Alfonso Leal Cerro

Summary: Objective Traumatic brain injury (TBI) has been associated with hypopituitarism and GH deficiency. However, TBI‐mediated hypopituitarism may be more frequent than previously thought. The present work, performed in patients with severe TBI at least 1 year before, had three aims: (i) to evaluate the prevalence of hypopituitarism, (ii) in particular to evaluate the prevalence of GH deficiency, and (iii) to compare three different tests of GH reserve in this cohort.Design and patients From a nonselected group of 249 patients admitted to our Clinical Centre for severe TBI over the last 5 years, 200 of them answered a custom made questionnaire of symptoms of hypopituitarism enclosed in the invitation letter to participate in the study. A total of 170 (99 men and 14 women), accepted to participate in the study (study cohort); 57 had normal questionnaires and were not further studied, 14 discontinued the study, and 99 attended the hospital for dynamic tests of pituitary hormone deficiencies. From these, 44 subjects with IGF‐I in the lower range were tested with GHRH+GHRP‐6; ITT; and glucagon tests of GH reserve, on three different occasions.Measurements Pituitary hormones plus IGF‐I and target gland hormones were analysed.Results With regard to the initial cohort of 170 subjects (100%), three (1·7%) showed diabetes insipidus; 10 (5·8%) TSH deficiency, 11 (6·4%) ACTH deficiency and 29 (17%) gonadotrophin deficiency. In 10 subjects (5·8%), GH deficiency was diagnosed by strict criteria. Finally, 15 (8·8%) showed combined deficit of several hormones.Conclusion After severe head trauma, gonadotrophin deficiency was the most common pituitary deficit. GH deficiency showed a prevalence similar to ACTH and TSH deficits, i.e. near 6% of the cohort. Taken together, 24·7% of the subjects studied showed any type of pituitary hormone deficiency.

Glial-derived neurotropic factor (GDNF) signaling is mediated through a 2-component system consisting of the so-called GDNF receptor-α (GFRα1), which binds to GDNF. This complex activates the tyrosine kinase receptor RET. In this paper we demonstrate GDNF, GFRα1, and RET mRNA and protein expression in the human anterior pituitary gland. Double immunohistochemistry of anterior pituitary sections showed GDNF immunoreactivity in more than 95% of somatotrophs and to a lesser extent in corticotrophs (20%); it was almost absent in the remaining cell types. Also, although more than 95% of somatotrophs were stained for RET, no positive immunostaining could be detected in other cell types. Furthermore, we have looked for GDNF and RET in human pituitary adenomas of various hormonal phenotypes. Strong positive immunostaining was found for c-RET in all of the GH-secreting adenomas screened as well as in 50% of ACTH-producing adenomas. Positive immunostaining for GDNF was found in all of the GH-secreting adenomas and in 10% of the corticotropinomas. Lastly, we found strong positive immunostaining for GFRα1 in 90% of the somatotropinomas and 50% of the corticotropinomas as well as in 1 of 8 prolactinomas and 1 of 13 nonfunctioning adenomas. All of the remaining pituitary tumors screened were negative for RET, GDNF, and GFRα1. This study indicates that GDNF may well be acting in the regulation of somatotroph cell growth and/or cell function in the normal human anterior pituitary gland. The expression of RET in all of the somatotropinomas and in 50% of the ACTH-producing tumors implies that GDNF and RET could be involved in the pathogenesis of pituitary tumors.

In Cushing's syndrome, GH secretion is blocked with all the stimuli tested. It has been reported that the acute pharmacological reduction of free fatty acids (FFA) leads to an enhancement of GH secretion in normal subjects and in pathological conditions associated with reduced GH secretion. To understand if the elevated FFA levels of hypercortisolism may be responsible for the altered GH secretion, 14 patients with active Cushing's syndrome underwent 2 paired tests with 100 micrograms i.v. of GHRH on 2 different occasions. In one test, they were pretreated with placebo and in the other one, with acipimox 250 mg p.o. 4 h before, and 250 mg p.o. 1 h before GHRH. The basal FFA levels (799 +/- 57 mmol/L) were reduced by acipimox throughout the whole test (values under 240 +/- 28 mmol/L). In the placebo pretreated group, GHRH-induced GH secretion was severely impeded, with a mean GH peak of 1.8 +/- 0.3 micrograms/L and area under the curve of 121.3 +/- 21.6 micrograms/L-120 min. All the patients showed a GHRH-mediated GH peak under 4 micrograms/L. Acute reduction of FFA by acipimox enhanced the GHRH action, with a mean GH peak of 11.1 +/- 1.8 micrograms/L and area under the curve of 652.9 +/- 110.3 micrograms/L-120 min (both P < 0.005). Individually analyzed after acipimox, all 14 subjects presented an enhancement in the GHRH-mediated GH peak, and 8 patients showed a response over 10 micrograms/L. In conclusion, acute FFA reduction by acipimox increased the GH secretion elicited by GHRH in chronic hypercortisolism. Elevated FFA may be a contributing factor to the deranged GH secretion observed in Cushing's syndrome.