E. Ghigo

Low doses of either intravenously or orally administered arginine are able to enhance growth hormone response to growth hormone releasing hormone in elderly subjects.

Reportedly, the responsiveness of somatotrope cells to GHRH is reduced in elderly humans but it is totally restored by arginine (ARG) which likely acts by inhibiting hypothalamic release of somatostatin. As this effect was observed after infusion of high doses of the amino acid, in this study, we compared the effect of iv administration of 30,10 and 5 g ARG(group A,B and C, respectively) as well as oral administration of 8 g ARG(group D) on the GH response to 1 μg/kg iv GHRH in 27 healthy elderly subjects (11 M and 16 F, age 70–86 yr, BMI 21–25 kg/m2). In group A (n=7) 30 g iv ARG strikingly enhanced the GHRH-induced GH rise (peak, mean±SE: 41.5±4.4 vs 11.7±5.3 μg/L, p<0.05). Similarly, in group B (n=6) and D (n=7) 10 g iv and 8 g oral ARG enhanced the GH response to GHRH (20.9±4.7 vs 8.3±2.8 μg/L, p<0.03 and 31.0±5.3 vs 11.4±3.4 μg/L, p<0.03, respectively). In contrast, in group C (n=7) 5 g iv ARG failed to modify the GHRH-induced GH rise (6.0±1.6 vs 3.5±0.9 μg/L). The GH responses to GHRH alone did not significantly differ amongst groups; the GH responses to GHRH and ARG were not significantly different among groups A, B and D and were greater than the GH response in group C. These results show that the GH response to GHRH in elderly subjects is enhanced even by low iv doses of arginine and by the orally administered amino acid, the lowest effective dose being 8 g. Moreover, they imply that the combined administration of GHRH and arginine may be a useful approach to restore the impaired function of the GH-IGF axis in aging.

Aging and Growth Hormone Releasing Peptides

It is widely accepted that growth hormone (GH) secretion undergoes an age-related decrease in all species (1,2). There is agreement that in man 24-hour integrated GH concentration is low in elderly subjects (3, 4) and similar to that usually observed in patients with GH deficiency (4). On the other hand, while some authors found that both day- and nighttime mean GH pulse amplitude and duration but not pulse frequency are reduced (3, 5), others found significant reduction in GH secretory burst frequency and half-life but not in other parameters (6). In agreement with the existence of a GH hyposecretory state, insulin-like growth factor-I (IGF-I) levels have been found reduced in aging (1, 2). Decreased IGF-I levels in the elderly could be due to changes in nutrition and/or lifestyle, particularly in physical exercise (1, 2). However, IGF-I response to exogenous GH administration has been reported preserved in aging (7), pointing to hypothalamopituitary impairment as cause of the reduced activity of the GH-IGF-I axis.

Neuroendocrine effects of Citalopram, a selective serotonin re-uptake inhibitor, during lifespan in humans

Objective: Serotonergic system contributes to the regulation of hypothalamus-pituitary-adrenal axis. In humans, serotonergic agonists increase PRL, ACTH, and cortisol, while serotonin (5HT) influence on GH is controversial. Central 5HT activity and neuroendocrine function change during lifespan. Design: To clarify the neuroendocrine response to 5HT across lifespan, we assessed ACTH, cortisol, DHEA, PRL, and GH responses to citalopram (CT) in young adults (YA) (no.=12, 29.2±1.7 yr mean±SEM), middle aged (MA) (no.=12, 54.3±0.9 yr), and elderly (ES) (no.=12, 69.3±0.9 yr) males. All the subjects received placebo (saline iv over 120 min) or CT (20 mg iv over 120 min). Blood samples were taken every 15 min up to 240 min. Results: During placebo, ACTH, cortisol, GH, and PRL were similar in all groups while DHEA showed an age-dependent reduction from middle age (p<0.001). During CT, ACTH, and cortisol were higher than during placebo in YA (p<0.05) and even more in MA (p<0.01 vs placebo, p<0.05 vs YA); in ES, the increase of both ACTH and cortisol (p<0.05 vs placebo) was lower than in MA (p<0.05) and higher than in YA (p<0.05 for cortisol only). No changes were observed for DHEA, GH, and PRL in any group. Conclusions: Corticotrope response to CT is age-dependent in normal men, being amplified starting from middle age, suggesting precocious changes in the serotonergic neuroendocrine control during lifespan. CT is a useful tool to evaluate the age-dependent serotonergic function in humans.

Primary hyperaldosteronism is associated with derangement in the regulation of the hypothalamus-pituitary-adrenal axis in humans

Hippocampal mineralocorticoid receptors (MR) play a major role in the control of hypothalamus-pituitary-adrenal (HPA) axis. The functional profile of HPA axis and the impact of MR blockade under chronic exposure to mineralocorticoid excess are unknown. To clarify this issue, ACTH, cortisol, and aldosterone secretions were studied in 6 patients with primary hyperaldosteronism (HA) and 8 controls (IMS) during placebo, placebo+human CRH (hCRH) (2 μg/kg iv bolus at 22:00 h), potassium canrenoate (CAN, 200 mg iv bolus at 20:00 h followed by 200 mg infused over 4 h) or CAN+hCRH. During placebo, both aldosterone and ACTH levels were higher (p<0.01) in HA than in NS, while cortisol levels were not significantly different. Both HA and NS showed significant ACTH and cortisol responses to hCRH (p<0.004), although the hormonal responses in HA were higher (p<0.02) than in NS. CAN infusion did not modify aldosterone levels in both HA and NS. Under CAN infusion, ACTH showed progressive rise in NS (p<0.05) but not in HA, while cortisol levels showed a significant (p<0.05) but less marked and delayed increase in HA compared to NS. CAN enhanced hCRH-induced ACTH and cortisol responses in NS (p<0.05), but not in HA. In conclusion, in humans primary hyperaldosteronism is associated with deranged function of the HPA axis. In fact, hyperaldosteronemic patients show basal and hCRH-stimulated HPA hyperactivity that is, at least partially, refractory to further stimulation by mineralocorticoid blockade with canrenoate. Whether this hormonal alteration can influence the clinical feature of hypertensive patients with primary hyperaldosteronism needs to be clarified.

Endocrine responses to GH secretagogues in relation to sex and age in humans

Growth hormone secretagogues (GHS) are synthetic peptidyl and nonpeptidyl molecules that possess strong, dose-dependent, and reproducible GH-releasing activity in vivo in several species and in humans after intravenous, subcutaneous, intranasal, and oral administration (1–4). In addition to GHRP-6, other members of the GHS family studied in humans include peptidyl analogs, such as GHRP-1 (a heptapeptide), GHRP-2 and Hexarelin (both hexapeptides), and nonpeptidyl GHRP mimetics, such as MK-0677, a spiroindoline, which shows high bioavailability and long-lasting effects after oral administration (1–4).

The Role of Neurotransmitters in Growth Hormone Secretion

It is now a tenet of neuroendocrinology that the secretion of anterior pituitary (AP) hormones is regulated by the central nervous system (CNS) through a family of hypophysiotropic neuropeptides, the releasing and inhibiting hormones. In addition, the neuroregulation of a given AP hormone is influenced by a host of neurotransmitters and neuropeptides, which at hypothalamic and suprahypothalamic levels provide intermediate and obligatory links between hypophysiotropic and both exogenous and endogenous influences on hormone secretion (1,2), Figure 1 depicts schematically how neurotransmitter-neurohormonal interactions may occur at the hypothalamic level. The complexity of the system stems from the abundance of different neurotransmitter and neuropeptide neurons present in the mediobasal hypothalamus (MBH) and the various ways they may reciprocally interact. Another reason for complexity is the phenomenon of coexistence, which ultimately results from cotransmission, i.e., occurrence and then release of two transmitter substances present in the same nerve endings (3). Though cotransmission undoubtedly provides greater versatility and sophistication to the vocabulary of synaptic transmission (3), it compounds the understanding of the physiology and pathophysiology of neuroendocrine control.