PITUARITY DYSFUNCTION AFTER CRANIAL RADIOTHERAPY

Commentary from Faculty Members Andrea Glezer and Marcello Bronstein

Appelman-Dijkstra NM, Kokshoorn NE, Dekkers OM, Neelis KJ, Biermasz NR, Romijn JA, Smit JW, Pereira AM
J Clin Endocrinol Metab. 2011 Aug; 96(8):2330-40
Changes clinical practice: Adults who received cranial radiotherapy for nonpituitary tumors should have their hypothalamic-pituitary axis periodically evaluated.
This is the first meta-analysis of hypopituitarism prevalence in adults who received cranial radiotherapy for nonpituitary tumors. Due to the high pooled prevalence found (0.66), the authors recommend endocrine surveillance in this population.
In children, endocrine surveillance must be performed after cranial radiation for intracerebral, nasopharyngeal and hematological malignancies because hypopituitarism is very prevalent. Any endocrinopathy is described in 43% of adults who received cranial radiotherapy during childhood.^[1] In adults treated with cranial radiotherapy, there is no endocrine surveillance program recommended because the prevalence of hypopituitarism is unknown. This prevalence depends on the time interval between radiotherapy and endocrine evaluation, radiation dose and methodology used to diagnose pituitary deficiencies.
This paper is the result of a systematic review and meta-analysis of hypopituitarism in adults who received cranial and/or total body irradiation for nonpituitary tumors. Starting with 849 articles, only 18 manuscripts met the inclusion criteria, comprising 813 patients -- 75% presented nasopharyngeal tumors and received a radiation dose ranged from 14 to 83Gy, while the remaining presented intracerebral tumors and received a radiation dose ranged from 40 to 97Gy. In nine studies, the estimated dose delivered to the pituitary was calculated ranging from 25 to 97Gy. Radiotherapy for pituitary tumors ranged from 30 to 50Gy, which roughly corresponds to 50-70Gy in nonpituitary brain tumors.^[2] The hypopituitarism prevalence varied between 25 to 100% in patients with nasopharyngeal tumors and from 37 to 77% in patients with intracerebral tumors. Concerning the growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis, only 61% of the patients had basal serum IGF-1 and/or stimulation test for GH. The prevalence of GH deficiency varied between 24 and 100%. Regarding the hypothalamic-pituitary-adrenal axis, only 61% of cases were tested by basal serum cortisol levels and/or stimulation test. Adrenal insufficiency was diagnosed in 0 to 50% of patients with nasopharyngeal tumors and in 3 to 62% of the patients with intracerebral tumors. Thyroid-stimulating hormone (TSH) deficiency was diagnosed in 26% of the patients. The pituitary-gonadal axis was evaluated in almost 58% of the patients and hypogonadotrophic hypogonadism was present in 30%. Prolactin levels were measured in 62% of the patients and hyperprolactinemia was found in 29%. The pooled prevalence of any degree of hypothalamic-pituitary insufficiency was 0.66. The pooled prevalence of GH deficiency was 0.45, 0.3 for luteinizing hormone (LH)/follicle-stimulating hormone (FSH) deficiency, 0.25 for TSH deficiency, 0.34 for hyperprolactinemia and 0.22 for adrenocorticotropic hormone (ACTH) deficiency.
Deficiencies did not vary according to tumor localization -- nasopharyngeal vs. intracerebral. Time of hypopituitarism was reported in only two studies and one of them detailed the classical sequential order of failure of pituitary functions:^[3] GH in 2.6 years, LH/FSH and hyperprolactinemia in 3.8 years, ACTH in 6 years and TSH after a mean of 11 years. Besides radiotherapy, patients with cancer could present hormonal deficiencies due to other causes: chemotherapy may also directly affect the thyroid and gonads; also thyroid gland and gonadal exposure to radiation. In conclusion, considering the high prevalence of hypopituitarism (which in fact could be underestimated in this meta-analysis due to the lack of rigorous hypothalamo-pituitary axis evaluation in most studies reviewed), periodically follow-up should include endocrine assessment.