GH Secretion In Man Research Articles

Disparate Effect of Aromatization on the Central Regulation of GH Secretion by Estrogens in Men and Postmenopausal Women.

Estrogen receptor antagonism by tamoxifen inhibits GH secretion in both men and postmenopausal women, suggesting that estrogen, albeit at low concentration, stimulates GH secretion. However, systemic estrogen replacement in postmenopausal women does not enhance GH secretion. To clarify the role of estrogen in mediating GH secretion, we investigated the effect of estrogen deprivation by using aromatase inhibitors. To determine whether estrogens mediate GH secretion in men and postmenopausal women. The effects of letrozole, an aromatase inhibitor, and tamoxifen were compared in an open-label crossover study. Eight men and 14 women received tamoxifen (20 mg/d) and letrozole (2.5 mg/d) for 2 weeks each. The primary endpoints were GH response to arginine stimulation and gonadal steroid levels. In men, letrozole significantly (P < 0.05) reduced the peak GH response to arginine (mean ± SEM; Δ -49.4% ± 18.1%). Tamoxifen also reduced the mean peak GH, but this did not reach statistical significance. In postmenopausal women, letrozole did not affect peak GH, whereas tamoxifen significantly (P < 0.05) reduced peak GH (Δ -47.3% ± 10%). In men, letrozole reduced circulating estradiol (from 43.1 ± 2.8 to 12.7 ± 1.3 pmol/L; P < 0.001), whereas in women estradiol was undetectable (<11 pmol/L) at baseline and throughout letrozole therapy. Because estrogen deprivation reduced circulating GH, we conclude that estrogens regulate GH secretion in men. In postmenopausal women, the neutral effect of aromatase inhibition is likely explained by pre-existing estrogen deficiency. The inhibition of GH secretion by tamoxifen in menopause suggests a non-estrogen receptor-mediated mechanism of action. In contrast to men, estrogen is unlikely to mediate GH secretion in postmenopausal women.

Gender Difference in the Neuroendocrine Regulation of Growth Hormone Axis by Selective Estrogen Receptor Modulators

In men, GH secretion is stimulated by estradiol derived locally from aromatization of testosterone. Recently, we showed that local estrogen also plays a major role in the central regulation of GH secretion in women. Tamoxifen and raloxifene are selective estrogen receptor modulators (SERMs), drugs that block central estrogen action but exert estrogen-like effects in the liver, inhibiting hepatic IGF-I production. The relative impact of SERMs on the GH-IGF-I axis in men and women has not been investigated. The aim of the study was to determine whether there is a gender difference in the impact of SERMs on the GH-IGF-I axis. We conducted a comparative, randomized, open-label, crossover study of tamoxifen and raloxifene. Ten healthy postmenopausal women and ten healthy men were randomized to 2-wk sequential treatment with tamoxifen (10 and 20 mg/d) and raloxifene (60 and 120 mg/d) with a washout of 2 wk between treatments. The GH response to arginine, IGF-I, testosterone, and SHBG was measured. In women, but not in men, tamoxifen significantly attenuated the GH response to arginine. The GH response was not significantly blunted by raloxifene in both sexes. Both SERMs significantly reduced mean IGF-I levels to a similar degree in men and women. In men, both SERMs significantly increased LH and testosterone levels. In summary, GH secretion was blunted by tamoxifen in women in the face of reduced IGF-I feedback inhibition but not in men in whom the gonadal axis was stimulated. We conclude that potential blunting of GH secretion in men by SERMs was counteracted by concomitant central stimulation of GH secretion by testosterone. In therapeutic doses, tamoxifen may induce detrimental metabolic effects in women, but not men.

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

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. 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. Three groups of eight normal volunteers (four female and four male in each group), aged 18-35 years, were randomly assigned to each protocol. 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. 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. 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.

Contributions of Gender and Systemic Estradiol and Testosterone Concentrations to Maximal Secretagogue Drive of Burst-Like Growth Hormone Secretion in Healthy Middle-Aged and Older Adults

To test whether concentrations of estradiol and testosterone predict GH responses to mechanistically distinct secretagogues in healthy older adults, we studied 16 volunteers (n = 10 men, n = 6 women, age 49-72 yr) in each of six randomly ordered sessions as follows: 1) saline; 2) l-arginine; 3) aerobic exercise; 4) GHRH; 5) GH-releasing peptide (GHRP)-2; and 6) somatostatin-induced rebound. Statistical comparisons disclosed that stimulus type (P < 0.001) and the interaction between gender and stimulus type (P = 0.023) determine GH secretion. In women, each secretagogue, except exercise and somatostatin-induced rebound, stimulated GH secretion by 2.6- to 6.4-fold over saline/rest (P < 0.023). In men, somatostatin-induced rebound drove GH secretion by 4.6-fold (P = 0.004), exercise by 16-fold (P < 0.001), and other secretagogues by 18- to 109-fold over saline/rest (each P < 0.001). Gender comparisons disclosed greater GH secretion in men than women after somatostatin-induced rebound (P = 0.008) and GHRP-2 injection (P < 0.001) and conversely greater GH secretion in women than men after saline (P = 0.013). Regression analysis showed that individual concentrations of estradiol (r = 0.80, P = 0.002) and testosterone (r = 0.63, P = 0.008) and their combination (r = 0.86, P < 0.001) strongly predict responses to GHRP-2 only. We conclude that among healthy middle-aged and older adults, the action of GHRP is uniquely determined by gender and physiological concentrations of testosterone and estradiol.

Influência dos glicocorticóides sobre o eixo somatotrófico

A secreção de hormônio de crescimento (growth hormone, GH) é modulada por uma interação complexa entre dois fatores hipotalâmicos: o hormônio liberador do GH (GH-releasing hormone, GHRH) e a somatostatina (SRIF). Recentemente foi sugerida a existência de uma terceira via fisiológica de regulação deste hormônio, mediada pelos GHS (growth hormone secretagogues) e provavelmente pelo peptídeo endógeno, ghrelina. Os glicocorticóides (GCs) influenciam a secreção de GH atuando em diversos níveis, apesar dos mecanismos envolvidos nessas múltiplas ações não estarem totalmente elucidados. Além disso, esses esteróides têm efeitos estimulatórios ou inibitórios na liberação de GH, dependendo do modelo experimental, duração da exposição, dose, tipo e via de administração, entre outros. Embora controvertida, a administração aguda de GCs aumenta a secreção de GH em humanos. No entanto, quando presente em níveis suprafisiológicos por períodos mais longos (meses ou anos), os GCs inibem a liberação de GH. O efeito desses esteróides na IGF-1 e IGFBPs são bastante controvertidos.

Effects of histaminergic antagonists on the GH-releasing activity of GHRH or hexarelin, a synthetic hexapeptide, in man.

The role of histamine in the neural control of GH secretion in man is still unclear, although a stimulatory influence has been hypothesized in man. To clarify this point, in 7 normal young women (23-28 yr) in their early follicular phase, we studied the effect of the histaminergic blockade by diphenhydramine (DPH, 80 mg os at -60 min) on the GH response to GHRH (2 micrograms/Hg iv) or Hexarelin (HEX, 2 micrograms/kg iv), a synthetic hexapeptide with strong GH-releasing effect. In 6 of the 7 women the effect of terfenadine (TRF, 120 mg os at -60 min), another H1-receptor antagonist, on the GH response to GHRH or HEX was also studied. As HEX has also PRL- and ACTH-releasing activity and histamine has been shown to have a stimulatory role in the neural control of these hormones, the effects of DPH or TRF on the HEX-induced PRL. ACTH and cortisol release were also studied. GHRH induced a GH rise (peak, mean +/- SEM: 35.4 +/- 6.5 vs 2.5 +/- 1.1 micrograms/l, p < 0.02, n = 7; 34.7 +/- 7.9 vs 3.9 +/- 1.5 micrograms/l, p < 0.02, n = 6) lower (p < 0.05) than that elicited by HEX (49.1 +/- 8.5 vs 3.9 +/- 1.0 micrograms/l, p < 0.01, n = 7; 48.7 +/- 8.9 vs 3.2 +/- 0.8 micrograms/l, p < 0.01, n = 6). DPH inhibited the GH response to both GHRH (AUC: 453.9 +/- 104.7 vs 1223.7 +/- 202.6 micrograms*min/l, p < 0.05) and HEX (922.0 +/- 215.4 vs 1636.4 +/- 267.5 micrograms*min/l, p < 0.05), although the HEX-induced GH rise persisted higher than that induced by GHRH (p < 0.05). TRF did not modify the GHRH-induced GH rise (950.5 +/- 369.2 mg*min/l vs 1115.3 +/- 255.6 micrograms*min/l) as well as the somatotrope responsiveness to HEX (1163.2 +/- 188.7 vs 1427.3 +/- 323.3 mg*min/l). HEX also significantly increased PRL (13.9 +/- 3.1 vs 6.5 +/- 0.8 micrograms/l, p < 0.03), ACTH (31.1 +/- 6.6 vs 16.6 +/- 2.9 pg/ml, p < 0.02) and cortisol (96.6 +/- 6.3 vs 82.2 +/- 6.2 micrograms/L, p < 0.05) levels. PRL, ACTH and cortisol responses to HEX were unaffected by DPH (536.5 +/- 85.6 vs 599.5 +/- 129.2 micrograms*min/l, 1068.5 +/- 306.0 vs 1282.8 +/- 222.0 pg*min/ml and 4277.4 +/- 588.4 vs 4738.3 +/- 355.3 micrograms*min/l, respectively) as well as by TRF (621.3 +/- 110.4 vs 530.3 +/- 131.4 micrograms*min/L, 972.4 +/- 189.6 vs 1060.2 +/- 224.7 pg*min/ml and 6203.8 +/- 1329.5 vs 5141.2 +/- 295.5 micrograms*min/l, respectively). In conclusion, our findings are against the hypothesis of a major role of H1-receptor-mediated histaminergic influence on GH secretion in humans. In fact, the H1-histaminergic blockade by TRF does not affect the GH response to GHRH or HEX; the inhibitory effect of DPH may probably be due to its intrinsic anticholinergic activity. Our data also confirm that Hexarelin releases more GH than GHRH and demonstrate that its effect on GH, PRL and ACTH release is not mediated by H1-receptors.

Differential impact of age, sex steroid hormones, and obesity on basal versus pulsatile growth hormone secretion in men as assessed in an ultrasensitive chemiluminescence assay.

A chemiluminescence-based GH assay with 30- to 100-fold increased sensitivity recently disclosed combined basal and pulsatile GH secretion in men. However, how age, sex steroid hormones, and obesity singly and jointly influence the basal vs. pulsatile modes of GH release is not known. We used the foregoing assay (detection threshold, 0.002-0.005 microgram/L) and high sensitivity and specificity (> or = 90% each) deconvolution analysis to quantitate basal and pulsatile GH secretion from 24-h serum GH concentration profiles in 26 healthy lean and obese men, whose ages spanned 18-63 yr and whose percentage body fat ranged from 12-47%. Concentrations of serum insulin-like growth factor I (IGF-I), IGF-I-binding protein-1 (IGFBP-1), and IGFBP-3 were related to specific measures of basal or pulsatile GH release. We observed that mean (24-h) serum GH concentrations embraced a 140-fold range from 0.013-1.8 micrograms/L and were related negatively to age (r = -0.50; P < 0.01), percentage body fat (r = -0.620; P < 0.01), and their interaction (r = -0.610; P < 0.01). In contrast, testosterone was a robustly positive statistical determinant of mean serum GH values (r = 0.628; P = 0.0006). Stepwise multivariate regression analysis disclosed that percentage body fat alone and jointly with the serum testosterone concentration controlled, respectively, 38% and 50% of the total variability in GH levels (P = 0.0013 and P = 0.0008). As assessed by deconvolution analysis, GH secretory burst mass was negatively related to percentage body fat (r = -0.621; P < 0.01) and positively to serum testosterone (r = 0.529; P = 0.0054). The calculated half-life of GH correlated positively with serum estradiol (r = 0.447; P = 0.032), and negatively with percentage body fat (r = -0.437; P = 0.048). Basal GH secretion rates were negatively related to serum estradiol (r = -0.485; P = 0.016). In contrast, GH secretory burst frequency and duration were unrelated to age, percentage body fat, or sex steroids. The fraction of total GH secreted in bursts was negatively correlated with the body mass index (r = -0.540; P < 0.01). Serum IGF-I concentrations were positively related to total pulsatile GH secretion (r = 0.690; P = 0.0011) and negatively to age (r = -0.597; P = 0.007) and percentage body fat (r = -0.611; P = 0.009).(ABSTRACT TRUNCATED AT 400 WORDS)

Glucocorticoids may inhibit growth hormone release by enhancing beta-adrenergic responsiveness in hypothalamic somatostatin neurons.

The aim of this study was to investigate the mechanisms by which glucocorticoids inhibit GH secretion in man. In 10 normal volunteers subjects we compared the pattern of GHRH-induced GH release to that elicited by similar challenge given 60 min after a pretreatment with drugs affecting adrenergic and muscarinic cholinergic neurotransmission, both in basal situations and after having induced hypercortisolism. In a first study (P), synthetic GHRH [GRF-(1-29); 1 microgram/kg, i.v.] was administered 60 min after giving placebo. In other experiments, the administration of propranolol (PRO; 40 mg, orally), or clonidine (CLO; 0.300 mg, orally), or pyridostigmine (PD; 120 mg, orally) was followed by GHRH administration 60 min later. These experiments were repeated after giving a nocturnal dose of dexamethasone (DEX; 8 mg, orally at 2300 h). The administration of DEX significantly (P < 0.05) blunted the GH response to GHRH (peaks: 10.7 +/- 3.9 vs. 20.3 +/- 5.5 micrograms/L; DEX vs. P study, respectively). Conversely, either beta-adrenergic blockade (PRO), or alpha 2-adrenergic agonism (CLO), or the enhancement of muscarinic cholinergic tone (PD) significantly increased the GH response to GHRH (peaks: 43 +/- 4.6, 55.6 +/- 5.6 and 51.2 +/- 7, micrograms/L; PRO, CLO, and PD, respectively; P < 0.01 vs. P study). After nocturnal DEX administration, both PRO and CLO, but not PD, were able to reverse the inhibitory effect of DEX on GHRH-elicited GH release (peaks: 39 +/- 5.5, 25.9 +/- 3.9 and 12.9 +/- 3.1, micrograms/L; DEX + PRO, DEX + CLO, and DEX + PD, respectively). However, whereas the potentiating effect of PRO on GHRH-elicited GH release was still observed under hypercortisolism, it was lacking for both CLO and PD when these drugs were given in this situation. These data suggest that the inhibitory effect of glucocorticoid excess on GH release is due to increased hypothalamic somatostatin secretion which appears to be dependent on DEX-induced enhanced beta-adrenergic responsiveness. Moreover, the data further support a major role of hypothalamic alpha 2-adrenergic and beta-adrenergic activities in GH neuroregulation in man.

Galanin reinstates the growth hormone response to repeated growth hormone-releasing hormone administration in man.

To clarify the mechanism by which galanin, a 29-amino-acid peptide, increases GH secretion in man. We studied the GH-releasing effect of this neurohormone (galanin, 15 micrograms/kg) infused over 60 minutes after 120 minutes of saline, following a previous GHRH bolus (GHRH 1 microgram/kg i.v. at 0 minutes, galanin infused from 120 to 180 minutes) and coadministered with the second of two consecutive GHRH boluses (GHRH every 120 minutes, galanin infused from 120 to 180 minutes). Fourteen healthy male subjects, aged 20-34 years, in two groups (group A, 20-31 years (n = 8); group B, 25-34 years (n = 6)) were studied. Blood samples were drawn every 15 minutes of 255 minutes. Serum GH was measured in duplicate by IRMA. Statistical analysis of the data was carried out by non-parametric ANOVA test. The GH response to galanin infused 120 minutes after saline overlapped with that induced by the neuropeptide infused following previous GHRH bolus (AUC, mean +/- SEM: 317.3 +/- 73.2 vs 326.8 +/- 54.2 micrograms/l/h). The GH-releasing effect of the second GHRH bolus (126.9 +/- 32.3 micrograms/l/h) was lower than that of the first one (503.4 +/- 41.3 micrograms/l/h; P = 0.0002). Galanin markedly enhanced the GH responses to the second GHRH bolus (1118.0 +/- 212.7 micrograms/l/h; P = 0.0002 vs second GHRH bolus alone) so that it did not significantly differ from the first one (710.9 +/- 107.8 micrograms/l/h). Our results show that the GH-releasing effect of galanin is not modified by GHRH pretreatment and that the neuropeptide reinstates the GH response to the repeated GHRH stimulation in man. They suggest that these effects are due to the inhibition of hypothalamic somatostatin release.

Growth Hormone-Releasing Hormone: Clinical Studies and Therapeutic Aspects

Growth hormone-releasing hormone (GHRH) stimulates GH secretion in man and the hormonal response is specific. The attenuation of GH response to bolus GHRH after prior exposure of GHRH of up to 24 h was not demonstrated in normal or GH-deficient subjects after more prolonged exposure. This suggests that the partial loss of responsiveness to GHRH may reflect short-term negative feedback by GH. The stimulatory effect of clonidine and L-dopa on GH release is mediated via GHRH. Other stimuli like hypoglycaemia, arginine and propranolol augment GH release in man by modulating hypothalamic somatostatin secretion. Although GHRH test can differentiate between hypothalamic or pituitary cause of GH deficiency, it is of little diagnostic value in children with short stature. Favourable results have been observed in 60-70% of GH-deficient children treated with GHRH, but the dose and mode of administration are still being explored. We found that low dose (1-2 micrograms/kg) GHRH given subcutaneously every 3 h by a pump was effective in promoting growth in 5 of 7 patients after 1 year. Treatment was continued for 2-4 years in 4 patients and growth velocities ranging from 4.5 to 8.2 cm/year were maintained using a dose of 3 micrograms/kg/pulse.

EFFECTS OF CALCITONIN ON GH RESPONSE TO PYRIDOSTIGMINE IN COMBINATION WITH hGHRH (1–29) NH2 IN NORMAL ADULT SUBJECTS

Studies in man demonstrated that salmon calcitonin (sCT) administration blunts the pituitary GH response to GH-releasing hormone (GHRH). However, the mechanisms underlying this inhibitory action of CT in man are unclear. Pyridostigmine (PD), an acetylcholinesterase inhibitor, is hypothesized to enhance the GH response to GHRH in normal subjects probably via a decrease in the somatostatinergic tone. The aim of the present study was to investigate the mechanism of the inhibitory action of sCT on the GH response to human GHRH (1-29) NH2 by concomitant PD administration in normal humans. The GH response to GHRH was significantly suppressed by prior administration of sCT. Pretreatment of subjects with PD significantly enhanced the GH response to GHRH but did not alter the inhibitory actions of sCT. We conclude that sCT is able to inhibit GHRH-stimulated GH secretion in man without influencing the hypothalamic somatostatinergic tone.

Plasma Glucose and Free Fatty Acids Modulate the Secretion of Growth Hormone, but not Prolactin, in the Rhesus and Java Monkey*

In 11 freely moving rhesus and 5 Java monkeys the plasma GH, PRL, and cortisol responses to suppression and elevation of plasma glucose and FFA concentrations were studied. Blood was sampled and infusions given via chronic jugular catheters, extended via a swivel into the adjacent room. In the rhesus monkeys, the mean plasma GH concentration rose during insulin-induced hypoglycemia from 4.7 +/- 1.9 to 17.4 +/- 2.5 micrograms/L at 60 min (P less than 0.001), and the mean plasma cortisol concentration from 320 +/- 55 to 700 +/- 133 nmol/L at 90 min (P less than 0.001). The mean plasma PRL concentration (basal value, 5 +/- 2.3 micrograms/L) did not change significantly. During glucose-induced hyperglycemia, the mean plasma GH concentration oscillated between 2.0-5.2 micrograms/L from 60-360 min (no significant change). Large GH secretory episodes occurred during hyperglycemia in individual animals. During nicotinic acid-induced plasma FFA suppression, the mean plasma GH concentration increased from 3.7 +/- 0.6 to 17.9 +/- 2.3 micrograms/L at 270 min (P less than 0.001). During lipid-induced plasma FFA elevation, the mean plasma GH concentration decreased consistently from 6.5 +/- 1.0 micrograms/L to values between 1.3 +/- 0.2 and 2.6 +/- 0.6 micrograms/L from 60-360 min (P less than 0.01). Plasma PRL and cortisol concentrations were not affected by plasma FFA changes. Compared with the spontaneous plasma GH pattern in a previously studied group of rhesus monkeys, the mean plasma GH concentration was increased during hypoglycemia and plasma FFA suppression. It was strongly suppressed during plasma FFA elevation and slightly suppressed during hyperglycemia. Similar effects were observed in the Java monkeys, although hyperglycemia tests were not performed. We conclude the following. 1) In rhesus and Java monkeys, as in man, GH secretion is stimulated by plasma FFA suppression and is inhibited by plasma FFA elevation. In both species, acute hypoglycemia stimulates the secretion of GH and cortisol. 2) These nonhuman primates differ from man in that hyperglycemia only weakly inhibits GH secretion in the rhesus monkey, if at all (Java monkeys had no hyperglycemia tests), and in neither species does acute hypoglycemia stimulate the secretion of PRL. 3) Both primate species can serve as models for the metabolic modulation of GH secretion in man, although a suppressive effect of hyperglycemia remains to be proven.

Histamine-induced paradoxical GH response to TRH/GnRH in men and women: Dependence on gonadal steroid hormones

A stimulatory GH response to TRH and GnRH occurs frequently in patients with various pathological conditions, but is absent in normal subjects. We have previously shown that histamine induced a paradoxical GH response to TRH in normal men. Since gonadal steroids influence GH secretion, we investigated whether infusion of histamine might induce a GH response to combined administration of TRH (200 micrograms) and GnRH (100 micrograms) in 6 normal women during the early follicular and luteal phase of the same menstrual cycle and in 7 normal men. Histamine had no effect on basal GH secretion in men or in women during the two phases of the menstrual cycle. However, compared with saline, histamine induced a GH response to TRH/GnRH in men (GH peak: 5.5 +/- 1.0 vs 1.4 +/- 0.3 micrograms/l; p less than 0.01) and in women during the luteal phase (GH peak: 5.2 +/- 1.6 vs 1.5 +/- 0.4 micrograms/l; p less than 0.025), but not during the early follicular phase of the cycle (GH peak: 1.7 +/- 0.5 vs 1.6 +/- 0.3 micrograms/l). In luteal-phase women the GH response to TRH/GnRH correlated with the serum estradiol-17 beta level (GH area/E2: r = 0.98; p less than 0.005) and the serum estrone level (GH area/E1: r = 0.81; p less than 0.05). In men the GH response to TRH/GnRH did not correlate with estrogen or androgen levels. We conclude that high physiological levels of estrogens are pertinent to the activation of a histamine-induced GH response to TRH/GnRH in women, whereas the role of androgens and estrogens for the induction of the response in men seems more complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Administration of Corticoids: A New and Peculiar Stimulus of Growth Hormone Secretion in Man*

It is widely accepted that chronic administration of corticoids in man inhibits the GH response to all of the stimuli tested so far. To study the action of corticoids administered acutely, several dexamethasone challenge tests were performed, after which GH levels were measured for 7 h. In eight volunteers, administration of 4 mg dexamethasone (Dex), iv, induced a clear-cut GH release compared with saline administration. The secretion followed an unusual pattern; basal GH levels (1.5 +/- 0.1 micrograms/L) started rising 2 h after Dex injection, reaching a peak of 17.5 +/- 4.4 micrograms/L after 3 or 3.5 h. Peak levels were maintained until 5 h post-Dex and decreased thereafter. Similar data were obtained when Dex was administered to five volunteers at the dose of 8 mg, orally, with a 30-min delay of the GH peak (19.6 +/- 7.9 micrograms/L). To study whether there was a cholinergic input responsible for the Dex action, another group of eight volunteers underwent three Dex tests (4 mg, iv) on three occasions, followed 90 min later by the administration of placebo (control), atropine (0.5 mg, iv), or pyridostigmine (120 mg, orally). The Dex-induced GH peak (20.8 +/- 5.2 micrograms/L) was not significantly increased by pyridostigmine (cholinergic agonist) treatment (24.2 +/- 4.0 micrograms/L). The blockade of muscarinic receptors by atropine induced a delay in the Dex-induced secretory peak, which appeared at 5 h. However, the Dex-atropine GH peak (14.9 +/- 4.1 micrograms/L) was not different from the Dex-placebo one. In conclusion, Dex alone is able to induce a clear-cut GH secretion in man. The stimulus followed a peculiar time pattern, with peaks levels attained 3 h after either iv or oral administration.

EFFECTS OF INTRANASAL CALCITONIN ADMINISTRATION ON PITUITARY GH RESPONSE TO hGHRH (1–29)NH2 IN NORMAL ADULT SUBJECTS

Studies in man demonstrated that intramuscular salmon (s) calcitonin (CT) administration blunted pituitary GH response to hypothalamic stimuli such as arginine infusion and insulin-induced hypoglycaemia. However, the mechanisms underlying this inhibiting action of CT are still unclear. The aim of our study was to investigate the effects of intranasal (i.n.) and i.m. sCT administration on GH secretion elicited by direct pituitary stimulation in man with human GH-releasing hormone (GHRH) (1-29)NH2. Seven healthy non-obese volunteers (five men, two women; mean age +/- SDM 25 +/- 2) underwent a bolus intravenous injection of GHRH, 100 micrograms, alone or associated with sCT, administered either i.n., 300 IU, or i.m., 100 IU. Our data demonstrate a significant decrease in GH secretion after GHRH when either i.n. or i.m. sCT is administered. GH peak (mean +/- SDM); GHRH alone 22.9 +/- 2.5 vs GHRH plus i.n. sCT, 8.9 +/- 1.5 micrograms/l, P less than 0.001; or vs GHRH plus i.m. sCT 12.3 +/- 2.5 micrograms/l, P less than 0.001. Area under the curve of GH secretion: GHRH alone 1211 +/- 196 vs GHRH plus i.n. sCT 551 +/- 116 micrograms 120 min/l. P less than 0.001; or vs GHRH plus i.m. sCT 700 +/- 167 micrograms 120 min/l, P less than 0.001. We conclude that sCT is able to inhibit GHRH-stimulated GH secretion in man.

Hormonal regulation of growth hormone secretion and messenger ribonucleic acid accumulation in cultured bovine pituitary cells.

In both primary cultures and transformed tumor cultures of rat pituitary cells, preincubation with T3 or dexamethasone increases GH secretion, mRNA accumulation, and gene transcription. GRF stimulates secretion and transcription in primary rat pituitary cultures. Sex steroids stimulate GH secretion in man, but contradictory findings have been reported in vitro. We studied the hormonal regulation of bovine GH (bGH) in primary monolayer cultures of adult bovine pituitaries. Neither T3 nor dexamethasone changed immunoreactive bGH secretion during a 3-h experimental incubation. After 72-h preincubation with T3 or dexamethasone, bGH secretion remained unchanged. T3 (10(-8) M) or dexamethasone (10(-8) M) did not alter the bGH secretory response to doses of GRF from 10(-12)-10(-8) M. However, T3 (P less than 0.001; r = 0.73) and dexamethasone (P less than 0.001; r = -0.71) decreased bGH mRNA content in dose-dependent fashions, as determined by Northern analysis and RNA dot blots probed with 32P-labeled bGH cDNA. T3 10(-7) M) decreased bGH mRNA content to 70% of the control value, 10(-7) M dexamethasone decreased bGH mRNA content to 77% of the control value, while GRF increased bGH mRNA content to 174% of the control value in a dose-dependent fashion (P less than 0.001; r = 0.72). Preincubation with testosterone or dihydrotestosterone did not change basal or GRF-stimulated GH secretion. Seventy-two-hour preincubation with 10(-8) M estradiol did not alter basal GH secretion, but increased the bGH secretory response to doses of GRF from 10(-11)-10(-8) M (P less than 0.001). Incubation with estradiol did not change bGH mRNA levels. These results demonstrate that, in contrast to rat GH mRNA, bGH mRNA accumulation is inhibited by T3 and dexamethasone. Estradiol augments the response to GRF, but this effect is not mediated by an increase in mRNA content. The hormonal responses of somatotropes vary significantly among mammalian species.

Growth hormone-releasing hormone in the diagnosis and treatment of growth hormone deficient children.

A growth hormone-releasing hormone (GHRH) has recently been extracted and synthesised, and appears to be identical to human hypothalamic GHRH. Immunoreactive GHRH is found in the venous blood of normal subjects and GH-deficient children, but is probably not hypothalamic in origin and therefore not important in GH regulation. GHRH is a potent specific stimulator of GH secretion in man, and provides a valuable diagnostic test in differentiating hypothalamic from pituitary causes of GH deficiency. Preliminary data suggests that GHRH may promote linear growth in some GH deficient children. GHRH may well prove an important alternative therapy for GH deficient children especially if depot preparations or intranasal administration prove effective.

Effects of GRF(1-40) and domperidone on GH secretion in normal man.

In eight normal adult men pituitary secretion following GRF(1-40) was studied. GRF administration (50 micrograms i.v.) was followed by an increase in GH release with a peak value between the 15 and 60 min. No effects were noticed on LH, FSH, PRL, TSH and ACTH secretion. GH and PRL release was also studied after domperidone (DOM) (5 mg i.v./h), and GRF plus DOM. PRL increased significantly after DOM and GRF plus DOM. During GRF plus DOM a more marked GH release was observed in comparison with the hormone response to GRF alone at 15-45 and 120 min (P less than 0.05). This phenomenon was found in in six out of eight subjects studied. Mean peak and secretory area was greater (P less than 0.05) after GRF plus DOM than after GRF alone. These data suggest that GRF(1-40) at the dose used is a useful tool in the study of GH secretion. The GH pattern during GRF plus DOM seems to indicate that dopaminergic tone may play a direct inhibitory role on GH secretion in man.

ACCELERATION OF LINEAR GROWTH AFTER REPEATED DOSES OF GROWTH HORMONE-RELEASING FACTOR (GRF)

GRF's are potent stimulators of GH secretion in man. We administered 1 μg/kg GRF 1-44 NH2 to 15 children with documented GH deficiency, ages 4-20 years. 12/15 had a measurable GH response. Following discontinuation of GH therapy for at least 2 months, 2 responders and 1 nonresponder then received 1 μg/kg GRF IV q 3 h for 10-12 d. Short-term growth was assessed by the lower leg measurement technique of Valk et al. (Growth 47:53, 1983). GH was measured q 20 min for 12 h on the 1st, and 5th or 7th days of multiple-dose therapy and for the first 12 hours off GRF. Somatomedin-C (SmC) levels were drawn daily. Baseline GH levels were <0.7 ng/ml. In the 2 responders, mean peak GH response to GRF increased, SmC rose, and lower leg growth velocity (GV) accelerated (Table). GH levels returned to baseline after GRF was stopped. The third patient had no hormonal or growth response. Thus most children with GH deficiency respond to GRF, and multiple doses of GRF can accelerate short-term linear growth. GRF may form the basis for an alternative treatment of GH deficiency.

Topographical and ontogenetic study of the neurons producing growth hormone-releasing factor in human hypothalamus.

Neurons producing growth hormone-releasing factor have been characterized and analyzed by immunohistochemistry in the hypothalami of human fetuses, neonates, infants and adults, using two antibodies against human pancreatic GRF (hpGRF). One of the antibodies recognized both the hpGRF(1-40)OH and hpGRF(1-44)NH2 in the mid portion (between the 28th and 39th amino acid), the other one specifically recognized the C-terminal end of hpGRF(1-44)NH2. These two antibodies stain a single neuronal system with cell bodies mainly located in the infundibular (arcuate) nucleus, and in the ventromedial and lateralis tuber nuclei. These neurons project to the median eminence where they give numerous endings in contact with portal vessels. These neurons are distinct from those containing LH-RH, somatostatin, CRF or pro-opiocortin. In fetuses, neurons immunoreactive with hpGRF antibodies are first detected at the 29th week. They display a neuroblastic aspect which persists after birth. Immunoreactive fibers are detectable in the median eminence after the 31st week. These results demonstrate that the infundibular nucleus plays a major role in control of GH secretion in man and that secretion of GRF appears late during fetal life; this suggests that the first stages of differentiation and development of GH producing cells in the human fetus do not depend on hypothalamic GRF secretion.