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The physiological role of endogenous circulating GHreleasing hormone (GHRH) and somatostatin (SRIH) on spontaneous pulsatile and neostigmine-induced secretion of GH was investigated in adult rams actively immunized against each neuropeptide. All animals developed antibodies at concentrations sufficient for immunoneutralization of GHRH and SRIH levels in hypophysial portal blood. In the anti GHRH group, plasma GH levels were very low; the amplitude of GH pulses was strikingly reduced, although their number was unchanged. No stimulation of GH release was observed after neostigmine administration. The reduction of GH secretion was associated with a decreased body weight and a significant reduction in plasma IGF-I concentration. In the antiSRIH group, no changes in basal and pulsatile GH secretion or the GH response to neostigmine were observed as compared to controls. Body weight was not significantly altered and plasma IGF-I levels were reduced in these animals. These results suggest that in sheep, circulating SRIH (in the systemic and hypophysial portal vasculature) does not play a significant role in pulsatile and neostigmine-induced secretion of GH. The mechanisms of its influence on body weight and production of IGF-I remain to be determined. Journal of Endocrinology (1995) 144, 83–90

The mechanisms involved in the genesis of pulsatile GH secretion are not well understood. Recently, methods for hypophyseal portal blood collection in conscious sheep became available. Using this method, GHRH and SRIH secretion into hypophyseal portal blood (HPB) and GH release from the pituitary gland were simultaneous assessed and the relationship between GHRH and SRIH changes in HPB and GH in peripheral blood was investigated. In 23 rams (9-11 month old, 35-45 kg bw), 126 hours of HPB were analysed. Fifty-four spontaneous GH peaks were detected. The majority of GH peaks (48.1%) was associated with an increased portal GHRH and a fall in somatostatin concentrations. A simultaneous increase in GHRH and somatostatin levels was observed in 18.5% of GH peaks while 12.9% of peaks occurred with a fall in SRIH and no modification in GHRH concentrations. Finally, 5/54 (9.3%) GH peaks occurred without any modification in portal GHRH and SRIH release. Our data indicate that the GHRH/SRIH interplay is complex. The occurrence of spontaneous GH peaks may be due not only to a coordinate increase in GHRH and reduction in SRIH release similar to male rat, but also to other patterns of GHRH/SRIH secretion.

The effects of acute stress on growth hormone (GH) secretion and the mechanisms involved in its changes have been investigated in sheep. An acute isolation-restraint stress induced a rapid and significant increase in jugular GH levels in 12 out of 14 rams. GH-releasing hormone (GHRH) and somatostatin secretion during the same stress were studied in 5 animals prepared for hypophysial portal blood collection. A 3.5-fold increase in portal GHRH levels was observed concomitantly with a slight elevation in portal somatostatin. Portal corticotropin-releasing hormone (CRH) and jugular cortisol plasma levels increased during the same stress. Our data suggest that an isolation-restraint stress stimulates GH secretion in the sheep and that GHRH may be responsible for GH response.

The acute effect of a new GH-releasing peptide, hexarelin (1 mg, iv), on GH secretion and the mechanisms involved in its changes were investigated in conscious sheep. Peripheral GH levels and GH-releasing hormone (GHRH) and somatostatin concentrations in hypophysial portal blood were measured in six rams. An increase in jugular GH levels was observed 15 min after hexarelin injection (9.1 +/- 1.8 vs. 3.9 +/- 0.8 ng/ml; P < 0.05). This was associated with a stimulation of GHRH release into hypophysial portal blood (145.4 +/- 19.9 vs. 59.2 +/- 10.8 pg/ml; P < 0.01) without a change in somatostatin secretion. Our data indicate that GH-releasing peptide-induced GH stimulation in the sheep involves an activation of GHRH neurons in addition to the previously demonstrated direct effect on the pituitary cells.

GH secretion is stimulated by the administration of cholinesterase inhibitors (such as pyridostigmine and neostigmine) in several species, including man. On the basis of indirect experiments, it has been postulated that this action is mediated by a decrease in hypothalamic somatostatin release. We have investigated the effect of neostigmine in sheep, since it is possible to collect hypophysial portal blood for GH-releasing hormone (GHRH) and somatostatin determination in this species under a conscious unstressed state. First, after i.v. injection of neostigmine (1 mg), a significant increase in plasma GH levels and an unequivocal potentiation of the GH response to GHRH were observed. Then, we observed that i.v. injection of neostigmine (1 mg) induced an immediate, short-lasting (30 min), and marked increase in GHRH (126.1 +/- 17 vs. 14.5 +/- 2.1 pg/ml; P < 0.01) levels in hypophysial portal blood of rams chronically implanted with perihypophysial cannulae. No change in somatostatin secretion was recorded during the same period. These data suggest that the stimulating effect of cholinergic drugs on GH secretion is mediated by stimulation of GHRH release. A direct effect of neostigmine at the level of pituitary gland is possible and may explain the potentiation of GHRH-induced GH release.

ACTH and cortisol diurnal variations and responses to two types of stress (insulin-induced hypoglycemia and isolation-restraint stress) and to an acute injection of CRF were determined in intact as well as in actively antiarginine vasopressin (AVP)-immunized rams. All immunized sheep developed antibodies to AVP, displayed diabetes insipidus, and looked healthy in spite of their lower gain weight. Basal secretion and diurnal variations of ACTH and cortisol were unaltered in the group of anti-AVP-immunized animals. In contrast, ACTH and cortisol responses to both types of stress and CRF injection were significantly reduced compared to those in controls. These results suggest that endogenous AVP plays a physiological role in the corticotropic response to stress. However, endogenous AVP does not appear to affect basal secretion and diurnal variations of ACTH and cortisol.

ACTH and cortisol diurnal variations and responses to two types of stress (insulin-induced hypoglycemia and isolation-restraint stress) or to an acute injection of lysine-vasopressin were studied in intact and anti-corticotropin-releasing factor (CRF) actively immunized rams. Immunization was obtained by the injection of synthetic ovine CRF coupled to BSA with carbodiimide. All animals developed antibodies anti-CRF and displayed an alteration of their general condition and a body weight reduction. The mean basal ACTH and cortisol secretion as well as the number and mean amplitude of diurnal pulses of these hormones was significantly reduced in the group of anti-CRF immunized rams. However, the reduction in all three parameters was much more pronounced for cortisol than for ACTH. No ACTH and cortisol response to insulin-induced hypoglycemia and isolation-restraint stress was observed. The stimulating action of lysine-vasopressin on ACTH release was significantly reduced as compared to controls. These results indicate that CRF is a major physiological component of the ovine hypothalamo-hypophysial-adrenal axis and participates in the events that regulate ACTH and cortisol diurnal variations and response to stress.