The activity of the GH-IGF-I axis undergoes an age-related reduction and in the elderly both spontaneous GH secretion and IGF-I levels are frequently low overlapping with those usually recorded in GH deficient patients. Hypoactivity of the GH-IGF-I axis could explain age-related changes in body composition, function and metabolism, as also indicated by evidence that treatment with rhGH reverses these alterations. The mechanisms underlying the hypoactivity of the GH-IGF-I axis in the aged likely include changes in nutrition and lifestyle, e.g. reduction of physical exercise. However, alterations of neurohormonal hypothalamic control of GH secretion, including reduced activity of GHRH-secreting neurons and somatostatinergic hyper-activity, seem to play a major role. The exaggerated somatostatinergic hyperactivity could be due, in turn, to the impairment of cholinergic activity found in the aging brain. Age-related variations in the activity of other neurotransmitters, such as catecholamines, amino acids, e.g. arginine, neuropeptides, e.g. galanin and/or a putative natural GHRP-like ligand, could play a key role in causing the reduced activity of the GH-IGF-I axis. It is still unclear whether it is of benefit to restore GH secretion in aging. As the pituitary GH releasable pool is preserved in the elderly, it would be more appropriate to increase GH by GH secretagogues such as the new synthetic GH-releasing peptides (GHRPs) or non-peptidyl GHRP mimetics which are active even with oral administration.
Hexarelin (HEX) is a synthetic growth hormone-releasing peptide (GHRP) which acts on specific receptors at both the pituitary and the hypothalamic level to stimulate GH release in an age-dependent manner. Like other GHRPs, HEX possesses also prolactin (PRL) and ACTH/cortisol-releasing activity. similar to that of human corticotropin-releasing hormone (hCRH). The mechanisms underlying the stimulatory effect of GHRPs on lactotrope and corticotrope secretion are even less clear and the influence of age on these endocrine activities of GHRPs is unknown. To clarify this point we studied the GH, PRL, ACTH and cortisol responses to the maximal effective dose of HEX (2.0 micrograms/kg i.v.) in: 12 prepubertal children (Pre-C, 8 male, 4 female, age 5.8-12.1 years); 12 pubertal normal short children (Pub-C, 5 male, 7 female, age 9.7-15.5 years, pubertal stage II-IV); 20 normal young adults (Young, 6 males, 14 females, age 23-32 years); and in 16 normal elderly people (Elderly, 5 male, 11 female, age 66-81 years). The GH response to HEX was clear in Pre-C (0-120 min area under curve, mean +/- S.E.M. 769.5 +/- 122.2 micrograms*min/l) but strikingly increased (P < 0.001) in Pub-C (1960.2 +/- 283.5 micrograms*min/l). The HEX-induced GH rise in Young (1829.7 +/- 243.1 micrograms*min/l) persisted similar to that in Pub-C, but decreased in Elderly (951.1 +/- 232.9 micrograms*min/I, P < 0.005); the latter was, in turn, similar to that in Pre-C. HEX induced a significant PRL increase which, however, showed no age-related variations, being similar in Pre-C (512.1 +/- 88.0 micrograms*min/l), Pub-C (584.0 +/- 106.0 micrograms*min/l), Young (554.9 +/- 56.0 micrograms*min/l) and Elderly (523.9 +/- 59.6 micrograms*min/l). The ACTH-releasing activity of HEX was present in Pre-C (1356.6 +/- 204.9 pg*min/ml) and was clearly enhanced (P < 0.02) in Pub-C (2253.5 +/- 242.8 pg*min/ml). The ACTH rise after HEX in Young (1258.1 +/- 141.2pg*min/ml) was lower (P < 0.02) than that in Pub-C and similar to that in Pre-C, while the ACTH response to HEX in Elderly (1786.5 +/- 340.1 pg*min/ml) showed a further trend toward increase, being similar to that in Pub-C. On the other hand, the cortisol response to HEX showed no significant age-related variations, being not different in Pre-C (7747.2 +/- 1031.6 micrograms*min/l), Pub-C (6106.0 +/- 862.9 micrograms*min/l), Young (6827.5 +/- 509.6 micrograms*min/I) and Elderly (7950.6 +/- 658.3 micrograms*min/l). In conclusion, our present data demonstrate that in humans the GH- and ACTH-releasing activities of HEX undergo different age-related variations, while its PRL-releasing activity is not dependent on age. These finding suggest that actions at different levels and/or on different receptor subtypes mediate the different age-related hormonal effects of GHRPs.
Galanin enhances both baseline and growth hormone-releasing hormone (GHRH)-induced GH secretion both in animals and in man. Although galanin has a clear influence on the secretion of other anterior pituitary hormones in animals, in man it increases prolactin (PRL) slightly but does not affect spontaneous thyrotropin (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH) or adrenocorticotropin (ACTH) secretion. The aim of our study was to verify the effect of galanin on basal and releasing hormone-stimulated release of gonadotropins, PRL, TSH, ACTH and cortisol secretion. As GH release has been shown to be inhibited by corticotropin-releasing hormone (CRH), we also studied the effect of CRH on galanin-stimulated GH increase. The effect of porcine galanin (15 micrograms/kg iv infused in 60 min) alone and in combination with thyrotropin-releasing hormone (TRH, 200 micrograms iv bolus), CRH (100 micrograms iv bolus) and gonadotropin-releasing hormone (GnRH, 100 micrograms iv bolus) on GH, PRL, TSH, ACTH, cortisol, FSH and LH secretion in seven normal young women (aged 25-30 years) was studied. Galanin infusion caused an increase in serum GH levels (p < 0.02) but failed to modify significantly the spontaneous PRL, LH, FSH, TSH, ACTH and cortisol secretion. The combined administration of TRH, GnRH and CRH caused a significant increase in PRL (p < 0.02), LH (p < 0.02), FSH (p < 0.02), TSH (p < 0.02), ACTH (p < 0.02) and cortisol (p < 0.05), but not in GH levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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 μg/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 μg/L, respectively) and macroadenoma (57.4 ± 9.0 pg/mL and 196.9 ± 20.1 μg/L, respectively) and were higher (P < 0.001) than those in NS (17.7 ± 2.0 pg/mL and 115.3 ± 6.7 μg/L, respectively). In microadenoma CD patients, HEX induced marked ACTH and F increases (▵ peak, mean ± sem: 261.2 ± 77.6 pg/mL and 226.1 ± 87.2μ g/L, respectively), which were higher (P < 0.04) than those induced by hCRH (45.6 ± 16.9 pg/mL and 84.6± 25.7 μg/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 ± 6.8μ g/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 ± 34.3μ g/L, respectively), which was not significantly different from that elicited by hCRH (20.0 ± 7.0 pg/mL and 54.8 ± 21.3 μg/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.
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.
Summary OBJECTIVE Anorexia nervosa is characterized by low IGF‐1 and high GH and free fatty acid (FFA) levels. As FFA exerts an inhibitory feedback action on GH secretion in physiological conditions, we hypothesized that somatotroph cells could be less sensitive to the negative feedback action of FFA in anorexia nervosa. PATIENTS Fifteen patients with anorexia nervosa (AN, age: mean ± SEM: 20·8 ± 1·2 years, BMI: 15·9 ± 0·3 kg/m 2 ) and 12 normal female controls (NW, age 27·2 ± 2·1 years, BMI 21·2 ± 2·2 kg/m 2 ). MEASUREMENTS We studied the effects of lipid‐heparin emulsion (Li‐He, Intralipid 10% 250 ml + heparin 2500 U iv from −60 to +90 minutes in seven AN and six NW) or acipimox (ACI, 250 mg p.o. at −60 minutes in eight AN and six NW), a lipolysis inhibitor, on the GH response to GHRH (1 µ g/kg iv as a bolus at 0 minutes). RESULTS Basal IGF‐1 levels were lower ( P <0·05) while GH levels were higher ( P <0·05) in AN than in NW. On the other hand, basal FFA levels in the two groups were not significantly different. In both groups Li‐He increased FFA levels ( P <0·05), which became higher ( P <0·02) in AN than in NW. Li‐He infusion inhibited ( P <0·05) basal GH levels in AN to levels overlapping those in NW. The GH response to GHRH in the whole AN group was higher than in NW ( P <0·03). Li‐He inhibited the somatotroph responsiveness to GHRH in AN ( P <0·03) as well as in NW ( P <0·03) and during Li‐He the GH response to GHRH in AN became similar to that in NW. Whilst ACI pretreatment enhanced the GH response to GHRH in AN ( P <0·02), it did not significantly increase that in NW. Interestingly, after ACI administration, FFA levels were inhibited in both groups ( P <0·05) persisting higher in AN than in NW ( P <0·05). CONCLUSION Though GH hypersecretion in anorexia nervosa occurs in presence of enhanced lipolysis, our present findings indicate that the sensitivity of somatotroph cells to the inhibitory feedback action of free fatty acid is preserved.
Summary OBJECTIVE It is well known that acetylcholine and arginine stimulate GH secretion while activation of β‐adrenergic receptors inhibits GH secretion in man. We aimed therefore to ascertain whether or not the inhibitory influence of β‐adrenergic receptors on GH secretion would over‐ride the stimulatory one of acetylcholine and arginine. DESIGN We studied the interaction of salbutamol, a β2‐adrenergic agonist (SAL, 0.08 mg/kg orally) with pyridostigmine, a cholinesterase inhibitor (PD, 120 mg orally), or arginine (0.5 g/kg i.v.) on both basal and GHRH (1 μg/kg i.v.)‐stimulated GH secretion. SUBJECTS Fourteen healthy male volunteers, aged 20–35 years, were studied. MEASUREMENTS Serum GH was measured in duplicate by immunoradiometric assay. RESULTS In study A, SAL inhibited the GH response both to GHRH ( P < 0.01) and ARG( P <0.002). ARG enhanced the GHRH‐induced GH rise ( P <0.01) but its effect was abolished ( P <0.02) by SAL pretreatment. In study B, SAL inhibited the GH response both to GHRH ( P <0.01) and PD ( P < 0.02). PD enhanced the GH response to GHRH ( P < 0.01) but its effect was abolished ( P <0.05) by SAL pretreatment. In both studies, the GH response to GHRH alone was similar to that to the neurohormone when combined with ARG + SAL or PD + SAL. CONCLUSION Our results show that β2‐adrenergic activation by salbutamol is able to inhibit not only the GH rise induced by GHRH, arginine and pyridostigmine, but even the potentiating effect of both arginine and pyridostigmine on the GH response to GHRH. They indicate that catecholamines, acetylcholine and arginine play a major role in GH secretion having opposite influences aimed to balance the function of the hypothalamus‐GH‐IGF‐l axis in man.
