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Radiotherapy near the base of the brain damages the gland that runs growth, puberty, the thyroid and the stress response, in that order of sensitivity. In 748 survivors treated with cranial radiotherapy, 46.5 per cent had growth hormone deficiency, 10.8 per cent sex hormone deficiency, 7.5 per cent thyroid deficiency and 4 per cent adrenal deficiency, and most of it had not been treated.
The hypothalamic-pituitary axis is the organ most reliably damaged by radiotherapy to the brain in childhood, and the one most often missed, because its failures look like ordinary life: tiredness, weight gain, late or absent periods, low mood, poor exercise tolerance.
The prevalences come from the St Jude Lifetime Cohort study of 748 survivors treated with cranial radiotherapy (394 men), mean age 34.2 years, observed for a mean of 27.3 years. Estimated point prevalence was 46.5 per cent for growth hormone deficiency, 10.8 per cent for luteinising hormone and follicle-stimulating hormone deficiency, 7.5 per cent for thyroid-stimulating hormone deficiency and 4 per cent for adrenocorticotropic hormone deficiency, and cumulative incidence increased with follow-up. The dose thresholds are useful: compared with cranial doses below 22 gray, 22 to 29.9 gray was significantly associated with growth hormone deficiency, doses of 22 gray or more with sex hormone deficiency, and doses of 30 gray or more with thyroid and adrenal deficiency. The axes fail roughly in order of radiosensitivity, and they keep failing for decades, so one normal test at the end of treatment settles nothing.
The untreated fraction is the finding that should change practice: growth hormone deficiency was not treated in 99.7 per cent of affected individuals and sex hormone deficiency in 78.5 per cent. Untreated growth hormone deficiency was significantly associated with decreased muscle mass and exercise tolerance; untreated sex hormone deficiency with hypertension, dyslipidaemia, low bone mineral density and slow walking; and both, independently, with abdominal obesity, low energy expenditure and muscle weakness. These are not cosmetic deficits.
Puberty can go either way. Low-dose radiation to the hypothalamus disinhibits the pubertal switch and brings puberty early, while higher doses knock out the gonadotrophins and delay or prevent it. In a study of 80 patients with central precocious puberty after tumours near or irradiation of the hypothalamic-pituitary axis, followed for 11.4 years on average, the prevalence of central precocious puberty was 15.2 per cent overall, 29.2 per cent after tumours of the axis itself and 6.6 per cent after radiotherapy for tumours elsewhere. Height below minus two standard deviations was more common at last follow-up than at the onset of puberty (21.4 against 2.4 per cent), obesity was more common at last follow-up than earlier (37.7 against 20.8 per cent at puberty onset), and 32.6 per cent went on to develop gonadotrophin deficiency. Longer treatment with a gonadotrophin-releasing hormone agonist, used to hold puberty back and protect final height, was associated with increased odds of a final height below minus two standard deviations (odds ratio 2.1, 95 per cent confidence interval 1.0 to 4.3), and the authors concluded that early diagnosis and treatment "may limit further deterioration of final height prospects".
The International Guideline Harmonization Group has published recommendations on hypothalamic-pituitary dysfunction surveillance, and the Children's Oncology Group guidelines set out which tests follow which exposure.
What comes back, and when: pituitary deficits after radiotherapy do not recover and tend to accumulate, so the correct expectation is lifelong testing rather than a discharge. What is recoverable is everything downstream: replacing a missing hormone restores the function it ran, and the cohort above shows how much function was being lost because nobody replaced it.
Hypothalamic and pituitary cell populations differ in radiosensitivity, with somatotrophs most vulnerable and corticotrophs least, which produces the characteristic sequence of growth hormone, then gonadotrophin, then thyrotrophin, then corticotrophin failure as dose rises. Low-dose irradiation can also remove the inhibitory hypothalamic input that holds the gonadotrophin pulse generator in check before puberty, which is why the same exposure produces precocious puberty at one dose and hypogonadism at another.
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