Histamine regulation of prolactin secretion through H1- and H2-receptors

Histamine (HA) regulates PRL secretion in the rat by a stimulatory effect through H1-receptors and an inhibitory effect through H2-receptors. The effect of HA antagonists on basal and TRH-stimulated PRL secretion was investigated in five normal men. During saline infusion, serum PRL declined, as seen normally after sleep. HA infusion caused a significantly higher PRL secretion than that observed during the saline infusion [maximum change in PRL (delta PRL), 28 +/- 20 vs. -71 +/- 30 microIU/ml; P less than 0.05]. This effect of HA on PRL secretion was inhibited during the combined infusion of HA and the H1-antagonist mepyramine (delta PRL, 28 +/- 20 vs. -77 +/- 13 microIU/ml; P less than 0.025). The PRL-stimulating effect of HA was strongly enhanced during the combined infusion of HA and the H2-antagonist cimetidine (delta PRL, -28 +/- 20 vs. 132 +/- 57 microIU/ml; P less than 0.0125). This effect of HA and cimetidine on PRL secretion was higher than the effect of cimetidine alone (delta PRL, 132 +/- 57 vs. 17 +/- 22 microIU/ml; P less than 0.05). This shows that the H2-antagonist is not the only stimulator of PRL secretion. During the different infusions, serum PRL concentrations were in the following rank order: mepyramine less than saline less than HA less than cimetidine less than HA plus cimetidine. The same rank order was found for the PRL responses to TRH during the different infusions. These data indicate a HA stimulatory effect through H1-receptors and an inhibitory effect through H2-receptors on PRL secretion in human males.     

Role of dopamine in the regulation of growth hormone secretion: dopamine and bromocriptine augment growth hormone (GH)-releasing hormone-stimulated GH secretion in normal man

The role of the dopaminergic system and its interaction with GH-releasing hormone (GHRH) in the regulation of GH secretion was investigated in normal men in two complementary studies. The men were given continuous iv infusions of 0.15 M saline (5 h), dopamine (4 micrograms/kg X min; 1 h), GHRH (2 ng/kg X min; 2 h), and GHRH (2 ng/kg X min; 2 h) plus dopamine (4 micrograms/kg X min; 1 h) on four separate occasions, and serum GH responses were measured. In a second study, on separate days, placebo or bromocriptine (2.5 mg/dose) was administered, and GH and PRL responses to a single iv GHRH dose were measured. A continuous infusion of dopamine and GHRH on separate days stimulated GH secretion in all subjects. The mean integrated GH secretion was 13.2 +/- 3.1 (+/- SEM) ng/mL X h during the dopamine infusion and 14.7 +/- 4.6 during GHRH, compared with 1.7 +/- 0.4 during the saline infusion. The combination of GHRH and dopamine resulted in the greatest stimulation of GH secretion (29.8 +/- 5.7 ng/ml X h; P less than 0.05 vs. 3 other study days). The oral dopamine agonist bromocriptine also augmented GHRH-stimulated GH secretion. Integrated GH secretion after a single iv injection of GHRH following two doses of bromocriptine was 160 +/- 29.5 ng/ml X h compared with 81.3 +/- 22.2 after placebo (P = 0.04). We suggest that these findings are compatible with the hypothesis that dopamine inhibits hypothalamic somatostatin secretion, which then allows for a greater stimulatory effect of GHRH.     

Growth hormone responses to continuous infusions of growth hormone-releasing hormone

The pattern of GH secretion during a continuous 4-h iv infusion of 1 microgram/kg.h GH-releasing hormone (1-44)-NH2 (GHRH-44) or saline was examined in 15 adult men. There was prompt release of GH beginning within 20 min of starting the GHRH-44 infusions, reaching peak GH levels of 43 +/- 11 (+/- SE) ng/ml within 60-90 min. This is similar to the peak GH level reached in men after a single 1 microgram/kg GHRH iv bolus dose (34 +/- 8 ng/ml). GH levels then fell progressively, but did not return to baseline during the GHRH infusions. After GHRH infusions, the response (delta) to a 1 microgram/kg GHRH bolus dose was markedly attenuated (delta GH, 2.7 +/- 0.9 ng/ml) compared to the response (delta GH, 23 +/- 3 ng/ml) after saline infusion. Dispersed rat pituicytes perifused with medium containing 10 nM GHRH-44 responded with an initial rapid rise in GH secretion, followed by a progressive decline, and after 150 min of continuous GHRH exposure, the response to pulses of an equal or higher (100 nM) GHRH concentration was blunted. These results indicate that the peak response to GHRH infusions is similar to that of maximally effective bolus doses; during infusions, the GH response is not sustained; and immediately after GHRH infusions, the response to previously effective bolus doses is reduced. These phenomena could reflect either receptor-mediated desensitization, the depletion of rapidly releasable GH stores, or both. A counterregulatory rise in hypothalamic somatostatin secretion is not necessary to produce these effects, since the same phenomenon occurs in vitro and in vivo.     

Differential effects of somatostatin (SRIH) and a SRIH analog, SMS 201-995, on the secretion of growth hormone and thyroid-stimulating hormone in man

We compared the ability of SRIH and SRIH analog, SMS 201-995 (SMS), to inhibit stimulated GH and TSH secretion in men who received 120-min iv infusions of saline, SRIH (5, 50, and 500 micrograms/h), and SMS (3, 30, and 300 ng/kg.h) together with a bolus iv injection of GHRH (1 microgram/kg) and TRH (500 micrograms). Integrated GH secretion during the 60 min after GHRH plus TRH injection was decreased compared to that after saline by (mean +/- SE) 32 +/- 14% (P = 0.059), 78 +/- 5% (P less than 0.001), and 88 +/- 3% (P less than 0.001) during the 5, 50, and 500 micrograms/h SRIH infusions, and by 13 +/- 7% (P = NS), 50 +/- 15% (P less than 0.05), and 80 +/- 6% (P less than 0.001) during the 3, 30, and 300 ng/kg.h SMS infusions. In contrast, integrated TSH secretion was unaltered during the 5 micrograms/h SRIH and 3 ng/kg.h SMS infusions; it decreased by only 43 +/- 5% (P less than 0.001) and 66 +/- 4% (P less than 0.001) during the 50 and 500 micrograms/h SRIH infusions and by 33 +/- 8% (P less than 0.05) and 50 +/- 3% (P less than 0.001) during the 30 and 300 ng/kg.h SMS infusions. Analysis of the dose-response curves indicated approximately 10- and 5-fold greater potencies of SRIH and SMS, respectively, in inhibiting GH as compared to TSH secretion. These results quantify the effect of SRIH as an inhibitor of GH secretion and suggest that if SRIH has a physiological role in the inhibition of TSH secretion in man, it is limited to conditions associated with marked suppression of GH.     

Hypothalamic somatostatin mediates the suppression of growth hormone secretion by centrally administered thyrotropin-releasing hormone in conscious rats

The effect and mechanism of action of central TRH on the regulation of GH secretion was studied in conscious male rats with indwelling intraatrial and intracerebroventricular (icv) cannulae. Plasma GH was measured every 10-20 min from 1000 h-1400 h by repeated blood sampling. In animals that received saline iv or icv, GH secretion was pulsatile, with peak hormone levels occurring at 1120-1200 h. TRH (10 micrograms), injected icv at 1100 h, inhibited spontaneous GH secretion, and mean plasma GH levels remained suppressed (less than 20 ng/ml) for at least 3 h after injection. In contrast, an iv injection of the same dose of TRH at 1100 h did not significantly affect spontaneous GH secretion. Intravenous injection of human GH-releasing factor [1-40] (hGRF, 1 micrograms) at 1100 h in animals injected 5 min earlier with saline (10 microliters, icv) stimulated GH release, with peak values (748 +/- 63 ng/ml, mean +/- SE) observed 10 min after injection. However, animals injected icv with TRH (10 micrograms) 5 min before the iv injection of hGRF exhibited an attenuated GH response to hGRF (peak values, 115 +/- 28 ng/ml; P less than 0.001 vs. saline icv + hGRF). The inhibition of GH secretion by central TRH was abolished by pretreatment of animals with antisomatostatin serum (0.5 ml, iv) but not with normal serum (P less than 0.001). These results suggest an inhibitory role of central TRH in the regulation of spontaneous GH secretion in the rat that is mediated by stimulation of hypothalamic somatostatin.     

Cholinergic mediation of growth hormone secretion elicited by arginine, clonidine, and physical exercise in man

The role of acetylcholine in human GH secretion was studied with atropine, which selectively blocks cholinergic muscarinic receptors and crosses the blood-brain barrier. Paired tests were performed in 22 normal subjects divided into 4 groups. The stimuli employed were arginine (30 g/30 min, iv), clonidine (300 micrograms, orally), physical exercise for 20 min, and saline. In the second test, atropine (1 mg, im) was administered before GH stimulation. Arginine elicited a GH secretory peak of 16.6 +/- 5 ng/ml (mean +/- SEM), which was completely blocked when atropine was administered with arginine (0.9 +/- 0.1 ng/ml). Atropine did not, however, modify the PRL secretory response; peak levels after arginine and atropine plus arginine were 16.3 +/- 3.1 and 16.8 +/- 2.5 ng/ml, respectively. Clonidine elicited a GH secretory peak (11.8 +/- 2.7 ng/ml) which also was blocked by pretreatment with atropine (1.2 +/- 0.2 ng/ml). Neither clonidine nor clonidine plus atropine altered PRL secretion. GH levels also were sharply increased after physical exercise, with a peak level of 19.4 +/- 4.9 ng/ml. Atropine completely blocked exercise-induced GH secretion (2 +/- 0.9 ng/ml). Atropine alone did not modify GH or PRL values compared with saline administration. The potency of the atropine-induced suppression of GH secretion by three different stimuli, each with presumably different mechanisms of action, suggests that acetylcholine plays an important role in the regulation of GH secretion.     

Impaired inhibitory effects of somatostatin on growth hormone (GH)-releasing hormone stimulation of GH secretion after short term infusion

We examined the effect of prior exposure to somatostatin (SRIH) on its inhibition of GH and TSH responses to GHRH and TRH stimulation to determine whether SRIH desensitization has physiological significance in man. Six men received GHRH (1 microgram/kg, iv) and TRH (0.3 microgram/kg, iv) 20 min after starting a saline or SRIH (5.5 ng/kg/min, iv) infusion and again 6 h later. Hormone responses were quantified by measuring the area under the curve, corrected for GH concentration at injection time. Similar results were obtained when GH responses were quantified by measuring the hormone secretory rate using the program Detect. Plasma GH and TSH responses to the two GHRH and TRH injections during saline were similar. However, the effects of prior exposure to SRIH were hormone specific. SRIH blunted GH responses to GHRH at 20 min (1609 +/- 286 micrograms/L.min vs. 451 +/- 224), but did not significantly inhibit the responses 6 h later (1422 +/- 410 micrograms/L.min vs. 1000 +/- 302). In contrast, SRIH inhibition of TSH responses to the two TRH injections was similar (first, 946 +/- 201 micrograms/L.min vs. 700 +/- 148; second, 813 +/- 175 micrograms/L.min vs. 562 +/- 66). We next used these results to study whether the previously reported attenuation of GH responses to repeated GHRH stimulation at 2-h intervals is mediated by SRIH. Eight men received GHRH (1 microgram/kg, iv) 380 min after starting a saline or SRIH (5.5 ng/kg/min, iv) infusion or 90 min after starting a primed (5 mg, iv) infusion of propranolol (80 micrograms/min, iv) and again 2 h later. As in the first protocol, GH responses to GHRH were not inhibited when preceded by a 6-h SRIH infusion. However, the 6-h SRIH infusion resulted in a partial restoration of plasma GH responses to the second GHRH injection (saline infusion: first, 1429 +/- 342 micrograms/L.min; second, 254 +/- 75; SRIH infusion: first, 1042 +/- 247 micrograms/L.min; second, 468 +/- 105). beta-Blockade by propranolol resulted in enhanced GH responses to GHRH, but did not prevent the attenuation of GH responses to the second GHRH injection (first, 1937 +/- 366 micrograms/L.min; second, 614 +/- 99). The desensitization to SRIH inhibition of GH responses to GHRH after a 6-h SRIH infusion provides evidence of physiological consequences of SRIH receptor down-regulation. The impaired GH responses to repeated GHRH stimulation are mediated at least in part by enhanced SRIH secretion, which appears independent of a beta-adrenergic mechanism.     

Evidence for a limited growth hormone (GH)-releasing hormone (GHRH)-releasable quantity of GH: effects of 6-hour infusions of GHRH on GH secretion in normal man

Human GH-releasing hormone [hGHRH-40 (GHRH)] stimulates GH release in a dose-dependent fashion when administered as single iv bolus doses or as continuous 90-min infusions. However, there has been variability in the GH responses, and it appears that there are waxing and waning effects of GHRH. To address whether these are a result of the dose of GHRH, time, or intermittent changes in sensitivity of the somatotrophs, we administered 6-h infusions of vehicle and different doses of GHRH to six normal men. In addition, an iv bolus injection of GHRH was given after 5.5 h of infusion to evaluate residual GH secretory capacity. The subjects were given infusions of either vehicle or GHRH (1, 3.3, and 10 ng/kg X min), followed by an iv bolus injection of 3.3 micrograms/kg on four separate occasions. GHRH infusions stimulated GH secretion compared to basal secretion. The changes from basal GH secretion (mean +/- SEM) were 2.0 +/- 1.6, 4.6 +/- 1.5, 12.7 +/- 5.1, and 8.2 +/- 1.8 ng/ml X h during the vehicle and GHRH (1, 3.3, and 10 ng/kg X min) infusions, respectively. The changes from basal GH secretion for 2 h after the iv bolus dose (after 5.5 h of infusion) were 33.3 +/- 8.7, 22.4 +/- 3.8, 14.0 +/- 3.6, and 10.5 +/- 2.0 ng/ml X h on the vehicle and GHRH (1, 3.3, and 10 ng/kg X min) infusion days, respectively. The magnitude of the GH response was inversely related to the GHRH infusion dose. The total amount of GH released during the 7.5-h study periods was not different among the vehicle and 3 GHRH infusion days. Thus, it appears that a finite amount of GH is released by GHRH. There was variability in the degree of responsiveness to the continuous infusions of GHRH. Surges of GH release occurred during the GHRH infusions, which may be attributed to intermittent secretion of a GH inhibitor, such a somatostatin.     

Growth hormone (GH) secretion during continuous infusion of GH-releasing peptide: partial response attenuation

The synthetic hexapeptide GH-releasing peptide (GHRP; SK&F 110679) specifically stimulates GH release in man. To determine the effect of a continuous GHRP infusion and whether response attenuation occurs in man, we administered to six healthy subjects a 6-h infusion of saline and three doses of GHRP, each followed by a 1.0 micrograms/kg bolus injection. GH was measured every 10 min using an immunoradiometric assay. During the saline infusion, spontaneous GH peaks occurred at variable times in four of the six subjects. During the continuous GHRP infusion, a single burst of GH release occurred with the two lower doses (0.1 and 0.3 micrograms/kg.h). With the highest dose of 1.0 micrograms/kg.h, a primary burst of GH release was followed by sporadic secretory episodes of lesser magnitude during the infusion; the GH concentrations remained above baseline before administration of the iv GHRP bolus in all six subjects. The mass of GH secreted was indirectly determined using waveform-independent deconvolution analysis. Mean GH secretion rates (micrograms per L distribution volume/h) were calculated by dividing the GH mass by the time interval. The GH secretion rates during the infusion period (0900-1430 h) were 2.40 +/- 0.68, 2.47 +/- 0.61, 7.67 +/- 1.86, and 14.75 +/- 2.32 on the saline and GHRP (0.1, 0.3, and 1.0 micrograms/kg.h) infusion days, respectively (P less than 0.05, 1.0 micrograms/kg.h vs. saline). The GH secretion rates after the iv GHRP bolus were 18.28 +/- 3.81, 19.01 +/- 2.03, 11.70 +/- 2.55, and 7.86 +/- 0.80 on the saline and GHRP (0.1, 0.3, and 1.0 micrograms/kg.h) infusion days, respectively (P less than 0.05, 1.0 micrograms/kg.h vs. saline). Compared with the saline infusion, the GH response to GHRP infusions was dose dependent (r = 0.81; P less than 0.001). The GH response to the iv bolus was inversely related to the dose of the preceding 5.5-h continuous GHRP infusion (r = -0.58; P = 0.003), and the total amount of GH secreted (constant infusion plus the bolus infusion periods) was not different among the GHRP doses. Constant GHRP infusion stimulates GH release in man, and partial response attenuation occurs with a subsequent 1.0 micrograms/kg GHRP bolus. We hypothesize that GHRP is active at multiple sites and may act as a functional somatostatin antagonist. Further studies are needed to better determine the site(s) of GHRP action and its potential use as a diagnostic and therapeutic agent.     

Effect of histamine on basal and TRH/LH-RH-stimulated PRL and LH secretion during different phases of the menstrual cycle in normal women

The neurotransmitter histamine (HA) may participate in the regulation of some pituitary hormones. We, therefore, investigated the effect of HA (50 micrograms/kg body weight/h, infusion 0-240 min) on basal and thyrotropin-releasing hormone (TRH) and luteinizing hormone releasing hormone (LH-RH) stimulated prolactin (PRL) and LH secretion in 5 normal women during the early follicular and the luteal phases of the same menstrual cycle. HA had no effect on the basal secretion of the two hormones. However, the PRL response to 200 micrograms TRH during the HA infusion was significantly increased compared to the response to a saline control infusion during the early follicular phase (peak responses were 1,902 +/- 398 vs. 1,228 +/- 230 microIU/ml, p less than 0.025) and during the luteal phase (peak responses were 2,261 +/- 335 vs. 1,647 +/- 245 microIU/ml, p less than 0.05). HA potentiated the LH response to 100 micrograms LH-RH during the early follicular phase (peak responses were 37.1 +/- 4.9 vs. 26.9 +/- 4.5 mIU/ml, p less than 0.05) and during the luteal phase (peak responses were 79.3 +/- 22.5 vs. 50.7 +/- 11.4 mIU/ml, p less than 0.025). We, therefore, found HA to have a potentiating effect on TRH/LH-RH-stimulated PRL and LH secretion in women. The results are similar to our previous findings in men, although the potentiating effects of HA were higher in women.     

Growth hormone and prolactin responses to bolus and sustained infusions of GRH-1-40-OH in man

To determine whether GRH stimulates PRL secretion we studied the effects of iv bolus injections and prolonged infusions of GRH 1-40-OH on PRL and GH serum levels in normal volunteers. Eight patients with acromegaly, two of whom had elevated basal levels of PRL, were also tested with single bolus injections. Six normal subjects given 3.3 micrograms/kg bolus injections of GRH showed a mean increment of GH of 22.0 +/- 1.7 ng/ml (mean +/- SE). A small rise in PRL was noted in 5 of the 6 subjects (mean peak level of 6.4 +/- 1.9 ng/ml vs basal level of 3.3 +/- 0.4 ng/ml, p less than 0.05). During the continuous intusion of GRH (10 ng/kg/min), GH levels rose gradually from a mean baseline of 1.1 +/- 0.1 ng/ml to a mean peak of 30.0 +/- 7.2 ng/ml at about 2 h and then slowly declined to a nadir of 4.2 +/- 0.4 ng/ml at 330 min. PRL levels did not rise significantly during the infusion. To determine whether the decline in GH levels in the face of continued infusion was due to loss of GH responsiveness, a 3.3 micrograms/kg bolus of GRH was given during the nadir at 330 min; this GH increment was significantly less than that obtained by the GRH bolus injection without the infusion (12.9 +/- 3.5 ng/ml vs 22.0 +/- 1.7 ng/ml, p less than 0.05). The PRL response to the GRH bolus was the same during the infusion of GRH as before. In each of 8 acromegalic patients (including two who had initially elevated basal PRL levels) GRH led to an increase in both GH and PRL levels. PRL and GH levels spontaneously fluctuated in parallel in 4 acromegalic cases studied with repeated samples over 6 h during placebo administration. These experiments show that GRH has significant, though weak, PRF effect in normals and that it is more potent PRF in acromegalic patients. Furthermore, the effects on GH and PRL of a sustained infusion of GRH for 5 1/2 h are both qualitatively and quantitatively different. These results suggest that the GRH effect is exerted either on different pituitary receptors for GH and PRL regulation, or that the releasable pools of the two hormones have different sizes and/or turnover times.     

EFFECT OF LOW-DOSE DOPAMINE INFUSION ON BASAL AND STIMULATED TSH AND PROLACTIN CONCENTRATIONS IN MAN

Dopamine (DA) infused at pharmacological doses in man inhibits thyrotrophin (TSH) secretion, although the physiological significance of this observation is unclear. The effect of low-dose DA infusion (0.1 microgram/kg/min) on TSH and prolactin (PRL) concentrations during stimulation with thyrotrophin releasing hormone (TRH) in normal male subjects is reported. Six subjects were given intravenous DA or placebo infusions for 165 min on separate days. A bolus of TRH (7.5 micrograms) was given at + 90 min, followed by infusion of the tripeptide (750 ng/min) for 45 min during both DA and placebo studies. In all subjects TRH administration caused a small rise in TSH which was partially inhibited by DA (peak 5.73 +/- 0.85 mU/l vs 4.58 +/- 1.09, P less than 0.05). PRL response to TRH was almost totally inhibited by DA (620 +/- 164 mU/l vs 234 +/- 96, P less than 0.05); integrated TSH and PRL responses to TRH were similarly inhibited by DA. Circulating plasma DA concentration during infusion of the catecholamine was 3.46 +/- 1.00 ng/ml, which is within the range reported in pituitary stalk plasma of other species. These data support the hypothesis that DA is a physiological modulator of TSH secretion in normal man. Major differences in the time course of TSH and PRL responses to TRH, and in the suppressive effect of DA on these responses suggest that there are fundamental differences in stimulus-secretion coupling for TRH and the lactotroph and thyrotroph.     

Effects of theophylline infusion on the growth hormone (GH) and prolactin response to GH-releasing hormone administration in acromegaly

Since theophylline has been shown to blunt the GH response to growth hormone-releasing hormone (GHRH) in normal subjects, we investigated whether the same effect of theophylline administration could be reproduced in patients with active acromegaly. Ten acromegalic patients received on two different days 100 micrograms GHRH iv alone and the same GHRH dose during a constant infusion of theophylline (3.56 mg/min), beginning 2 h before GHRH administration. In the whole group theophylline did not affect basal GH secretion significantly (from a mean of 44.6 +/- 14.4 at 0 min to 41.8 +/- 13.5 ng/ml at 120 min). However, the amount of GH released after GHRH stimulation was lower when theophylline was concomitantly infused (7525 +/- 3709 ng min/ml vs. 12038 +/- 6337 ng min/ml; p less than 0.05). The inhibitory effect of theophylline was not homogeneous, since either marked or minimal reductions of the GHRH-stimulated GH secretion occurred. Serum PRL levels increased after GHRH administration in 6 patients and theophylline infusion had no influence upon this response. Peak GHRH levels were not different in both studies (14.9 +/- 1.7 and 17.1 +/- 4.0 ng/ml, respectively). Free fatty acid levels rose progressively during theophylline administration (from 0.66 +/- 0.10 at 0 min to 1.04 +/- 0.10 mEq/l at 240 min) and were significantly higher than after GHRH stimulation alone from 180 min up to the end of the test. Our results demonstrate that in active acromegaly theophylline blunts the GH response to GHRH, though this effect is not uniformly seen in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

EFFECT OF FENOLDOPAM, A DOPAMINE D-1 RECEPTOR AGONIST, ON PITUITARY, GONADAL AND THYROID HORMONE SECRETION

The influence of fenoldopam, a dopamine (DA) D-1 receptor agonist, on basal and GnRH/TRH stimulated PRL, GH, LH, TSH, testosterone and thyroid hormone secretion was studied in nine normal men. All men received 4-h infusions of either 0.9% saline or fenoldopam at an infusion rate of 0.5 microgram/kg min, 12-16 ml/h, adjusted according to weight. After 3 h of infusion, 50 micrograms GnRH and 100 micrograms TRH was given i.v. Blood samples were collected every 15 min from 1 h before to 1 h after the infusion for a total of 6 h for measurements of PRL, LH, FSH, GH, TSH, testosterone, T4 and T3. The median PRL concentration increased significantly (P less than 0.01) to 128%, range 87-287, of preinfusion levels, compared to the decline during control infusion (85%, 78-114). Basal TSH levels declined significantly to 71% (60-91) during fenoldopam compared with 82% (65-115) during control infusion (P less than 0.05). Basal LH, FSH, GH and thyroid hormones were similar during fenoldopam and control infusions (P greater than 0.05). The LH response to GnRH/TRH was significantly (P less than 0.02) increased by fenoldopam infusion. Basal and stimulated testosterone concentration was lower during fenoldopam (P less than 0.01) infusion compared with control. Other hormones were similar after GnRH/TRH stimulation during fenoldopam and saline infusions. These results suggest that DA D-1 receptors are involved in the modulation of pituitary hormone secretion. We suggest that the effect of fenoldopam on PRL and TSH is mainly at the hypothalamic level. Regarding the effect on LH concentrations, an additional direct effect of fenoldopam on testosterone regulation can not be excluded.     

INTERACTION OF THYROTROPHIN RELEASING HORMONE AND THE ENKEPHALIN ANALOGUE DAMME ON PITUITARY HORMONE SECRETION

Because TRH counteracts the inhibitory effect of opiate peptides on LH secretion in cultured cells from normal pituitaries, six normal postmenopausal women were studied to determine whether TRH interacts in vivo with opioid peptides in the regulation of pituitary hormone secretion. At two different times a constant 3 h infusion of either saline or TRH (5 micrograms/min) was initiated. At 60 min a 250 micrograms bolus of the opiate agonist peptide D-Ala2-MePhe4-met-enkephalin-0-ol (DAMME) was injected in one of the two saline and TRH infusion tests. The four treatments, i.e. saline infusion alone, saline infusion with a DAMME bolus, TRH infusion alone; and TRH infusion with DAMME bolus were given at random with an interval of at least 7 d. Blood samples were taken every 15 min during the 3 h study. DAMME induced a significant fall (P less than 0.05) in serum LH (from 35 +/- 8.5 to 18.3 +/- 5.1 mIU/ml) (mean +/- SEM) without significantly affecting FSH levels (from 29 +/- 11.2 to 26.9 +/- 12.4 mIU/ml). These changes were not antagonized by the continuous infusion of TRH. PRL had a monophasic response pattern to continuous isolated TRH infusion; the basal levels increased from 4.2 +/- 1.2 to 24.5 +/- 6.8 ng/ml at 30 min and then slowly decreased with a plateau from 90 min until the end of the study. DAMME administration at 60 min induced a significant second peak of PRL secretion (44 +/- 6.5 ng/ml) 30 min later (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Growth hormone (GH) autofeedback on GH response to GH-releasing hormone. Role of free fatty acids and somatostatin.

Methionyl-GH (met-GH) infusions inhibit the GH response to GH-releasing hormone (GHRH). Met-GH infusions induce lipolysis with a rise of plasma FFA that are known to suppress GH release, but the met-GH inhibition of the GH response to GHRH occurs also when lipolysis is pharmacologically blocked by acipimox. In addition, the inhibition of GH release might be due to an enhanced release of hypothalamic somatostatin. The aim of this study was to evaluate the effect of a met-GH infusion on the GH response to GHRH when lipolysis and hypothalamic somatostatin release are pharmacologically blocked. Twelve normal subjects, randomly allocated to two groups (A and B), received GHRH (50 micrograms, iv) at 1300 h after a 4-h saline infusion or met-GH infusion (80 ng/kg.min). To block lipolysis and hypothalamic somatostatin release, subjects in group B received acipimox, an antilipolytic agent (500 mg), and pyridostigmine, an acetylcholinesterase inhibitor (60 mg), during the 6 h before iv GHRH. GHRH induced a clear GH release during saline infusion in both groups, significantly higher in group B (43.6 +/- 4.8 micrograms/L) than in group A (20.1 +/- 6.1 micrograms/L; P less than 0.02 vs. A), and only a slight increase during met-GH infusions (10.4 +/- 4.1 micrograms/L in group A; 16.7 +/- 4.2 micrograms/L in group B; P = NS). These data indicate that the GH response to GHRH is inhibited by met-GH infusions when peripheral lipolysis and hypothalamic somatostatin release are pharmacologically blocked, suggesting the possibility of autoinhibition of GH at the pituitary level.     

Plasma growth hormone (GH) and somatomedin C response to continuous growth hormone-releasing factor (GRF) infusion in patients with GH deficiency

Pituitary growth hormone (GH) responses during a 10-h iv infusion of saline or human GH-releasing factor (hGRF-44) at 500 ng/kg/h, followed by an iv bolus injection of hGRF-44 at 2 micrograms/kg body weight, were studied in 10 patients with GH deficiency. During saline infusion in 4 patients, small plasma GH increase were observed in 2 patients. However, during hGRF infusion in 6 patients, up to 4 or 13 pulses of GH secretion were observed. The mean integrated GH pulse area during hGRF infusion was 22.5 +/- 5.2 (SE) ng/ml X h, which was greater than that obtained during saline infusion. Plasma somatomedin C levels did not increase after hGRF infusion. After saline or hGRF infusion all patients responded to an iv bolus injection of the peptide. These results indicate that hGRF infusion augments GH secretion by increasing the number and amplitude of GH pulses and that the infusion does not cause pituitary somatotrophs to lose their capacity to respond to hGRF subsequently.     

The effect of pulsatile administration, continuous infusion, and diurnal variation on the growth hormone (GH) response to GH-releasing hormone in normal men

To examine the relative effectiveness of GH-releasing hormone (GHRH) given either as multiple iv pulses or as a continuous iv infusion, we studied the GH response to a nearly equivalent total dose of GHRH-44 administered by both routes in a group of normal men. Further, in view of the pulsatile nature of GH secretion and its augmentation with sleep, we investigated whether a diurnal difference in GH release was present during chronic pulsatile administration of GHRH during day and night. Seven men received six GHRH pulses (1 microgram/kg, iv) at 2-h intervals during both day (0900-2100 h) and night (2100-0900 h), and four underwent nighttime placebo pulsing. Eight men received a daytime continuous GHRH infusion (0.15 microgram/kg X h for 5 h, followed by 0.75 microgram/kg X h for 5 h) and a separate 10-h placebo infusion. The GH response to a bolus dose of GHRH (1 microgram/kg, iv) was determined after both continuous GHRH and placebo infusions. No significant difference was found in the GH area response (mean +/- SEM) during total day and night GHRH pulsing periods (6095 +/- 1192 vs. 6506 +/- 1483 ng/min X ml; P = NS). GH secretion was blunted after the initial daytime GHRH pulse (P = 0.02), and only two of seven men had a GH increase after the second pulse; responsiveness was restored after the fourth pulse. In contrast, all subjects responded to the second nighttime GHRH pulse. During continuous GHRH infusions, GH secretion was unsustained and pulsatile. The incremental GH response to a single GHRH bolus dose was decreased after GHRH infusion compared to that after placebo (4.4 +/- 1.8 vs. 10.3 +/- 3.4 ng/ml; P less than 0.05). No difference was found in the total GH area response to a nearly equivalent dose of GHRH administered as either multiple pulses or continuous infusion followed by a single GHRH bolus dose. The apparent pulsatile nature of GH secretion during continuous GHRH infusion and the lack of a significant difference in the GH response to a nearly equivalent dose of GHRH administered as either multiple pulses or a continuous infusion suggest that GHRH need not be administered in a pulsatile manner to be an effective therapeutic agent for the stimulation of GH secretion in children with hypothalamic GHRH deficiency.     

Effect of overnight constant infusion of human growth hormone (GH)-releasing hormone-(1-44) on 24-hour GH secretion in children with partial GH deficiency

A continuous infusion (0.5 or 1 microgram/kg X h) of GH-releasing factor-(1-44) [GHRH-(1-44)] was administered from 2000-0800 h to 16 children with GH deficiency, defined as a maximum peak plasma GH less than 11 ng/ml in response to 2 provocative tests [first test; mean, 7.4 +/- 2.6 (+/- SD) ng/ml; second test; mean, 8.4 +/- 2.4 ng/ml]. Eight were boys and 8 girls; their average age was 10 yr, 5 months; and growth was retarded in all [mean, -3 +/- 0.6 (+/- SD)]. Polygraphic monitoring was carried out during the night, and blood samples for plasma GH measurements were drawn every 20 min during the night and the following day. A control study had been carried out in the preceding months with the same children. During GHRH infusion, a significant increase in nocturnal GH secretion occurred; the mean maximum peak increased from 17.5 +/- 3.4 (+/- SD) to 38.7 +/- 3.2 ng/ml, the mean area under the curve from 2243 +/- 459 to 5348 +/- 710 ng/ml, the mean integrated concentration from 4.2 +/- 0.8 to 9.9 +/- 1.3 ng/ml X min, and the mean number of peaks above 5 ng/ml from 2.7 +/- 0.3 to 4.7 +/- 0.4. During GHRH infusion, the 16 children had 2 peaks during the first 4 h of sleep and a third peak at the end of the night. Plasma GH levels the day after the infusions were not significantly increased. We conclude that continuous nocturnal GHRH infusion increases pulsatile sleep GH secretion throughout the night in children with partial GH deficiency.     

Growth hormone and prolactin secretion by dispersed cell cultures of a normal human pituitary: effects of thyrotrophin releasing hormone, theophylline, somatostatin, and 2-bromo-alpha-ergocryptine

Growth hormone (GH) and prolactin (Prl) secretion by a normal human pituitary in dispersed cell culture has been investigated. Prl secretion was significantly stimulated after 0.5, 1, 2 and 4 h exposure to 1, 10, 100 and 1000 ng/ml thyrotrophin releasing hormone (TRH). Maximal effects were obtained with 10 ng/ml TRH at 2 h, higher doses being less effective. GH secretion was unchanged with the exception that 1 ng/ml TRH produced a small decrease at 4 h. GH and Prl secretion was significantly inhibited by incubation with 0.01, 0.1, 1 or 10 micrograms/ml 2-bromo-alpha-ergocryptine (bromocriptine). The inhibition persisted for a further 24 h after removal of bromocriptine. Theophylline (10(-2) M) significantly increased GH and Prl secretion during a 4 h incubation and this effect was blocked by co-incubation with 10 ng/ml somatostatin (SRIF). SRIF also inhibited basal GH and Prl secretion during 4 h and removal of SRIF and incubation for at further 4 h led to a rebound in GH and Prl secretion to levels greater than control. It is concluded that cell culture techniques previously applied to the study of hormone secretion by pituitary adenomas can be equally applied to the normal human pituitary.