Long-term treatment with 2-Br-alpha-ergocryptine in acromegaly.

Thirty acromegalic subjects underwent chronic CB154 therapy (10-20 mg daily) for periods ranging from 3 months up to 2 years. In 18 out of 21 patients, who exhibited consistent HGH reduction following acute administration of the drug, there was also during chronic treatment, a suppression of the plasma HGH levels exceeding 50% of base line values, e.g. from mean daily values between 14-197 ng/ml (mean +/- SEM = 57.8 +/- 12.4 ng/ml pre-treatment) to 2-19 ng/ml (mean 8.3 +/- 1.2 ng/ml post-treatment). In 12 of the subjects who responsed to chronic CB154 treatment, the mean daily values of HGH were below 10 ng/ml. The suppression of plasma HGH was maintained unaltered throughout the whole course of therapy. In the 9 subjects, in whom no consistent HGH decrease was evidenced with acute CB154 administration, there was accordingly a minor or no suppression of HGH values during the chronic treatment. In 13 subjects, irrespective of the degree of their GH responses, the plasma prolactin levels were constantly inhibited by CB154; instead the drug failed to modify significantly the TRH or insulin-induced GH release. These changes in the hormonal parameters were paralleled by marked clinical amelioration and improvement of some of the metabolic alterations frequently encountered in acromegaly, e.g. reduced carbohydrate tolerance, increased insulin resistance, diminished fall of plasma phosphorus after insulin, decreased urinary excretion of phosphate, hyper-hydroxyprolinuria and hyper-calciuria. Collectively, these data demonstrate that CB154 thrapy is effective in reducing HGH hyper-secretion in many acromegalic patients during long-term treatment.     

Effects of nomifensine on growth hormone and prolactin secretion in normal subjects and in pathological hyperprolactinemia

We have studied the effect of the oral administration of 200 mg nomifensine (nom), a drug which activates the dopaminergic system, on GH and PRL secretion in 15 normal subjects, 18 patients with idiopathic hyperprolactinemia, and 17 patients with tumoral hyperprolactinemia. GH levels increased significantly after nom in normal subjects (basal, 0.96 +/- 0.76 ng/ml; peak 4.6 +/- 0.61 ng/ml; P less than 0.01) and patients with hyperprolactinemia, both idiopathic (basal, 1.0 +/- 0.38 ng/ml; peak, 4.2 +/- 1.0 ng/ml; P less than 0.05) and tumoral (basal 0.88 +/- 0.3 ng/ml, peak 6.68 +/- 1.2 ng/ml; P less than 0.01). Peak GH levels higher than 5 ng/ml were observed in 8 of 15 normal subjects, 6 of 18 patients with idiopathic hyperprolactinemia, and 8 of 17 patients with tumoral hyperprolactinemia. PRL levels decreased in response to nom in normal subjects, but not in patients with idiopathic or tumoral hyperprolactinemia. A reduction in plasma PRL levels of at least 30% below the baseline was observed only in two patients with idiopathic hyperprolactinemia and in none of the patients with tumoral hyperprolactinemia. These results demonstrate that nom does not discriminate between idiopathic and tumoral hyperprolactinemia. Since nom probably requires a hypothalamic pool of dopamine to bring about its GH stimulatory effect, the suggestion that the lack of a PRL-lowering effect of the drug is attributable to a dopamine deficiency is not supported by our data.     

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.     

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.     

Growth hormone (GH) and prolactin responses to repetitive administration of GH-releasing hormone in acromegaly

We investigated the pattern of GH secretion in response to repetitive GH-releasing hormone (GHRH) administration in patients with active acromegaly and in normal subjects. Twelve acromegalic patients (nine women and 3 men; aged 21-76 yr) were studied. Eight had never been treated, whereas four had undergone neurosurgery but still had active disease. All patients and eight normal subjects received three doses of 50 micrograms GHRH, iv, at 2-h intervals. Seven patients were retested 6-8 weeks after transsphenoidal removal of a pituitary adenoma. There was a marked serum GH rise in acromegalic patients and normal subjects after the first GHRH dose [area under the curve, 2070 +/- 532 (+/- SE) vs. 1558 +/- 612 ng/min X ml, respectively; P = NS]. Successive GHRH doses stimulated GH release only in acromegalic patients (second dose, 1123 +/- 421 ng/min X ml; third dose, 2293 +/- 1049 ng/min X ml). In normal subjects, the GH response to the second and third GHRH doses was blunted (second dose, 86 +/- 32 ng/min X ml; third dose, 210 +/- 63 ng/min X ml; P less than 0.01). PRL secretion did not change in normal subjects, whereas 6 of 12 acromegalic patients had PRL release after each GHRH dose (PRL responders to GHRH). Transsphenoidal surgery led to normalization (less than 5 ng/ml) of the preoperatively elevated GH levels in all but 2 patients, who, however, had reduction of somatomedin-C levels. The amount of GH released in the postoperative test was significantly lower than that released preoperatively (first dose, 722 +/- 209 vs. 2945 +/- 743 ng/min X ml; second dose, 358 +/- 117 vs. 1737 +/- 633 ng/min X ml; third dose, 320 +/- 144 vs. 1776 +/- 676 ng/min X ml, respectively; P less than 0.05 in all instances). Thus, patients with active acromegaly, but not normal subjects, respond to repetitive GHRH administration at 2-h intervals with an increase in GH levels. This increase may be due to a larger releasable GH pool and/or faster GH turnover in the adenomatous cell.     

Decreased growth hormone (GH) response to oral clonidine in endemic cretinism: effect of L-T3 therapy

As GH secretion is dependent upon thyroid hormone availability, the GH responses to clonidine (150 micrograms/m2) and the TSH and PRL response to TRH were studied in eight endemic (EC) cretins (3 hypothyroid, 5 with a low thyroid reserve) before and after 4 days of 100 micrograms of L-T3. Five normal controls (N) were also treated in similar conditions. Both groups presented a marked increase in serum T3 after therapy (N = 515 +/- 89 ng/dl; EC = 647 +/- 149 ng/dl) followed by a decrease in basal and peak TSH response to TRH. However, in the EC patients an increase in serum T4 levels and in basal PRL and peak PRL response to TRH after L-T3 therapy was observed. One hypothyroid EC had a markedly elevated PRL peak response to TRH (330 ng/dl). There were no significant changes in basal or peak GH values to treatment with L-T3 in normal subjects. In the EC group the mean basal plasma GH (2.3 +/- 1.9 ng/ml) significantly rose to 8.8 +/- 3.2 ng/ml and the mean peak response to clonidine (12.7 +/- 7.7 ng/ml) increased to 36.9 +/- 3.1 ng/ml after L-T3. Plasma SM-C levels significantly increased in N from 1.79 +/- 0.50 U/ml to 2.42 +/- 0.40 U/ml after L-T3 (p less than 0.01) and this latter value was significantly higher (p less than 0.05) than mean Sm-C levels attained after L-T3 in the EC group (respectively: 1.14 +/- 0.59 and 1.78 +/- 0.68 U/ml). These data indicate that in EC the impaired GH response to a central nervous system mediated stimulus, the relatively low plasma Sm-C concentrations, and the presence of clinical or subclinical hypothyroidism may contribute to the severity of growth retardation present in this syndrome.     

Effect of oral administration of L-dopa on the plasma levels of growth hormone-releasing hormone (GHRH) in normal subjects and patients with various endocrine and metabolic diseases

The responses of plasma growth hormone-releasing hormone (GHRH) and growth hormone (GH) to oral administration of L-dopa were studied in normal subjects and patients with various endocrine and metabolic diseases to clarify the pathophysiological role of the GHRH-GH axis. In normal subjects, the plasma GHRH concentration was increased from the basal value of 9.8 +/- 1.4 pg/ml (mean +/- SE) to 34.8 +/- 3.1 pg/ml at 30 approximately 90 min after oral administration of 500 mg L-dopa, followed by a rise of GH release (plasma GH level from less than 1 ng/ml to 21.7 +/- 4.7 ng/ml) in most cases, indicating that L-dopa stimulates GH secretion via hypothalamic GHRH. On L-dopa administration, no apparent increases in both plasma GHRH and GH concentrations were observed in patients with hypothalamic hypopituitarism, whereas GHRH administration induced almost normal GH response. In patients with acromegaly, the plasma levels of GHRH remained stationary after the L-dopa administration and did not correlate with plasma GH levels. In subjects with simple obesity, the responses of plasma GHRH (peak 13.2 +/- 1.2 pg/ml) and GH (peak 4.3 +/- 1.7 ng/ml) to L-dopa were significantly lower than those in normal subjects (p less than 0.01). In patients with primary hypothyroidism, peak levels of plasma GHRH (12.6 +/- 1.3 pg/ml) and GH (2.4 +/- 0.6 ng/ml) were significantly lower than those in normal subjects (p less than 0.01). In patients with non-insulin dependent diabetes mellitus (NIDDM), the responses of GHRH and GH were divided into 2 groups; in the responder the peak values of GHRH and GH were 19.4 +/- 8.6 pg/ml and 12.2 +/- 1.4 ng/ml and in the low or non responder 14.7 +/- 1.5 pg/ml and 2.0 +/- 0.6 ng/ml, respectively. Between both groups, there was a significant difference in the values of fasting blood sugar and HbA1 and mean suffering period. These findings suggest that GH secretion evoked by the L-dopa administration is induced by GHRH released from the hypothalamus, and impairment of GH secretion associated with simple obesity, primary hypothyroidism, or NIDDM may be in part attributed to insufficiency of GHRH release from the hypothalamus, and indicate that L-dopa test is clinically useful for evaluating the ability of intrinsic GHRH release in such diseased states.     

Somatotroph responsiveness to low dose dopamine infusion in normal subjects and acromegalic patients

We have investigated the effects of intravenous administration of a low dose of dopamine (DA) on plasma growth hormone (GH) concentrations in acromegalic patients and normal subjects with the aim of defining the somatotroph responsiveness to peripheral (i.e., outside the blood-brain barrier) specific dopaminergic stimuli. DA (0.02 micrograms/kg/min) was infused for 180 min into 12 acromegalic patients and 10 normal subjects. DA infusion discriminated between two groups of acromegalics. In group I (n = 7), the elevated plasma GH levels (64.1 +/- 29.9 ng/ml, mean basal value +/- SEM) decreased significantly (mean overall GH inhibition, 26% reduction from basal levels; range, 10-49), whereas in group II (n = 5) plasma GH levels (29.8 +/- 12.5 ng/ml) remained elevated (mean GH variation, 8% above baseline; range, 0-15). Plasma GH concentrations showed a significant rebound above baseline values after stopping DA infusion only in group I. In contrast, the responsiveness to TRH was not significantly different between the groups (percentage increase 767 +/- 317% in group I vs. 382 +/- 210% in group II) and they were also comparable with regard to sex, age, glucose tolerance, plasma prolactin (PRL) concentrations and adenoma size. However, the mean duration of the disease was significantly (p less than 0.02) longer in group I (12.8 +/- 2.6 years) than in group II (4.5 +/- 1.5 years). Further, 3 patients with previous radiotherapy for invasive adenomas were nonresponders to DA. In normal subjects, DA infusion had no significant effect on plasma GH levels. It is concluded that: somatotroph responsiveness to DA is not a constant feature of acromegaly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Subnormal prolactin responsiveness to thyrotropin-releasing hormone (TRH) in women with primary empty sella syndrome

Basal prolactin (PRL) levels and PRL responsiveness to thyrotropin-releasing hormone (TRH) were studied in 10 women with primary empty sella (PES) syndrome (mean age 38.2 yr). Hyperprolactinemia (34 to 72 ng/ml) was found in 5 patients (hyperprolactinemic PES, H-PES), whereas 5 patients showed normal (9.5 to 19 ng/ml) PRL levels (normoprolactinemic PES, N-PES). The results were compared with those obtained in 10 healthy women (mean age 32.8 yr, PRL = 7 to 15 ng/ml) and in 8 women with a PRL-secreting pituitary microadenoma (MA) (mean age 37.5 yr, PRL = 39 to 85 ng/ml). The mean basal levels of PRL were significantly higher in patients with H-PES (50.8 +/- 13.2 ng/ml) or MA (64.0 +/- 18.3 ng/ml) than in the control group (10.9 +/- 2.6 ng/ml, p less than 0.02) and in the patients with N-PES (13.9 +/- 3.7 ng/ml, p less than 0.02). In contrast, the relative maximum response (RMR) of PRL to TRH (peak PRL/basal PRL) was significantly lower in the patients with PES (both H-PES and N-PES) or MA (1.4 +/- 0.4, 2.3 +/- 0.7 and 1.2 +/- 0.2, respectively) than in the control subjects (3.6 +/- 1.1; p less than 0.02, less than 0.05 and less than 0.02, respectively). Our results show that the pituitary responsiveness to the acute stimulation with TRH is significantly decreased both in patients with a PRL-secreting pituitary MA and in those with PES. Therefore, the clinical value of the TRH test in distinguishing the PES syndromes from prolactinomas seems to be questionable.     

Influence of norepinephrine administration upon pituitary hormone secretion in normal men

This study has investigated the effects of 6.2, 12.5, 25, 50 and 100 ng/kg/min/60 min of NE infused to normal men. Blood samples were obtained every 10 min, before, during and after drug administration for 3 consecutive h. Plasma levels on NE, LH, FSH, PRL, and GH were measured in all samples. The administration of 12.5 ng/kg/min over 60 min of NE induced a significant increase (p less than 0.001) in plasma NE levels (n = 5) from a mean (+/- SE) baseline of 239 +/- 14 ng/L to 706 +/- 54 ng/L which peaked and plateaued at 40 min. The calculated area under the curve was 18562 +/- 3537 ng/L/h of NE and significantly higher (p less than 0.001) than during the h before the infusion (2358 +/- 780 ng/L/h). This increase in plasma NE correlated well with the rise in plasma LH which showed a steady increase from baseline of 7.4 +/- 1.3 mIU/ml to a significant (p less than 0.05) peak of 11 +/- 1.9 mIU/ml at the end of the infusion. Furthermore, analysis of the area under the curve revealed a greater (p less than 0.05) LH release during the NE infusion (180 +/- 18 mIU/ml/h) than before the infusion (92 +/- 17 mIU/ml/h). With the exception of the studies utilizing 12.5 ng/kg/min/60 min, all other doses of NE resulted in no significant and/or consistent changes in plasma concentration of LH, FSH, GH and PRL. Thus, the direct participation of NE in the control of LH secretion in humans seems to occur in a very narrow window.     

Exaggerated growth hormone response to arginine infusion in Huntington's disease.

Growth hormone regulation was studied in 10 patients with Huntington's disease after intravenous administration of arginine. In 20 control subjects arginine infusion resulted in a rise of plasma growth hormone levels from a mean baseline value of 3.2+/-0.6 ng/ml to a peak level of 17.6+/-2.7 ng/ml at 60 min. Growth hormone rise in the majority of patients with Huntington's disease was clearly intact and significantly greater than normal in magnitude, increasing from the baseline level of 2.6+/-0.5 ng/ml to a peak level of 28.3+/-3.7 ng/ml at 60 min (P = less than 0.05). Carbohydrate tolerance of these patients was previously examined, and 4 with normal glucose tolerance and normal insulin responses to arginine infusion had growth hormone levels significantly higher than controls at 30 min. Six patients with impaired carbohydrate tolerance and exaggerated insulin responses to arginine had significantly higher growth hormone responses at 30 min and also at 60 min. Neuronal degeneration of several hypothalamic nuclei has been reported in Huntington's disease. The observations that growth hormone responds in an exaggerated fashion to stimulation by arginine infusion or falling glucose levels as previously described may be explained by intrahypothalamic dysfunction such as impairment of somatostatin secretion.     

GROWTH HORMONE AND PROLACTIN SECRETION AFTER GROWTH HORMONE-RELEASING HORMONE ADMINISTRATION, IN ANOREXIA NERVOSA PATIENTS, NORMAL CONTROLS AND TAMOXIFEN-PRETREATED VOLUNTEERS

Anorexia nervosa is associated with several abnormalities in GH secretion elicited by different stimuli. To investigate the precise mechanism of this alteration, GHRH was administered to 14 women: a group of eight anorexia nervosa patients in the acute phase of their illness and a control group of six age-matched volunteers. As patients with anorexia nervosa have chronic low oestrogen values, the volunteer women of the control group underwent a second GHRH test after pretreatment with the oestrogen receptor blocker tamoxifen. GHRH 1-29 (1 μ g/kg i.v.) induced a GH peak (mean±SEM) of 28.2 ±5.1 ng/ ml (GH ng/ml ± 2 = mU/l) at 30 min in the anorectic patients. This value was no different from the GHRH-stimulated GH peak in the control women (28.1 ± 100 ng/ml). Tamoxifen pretreated women had a GH peak after GHRH of 35.6 ± 9.7 ng/ml, not significant versus control test. Compared with the control group, oestrogen levels were significantly lower in anorectic patients and higher in tamoxifen-treated women. GHRH administration induced a small PRL peak at 15 min that was similar in the three groups tested. After this 15 min peak, PRL in both anorexic and tamoxifen-treated women returned toward basal values steadily. However, in untreated control women a second PRL peak was evident at 60 min. In conclusion, GHRH-induced GH secretion in anorexia nervosa patients was similar to that in control subjects and in controls under oestrogen receptor blockade.     

Effect of the new ergot derivative terguride on plasma PRL and GH levels in patients with pathological hyperprolactinemia or acromegaly

Terguride, a derivative of lisuride, has been shown to possess a mixed dopaminergic-antidopaminergic activity in experimental models. We have studied the effects on PRL and GH levels of 0.2 mg po of terguride in 8 normal subjects, in 15 patients with pathological hyperprolactinemia (PHP) and in 17 patients with active acromegaly. In PHP, PRL levels were significantly reduced up to 300 min after terguride with a nadir (45 +/- 4.0% SE) significantly lower (p less than 0.05) than the one observed in the 8 normal subjects (72 +/- 3.5%). There was no significant difference in plasma PRL levels after 0.2 mg terguride or lisuride in 7 out of 15 patients tested with both drugs. Terguride did not significantly modify GH levels in PHP and in normals but when considering basal and peak (occurring between 60 and 150 min) GH values, a significant difference was found (p less than 0.01). Mean peak of GH did not differ significantly between PHP (5.0 +/- 1.1 ng/ml) and normals (6.8 +/- 1.7 ng/ml). Plasma GH levels of 17 acromegalics were not modified by 0.2 mg of terguride but were significantly reduced by 2.5 mg of bromocriptine. Terguride and bromocriptine reduced PRL levels in acromegalics (p less than 0.01) without any significant difference between the two drug. 0.2 mg terguride bid given for 15 days to 7 healthy volunteers significantly reduced both basal and sulpiride (25 mg im)-stimulated PRL levels. Side effects were observed only in 4 out of 47 subjects tested with terguride and in 8 out of 34 tested with bromocriptine.     

Growth hormone and somatomedin-C response to synthetic human pancreatic tumor GH-releasing factor in hypopituitary and constitutionally short children

GH and somatomedin-C response to acute hpGRF-44 iv administration (1 microgram/Kg bw) was studied in 16 patients with hypopituitarism (GHD) and in 7 constitutionally short subjects. GH-deficient patients evidenced a significant GH increase peaking between 15 and 60 min. (4.95 +/- 0.88 ng/ml, mean +/- SE) (p less than 0.01 vs placebo). In non GH-deficient subjects GH increase was more pronounced (peak 18.00 +/- 3.01 ng/ml; p less than 0.01 vs both placebo and GHD group). Acid-extractable somatomedin-C was slightly, but significantly higher than baseline at 12th h (p less than 0.01) in both patients with hypopituitarism (basal value: 0.067 +/- 0.021 U/ml; 12 h: 0.096 +/- 0.024 U/ml) and constitutionally short subjects (basal value 0.62 +/- 0.13; 12h 0.72 +/- 0.16 U/ml). In 3 subjects with hypopituitarism multiple iv administrations (1 microgram/kg bw at 09:30 and 21:30 h for 4 days) produced on the average a modest increase of the GH responsiveness, were more effective to enhance somatomedin-C concentration, but not sufficient to reach normal levels. Sc administration of the same dose at 4-h intervals by a programmable portable pump - performed on 6 GHD subjects - produced an increase of GH peak response on the 4th day of treatment (1.38 +/- 0.31 ng/ml) with respect to the one observed on the first day (0.42 +/- 0.09 ng/ml). Somatomedin-C increase was low and inconstant. These data support the use of a 4-5-day pulsatile treatment in the differentiation between hypothalamic and pituitary deficiency, and the possibility of therapeutical use of GRF with the same protocol when a response is evidenced.     

The effect of synthetic human pancreatic growth hormone-releasing factor (hpGRF-44) on serum growth hormone response in normal and obese subjects

Synthetic human pancreatic growth hormone-releasing factor (hpGRF-44) was given by i.v. bolus injection to 15 normal non-obese and 32 obese subjects who were divided into two groups according to their ages--group A: young subjects, 20-50 yrs., and group B: old subjects, more than 60 yrs. In normal subjects, hpGRF-44 had no effect on the secretion of PRL, TSH, LH, FSH, IRI and cortisol. hpGRF-44 stimulated GH secretion selectively. However, the serum GH responses were different between the young and old groups, the peak GH levels being significantly higher in the young group than in the old group (20.1 +/- 4.2 vs. 7.5 +/- 1.6 ng/ml; group A vs. B; p less than 0.05). At the doses of 0.5, 1.0, 2.0 and 4.0 micrograms/kg B.W., the serum GH responses were similar in an individual subject. In young obese subjects, the peak GH levels to hgGRF-44, 1.0 microgram/kg B.W. were significantly lower than those in young normal subjects (4.3 +/- 0.6 vs. 20.1 +/- 4.2 ng/ml; obese vs. normal; p less than 0.01). In old subjects, the peak GH levels to hpGRF-44, 1.0 microgram/kg B.W. were similarly diminished in both normal and obese subjects. However, the integrated response of GH was significantly lower in obese subjects than in normal subjects (405.9 +/- 58.7 vs. 755.9 +/- 134.2 ng X min/ml; obese vs. normal; p less than 0.05). In 5 young obese subjects, regular insulin (RI) injection (0.15 U/kg B.W.) and arginine drip infusion (0.5 g/kg B.W.) alone, and simultaneous injection of hpGRF-44, 1.0 microgram/kg B.W. and RI, 0.15 U/kg B.W. were done. In these subjects, GH responses to RI or arginine infusion were diminished as in the case of hpGRF-44 administration, whereas the peak GH levels were higher in the RI stimulation. The combination of hpGRF-44 and RI partially restored GH response. (peak GH levels; 14.6 +/- 0.8 ng/ml). These results confirm the age difference of serum GH response to hpGRF-44 and also indicate that obese subjects show low or no response to hpGRF-44 administration. The fact that insulin hypoglycemia induced larger serum GH response that hpGRF-44 in obese subjects may suggest the existence of GH-releasing substances other than hpGRF-44.     

DOPAMINERGIC CONTROL OF GONADOTROPHIN SECRETION IN NORMAL WOMEN AND IN PATIENTS WITH PATHOLOGICAL HYPERPROLACTINAEMIA

The role of dopaminergic mechanisms in the control of gonadotrophin secretion in normal and hyperprolactinaemic subjects is controversial. Whilst bromocriptine, a potent dopamine agonist, has been used to restore normal gonadotrophin secretion in subjects with pathological hyperprolactinaemia (PHP), dopamine and dopamine agonists have been reported to suppress basal and stimulated gonadotrophin release. We therefore investigated the importance of dopaminergic control of gonadotrophin secretion by studying LH, FSH and PRL responses in normal and PHP subjects to central dopamine synthesis inhibition using monoiodotyrosine (MIT) and to a 4 h dopamine infusion designed to elevate peripheral plasma dopamine concentration to levels reported for pituitary portal plasma (1-6 ng/ml). MIT administration resulted in a significant release of PRL (peak increment 520 +/- 84% above basal) but not of LH or FSH in normal subjects. In PHP subjects there was a blunted PRL response (peak 13.3 +/- 3.5%) to MIT administration and significant LH (P less than 0.05) but not FSH release. Dopamine infusion (0.5 microgram/kg/min) resulted in suppression of PRL (min 19 +/- 3% of basal) but not of LH or FSH. A rebound of PRL (peak 188 +/- 68% of basal) but not LH or FSH occurred on cessation of dopamine. There was an apparent rise in LH (P less than 0.02 vs. normals) but not FSH in PHP patients during dopamine infusion. Plateau dopamine levels achieved during the infusion were 2.9 +/- 0.3 ng/ml and 5.9 +/- 0.8 ng/ml in normal and PHP subjects respectively. The responses to MIT show that dopamine functions as an inhibitor of PRL but not of LH or FSH in normal subjects. In PHP patients the responses suggest increased dopaminergic inhibition of LH release but loss of inhibitory control of PRL release. Physiological concentrations of plasma dopamine do not significantly inhibit LH or FSH release in normal subjects but paradoxically results in an apparent release of LH in PHP patients. We conclude that dopamine mechanisms do not play a significant role in modulating gonadotrophin release in normal subjects. In PHP patients, PRL feedback results in increased hypothalamic dopamine activity which in turn inhibits LH release. We conclude that the inhibitory action of dopamine on PRL release restores LH secretion by removing central dopaminergic inhibition through hypothalamic feedback of PRL.     

Dopamine affects basal and augmented pituitary hormone secretion.

Although the role of the neurotransmitter, dopamine (DA), in the regulation of PRL has been well documented, controversy exists regarding its participation in the regulation of the other pituitary hormones. Consequently, we infused DA into six healthy male subjects (ages 19-32) and studied its effects on both basal pituitary hormone levels and augmented hormonal release induced by insulin hypoglycemia (ITT), TRH, and gonadotropin-releasing hormone (GnRH). DA alone produced a modest though significant increase in GH concentration from 2.2 +/- 0.5 to 11.9 +/- 3.7 ng/ml (P less than 0.05) by 60 min, but the peak incremental GH response to ITT was significantly inhibited by DA (43.5 +/- 5.0 vs. 16.3 +/- 3.3 ng/ml; P less than 0.01). PRL concentrations fell during the DA infusion (20.4 +/- 3.0 to 10.6 +/- 1.5 ng/ml; P less than 0.02) at 235 min, and the PRL responses to both ITT and TRH were completely abolished. Although the basal LH and FSH concentrations were unaffected by DA, the incremental LH response to GnRH was inhibited (45.5 +/- 10.6 to 24.4 +/- 5.4 mIU/ml; P less than 0.05), while the FSH response was unchanged. DA significantly reduced the basal TSH concentration from 3.9 +/- 0.2 to 2.5 +/- 0.2 micro U/ml (P less than 0.01) at 230 min and blunted the peak incremental TSH response to TRH (6.0 +/- 1.5 vs. 2.9 +/- 0.9 microU/ml; P less than 0.01). DA had no effect on basal cortisol levels, the cortisol response to ITT, basal plasma glucose, or the degree of hypoglycemia after ITT. Our data provide new evidence that DA has an inhibitory as well as a stimulatory role in the regulation of GH secretion in normal humans. It inhibits centrally as well as peripherally mediated PRL secretion and blunts the LH response to GnRH. In addition, DA lowers both basal and TRH-mediated TSH release, confirming the reports of other investigators.     

Evaluation of the dopaminergic neuroendocrine control of prolactin release during labor in humans

Eight women with normal term pregnancy were i.v. administered 10 mg Metoclopramide (M), dopamine antagonist, before and during labor. Serum prolactin (PRL), TSH, GH and cortisol levels were measured at -30, 0, 30 and 60 minutes after M administration by specific radioimmunoassay. Basal serum PRL levels before labor, 287.5 +/- 28.6 ng/ml (mean +/- S.E.), significantly declined during labor to 237.0 +/- 22.4 and 216.4 +/- 22.9 ng/ml (p less than 0.05 at both) at 0 and 30 minutes before M administration, respectively. The increments in serum PRL at 30 and 60 minutes after M administration during labor (209.5 +/- 33.9 and 120.0 +/- 27.1 ng/ml, respectively) were not significantly different from those before labor (202.1 +/- 48.7 and 89.9 +/- 30.1 ng/ml, respectively), suggesting that the decline in serum PRL levels during labor is not due to the dopaminergic control. Basal serum TSH and GH levels were not significantly changed by labor and M administration either before or during labor. Serum cortisol levels tended to increase during labor, but these changes were not significant. The data suggest that the PRL releases from the pituitary during labor are not controlled by the dopaminergic mechanism.     

Naloxone inhibits exercise-induced release of PRL and GH in athletes

Opiate peptides stimulate the release of GH and PRL, and such changes have also been reported following physical exercise. To investigate opiate involvement in the exercise-induced release of these hormones, eight professional athletes were exercised to 80% of their maximal heart rate on a bicycle ergometer. This exercise alone induced an increase in circulating mean GH (basal to maximal level, 3.1 +/- 0.9 ng/ml-27.3 +/- 5.9 ng/ml) and mean PRL level (6.1 +/- 1.1 ng/ml-19.5 +/- 1.9 ng/ml). Infusion of naloxone (0.3 mg/min) antagonized these responses in mean serum GH (5.6 +/- 1.0 ng/ml to 8.6 +/- 1.1 ng/ml) and PRL levels (6.4 +/- 1.1 ng/ml-8.1 +/- 1.2 ng/ml), which were both significantly less than during the control infusions (P less than 0.01). It is suggested that certain forms of stress stimulate the release of PRL and GH via endogenous opiate peptides.     

Effect of 1-5 hydroxytryptophan infusion on growth hormone and prolactin secretion in man.

The effect of a new soluble ester of 1-5 hydroxytryptophan (1-5 HTP, Ro 3-5940, 200 mg infusion) on prolactin (PRL) and growth hormone (GH) release was tested in 11 young, healthy subjects (6 men, 5 women). To minimize side-effects, peripheral decarboxylase inhibition was achieved with benserazide (Ro 4-4602.) PRL increased significantly (P less than 0.01) after benserazide alone in all subjects. A further significant increase (P less than 0.01) of PRL plasma levels occurred only in women up to 90 min after the infusion of 1-5 HTP was discontinued. Benserazide administration had no effect of basal GH levels, but a significant increase of GH release (P less than 0.01) was noticed 30-120 min after the end of 1-5 HTP infusion in both men and women. The mean peak value of GH plasma levels after 1-5 HTP administration was 32.0 +/- 8.8 ng/ml. It was postulated that benserazide penetrated at the level of the pituitary, decreasing the synthesis of dopamine and consequently reducing its known inhibitory effect on PRL release. The PRL increase (statistically significant only in women), as well as the release of GH after 1-5 HTP infusion, was considered as further evidence for stimulatory serotoninergic control of both PRL and GH secretion.