Pyridostigmine Enhances Even if it Does Not Normalize the Growth Hormone Responses to Growth Hormone-Releasing Hormone in Patients with Cushing&amp;rsquo;s Disease

Giustina, Andrea; Bossoni, Simonetta; Bodini, Corrado; Ferrari, C; Pizzocolo, G; Scalvini, Tiziano; Schettino, Maurizio; Wehrenberg, William B.

doi:10.1159/000181882

Cited by 21 publications

(13 citation statements)

References 23 publications

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“…These findings are consistent with several reports on the glucocorticoid-induced inhibition of GH secretion in animal models and in humans (15,18,30). The increases in serum GH concentrations in response to commonly used pharmacological stimuli are typically inhibited in patients with significant endogenous hypercortisolism (10,31).…”

Section: Discussionsupporting

confidence: 92%

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

Terzolo

Bossoni

Alı̀

et al. 2000

The Journal of Clinical Endocrinology & Metabolism

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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...

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Section: Discussionsupporting

confidence: 92%

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

Terzolo

Bossoni

Alı̀

et al. 2000

The Journal of Clinical Endocrinology & Metabolism

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“…Because most of the GH stimulation studies in Cushing's syndrome lack body weight-matched controls, the specificity of this finding might be questioned. GH release after reduction of the endogenous somatostatin tonus is also greatly diminished in hypercortisolism, e.g., by pretreatment with pyridostigmine or arginine infusion or after abrupt cessation of an intravenous infusion with somatostatin (13,29,32). Collectively, these results could point to a (reversible) defect of the pituitary gland, i.e., the somatotropic cell.…”

Section: Discussionmentioning

confidence: 99%

Growth hormone secretion in primary adrenal Cushing's syndrome is disorderly and inversely correlated with body mass index

Aken

Pereira

Frölich

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

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. Growth hormone secretion in primary adrenal Cushing's syndrome is disorderly and inversely correlated with body mass index. Am J Physiol Endocrinol Metab 288: E63-E70, 2005. First published August 24, 2004; doi:10.1152/ajpendo.00317.2004.-To evaluate the impact on the somatotropic axis of endogenous cortisol excess in the absence of primary pituitary disease, we investigated spontaneous 24-h growth hormone (GH) secretion in 12 adult patients with ACTH-independent hypercortisolism. Plasma GH concentration profiles (10-min samples) were analyzed by deconvolution to reconstruct secretion and approximate entropy to quantitate orderliness of the release process. Comparisons were made with a body mass index (BMI)-, age-, and gender-matched control group and an age-and gender-matched lean control group. GH secretion rates did not differ from BMI-matched controls but were twofold lower compared with lean subjects, mainly due to a 2.5-fold attenuation of the mean secretory burst mass (P ϭ 0.001). In hypercortisolemic patients, GH secretion was negatively correlated with BMI (R ϭ Ϫ0.55, P ϭ 0.005) but not cortisol secretion. Total serum IGF-I concentrations were similar in the three groups. Approximate entropy (ApEn) was increased in patients with Cushing's syndrome compared with both control groups (vs. BMI-matched, P ϭ 0.04; vs. lean, P ϭ 0.001), denoting more irregular GH secretion patterns. ApEn in patients correlated directly with cortisol secretion (R ϭ 0.77, P ϭ 0.003). Synchrony between cortisol and GH concentration series was analyzed by cross-correlation, cross-ApEn, and copulsatility analyses. Patients showed loss of pattern synchrony compared with BMImatched controls, but copulsatility was unchanged. We conclude that hyposomatotropism in primary adrenal hypercortisolism is only partly explained (ϳ30%) by increased body weight and that increased GH secretory irregularity and loss of synchrony suggest altered coordinate regulation of GH release. cortisol; entropy; adrenal adenoma CUSHING'S SYNDROME is characterized by increased cortisol secretion and is caused by ACTH-dependent cortisol excess (Cushing's disease or the rare ectopic tumoral ACTH production syndrome) or by ACTH-independent cortisol excess. The latter syndrome is caused by a unilateral adenoma (seldom a carcinoma) and less frequently by ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH). The latter syndrome is characterized by bilateral nodular enlargement of the adrenal glands and clinical and biochemical signs of cortisol excess with low or undetectable ACTH concentrations (25). The detrimental metabolic consequences of chronic cortisol excess are manifold and include loss of lean body mass, increased adiposity, bone loss, and repression of the thyrotropic, gonadotropic, and somatotropic axes. Indeed, the diminished growth hormone (GH) response to various stimuli, including insulin-induced hypoglycemia, GH-releasing hormone (GHRH), growth hormone secretagogues (GHS), and ghrelin, is well described in pituitary-dependent hyperco...

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“…In the rat, a 4-day administration of dexamethasone inhibits the GH response to GHRH [10], Normal human subjects after both short-and long-term administration of glucocorticoids [3][4][5] and patients with Cushing's disease [6,27] have impaired GH responses to insulin-induced hypoglycemia and GHRH.…”

Section: Discussionmentioning

confidence: 99%

“…Children receiving high-dose glucocorticoid treatment [1] or who have Cushing's disease [2] exhibit impaired growth. Normal subjects, after administration of supraphysiological doses of glucocorticoids and patients with Cushing's disease, have blunted growth hormone (GH) responses to the stimuli [3][4][5][6], On the other hand, gluco corticoids enhance GH release by cultured human pitu itary somatotropes [7]. Moreover, GH deficiency in pa tients with idiopathic corticotropin deficiency resolves during glucocorticoid replacement therapy [8].…”

Section: Introductionmentioning

confidence: 99%

Effect of Galanin and Arginine, Alone or in Combination, on Growth Hormone Secretion in Adult Patients Treated with Glucocorticoids

et al. 1993

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Glucocorticoids are known to decrease growth hormone (GH) secretion in man. Galanin, a 29-amino acid peptide, and arginine stimulate GH secretion through different hypothalamic mechanisms. The aim of our study was to investigate the effect of arginine and galanin (alone or in combination) on GH secretion in 7 adult patients with nonendocrine diseases receiving chronic daily immunosuppressive glucocorticoid treatment (5 F, 2 M; mean age 48.4 ± (SEM) 3.7 years). Five normal adults (3 F, 2 M; mean age 34.6 ± 2.2 years) served as controls. All subjects underwent in random order: (1) infusion of arginine hydrochloride (30 g i.v. in 100 ml saline) from -30 to 0 min; (2) infusion of synthetic porcine galanin (500 µg i.v. in 100 ml saline) from -15 to 30 min; (3) intravenous infusion of arginine hydrochloride from -30 to 0 min combined with synthetic porcine galanin from -15 to 30 min. In normal subjects GH peak after arginine (8.6 ± 3.3 µg/1) and galanin (6.6 ± 3.2 µg/1) did not show significant differences; the GH peak after arginine + galanin (21.4 ± 6.1 µg/1) was significantly higher with respect to galanin or arginine alone. In glucocorticoid-treated patients the GH peak after arginine (4.6 ± 1.5 µg/1) was significantly (p < 0.05) higher with respect to galanin (1.8 ± 1.0 µg/1); after arginine + galanin the GH peak (8.2 ± 2.3 µg/1) was significantly (p < 0.05) enhanced with respect to either galanin or arginine alone. The GH response to arginine was not significantly different in normal and glucocorticoid-treated patients. Normal subjects showed higher GH peaks after galanin alone and arginine + galanin with respect to the steroid-treated group. Moreover, we hypothesize that the inhibitory action of glucocorticoids on GH secretion in man is mediated not only by an increase in somatostatin tone but also by a decrease in endogenous hypothalamic GHRH release.

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Pyridostigmine Enhances Even if it Does Not Normalize the Growth Hormone Responses to Growth Hormone-Releasing Hormone in Patients with Cushing’s Disease

Cited by 21 publications

References 23 publications

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

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

Growth hormone secretion in primary adrenal Cushing's syndrome is disorderly and inversely correlated with body mass index

Effect of Galanin and Arginine, Alone or in Combination, on Growth Hormone Secretion in Adult Patients Treated with Glucocorticoids

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