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      The late effects of cranial irradiation in childhood on the hypothalamic–pituitary axis: a radiotherapist’s perspective


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          Brain tumours make up nearly one-third of paediatric malignancies. Over time, advancements in oncological treatments like radiotherapy have helped reduce normal-tissue toxicity when treating cancers in the brain. However, clinicians are still facing a trade-off between treatment efficacy and potential side effects. The aim of this review is to address the late effects of cranial irradiation on the neuroendocrine system and to identify factors that make patients more vulnerable to radiation-induced endocrine sequelae. Radiation damage to the hypothalamic–pituitary axis, which orchestrates hormone release, can lead to endocrinopathy; up to 48.8% of children who have undergone cranial irradiation develop a hormone deficiency. This may lead to further health complications that can appear up to decades after the last treatment, lowering the patients’ quality of life and increasing long-term costs as lifelong hormone replacement therapy may be required. Growth hormone deficiency is the most common sequelae, followed by either thyroid or gonadotropic hormone deficiency. Adrenocorticotropic hormone deficiency tends to be the least common. Identified factors that increase the risk of late endocrine deficiency include total radiation dose, age at treatment, and time since last treatment. However, as there are various other factors that may potentiate the damage, a universal solution proven to be most effective in sparing the endocrine tissues is yet to be identified. Until then, accounting for the identified risk factors during treatment planning may in some cases help reduce the development of endocrine sequelae in childhood cancer survivors.

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          Anterior hypopituitarism in adult survivors of childhood cancers treated with cranial radiotherapy: a report from the St Jude Lifetime Cohort study.

          To estimate the prevalence of and risk factors for growth hormone deficiency (GHD), luteinizing hormone/follicle-stimulating hormone deficiencies (LH/FSHD), thyroid-stimulatin hormone deficiency (TSHD), and adrenocorticotropic hormone deficiency (ACTHD) after cranial radiotherapy (CRT) in childhood cancer survivors (CCS) and assess the impact of untreated deficiencies.
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            Endocrine Deficiency as a Function of Radiation Dose to the Hypothalamus and Pituitary in Pediatric and Young Adult Patients With Brain Tumors

            Purpose There are sparse data defining the dose response of radiation therapy (RT) to the hypothalamus and pituitary in pediatric and young adult patients with brain tumors. We examined the correlation between RT dose to these structures and development of endocrine dysfunction in this population. Materials and Methods Dosimetric and clinical data were collected from children and young adults (< 26 years of age) with brain tumors treated with proton RT on three prospective studies (2003 to 2016). Deficiencies of growth hormone (GH), thyroid hormone, adrenocorticotropic hormone, and gonadotropins were determined clinically and serologically. Incidence of deficiency was estimated using the Kaplan-Meier method. Multivariate models were constructed accounting for radiation dose and age. Results Of 222 patients in the study, 189 were evaluable by actuarial analysis, with a median follow-up of 4.4 years (range, 0.1 to 13.3 years), with 31 patients (14%) excluded from actuarial analysis for having baseline hormone deficiency and two patients (0.9%) because of lack of follow-up. One hundred thirty patients (68.8%) with medulloblastoma were treated with craniospinal irradiation (CSI) and boost; most of the remaining patients (n = 56) received involved field RT, most commonly for ependymoma (13.8%; n = 26) and low-grade glioma (7.4%; n = 14). The 4-year actuarial rate of any hormone deficiency, growth hormone, thyroid hormone, adrenocorticotropic hormone, and gonadotropin deficiencies were 48.8%, 37.4%, 20.5%, 6.9%, and 4.1%, respectively. Age at start of RT, time interval since treatment, and median dose to the combined hypothalamus and pituitary were correlated with increased incidence of deficiency. Conclusion Median hypothalamic and pituitary radiation dose, younger age, and longer follow-up time were associated with increased rates of endocrinopathy in children and young adults treated with radiotherapy for brain tumors.
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              Hypothalamic-Pituitary Disorders in Childhood Cancer Survivors: Prevalence, Risk Factors and Long-Term Health Outcomes

              Data on hypothalamic-pituitary (HP) disorders in systematically evaluated childhood cancer survivors are limited. To describe prevalence, risk factors, and associated adverse health outcomes of deficiencies in GH deficiency (GHD), TSH deficiency (TSHD), LH/FSH deficiency (LH/FSHD), and ACTH deficiency (ACTHD), and central precocious puberty (CPP). Retrospective with cross-sectional health outcomes analysis. Established cohort; tertiary care center. Participants (N = 3141; median age, 31.7 years) were followed for a median 24.1 years. Multivariable logistic regression was used to calculate ORs and 95% CIs for associations among HP disorders, tumor- and treatment-related risk factors, and health outcomes. The estimated prevalence was 40.2% for GHD, 11.1% for TSHD, 10.6% for LH/FSHD, 3.2% for ACTHD, and 0.9% for CPP among participants treated with HP radiotherapy (n = 1089), and 6.2% for GHD, and 30 Gy for ACTHD), alkylating agents (GHD, LH/FSHD), intrathecal chemotherapy (GHD), hydrocephalus with shunt placement (GHD, LH/FSHD), seizures (TSHD, ACTHD), and stroke (GHD, TSHD, LH/FSHD, ACTHD). Adverse health outcomes independently associated with HP disorders included short stature (GHD, TSHD), severe bone mineral density deficit (GHD, LH/FSHD), obesity (LH/FSHD), frailty (GHD), impaired physical health-related quality of life (TSHD), sexual dysfunction (LH/FSHD), impaired memory, and processing speed (GHD, TSHD). HP radiotherapy, central nervous system injury, and, to a lesser extent, chemotherapy are associated with HP disorders, which are associated with adverse health outcomes. In a large cohort of systematically assessed childhood cancer survivors, associations between HP disorders, tumor and treatment variables, and adverse health outcomes were elicited.

                Author and article information

                Endocr Connect
                Endocr Connect
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                21 October 2022
                01 December 2022
                : 11
                : 12
                : e220298
                [1 ]Division of Cancer Sciences , School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
                [2 ]Radiotherapy Related Research , The Christie NHS Foundation Trust, Manchester, UK
                Author notes
                Correspondence should be addressed to I Lövgren: izabellelovgren@ 123456gmail.com
                Author information
                © The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                : 26 September 2022
                : 21 October 2022

                neuroendocrine disruption,hypothalamic–pituitary axis,radiotherapy,hormone deficiency


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