EFFECT OF FLUPHENAZINE ON PITUITARY FUNCTION IN MAN

The growth hormone (hGH) and prolactin (hPRL) response to insulin induced hypoglycaemia was studied in six alcoholics on two occasions before and after treatment with a single intramuscular injection of fluphenazine (Modecate). On both occasions blood samples were taken at intervals before and after the intravenous injection of soluble insulin (0.1 u/kg body weight). The patients were investigated on the first occasion, 2-7 days after cessation of drinking and they all demonstrated an adequate hGH response. They then received an injection of fluphenazine (Modecate 12.5 mg) and were reinvestigated 1 week later. The hGH response to hypoglycaemia was significantly impaired after treatment with fluphenazine. Basal hPRL concentrations were significantly increased and increased concentrations of hPRL in response to hypoglycaemia occurred after treatment. We conclude that a single injection of fluphenazine (Modecate 12.5 mg) has a marked effect on hypothalamic-pituitary mechanisms controlling hGH and hPRL release.     

VASOACTIVE INTESTINAL PEPTIDE AND ANTERIOR PITUITARY FUNCTION

Vasoactive intestinal peptide (VIP) is a highly basic 28 amino-acid peptide which was first isolated from porcine small intestine (Said & Mutt, 1970). It is related to several other peptides including PHI (peptide with N-terminal histidine and C-terminal isoleucine amide), secretin, glucagon, and has some sequences similar to those of growth hormone releasing hormone (Fig. 1). The amino-acid sequence of human VIP is identical with that of the porcine form (Itoh et al., 1983). It has been shown that human VIP is cosynthesized with PHM (peptide with N-terminal histidine and C-terminal methionine amide, the human analogue of PHI) from the same large precursor protein (Itoh et al., 1983).     

FAILURE OF BOMBESIN TO ALTER ANTERIOR PITUITARY HORMONE SECRETION IN MAN

Because of the stimulating effects of bombesin on growth hormone and prolactin secretion in the rat, we have studied the effects of bombesin infusions on anterior pituitary hormone secretion in man. Biological activity of the infused bombesin was confirmed by observing a brisk increase in serum gastrin concentrations and in gastric acid secretion during the lowest dose of bombesin infused. We could demonstrate no effect of bombesin in doses from 200 to 600 pmol.kg⁻¹.h⁻¹ on growth hormone, prolactin, thyrotrophin, luteinizing hormone and follicle stimulating hormone.     

THE EFFECT OF LISURIDE HYDROGEN MALEATE, AN ERGOT DERIVATIVE ON ANTERIOR PITUITARY HORMONE SECRETION IN MAN

The effects of single oral doses of 0.2 mg of lisuride hydrogen maleate, a semisynthetic ergot derivative, on serum levels of prolactin (PRL), growth hormone (GH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH), cortisol and blood glucose were studied in six normal males. Lisuride effectively inhibited basal PRL secretion as well as the PRL response to TRH given 3 h later. In addition, the drug raised basal GH levels and decreased basal and TRH stimulated TSH secretion. No significant differences between lisuride and control were observed in basal LH and FSH, LHRH stimulated gonadotrophins or in cortisol. Drowsiness was noted by all subjects, one became nauseated and another vomited, 60 and 90 min respectively after administration of lisuride. No changes were seen in pulse rate and blood pressure. The endocrine effects of lisuride were attenuated by the prior administration of the dopamine antagonist metoclopramide. These results suggest that lisuride acts as a long-acting dopamine agonist and that therefore this drug could be of therapeutic use in hyperprolactinaemic states and acromegaly.     

ANTERIOR PITUITARY FUNCTION IN PATIENTS WITH NEWLY DIAGNOSED RHEUMATOID ARTHRITIS

Hormonal dysfunction involving the hypothalamic-pituitary-adrenal(HPA) axis, prolactin (PRL) secretion and sex hormone statushas been supposed to contribute to the development or persistenceof rheumatoid arthritis (RA). In addition, a reduced numberof glucocorticoid receptors on circulating lymphocytes has beenfound in patients with RA. However, so far most studies havebeen performed in pre-treated patients. A combined test fortotal anterior pituitary reserve was performed in 10 patientswith newly diagnosed untreated RA. Before and after stimulationwith the respective hypothalamic releasing hormones, RA patientsshowed no difference in plasma concentrations of adrenocorticotrophichormone (ACTH), cortisol, prolactin (PRL) and thyroid-stimulatinghormone (TSH) when compared to healthy controls. In contrast,the growth hormone (GH) response to growth hormone-releasinghormone (GHRH) was blunted in RA patients. The hypothalamic-pituitary-thyroid/gonadaland adrenal axes seem to be unaltered in RA. However, if oneconsiders the presence of chronic inflammation, normal plasmaACTH and cortisol concentrations must be considered as inappropriatelylow. The observed blunted GH release could be mediated by cytokines(e.g. IL-1), which are known to be elevated in RA. KEY WORDS: Rheumatoid arthritis, Autoimmunity, Pituitary function     

PITUITARY FUNCTION IN IDIOPATHIC HÆMOCHROMATOSIS AND CIRRHOSIS OF THE LIVER

Testicular atrophy was found in 13 of 23 male patients with idiopathic hæmochromatosis and in 10 of 14 patients with cirrhosis of the liver from other causes. Other indices of gonadal hypofunction were common in both men and women with hæmochromatosis, but only in men with cirrhosis. There was depression of plasma-luteinising-hormone in 44% of 32 patients with hæmochromatosis, but in none of 18 patients with cirrhosis. These and other endocrine studies suggested that generalised depression of pituitary function occurs in hæmochromatosis but not in cirrhosis. Testicular atrophy in hæmochromatosis is probably due to loss of gonadotrophins, in contrast to cirrhosis of the liver, where an imbalance between oestrogens and androgens may have a more direct effect on the testis.     

SECRETION OF ALPHA AND BETA SUBUNITS OF TSH BY THE ANTERIOR PITUITARY

We have attempted to determine whether blood concentrations of the α chains of TSH arise by direct pituitary secretion of α chain or by degratation of the intact hormone after secretion. Highly purified human TSH was administered by infusion to euthyroid volunteers; blood TSH concentrations were raised to 36 μu/ml. After TSH infusion, circulating blood α chain concentrations did not change. The same volunteers received an infusion of TRH which stimulated pituitary secretion of TSH, raising blood concentrations to 15 μ/ml in one series of subjects and to 23 μu/ml in a second series. After TRH, blood concentrations of α chain increased from undetectable to over 400 pg/ml. We conclude that α subunits of TSH are directly secreted by the pituitary gland and are not formed by degradation of intact TSH in the peripheral circulation.     

生长落后儿童下丘脑—垂体后叶功能探讨

通过禁水加压素试验对27例生长落后儿童进行了下丘脑-垂体后叶功能检测,并与13例尿崩症和10例正常儿童进行对照。结果表明:(1)GH缺乏、伴多饮多尿症状的生长落后儿童均为ADH严重缺乏;(2)GH缺乏、无多次多尿症状的生长落后儿童11例中7例为潜在性ADH缺乏;(3)GH正常、伴多饮多尿症状的生长落后儿童都为ADH部分缺乏;(4)GH正常、无多饮多尿症状的生长落后儿童的下丘脑-垂体后叶功能基本正常。因此应对生长落后儿童的下丘脑-垂体后叶功能进行评价,禁水加压素试验是一种适合临床的简便、准确的方法。     

EVIDENCE FOR DOPAMINERGIC CONTROL OF ALDOSTERONE IN MAN

The effect of L-dopa (0·50 g, orally) on serum aldosterone, cortisol and potassium levels, plasma renin activity, and on urinary aldosterone excretion has been studied in normotensive subjects, before and after dexamethasone-induced ACTH suppression. L-dopa caused a further reduction in the levels of aldosterone but not cortisol, in the dexamethasone treated subjects. It is therefore suggested that the inhibitory action of L-dopa on aldosterone secretion is mediated by the dopaminergic system.     

PROTEIN HORMONES IN CEREBROSPINAL FLUID: EVIDENCE FOR RETROGRADE TRANSPORT OF PROLACTIN FROM THE PITUITARY TO THE BRAIN IN MAN

Plasma and cerebrospinal fluid (CSF) levels of two hormones of similar molecular size, pituitary prolactin (PRL) and human chorionic somatomammotropin (hCS), and of the bigger hormone human chorionic gonadotropin (hCG) were measured in six pregnant women without pituitary disease. For all three hormones, the plasma and CSF levels were closely correlated. The plasma/CSF concentration ratio for hCG (571 ± 378, mean ± SD) was significantly different (P < 0.01) from the hCS ratio (24.6 ± 6.1); the hCS ratio was significantly different (P < 0.005) from the PRL ratio (7.2 ± 1.5). We conclude that (1) the CSF concentration of a protein hormone depends on the plasma concentration and on its molecular size, and (2) pituitary hormones reach the CSF not only via filtration of peripheral blood at the choroid plexuses, but also more directly via retrograde transport from the pituitary to the brain.     

ENDOCRINE EFFECTS OF DOMPERIDONE: A PERIPHERAL DOPAMINE BLOCKING AGENT

In the present study, effects of domperidone, a peripheral dopamine blocking agent, on prolactin and growth hormone were examined to determine whether dopamine regulation of these hormones involved structures external to the blood-brain barrier. A clearcut elevation in prolactin was produced by domperidone. GH response to apomorphine was partially blocked by domperidone.     

PITUITARY FUNCTION IN PATIENTS WITH EVIDENCE OF SPONTANEOUS DISAPPEARANCE OF A PITUITARY ADENOMA

Forty-four untreated patients with an enlarged sella were studied (excluding patients with acromegaly, Cushing's disease, and those with radiological evidence of suprasellar extension). In 20 patients CT revealed a completely or partially empty sella. Based on recent studies we take this finding to signify the previous presence of a pituitary adenoma which has undergone complete or partial necrosis. Ten of the 20 patients had in fact experienced symptoms typical of a pituitary apoplexy compared with only one out of the other 24 patients. Adrenal, thyroid, and growth-hormone insufficiency occurred as often in patients with an empty sella as in those with a solid pituitary tumour. In contrast, plasma prolactin levels were much lower in patients with an empty sella than in patients with a solid tumour (11 vs 166 ng/ml). It is assumed that this discrepancy reflects previous necrosis occurring in an adenoma hyper-secreting prolactin. These results emphasize the importance of taking the spontaneous course of pituitary adenomas into account when assessing the effect of various treatment protocols.     

THE DISAPPEARANCE OF HCG AND RETURN OF PITUITARY FUNCTION AFTER ABORTION

Plasma concentrations of HCG/LH and FSH were monitored after a first trimester abortion in eighteen healthy female volunteers three times weekly until the onset of first menstruation. Plasma concentrations of the HCG were measured with a specific RIA for the beta subunit (beta-sub-HCG) from the samples of six of these subjects. The elimination of HCG during the first 12 days was studied from plasma concentrations measured by the radioimmunoassay of LH. The experimental data were well explained by a mathematical model consisting of three exponentially decreasing components. The half-lives of the two more slowly decreasing components were 27 and 168 h. The estimate of the complete disappearance of HCG was 37.7 days, when the specific (beta-sub-HCG) assay was used. Recovery of pituitary function occurred within 4--9 days after abortion, as judged by increased plasma FSH concentrations. In fourteen of eighteen subjects a midcycle LH peak was observed which occurred between 16 and 29 days after abortion. Plasma oestradiol concentrations increased 2--16 days after the rise in plasma FSH. Considerable amounts of HCG still circulated in the blood but the preovulatory peak of oestradiol never began before HCG/LH concentrations had decreased to below the range of the mid-cycle LH peak.     

STUDIES ON THE ROLE OF HISTAMINE IN HUMAN PITUITARY FUNCTION

To elucidate further the role of histamine in pituitary regulation, TRH and L-DOPA stimulation tests were performed with and without diphenhydramine, cimetidine, or betazole pre-treatment. Betazole blunted the GH response to L-DOPA and slightly enhanced the T3 response to TRH without altering the TSH or PRL increments. Neither diphenhydramine nor cimetidine had any acute effect on the hormonal responses examined. Histamine appears to play only a limited role in these aspects of human pituitary regulation.     

THE FUNCTION OF THE PITUITARY-THYROIDAL AXIS IN ACROMEGALIC PATIENTS V. PATIENTS WITH HYPERPROLACTINAEMIA AND A PITUITARY TUMOUR

The function of the pituitary-thyroidal axis was examined in fifty-three of sixty-two patients with hyperprolactinaemia and a pituitary tumour and in forty of forty-four acromegalic patients, in whom one or more indices of the pituitary-thyroid function were determined before treatment. In the patients with hyperprolactinaemia and a pituitary tumour, sellar + extrasellar tissue (EST) size showed a significant negative correlation with the response of TSH to TRH (ΔTSH) as well as with the circulating T4 and T3 levels. These correlations were not present in the acromegalic patients. In the prolactinoma group a sharp decrease in mean serum T4 and T3 levels was found at sellar + EST sizes exceeding 3 cm². In twenty-three patients with a sellar + EST size of 3 cm² or more, thirteen (57%) showed a T4 level of less than 6 μg/dl against none of twenty-eight patients with a sellar + EST size of less than 3 cm². For T3, using a limit of 120 ng/dl, the corresponding numbers were eight out of thirteen (62%) and none of ten patients respectively. A positive correlation was observed between ΔTSH and the T3 levels but not between ΔTSH and T4, while in the acromegalic patients there was no correlation between TSH reserve and T3 or T4. In the patients with hyperprolactinaemia and a pituitary tumour positive correlations between basal TSH and ΔTSH as well as between T4 and T3 levels were observed. These correlations were not found in the acromegalic patients.
In conclusion: (1) Thyroid function appears to be independent of pituitary tumour size in patients with acromegaly but not in patients with hyperprolactinaemia and a pituitary tumour. (2) In acromegalic patients the high incidence of an impaired TSH response (without hypothyroidism and independent of tumour size) may be caused by suppression of TSH secretion rather than by destruction of thyrotrophic cells.