Overall, a recent meta-analysis of data from 18 studies concluded that RIH occurs to some degree in 66% of adult patients whose hypothalamus or pituitary glands were included in cranial radiotherapy fields for nonpituitary (brain or nasopharyngeal) tumors; growth hormone deficiency prevalence was 45%.4
Little is yet known about the interactions of potentially endocrinopathic chemotherapies and immunotherapies, with RIH risk. Alkylating agents may potentiate radiation’s impacts on growth hormone deficits, leading to growth retardation.2,3
“The onset and severity of radiation-induced hypopituitarism primarily depends on the total radiation dose, the fraction size, and the time allowed between fractions for tissue repair (ie, duration of the radiation schedule),” notes Darzy.10 Larger radiation dose fractions “inflict more damage on the H-P axis than do schedules administered over a long duration” with smaller fraction doses.
Generally, radiation doses less than 40 Gy are associated with isolated RIH-associated deficiencies in growth hormone or gonadotropin (the second most common manifestation of RIH).3 Intensive radiotherapy doses exceeding 50 to 60 Gy can cause deficiencies in multiple other hormones as well, including adrenocorticotropic hormone (ACTH), in up to 60% of patients at 10 years postradiation.3,10 ACTH deficiencies can trigger hypoadrenalism and cortisol deficiency, which can cause fatigue, muscle weakness, nausea, dizziness, weight loss, and hypoglycemia.13 In prepubertal children, and particularly girls, even radiation doses less than 25 Gy can increase the risk of precocious puberty.2
Prolactin and TSH hormone levels can be assessed using blood tests, as indicated by signs and symptoms of RIH, and treated with dopamine agonists such as cabergoline and L-thyroxine replacement therapy, respectively.2 Gonadotropin dysfunction is inferred by low serum testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in males, and low FSH, LH, and estradiol in women on menstrual cycle day 2, or simply low FSH and LH among postmenopausal women.2 In children, growth hormone-releasing hormone analog therapy can correct gonadotropin deficiencies.2
SURVEILLANCE AND FOLLOW-UP
The hormones affected by RIH include growth hormone, and less frequently, gonadotropin, ACTH, prolactin, and thyroid-stimulating hormone (TSH).2 Because the risk and severity of radiation-induced endocrinopathies increase over time after radiotherapy, posttreatment plans should include long-term monitoring for hypopituitarism for children and adolescents, to ensure timely detection and intervention with hormone replacement therapies.3,10 For adult cancer survivors, testing is undertaken only if signs and symptoms of endocrinopathy, emerge.
The Insulin Tolerance Test (ITT) is considered a “gold standard” for identifying RIH growth hormone deficiency.3 “A failed response to the ITT in cranially-irradiated patients is accepted as diagnostic of GH deficiency without the need to resort to further tests,” he notes.10 (Arginine-stimulating testing [AST] is not as sensitive for detecting RIH as ITT.10) Typically, growth hormone therapy is deemed indicated if peak growth hormone response to ITT is 7μg/l or less for a child, or 3μg/l or less for an adult.10