Late Effects of the Neuroendocrine System
Survivors of childhood cancer are at risk for a spectrum of neuroendocrine abnormalities, primarily due to the effect of radiation therapy on the hypothalamus. Essentially all of the hypothalamic-pituitary axes are at risk.[1,2,3] The six anterior pituitary hormones and their major hypothalamic regulatory factors are outlined in Table 10.
Table 10. Anterior Pituitary Hormones and Major Hypothalamic Regulatory Factors
(-) = inhibitory; (+) = stimulatory.
|Pituitary Hormone ||Hypothalamic Factor||Hypothalamic Regulation of the Pituitary Hormone|
|Growth hormone||Growth hormone-releasing hormone ||+|
|Luteinizing hormone||Gonadotropin-releasing hormone||+|
|Follicle-stimulating hormone ||Gonadotropin-releasing hormone||+|
|Thyroid-stimulating hormone||Thyroid-releasing hormone ||+|
|Adrenocorticotropin||Corticotropin-releasing hormone ||+|
Growth hormone deficiency (GHD) is the first and most common side effect of cranial irradiation in brain tumor survivors. The risk increases with radiation dose and time after treatment. GHD is the earliest hormone deficiency and sensitive to low doses. Other hormone deficiencies require higher doses and their time to onset is much longer than for GHD. The prevalence in pooled analysis was found to be approximately 35.6%. The potential for neuroendocrine damage is likely to decrease because of the use of more focused radiation therapy and a decrease in dose for some malignancies such as medulloblastoma.
Growth Hormone Deficiency
Approximately 60% to 80% of irradiated pediatric brain tumor patients who have received doses greater than 30 Gy will have impaired serum growth hormone (GH) response to provocative stimulation, usually within 5 years of treatment. The dose-response relationship has a threshold of 18 Gy to 20 Gy; the higher the radiation dose, the earlier that GHD will occur after treatment. A study of conformal radiation therapy in children with central nervous system (CNS) tumors indicates that GH insufficiency can usually be demonstrated within 12 months of radiation therapy, depending on hypothalamic dose-volume effects. Children treated with CNS irradiation for leukemia are also at increased risk of GHD. One study evaluated 127 patients with acute lymphocytic leukemia (ALL) treated with 24 Gy, 18 Gy, or no cranial irradiation. The change in height, compared with population norms expressed as the standard deviation score (SDS), was significant for all three groups with a dose-response of -0.49 � 0.14 for the no radiation therapy group, -0.65 � 0.15 for the 18 Gy radiation therapy group, and -1.38 � 0.16 for the 24 Gy group. Another study found similar results in 118 ALL survivors treated with 24 Gy cranial irradiation, in which 74% had SDS score of -1 or greater and the remainder had -2 or greater. However, survivors of childhood ALL who are treated with chemotherapy alone are also at increased risk for adult short stature, though the risk is highest for those treated with cranial and craniospinal radiation therapy at a young age. In this cross-sectional study, attained adult height was determined among 2,434 ALL survivors participating in the Childhood Cancer Survivor Study (CCSS). All survivor treatment exposure groups (chemotherapy alone and chemotherapy with cranial or craniospinal radiation therapy) had decreased adult height and an increased risk of adult short stature (height standard deviation score < -2) compared with siblings (P < .001). Compared with siblings, the risk of short stature for survivors treated with chemotherapy alone was elevated (odds ratio = 3.4; 95% confidence interval [CI], 1.9-6.0). Among survivors, significant risk factors for short stature included diagnosis of ALL before puberty, higher-dose cranial radiation therapy (?20 Gy vs. <20 Gy), any radiation therapy to the spine, and female gender. GHD has been reported in 14% of survivors of childhood nasopharyngeal carcinoma, which is secondary to the hypothalamic/pituitary radiation. This incidence is likely an underestimate since screening was selective.