The role of endogenous opioid receptors on anterior pituitary hormone secretion was evaluated by the administration of the opioid receptor antagonist naloxone. The infusion of naloxone (8 mg iv followed by 4 mg/h for 3 h) did not alter basal growth hormone (GH), prolactin (Prl) and thyrotrophin (TSH) secretion but produced a significant rise in cortisol and gonadotrophins in normal man. The infusion of the opiate antagonist appeared to increase the rate and amplitude of luteinizing hormone (LH) pulsatility. Naloxone pre-medication (10 mg iv 30 min before testing) did not alter the pituitary response to TRH and LRH stimulation.These results demonstrate that naloxone can modify basal anterior pituitary hormone secretion and strongly suggest an endogenous opioid modulation of some of these hormones.It has been long known that morphine and related compounds can influence pituitary hormone secre¬ tion by virtue of action on the central nervous system (Meites et al. 1979). The recent discovery of opiate receptors in the brain of mammals as well as the isolation of endogenous opioid-like substances (Hughes et al. 1975), has led to considerable spe¬ culation regarding their physiological role in the control of the hypothalamus-pituitary-axis. Exogenously administered endorphins and enkephalins have been shown to affect pituitary hormone secre¬ tion in experimental animals (Bruni et al. 1977) and the reversal or attenuation of the effect by naloxone, an opiate antagonist, is taken as neuropharmacological evidence for the involvement of opiate receptors in this process.In man, morphine raised basal prolactin (Prl) levels, but did not alter basal growth hormone (GH) and cortisol secretion (Tolis et al. 1975), whereas a long-acting analogue of met-enkephalin released Prl, GH and decreased gonadotrophins and cortisol (Von Graffenried et al. 1978; Stubbs et al. 1978). The prior administration of naloxone blunted these effects (Stubbs et al. 1978).To further investigate the role of opiate recep¬ tors and, possibly, identify an action of endogenous opiate receptors on anterior pituitary function, we have studied the effect of naloxone, a potent opiate antagonist compound, on basal and TRH/LRH stimulated pituitary hormone secretion in man. Materials and Methods Naloxone infusionSix normal males, aged 20-38 years, were studied fast¬ ing and single (subject) blind. Each subject was tested on two different days, the two treatments being given in random order at least 7 days apart. Starting at 08.30 h, an iv cannula was inserted in an antecubital vein for blood sampling and kept patent with 0.9% saline. A second iv cannula was placed in the opposite arm for the infusion of 0.9% saline or naloxone (Naloxone HC1, Endo Labo¬ ratories, Inc., New York, USA). Thirty min after cannuladon, half hourly sampling was started for 420 min.

The effect of propranolol on plasma triiodothyronine (T3), thyroxine (T4) and triiodothyronine uptake by Sephadex G-25 (RT3U%) was studied in fourteen thyrotoxic patients and eight normal volunteers. 40 mg of propranolol as a single oral dose caused significant reduction in total serum T3 which began 60 min after administration. No significant changes were observed in T4 and RT3U% values. Plasma T3 levels remained suppressed during a 5 day course of treatment with propranolol. These results suggest that propranolol has a direct effect on peripheral metabolism of T3 rather than on thyroid hormone secretion.

The effect of acute and chronic administration of metoclopramide on serum prolactin levels in normal subjects was studied. Metoclopramide 10 mg i.v. induced a prompt rise in serum prolactin levels in all subjects. At 180 min the levels remained high. Prolactin levels were markedly elevated during a 5 day course of treatment with metoclopramide in six subjects. It is suggested that metoclopramide could be used in the functional exploration of the hypothalamic-pituitary axis.

Domperidone, an extracerebral dopamine receptor antagonist, was given im to 12 normal subjects and to a group of patients with subclinical hypothyroidism to study its effect on PRL and TSH secretion. Domperidone induced in all subjects a quick and marked increment of serum PRL. At 180 min, the levels remained high. A small but significant increase of TSH was also observed in normal as well as in hypothyroid subjects. Since domperidone does not cross the blood-brain barrier, the hormonal changes observed may be mediated through the pituitary and median eminence, tissues which lie outside of the blood-brain barrier.

Abstract. The effects of acute administration of haloperidol (4 mg im) and pimozide (4 mg orally) on TSH and Prl secretion were studied in normal and hypothyroid man. The TRH-induced TSH secretion before and after pre-medication with pimozide and domperidone, a peripheral dopamine (DA) blocker, was also evaluated in a group of normal subjects. Haloperidol and pimozide induced a marked increment in serum Prl; mean Prl levels were still significantly elevated 12 h following pimozide administration. A small but significant TSH increase was observed following haloperidol and pimozide in normal as well as hypothyroid subjects. Both domperidone and pimozide significantly enhanced TRH-induced TSH release. In another experiment 3 women with primary thyroid failure received an infusion of DA (4 (μg/kg/min for 4 h) with and without domperidone administration. TSH and Prl levels were suppressed by DA, but the effect was completely abolished by domperidone. The results suggest that psychotrophic drugs, such as haloperidol and pimozide, can, like substituted benzamides, stimulate TSH release in man. Since domperidone and DA do not cross the blood-brain-barrier and domperidone significantly enhanced the TSH response to TRH, the data also support the hypothesis that human TSH is regulated by DA at the hypothalamus (median eminence) and/or pituitary level.

A single dose of pyridoxine (300 mg iv) produced significant rises in peak levels of immunoreactive growth hormone GH and significant decrease of plasma prolactin PRL in 8 hospitalized healthy subjects. Serum glucose, luteinizing hormone LH, follicle stimulating hormone FSH and thyrotropin TSH were not altered significantly. In addition, in 5 acromegalic patients who were studied with both L-dopa and pyridoxine, inhibition of GH secretion followed either agent in a similar pattern. These data suggest a hypothalamic dopaminergic effect of pyridoxine.

To assess the role of dopamine receptors in naloxone-induced hormonal changes, the effects of dopamine and metoclopramide on anterior pituitary hormone secretion were studied during the infusion of the opiate blocker in normal men. Naloxone stimulated LH and cortisol secretion in all subjects, whereas FSH, TSH, PRL, and GH did not change. The infusion of dopamine completely suppressed the naloxone-induced LH rise; on the contrary, metoclopramide failed to alter the magnitude of the increments in LH observed during the infusion of the opiate blocker. The cortisol response to naloxone remained unchanged during dopamine and metoclopramide infusion. Metoclopramide stimulated PRL and TSH release during naloxone treatment, whereas dopamine suppressed PRL and TSH secretion. The data do not suggest a participation of dopamine receptors in the naloxone-induced hormonal changes in man and confirm a suppressive effect of dopamine infusion on LH release in humans.

In six acromegalite patients oral administration of 4 mg of metergoline, an antiserotonin agent, produced a fall in plasma growth hormone (GH) and prolactin (PRL) concentrations. In the same patients this inhibitory effect was observed after administration of dopaminergic drugs, L-Dopa and 2-Br-alpha-ergocryptine. Both GH and PRL levels remained suppressed during a 6 day course of treatmnt with metergoline. These results are consistent with the hypothesis that the inhibitory effect of netergoline on GH and PRL release is determined by inactivation of serotonin receptors in the hypothalamus or at the pituitary.