a cross-sectional study. Pediatr. Blood Cancer 59, 271–277 (2012).

    Article  PubMed  Google Scholar 

  71. van Dorp, W. et al. Long-term endocrine side effects of childhood Hodgkin's lymphoma treatment: a review. Hum. Reprod. Update 18, 12–28 (2012).

    Article  CAS  PubMed  Google Scholar 

  72. Green, D. M. et al. Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study. J. Clin. Oncol. 27, 2374–2381 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Wikström, A. M., Hovi, L., Dunkel, L. & Saarinen-Pihkala, U. M. Restoration of ovarian function after chemotherapy for osteosarcoma. Arch. Dis. Child. 88, 428–431 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Gaspar, N. et al. Ewing sarcoma: current management and future approaches through collaboration. J. Clin. Oncol. 33, 3036–3046 (2015).

    Article  CAS  PubMed  Google Scholar 

  75. Kubota, M. et al. Long-term follow-up status of patients with neuroblastoma after undergoing either aggressive surgery or chemotherapy — a single institutional study. J. Pediatr. Surg. 39, 1328–1332 (2004).

    Article  PubMed  Google Scholar 

  76. Martin, A. et al. Secondary malignant neoplasms after high-dose chemotherapy and autologous stem cell rescue for high-risk neuroblastoma. Pediatr. Blood Cancer 61, 1350–1356 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. Clement, S. C. et al. Long-term follow-up of the thyroid gland after treatment with 131I-Metaiodobenzylguanidine in children with neuroblastoma: importance of continuous surveillance. Pediatr. Blood Cancer 60, 1833–1838 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Punyko, J. A. et al. Long-term medical effects of childhood and adolescent rhabdomyosarcoma: a report from the childhood cancer survivor study. Pediatr. Blood Cancer 44, 643–653 (2005).

    Article  PubMed  Google Scholar 

  79. Lam, K. S. et al. Effects of cranial irradiation on hypothalamic-pituitary function — a 5-year longitudinal study in patients with nasopharyngeal carcinoma. Q. J. Med. 78, 165–176 (1991).

    CAS  PubMed  Google Scholar 

  80. Liamis, G., Milionis, H. J. & Elisaf, M. Endocrine disorders: causes of hyponatremia not to neglect. Ann. Med. 43, 179–187 (2011).

    Article  PubMed  Google Scholar 

  81. Diederich, S., Franzen, N. F., Bähr, V. & Oelkers, W. Severe hyponatremia due to hypopituitarism with adrenal insufficiency: report on 28 cases. Eur. J. Endocrinol. 148, 609–617 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Sklar, C. A. & Constine, L. S. Chronic neuro-endocrinological sequelae of radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 31, 1113–1120 (1995).

    Article  CAS  PubMed  Google Scholar 

  83. Laughton, S. J. et al. Endocrine outcomes for children with embryonal brain tumors after risk adapted craniospinal and conformal primary-site irradiation and high-dose chemotherapy with stem cell rescue on the SJMB-96 trial. J. Clin. Oncol. 26, 1112–1118 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Brennan, B. M. et al. Growth hormone status in adults treated for acute lymphoblastic leukemia in childhood. Clin. Endocrinol. (Oxf.) 48, 777–783 (1998).

    Article  CAS  Google Scholar 

  85. Robinson, I. C., Fairhall, K. M., Hendry, J. H. & Shalet, S. M. Differential radiosensitivity of hypothalamo-pituitary function in the young adult rat. J. Endocrinol. 169, 519–526 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. Darzy, K. H. Radiation-induced hypopituitarism after cancer therapy: who, how and when to test. Nat. Clin. Pract. Endocrinol. Metab. 5, 88–99 (2009).

    Article  CAS  PubMed  Google Scholar 

  87. Blatt, J. et al. Reduced pulsatile growth hormone secretion in children after therapy for acute lymphoblastic leukemia. J. Pediatr. 104, 182–186 (1984).

    Article  CAS  PubMed  Google Scholar 

  88. Merchant, T. E. et al. Growth hormone secretion after conformal radiation therapy in pediatric patients with localized brain tumors. J. Clin. Oncol. 29, 4776–4780 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Gilchrist, F. J., Murray, R. D. & Shalet, S. M. The effect of long-term untreated growth hormone deficiency (GHD) and 9 years of GH replacement on the quality of life (QoL) of GH-deficient adults. Clin. Endocrinol. (Oxf.) 57, 363–370 (2002).

    Article  CAS  Google Scholar 

  90. Sklar, C. A. Growth and neuroendocrine dysfunction following therapy for childhood cancer. Pediatr. Clin. North Am. 44, 489–503 (1997).

    Article  CAS  PubMed  Google Scholar 

  91. Leung, W. et al. Late effects of treatment in survivors of childhood acute myeloid leukemia. J. Clin. Oncol. 18, 3273–3279 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Leung, W. et al. Outcomes of growth hormone replacement therapy in survivors of childhood acute lymphoblastic leukemia. J. Clin. Oncol. 20, 2959–2964 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Shalet, S. M. Growth hormone deficiency after treatment of acute leukemia in children. Arch. Dis. Child. 51, 489–493 (1976).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Shalet, S. M. Radiation and pituitary dysfunction. N. Engl. J. Med. 328, 131–133 (1993).

    Article  CAS  PubMed  Google Scholar 

  95. Schmiegelow, M. et al. Growth hormone response to a growth hormone-releasing hormone stimulation test in a population-based study following cranial irradiation of childhood brain tumors. Horm. Res. 54, 53–59 (2000).

    CAS  PubMed  Google Scholar 

  96. Darzy, K. H., Pezzoli, S. S., Thorner, M. O. & Shalet, S. M. The dynamics of growth hormone (GH) secretion in adult cancer survivors with severe GH deficiency acquired after brain irradiation in childhood for nonpituitary brain tumors: evidence for preserved pulsatility and diurnal variation with increased secretory disorderliness. J. Clin. Endocrinol. Metab. 90, 2794–2803 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. J. Clin. Endocrinol. Metab. 85, 3990–3993 (2000).

  98. Wilson, T. A. et al. Update of guidelines for the use of growth hormone in children: The Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee. J. Pediatr. 143, 415–421 (2003).

    Article  PubMed  Google Scholar 

  99. Rose, S. R. et al. The advantage of measuring stimulated as compared with spontaneous growth hormone levels in the diagnosis of growth hormone deficiency. N. Engl. J. Med. 319, 201–207 (1988).

    Article  CAS  PubMed  Google Scholar 

  100. Sklar, C., Sarafoglou, K. & Whittam, E. Efficacy of insulin-like growth factor binding protein 3 in predicting the growth hormone response to provocative testing in children treated with cranial irradiation. Acta Endocrinol. (Copenh.) 129, 511–515 (1993).

    Article  CAS  Google Scholar 

  101. Cummings, D. E. & Merriam, G. R. Growth hormone therapy in adults. Annu. Rev. Med. 54, 513–533 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Adan, L. et al. GH deficiency caused by cranial irradiation during childhood: factors and markers in young adults. J. Clin. Endocrinol. Metab. 86, 5245–5251 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Molitch, M. E. et al. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 96, 1587–1609 (2011).

    Article  CAS  PubMed  Google Scholar 

  104. Cook, D. M. et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in growth hormone-deficient adults and transition patients — 2009 update. Endocr. Pract. 15 (Suppl. 2), 1–29 (2009).

    Article  PubMed  Google Scholar 

  105. Darendeliler, F. et al. Recurrence of brain tumours in patients treated with growth hormone: analysis of KIGS (Pfizer International Growth Database). Acta Paediatr. 95, 1284–1290 (2006).

    Article  PubMed  Google Scholar 

  106. Chung, T. T. et al. Tumour surveillance imaging in patients with extrapituitary tumours receiving growth hormone replacement. Clin. Endocrinol. (Oxf.) 63, 274–279 (2005).

    Article  CAS  Google Scholar 

  107. Ferry, R. J. Jr, Cohen, P. & Levitt Katz, L. E. Pharmacodynamic considerations with recombinant human insulin-like growth factor-I in children. Horm. Res. 63, 220–227 (2005).

    PubMed  CAS  Google Scholar 

  108. Appelman-Dijkstra, N. M. et al. Pituitary dysfunction in adult patients after cranial irradiation for head and nasopharyngeal tumours. Radiother. Oncol. 113, 102–107 (2014).

    Article  PubMed  Google Scholar 

  109. Hovi, L., Saarinen-Pihkala, U. M., Vettenranta, K., Lipsanen, M. & Tapanainen, P. Growth in children with poor-risk neuroblastoma after regimens with or without total body irradiation in preparation for autologous bone marrow transplantation. Bone Marrow Transplant. 24, 1131–1136 (1999).

    Article  CAS  PubMed  Google Scholar 

  110. Follin, C., Thilén, U., Ahrén, B. & Erfurth, E. M. Improvement in cardiac systolic function and reduced prevalence of metabolic syndrome after two years of growth hormone (GH) treatment in GH-deficient adult survivors of childhood-onset acute lymphoblastic leukemia. J. Clin. Endocrinol. Metab. 91, 1872–1875 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Maiter, D. et al. Baseline characteristics and response to GH replacement of hypopituitary patients previously irradiated for pituitary adenoma or craniopharyngioma: data from the Pfizer International Metabolic Database. Eur. J. Endocrinol. 155, 253–260 (2006).

    Article  CAS  PubMed  Google Scholar 

  112. Child, C. J. et al. Incidence of primary cancers and intracranial tumour recurrences in GH-treated and untreated adult hypopituitary patients: analyses from the Hypopituitary Control and Complications Study. Eur. J. Endocrinol. 172, 779–790 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. van den Heijkant, S. et al. Effects of growth hormone therapy on bone mass, metabolic balance, and well-being in young adult survivors of childhood acute lymphoblastic leukemia. J. Pediatr. Hematol. Oncol. 33, e231–e238 (2011).

    Article  CAS  PubMed  Google Scholar 

  114. Brod, M. et al. Impact of adult growth hormone deficiency on daily functioning and well-being. BMC Res. Notes 7, 813 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Rose, S. R. Isolated central hypothyroidism in short stature. Pediatr. Res. 38, 967–973 (1995).

    Article  CAS  PubMed  Google Scholar 

  116. Baloch, Z. et al. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 13, 3–126 (2003).

    Article  PubMed  Google Scholar 

  117. Rose, S. R. et al. Diagnosis of hidden central hypothyroidism in survivors of childhood cancer. J. Clin. Endocrinol. Metab. 84, 4472–4479 (1999).

    CAS  PubMed  Google Scholar 

  118. Ferretti, E. et al. Evaluation of the adequacy of levothyroxine replacement in patients with central hypothyroidism. J. Clin. Endocrinol. Metab. 84, 924–929 (1999).

    CAS  PubMed  Google Scholar 

  119. Kazlauskaite, R. et al. Corticotropin tests for hypothalamic-pituitary adrenal insufficiency: a metaanalysis. J. Clin. Endocrinol. Metab. 93, 4245–4253 (2008).

    Article  CAS  PubMed  Google Scholar 

  120. Rose, S. R. et al. ACTH deficiency in childhood cancer survivors. Pediatr. Blood Cancer 45, 808–813 (2005).

    Article  PubMed  Google Scholar 

  121. Bornstein, S. R. et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 101, 364–389 (2016).

    Article  CAS  PubMed  Google Scholar 

  122. Constine, L. S. et al. Hypothalamic-pituitary dysfunction after radiation for brain tumors. N. Engl. J. Med. 328, 87–94 (1993).

    Article  CAS  PubMed  Google Scholar 

  123. Yanovski, J. A. et al. Treatment with a luteinizing hormone-releasing hormone agonist in adolescents with short stature. N. Engl. J. Med. 348, 908–917 (2003).

    Article  CAS  PubMed  Google Scholar 

  124. Oberfield, S. E. et al. Age at onset of puberty following high-dose central nervous system radiation therapy. Arch. Pediatr. Adolesc. Med. 150, 589–592 (1996).

    Article  CAS  PubMed  Google Scholar 

  125. Armstrong, G. T. et al. Abnormal timing of menarche in survivors of central nervous system tumors: a report from the Childhood Cancer Survivor Study. Cancer 115, 2562–2570 (2009).

    Article  PubMed  Google Scholar 

  126. Ogilvy-Stuart, A. L., Clayton, P. E. & Shalet, S. M. Cranial irradiation and early puberty. J. Clin. Endocrinol. Metab. 78, 1282–1286 (1994).

    CAS  PubMed  Google Scholar 

  127. Walvoord, E. The timing of puberty: is it changing? Does it matter? J. Adolesc. Health 47, 433–439 (2010).

    Article  PubMed  Google Scholar 

  128. Carel, J. C. & Leger, J. Precocious puberty. N. Engl. J. Med. 358, 2366–2377 (2008).

    Article  CAS  PubMed  Google Scholar 

  129. Berberoglu, M. Precocious puberty and normal variant puberty: definition, etiology, diagnosis and current management. J. Clin. Res. Pediatr. Endocrinol. 1, 164–174 (2009).

    Article  PubMed  Google Scholar 

  130. Carel, J. C. et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics 123, e752–e762 (2009).

    Article  PubMed  Google Scholar 

  131. Cassorla, F. et al. Effects of luteinizing hormone-releasing hormone analog-induced pubertal delay in growth hormone (GH)-deficient children treated with GH: preliminary results. J. Clin. Endocrinol. Metab. 82, 3989–3992 (1997).

    CAS  PubMed  Google Scholar 

  132. Cafasso, M. et al. Clinical efficacy of three month depot GnRH agonist in suppression of central puberty. J. Nurse Pract. 11, 686–694 (2015).

    Article  Google Scholar 

  133. Hirsch, H. J. et al. The histrelin implant: a novel treatment for central precocious puberty. Pediatrics 116, e798–e802 (2005).

    Article  PubMed  Google Scholar 

  134. Leader, A., Lishner, M., Michaeli, J. & Revel, A. Fertility considerations and preservation in haemato-oncology patients undergoing treatment. Br. J. Haematol. 15, 291–308 (2011).

    Article  Google Scholar 

  135. [No authors listed.] Committee opinion no. 607. Gynecologic concerns in children and adolescents with cancer. Obstet. Gynecol. 124, 403–408 (2014).

  136. Waimey, K. E. et al. Understanding fertility in young female cancer patients. J. Womens Health 24, 812–818 (2015).

    Article  Google Scholar 

  137. Knobf, M. T. The influence of endocrine effects of adjuvant therapy on quality of life outcomes in younger breast cancer survivors. Oncologist 11, 96–110 (2006).

    Article  PubMed  Google Scholar 

  138. Nieman, C. L. et al. Cancer survivors and infertility: a review of a new problem and novel answers. J. Support. Oncol. 4, 171–178 (2006).

    PubMed  Google Scholar 

  139. Green, D. M. et al. Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study. J. Clin. Oncol. 27, 2374–2381 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Sadri-Ardekani, H. & Atala, A. Testicular tissue cryopreservation and spermatogonial stem cell transplantation to restore fertility: from bench to bedside. Stem Cell Res. Ther. 5, 68 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Rowley, M. J., Leach, D. R., Warner, G. A. & Heller, C. G. Effect of graded doses of ionizing radiation on the human testis. Radiat. Res. 59, 665–678 (1974).

    Article  CAS  PubMed  Google Scholar 

  142. Izard, M. A. Leydig cell function and radiation: a review of the literature. Radiother. Oncol. 34, 1–8 (1995).

    Article  CAS  PubMed  Google Scholar 

  143. Faddy, M. J. Follicle dynamics during ovarian ageing. Mol. Cell. Endocrinol. 163, 43–48 (2000).

    Article  CAS  PubMed  Google Scholar 

  144. Committee on Gynecologic Practice. Committee opinion no. 618. Ovarian reserve testing. Obstet. Gynecol. 125, 268–273 (2015).

  145. Nelson, L. M. Clinical practice. Primary ovarian insufficiency. N. Engl. J. Med. 360, 606–614 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Welt, C. K. Primary ovarian insufficiency: a more accurate term for premature ovarian failure. Clin. Endocrinol. (Oxf.) 68, 499–509 (2008).

    Article  Google Scholar 

  147. Chemaitilly, W. et al. Acute ovarian failure in the childhood cancer survivor study. J. Clin. Endocrinol. Metab. 91, 1723–1728 (2006).

    Article  CAS  PubMed  Google Scholar 

  148. Sklar, C. A. et al. Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J. Natl Cancer Inst. 98, 890–896 (2006).

    Article  PubMed  Google Scholar 

  149. Metzger, M. L. et al. Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J. Clin. Oncol. 31, 1239–1247 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Levi, M. et al. Anti-Müllerian hormone is a marker for chemotherapy-induced testicular toxicity. Endocrinology 156, 3818–3827 (2015).

    Article  CAS  PubMed  Google Scholar 

  151. Pfaff, T. et al. Inhibin B as a marker of sertoli cell damage and spermatogenic disturbance in the rat. Birth Defects Res. B. Dev. Reprod. Toxicol. 98, 91–103 (2013).

    Article  CAS  PubMed  Google Scholar 

  152. Tuttelmann, F. et al. Anti-Müllerian hormone in men with normal and reduced sperm concentration and men with maldescended testes. Fertil. Steril. 91, 1812–1819 (2009).

    Article  CAS  PubMed  Google Scholar 

  153. DiVasta, A. D. & Gordon, C. M. Hormone replacement therapy for the adolescent patient. Ann. NY Acad. Sci. 1135, 204–211 (2008).

    Article  CAS  PubMed  Google Scholar 

  154. Han, T. S. & Bouloux, P. M. What is the optimal therapy for young males with hypogonadotrophic hypogonadism? Clin. Endocrinol. (Oxf.) 72, 731–737 (2010).

    Article  CAS  Google Scholar 

  155. Davenport, M. L. Moving toward an understanding of hormone replacement therapy in adolescent girls: looking through the lens of Turner syndrome. Ann. NY Acad. Sci. 1135, 126–137 (2008).

    Article  CAS  PubMed  Google Scholar 

  156. Van Kasteren, Y. M. & Schoemaker, J. Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum. Reprod. Update 5, 483–492 (1999).

    Article  CAS  PubMed  Google Scholar 

  157. Ethics Committee of American Society for Reproductive Medicine. Fertility preservation and reproduction in patients facing gonadotoxic therapies: a committee opinion. Fertil. Steril. 100, 1224–1231 (2013).

  158. Gracia, C. R. et al. Ovarian tissue cryopreservation for fertility preservation in cancer patients: successful establishment and feasibility of a multidisciplinary collaboration. J. Assist. Reprod. Genet. 29, 495–502 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Marchak, J. G. et al. Perceptions of infertility risks among female pediatric cancer survivors following gonadotoxic therapy. J. Pediatr. Hematol. Oncol. 37, 368–372 (2015).

    Article  CAS  Google Scholar 

  160. Loren, A. W. et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J. Clin. Oncol. 31, 2500–2510 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Blumenfeld, Z., Katz, G. & Evron, A. 'An ounce of prevention is worth a pound of cure': the case for and against GnRH-agonist for fertility preservation. Ann. Oncol. 25, 1719–1728 (2014).

    Article  CAS  PubMed  Google Scholar 

  162. Milsom, S. et al. Treatment of infertility with hypogonadotropic hypogonadism: 10-year experience in Auckland, New Zealand. Aust. N. Z. J. Obstet. Gynaecol. 52, 293–298 (2012).

    Article  PubMed  Google Scholar 

  163. Dwyer, A. A., Raivio, T. & Pitteloud, N. Gonadotrophin replacement for induction of fertility in hypogonadal men. Best Pract. Res. Clin. Endocrinol. Metab. 29, 91–103 (2015).

    Article  CAS  PubMed  Google Scholar 

  164. Critchley, H. O. et al. Abdominal irradiation in childhood: the potential for pregnancy. Br. J. Obstet. Gynaecol. 99, 392–394 (1992).

    Article  CAS  PubMed  Google Scholar 

  165. Ben-Nagi, J. & Penay, N. et al. Premature ovarian insufficiency: how to improve reproductive outcome? Climacteric 17, 22–26 (2014).

    Article  Google Scholar 

  166. Blumenfeld, Z. & von Wolff, M. GnRH-analogues and oral contraceptives for fertility preservation in women during chemotherapy. Hum. Reprod. Update 14, 543–552 (2008).

    Article  CAS  PubMed  Google Scholar 

  167. Turner, N. H. et al. Utility of gonadotropin-releasing hormone agonists for fertility preservation in young breast cancer patients: the benefit remains uncertain. Ann. Oncol. 24, 2224–2235 (2013).

    Article  CAS  PubMed  Google Scholar 

  168. Westphal, L. M. & Massie, J. A. M. in Oncofertility Medical Practice: Clinical Issues and Implementation (eds Gracia, C. & Woodruff, T. K.) 51–61 (Springer, 2012).

    Book  Google Scholar 

  169. Cardozo, E. R. et al. Ovarian stimulation and in-vitro fertilization outcomes of cancer patients undergoing fertility preservation compared to age matched controls: a 17-year experience. J. Assist. Reprod. Genet. 32, 587–596 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Society for Assisted Reproductive Technology. Clinic summary report 2013. sartcors[online], (2013).

  171. Mahajan, N. Fertility preservation in female cancer patients: an overview. J. Hum. Reprod. Sci. 8, 3–13 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Uzelac, P., Christensen, G. & Nakajima, S. in Oncofertility Medical Practice: Clinical Issues and Implementation (eds Gracia, C. & Woodruff, T. K.) 77–89 (Springer, 2012).

    Book  Google Scholar 

  173. Salama, M. & Woodruff, T. K. New advances in ovarian autotransplantation to restore fertility in cancer patients. Cancer Metastasis Rev. 34, 807–822 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Oktay, K. & Sonmezer, M. Ovarian tissue banking for cancer patients: fertility preservation, not just ovarian cryopreservation. Hum. Reprod. 19, 477–480 (2004).

    Article  PubMed  Google Scholar 

  175. Knopman, J. M. & Noyes, N. in Oncofertility Medical Practice: Clinical Issues and Implementation (eds Gracia, C. & Woodruff, T. K.) 91–104 (Springer, 2012).

    Book  Google Scholar 

  176. Clough, K. B. et al. Laparoscopic unilateral ovarian transposition prior to irradiation: a prospective study of 20 cases. Cancer 77, 2638–2645 (1996).

    Article  CAS  PubMed  Google Scholar 

  177. Cutillo, G. et al. Conservative treatment of reproductive and sexual function in young woman with squamous carcinoma of the vagina. Gynecol. Oncol. 103, 234–237 (2006).

    Article  PubMed  Google Scholar 

  178. Trost, L. & Branningan, R. in Oncofertility Medical Practice: Clinical Issues and Implementation (eds Gracia, C. & Woodruff, T. K.) 27–50 (Springer, 2012).

    Book  Google Scholar 

  179. Muller, J. et al. Cryopreservation of semen from pubertal boys with cancer. Med. Pediatr. Oncol. 34, 191–194 (2000).

    Article  CAS  PubMed  Google Scholar 

  180. Bober, S. L. et al. Sexual function in childhood cancer survivors: a report from project REACH. J. Sex. Med. 10, 2084–2093 (2013).

    Article  PubMed  Google Scholar 

  181. Zebrack, B. J. et al. Sexual functioning in young adult survivors of childhood cancer. Psychooncology 19, 814–822 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  182. Schover, L. R. et al. Sexual dysfunction and infertility as late effects of cancer treatment. EJC Suppl. 12, 41–53 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Markey, K. A., Macdonald, K. P. & Hill, G. R. The biology of graft versus host disease: experimental systems instructing clinical practice. Blood 124, 354–362 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Hirsch, P. et al. Female genital chronic graft-versus-host disease: importance of early diagnosis to avoid severe complications. Transplantation 93, 1265–1269 (2012).

    Article  PubMed  Google Scholar 

  185. Rosen, R. C. Assessment of sexual dysfunction in patients with benign prostatic hyperplasia. BJU Int. 97 (Suppl. 2), 29–33 (2006).

    Article  PubMed  Google Scholar 

  186. Meston, C. M. & Derogatis, L. R. Validated instruments for assessing female sexual function. J. Sex. Marital. Ther. 28 (Suppl. 1), 155–164 (2002).

    Article  PubMed  Google Scholar 

  187. Wasilewski-Masker, K. et al. Bone mineral density deficits in survivors of childhood cancer: long-term follow-up guidelines and review of the literature. Pediatrics 121, e705 (2008).

    Article  PubMed  Google Scholar 

  188. Wilson, C. L. et al. Fractures among long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer 118, 5920–5928 (2012).

    Article  PubMed  Google Scholar 

  189. Cummings, E. A. et al. Incident vertebral fractures in children with leukemia during the four years following diagnosis. J. Clin. Endocrinol. Metab. 100, 408–3417 (2015).

    Article  CAS  Google Scholar 

  190. Kaste, S. C. et al. Bone mineral decrements in survivors of childhood acute lymphoblastic leukemia: frequency of occurrence and risk factors for their development. Leukemia 15, 728–734 (2001).

    Article  CAS  PubMed  Google Scholar 

  191. Polgreen, L. E. et al. Modifiable risk factors associated with bone deficits in childhood cancer survivors. BMC Pediatr. 12, 40 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  192. Choudhary, A., Chou, J., Heller, G. & Sklar, C. Prevalence of vitamin D insufficiency in survivors of childhood cancer. Pediatr. Blood Cancer 60, 1237–1239 (2013).

    Article  PubMed  Google Scholar 

  193. Wallace, G. et al. Vitamin D deficiency and survival in children after hematopoietic stem cell transplant. Biol. Blood Marrow Transplant. 21, 1627–1631 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Neville, K. A. & Cohn, R. J. Bone health in survivors of childhood cancer. Lancet Diabetes Endocrinol. 3, 496–497 (2015).

    Article  PubMed  Google Scholar 

  195. Kalkwarf, H. J. et al. The bone mineral density in childhood study: bone mineral content and density according to age, sex, and race. J. Clin. Endocrinol. Metab. 92, 2087–2099 (2007).

    Article  CAS  PubMed  Google Scholar 

  196. Zemel, B. S. et al. Height adjustment in assessing dual energy x-ray absorptiometry measurements of bone mass and density in children. J. Clin. Endocrinol. Metab. 95, 1265–1273 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  197. The International Society for Clinical Densitometry. 2013 ISCD combined official positions. [online], (2013).

  198. Kanis, J. A. et al. The diagnosis of osteoporosis. J. Bone Miner. Res. 9, 1137–1141 (1994).

    Article  CAS  PubMed  Google Scholar 

  199. Holick, M. F. et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 96, 1911–1930 (2011).

    Article  CAS  PubMed  Google Scholar 

  200. Fan, C., Foster, B. K., Wallace, W. H. & Xian, C. J. Pathobiology and prevention of cancer chemotherapy-induced bone growth arrest, bone loss, and osteonecrosis. Curr. Mol. Med. 11, 140–151 (2011).

    Article  CAS  PubMed  Google Scholar 

  201. Neville, K. A. et al. Hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus in survivors of childhood cancer: prevalence and risk factors. J. Clin. Endocrinol. Metab. 91, 4401–4407 (2006).

    Article  CAS  PubMed  Google Scholar 

  202. Talvensaari, K. K., Lanning, M., Tapanainen, P. & Knip, M. Long term survivors of childhood cancer have an increased risk of manifesting the metabolic syndrome. J. Clin. Endocrinol. Metab. 81, 3051–3055 (1996).

    CAS  PubMed  Google Scholar 

  203. Nottage, K. A. et al. Metabolic syndrome and cardiovascular risk among long-term survivors of acute lymphoblastic leukaemia — from the St. Jude Lifetime Cohort. Cancer 120, 2742–2750 (2014).

    Article  PubMed  Google Scholar 

  204. Van Waas, M., Neggers, S. J., Pieters, R. & Van den Heuvel-Eibrink, M. M. Components of metabolic syndrome in 500 adult survivors. Ann. Oncol. 21, 1121–1126 (2010).

    Article  CAS  PubMed  Google Scholar 

  205. de Haas, E. C. et al. The metabolic syndrome in cancer survivors. Lancet Oncol. 11, 193–203 (2010).

    Article  CAS  PubMed  Google Scholar 

  206. Wei, C. et al. Reduced β-cell reserve and pancreatic volume in survivors of childhood acute lymphoblastic leukaemia treated with bone marrow transplantation and total body irradiation. Clin. Endocrinol. 82, 59–67 (2015).

    Article  CAS  Google Scholar 

  207. Meacham, L. R. et al. Diabetes mellitus in long-term survivors of childhood cancer. Increased risk associated with radiation therapy: a report for the childhood cancer survivor study. Arch. Intern. Med. 169, 1381–1388 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  208. De Vathaire, F. et al. Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study. Lancet Oncol. 13, 1002–1010 (2012).

    Article  PubMed  Google Scholar 

  209. Ehrhardt, M. J. & Mulrooney, D. A. Metabolic syndrome in adult survivors of childhood cancer: the intersection of oncology, endocrinology and cardiology. Lancet Diabetes Endocrinol. 3, 494–496 (2015).

    Article  PubMed  Google Scholar 

  210. Kim, J. H. & Choi, J.-H. Pathophysiology and clinical characteristics of hypothalamic obesity in children and adolescents. Ann. Pediatr. Endocrinol. Metab. 18, 161–167 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  211. Lustig, R. H. Hypothalamic obesity after craniopharyngioma: mechanisms, diagnosis, and treatment. Front. Endocrinol. (Lausanne) 2, 60 (2011).

    Article  Google Scholar 

  212. Elowe-Gruau, E. et al. Childhood craniopharyngioma: hypothalamus-sparing surgery decreases the risk of obesity. J. Clin. Endocrinol. Metab. 98, 2376–2382 (2013).

    Article  CAS  PubMed  Google Scholar 

  213. Haliloglu, B. & Bereket, A. Hypothalamic obesity in children: pathophysiology to clinical management. J. Pediatr. Endocrinol. Metab. 28, 503–513 (2015).

    Article  PubMed  Google Scholar 

  214. Inoue, S. et al. Role of the efferent and afferent vagus nerve in the development of ventromedial hypothalamic (VMH) obesity. Brain Res. Bull. 27, 511–515 (1991).

    Article  CAS  PubMed  Google Scholar 

  215. King, B. M. & Frohman, L. A. The role of vagally-medicated hyperinsulinemia in hypothalamic obesity. Neurosci. Biobehav. Rev. 6, 205–214 (1982).

    Article  CAS  PubMed  Google Scholar 

  216. Inoue, S. & Bray, G. A. The effects of subdiaphragmatic vagotomy in rats with ventromedial hypothalamic obesity. Endocrinology 100, 108–114 (1977).

    Article  CAS  PubMed  Google Scholar 

  217. De Silva, A. & Bloom, S. R. Gut hormones and appetite control: a focus on PYY and GLP-1 as therapeutic targets in obesity. Gut Liver 6, 10–20 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  218. O'Gorman, C. S., Simoneau-Roy, J., Pencharz, M. P., Adeli, K. & Hamilton, J. Delayed ghrelin suppression following oral glucose tolerance test in children and adolescents with hypothalamic injury secondary to craniopharyngioma compared with obese controls. Int. J. Pediatr. Obes. 6, 285–288 (2011).

    Article  PubMed  Google Scholar 

  219. Rakhshani, N. et al. Evaluation of a comprehensive care clinic model for children with brain tumor and risk for hypothalamic obesity. Obesity (Silver Spring) 18, 1768–1774 (2010).

    Article  CAS  Google Scholar 

  220. Lustig, R. H. et al. Hypothalamic obesity caused by cranial insult in children: altered glucose and insulin dynamics and reversal by a somatostatin agonist. J. Pediatr. 135, 162–168 (1999).

    Article  CAS  PubMed  Google Scholar 

  221. Deepak, D., Furlong, N. J., Wilding, J. P. H. & MacFarlane, I. Cardiovascular disease, hypertension, dyslipidaemia and obesity in patients with hypothalamic-pituitary disease. Postgrad. Med. J. 83, 277–280 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  222. Elfers, C. T. & Roth, C. L. Effects of methylphenidate on weight gain and food intake in hypothalamic obesity. Front. Endocrinol. (Lausanne) 2, 78 (2011).

    Article  Google Scholar 

  223. Mason, P. W., Krawiecki, N. & Meacham, L. R. The use of dextroamphetamine to treat obesity and hyperphagia in children treated for craniopharyngioma. Arch. Pediatr. Adolesc. Med. 156, 887–892 (2002).

    Article  PubMed  Google Scholar 

  224. Hamilton, J. K. et al. Hypothalamic obesity following craniopharyngioma surgery: results of a pilot trial of combined diazoxide and metformin therapy. Int. J. Pediatr. Endocrinol. 2011, 417949 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  225. Lustig, R. H. et al. Insulin dynamics predict body mass index and z-score response to insulin suppression or sensitization pharmacotherapy in obese children. J. Pediatr. 148, 23–29 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  226. Zoicas, F. et al. GLP-1 analogues as a new treatment option for hypothalamic obesity in adults: report of nine cases. Eur. J. Endocrinol. 168, 699–706 (2013).

    Article  CAS  PubMed  Google Scholar 

  227. Laferrère, B. et al. Effect of weight loss by gastric bypass surgery versus hypocaloric diet on glucose and incretin levels in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 93, 2479–2485 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  228. Sarson, D. L., Scopinaro, N. & Bloom, S. R. Gut hormone changes after jejunoileal (JIB) or biliopancreatic (BPB) bypass surgery for morbid obesity. Int. J. Obes. 5, 471–480 (1981).

    CAS  PubMed  Google Scholar 

  229. Lustig, R. H. et al. Octreotide therapy of pediatric hypothalamic obesity: a double-blind, placebo-controlled trial. J. Clin. Endocrinol. Metab. 88, 2586–2592 (2003).

    Article  CAS  PubMed  Google Scholar 

  230. Inge, T. H. et al. Gastric bypass surgery for treatment of hypothalamic obesity after craniopharyngioma therapy. Nat. Clin. Pract. Endocrinol. Metab. 3, 606–609 (2007).

    Article  PubMed  Google Scholar 

  231. Rottembourg, D. et al. Outcome after bariatric surgery in two adolescents with hypothalamic obesity following treatment of craniopharyngioma. J. Pediatr. Endocrinol. Metab. 22, 867–872 (2009).

    Article  PubMed  Google Scholar 

  232. Blum, R. W. et al. Transition from child-centered to adult health-care systems for adolescents with chronic conditions: a position paper of the Society for Adolescent Medicine. J. Adolesc. Health 14, 570–576 (1993).

    Article  CAS  PubMed  Google Scholar 

  233. McManus, M. A. et al. Current status of transition preparation among youth with special needs in the United States. Pediatrics 131, 1090–1097 (2013).

    Article  PubMed  Google Scholar 

  234. Cooley, W. C. & Sagerman, P. J. Supporting the health care transition from adolescence to adulthood in the medical home. Pediatrics 128, 182–200 (2011).

    Article  PubMed  Google Scholar 

  235. Gan, H. W. & Spoudeas, H. A. Long-term follow-up of survivors of childhood cancer (SIGN Clinical Guideline 132). Arch. Dis. Child. Educ. Pract. Ed. 99, 138–143 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  236. Overholser, L. S. et al. Development of a primary care-based clinic to support adults with a history of childhood cancer: The Tactic Clinic. J. Pediatr. Nurs. 30, 724–731 (2015).

    Article  PubMed  Google Scholar 

  237. Tonorezos, E. S. et al. Screening and management of adverse endocrine outcomes in adult survivors of childhood and adolescent cancer. Lancet Diabetes Endocrinol. 3, 545–555 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  238. Brignardello, E. et al. Endocrine health conditions in adult survivors of childhood cancer: the need for specialized adult-focused follow-up clinics. Eur. J. Endocrinol. 168, 465–472 (2013).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

S.R.R., V.E.H., J.H. and S.D.C. researched data for the article, contributed to discussion of content, wrote the article and reviewed and/or edited the article before submission. S.A.L. researched data for the article and wrote the article. M.M.R. researched data for the article, contributed to discussions of content and wrote the article. G.E.T. researched data for the article, wrote the article and reviewed and/or edited the article before submission.

Corresponding author

Correspondence to Susan R. Rose.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rose, S., Horne, V., Howell, J. et al. Late endocrine effects of childhood cancer. Nat Rev Endocrinol 12, 319–336 (2016). https://doi.org/10.1038/nrendo.2016.45

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2016.45

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing