M. F. Scanlon

Dopamine is a physiological regulator of thyrotrophin (TSH) secretion in normal man.

Using a sensitive and precise radioimmunoassay for human TSH we have demonstrated significant elevations in serum TSH levels in euthyroid volunteers following administration of the dopamine receptor blocking drug metoclopramide when compared with placebo. The degree of TSH response is significantly greater in females than in males and is sustained over a 3‐hour period after a single oral 10 mg dose of metoclopramide. The degree of TSH release after metoclopramide is inversely related to the basal TSH level suggesting that dopamine is a determinant of low daytime TSH levels and is thus implicated in the circadian rhythm of TSH secretion. Pretreatment with 10 mg of metoclopramide orally, one hour before TRH administration leads to significant enhancement of the TSH response to TRH. Our findings provide further evidence for the physiological inhibitory role of dopamine in the control of TSH secretion in normal man. The possible mode of action of dopamine and the clinical implications of this neuroregulatory pathway are discussed.

ALTERED DOPAMINERGIC REGULATION OF THYROTROPHIN RELEASE IN PATIENTS WITH PROLACTINOMAS: COMPARISON WITH OTHER TESTS OF HYPOTHALAMIC‐PITUITARY FUNCTION

This study was carried out to test the hypothesis that sustained hyperprolactinaemia in patients with prolactinomas stimulates hypothalamic dopaminergic activity via a short loop positive feedback effect of prolactin (PRL). The intensity of dopamine (DA) effects on the pituitary around the adenoma was evaluated by measuring thyroid stimulating hormone (TSH) responses to intravenous injection of domperidone (10 mg) a new DA receptor blocking drug that does not penetrate the blood‐brain barrier. TSH responses have been compared with those of PRL to the same agent. Eight females with prolactinomas showed greater TSH release after domperidone than nine normal females (sum of TSH increments over 120 min 17·5 ± 1·7 v. 8·9±1·5 mu/l, P < 0·001) whilst PRL release was reduced (sum of PRL increments over 120 min 5·9 ± 2·4 v. 21·8 ± 3·8 mu/l ± 10−3, P < 0·01). Amongst nineteen hyperprolactinaemic females with apparently normal pituitary fossae (plain skull X‐ray), ten showed an exaggerated TSH response (ΔTSH, 4·2 ± 0·6 mu/l, range 2·5–9·40 mu/l) and reduced PRL response to domperidone, comparable with established tumour cases. In the remaining nine normal fossa hyperprolactinaemic females, the TSH and PRL responses to domperidone were similar to normal females.

EVIDENCE FOR DOPAMINERGIC CONTROL OF THYROTROPHIN SECRETION IN MAN

After administration of the dopamine-receptor-blocking drug, metoclopramide (10 mg orally), there is significant release of thyrotrophin (T.S.H.) in hypothyroid patients which is not evident in euthyroid subjects. This is not due to spontaneous fluctuation in basal T.S.H. levels, and it indicates inhibitory dopaminergic control of T.S.H. release in man. The lack of significant T.S.H. release in euthyroid subjects may be due to the inhibitory effects of normal circulating levels of T3 and T4 on T.S.H. release. The T.S.H. response in hypothyroidism is significantly correlated with both T3 and T4 levels, suggesting suppression of this inhibitory pathway in increasingly severe hypothyroidism.

EFFECT OF THYROXINE REPLACEMENT THERAPY ON PLASMA INSULIN‐LIKE GROWTH FACTOR 1 LEVELS AND GROWTH HORMONE RESPONSES TO GROWTH HORMONE RELEASING FACTOR IN HYPOTHYROID PATIENTS

The aim of this study was to evaluate the effect of T4 replacement therapy on plasma insulin‐like growth factor 1 (IGF‐1) levels in patients with primary hypothyroidism to see whether recovery of pituitary GH responsiveness to GRF was associated with increased plasma IGF‐1 levels. IGF‐1 levels and GH responses to GRF (1 μg/kg) were measured in 21 patients with primary hypothyroidism before and after T4 replacement therapy. T4 increased plasma IGF‐1 levels (57.2 ± 4.4 vs 75.9 ± 8‐8 ng/ml, mean ± SEM, P<0.05) and GH responses to GRF as assessed both by peak GH levels (9 ± 1.5 ng/ml before treatment vs 16.7 ± 3 ng/ml after treatment, mean ± SEM, P <0.05) and area under curve (496 ± 92 before treatment vs 896 ± 161 after treatment, mean‐± SEM, P < 0.05). Linear regression analysis showed a positive correlation between free T3 and IGF‐1 levels after treatment (r= 0‐37, P <0.05) and a negative relationship between plasma IGF‐1 levels before treatment and a IGF following T4 replacement therapy (r= 0.45, P < 0.025). However, no correlation was found between plasma IGF‐1 levels and GH responses to GRF, suggesting that GH responses to GRF are of no predictive value in relation to the recovery of plasma’ IGF‐1 levels following T4 replacement therapy in hypothyroid patients.

INFLUENCE OF DOPAMINERGIC, ADRENERGIC AND CHOLINERGIC BLOCKADE AND TRH ADMINISTRATION ON GH RESPONSES TO GRF 1–29

In order to establish the influence of dopaminergic, á‐adrenergic and cholinergic pathways on GRF‐mediated GH release we have studied the GH responses to GRF 1–29 (100 or 50 μg as i.v. bolus) alone and in combination with metoclopramide (MCP, 10 mg, i.v.), thymoxamine (THYM, 210 μg/min, 150 min infusion), and atropine (1.2 mg, i.v.). We have also investigated any possible interaction between TRH and GRF in view of the reported inhibitory effects of TRH infusion on stimulated GH release. Dopaminergic and á‐adrenergic blockade with MCP and THYM respectively, did not have any effect on the GH responses to GRF. This lack of effect strongly suggests that any action which these neurotransmitters may exert on GH secretion is not at a pituitary level. TRH did not modify the GH response to GRF suggesting that the inhibitory effect on stimulted GH secretion is exerted at a hypothalamic level. In contrast, GH responses to GRF were significantly reduced by prior administration of atropine. These data support the view that cholinergic pathways play an important role in the regulation of GH secretion and such control may be exerted at both hypothalamic and pituitary levels.

DOMPERIDONE: A NOVEL AGENT FOR THE INVESTIGATION OF ANTERIOR PITUITARY FUNCTION AND CONTROL IN MAN

Administration of the novel agent domperidone (10 mg iv), which combines the properties of specific dopamine receptor blockade and inability to cross the blood‐brain barrier, leads to acute and significant TSH and PRL release in man. This suggests that the in vivo site of action of endogenous dopamine in the inhibitory control of these two hormones is either the anterior pituitary or median eminence, since these tissues lie outside the blood‐brain barrier. This class of drug is of potential value both clinically and experimentally in the investigation of anterior pituitary control mechanisms.

ALPHA‐2‐ADRENERGIC PATHWAYS RELEASE GROWTH HORMONE VIA A NON‐GRF‐DEPENDENT MECHANISM IN NORMAL HUMAN SUBJECTS

Administration of a supramaximal dose of GRF 1‐44 (200 μg, i.v.) to normal human volunteers increased GH levels while a further bolus of GRF (200 μg i.v.) given 2 hours later failed to increase plasma GH levels. In contrast, alphaadrenergic receptor agonism with either propranolol‐adrenaline infusion or clonidine increased plasma GH levels at a time when GH responses to this supramaximal dose of GRF were absent. This indicates that alpha‐adrenergic pathways stimulate GH secretion through a non‐GRF‐dependent mechanism in normal human subjects.

Growth hormone responses to GRF 1-29 in patients with primary hypothyroidism before and during replacement therapy with thyroxine

It is well known that hypothyroidism is frequently associated with impaired GH responses to different stimuli. In the present study we have evaluated GH responses to GH‐releasing factor (GRF) in patients with primary hypothyroidism before and during T4 replacement therapy. Fourteen patients (age range 26–60 years) underwent two GRF tests (1 μg/kg) before and during replacement therapy (150 μg/d). Administration of T4 increased peak GH responses to GRF in 9 patients and in the group as a whole (mean ± SEM, 17·0 ± 2·8 vs 32·6 ± 5·7 mU/l, P > 0·02). When the data are analysed by means of area under the curve (AUC), the GH response to GRF was increased by T4 in 10 patients and in the group as a whole (mean ± SEM, 51·7 ± 14·3 vs 101·5 ± 28·1, P > 0·02). These data indicate that thyroid hormone replacement therapy enhances the responsiveness of the somatotroph to GRF 1–29 in patients with primary hypothyroidism.

Pituitary effects of somatostatin

Abstract Somatostatin (SRIF) has been shown to have a variety of effects on pituitary hormone secretion. Studies with SRIF may be divided into three categories: pharmacologic, pathologic, and physiologic. In pharmacologic studies SRIF is given by intravenous infusion to normal volunteers and circulating levels of pituitary hormones are measured, usually by radioimmunoassay. Conclusions drawn from such an approach may not reflect the physiologic situation since SRIF is administered into the systemic venous circulation, usually in large doses, whereas it is likely that normally much smaller amounts of SRIF reach the pituitary via the portal venous circulation or reach other areas in the hypothalamus by axonal flow or local diffusion. Again, incubation of pituitary fragments in vitro with SRIF is a highly artificial situation for measurement of hormone in the gland or medium. In pathologic studies infusions of SRIF are given to patients with a variety of pituitary diseases. Tumor tissue may well respond in an abnormal way, and SRIF and other hormone receptors on tumor cells may differ from those on normal pituitary cells. Physiologic studies bearing on the role of SRIF in hypothalamic-pituitary function in normal man are difficult to perform. It is not possible to measure SRIF in the portal venous circulation, and assays of peripheral levels of SRIF are subject to methodologic problems. One ingenious approach has been devised by Ferland et al. 1 and Tanjasiri et al. 2 These workers either incubated rat pituitary tissue with antibodies to SRIF or infused the antiserum into rats and observed the effects on pituitary hormone secretion. In the event of a role of SRIF in the physiologic control of growth hormone (GH) and thyrotropin (TSH) secretion the antiserum should neutralize endogenous SRIF and lead to an increase in the plasma or medium levels of these two hormones. The release of both GH and TSH in these experiments lends strong support to the view that SRIF exerts a physiologic effect in the control of GH and TSH secretion in the rat. Unfortunately, it is not possible to carry out similar studies in man, but if pharmacologic methods can be developed to inhibit or stimulate endogenous secretion of SRIF, similar information might be obtained.

COMPARISON OF LONG-ACTING ANALOGUES OF LUTEINIZING HORMONE RELEASING HORMONE IN MAN

Currently, LHRH, when used therapeutically, is given by parenteral injection every 8 h. We have looked at the release of LH and FSH induced by five analogues of LHRH and compared this with gonadotrophin release after synthetic LHRH. The analogues were substituted in position 6 or in positions 6 and 10 and were given intravenously, intranasally or subcutaneously in three separate studies. After intravenous administration of 100μg, all analogues caused greater release of LH and FSH than did synthetic LHRH. Given intranasally in a dose of 500 μg, three of the four analogues tested caused greater LH and FSH release than did LHRH. With tryptophan substitution in position 6 (D‐TRP6‐LHRH), mean LH levels in five subjects were still above the normal range 24 h after a single intranasal dose. The intranasal administration of selected analogues of LHRH has great potential in the treatment of conditions associated with deficient gonadotrophin secretion, provided that pituitary overstimulation, which may eventually lead to a decrease in LH and FSH output by the anterior pituitary, is avoided.