FAILURE OF NALOXONE TO ALTER GROWTH HORMONE AND PROLACTIN LEVELS IN ACROMEGALIC AND IN HYPERPROLACTINAEMIC PATIENTS

We examined the effects of high-dose intravenous naloxone administration in four acromegalic patients (mean serum growth hormone level 72 ng/ml) and in seven hyperprolactinaemic women (mean serum prolactin level 59 ng/ml), in order to assess whether this opiate antagonist would be effective in lowering growth hormone and prolactin levels. No effect was observed. This lack of effect suggests that an opioid pathway is not involved in the maintenance of elevated growth hormone or prolactin secretion in these patients. However, conclusions regarding the possible role of endogenous opioids in regulation of pituitary function in normal individuals cannot be drawn from this study.     

SERUM GROWTH HORMONE AND ULTRASTRUCTURAL STUDIES OF ADENOHYPOPHYSIAL TISSUE IN BROMOCRIPTINE TREATED ACROMEGALIC PATIENTS

The therapeutic effectiveness of bromocriptine as well as the post-operative ultrastructural aspects of treated pituitary adenomas were investigated in five acromegalic patients. Although concentrations of GH basal decreased and the glucose tolerance test and the TSH responses were significantly improved, the release of GH induced by TRH was not prevented by the dopaminergic agonist. Adenomatous cells were densely granulated and contained a dilated endoplasmic reticulum. Misplaced exocytosis was frequently observed. These findings clearly indicate that bromocriptine inhibits the spontaneous release of GH but does not interfere with the abnormal GH response to TRH. This suggests a separate site of action. The drug seems not to block the synthesizing activity of the adenomatous cell, a finding in accordance with clinical observations that warns against its use as a single therapeutic agent.     

EFFECT OF SUBACUTE CABERGOLINE TREATMENT ON PROLACTIN, THYROID STIMULATING HORMONE AND GROWTH HORMONE RESPONSE TO SIMULTANEOUS ADMINISTRATION OF THYROTROPHIN-RELEASING HORMONE AND GROWTH HORMONE-RELEASING HORMONE IN HYPERPROLACTINAEMIC WOMEN

It is known that dopaminergic neurotransmission is involved in the control of PRL, TSH and GH secretion. Cabergoline (CAB) is a new ergolinic derivative with a long-acting dopaminergic activity. We evaluated 11 women with pathological hyperprolactinaemia before and during sub-acute CAB treatment (0.8-1.2 mg/p.o.; 8 weeks). Simultaneous administration of TRH (200 micrograms i.v.) and GHRH 1-44 (50 micrograms i.v.) were carried out before and after 4, 8 and 10 week intervals from the beginning of CAB treatment. Basal PRL levels (2453.5 +/- S.E. 444.5 mU/l) were significantly reduced during CAB administration (week 4: 164.5 +/- 66.5 mU/l; week 8: 168.0 +/- 66.5 mU/l; P less than 0.01) and no variations were observed 2 weeks after drug discontinuation (week 10: 210.0 +/- 98.0 mU/l). PRL percentage change after TRH was increased by CAB (P less than 0.05). No variation in basal and TRH-stimulated TSH levels was found during CAB administration. A slight increase in GH basal levels (3.0 +/- 0.6 mU/l) was found after weeks 4 (6.4 +/- 2.0 mU/l) and 10 (5.8 +/- 1.6 mU/l) (P less than 0.05). GH response to GHRH was significantly enhanced (ANOVA: P less than 0.01) during sub-acute CAB treatment. A positive correlation was found between GH secretory area and weeks of CAB therapy (P less than 0.01). Our data show that CAB is very effective in lowering PRL secretion in hyperprolactinaemia, and is able to modify PRL and GH responses after TRH and GHRH. The increasing trend in GH basal and GHRH-stimulated GH levels seems to indicate that CAB can override the central dopaminergic tone which is operative in hyperprolactinaemia.     

正常成人及肢端肥大症患者的生长激素谱测定

对10例正常成人及4例肢端肥大症(肢大)患者进行生长激素(GH)谱测定,正常人GH分泌型式为长期分泌静止,间以脉冲分泌,在第1次深睡后有GH分泌大峰;女性GH分泌波动较男性明显。肢大患者均无夜间GH分泌大峰。2例测24小时GH谱的肢大患者中,1例血糖水平正常男性患者GH分泌峰数增多,另1例并有高血糖女性患者GH分泌频率明显减少。测定结果表明垂体GH分泌瘤的功能虽系自主性,但仍部分受下丘脑释放激素的调控。     

糖尿病患者血中降钙素和甲状旁腺激素水平的变化及其临床意义

本文共观测了51例糖尿病患者血中钙(Ca)、磷(P)、碱性磷酸酶(AKP)、甲状旁腺激素(PTH)、降钙素(CT)及血糖水平的变化。与正常对照组相比,在糖尿病各组中血Ca、P水平正常;AKP活性及PTH水平明显升高;在病情较重的糖尿病中血CT水平下降。糖尿病患者血PTH水平升高和CT水平的下降是机体的一种代偿调节,以使血Ca、P水平维持正常,但这种变化可以引起糖尿病性骨质疏松。     

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.     

PROLACTIN AND GROWTH HORMONE DYNAMICS IN EPILEPTIC PATIENTS RECEIVING PHENYTOIN

Resting growth hormone and prolactin levels and dynamic responses to bromocriptine and metoclopramide have been measured in epileptic patients before treatment, and compared with a matched group taking phenytoin alone. Mean resting levels of prolactin were higher in patients taking phenytoin (untreated patients 204 mU/l, phenytoin treated patients 302 mU/l), but dynamic responses to metoclopramide and bromocriptine were unaffected. Mean resting levels of growth hormone were also higher in patients taking phenytoin (untreated patients 1.4 mU/l, phenytoin treated patients 6.0 mU/l) and paradoxical suppression was seen following bromocriptine. Phenytoin is unlikely to have any major action on the D2 receptor present on the lactotroph. The abnormalities in growth hormone may explain the well recognized effects of phenytoin on connective tissue.     

IMMUNOCYTOCHEMICAL GROWTH HORMONE AND PROLACTIN IN PITUITARY ADENOMAS CAUSING ACROMEGALY AND THEIR RELATIONSHIP TO BASAL SERUM HORMONE LEVELS AND THE GROWTH RESPONSE TO THYROTROPHIN RELEASING HORMONE

Basal prolactin levels and the dynamics of growth hormone secretion in response to intravenous TRH in 34 untreated acromegalic patients were compared with immunocytochemical localization of growth hormone and prolactin in the adenoma cells. The serum prolactin level was elevated in 13 patients. All adenomas contained growth hormone detectable by immunocytochemistry. Twelve adenomas contained prolactin as well; of these only six were associated with hyperprolactinaemia. In six patients with a mixed adenoma the serum prolactin levels were in the normal range. In 17 patients the growth hormone value more than doubled after TRH. Eight of these patients had hyperprolactinaemia, and in only six did the adenomas contain immunoreactive prolactin; eight were associated neither with hyperprolactinaemia nor with positive immunostaining for prolactin. Eight adenomas had suprasellar extension, six of these were associated with hyperprolactinaemia. Of the seven adenomas with hyperprolactinaemia but no adenomatous prolactin immunoreactivity, four had supprasellar extension. In three patients hyperprolactinaemia was associated neither with prolactin immunoreactivity in the adenoma cells nor with suprasellar extension of the tumour. It is concluded that in acromegalics (1) there is no relation between hyperprolactinaemia, and the presence of prolactin in the adenoma cells; (2) the hyperprolactinaemia may be due either to adenomatous prolactin secretion or possibly suprasellar mass interference of hypothalamic control of normal prolactin cells; and (3) the presence of hyperprolactinaemia or immunocytochemically defined adenomatous prolactin does not correlate with the reactivity of the adenomatous growth hormone cells to TRH.     

PROLACTIN AND LUTEINIZING HORMONE PROFILES OF CURED ACROMEGALIC SUBJECTS

The 24-h PRL and LH hormone profiles were analysed of 16 cured male acromegalic patients who had undergone selective transsphenoidal surgery 4-9 years previously. Eight of these patients also underwent pituitary irradiation. Blood samples were taken at 20-min intervals; the PRL and LH data were analysed with the cluster program. ARIMA modelling, cross-correlation techniques, Fourier analysis, and cosinor analysis. About 10-11 PRL and LH peaks were demonstrated for both non-irradiated and irradiated patients. The absolute heights of PRL pulses and the mean valley levels were significantly greater for irradiated patients than for non-irradiated patients, but the increment in amplitude did not differ. A significant diurnal rhythm for PRL was found for all non-irradiated patients but for only one irradiated patient. LH pulse area and amplitude were lower in the group of irradiated patients. The incremental responses of LH and PRL to GnRH and TRH, respectively, were lower in irradiated patients than in non-irradiated patients. During the night (0200-0800 h) the number of PRL pulses decreased in non-irradiated patients but not in irradiated patients. Pulse nadirs and amplitudes increased during the evening and night in non-irradiated patients but were constant in irradiated subjects. Bivariate modelling of the data for 14 patients revealed significant cross-correlations between LH and PRL pulses in nine subjects. This study demonstrates that the pulsatile secretion of PRL and LH in treated acromegalics is basically normal. Additional radiation therapy, however, may lead to damage of the hypothalamus, as reflected by the absence of a circadian PRL rhythm. A direct influence on the pituitary by radiation is indicated by the decreased magnitude of LH pulses and the diminished response of LH and PRL after injection of GnRH and TRH, respectively.     

FAILURE OF LONG-TERM CYPROHEPTADINE THERAPY IN LOWERING GROWTH HORMONE LEVELS IN ACROMEGALY

Basal and post-glucose growth hormone (GH) responses were evaluated in 10 acromegalics receiving cyproheptadine (cypro) 4 mg 6 hourly at 2 and 21 days after initiating therapy. Of the 10 patients, six had macroadenomas with varying degree of suprasellar extensions, one a microadenoma and three had persistent hypersomatotropism despite pituitary adenomectomy due to residual tumour. The basal and post-glucose GH showed no significant change in all, except one with a pituitary microadenoma. His GH was reduced from 680 to 108 mU/L on the second and 82 mU/I on the 21st day of cypro therapy. These data do not suggest any therapeutic role of cypro in the management of acromegaly.     

INHIBITORY EFFECT OF SEROTONIN ANTAGONISTS ON GROWTH HORMONE RELEASE IN ACROMEGALIC PATIENTS

We evaluated the effect of the serotonin antagonists cyproheptadine (Cypro) and methysergide (Methy) on growth hormone secretion in six patients with acromegaly. Two days administration of Cypro deceased the plasma GH concentration during oral glucose tolerance tests in four of the six patients evaluated; 2 days administration of Methy reduced the plasma GH levels of only one of the four patients evaluated. The one patient whose palsma GH concentration was lowered by Methy, did not have a decerase in plasma GH concentration after Cypro administration. Acromegalic patients have normal serum serotonin concentration and normal 5-hydroxyindoleacetic acid excretion. If Cypro lowers plasma GH by antagonizing serotonin, our data would suggest that serotoninergic neruonal pathways are important in the regulation of pituitary GH secretion in some patients with acromegaly.     

血透患者血浆皮质醇促肾上腺皮质激素及心钠素改变和意义

目的探讨皮质醇(CTS)、促肾上腺皮质激素(ACTH)与心钠素(ANF)等在血透患者血透前后的改变及意义.方法采用放射免疫法检测了慢性肾功能衰竭(CRF)患者血透前后血浆皮质醇(PCTS)、促肾上腺皮质激素(PACTH)及心钠素(PANF)的变化.结果透析前PCTS及PACTH较低,分别为173.4±42.1μg/L及17.5±10.8ng/L;而PANF为406.8±177.1ng/L,则明显高于正常对照组(P＜0.01).透析后PCTS为200±88μg/L,轻微升高(P＞0.05);PACTH31.2±22.2ng/L明显增高(P＜0.05);而PANF201.8±111.7ng/L显著降低(P＜0.01)结论本结果支持PANF浓度是判断细胞外液容量的敏感指标.且进一步提示ANF是ACTH及CTS分泌的抑制剂.     

用联合下丘脑释放激素兴奋试验评价特发性生长激素缺乏性侏儒其他垂体前叶激素的储备功能

联合使用GHRH、TRH、LHRH和CRH四种下丘脑释放激素检查6例正常青少年和50例未治疗IGHD患者血PRL、TSH、LH及F的反应,并从基础值、峰值、峰值增加值、峰值/基础值比值、激素反应曲线下面积和阳性反应率等六个方面比较两组结果。IGHD患者血PRL、TSH及F六项指标的反应与对照组比较差异无显著性,表明IGHD患者垂体PRL、TSH及ACTH细胞的储备功能正常。约2/3IGHD患者LH细胞的储备功能低下。在青春发育年龄的IGHD患者LH对LHRH的反应除峰值/基础值比值以外,另五项指标均非常明显低于对照组(P<0.001),这可能是成年IGHD患者性发育延迟及差的原因。     

GROWTH HORMONE RESPONSIVENESS TO HUMAN PANCREATIC GROWTH HORMONE RELEASING FACTOR IN ACROMEGALY: MODULATORY EFFECTS OF BASAL HORMONE LEVELS AND OF CONCOMITANT SOMATOSTATIN ADMINISTRATION

Human pancreatic growth hormone releasing factor 1-44 (hpGRF), 100 micrograms was administered as an i.v. bolus injection to eleven patients with acromegaly. The mean serum growth hormone (GH) levels rose (P less than 0.001) from 54 +/- 20 ng/ml to 215 +/- 126 ng/ml (+/- SEM) 20 min after the injection. Although the maximum response of GH levels was highly variable it correlated positively with the individual GH levels (P less than 0.01, Rs = +0.80). Thus the higher the GH levels, the greater the responsiveness to hpGRF. Administration of somatostatin (SRIF), 300 micrograms/h, lowered basal GH levels from 76 +/- 38 ng/ml to 13 +/- 5 ng/ml (P less than 0.01) after 1 h. hpGRF administration during concomitant SRIF infusion also led to highly variable growth hormone responses. The maximum GH responses again correlated positively with the GH level before hpGRF after 1 h of SRIF administration (P less than 0.05, Rs = +0.79). GH responses to hpGRF were completely blocked by SRIF in three out of four patients whose GH levels decreased to normal levels during SRIF infusion. Our data illustrate that the pituitary in acromegaly is normally responsive to both SRIF and hpGRF but at a higher setting of basal GH levels.     

DISTINCTIVE FEATURES OF PROLACTIN SECRETION IN ACROMEGALIC PATIENTS WITH HYPERPROLACTINAEMIA

We have investigated the relationship between the plasma PRL concentrations of 98 untreated acromegalic patients and the GH levels during basal and dynamic conditions. Hyperprolactinaemia was present in 27 patients. In patients with marked hyperprolactinaemia (PRL greater than 80 ng/ml or greater than 1600 mU/l), basal plasma PRL and the TRH-induced response correlated with basal plasma GH (correlation coefficients of 0.9, P less than 0.001 and 0.74, P less than 0.02, respectively). The PRL response to TRH also correlated with GH response to TRH (r = 0.38, P less than 0.01). In contrast, in patients with moderately elevated PRL (20 to 80 ng/ml), and in those with normal plasma PRL (less than 20 ng/ml or less than 400 mU/l), no such correlations were found. Immunostaining for PRL was positive in 24 out of 25 adenomas of patients with hyperprolactinaemia, while no PRL was found in the tumour tissue of 10 normoprolactinaemic patients. In conclusion, our data suggest the existence of two populations of acromegalic patients with hyperprolactinaemia, one group with correlations between GH and PRL secretion, and the other without.     

GLYCOPROTEIN HORMONE ALPHA-SUBUNIT AND PROLACTIN RELEASE BY CULTURED PITUITARY ADENOMA CELLS FROM ACROMEGALIC PATIENTS: CORRELATION WITH GH RELEASE

In-vitro data of pituitary adenoma cells from 28 acromegalic patients were evaluated. In addition to GH, PRL was produced by 16 adenomas (57%) and alpha-subunit by 15 adenomas (54%) while there was a significantly higher incidence of tumours producing PRL and alpha-subunit simultaneously. From 26 pituitary adenomas enough cells were obtained in order to perform secretion studies. Percentage basal hormone release (medium: (medium + intracellular hormone)) x 100% of GH and alpha-subunit by 11 adenomas showed a close correlation while such a correlation for GH and PRL was present only in a subgroup of 10 of 13 adenomas. The responses of GH and alpha-subunit release to 10nM SMS201-995, 10nM bromocriptine, 100 nM TRH and 10nM GHRH were closely related in that a response or an absent response of GH release to the four secretagogues was virtually always attended with a response or an absent response respectively of alpha-subunit release. Such a relationship was less evident with respect to the effects of SMS201-995, bromocriptine. TRH and GHRH on GH and PRL release. We conclude that basal and secretagogue-induced alpha-subunit release by cultured pituitary adenoma cells from acromegalic patients closely follows the pattern of GH release while such a relationship for GH and PRL is present only in a subgroup of the adenomas secreting GH and PRL simultaneously.     

EFFECT OF SOMATOSTATIN ON ABNORMAL GROWTH HORMONE AND PROLACTIN SECRETION IN PATIENTS WITH THE CARCINOID SYNDROME

Growth hormone (GH) secretion has been studied in two patients with the carcinoid syndrome during glucose loading and growth hormone-release inhibiting hormone (GHRIH, somatostatin) infusion. Both patients had elevated fasting GH levels which were not suppressed by glucose; GH levels fell rapidly during GHRIH infusion. One patient also had hyperprolactinaemia with galactorrhoea and the prolactin (PRL) levels were unaltered by GHRIH. The association between carcinoid tumours and abnormalities of GH and PRL secretion is discussed.     

COMPARISON OF THE EFFECT OF APOMORPHINE AND l-DOPA ON SERUM GROWTH HORMONE LEVELS IN NORMAL MEN

Apomorphine hydrochloride (0.75 mg s.c.) has been compared with L-dopa (500 mg p.o.) in their effects on growth hormone secretion in a double blind cross-over study involving nine healthy men. Apomorphine increased serum GH levels above 10 ng/ml in all nine subjects 30-60 min after injection. In contrast, only six of these subjects showed a similar elevation with L-DOPA and in only three had the level increased above 6 ng/ml by 60 min. One subject failed to respond to L-dopa and in two others the peak was less than 6 ng/ml. GH levels were significantly higher at 30, 45 and 60 min following apomorphine than following L-dopa. Apomorphine-induced GH release was not related to changes in serum cortisol or blood sugar. Benztropine mesylate (1 mg i.m.) had no effect on apomorphine-induced GH release. These results suggest: (a) apomorphine may have advantages over L-dopa as a provocative agent to assess GH secretory capacity; (b) a dopaminergic mechanism subserves GH secretion; (c) cholinergic mechanisms do not antagonize dopaminergic-related GH release.