hexarelin and Acromegaly

Impaired cardiovascular function has recently been demonstrated to potentially reduce life expectancy both in GH deficiency and excess. Experimental and clinical studies have supported the evidence that GH and IGF-I are implicated in cardiac development. In most patients with acromegaly a specific cardiomyopathy, characterized by myocardial hypertrophy with interstitial fibrosis, lympho-mononuclear infiltration and areas of monocyte necrosis, results in biventricular concentric hypertrophy. In contrast, patients with childhood or adulthood-onset GH deficiency (GHD) may suffer both from structural cardiac abnormalities, such as narrowing of cardiac walls, and functional impairment, that combine to reduce diastolic filling and impair left ventricular response to peak exercise. In addition, GHD patients may have an increase in vascular intima-media thickness and a higher occurrence of atheromatous plaques, that can further aggravate the haemodynamic conditions and contribute to increased cardiovascular and cerebrovascular risk. However, several lines of evidence have suggested that the cardiovascular abnormalities can be partially reversed by suppressing GH and IGF-I levels in acromegaly or after GH replacement therapy in GHD patients. Recently, much attention has been focussed on the ability of GH to increase cardiac mass suggesting its possible use in the treatment of chronic nonendocrine heart failure. In fact, GH administration can induce an improvement in haemodynamic and clinical status in some patients. Although these data need to be confirmed in more extensive studies, such promising results seem to open new perspectives for GH treatment in humans.

Topics: Acromegaly; Adult; Animals; Case-Control Studies; Child; Female; Growth Hormone; Heart; Heart Diseases; Hemodynamics; Hormones; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Octreotide; Oligopeptides; Rats; Stroke Volume

In man, new synthetic peptides such as hexarelin have been shown to have a potent and dose dependent GH releasing activity. Furthermore, a significant PRL releasing activity has also been demonstrated, but this has been investigated in less detail. We have therefore evaluated the effect of hexarelin on PRL and GH secretion in patients with active acromegaly or pathological hyperprolactinaemia.. Hexarelin (2 micrograms/kg i.v.), a modified derivative of GHRP-6 of the following structure: His-2-Me-D-Trp-Ala-Trp-D-Phe-Lys-NH2, or placebo, was administered in random order on two separate occasions.. Eight patients with active acromegaly (ACRO, 6 F and 2 M, mean age 61.7 years, range 56-73), 6 with macroadenomas and 2 without radiological signs of tumour, and 6 female patients with pathological hyperprolactinaemia (HPRL, mean age 31.2 years, range 18-47) 5 with microadenomas and 1 with empty sella, were studied. Fourteen normal subjects (NS, 8 F and 6 M, 27.1 years, 24-30) were studied as controls.. GH and PRL levels were evaluated every 15 minutes for 2 hours after hexarelin or placebo. Both hormones were measured using commercial IRMA kits. Basal IGF-I was measured in all subjects using an RIA following acid-ethanol extraction.. Hexarelin induced a significant increase in PRL levels in NS (median, range, delta peak HEX vs placebo: 150 (-14-402) vs 10 (-34-24) mU/l; delta AUC HEX vs placebo: 7710 (2,100-3 2540) vs 30 (-2,566-2,040) mU min/l, P < 0.01) and in ACRO (190 (-10-496) vs 6 (-100-34) mU/l; 10,170 (-5,310-51,436) vs -82 (-6,030-1,410) mU min/l, P < 0.02), but not in HPRL (10 (-180-80) vs 50 (-100-240) mU/l; -600 (-16,996-10,140) vs -1,950 (-8,540-14,160) mU min/l). Hexarelin also induced a lower increase of GH in HPRL (60 (30-82) vs 1.8 (-0.2-2.2) mU/l; 2,853 (1,477.6-4,372.6 vs 91.6 (-160.6-174) mU min/l, P < 0.05) than in NS (90.8 (50.6-181) vs 0.8 (-1.2-6.8) mU/l; 6642 (2,004-13,252.6 vs 42 (456-900) mU min/l, P < 0.01) or in ACRO (117.2 (21.2-420.6 vs 3.8 (-2.2-18) mU/l; 6645 (1,554-22,138.6 vs 334.6 (-324-1,065) mU min/l, P < 0.02).. Our data show that the PRL releasing effect of hexarelin is preserved in acromegaly but lost in pathological hyperprolactinaemia. In contrast with acromegaly, the GH releasing effect of hexarelin is also blunted in hyperprolactinaemic patients. These data demonstrate that patients with pathological hyperprolactinaemia are partially refractory to the activity of hexarelin.

Topics: Acromegaly; Adolescent; Adult; Aged; Female; Growth Hormone; Growth Substances; Hormones; Humans; Hyperprolactinemia; Male; Middle Aged; Oligopeptides; Prolactin; Stimulation, Chemical

Due to persistent qualitative abnormalities in GH secretion following treatment, and lack of a sensitive marker of GHD in mid-adult life it is extremely difficult to diagnose GHD in treated acromegalic patients. The diagnosis of GHD in patients with pituitary disease relies on provocative tests of GH reserve. Arginine releases GH by reducing somatostatin inhibition of GH release, whereas GH secretagogues (GHS) affect GH release by direct stimulation of the GHS receptor, though an intact GH releasing hormone (GHRH) axis is a prerequisite. The peak GH response to insulin-induced hypoglycaemia and arginine in acromegalic patients, in whom basal serum GH levels of less than 5 mU/l have been achieved, is greatly diminished in those treated by hypothalamo-pituitary irradiation. We aimed to study the response of successfully treated acromegalic patients to the growth hormone secretagogue hexarelin in view of its different putative mechanism of action, and in addition, to determine whether it has any value in the diagnosis of GH deficiency in this subset of patients. Nineteen acromegalic patients, in whom mean serum GH levels below 5 mU/l have been achieved through treatment, were recruited. Eight of the patients had been treated by surgery alone (Group A) and 11 had received primary or postoperative irradiation (Group B). All patients underwent 20 min blood sampling to provide a 24-h GH profile. Serum IGF-I was measured from a sample drawn between 0900 h and 1000 h. On a second visit arginine 20 g/m2 was infused over 30 min, blood samples were taken before commencing the infusion and at 30-min intervals thereafter for 180 min. At the final visit hexarelin 1.5 mcg/kg was administered as an intravenous bolus at t = 0. Blood was drawn at 15-min intervals from - 30 to 180 min. All patients in group A showed an increment in serum GH following hexarelin (DeltaGHHEX) > 20 mU/l, a normal response to arginine, and a mean 24-h GH > 0.5 mU/l. In group B only 4/11 achieved a DeltaGHHEX > 20 mU/l, 5/11 producing a response of < 2 mU/l. Four of the five patients with a DeltaGHHEX < 2 mU/l were also demonstrated to have a mean 24-h GH of < 0.5 mU/l and serum IGF-I SDS < + 0.5. All four patients in Group B who achieved a DeltaGHHEX > 20 mU/l, were observed to show an absent or minimal GH response to arginine. Despite loss of the GH response to arginine, the DeltaGHHEX is retained in a proportion of those patients in whom "safe" GH levels were achieved following irradiation. Fro

Topics: Acromegaly; Adult; Aged; Arginine; Female; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Insulin-Like Growth Factor I; Male; Middle Aged; Oligopeptides; Radiography; Statistics, Nonparametric; Stimulation, Chemical

Hexarelin (His-D-2-Methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) is a GHRP-6 analog with the substitution of D-tryptophan with its 2-methyl derivative. The aim of our study was to ascertain whether hexarelin was able to counteract the glucocorticoid-mediated increase in hypothalamic somatostatin tone and consequent inhibition on serum GH levels in acromegalic patients. Ten patients (5 males, 5 females; age range 27-71 years; BMI range 23.3-35 kg/m2) with active acromegaly underwent: 1) hydrocortisone alone: a bolus iv injection of 100 mg hydrocortisone succinate in 2 mL saline, at time -60 followed by a 120 min iv infusion of 250 mg hydrocortisone succinate in 250 mL saline, from -60 to 60 min; 2) hexarelin+hydrocortisone: a bolus iv injection of hexarelin 100 micrograms, 60 min after initiation of a 2-hour hydrocortisone infusion; 3) hexarelin alone: a bolus iv injection of hexarelin at time 0, 60 min after initiation of a 2-hour saline infusion. The mean GH peak, expressed as percent change with respect to baseline level (mean of -75 and -60 minute samples), after hexarelin (1750 +/- 1157%) did not differ significantly with respect to that observed after hexarelin+hydrocortisone (1120 +/- 770%). After hydrocortisone alone the patients showed a mean decrease in GH levels as compared to baseline levels, of 47 +/- 7%. Our data show that the GH response to hexarelin in acromegaly is resistant to the inhibitor action of an acute and sustained elevation of serum cortisol levels. That hexarelin counteracts the glucocorticoid-mediated inhibition of GH secretion supports the hypothesis of an hexarelin-induced decrease in endogenous somatostatin tone.

Topics: Acromegaly; Adult; Aged; Amino Acid Sequence; Female; Growth Hormone; Growth Substances; Humans; Hydrocortisone; Kinetics; Male; Middle Aged; Molecular Sequence Data; Oligopeptides