Hypopituitarism following radiotherapy

Abstract

Deficiencies in anterior pituitary hormones secretion ranging from subtle to complete occur following radiation damage to the hypothalamic-pituitary (h-p) axis, the severity and frequency of which correlate with the total radiation dose delivered to the h-p axis and the length of follow up. Selective radiosensitivity of the neuroendocrine axes, with the GH axis being the most vulnerable, accounts for the high frequency of GH deficiency, which usually occurs in isolation following irradiation of the h-p axis with doses less than 30 Gy. With higher radiation doses (30-50 Gy), however, the frequency of GH insufficiency substantially increases and can be as high as 50-100%. Compensatory hyperstimulation of a partially damaged h-p axis may restore normality of spontaneous GH secretion in the context of reduced but normal stimulated responses; at its extreme, endogenous hyperstimulation may limit further stimulation by insulin-induced hypoglycaemia resulting in subnormal GH responses despite normality of spontaneous GH secretion in adults. In children, failure of the hyperstimulated partially damaged h-p axis to meet the increased demands for GH during growth and puberty may explain what has previously been described as radiation-induced GH neurosecretory dysfunction and, unlike in adults, the ITT remains the gold standard for assessing h-p functional reserve. Thyroid-stimulating hormone (TSH) and ACTH deficiency occur after intensive irradiation only (>50 Gy) with a long-term cumulative frequency of 3-6%. Abnormalities in gonadotrophin secretion are dose-dependent; precocious puberty can occur after radiation dose less than 30 Gy in girls only, and in both sexes equally with a radiation dose of 30-50 Gy. Gonadotrophin deficiency occurs infrequently and is usually a long-term complication following a minimum radiation dose of 30 Gy. Hyperprolactinemia, due to hypothalamic damage leading to reduced dopamine release, has been described in both sexes and all ages but is mostly seen in young women after intensive irradiation and is usually subclinical. A much higher incidence of gonadotrophin, ACTH and TSH deficiencies (30-60% after 10 years) occur after more intensive irradiation (>60 Gy) used for nasopharyngeal carcinomas and tumors of the skull base, and following conventional irradiation (30-50 Gy) for pituitary tumors. The frequency of hypopituitarism following stereotactic radiotherapy for pituitary tumors is mostly seen after long-term follow up and is similar to that following conventional irradiation. Radiation-induced anterior pituitary hormone deficiencies are irreversible and progressive. Regular testing is mandatory to ensure timely diagnosis and early hormone replacement therapy.

p21 Cip1 restrains pituitary tumor growth

“…These observations underscore the sensitivity of GH-secreting cells to PTTG-induced genomic instability, and resultant p21 induction and senescence may constrain tumor growth. This postulate is consistent with experimental and clinical observations that somatotrophs are more sensitive to aging, radiation damage, or compressive damage than other pituitary cell types (50,51). Our data (not shown) indicate that, unlike rat thyroid FRTL cells, GH 3 cells are extremely sensitive to etoposide-induced DNA damage responding with p21 induction and senescence.…”

Fractionated stereotactic radiotherapy in patients with acromegaly: an interim single-centre audit

“…Hypopituitarism is a serious side effect of RT of the pituitary gland in general (4,24), and the incidence of new anterior pituitary hormonal deficiencies varies from 0% in the first years to 66% after a median follow-up of up to 17 years (38). Due to a slowly progressing effect of radiation on the pituitary gland, the highest incidence of hypopituitarism has been reported in the series of patients with the longest follow-up (38,39).…”

“…Due to a slowly progressing effect of radiation on the pituitary gland, the highest incidence of hypopituitarism has been reported in the series of patients with the longest follow-up (38,39). Risk of deficiency, though, seems maximal during the first 96 months after radiation (40).…”

“…Risk of deficiency, though, seems maximal during the first 96 months after radiation (40). Evaluation of post-radiation hypopituitarism is difficult because of confounding factors such as previous surgery and/or radiation and differences in radiation of the tumour margin (38). The radiation dose in general, and to the pituitary stalk and the hypothalamus in particular, increased the incidence of hypopituitarism (6).…”

“…The higher radiation precision by stereotactic techniques has not been proven to improve the cumulative incidence in long-term follow-up studies compared with conventional RT (38). Hypopituitarism is, like acromegaly, combined with increased mortality (41), which is an important reason for evaluating this side effect during the development of new radiation techniques.…”