Growth Hormone (GH) Responses to GH-Releasing Hormone Alone or Combined with Arginine in Patients with Adrenal Incidentaloma: Evidence for Enhanced Somatostatinergic Tone

Abstract

Spontaneous and stimulated GH secretion is blunted in hypercortisolemic states due to increased hypothalamic somatostatinergic tone. However, no data are available on the characteristics of GH secretion in patients with incidentally discovered adrenal adenomas. They represent an interesting model for studying GH secretion, as a slight degree of cortisol excess may frequently be observed in such patients who do not present with any clear Cushingoid sign. In the present study, 10 patients (3 men and 7 women, aged 48 -63 yr) with an adrenal mass discovered serendipitously underwent, on separate occasions, a GHRH injection alone or combined with an infusion of the functional somatostatin antagonist, arginine. Thirteen age-matched healthy volunteers served as controls. Briefly, arginine (30 g) was infused from Ϫ30 to 0 min, and GHRH (100 g) was injected as a bolus at 0 min, with measurement of serum GH [immunoradiometric assay (IRMA)] every 15 min for 150 min. Plasma IGF-I (RIA after acidethanol extraction) was measured in a morning sample. The diagnosis of cortical adenoma was based on computed tomography features and pattern of uptake on adrenal scintigraphy. Patients with obesity and/or diabetes were excluded. The study design included also an endocrine work-up aimed to study the hypothalamic-pituitary-adrenal axis [urinary free cortisol (UFC) excretion, serum cortisol at 0800 h, plasma ACTH at 0800 h, morning cortisol after overnight 1 mg dexamethasone]. Five of 10 patients showed abnormalities of the hypothalamic-pituitary-adrenal axis, including borderline or increased UFC excretion in 4 of them accompanied by blunted ACTH in 2 cases and failure of cortisol to suppress after dexamethasone in 1; the fifth patient displayed low ACTH and resistance to dexamethasone suppression. However, all patients had a unilateral uptake of the tracer on the side of the mass with suppression of the contralateral normal adrenal gland. As a group, the patients displayed greater UFC excretion and lower ACTH concentrations than the controls. GH release after GHRH treatment was blunted in patients bearing adrenal incidentaloma compared with controls (GH peak, 5.7 Ϯ 5.2 vs. 18.0 Ϯ 7.0 g/L; P Ͻ 0.0001), whereas GHRH plus arginine was able to elicit a comparable response in the 2 groups (GH peak, 33.5 Ϯ 20.3 vs. 33.7 Ϯ 17.5 g/L; P ϭ NS). The ratio between GH peaks after GHRH plus arginine and after GHRH plus saline was significantly greater in patients than in controls (751 Ϯ 531% vs. 81 Ϯ 45%; P ϭ 0.0001). Similar data were obtained when comparing GH area under the curve after GHRH plus saline or GHRH plus arginine between the 2 groups. In summary, the present data suggest that in patients with incidental adrenal adenomas the GH response to GHRH is blunted due to increased somatostatinergic tone, as it can be restored to normal by pretreatment with the functional somatostatin antagonist arginine. The blunted GH release to GHRH may be an early and long lasting sign of autonomous cortisol secretion by the adrenal adenoma. (J Cli...

The Nocturnal Serum Thyrotropin Surge is Inhibited in Patients with Adrenal Incidentaloma

“…24 An increased somatostatinergic tone is thought to be produced even by a very mild increase of glucocorticoids and in the absence of symptoms of hypercortisolism. 23 In our patients with incidentaloma, this condition may have been responsible for the slight but significant inhibition of TSH secretion unmasked by the lack of the nocturnal TSH surge. In fact, somatostatin is a well-known inhibitor of TSH secretion at the hypothalamic-pituitary level.…”

“…In agreement with this hypothesis, blunted growth hormone (GH) responses to GH-releasing hormone have been reported not only in patients who have been chronically treated with pharmacological doses of glucocorticoids 21,22 but also in subjects with a slight cortisol excess due to incidental adenomas. 23 Of interest, in both experimental conditions, the administration of arginine restored a normal GH responsiveness to GH-releasing hormone, which suggests a possible role of somatostatin in the inhibitory activity of glucocorticoids on GH secretion, 23 because arginine is a well-known functional somatostatin antagonist. 24 An increased somatostatinergic tone is thought to be produced even by a very mild increase of glucocorticoids and in the absence of symptoms of hypercortisolism.…”

Evaluation of GH reserve in patients with adrenal incidentalomas and biochemical evidence of subclinical autonomous glucocorticoid hypersecretion

“…To our knowledge, assessment of GH responsiveness in patients with adrenal incidentalomas has been previously reported only in one report 23 . These authors studied 10 patients with adrenal incidentalomas in comparison to normal control subjects.…”

Musculoskeletal complications of Cushing syndrome

“…Growth hormone directly and through IGF-1 stimulates the process of bone formation [17]. Functional GH deficiency was observed even when the GCs excess was mild, as in patients treated with inhaled GC and in those with "subclinical" endogenous hypercortisolism [17,34,35].…”