Search Results

ABSTRACT

The aim of this study was to investigate the role of thyroid hormones and glucocorticoids on GH secretion. Secretion of GH in response to GH-releasing hormone (GHRH) (5 μg/kg) was markedly (P < 0·001) decreased in hypothyroid rats in vivo (peak GH responses to GHRH, 635 ± 88 μg/l in euthyroid rats vs 46 ±15 μg/l in hypothyroid rats). Following treatment with tri-iodothyronine (T₃; 20 μg/day s.c. daily for 2 weeks) or cortisol (100 pg/day s.c. for 2 weeks) or T₃ plus cortisol, a marked (P <0·01) increase in GH responses to GHRH was observed in hypothyroid rats (peak GH responses, 326 ±29 μg/l after T₃ vs 133+19 μg/l after cortisol vs 283 ± 35 μg/l after cortisol plus T₃). In contrast, none of these treatments modified GH responses to GHRH in euthyroid animals. Hypothyroidism was also associated with impaired GH responses to the GH secretagogue, Hisd-Trp-Ala-Trp-d-Phe-Lys-NH₂ (GHRP-6). Secretion of GH in response to GHRP-6 in vivo was reduced (P <0·01) in hypothyroid rats (peak GH responses, 508 ± 177 μg/l in euthyroid rats vs 203 ± 15 μg/l in hypothyroid rats). In-vitro studies carried out using monolayer cultures of rat anterior pituitary cells derived from euthyroid and hypothyroid rats showed a marked impairment of somatotroph responsiveness to both GHRP-6 and somatostatin in cultures derived from hypothyroid rats. In summary, our data suggest that thyroid hormones and glucocorticoids influence GH secretion by modulating somatotroph responsiveness to different GH secretagogues.

Journal of Endocrinology (1989) 121, 31–36

ABSTRACT

His-d-Trp-Ala-Trp-d-Phe-Lys-NH₂ (GHRP-6) is a synthetic peptide unrelated to any known hypothalamic-releasing hormone including growth hormone-releasing hormone (GHRH). Interestingly, this peptide induces a dose-related increase in plasma GH levels in all species tested so far. The aim of this study was to investigate the action of GHRP-6 alone or in combination with GHRH on GH release in dogs. In addition, the activation or blockade of endogenous cholinergic tone and α-1 adrenoceptors on GHRP-6-stimulated GH secretion was assessed.

In adult Beagle dogs (n = 10), GHRP-6 (90 μg i.v.) increased basal GH levels from 2·6 ± 1·5 to 14·4 ± 3·1 μg/l (mean ± s.e.m.) after 15 min. GHRH (50 μg i.v.) induced a GH peak of 9·7 ± 2·2 μg/l at 15 min. The combined administration of GHRP-6 and GHRH strikingly potentiated canine GH release with a peak of 54 ± 9·0 μg/l (P <0·01). Pretreatment with the cholinergic agonist pyridostigmine (30 mg per os) increased GHRP-6-stimulated GH secretion (37·9 ± 10·1 μg/l P <0·05), while the muscarinic blocker atropine (100 μg i.v.) completely abolished (GH peak lower than 2 μg/l) the stimulatory action of GHRP-6. On the other hand, administration of the α-2 adrenergic agonist clonidine (4 pg/kg i.v.) increased basal plasma GH levels without affecting GH responses to GHRP-6. Finally, while the α-1 adrenergic agonist methoxamine (5 mg i.v.) did not significantly increase GH responses to GHRP-6, administration of the α-1 adrenoceptor antagonist prazosin (20 mg i.v.) reduced GHRP-6-induced GH secretion (area under curve, 206 ± 39 vs 557 ± 172, P <0·05).

In summary, the synergistic effect of the combined administration of maximal doses of GHRP-6 and GHRH suggests that these two peptides act through different mechanisms. The finding that cholinergic drugs were able to modulate the GH secretion elicited by GHRP-6 argues against the hypothesis that such a peptide acts by influencing hypothalamic somatostatin release and suggests that it acts directly at the pituitary level. Finally, the unexpected lack of effect of clonidine and the inhibitory effect of prazosin on GHRP-6-induced GH secretion suggests that the role of α-adrenergic pathways in GH secretion is more complex than previously thought.

Journal of Endocrinology (1993) 138, 211–218

ABSTRACT

We have tested the hypothesis that α-adrenergic drive is involved in the nocturnal increase in TSH in man. Seven mildly hypothyroid women (basal TSH levels 5·0–11·0 mU/1), aged 38–60 years, and nine euthyroid women, aged 27–60 years, were studied. Subjects underwent α-adrenergic blockade by infusion of thymoxamine (210 μg/min from 19.00 to 24.00 h); the same women were used as controls, with saline infused on different nights. Subjects were not allowed to sleep during the study period.

A clear evening rise in basal TSH levels was apparent in both normal subjects and patients. Although overall secretion of TSH was slightly decreased in normal subjects (mean ± s.e.m. area under the curve, 29·93 ± 0·96 vs 30·71 ±mU/1 per h; P<0·05), thymoxamine infusion did not produce any major alteration in the gradual rise in TSH levels during the evening (incremental change above baseline +0·96± 0·21 during control infusion and + 0·97 ± 0·27 mU/1 during thymoxamine infusion). In mildly hypothyroid patients the TSH changes were exaggerated and α-adrenergic blockade caused a reduction in basal TSH levels and a delayed rise in TSH (incremental change above baseline +2·93 ± 1·42 during control infusion and +2·26 ± 0·73 mU/1 during thymoxamine infusion; P < 0·02). Overall TSH secretion was significantly decreased by thymoxamine (mean ± s.e.m. area 106 ± 2·45 mU/1 per h vs 123·32 ± 3·68 in the control study; P<0·0001). As expected, no circadian change was observed in basal prolactin levels in either controls or patients.

Although α-adrenergic pathways may play a role in modulating the nocturnal increase in basal TSH levels, our data suggest that the evening rise in TSH is not a consequence of a primary increase in α-adrenergic drive. The increased TSH changes of mildly hypothyroid patients may, however, be sustained by increased central α-adrenergic stimulation of the TSH secretion.

J. Endocr. (1987) 115, 187–191

ABSTRACT

Recent data suggest that the response of GH to GH-releasing factor (GRF) is reduced following prior exposure to high concentrations of GRF. However, it is unknown whether this is due to alterations in GRF receptors, adenylate cyclase activity or the size of a GRF-releasable storage pool of GH. In order to clarify these questions we have compared the effects of pretreatment with GRF (10 nmol/l every 2 h for 12 h) with those of pretreatment with somatostatin (SRIF; 1 μmol/l), forskolin (10 μmol/l) and GRF plus SRIF (10 nmol/l and 1 μmol/l added together) on the subsequent responses of GH to GRF (1 pmol/l–10 nmol/l), cholera toxin (10 nmol/l), 3-isobutyl-1-methylxanthine (IBMX) (100 μmol/l) and forskolin (10 μmol/l). Experiments were performed on 4-day monolayer cultures of rat anterior pituitary cells. The cells were pretreated with test substances every 2 h for 12 h and incubated with GRF or forskolin for 3 h.

Per cent maximal (B_max) GH responses to GRF (10 nmol/l) were reduced after pretreatment with both GRF (control, 173% of basal; GRF, 25% of basal; P < 0·001) and forskolin (98% of basal; P < 0·001), but were increased after pretreatment with SRIF (246% of basal; P < 0·02). However, GH responses after pretreatment with GRF plus SRIF were not significantly different from those of the control. The dose giving 50% maximum stimulation (ED₅₀) of GRF action was unaltered by SRIF pretreatment (control 48·5 ± 9·2 (s.e.m.) pmol/l vs 140 ± 38 pmol/l; P > 0·05) or by forskolin pretreatment (140 ± 70 pmol/l; P > 0·05), but was increased by GRF pretreatment (900 ± 230 pmol/l; P < 0·05) and GRF plus SRIF pretreatment (1010 ± 730 pmol/l; P < 0·01). Growth hormone responses to forskolin (32% of basal after GRF pretreatment vs 121% of basal in the control saline-treated cells; P < 0·01), cholera toxin (40% of basal after GRF pretreatment vs 106% of basal in the control cells; P < 0·025) and IBMX (195% of basal in the GRF-pretreated cells vs 133% of basal in the control cells; P < 0·025) were also decreased after GRF pretreatment in comparison with controls. Responses of cAMP to 10 μmol forskolin/l were not different from controls after pretreatment with either GRF, SRIF or GRF plus SRIF. However, cAMP responses to 10 nmol GRF/l were reduced after pretreatment with GRF, SRIF, GRF plus SRIF or forskolin.

Reduction of B_max GH responses to GRF, cholera toxin, IBMX and forskolin by GRF pretreatment, and the reversal of this action by combined SRIF plus GRF pretreatment, suggests that depletion of the GRF-sensitive releasable pool of GH may contribute to the desensitization phenomenon. In addition, however, the increase in ED₅₀ of GRF following GRF or GRF plus SRIF pretreatment, as compared with control or SRIF pretreatment alone, together with decreased cAMP responses to GRF after GRF plus SRIF pretreatment, supports the view that uncoupling of the regulatory protein of adenylate cyclase, N_s, also plays a role in this phenomenon.

J. Endocr. (1988) 116, 185–190

ABSTRACT

We have studied the effect of dopamine together with agonist and antagonist drugs of different specificities on the release of TRH from the perfused, intact hypothalamus of the adult rat in vitro. Dopamine produced a dose-related stimulatory effect on TRH release with maximal effect being achieved at 1 μmol/l (increase over basal, 118 ±16·5 (s.e.m.) fmol TRH; P <0·001 vs basal). This effect was mimicked by the specific D₂-agonist drugs bromocriptine (0·1 μmol/l) and LY 171555 (0·1 μmol/l) (increase over basal values, 137·5±13·75 fmol and 158·6± 10·7 fmol respectively; P <0·001 vs basal), but not by the D₁-agonist SKF 38393A. The stimulatory effect of dopamine (1 μmol/l) was blocked in a stereospecific manner by the active (d) but not by the inactive (l) isomers of the dopamine antagonist butaclamol. Similar blockade was achieved with the specific D₂-antagonist domperidone (0·01 μmol/l) whereas the D₁-antagonist SCH 23390 was only effective when used at a concentration 100 times greater. Lower concentrations (0·01 μmol/l) of this D₁ -antagonist did not block the stimulatory effect of dopamine. High-performance liquid chromatography characterization of the material secreted within the hypothalamus showed one single peak of immunoreactive material which coeluted with synthetic TRH. These data suggest that dopamine exerts a stimulatory role in the control of hypothalamic TRH release by acting at specific D₂-receptors.

J. Endocr. (1987) 115, 419–424

ABSTRACT

Effects of thyroid status on brain catecholamine turnover in adult rats were investigated using a steady-state method. Rats were treated for 3 weeks with s.c. injections of l-thyroxine (0·4 mg/kg), aminotriazole in drinking water (0·1%, w/v) or vehicle. After 2 weeks of treatment rats were implanted chronically with lateral intracerebroventricular (i.c.v.) cannulae. They were injected i.c.v. with [³H]tyrosine 1 week later. Catecholamine and tyrosine content and specific activity were measured in mediobasal hypothalamus, anterior hypothalamus and striatum, using high-performance liquid chromatography with electrochemical detection. Thyroxine treatment resulted in a significant increase in noradrenaline and dopamine synthesis localized to the mediobasal hypothalamus. Conversely, aminotriazole treatment resulted in a significant decrease in noradrenaline synthesis localized to the mediobasal hypothalamus. The localization of these changes in catecholamine turnover to the mediobasal hypothalamus suggests that they may be specific functional effects which are of importance in the overall integrated control of thyroid function.

J. Endocr. (1986) 111, 383–389