Radiotherapy-induced Hypothalamic-Pituitary axis dysfunction in adult Brain, head and neck and skull base tumor patients – A systematic review and Meta-Analysis

•Hypothalamic-pituitary axis dysfunction in patients, irradiated for brain, head and neck and skull base tumors, is significant.•The literature reviewed shows a wide variation in reported endocrine insufficiency.•Further research on hypothalamic-pituitary axis dysfunction, related to radiation dose is needed for the development of guidelines for dose tolerance and for endocrine follow-up for these patient groups.•Research on issues such as sleep disorder, anxiety and depression and their relation to dose delivery to the hypothalamic-pituitary axis is recommended. Radiotherapy for brain, head & neck (HN), and skull base (SB) tumors may deliver significant radiation dose to the hypothalamic-pituitary axis (HPA), leading to impaired functioning of this region and hence, to endocrine disorders. The purpose of this systematic review and meta-analysis is to investigate literature on HP dysfunction after radiation for non-pituitary brain, HN, or SB tumors at adult age, aiming to give insight in the prevalence of HP dysfunction related to radiation dose. Literature search of the PubMed database was performed for HP dysfunction after radiotherapy in adult patients. A risk of bias assessment was performed to rate the quality of the included papers. Besides clinical and treatment variables, reported insufficiencies for adrenocorticotrophic hormone, thyroid stimulating hormone, growth hormone, prolactin and follicle stimulating hormone and luteinizing hormone and for insufficiency of any axis were extracted. The prevalence for hormonal insufficiency per axis and for multiple axes was calculated using a random effects meta-regression with a random effect at the study level. The literature selection process resulted in a total of 22 original papers, suitable for full assessment (n = 1,462 patients). Literature showed a wide variation in HP dysfunction, along with wide dose ranges given to the hypothalamus and pituitary, with varying follow-up times. The calculated prevalence for any pituitary insufficiency was on average 0.61 (95 % CI 0.44–0.75). For growth hormone the mean prevalence was 0.40 (95 % CI 0.22–0.61), for prolactin 0.22 (95 % CI 0.17–0.28), for gonadotropin 0.20 (95 % CI 0.14–0.28), for adrenocorticotropic hormone 0.16 (95 % CI 0.08–0.30) and for thyroid stimulating hormone 0.16 (95 % CI 0.11–0.23). The prevalence for any insufficiency of 1 axis was 0.19 (95 % CI 0.11–0.30), of 2 axes 0.22 (95 % CI 0.12–0.38), of 3 axes 0.05 (95 % CI 0.03–0.09) and of panhy