Late Effects of the Endocrine System
Table 8. Anterior Pituitary Hormones and Major Hypothalamic Regulatory Factors continued...
Pubertal development can be adversely affected by cranial radiation. Doses greater than 30 Gy to 40 Gy may result in gonadotropin deficiency, while doses greater than 18 Gy can result in precocious puberty. Precocious puberty has been reported in some children receiving cranial irradiation, mostly in girls who receive cranial radiation in doses of 24 Gy or higher. Earlier puberty and earlier peak height velocity, however, have been observed in girls treated with 18 Gy cranial radiation.[44,45] Another study showed that the age of pubertal onset is positively correlated with age at the time of cranial irradiation. The impact of early puberty in a child with radiation-associated GHD is significant, and timing of GH therapy is especially important for GH-deficient females also at risk of precocious puberty. With higher doses of cranial irradiation (>35 Gy), deficiencies in the gonadotropins can be seen, with a cumulative incidence of 10% to 20% at 5 to 10 years posttreatment.[46,47,48]
Central hypothyroidism in survivors of childhood cancer can have profound clinical consequences and be underappreciated. Symptoms of central hypothyroidism (e.g., asthenia, edema, drowsiness, and skin dryness) may have a gradual onset and go unrecognized until thyroid replacement therapy is initiated. In addition to delayed puberty and slow growth, hypothyroidism may cause fatigue, dry skin, constipation, increased sleep requirement, and cold intolerance. Radiation dose to the hypothalamus in excess of 42 Gy is associated with an increase in the risk of developing thyroid-stimulating hormone (TSH) deficiency, 44% ± 19% (dose ≥42 Gy) and 11% ± 8% (dose <42 Gy). It occurs in as many as 65% of survivors of brain tumors, 43% of survivors of childhood nasopharyngeal tumors, 35% of bone marrow transplant recipients, and 10% to 15% of leukemia survivors.[31,50]
Mixed primary and central hypothyroidism can also occur and reflects separate injuries to the thyroid gland and the hypothalamus (e.g., radiation injury to both structures). TSH values may be elevated and, in addition, the secretory dynamics of TSH are abnormal with a blunted or absent TSH surge or a delayed peak response to thyrotropin-releasing hormone (TRH).[22,51] In a study of 208 childhood cancer survivors referred for evaluation of possible hypothyroidism or hypopituitarism, mixed hypothyroidism was present in 15 (7%) patients. Among patients who received TBI (fractionated total doses of 12 Gy-14.4 Gy) or craniospinal irradiation (fractionated total cranial doses higher than 30 Gy), 15% had mixed hypothyroidism. In one study of 32 children treated for medulloblastoma, 56% developed hypothyroidism, including 38% with primary hypothyroidism, and 19% with central hypothyroidism.