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。     

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)     

THE EFFECT OF OXANDROLONE ON THE GROWTH HORMONE RESPONSE TO GROWTH HORMONE RELEASING HORMONE IN CHILDREN WITH CONSTITUTIONAL GROWTH DELAY

The effect of treatment with oxandrolone, an anabolic steroid, on GH response to GH-releasing hormone (GHRH) has been evaluated in children with constitutional growth delay. Five subjects, four males and one female, aged 11.0-17.1 years were given oxandrolone 0.1 mg/kg p.o. daily for 2 months, and underwent acute administration of GHRH (GRF 1-40, 1 microgram/kg i.v.) before and after withdrawal of oxandrolone therapy. GHRH administration induced a much greater GH response, evaluated either as a peak plasma GH levels or plasma GH integrated area, after than it did before oxandrolone treatment. These findings indicate that in children with constitutional growth delay oxandrolone increases the sensitivity of somatotrophs to exogenous GHRH and, likely, to the endogenously-released neurohormone.     

LACK OF INHIBITION OF ANTERIOR PITUITARY HORMONE RELEASE DURING CHRONIC TREATMENT WITH CALCIUM ANTAGONISTS

Calcium antagonists are widely used for the treatment of cardiovascular disorders, especially ischaemic heart disease. It has been demonstrated that these drugs, either in vitro or acutely administered in humans, inhibit the basal and stimulated secretion of pituitary hormones by blocking calcium influx through slow calcium channels. To see if a similar effect could be detected after their chronic administration, we studied the basal, TRH- and LHRH-stimulated TSH, PRL, LH and FSH release in 18 male subjects with chronic stable angina before and on the 30th day of oral treatment with verapamil (n=8; 80 mg three times a day) or with nifedipine (n=10; 10 mg three times a day). Neither drug had any effect on basal TSH, PRL, LH and FSH values or on their response to the specific hypothalamic-releasing hormones. These results suggest that the chronic administration of calcium antagonists, at the usual therapeutic doses, does not effect the process of stimulus-secretidn coupling of anterior pituitary hormones, ruling out any impairment of the related target glands which have been expected on the basis of previous studies.     

THE INTERACTION BETWEEN CLONIDINE AND GROWTH HORMONE RELEASING HORMONE IN THE STIMULATION OF GROWTH HORMONE SECRETION IN MAN

Six normal adult males were given clonidine and GHRH either separately, or in combination, in random order. The peak serum GH concentrations elicited by clonidine or GHRH were variable but one factor influencing the GH response to GHRH was the GH secretory status in the hour prior to the administration of the GHRH. Peak serum GH concentrations attained were significantly greater when serum GH concentrations were rising (mean 52.9 mU/l, SD 17.2) than if they were falling (mean 27.5 mU/l, SD 13.3) or unchanged/undetectable (mean 20.6 mU/l, SD 9.8) (one-way ANOVA, F = 8.77; P = 0.004). The GH response to clonidine was not influenced by the secretory status in the hour prior to administration of clonidine. Pretreatment with clonidine did not augment the peak serum GH response to GHRH but the direction of response was more predictable than when GHRH was administered separately or repeatedly. Prior treatment with GHRH(1-29)-NH2 led to a marked attenuation of the peak serum GH response to clonidine. These results suggest that the alpha-2 adrenergic agonists probably stimulate GH secretion through pathways other than just GHRH.     

THE INFLUENCE OF BROMOCRIPTINE ON SERUM LEVELS OF GROWTH HORMONE AND OTHER PITUITARY HORMONES AND ITS METABOLIC EFFECTS IN ACTIVE ACROMEGALY

The effect of treatment with bromocriptine for 12--18 months on serum GH and metabolic responses was studied in sixteen patients with active acromegaly. Of this group ten patients showing a sustained GH reduction of more than 50% during an 8 h bromocriptine test, proved to be responsive to long-term therapy. In the responding patients GH levels decreased to 38% of the pretreatment level after 12 months of therapy. A dose higher than 10 mg did not produce a significantly greater effect. Prolactin and LH levels decreased in all patients, FSH levels showed a significant rise. Testosterone levels in the male patients increased significantly, indicating that the state of hypogonadism can at least be partially reversed. The GH levels became normal in only one patient. We conclude that the role of bromocriptine in acromagaly is limited and selective pituitary operation and/or irradiation is preferred as definitive treatment in most patients.     

ADDITIVE EFFECTS OF GROWTH HORMONE RELEASING FACTOR AND INSULIN HYPOGLYCAEMIA ON GROWTH HORMONE RELEASE IN MAN

We have measured GH and PRL changes following separate and combined administration of insulin and GH releasing factor (GRF) in six normal males. Peak GH responses to separate administration of insulin and GRF were comparable (71.4 +/- 10.2 vs 70.1 +/- 27.7 mU/l; mean +/- SEM). However, the peak GH response following combined administration was significantly higher (120.8 +/- 29.7, P less than 0.05) as was the total GH released as calculated by measuring the area under the curve (P less than 0.05). In contrast the PRL response to hypoglycaemia was not altered by the combined administration of insulin and GRF. This effect was not due to any direct action of hypoglycaemia or insulin at pituitary level since basal and 10(-8) M GRF stimulated GH release from rat anterior pituitary cells in vitro was not influenced by varying glucose and insulin levels. Our findings support the hypothesis that GRF and insulin-induced hypoglycaemia release GH via different pathways which are, at least in part, additive.     

THE COMBINED EFFECT OF GROWTH HORMONE AND METHANDROSTENOLONE ON THE LINEAR GROWTH OF PATIENTS WITH MULTIPLE PITUITARY HORMONE DEFICIENCIES

Six patients with multiple pituitary hormone deficiencies (MPHD) were initially treated with separate courses of methandrostenolone and growth hormone and later with the two drugs combined. During the basal period the mean growth velocity was 2.8 cm/year. Methandrostenolone alone, 0.02-0.05 mg/kg/day given to four of the patients led to an acceleration of the growth velocity to a mean of 5.0 cm/year, while growth hormone 6 mg/week alone accelerated the growth rate to a mean of 6.0 cm/year. Combined therapy led to a striking increase in the mean growth rate to 9.3 cm/year. The shortcoming of the combined growth hormone-androgen therapy was the fast acceleration in skeletal maturation even after short-term administration.     

HYPOTHALAMIC GROWTH HORMONE RELEASING FACTOR DEFICIENCY FOLLOWING CRANIAL IRRADIATION

The effect of synthetic human pancreatic tumour GH releasing factor (hp GRF1–44) on GH release has been studied in 10 patients with radiation-induced GH deficiency and four normal subjects. All 10 patients showed subnormal GH responses to both an ITT (median peak GH 3.2 mU/l) and to arginine stimulation (median peak GH 2.9 mU/l), although the remainder of pituitary function was intact. Following an acute intravenous bolus (100 /μg) of hp GRF1-44, there was no GH response in two patients and a subnormal but definite GH response in a further four. The remaining four patients showed a significant GH response (median peak GH level 29 mU/l; range 22–57 mU/l) to hp GRF1-44, similar in magnitude and timing to that seen in the four normals. This strongly suggests that in these four subjects, the discrepancy in GH responses to hp GRF1-44, ITT and to arginine was a result of radiation-induced hypothalamic damage leading to a deficiency of endogenous GRF. The availability of synthetic hp GRF capable of stimulating GH secretion means that the distinction between hypothalamic and pituitary causes of GH deficiency will be of considerable therapeutic importance in the future.     

GROWTH HORMONE RELEASING FACTOR-TEST IN ACROMEGALY: COMPARISON WITH OTHER DYNAMIC TESTS

Human pancreatic growth hormone releasing factor (hpGRF1-44) was given intravenously as a 100 micrograms bolus to 20 patients with active acromegaly. The GH-responses were variable, ranging from an increase of 8 to 2813% from the basal level (mean +/- SE, 428 +/- 136%). Sixteen GRF-responders (delta% greater than or equal to 100%) were arbitrarily distinguished from four GRF non-responders, whose GH-levels increased less than 100% from basal level after GRF-administration. The outcome of the GRF-test did not correlate with the results of other dynamic tests of GH-secretion in acromegaly (oral glucose tolerance test, insulin hypoglycaemia, TRH-, LHRH-, CRF-stimulation). In 10 patients who had not been treated before, the GH-increments after GRF were higher than those in seven patients who had previously been subjected to transsphenoidal surgery, though they still had clinically and biochemically active acromegaly. Ten acromegalics, who were tested with GRF, were later treated surgically by the transsphenoidal route and were reevaluated with GRF-stimulation 2 months after surgery. Eight patients appeared clinically cured of whom four had complete normalization and four had significantly lower basal and conventionally stimulated GH-levels postoperatively. These patients also had normal postoperative GH-responses to GRF, which had been significantly higher before surgery compared with normal controls. It is concluded that the GRF-test in acromegaly does not help in establishing the diagnosis. The normalization of the GH-response to GRF after transsphenoidal surgery seems to represent additional evidence for normalization of GH-secretion, though the latter is not proven by the normal outcome of this test.     

单层培养的垂体生长激素分泌瘤细胞对生长激素释放激素和生长抑素的反应

本文研究7例肢端肥大症患者垂体单纯生长激素(GH)分泌瘤单层培养细胞对GH释放激素(GRF)和生长抑素(SS)的反应。培养液中10~(-8)M GRF使5例瘤细胞GH分泌增加171.6±22.6％,10~(-7) M GRF使全部7例瘤细胞GH分泌明显升高到220.6±47.7％。10~(-9)～10~(-7) M SS使5例瘤细胞GH基础分泌下降到50.4±9.8％。同时加入10~(-8)或10~(-7) M的GRF和SS,在7例瘤细胞上均看到GRF兴奋GH分泌的作用被完全阻断。3例病人术前接受GRF和SS试验,血清GH水平的变化分别为对照的222.0±30.6％和10.7±4.7％。结果表明单层培养的垂体GH瘤细胞对GRF和SS仍有反应。     

重组人生长激素治疗生长激素缺乏性侏儒症

20例原发性垂体性侏儒症、2例单纯性GH缺乏IA型及1例宫内生长停滞的患儿用经典性药物进行激发试验并于夜睡眠中采血测GH,确认有GH缺乏。全部病例用重组hGH治疗。20例用191肽的Genotropin,3例用192肽的Somatonorm,疗程12个月(后一组中1例治疗6个月)。结果一年后身高增长Genotropin组为13.3±1.8cm,Somatonorm组2例各为16.0、16.6cm,1例治疗6个月后为7.9cm。疗程中出现血清T_4下降、轻度肝肿大、一过性血尿者各占47.8％、30.4％、30.4％。     

THE EFFECT OF HYPOTHALAMIC LUTEINIZING HORMONE RELEASING HORMONE (LH-RH) ON PLASMA GONADOTROPHIN LEVELS IN NORMAL SUBJECTS

The release of gonadotrophin following the injection of synthetic LH-RH (Hoechst) was studied in various physiological and experimental circumstances. In the male, 25 μg of LH-RH led to simultaneous release of FSH and LH prior to and during puberty. In adults, on the other hand, the same dose led only to an increase in LH while FSH levels remained unchanged. At higher doses there was FSH release and an increase in LH proportional to the amount of LH-RH injected. When FSH was released the increase was clearly less than that of LH and often occurred considerably later. In the female, 25 μg of LH-RH led to a clear-cut release of FSH and a small release of LH prior to puberty. After the onset of puberty the degree of response was inverted: the increase in LH was greater than that of FSH. In normally menstruating women the FSH and LH response was greater during the luteal phase than during the preovulatory phase. Treatment with non-sequential hormonal contraceptives blocked FSH and LH release normally produced by the injection of 50 μg of LH-RH. There was no effect when a dose of 100 μg was injected. In post-menopausal women, only LH rose following the administration of 25 μg of LH-RH. After 5 days of treatment with 200 μg ethinyl oestradiol the same dose of LH-RH led to simultaneous release of LH and of FSH. From the above studies it can be concluded that the secretory response of the gonadotrophins to LH-RH is influenced by the endocrine equilibrium and more particularly by the interaction of the gonadal steroids which can alter the synthesis and/or the release of the pituitary gonadotrophins.     

THE HIGHER THE GROWTH HORMONE RESPONSE TO GROWTH HORMONE RELEASING HORMONE THE LOWER THE RESPONSE TO BROMOCRIPTINE AND THYROTROPHIN RELEASING HORMONE IN ACROMEGALY

In acromegaly a direct relationship has been demonstrated between GH responsiveness to TRH and to the dopaminergic agent bromocriptine (Br). Recent data show an inverse relationship between GH responsiveness to Br and to GH releasing hormone (GHRH), but not between the GH responses to GHRH and TRH. Thirty-one acromegalic patients, 18 women and 13 men (age 46.2 +/- (SD) 13 years) were studied. Four patients had been treated, but all still had active disease. The GH responses to GHRH (hpGHRH1-44, Bachem 100 micrograms i.v. bolus), TRH (Thyroliberin, Hoechst 200 micrograms i.v. bolus) and Br (Parlodel 5 mg orally) were assessed in most of the patients. The GH responses to GHRH showed a wide interindividual variation (delta GH 1-995 ng/ml), which correlated significantly with the basal GH levels (r = +0.85, P less than 0.0001, n = 31). GH increments in response to GHRH were inversely related to the responses to Br, i.e. the lower the GH increase after GHRH the greater the GH decrease after Br (r = -0.49, P less than 0.01, n = 30). This decrease correlated with the basal PRL level (r = +0.45, P less than 0.02, n = 29) and also the GH response to TRH (r = +0.66, P less than 0.0001, n = 30). An inverse correlation was also found between the GH responses to TRH and to GHRH (r = -0.43, P less than 0.02, n = 29). The data are consistent with the existence of GH-secreting adenomas which are more sensitive to GHRH and less to Br and TRH (pure somatotroph adenomas) and of mixed (lactotroph-like adenomas) responsive to TRH and Br but less responsive to GHRH.     

AMIODARONE AND THYROID HORMONE EFFECTS ON ANTERIOR PITUITARY HORMONE GENE EXPRESSION

Amiodarone therapy results in marked changes in circulating thyroid hormone and TSH concentrations in man. In the present study we have demonstrated that amiodarone treatment of the rat increases serum TSH and pituitary cytoplasmic concentrations of TSH beta and alpha subunit messenger RNAs (mRNAs) and reduces PRL mRNA as measured by cytoplasmic dot hybridization with specific complementary (c) DNA probes. The fall in circulating TSH and TSH mRNA resulting from thyroid hormone treatment was less marked in animals receiving amiodarone in addition to T3 and T4. In contrast, in the hypothyroid state, increases in serum TSH, TSH beta and alpha mRNA, and reductions in PRL and GH mRNA were less marked in rats treated with amiodarone. In studies of rat anterior pituitary cells in primary monolayer culture we demonstrated a direct effect of amiodarone on PRL gene expression which was antagonized by T3. Changes in circulating thyroid hormone concentrations and deiodination of T4 and T3 induced by amiodarone in vivo may be important in the regulation of pituitary hormone gene expression but we have, in addition, shown a direct interaction between amiodarone and T3 effects on the anterior pituitary cell.     

THE EFFECT OF PLASMA GLUCOSE ON THE GROWTH HORMONE RESPONSE TO HUMAN PANCREATIC GROWTH HORMONE RELEASING FACTOR IN NORMAL SUBJECTS

Pituitary responsiveness to 44 amino acid human pancreatic growth hormone releasing factor was tested under conditions of euglycaemia and hyperglycaemia in six normal subjects. A 100 μg dose of growth hormone releasing factor was given at a fasting blood glucose of 5.1 ± 0.4 mmols/1 (mean ± S.D.), and at a blood glucose level of 10.9 ± 1.5. Under conditions of hyperglycaemia, the GH response to releasing factor was significantly depressed when compared to results obtained at fasting blood glucose ( n = 6, t = 3.902, P = 0.0114). This is in keeping with the hypothesis that hyperglycaemia, mediated by the hypothalamus, causes decreased pituitary sensitivity to natural growth hormone releasing hormone.     

THE EFFECT OF METHANDROSTENOLONE ON PITUITARY GROWTH HORMONE SECRETION IN PREPUBERTAL CHILDREN

The effect of methandrostenolone on plasma growth hormone levels was studied in twenty-two apparently healthy prepubertal children (nineteen males and three females) with idiopathic growth retardation, following insulin hypoglycaemia (eight children) or arginine infusion (fourteen children). The tests were performed before and after 5 days or 34 months of peroral administration of methandrostenolone (0.1 54.33 or 0.03-0.05 mg/kg/day, respectively).     

THE INTERACTION OF HUMAN PANCREATIC GROWTH HORMONE RELEASING FACTOR 1–44 WITH SOMATOSTATIN IN VIVO IN NORMAL MAN

The interaction between the stimulatory effects of hpGRF 1-44 and the inhibitory effects of somatostatin on GH release have been investigated in six normal male subjects receiving continuous 4 h infusions of these peptides alone and in combination. hpGRF 1-44 0.3 microgram/kg/h alone produced a peak GH response of 27.0 +/- 7.6 mU/l (mean +/- SEM). Somatostatin 1.0 microgram/kg/h markedly inhibited the GH response to hpGRF 1-44 with mean levels less than 4.0 mU/l during the infusion, though a rebound rise in GH levels to 26.1 +/- 9.0 mU/l was observed at the end of the infusion period. Somatostatin 0.2 microgram/kg/h inhibited the GH response to hpGRF 1-44 to a lesser degree (peak GH during the infusion 11.7 +/- 2.5 mU/l) and the rebound rise in GH levels (maximum 13.2 +/- 4.3 mU/l) was less than that observed with high dose somatostatin. During somatostatin 1.0 microgram/kg/h alone GH levels were suppressed less than 1.0 mU/l followed by a rebound at the end of the infusion in only two subjects. These data demonstrate a dose-dependent inhibition of hpGRF 1-44 by somatostatin in vivo in man.