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PubMed1990

Cocaine effects on luteinizing hormone-releasing hormone-stimulated anterior pituitary hormones in female rhesus monkey.

The effects of acute cocaine administration on synthetic LHRH-stimulated anterior pituitary hormones (LH, FSH, and PRL) were studied in 6 female rhesus monkeys during the follicular phase of the menstrual cycle (days 4-7). Integrated plasma samples were collected every 10 min for 40 min before iv administration of cocaine (0.4 or 0.8 mg/kg) or an equal volume of vehicle control solution. Synthetic LHRH (100 micrograms, iv) was administered 10 min after cocaine or placebo-cocaine administration, and 10 plasma samples were collected for an additional 100 min. LHRH stimulated a significant increase in LH within 10 min after placebo-cocaine administration (P less than 0.05) and after each dose of cocaine (P less than 0.0001). Cocaine (0.4 mg/kg) significantly enhanced LHRH stimulation of LH compared to placebo or 0.8 mg/kg cocaine administration (P less than 0.01). FSH increased significantly within 20-30 min after LHRH alone (P less than 0.008) and after 0.4 mg/kg cocaine (P less than 0.0001). LHRH-stimulated FSH levels also were significantly higher after 0.4 mg/kg cocaine than after placebo or 0.8 mg/kg cocaine (P less than 0.01). These data indicate that cocaine does not suppress LHRH stimulation of pituitary gonadotropins, and low doses of cocaine significantly enhance LH and FSH release. Consequently, cocaine does not compromise anterior-pituitary function at the level of the gonadotroph and may stimulate hypothalamic release of endogenous LHRH. PRL levels were unchanged by LHRH and placebo-cocaine administration. After LHRH and cocaine administration, PRL levels decreased significantly (P less than 0.05-0.01) and remained suppressed throughout the 110-min postcocaine sampling period. These data indicate that cocaine's significant suppression of PRL is not blocked by LHRH. These findings are consistent with dopaminergic inhibitory control of PRL and suggest that cocaine's inhibition of dopamine reuptake down-regulates pituitary lactotroph activity in rhesus monkey.

Animals↗
PubMed1992

Abrogation by a potent gonadotropin-releasing hormone antagonist of the estrogen/progesterone-stimulated surge-like release of luteinizing hormone and follicle-stimulating hormone in postmenopausal women.

In both the rodent and primate, administration of progesterone elicits an acute surge-like release of LH in the setting of prior estrogen treatment. Whether these facilitative effects of estrogen and progesterone on gonadotropin secretion reside at pituitary or hypothalamic loci is not known. To further investigate the mechanisms by which estrogen combined with progesterone amplifies gonadotropin secretion, we studied the responses of seven estrogen-primed postmenopausal women to progesterone administration with or without cotreatment with a potent GnRH antagonist, [Ac-D2Nal1,D4ClPhe2,D3Pal3,Arg5,DGlu6(AA), DAla10]GnRH. Repetitive blood sampling for the later measurement of serum concentrations of LH, FSH, and PRL was begun 4 h before the administration of progesterone and continued for 36 h. We observed that progesterone administration after 72 h of priming with ethinyl estradiol resulted in a surge-like release of LH and FSH in all subjects. Concomitant administration of the GnRH antagonist abolished the surge-like release of both gonadotropins in all subjects. In contrast, administration of the antagonist had no effect on PRL release. These results indicate that endogenous GnRH action is an obligatory component of the progesterone-induced surge-like release of both gonadotropic hormones in the estrogen-primed human.

Estrogens↗
PubMed1989

Cloning and characterization of mouse growth hormone-releasing hormone (GRH) complementary DNA: increased GRH messenger RNA levels in the growth hormone-deficient lit/lit mouse.

We have isolated and cloned the full length cDNA for mouse GH-releasing hormone (mGRH) from mouse hypothalamus using a recently described strategy involving the polymerase chain reaction technique (PCR). Degenerate oligonucleotide primers were selected based on short (six amino acids) conserved regions in the human and rat GRH peptides that would recognize DNA sequences encoding similar amino acids regardless of codon usage. Primer-extended cDNA was amplified by PCR on cDNA templates prepared by reverse transcribing total mouse hypothalamic RNA. After cloning and sequencing the initial product, the 3' and 5' ends of mGRH were generated using a separate PCR strategy (RACE protocol). The mGRH cDNA encodes a 103-amino acid reading frame, structurally similar to the human and rat GRH genes, containing a signal sequence, a 42-residue GRH peptide, and a 31-residue C-terminal region. Although the structures of mouse and rat GRH are highly conserved in the signal peptide and C-terminal region, there is considerable diversity in the GRH region, which exhibits nearly comparable homology with the rat (68%) and human (62%) structures. Differences between mouse and rat GRH were also found in the amino acid cleavage sites at the 5' and 3' ends of the mature peptide and at the polyadenylation signal.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Mutations of the rat growth hormone promoter which increase and decrease response to thyroid hormone define a consensus thyroid hormone response element.

We have previously identified sequences required for thyroid hormone (T3) induction of the rat GH (rGH) promoter, which lie in a region from -188 to -164 upstream of the mRNA start site. Within this region, Domains A, -189 to -184 and B, -179 to -174, are imperfect direct repeats, and domain C, -172 to -167, is a divergent inverted copy that matches the A domain at 4/6 positions. A series of synthetic mutant versions of this sequence were inserted upstream of a truncated rGH promoter, or as a replacement for wild-type sequences in a synthetic 237 base pair rGH promoter or upstream of the heterologous thymidine kinase promoter. Mutations changing the B domain to a perfect copy of the A domain significantly increased T3 induction (21.3-fold) relative to the wild type (3.6-fold). A single point mutation making the C domain a better match to the A domain also increased T3 induction to 16.2-fold. Combining this up-mutation with any of three down-mutations in the A, B, or C domains strongly decreased response, showing that all three domains contribute to the amplified T3 response. Binding affinity of the various mutant oligonucleotides was assessed using in vitro translated receptor and affinity paralleled the functional responses for most binding site mutations. Requirements for in vitro binding were, however, less rigorous than those for functional T3 induction. Based on these results, we propose a consensus T3 receptor binding half-site, AGGT(C/A)A, at least two copies of which are required for a T3 response.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Differential growth hormone responses to glucose and growth hormone releasing hormone in lactating dairy cows.

Dairy cows in early lactation were reported to secrete growth hormone in response to declining glucose concentrations at day 5 but not day 30 post-partum, whereas GH responses to TRH were reported to be enhanced after day 30 post partum. The present study examined GH response following glucose infusion and the effect of GHRH as well as effects of SRIH on GHRH-stimulated GH release. Declining plasma glucose concentrations after glucose infusion stimulated GH release at day 5 post partum but not in nonpregnant, nonlactating cows or in cows at days 30 and 90 post partum. GHRH stimulated GH release on all days tested, but the response was highest at day 30 post partum when compared to other days. Somatostatin infusion inhibited GHRH effects on GH concentrations only at day 30 post partum and in nonpregnant, nonlactating cows. Thus, a differential response of the GH regulatory system could be demonstrated between days 5 and 30 post partum utilizing different stimuli. Evaluation of plasma glucose and free fatty acid concentrations on days 5, 10, 20, and 30 post partum revealed a progressive decrease in FFA but not glucose as lactation progressed. Decreased plasma FFA concentrations were paralleled by a decrease in basal GH, somatomedin-C and epinephrine. Thus, a decline in FFA may be responsible for the disparity between effects of GHRH and glucose on GH release between days 5 and 30 post partum.

Animals↗
PubMed1991

Effects of cytidine 5'-diphosphocholine administration on basal and growth hormone-releasing hormone-induced growth hormone secretion in elderly subjects.

The basal and GH-releasing hormone-stimulated secretion of GH declines in the elderly. We tested the ability of cytidine 5'-diphosphocholine, a drug used in the treatment of stroke and Parkinson's disease, to alter GH secretion in 11 healthy elderly volunteers, aged 69-84. Each subject received an iv infusion of 2 g of cytidine 5'-diphosphocholine or normal saline. GHRH and TRH were also administered during cytidine 5'-diphosphocholine infusions. The infusion of cytidine 5'-diphosphocholine induced a 4-fold (p less than 0.05) increase in serum GH levels over basal values. A small increase in GH was seen after GHRH administration. However, the addition of GHRH to the cytidine 5'-diphosphocholine infusion resulted in a GH response which was significantly greater than that seen after GHRH alone; the integrated concentration of GH was more than 2-fold greater in the cytidine 5'-diphosphocholine treated group (706.85 +/- 185.1 vs 248.9 +/- 61.4 micrograms.l-1.(120 min)-1; p = 0.01). The PRL and TSH responses to TRH were not significantly affected by cytidine 5'-diphosphocholine infusion, indicating that dopaminergic mechanisms are not involved. These studies demonstrate that cytidine 5'-diphosphocholine can enhance basal and GHRH-stimulated GH release in the elderly, but the mechanism of action of the drug remains unclear.

Aged↗
PubMed1991

Decreased growth hormone response to growth hormone-releasing hormone in Turner's syndrome: relation to body weight and adiposity.

A decreased growth hormone response to various secretagogues has been described in Turner's syndrome, but the mechanisms responsible for this decrease are unknown. Seventeen prepubertal girls with Turner's syndrome (age 6.4 to 15.7 years; height -0.2 to -5.4 SD, bone age -3.7 to -0.3 SD; weight 93 to 169% of ideal body weight) underwent a stimulation test with GHRH (0.5 micrograms/kg). Plasma GH and prolactin were measured by radioimmunoassay from -30 to +120 min and insulin-like growth factor-I at time 0. These values were compared with those observed in lean children with constitutional short stature. Peak plasma GH after GHRH was 17.0 +/- 3.6 micrograms/l (mean +/- SEM), significantly lower (p less than 0.001) than in the short lean children (39.2 +/- 5.1 micrograms/l). In Turner's syndrome patients, the peak GH value was negatively correlated with the percentage of ideal body weight (r = -0.58, p less than 0.02) and of body fat (r = -0.59, p less than 0.02). Plasma prolactin levels in Turner's syndrome did not rise after GHRH and showed a normal circadian variation, from 8.0 +/- 1.0 micrograms/l at 08.30 h to 5.0 +/- 0.7 micrograms/l at 11.00 h (mean +/- SEM). Mean (+/- SEM) baseline plasma insulin-like growth factor-I concentrations was 0.88 +/- 0.14 kU/l, higher than in the short lean children (0.49 +/- 0.08 kU/l, p less than 0.05). We conclude that the decreased GH response to GHRH of girls with Turner's syndrome is related, at least in part, to their excess body weight and fat and is associated with higher IGF-I levels than in short lean children.

Adipose Tissue↗
PubMed1991

Acromegaly due to ectopic growth hormone-releasing hormone secretion by a bronchial carcinoid tumour. Dynamic hormonal responses to various stimuli.

Ectopic GHRH is a relatively uncommon cause of acromegaly, which should be differentiated from pituitary adenoma, in order to avoid damage to the pituitary gland from unnecessary interventions. We report here on a 66-year-old man with acromegaly due to a GHRH-secreting bronchial carcinoid tumour, who recovered completely following removal of the tumour. His hormonal status was studied before and after the operation. Basal GH, GHRH, IGF-I and PRL levels, as well as plasma GH response to glucose load and TRH administration were abnormal before the operation, and became normal thereafter. The somatostatin analogue SMS 201-995 was found to be a potent inhibitor of the ectopic GHRH and the GH secretion (greater than 500 to 42 ng/l and 15.4 micrograms/l to 0.8 microgram/l, respectively). The effect on GHRH proved to be due to direct effect of somatostatin on the tumour cells, as demonstrated in tissue culture studies. A mixed meal was found immediately to suppress GHRH levels without such an effect on GH secretion. We conclude that the neuroendocrine tests usually practised in acromegaly cannot differentiate between ectopic GHRH secretion and pituitary adenoma. High plasma GHRH levels may serve as a diagnostic test for excessive GHRH production, which is almost always ectopic. These high levels are suppressible by somatostatin and a mixed meal.

Acromegaly↗
PubMed1992

Galanin does not affect the growth hormone-releasing hormone-stimulated growth hormone secretion in patients with hyperthyroidism.

Patients with hyperthyroidism have reduced spontaneous and stimulated growth hormone (GH) secretion. The aim of our study was to evaluate the effects of galanin, a novel neuropeptide which stimulates GH secretion in man, on the GH response to GHRH in patients with hyperthyroidism. Eight untreated hyperthyroid patients with Graves' disease (6F, 2M, aged 25-50 years) and six healthy volunteers (3F, 3M, aged 27-76 years) underwent from -10 to 30 min in random order: (i) porcine galanin, iv, 500 micrograms in 100 ml saline; or (ii) saline, iv, 100 ml. A bolus of human GHRH(1-29)NH2, 100 micrograms, was injected iv at 0 min. Hyperthyroid patients showed blunted GH peaks after GHRH+saline (10.2 +/- 2.5 micrograms/l) compared to normal subjects (20.7 +/- 4.8 micrograms/l, p < 0.05). GH peaks after GHRH+galanin were also significantly lower in hyperthyroid subjects (12.5 +/- 3 micrograms/l) compared to normal subjects (43.8 +/- 6 micrograms/l, p < 0.05). That galanin is not able to reverse the blunted GH response to GHRH in hyperthyroidism suggests that hyperthyroxinemia may either increase the somatostatin release by the hypothalamus or directly affect the pituitary GH secretory capacity.

Adult↗
PubMed1981

Effects of oestradiol, hypothalamic extracts and luteinizing hormone releasing hormone on rat anterior pituitary gland gonadotrophin release in vitro before and after the preovulatory luteinizing hormone surge at pro-oestrus.

Changes at the anterior pituitary and/or hypothalamic levels which result in selective FSH release during late pro-oestrus in the cyclic rat were investigated. The possible involvement of decreasing serum concentrations of oestrogen during pro-oestrus in such changes was studied. Rats were decapitated at 12.00 h on pro-oestrus, before the onset of the LH surge and first phase of FSH release, or at 24.00 h on pro-oestrus, shortly after the onset of the second or selective phase of FSH release. Other rats were given oestrogen (OE2) at 14.00 h and killed at 24.00 h pro-oestrus. Paired hemi-anterior pituitary glands were incubated with vehicle or OE2 with or without synthetic LH-releasing hormone (LH-RH) or hypothalamic acid extracts prepared from rats killed at 12.00 or 24.00 h on pro-oestrus. At 24.00 h pro-oestrus, serum FSH concentration was high while serum LH concentration was low regardless of whether rats were given OE2. Glands collected and incubated at 24.00 h released more FSH and less LH than did glands collected and incubated at 12.00 h pro-oestrus. Administration of OE2 in vivo and/or in vitro did not affect these responses. The increments in LH and FSH release attributed to LH-RH or hypothalamic extracts in the glands incubated at 24.00 h were not different from those of the glands incubated at 12.00 h. Also, the hypothalamic extracts prepared from rats killed at 24.00 h were no more effective than the extracts prepared from rats killed at 12.00 h in releasing LH or FSH from glands incubated at 12.00 or 24.00 h pro-oestrus. Administration of OE2 in vivo caused a small suppression of LH-RH-induced FSH release. We suggest that a change occurs at the level of the anterior pituitary gland during the period of the LH surge and first phase of FSH release to increase basal FSH secretion selectively and cause, at least in part, the second phase of increased serum FSH. This change is not mediated by a decrease in serum oestrogen concentration. We failed to observe any evidence that LH-RH causes preferential FSH release during late pro-oestrus or that a hypothalamic peptide with a preferential FSh releasing ability is involved in FSH release at this time.

Animals↗
PubMed1981

Response of luteinizing hormone from columns of dispersed rat pituitary cells to a highly potent analogue of luteinizing hormone releasing hormone.

The response of LH from a perfused column of dispersed rat anterior pituitary cells to LH releasing hormone (LH-RH) and the analogue, D-Ser(But)6-desGly10-Proethylamide9-LH-RH (Hoe 766), was investigated. Dose-response curves showed non-parallelism between LH-RH and the analogue. but it was evident that the analogue was considerably more potent. After a single pulse of LH-RH, LH output returned to basal values in 8 min; this was prolonged to 20 min in the case of the analogue. During this 20 min the cells were refractory to pulses of LH-RH but pulses of the analogue maintained output of LH. During constant-dose perfusion with either synthetic LH-RH or the analogue, output of LH rapidly reached a peak and then gradually fell over several hours to approach baseline values. However, a pulse of 50 mmol potassium chloride/l was still able to release LH at this time. The data are consistent with the view that this analogue of LH-RH is highly potent and is strongly bound by the LH-RH receptor. Furthermore, since it desensitizes the LH-RH receptor, it appears that continued turnover of either LH-RH or the analogue at the receptor is necessary for output of LH to be maintained.

Animals↗
PubMed1982

Effect of cortisol or adrenocorticotrophin on release of luteinizing hormone induced by luteinizing hormone releasing hormone in the dairy heifer.

During treatment with cortisol or ACTH, dairy heifers were given two doses of LH releasing hormone (LH-RH) spaced 1.5 h apart. Serum concentrations of cortisol and LH were monitored during each treatment. Treatment with both ACTH and cortisol raised plasma cortisol levels above the respective saline controls (P less than 0.001). Neither treatment affected basal LH concentrations. A slight depression in LH response was seen in the cortisol-treated animals after the first LH-RH injection, as shown by a statistically significant depression at three of the sample times. There was no significant difference between treated and control LH values after the second LH-RH administration. Treatment with ACTH resulted in significantly reduced LH values at all sample times after both injections of LH-RH.

Adrenocorticotropic Hormone↗
PubMed1984

Blockade of LH and FSH secretion by LH-releasing hormone, by the LH-releasing hormone analogue, buserelin, and by combined treatment with LH-releasing hormone and oestradiol benzoate.

The LH and FSH release-stimulating (experiment 1) and -blocking (experiment 2) effects of LH-releasing hormone (LHRH) and of the LHRH analogue D-Ser(But)6-des-Gly10-LHRH-ethylamide (buserelin), as well as the effect of combined treatment with LHRH and oestradiol benzoate (OB; experiment 3) on the 'supra-maximally' LHRH-stimulated release of LH and FSH were studied in rats ovariectomized for 2 weeks. Pretreatment with LHRH (250 or 500 ng/h) or buserelin (250 ng/h) for 6 days was effected by means of subcutaneously implanted Alzet osmotic minipumps; control rats received a 'sham pump', i.e. a piece of silicone elastomer with the dimensions of a minipump. Oestradiol benzoate (3 micrograms/injection) or solvent was injected subcutaneously 75 and 27 h before the induction of LH/FSH responses. Experiment 1 revealed that after infusion of LHRH and buserelin, both at the rate of 1 microgram/h, plasma LHRH concentrations were established which were about twice as low as the plasma buserelin concentrations. This might suggest that buserelin has a longer half-life than LHRH. As an LH and FSH release-stimulating substance, however, it appeared that buserelin was about as effective as LHRH. Experiment 2, however, suggested that as an LH/FSH release-blocking agent buserelin was much more effective than LHRH. In addition, after buserelin pretreatment the pituitary glands contained much less LH and FSH than after LHRH pretreatment at both dose levels used.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Cholinergic agonist and antagonist drugs modulate the growth hormone response to growth hormone-releasing hormone in the rat: evidence for mediation by somatostatin.

Recently, data have been presented showing that muscarinic cholinergic agonists or antagonists can modulate, in opposite ways, GH-releasing hormone GHRH)-induced GH release in man. The aim of the present study was, first, to confirm these findings in the rat and, secondly, if confirmed, to investigate the mechanism(s) subserving the effect of cholinergic drugs. In adult male rats bearing chronic indwelling atrial cannulae, pretreatment with the cholinergic antagonists pirenzepine (0.5 mg/kg, i.v.) or atropine (0.5 mg/kg, i.v.) significantly reduced the rise in plasma GH induced by GHRH (2 micrograms/kg, i.v.), while pretreatment with the cholinergic agonist pilocarpine (3 mg/kg, i.v.) potentiated it. In rats with hypothalamic somatostatin (SRIF) depletion, i.e. rats with anterolateral deafferentation of the mediobasal hypothalamus or rats treated with cysteamine, the modulatory action of cholinergic drugs on the neuroendocrine effect of GHRH was completely lacking. In these two experimental models, an antiserum raised against SRIF failed to elicit a rise in plasma GH and measurement of hypothalamic SRIF content revealed a clear-cut reduction of the neuropeptide. Atropine (1 mumol/l) and pilocarpine (1 mumol/l), added to pituitary cells in vitro, failed to alter GHRH-induced GH release. The present results indicate that muscarinic cholinergic agonists and antagonists modulate GHRH-induced GH release in the rat and suggest that the effect of cholinergic modulation takes place through SRIF.

Afferent Pathways↗
PubMed1991

Effects of glucocorticoid treatment and acute passive immunization with growth hormone-releasing hormone and somatostatin antibodies on endogenous and stimulated growth hormone secretion in the male rat.

Despite causing marked inhibition of somatic growth, glucocorticoids enhance both the response to GH-releasing hormone (GHRH) and the amplitude of naturally occurring GH secretory pulses in the male rat. The relative contribution of the two major hypothalamic regulatory factors for GH (somatostatin and GHRH) to these observed effects remains speculative. In the present studies, we have investigated endogenous and stimulated GH release in rats pretreated with glucocorticoid or vehicle, and the effects of passive immunoneutralization of somatostatin or GHRH. In an initial study, four groups of eight rats were treated with either saline or various doses of a depot preparation of betamethasone: low dose, 0.85 mg; medium dose, 1.7 mg; high dose, 3.4 mg. All doses significantly suppressed body weight gain, total adrenal weight and concentrations of both plasma corticosterone and pituitary ACTH. Seven days after betamethasone treatment, GH responses to an i.v. injection of 1 microgram human GHRH(1-29) were evaluated during pentobarbitone anaesthesia. Compared with saline-treated controls (peak GH concentration of 506.0 +/- 68.5 micrograms/l), peak GH levels were enhanced by the low dose (704.4 +/- 47.8 micrograms/l, P less than 0.05), unaltered by the medium dose (543 +/- 65.8 micrograms/l) and suppressed by the high dose (312.7 +/- 55.2 micrograms/l, P less than 0.05) of betamethasone. Similarly, the area under the secretory curves was increased by 46% following the low dose (P less than 0.01), unaltered by the medium dose and reduced by 33% after the high dose of betamethasone. In a second study, rats were pretreated for 7 days before blood sampling with either the medium dose of betamethasone or saline. On day 5, 48 h before blood sampling, an indwelling venous catheter was fitted enabling sampling of conscious rats. On the day of study, blood samples were taken at 30-min intervals over an initial 2-h period (10.00-12.00 h). Following the sample at 12.00 h, rats were given the reconstituted and dialysed immunoglobulin fraction from either control sheep serum (NSIgG), sheep anti-rat GHRH serum (GHRHab) or sheep anti-somatostatin serum (SRIHab), and samples were taken for a further 90 min (12.30-14.00 h). Directly after the sample at 14.00 h, GH stimulation was effected in all rats using 1 microgram human GHRH(1-29) with samples taken at 5, 10, 20 and 40 min following stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Effect of actively immunizing sheep against growth hormone-releasing hormone or somatostatin on spontaneous pulsatile and neostigmine-induced growth hormone secretion.

The physiological role of endogenous circulating GH-releasing 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 anti-SRIH 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.

Animals↗
PubMed1994

Octreotide administration, under particular temporal conditions, enhances the responses of growth hormone to growth hormone-releasing hormone in normal subjects.

OBJECTIVE: Somatostatin not only inhibits basal and GHRH-stimulated GH secretion but might also enhance pituitary GH responsivity to GHRH under different temporal conditions. We investigated whether octreotide, a long-acting somatostatin analogue, has any positive actions on GHRH-induced GH release in normal human subjects. DESIGN: The study consisted of three protocols. At 0800 hours, after fasting overnight, all subjects received 1 microgram/kg GHRH i.v. bolus at 0 minutes. In each protocol, either octreotide (200 micrograms s.c.) or placebo were given respectively 8, 12, or 16 hours prior to GHRH challenge. SUBJECTS: Three groups of eight normal volunteers (four female and four male in each group), aged 18-35 years, were randomly assigned to each protocol. MEASUREMENTS: Growth hormone was measured by IRMA. Samples for GH assay were taken at -30 and 0 minutes and then at 15-minute intervals up to 120 minutes. RESULTS: When placebo or octreotide were administered 8 hours before GHRH, peak GH levels were respectively (mean +/- SE, mU/l) 56.2 +/- 16.6 and 60.8 +/- 11.4 (NS). Also, when placebo or the somatostatin analogue were administered 16 hours prior to GHRH, peak GH levels were comparable (61.0 +/- 7.4 vs 58.8 +/- 7.4, NS). However, in the group receiving placebo or octreotide 12 hours prior to GHRH, the GH responses to GHRH were clearly enhanced by octreotide administration (peak GH levels, mU/l, 55.6 +/- 21.6 vs 104.0 +/- 17.4, P < 0.02). This enhancement of GH responses was observed in all subjects. CONCLUSIONS: Octreotide administration did not affect GH responses to GHRH when given either 8 or 16 hours prior to GHRH. However, octreotide enhanced GHRH-induced GH release when administered 12 hours prior to GHRH. It thus appears that, under particular temporal conditions, octreotide may act positively on GH secretion in man.

Adolescent↗
PubMed1997

Effect of fetal ethanol exposure on the in vitro release of growth hormone, somatostatin and growth hormone-releasing factor induced by clonidine and growth hormone feedback in male and female rats.

This study was designed to examine the effect of fetal ethanol (ETOH) exposure on the sensitivity of the hypothalamic-growth hormone (GH) axis to clonidine (an alpha 2-adrenoreceptor agonist) stimulation and GH feedback. During gestation, dams were fed either a liquid diet in which 36% of the calories were derived from ETOH, or pair-fed an isocaloric control liquid diet without ETOH. A second set of controls were fed lab chow ad libitum. After birth, offspring of ETOH-fed dams were cross-fostered to a separate group of ad libitum control dams. The hypothalami and pituitaries of 10-, 20-, 30-, and 50-day-old offspring were separated by age, diet, and sex; pooled 6 to 8 per chamber; and tested in a hypothalamic-pituitary coperifusion system. Chambers were perifused with either clonidine (2 x 10(-8) M) alone, which mimics the endogenous trigger for GH release, or clonidine in combination with human GH (2 x 10(-9) M) to determine sensitivity of tissue to feedback regulation. Both stimuli act at the hypothalamic level and indirectly modulate GH release via effects on hypothalamic factors. Results of this study indicate that tissue from control male rats is responsive to the clonidine-induced GH surge by 10 days of age and to feedback depression of GH release by 20 days of age. This sensitivity persists after puberty and is associated with corresponding changes in somatotropin-release inhibiting factor (SRIF) and GH-releasing factor (GRF) release (i.e., clonidine inhibits SRIF and stimulates GRF release, and human GH reverses this pattern). Fetal ETOH exposure depresses GH sensitivity to both stimuli in male pups (age x diet x drug: p < 0.002), and this depressed sensitivity is expressed by 30 days of age by reduced responses to alpha 2-adrenergic stimulation and GH feedback (drug x diet: p < 0.002 and p < 0.001 for 30 and 50 days of age, respectively). This effect of ETOH on GH release was associated with feedback insensitivity of SRIF (drug x diet: p < 0.003, at 50 days of age) and GRF [drug x diet; p < 0.044 at 30 days; clonidine vs. clonidine and GH: p > 0.05 (NS) at 50 days of age for ETOH pups]. The depressed response of GH to clonidine after puberty may be attributable to a combination of the trends toward decreased sensitivity of both SRIF and GRF at this age. The female GH axis was both less sensitive to stimuli and less effected by ETOH than corresponding tissue from male rats (sex x age x drug x diet: p < 0.011). GH release from control female pituitaries was sensitive to clonidine before, but not after, puberty and insensitive to GH feedback at both developmental stages. On the other hand, there was a specific effect of ETOH on SRIF release at 10 days of age (diet x drug: p < 0.014), and SRIF release remained sensitive to clonidine in pups from all diet groups after puberty. Because GH release was not influenced by these changes in SRIF, these findings suggest that GH release is less sensitive to SRIF in females. In conclusion, this study suggests that fetal ETOH exposure interferes with the development of the sensitivity of the GH axis to alpha 2-adrenergic stimulation and feedback in males. Thus, the male GH axis is both more sensitive to the stimuli tested in this study and more effected by ETOH than the female axis. Furthermore, the effects of ETOH on these mechanisms do not alter GH release in males until the peripubertal period. It is likely, therefore, that the GH regulatory mechanism examined in this study does not contribute to growth retardation before puberty. If the effects of ETOH on GH release contributes to growth retardation in prepubertal males and in females, it most likely involves other regulatory mechanisms. On the other hand, because the adult pattern of GH release is programmed during development, the influence of ETOH on these developmental events may influence the male pattern of GH release and GH activity in adulthood.

Adrenergic alpha-Agonists↗