ABSTRACT

Adult male Sprague–Dawley rats were hypophysectomized and connected to an automatic i.v. infusion system. The same daily dose of human GH (hGH) was given either as eight daily pulses (3-h intervals) to mimic the male specific secretory pattern of GH or as a continuous infusion of GH, to mimic the female secretory pattern. Hypophysectomized rats received i.v. replacement therapy with l-thyroxine and cortisol. The rats were treated for 5 days. The serum cholesterol concentration was higher when hGH was given continuously than when hGH was given as eight daily pulses. The concentration of high-density lipoprotein (HDL)-cholesterol was not influenced by intermittent GH treatment, but increased when hGH was given as a continuous infusion. The serum concentration of apolipoprotein (Apo) E increased following treatment with a continuous infusion of hGH, whereas eight daily pulses of hGH had no effect. The serum concentration of ApoA-I was unaffected by hGH treatment. The serum concentration of ApoB decreased to the same degree whether hGH was given as a continuous infusion or as eight daily pulses. The serum concentration of triglycerides was not affected by hGH treatment.

These results indicate that the higher serum HDL-cholesterol and serum ApoE concentrations of female rats may be due to their more continuous secretion of GH. In contrast, the effects of GH on the serum concentration of ApoB, which is not sexually differentiated, may be independent of the mode of GH secretion.

Journal of Endocrinology (1991) 128, 433–438

ABSTRACT

An automatic method for repetitive microsampling of blood from conscious animals was used to obtain detailed GH secretory profiles from normal female rats, which were compared with those in males and ovariectomized females. Female rats showed a highly variable GH secretory pattern, with sustained periods of low, almost continuous secretion, followed by very rapid bursts of high amplitude and short duration, occurring mostly at night. There was no clear relationship between the pattern of GH secretion and the phase of the oestrous cycle in rats continuously sampled over a 5-day period. In ovariectomized rats, the day:night difference was maintained, though the nocturnal GH surges were larger and of longer duration than in intact females. Male rats produced multicomponent GH bursts which continued unchanged throughout the day and night. This study shows for the first time that female rats switch to a rapid, highly pulsatile pattern of GH release at night, which can only be resolved by rapid blood sampling over extended periods in conscious undisturbed animals.

J. Endocr. (1987) 114, 399–407

ABSTRACT

Growth hormone inhibits its own secretion in animals and man but the mechanism for this inhibition is unclear: both stimulation of somatostatin release and inhibition of GH-releasing factor (GRF) release have been implicated. We have now studied the GRF responsiveness of conscious male and female rats under conditions of GH feedback induced by constant infusion of exogenous human GH (hGH). Intravenous infusions of hGH (60 μg/h) were maintained for 3 to 6 h whilst serial injections of GRF(1–29)NH₂ (0·2–1 μg) were given at 45-min intervals. The GH responses were studied by assaying blood samples withdrawn at frequent intervals using an automatic blood sampling system. We have confirmed that male and female rats differ in their ability to respond to a series of GRF injections; female rats produced consistent GH responses for up to 13 consecutive GRF injections, whereas male rats showed a 3-hourly pattern of intermittent responsiveness. In female rats, multiple injections of GRF continued to elicit uniform GH responses during hGH infusions, whereas hGH infusions in male rats disturbed their intermittent pattern of responsiveness to GRF, and their regular 3-hourly cycle of refractoriness was prolonged. We suggest that this sex difference in GH feedback may be due to GH altering the pattern of endogenous somatostatin release differentially in male and female rats. Such a mechanism of GH autofeedback could be involved in the physiological control of the sexually differentiated pattern of GH secretion in the rat.

Journal of Endocrinology (1990) 126, 27–35

ABSTRACT

The effects of streptozotocin-induced diabetes on weight gain, bone growth and GH secretion have been studied in conscious chronically cannulated male rats. In addition to the classic diabetic symptoms (hyperphagia, polydipsia, polyuria, glycosuria and hyperglycaemia), the slow body weight gain (0·95 ± 0·5 compared with 2·63 ± 0·5 g/day in non-diabetic controls) was associated with a reduction in bone growth (from 162 ± 9 to 48 ± 4 μm/day) and a reduced pituitary GH content (from 1·5 ± 0·2 to 0·6 ± 0·06 mg/gland). Serial blood sampling during the day or overnight showed that the normal male episodic GH secretory pattern was obliterated in the diabetic animals. The constant osmotic stimulation of hyperglycaemia and high fluid turnover was reflected in a significant reduction in pituitary oxytocin and arginine vasopressin (AVP) stores. Intravenous insulin infusions (67–1340 pmol/h for 4 or 7 days) caused a large initial weight gain (> 20 g in 2 days) followed by a slower increase, and stimulated tibial bone growth (to 100 ± 16 and 126 ± 8 μm/day after 4 or 7 days respectively). Insulin infusion for 7 days also increased pituitary GH content (to 1 ± 0·15 mg/gland), and the normal episodic GH secretory pattern returned. Intravenous infusions of insulin which reduced, but did not completely normalize, blood glucose levels, allowed the resumption of growth and pulsatile GH secretion. Continuous infusion of recombinant human insulin-like growth factor-I (hIGF-I) at 1110 pmol/h for 54 h also caused a large initial rise in body weight in diabetic rats (17·1 ± 1·6 compared with 7·5 ± 2·8 g in saline-infused controls) due primarily to increased fluid retention. This effect of hIGF-I occurred without any significant changes in pituitary GH, AVP, oxytocin, blood glucose or bone growth over this short-term infusion, nor was there any obvious effect on spontaneous GH secretion, monitored over the entire infusion period. We conclude that the diabetic rat is not a good model to study growth stimulation by short-term insulin or IGF-I treatments because the insulin-like effects of these peptides obscure their specific growth-promoting activities in this model.

Journal of Endocrinology (1989) 122, 661–670

ABSTRACT

The negative-feedback effects of GH on its own secretion were studied in conscious male and female rats bearing indwelling double-bore venous cannulae. Intravenous infusions of human GH (hGH; 20–60 μg/h) or somatostatin (SS; 10 μg/h) were given while frequent serial microsamples of blood were withdrawn using an automatic blood-sampling system. In both sexes, i.v. infusions of hGH for 6 h inhibited endogenous GH secretory pulses, with a slow onset of the inhibition. There was no rebound GH secretion immediately following the removal of the hGH infusion, but spontaneous GH secretion gradually returned to normal. Infusions of hGH did not inhibit the pituitary GH response to repeated GH-releasing factor (GRF) injections (1 μg) given i.v. every 40 min to female rats. By contrast, infusions of SS, which also blocked spontaneous GH release, dramatically reduced the GH responses to serial GRF injections. When SS Infusions were stopped, the subsequent GRF-induced GH secretory responses were enhanced. These results show that GH can inhibit its own release when given by i.v. infusion to conscious male and female rats. Since GH responses to GRF are maintained during a GH infusion, the feedback effect of GH is unlikely to be exerted directly on the pituitary or by increasing SS release. Our results are consistent with the idea that GH feedback in the conscious rat involves an inhibition of GRF release.

J. Endocr. (1988) 119, 201–209

ABSTRACT

We have studied the rebound secretion of GH following short-term somatostatin (SS) infusions in conscious rats, using an automatic sampling system for withdrawing frequent microsamples of blood. Intravenous infusions of SS (5–50 μg/h per rat) inhibited spontaneous GH secretion, but when SS was withdrawn there was a large burst of rebound GH secretion. A sub-anaesthetic dose of urethane reduced such rebound bursts of GH, suggesting a hypothalamic involvement in rebound GH secretion. Passive immunization with an antibody against rat GH-releasing factor (GRF) attenuated the rebound GH secretory response to the withdrawal of an SS infusion (GH concentration during rebound secretion was 26±21 μg/l vs 475 ± 127 μg/l (mean ± s.e.m.), after 0·5 ml anti-GRF serum or non-immune serum respectively). The inhibition of GH rebound secretion was related to the dose of anti-GRF serum administered. Intravenous infusions of human GH (20– 100 μg/h per rat) also reduced the size of the rebound GH secretion following SS withdrawal, in both male and female rats. We suggest that the rebound GH secretion that follows SS withdrawal in vivo is caused mainly by a hypothalamic release of GRF. Exogenous GH inhibits SS-induced rebound GH secretion in the conscious rat, possibly by inhibiting hypothalamic GRF release.

J. Endocr. (1988) 119, 397–404

ABSTRACT

There are GH-binding proteins (GHBPs) present in the blood of many species, and these correspond to the extracellular GH-binding domain of the GH receptor. In the rat, GHBP arises by alternative splicing of the GH receptor mRNA, but little is known of the physiological role of circulating GHBP, or its relationship with episodic GH secretion. We have developed a sensitive radioimmunoassay based on recombinant GHBP, and have measured rat GHBP levels in small samples of plasma from normal and GH-deficient dwarf rats. In normal adult rats, GHBP levels were two- to threefold higher in females than in males (16·6 ± 0·8 vs 6·4 ± 0·4μg/l, P < 0·001), but this sex difference was not seen in dwarf rats. A continuous infusion of human GH in dwarf males raised plasma GHBP to 23·5 ± 3·5 μg/l compared with 6·7 ± 0·5 μg/l in sham-infused animals, whereas suppression of GH by continuous infusion of a long-acting somatostatin analogue in female dwarf rats had no effect on GHBP. In anaesthetized rats, large changes in plasma GH caused by i.v. administration of rat GH, somatostatin or GH-releasing factor did not affect GHBP acutely. Both GH and GHBP were also measured in serial blood samples from conscious normal and dwarf rats. A sexually dimorphic GH secretory pattern was observed in both strains. Males showed peaks and troughs of GH every 3 h varying over a 100-fold range, whereas females exhibited more continuous GH secretion. Despite the large fluctuations in endogenous GH, GHBP levels remained relatively constant in individual normal or dwarf males, as well as in females of both strains, and there was no significant correlation between GH and GHBP either in individual rats or as a group. Our results suggest that GHBP is GH-dependent in the longer term, and that the higher GHBP levels in female rats require their continuous GH secretory pattern. However, plasma GHBP levels remain stable and are not affected by acute changes in endogenous or exogenous GH.

Journal of Endocrinology (1992) 135, 447–457