The IGF-I response to very low rhGH doses is preserved in human aging.
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Adult↗
Biomedical subjects
E Arvat
Publications and source records attributed to E Arvat.
The GH response to GHRH in normal adults is not affected by enalapril or furosemide while is blunted by digoxin.
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Adult↗
Activity of GH/IGF-I axis in patients with dilated cardiomyopathy.
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Arginine↗
Corticotroph and adrenal responsiveness to hCRH, hexarelin and ACTH in young and elderly subjects.
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Adrenal Glands↗
Effects of beta-adrenergic agonists and antagonists on the growth hormone response to growth hormone-releasing hormone in anorexia nervosa.
BACKGROUND: In anorexia nervosa (AN), growth hormone (GH) hypersecretion and low insulin-like growth factor I (IGF-I) levels are present. It is unclear whether this is due to a peripheral GH resistance and a reduced IGF-I negative feedback on GH secretion or to a primary hypothalamic dysfunction. In AN, in contrast to normal subjects, cholinergic antagonists and agonists, whose action is somatostatin (SS)-mediated, have reduced and absent effects on the GH response to growth hormone-releasing hormone (GHRH). Since arginine, another substance acting via inhibition of SS, maintains its potentiating effect on GH secretion in AN, it has been hypothesized that somewhat specific alteration of the SS-mediated cholinergic influence may be present in this condition. To further clarify the neural control of AH secretion in AN, we evaluated the effects of beta-adrenergic agonists and antagonists, which are known to inhibit and increase, respectively, the GHRH-induced GH secretion in normal subjects. METHODS: We studied the effect of atenolol (ATE), a beta 1-adrenergic antagonist, and salbutamol (SALB), a beta 2-adrenergic agonist, on the GHRH-induced GH release in 10 patients with AN and in 10 normal age-matched women (NW). RESULTS: Basal GH levels were higher, whereas IGF-I were lower in AN than in NW. The GHRH-induced GH rise in AN was higher than that in NW. ATE significantly enhanced the GH response to GHRH in NW, but not in AN. The GH responses to GHRH after ATE pretreatment were similar in NW and in AN. The GH response to GHRH was inhibited by SALB in both NW and AN. The GH responses to GHRH after SALB pretreatment were similar in NW and AN. CONCLUSIONS: These data reveal an exaggerated somatotrope responsiveness to GHRH in AN that is not further increased by beta-adrenergic blockade, while is abolished by beta-adrenergic activation. This suggests that an impairment of beta-adrenergic influence on GH secretion is present in anorexia nervosa.
Adolescent↗
Growth hormone-releasing peptides and their analogs.
Growth hormone-releasing peptides (GHRPs) are a series of hepta (GHRP-1)- and hexapeptides (GHRP-2, GHRP-6, Hexarelin) that have been shown to be effective releasers of GH in animals and humans. More recently, a series of nonpeptidyl GH secretagogues (L-692,429, L-692,585, MK-0677) were discovered using GHRP-6 as a template. Some cyclic peptides as well as penta-, tetra-, and pseudotripeptides have also been described. This review summarizes recent developments in our understanding of the GHRPs, as well as the current nonpeptide pharmacologic analogs. GHRPs and their analogs have no structural homology with GHRH and act via specific receptors present at either the pituitary or the hypothalamic level. The GHRP receptor has recently been cloned and it does not show sequence homology with other G-protein-coupled receptors known so far. This evidence strongly suggests the existence of a natural GHRP-like ligand which, however, has not yet been found. Although the exact mechanism of action of GHRPs has not been fully established, there is probably a dual site of action on both the pituitary and the hypothalamus, possibly involving regulatory factors in addition to GHRH and somatostatin. Moreover, the possibility that GHRPs act via an unknown hypothalamic factor (U factor) is still open. The marked GH-releasing activity of GHRPs is reproducible and dose-related after intravenous, subcutaneous, intranasal, and even oral administration. The GH-releasing effect of GHRPs is the same in both sexes, but undergoes age-related variations. It increases from birth to puberty and decreases in aging. The GH-releasing activity of GHRPs is synergistic with that of GHRH and not affected by opioid receptor antagonists, while it is only blunted by inhibitory influences that are known to nearly abolish the effect of GHRH, such as neurotransmitters, glucose, free fatty acids, glucocorticoids, rhGH, and even exogenous somatostatin. GHRPs maintain their GH-releasing effect in somatotrope hypersecretory states, such as acromegaly, anorexia nervosa, and hyperthyroidism. On the other hand, GHRPs and their analogs have been reported to be effective in idiopathic short stature, in some situations of GH deficiency, in obesity, and in hypothyroidism, while in patients with pituitary stalk disconnection and in Cushing's syndrome the somatotrope responsiveness to GHRPs is almost absent. A potential role in the treatment of short stature, aging, catabolic states, and dilated cardiomyopathy has been envisaged.
Animals↗
The activity of GH/IGF-I axis in anorexia nervosa and in obesity: a comparison with normal subjects and patients with hypopituitarism or critical illness.
GH/IGF-I axis activity changes have been reported both in anorexia nervosa (AN) and in obesity (OB). AN is characterized by GH hypersecretion and very low IGF-I levels as a result of undernutrition and acquired peripheral GH resistance. On the other hand OB is a GH hyposecretory state but IGF-I levels are generally preserved. The activity of GH/IGF-I axis in AN and OB has never been directly compared with that of other pathophysiological conditions such as hypopituitarism and critical illness in which a reduction of both GH and IGF-I secretion has been demonstrated. To this aim, we evaluated IGF-I levels and both basal and GHRH (1 microgram/kg) IV-induced GH secretion in 20 female patients with anorexia nervosa (mean age: 19.1 +/- 0.8 years) and in 15 female and 5 male patients with simple obesity (mean age: 39.0 +/- 3.0 years). We then compared the results with those of hypopituitaric patients with severe GH deficiency (GHD), including 10 female and 10 patients (mean age: 32.0 +/- 2.1 years), and with 4 female and 7 male patients with critical illness (CRI) following multiple trauma 72 hours after ICU admission (mean age: 59.2 +/- 1.2 years). Twenty-six normal subjects (NS) including 14 female and 12 male patients (mean age: 37.8 +/- 3.7 years) were studied as controls. Basal IGF-I levels in AN patients (93.5 +/- 11 micrograms/L) were lower (p < 0.001) than in the NS (201.7 +/- 13.5 micrograms/L) and OB (194.5 +/- 28.6 micrograms/L), which, in turn, were similar. IGF-I levels in AN patients were lower than in CRI patients (162.8 +/- 17.4 micrograms/L) and higher than in GHD patients (76.7 +/- 13.5 micrograms/L) but these differences did not attain statistical significance. Basal GH levels in AN patients (7.6 +/- 2.5 micrograms/L) were higher (p < 0.001) than in NS (1.8 +/- 0.3 micrograms/L), OB patients (1.1 +/- 0.5 micrograms/L), CRI patients (1.8 +/- 0.5 micrograms/L) and GHD patients (0.3 +/- 0.1 microgram/L), which were the lowest (p < 0.01). The GHRH-induced GH rise in AN patients (AUC: 2032.9 +/- 253.5 micrograms/L/h) was three fold higher (p < 0.001) than in NS (662.1 +/- 80.3 micrograms/L). On the other hand in OB (332.4 +/- 74.7 micrograms/L/h) the GH response to GHRH was similar to that in CRI (199.6 +/- 98.8 micrograms/L/h); both were clearly higher (p < 0.01) than in GHD patients (25.1 +/- 5.2 micrograms/L/h) but lower (p < 0.01) than in NS. These findings demonstrate that in AN patients, in spite of a clear increase of both basal and GHRH-induced GH secretion, IGF-I synthesis and release are as markedly impaired as in patients with panhypopituitarism and severe GHD. On the other hand in OB and in CRI, IGF-I synthesis and release are preserved despite marked impairment to GHRH-induced GH secretion. These results reinforce the major role of nutrition in conditioning the activity of GH/IGF-I axis in different patho-physiological states.
Adolescent↗
Hexarelin, a synthetic GH-releasing peptide, is a powerful stimulus of GH secretion in pubertal children and in adults but not in prepubertal children and in elderly subjects.
GH-releasing peptides (GHRPs) and their non-peptidly mimetics are synthetic molecules which possess marked, dose-related and reproducible GH-releasing effect even after oral administration. Their potent stimulatory effect on GH secretion suggested that GHRP could be useful as provocative test on the diagnosis of GH deficiency. We compared the GH response to the maximal effective dose of Hexarelin (2 micrograms/kg i.v.), an hexapeptide belonging to GHRP family, with that of GHRH (1 microgram/kg i.v.) alone and combined with arginine (ARG, 0.5 g/kg i.v.), which likely acts via inhibition of hypothalamic somatostatin release. We studied 6 prepubertal (4 boys and 2 girls, age 2.6-12.2 yr) and 6 pubertal children with normal short stature (3 boys and 3 girls, age 10.3-14.4 yr) as well as 12 normal young adults (6 males and 6 females, age 22-30 yr) and 12 normal elderly subjects (6 males and 6 females, age 53-79 yr). In prepubertal children, the GH response to HEX (19.0 +/- 4.6 micrograms/l; 611.5 +/- 121.4 micrograms/l/h) was lower than that to GHRH (27.4 +/- 12.7 micrograms/l; 1209.0 +/- 590.9 micrograms/l/h) but this difference did not attain statistical significance. Both these responses were, in turn, lower (p < 0.05) than that to ARG + GHRH (57.9 +/- 15.1 micrograms/l; 2483.6 +/- 696.6 micrograms/l/h). In pubertal children, the GH response to HEX (67.6 +/- 12.7 micrograms/l; 2755.3 +/- 547.3 micrograms/l/h) was higher than that to ARG + GHRH (49.1 +/- 8.9 micrograms/l; 2554.1 +/- 356.6 micrograms/l/h) but this difference did not attain statistical significance; both these responses were, in turn, clearly higher (p < 0.05) than that to GHRH alone (23.1 +/- 7.9 micrograms/l; 1004.8 +/- 214.3 micrograms/l/h). In young adults, the GH response to HEX 60.9 +/- 8.0 micrograms/l; 2401.0 +/- 376.2 micrograms/l/h) was similar to that to ARG + GHRH (68.9 +/- 11.7 micrograms/l; 3035.7 +/- 466.6 micrograms/l/h) and both were clearly higher (p < 0.001) than that to GHRH alone (21.6 +/- 3.6 micrograms/l; 790.0 +/- 137.0 micrograms/l/h). In elderly subjects, the GH response to HEX (22.4 +/- 4.9; 855.0 +/- 199.0 micrograms/l/h) was higher (p < 0.01) than that to GHRH (3.6 +/- 0.8 micrograms/l; 151.8 +/- 24.6 micrograms/l/h) but lower (p < 0.05) than that to ARG + GHRH (48.1 +/- 4.6 micrograms/l; 1758.2 +/- 149.1 micrograms/l/h). In conclusion, GHRPs are a powerful stimulus of GH secretion in pubertal children and young adults only. On the other hand, the age-related variations in the GH response to GHRPs probably limit their reliability for the evaluation of GH releasable pool in prepubertal children and elderly subjects.
Adolescent↗
Low IGF-I levels are often uncoupled with elevated GH levels in catabolic conditions.
Increased GH together with decreased IGF-I levels pointing to peripheral GH insensitivity in critically ill patients have been reported by some but not by other authors. To clarify whether elevated GH levels are coupled with low IGF-I levels in all catabolic conditions, basal GH and IGF-I levels were evaluated in patients with sepsis (SEP, no.=13; age [mean+/-SE]=59.2+/-1.2 yr), trauma (TRA, no.=16; age=42.3+/-3.4 yr), major burn (BUR, no.=26; age=52.8+/-4.2 yr) and post-surgical patients (SUR, no.=11; age=55.0+/-4.7 yr) 72 hours after ICU admission or after cardiac surgery. GH and IGF-I levels were also evaluated in normal subjects (NS, no.=75; age=44.0+/-1.5 yr), in adult hypopituitaric patients with severe GH deficiency (GHD, no.=54; age=44.8+/-2.3 yr), in patients with liver cirrhosis (LC, no.=12; age=50.4+/-2.8 yr) and in patients with anorexia nervosa (AN, no.=19; age=18.7+/-0.8 yr). Basal IGF-I and GH levels in GHD were lower than in NS (68.6+/-6.4 vs 200.9+/-8.7 microg/l and 0.3+/-0.1 vs 1.4+/-0.2 microg/l; p<0.01). On the other hand, AN and LC showed IGF-I levels (70.4+/-9.1 and 52.4+/-10.5 microg/l) similar to those in GHD while GH levels (10.0+/-2.8 and 7.9+/-2.1 microg/l) were higher than those in NS (p<0.01). IGF-I levels in SEP (84.5+/-8.8 microg/l) were similar to those in GHD, AN and LC and lower than those in NS (p<0.01). IGF-I levels in BUR (105.2+/-10.9 microg/l) were lower than in NS (p<0.01) but higher than those in GHD, AN, LC and SEP (p<0.01). On the other hand, in TRA (162.8+/-17.4 microg/l) and SUR (135.0+/-20.7 microg/l) IGF-I levels were lower but not significantly different from those in NS and clearly higher than those in GHD, AN, LC, SEP and BUR. Basal GH levels in SEP (0.6+/-0.2 microg/l), TRA (1.8+/-0.5 microg/l), SUR (2.2+/-0.5 microg/l) and BUR (2.2+/-0.5 microg/l) were similar to those in NS, higher (p<0.05) than those in GHD and lower (p<0.01) than those in AN and LC. In conclusion, our data demonstrate that low IGF-I levels are not always coupled with elevated GH levels in all catabolic conditions. Differently from cirrhotic and anorectic patients, in burned and septic patients GH levels are not elevated in spite of very low IGF-I levels similar to those in panhypopituitaric GHD patients. These findings suggest that in some catabolic conditions peripheral GH insensitivity and somatotrope insufficiency could be concomitantly present.
Adolescent↗
Influence of galanin and serotonin on the endocrine response to Hexarelin, a synthetic peptidyl GH-secretagogue, in normal women.
Hexarelin (HEX) is a synthetic GH-secretagogue (GHS) which acts on specific receptors either at the pituitary or the hypothalamic level to stimulate GH release both in animal and in man. Like other GHS, HEX possesses also PRL-, ACTH- and cortisol (F)-releasing activity but the mechanisms underlying these effects are even less clear. On the other hand, galanin (GAL) and serotonin play an important role in the neural control of GH, PRL and ACTH secretion both in animal and in man. In order to study the interaction between HEX and GAL and to verify whether serotoninergic mechanisms underly the endocrine effects of GHS, in 12 normal young volunteers (24-30 yr) the following tests were performed: group A (N = 5), HEX (2.0 micrograms/kg i.v. at 0 min), GAL (15.0 micrograms/kg i.v. from 0 to 60 min) and HEX + GAL; group B (N = 7), HEX alone and preceeded by cyproeptadine (CYPRO, 8 mg os at -60 min). In group A, the GH response to HEX (1204.2 +/- 312.9 micrograms*min/L) was higher (p < 0.05) than that to GAL alone (305.6 +/- 35.5 micrograms*min/L) and was not modified by GAL co-administration (1021.8 +/- 249.9 micrograms*min/L). PRL secretion was increased to the same extent by HEX and GAL (507.9 +/- 81.1 and 743.0 +/- 164.7 micrograms*min/L) which showed no interaction (603.5 +/- 75.7 micrograms*min/L). HEX elicited an increase in both ACTH and F secretion (924.5 +/- 169.7 pg*min/ml and 6131.3 +/- 616.6 micrograms*min/L) while GAL had no effect when given alone (759.5 +/- 185.5 pg*min/ml and 5350.3 +/- 755.6 micrograms*min/L) and did not modify the effect of HEX (891.3 +/- 159.2 pg*min/ml and 5877.8 +/- 554.4 micrograms*min/L). In group B, the GH response to HEX (1636.4 +/- 267.5 micrograms*min/L) was blunted by CYPRO (1164.8 +/- 212.3 micrograms*min/L) but this difference did not attained statistical significance. On the other hand, CYPRO did not modify the HEX-induced PRL (599.5 +/- 129.2 vs 638.9 +/- 131.9 micrograms*min/L), ACTH (1282.8 +/- 222.0 vs 1330.2 +/- 347.0 pg*min/ml) and F response (4738.3 +/- 355.3 vs 4580.9 +/- 857.3 micrograms*min/L). Our present data demonstrate that Hexarelin has no interaction with galanin; thus thereotically, the stimulatory effect of GHS on GH and PRL secretion could involve, at least partially, a galanin-mediated mechanism. On the other hand, our data demonstrate that serotonin does not mediate the stimulatory effect of GHS on PRL, ACTH and cortisol; the intrinsic anticholinergic property of cyproeptadine could account for the trend toward its blunting effect on the GH response to Hexarelin.
Adrenocorticotropic Hormone↗
Diagnostic and therapeutic uses of growth hormone-releasing substances in adult and elderly subjects.
The aim of this review is to answer two questions. The first question is: is there any alternative provocative test equal to, or even better than, the insulin-tolerance test (ITT), the so-called gold standard, for the diagnosis of growth hormone deficiency (GHD) in adults and the elderly? The answer is 'yes'. In fact, when combined with arginine or pyridostigmine, growth hormone-releasing hormone (GHRH) becomes one of the most potent and reproducible tests for distinguishing patients with severe GHD from normal subjects. Owing to its tolerability and its suitability for use in the elderly, the GHRH + arginine test is the best alternative choice and is at least as sensitive as the ITT provided that appropriate cut-off limits are given. The second question is: is there any therapeutic approach alternative to recombinant human growth hormone (rhGH) for adult and elderly patients with GHD and/or for the somatopause? At present, the answer is 'no'. Growth hormone (GH)-releasing substances need the functional integrity of somatotroph cells to induce the release of growth hormone. Probably only patients with childhood-onset, isolated GHD (frequently hypothalamic-dependent) could benefit from treatment with GHRH or growth hormone secretagogues (GHS). Whenever restoration of the activity of the GH/insulin-like growth factor-1 (IGF-1) axis in the elderly would be of use, GHRH and/or GH secretagogues would be good candidates. In fact, the existence of a considerable pool of releasable growth hormone has been demonstrated in the elderly.
Adult↗
Diagnosis of GH deficiency in adults.
Within an appropriate clinical context, growth hormone deficiency (GHD) in adults must be demonstrated biochemically. The assays of insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) per se do not establish the diagnosis of adult GHD. Similarly, the evaluation of spontaneous growth hormone (GH) secretion over 24 h has no diagnostic value in adulthood even when an ultra-sensitive GH assay is used. The diagnosis of adult GHD is established by provocative testing of GH secretion, and insulin-induced hypoglycaemia using the insulin tolerance test (ITT) is indicated as the test of choice. Alternative provocative tests of GH secretion have been proposed and have to be used with appropriate cut-off limits. Testing with GH releasing hormone (GHRH) alone has no diagnostic value, but when GHRH is given in combination with arginine or pyridostigmine it becomes the most potent and reproducible provocative test to evaluate the maximal secretory capacity of somatotrope cells. The potentiating effect of arginine on the GHRH-induced GH response is fully preserved while the stimulatory effect of GHRH + pyridostigmine is reduced in ageing. The GHRH + arginine test is well tolerated and reproducibly distinguishes between normal and GHD adult and elderly subjects. Thus, the GHRH + arginine test is the most promising alternative to the ITT provided that cut-off limits appropriate to its potent stimulatory effect are considered.
Adult↗
Growth hormone secretagogues as corticotrophin-releasing factors.
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Adrenocorticotropic Hormone↗
Age-related variations in the neuroendocrine control, more than impaired receptor sensitivity, cause the reduction in the GH-releasing activity of GHRPs in human aging.
The mechanisms underlying the reduction in the GH-releasing activity of GHRPs in aging are still unclear. Aim of our study was to verify in man whether age-related impairment of the neurohormonal control of GH secretion and/or receptor alterations are involved in the reduced GH response to GHRPs in aging. To this goal, in 16 normal elderly subjects (E, 66-81 yr) and 12 young controls (Y, 24-28 yr) we studied the effects of 1.0, 2.0 and 3.0 micrograms/kg i.v. Hexarelin (HEX), a synthetic hexapeptide, or GHRH, as well as the interaction among HEX (2.0 micrograms/kg), GHRH (2.0 micrograms/kg) and arginine (ARG, 0.5 gr/kg) on GH secretion. In Y the GH response to increasing doses of HEX (1.0 vs. 2.0 vs. 3.0 micrograms/kg; AUC0;v-120 +/- SEM: 1728.4 +/- 406.4 vs. 2265.9 +/- 298.4 vs. 2934.3 +/- 482.2 micrograms/L/h, p < 0.05 for 1.0 vs. 2.0 micrograms/kg) and GHRH (649.6 +/- 111.4 vs. 792.2 +/- 117.6 vs. 1402.6 +/- 363.0 micrograms/L/h) showed a progressive increase. Two micrograms/kg HEX and 1 microgram/kg GHRH were the maximal effective doses. Similarly, in E the GH response to increasing doses of HEX (336.7 +/- 50.0 vs. 742.8 +/- 157.9 vs. 1205.1 +/- 178.1 micrograms/L/h, p < 0.05 for 1.0 vs. 2 micrograms/kg, p < 0.001 for 1.0 vs. 3.0 micrograms/kg and p < 0.03 for 2.0 vs. 3.0 micrograms/kg) and GHRH (183.8 +/- 27.3 vs. 260.9 +/- 17.3 vs. 356.1 +/- 46.3 micrograms/L/h, p < 0.005 for 1.0 vs. 3.0 micrograms/kg and p < 0.05 for 2.0 vs. 3.0 micrograms/kg) showed a progressive increase. In E the GH response to 3 micrograms/kg HEX or GHRH were clearly higher than those to 2 micrograms/kg. However, at each dose the GH responses to HEX or GHRH in E were lower (p < 0.05) than those in Y. In Y the GH response to HEX + GHRH was synergistical (4259.2 +/- 308.0 micrograms/L/h, p < 0.05). ARG strikingly potentiated the GHRH-induced GH rise (2640.8 +/- 273.6 micrograms/L/h, p < 0.01) but not the HEX-induced one (2371.7 +/- 387.2 micrograms/L/h) as well as the synergistical effect of HEX and GHRH (4009.1 +/- 360.8 micrograms/L/h). In E the GH response to HEX and GHRH was still synergistical (1947.7 +/- 306.0 micrograms/L/h, p < 0.05) but these responses were lower than those in young (p < 0.01). On the other hand, in E ARG restored the GH response to GHRH (1858.9 +/- 172.8 micrograms/L/h, p < 0.01) and even those to HEX (2069.5 +/- 528.7 micrograms/L/h, p < 0.01) and HEX + GHRH (4406.0 +/- 1079.2 micrograms/L/h, p < 0.05). Our present results indicate that the impairment of GHRP and GHRH receptor activity may have a role in the reduction of the somatotrope responsiveness in aging. However, the age-related reduction in the GH-releasing activity of GHRPs seems mainly dependent on age-related variations in the neural control, i.e. concomitant GHRH hypoactivity and somatostatinergic hyperactivity.
Adult↗
The IGF-I response to very low rhGH doses is preserved in human ageing.
OBJECTIVES: The activity of the GH/IGF-I axis varies during life and is clearly reduced in the elderly. In fact, GH, IGF-I and IGFBP-3 levels in older people are clearly reduced and similar to those observed in patients with GH deficiency. The declining activity of the GH/IGF-I axis with advancing age may contribute to changes in body composition, structure, function and metabolism. In fact, treatment with pharmacological doses of rhGH restored plasma IGF-I levels, increased lean body mass and muscle strength while decreased adipose tissue mass in healthy elderly subjects. At present it is unclear whether peripheral GH sensitivity is preserved in aging. To clarify this point, we aimed to verify the effect of both single dose and short term treatment with very low rhGH doses on the IGF-I levels in normal elderly subjects. Normal young adults were studied as controls. DESIGN: We studied the IGF-I response to rhGH administration after single (20 micrograms/kg s.c.) or repeated administrations (5 micrograms/kg s.c. for 4 days) in two groups of young and elderly subjects. SUBJECTS: Twenty-seven healthy elderly (ES, 14 F and 13 M, age mean +/- SEM: 69.4 +/- 1.3 years, BMI: 23.9 +/- 0.5 kg/m2) and 21 young adult subjects (YS, 12 F and 9 M, 29.8 +/- 1.2 years, 23.8 +/- 0.5 kg/m2) were studied, divided into two groups. MEASUREMENTS: Group 1: blood samples for IGF-I and IGFBP-3 assay were drawn basally and 12 h after rhGH administration (20 micrograms/kg). Group 2: blood samples for IGF-I, IGFBP-3, glucose and insulin assays were drawn basally, 12 h after the first and the last rhGH administration (5 micrograms/kg). Free T3 (fT3), free T4 (fT4) and TSH levels were also assayed basally and after the last rhGH administration; oestradiol and testosterone levels were measured basally. RESULTS: Basal IGF-I levels were lower in ES (whole group) than in YS (whole group) (123.1 +/- 8.9 vs. 230.4 +/- 16.1 micrograms/l, P < 0.001) while IGFBP-3 levels in the two groups were similar (2.7 +/- 0.2 vs. 3.1 +/- 0.2 mg/l). No sex-related differences in IGF-I and IGFBP-3 levels were recorded in either group. Group 1: the single administration of 20 micrograms/kg rhGH induced a significant (P < 0.001) IGF-I rise both in YS (318.0 +/- 25.3 vs. 256.0 +/- 21.6 micrograms/l) and ES (187.2 +/- 16.8 vs. 100.4 +/- 9.5 micrograms/l). IGF-I levels after rhGH in ES persisted lower than those in YS (P < 0.001), but the percentage IGF-I increase after rhGH was higher (P < 0.001) in ES (91.6 +/- 12.9%) than in YS (23.9 +/- 5.0%) subjects. Both in YS and ES IGFBP-3 levels were significantly increased to the same extent by 20 micrograms/kg rhGH (3.0 +/- 0.2 vs. 2.3 +/- 0.2 mg/l; 2.9 +/- 0.2 vs. 2.6 +/- 0.2 mg/l, P < 0.001 vs. baseline). Group 2: basal glucose, insulin, fT3, fT4 and TSH levels in YS and ES were similar; testosterone levels in aged and young men were similar while oestradiol levels in aged women were lower (P < 0.01) than in the young ones. IGF-I levels were significantly increased 12 h after the first administration of 5 micrograms/kg rhGH both in ES (166.6 +/- 15.7 vs. 138.3 +/- 12.1 micrograms/l, P < 0.03) and YS (272.2 +/- 16.1 vs. 230.4 +/- 16.1 micrograms/l, P < 0.001). Twelve hours after the last rhGH administration IGF-I levels were further increased (P < 0.001) both in ES (208.7 +/- 21.1 micrograms/l) and YS (301.7 +/- 17.6 micrograms/l). IGF-I levels in ES persisted lower than those in YS at each time point (P < 0.001); however, the percentage IGF-I increase after rhGH in ES and YS was similar (after the first administration: 22.4 +/- 5.1 vs. 21.7 +/- 5.1%; after the last administration: 52.9 +/- 9.5 vs. 39.5 +/- 9.9%). No significant variation in IGFBP-3, glucose, insulin, fT3, fT4 or TSH levels was recorded in either ES or YS. CONCLUSIONS: Our data demonstrate that IGF-I levels in aging are reduced but the peripheral sensitivity to rhGH is preserved. In fact, in aged subjects the percentage rhGH-induced IGF-I increase is similar or even highe
Adult↗
Effects of dexamethasone and alprazolam, a benzodiazepine, on the stimulatory effect of hexarelin, a synthetic GHRP, on ACTH, cortisol and GH secretion in humans.
Hexarelin (HEX) is a synthetic GHRP which acts on specific receptors at both the pituitary and the hypothalamic level to stimulate GH release both in animals and in humans. Like other GHRPs, HEX possesses also acute ACTH and cortisol-releasing activity similar to that of hCRH. The mechanisms underlying the stimulatory effect of GHRPs on hypothalamo-pituitary-adrenal (HPA) axis are still unclear, although a CNS-mediated action has been demonstrated. In 6 normal healthy young women (26-34 years) we studied the effects on ACTH and cortisol secretion of HEX (2.0 microg/kg i.v. at 0 min) alone and preceded by dexamethasone (DEXA, 1 mg p.o. at 23.00 h on the previous night) or alprazolam (ALP, 0.02 mg/kg p.o. at -90 min), a benzodiazepine which binds to GABA receptors and possesses CRH-mediated inhibitory activity on HPA axis. ACTH and cortisol secretion after saline administration as well as the GH response to HEX alone and preceded by DEXA or ALP were also studied. HEX administration elicited an increase in ACTH (peak vs. baseline, mean +/- SEM: 28.0 +/- 6.7 vs. 11.7 +/- 2.2 pg/ml, p < 0.05) and cortisol secretion (162.6 +/- 15.0 vs. 137.7 +/- 12.6 microg/l, p < 0.05). DEXA pretreatment strongly inhibited basal ACTH (3.2 +/- 0.7 pg/ml, p < 0.01) and cortisol levels (11.3 +/- 2.5 microg/l, p < 0.001) and abolished the ACTH and cortisol responses to HEX (3.6 +/- 0.9 pg/ml, p < 0.01 and 10.7 +/- 2.0 microg/l, p < 0.001), respectively. On the other hand, ALP pretreatment did not significantly modify basal ACTH (7.9 +/- 2.0 pg/ml) and cortisol levels (127.6 +/- 14.5 microg/l) but abolished the HEX-induced ACTH and cortisol secretions (8.6 +/- 2.4 pg/ml, p < 0.05 and 111.0 +/- 6.0 microg/l, p < 0.05), respectively. ACTH and cortisol levels after HEX when preceded by ALP overlapped with those recorded during saline. HEX induced a clear GH response (peak at 15 min vs. baseline: 65.5 +/- 20.5 vs. 2.2 +/- 0.7 microg/l, p < 0.03) which was blunted by ALP (peak at 15 min: 21.5 +/- 5.5 microg/l, p < 0.05) while it was not modified by DEXA pretreatment (78.7 +/- 7.6 microg/l). In conclusion, our present data demonstrate that the ACTH- and cortisol-releasing effect of HEX is abolished by either dexamethasone or alprazolam, a benzodiazepine, which is even able to blunt the GH-releasing activity of the hexapeptide. These findings suggest that, in physiological conditions, the stimulatory effect of GHRPs on HPA axis is sensitive to the negative glucocorticoid feedback and could be mediated by GABAergic mechanisms; the latter seem also involved in the GH-releasing activity of GHRPs.
Adrenocorticotropic Hormone↗
Adrenocorticotropin and cortisol hyperresponsiveness to hexarelin in patients with Cushing's disease bearing a pituitary microadenoma, but not in those with macroadenoma.
We previously reported that in Cushing's disease (CD) the ACTH- and cortisol (F)-releasing activity of Hexarelin (HEX), a GH secretagogue, is exaggerated with respect to that in normal subjects and is higher than that of human CRH (hCRH), but it is absent in Cushing's syndrome. Our aim was to extend the study about the effects of HEX (2.0 microg/kg, iv) on ACTH and F secretion in 21 patients with CD (3 men and 18 women, 16-68 yr old). Based on magnetic resonance imaging, 15 CD patients had pituitary microadenoma, and 6 had macroadenoma. The results in CD patients were compared with those in 27 normal age-matched controls (NS; 10 men and 17 women, 24-69 yr old). Basal ACTH and F levels in CD were similar in patients with microadenom (mean+/-SEM, 78.3+/-7.2 pg/mL and 237.1+/-23.6 microg/L, respectively) and macroadenoma (57.4+/-9.0 pg/mL and 196.9+/-20.1 microg/L, respectively) and were higher (P < 0.001) than those in NS (17.7+/-2.0 pg/mL and 115.3+/-6.7 microg/L, respectively). In microadenoma CD patients, HEX induced marked ACTH and F increases (delta peak, mean+/-SEM: 261.2+/-77.6 pg/mL and 226.1+/-87.2 microg/L, respectively), which were higher (P < 0.04) than those induced by hCRH (45.6+/-16.9 pg/mL and 84.6+/-25.7 microg/L, respectively). Moreover, in microadenoma CD patients, the ACTH and F responses to HEX were higher (P < 0.001) than those in NS (18.5+/-4.0 pg/mL and 36.1+/-6.8 microg/L, respectively). In macroadenoma CD patients, HEX induced a slight, but significant increase (P < 0.02) in ACTH and F levels (33.9+/-18.0 pg/mL and 89.6+/-34.3 microg/L, respectively), which was not significantly different from that elicited by hCRH (20.0+/-7.0 pg/mL and 54.8+/-21.3 microg/L, respectively). In macroadenoma CD patients, the ACTH and F responses to HEX and hCRH were, in turn, similar to those in NS. In conclusion, our findings demonstrate that the ACTH and F hyperresponsiveness to HEX is present in Cushing's disease with micro-, but not macro- ACTH-secreting pituitary adenoma. This finding agrees with other evidence pointing toward differences in the hormonal behavior between micro- and ACTH-secreting pituitary macroadenomas.
Adenoma↗
Comparison between insulin-induced hypoglycemia and growth hormone (GH)-releasing hormone + arginine as provocative tests for the diagnosis of GH deficiency in adults.
There is now wide consensus that, within an appropriate clinical context, GH deficiency (GHD) in adults must be shown biochemically by provocative testing of GH secretion and that appropriate cut-off limits have to be defined for each provocative test. Insulin-induced hypoglycemia (ITT) is indicated as the test of choice, and severe GHD, to be treated with recombinant human GH replacement, is defined by a GH peak response to ITT of less than 3 micrograms/L. GHRH + arginine (GHRH + ARG) is one of the most promising tests in alternative to ITT. In fact, it has been reported as a potent, reproducible, and age-independent test and that it is able to distinguish between GHD and normal adults. The aim of the present study was to compare the GH response to ITT and GHRH + ARG in a large group of hypopituitary adults (n = 40; 29 male and 11 female; age: 36.4 +/- 2.1 yr). The third centile limit of the peak GH response to ITT has been reported as 5 micrograms/L, whereas in our lab, that to GHRH + ARG is 16.5 micrograms/L. In hypopituitary adults, the mean peak GH response to ITT (1.5 +/- 0.2 micrograms/L, range: 0.1-8.5 micrograms/L) was lower (P < 0.001) than that to GHRH + ARG (3.0 +/- 0.4 micrograms/L, range 0.1-12.0 micrograms/L), though there was positive correlation (r = 0.61, P < 0.001) between the GH responses to the 2 tests. The peak GH response to GHRH + ARG, but not that to ITT, was positively (though weakly) associated with insulin-like growth factor-I levels (r = 0.35, P < 0.03). Childhood and adult onset GHD patients, as well as patients with single and multiple pituitary insufficiencies, had similar peak GH responses to ITT or GHRH + ARG. Analyzing individual GH responses, 4/40 (10%) of the hypopituitary patients had GH peaks higher than 5 micrograms/L after ITT; moreover, 3 other patients (7%) had GH peaks, after ITT, higher than 3 micrograms/L. On the other hand, after GHRH + ARG, all patients had GH peaks lower than 16.5 micrograms/L, whereas 21/40 (52.5%) had GH peaks higher than 3 micrograms/L. Because 3 micrograms/L is the arbitrary cut-off for ITT, the third centile limit of which is 5 micrograms/L, we arbitrarily considered 9 micrograms/L as the cut-off point for GHRH + ARG. It is noteworthy that 37/40 (92.5%) patients had a GH peak, after GHRH + ARG, below this limit. In conclusion, our present results confirm that the ITT test is a reliable provocative test for the diagnosis of adult GHD, whereas they show that the GHRH + ARG test is, at least, as sensitive as the ITT test (provided that appropriate cut-off limits are considered). Note that even the arbitrary cut-off point below which severe GHD is demonstrated has to be appropriate to the potency of the test.
Adult↗