P. M. Christiansen

THE ACUTE AND LONG TERM EFFECT OF THE H2‐RECEPTOR ANTAGONISTS CIMETIDINE AND RANITIDINE ON THE PITUITARY‐GONADAL AXIS IN MEN

We have investigated the effect on the human pituitary–gonadal axis of the H2‐receptor antagonists cimetidine 300 mg and ranitidine 50, 100, and 200 mg by i.v. bolus, or treatment for 6 months with either cimetidine (1000 mg/day for 1·5 months followed by 400 mg/day for 4·5 months) or ranitidine (200–400 mg/day for 1·5 months followed by 100–200 mg/day for 4·5 months). Administration of the H2‐antagonists (i.v.) to normal men did not cause any release of LH, FSH, or testosterone. Long‐term treatment with cimetidine of duodenal ulcer patients caused a significant rise in basal LH (6 weeks) and FSH secretion (11 weeks). Following reduction of the cimetidine dose LH and later FSH returned to pre‐treatment values. However, despite reduction of the cimetidine dose, the LH and FSH responses to LHRH stimulation were still significantly higher after 6 months of treatment compared with pre‐treatment responses. No changes were found in basal or in LHRH stimulated testosterone or dihydrotestosterone secretion. Treatment with the more potent H2‐antagonist ranitidine did not cause any change in basal or in LHRH stimulated LH and FSH secretion. The effects on LH and FSH secretion observed during cimetidine treatment might therefore be caused by other mechanisms than blockade of H2‐receptors. It is possible that cimetidine, having anti‐androgen properties, blocks pituitary or hypothalamic androgen receptors.

COMPARISON BETWEEN DOSE‐RESPONSES OF PROLACTIN, THYROID STIMULATING HORMONE AND GROWTH HORMONE TO TWO DIFFERENT HISTAMINE H2‐RECEPTOR ANTAGONISTS IN NORMAL MEN

The effects of the histamine H2‐receptor antagonists, ranitidine and cimetidine on prolactin (PRL), thyroid stimulating hormone (TSH), and growth hormone (GH) were studied in six normal males. Intravenous bolus injections of saline and of 50, 100, and 200 mg ranitidine and 300 mg cimetidine were tested. Ranitidine (100 and 200 mg) and cimetidine (300 mg) caused a significant increase in PRL secretion, whereas saline and ranitidine (50 mg) did not. TSH and GH secretion were unaffected by all doses. A dose‐response relationship between ranitidine and PRL was established, and a dose of 65 mg ranitidine was found to be the minimal effective PRL‐releasing dose. Plasma ranitidine concentration was measured by specific RIA. The results indicate an effect of H2‐receptor antagonists on physiological functions in the control of PRL secretion. Histamine, therefore, may play a role in the regulation of PRL secretion.

Modulation of Basal and LRH-Stimulated Gonadotrophin Secretion by Histamine in Normal Men

The effects of histamine (HA) and of HA in combination with H1- and H2-receptor antagonists on basal and LRH-receptor antagonists on basal and LRH-stimulated LH and FSH secretion were investigated in 10 normal men. HA enhanced the LH response to LRH (p less than 0.05), but had no effect on basal LH secretion. The enhancement of LRH-stimulated LH secretion was not observed when either an H1- (mepyramine) or an H2- (cimetidine) receptor antagonist was administered concomitantly with HA. Cimetidine administered alone had no effect on basal or LRH-stimulated LH secretion. HA had no effect on basal or LRH-stimulated FSH secretion. We conclude that the effect of HA on LRH-stimulated LH secretion is mediated through a combined stimulation of H1- and H2-receptors.

Temporal responses of cutaneous blood flow and plasma catecholamine concentrations to histamine H1- or H2-receptor stimulation in man

SummaryWe have studied the effect of histamine and H1- or H2-receptor antagonists on cutaneous blood flow and catecholamine release in man.Histamine was infused alone or in combination with mepyramine, an H1-antagonist or cimetidine, an H2-antagonist for 2 h. Cutaneous blood flow was measured continously with a laser Doppler flowmeter, and noradrenaline and adrenaline concentrations were determined in blood samples drawn every 15 min.The infusion of histamine caused an immediate and sustained vasodilatation. The Concomitant infusion of mepyramine prevented the immediate vasodilatation, but had no effect on the sustained response. The Concomitant infusion of cimetidine was without effect on the immediate vasodilatation, but abolished the sustained response. Infusion of the antagonists alone had no effect on cutaneous blood flow.Histamine caused a rapid and sustained increase in plasma noradrenaline, while the increase during concomitant H1-receptor blockade was delayed but achieved the level observed during the histamine infusion. The response to histamine during H2-receptor blockade was small and transient. The rise in plasma adrenaline was not significant.These findings suggest that histamine causes an immediate cutaneous vasodilatation through H1-receptors and a more sustained response through H2-receptors. The vasodilatation is accompanied by an increase in plasma catecholamine concentrations. Despite the continuous infusion of histamine, blood flow decreased during the last hour of histamine infusion, while the plasma noradrenaline concentration was still elevated.

Effect of histamine on basal and TRH/LH-RH-stimulated PRL and LH secretion during different phases of the menstrual cycle in normal women.

The neurotransmitter histamine (HA) may participate in the regulation of some pituitary hormones. We, therefore, investigated the effect of HA (50 micrograms/kg body weight/h, infusion 0-240 min) on basal and thyrotropin-releasing hormone (TRH) and luteinizing hormone releasing hormone (LH-RH) stimulated prolactin (PRL) and LH secretion in 5 normal women during the early follicular and the luteal phases of the same menstrual cycle. HA had no effect on the basal secretion of the two hormones. However, the PRL response to 200 micrograms TRH during the HA infusion was significantly increased compared to the response to a saline control infusion during the early follicular phase (peak responses were 1,902 +/- 398 vs. 1,228 +/- 230 microIU/ml, p less than 0.025) and during the luteal phase (peak responses were 2,261 +/- 335 vs. 1,647 +/- 245 microIU/ml, p less than 0.05). HA potentiated the LH response to 100 micrograms LH-RH during the early follicular phase (peak responses were 37.1 +/- 4.9 vs. 26.9 +/- 4.5 mIU/ml, p less than 0.05) and during the luteal phase (peak responses were 79.3 +/- 22.5 vs. 50.7 +/- 11.4 mIU/ml, p less than 0.025). We, therefore, found HA to have a potentiating effect on TRH/LH-RH-stimulated PRL and LH secretion in women. The results are similar to our previous findings in men, although the potentiating effects of HA were higher in women.

Plasma concentrations of pituitary and peripheral hormones during ranitidine treatment for two years in men with duodenal ulcer

SummaryThe effects of treatment for 2 years with the histamine H2-receptor antagonist ranitidine (100 or 200 mg b.d. for 6 weeks followed by 100 or 200 mg daily) on plasma concentrations of pituitary and peripheral hormones in ten men with duodenal ulcer have been investigated. Stimulation tests with TRH 200 µg i.v. and LHRH 100 µg i.v. were performed before, during (6 and 24 months), and at least 6 months after treatment.Basal and TRH-stimulated prolactin (PRL) secretion was marginally reduced after treatment for 6 months, but not for 24 months. The LH response to LHRH was slightly increased after treatment for 6 months and 24 months and after the end of treatment. The plasma concentrations of TSH, FSH, cortisol, androgenic hormones, and thyroid hormones did not change significantly during treatment. No adverse effects were reported during the observation period.The few, minor changes in pituitary hormone concentrations were all within the reference range. They may be related to ranitidine treatment, but are more likely to be due to age-dependent alterations in hormone secretion. It is concluded that long-term treatment with ranitidine does not cause major changes in circulating hormone concentrations.