ACUTE ENDOCRINE PROFILE OF SULPIRIDE IN THE HUMAN*
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Abstract:
Normal men and normally menstruating women received i.m. injections of 0.1 to 4.0 mg/kg sulpiride. This psychotropic drug induced a very rapid (already significant after 5 minutes) and sustained (still significant after 7 hours) elevation of prolactin (PRL) concentrations in all subjects with no consistent modification of LH and FSH. After injection of 4.0 mg/kg, there was similarly no modification of mean TSH concentrations in the women tested in the luteal phase, as well as of mean GH levels in men. Sulpiride prevented the inhibitory effect on PRL levels of 500 mg levodopa, administered orally simultaneously; levodopa administered 2 hours prior to sulpiride failed to counteract the PRL-stimulatory effect of sulpiride. Under chronic sulpiride-induced hyperprolactinaemia, levodopa exhibited however a very slight inhibitory effect on PRL concentrations. These data are in agreement with the hypothesis that sulpiride acts mainly at the pituitary level by blocking dopamine receptors of the lactotropes and support the concept that the menstrual cycle perturbations observed under chronic sulpiride administration result from hyperprolactinaemia itself or from a mechanism quite similar to that by which sulpiride induces hyperprolactinaemia.Keywords:
Sulpiride
Hyperprolactinaemia
Summary: Ninety‐eight women with mild hyperprolactinaemia (<4N) were followed for a mean duration of 5.5 years. Where pregnancy was desired treatment with bromocriptine (pM clomiphene) was effective in 87%. Following cessation of bromocriptine therapy almost one‐third had a ‘spontaneous' resolution of hyperprolactinaemia and resumed cyclical menstrual activity and fertility. Pituitary tumours were identified on coned‐view assessment in 9% of patients at the time of presentation and a further 10% during follow‐up. Although some of these latter tumours may have been diagnosed earlier had CAT scans been performed routinely in all hyperprolactinaemic patients, such a policy would be hard to justify for those with mild hyperprolactinaemia as the tumours were small, produced no harmful effects, and would almost certainly have responded to bromocriptine should this have been administered. All patients found to have pituitary tumours and given bromocriptine, showed no evidence of tumour progression subsequently, even where pregnancy occurred and the bromocriptine therapy was ceased. In addition, patients without pituitary tumours who were given bromocriptine to achieve pregnancy, were less likely to develop tumours during follow‐up even when pregnancy had occurred. Bromocriptine therapy can thus be justified in mildly hyperprolactinaemic patients to reduce troublesome galactorrhoea, achieve pregnancy, improve the chance of ‘spontaneous' resolution of the menstrual problem and infertility, control or reduce tumour growth where a pituitary tumour has been identified, and reduce the risk of tumour development in patients with normal radiographs at the time of presentation.
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Abstract. CU 38085 (mesulergin) was given at doses ranging from 0.5 to 5 mg/day to 37 patients with pathological hyperprolactinaemia of varying aetiology. The effectiveness of this drug on the suppression of hyperprolactinaemia and on the recovery of gonadal functions was equivalent to that of bromocriptine previously given to a different group of 83 hyperprolactinaemic patients. Tumour shrinkage during treatment with CU 32085 was ascertained in two cases of macroprolactinoma. Histological examination after adenomectomy revealed extensive peri-vascular fibrosis in both cases. In most patients, the efficient doses of CU 32085 were 5-fold lower than those of bromocriptine. After acute oral administration in 10 previously untreated patients, 0.5 mg of CU 32085 had a more prolonged suppressive effect on Prl levels than 2.5 mg of bromocriptine (approximately 18 vs 12 h). According to this, 0.5 mg CU 32085 once a day was sufficient to maintain Prl levels within the normal range in 16 patients. Side-effects were similar in nature and frequency to those induced by bromocriptine and seemed to be dose-dependent. They can be avoided by slowly increases of dose at initiation of treatment.
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Serum prolactin levels were estimated in 100 infertile patients along with the other investigations for infertility. Hyperprolactinaemia was noted in 41% of the infertile patients. Prevalence of hyperprolactinaemia was greater in patients with ovulatory cycles ie, 55% compared to 31.66% in patients with anovulatory and oligo-ovulatory cycles. Fifty per cent of the patients with regular menses had hyperprolactinaemia. Conception occurred in 9 out of 18 hyperprolactinaemic infertile patients (a pregnancy rate of 50%) treated with bromocriptine. Eleven patients (group 1) were treated with bromocriptine from day 5 to day 30 throughout the menstrual cycle and 5 conceptions occurred. Six patients (group 2) with ovulatory cycles were treated with bromocriptine during the luteal phase, from the day of ovulation till next menses and 4 conceived. One patient of prolactinoma treated with bromocriptine failed to conceive. Bromocriptine therapy restricted to the luteal phase in ovulatory patients has yielded successful results. Based on these observations it is suggested that all patients of infertility need serum prolactin estimation.
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CV205-502 is a new non-ergot dopamine agonist currently being studied for the treatment of hyperprolactinaemia. We have assessed the effects of CV205-502 on prolactin secretion and the clinical consequences of hyperprolactinaemia in 16 patients with hyperprolactinaemia who had previously been unsuccessfully treated with bromocriptine. These patients had been either intolerant of and/or resistant to the effects of bromocriptine. Sixteen patients, all women in an age range between 20 and 49 years (mean 31.5 years), were treated for periods of between 8 and 52 weeks with doses of CV205-502 ranging from 0.075 to 0.3 mg taken once daily at night. Seven out of 10 of the patients, who were intolerant of bromocriptine, tolerated CV205-502 better with fewer side effects although the nature of the side effects was similar to that associated with bromocriptine. Only 1 patient from this group stopped taking CV205-502 due to side effects. Six of 11 patients exhibiting bromocriptine resistance showed a significant reduction in the degree of hyperprolactinaemia but normoprolactinaemia was achieved in only 1. Galactorrhoea ceased in 2 of 6 patients, menstruation resumed in 6 of 11 patients presenting with amenorrhoea, and 2 patients conceived. In patients with bromocriptine intolerance and/or resistance, CV205-502 is useful as a second line treatment.
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The effect of sulpiride, a neuroleptic agent, on the secretion of prolactin by the anterior pituitary gland of the rat was studied. A significant increase in serum prolactin was observed after subcutaneous administration of the drug. Although sulpiride (0-10 micronmol/1 or 0-14 mmol/1) had no effect on the secretion of newly synthesized or radioimmunoassayable prolactin in vitro, the drug significantly overcame the inhibitory action that dopamine (0-50 micronmol/1) exerted on prolactin secretion. Rats implanted with a prolactin-secreting pituitary tumour MtTW15 showed an inhibition of prolactin biosynthesis and release. Injection of these rats with sulpiride restored prolactin biosynthesis and release of the hormone toward normal levels. These results demonstrate that sulpiride has a direct effect on the pituitary antagonizing the inhibitory effects exerted by dopaminergic mechanisms, although the drug itself does not stimulate the secretion of prolactin in vitro. Sulpiride may have a direct action on the pituitary lactotrophs in vivo, but effects at higher centres have not been excluded.
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Six adolescents, five males with prolactin-secreting pituitary macroadenomas and one female with idiopathic hyperprolactinaemia, are described. Their ages at presentation ranged from 13 years 7 months to 16 years 6 months. Presenting symptoms included headache, visual field defect, arrested growth and puberty. Only two cases had galactorrhoea. Every case had an elevated serum prolactin level. Three had surgery before the results of serum prolactin were to hand. Each patient was treated with bromocriptine. Bromocriptine suppressed serum prolactin level to normal in four cases, but in the girl with idiopathic hyperprolactinaemia, bromocriptine was not useful. In two boys, serum prolactin was not suppressed with bromocriptine therapy alone, and they were subsequently treated with cabergoline, surgery and irradiation. Nevertheless, in children and adolescents with prolactin-secreting pituitary adenoma, bromocriptine should be the first line of treatment.
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Four hyperprolactinaemic women with large pituitary adenomas with suprasellar extension were given primary tumour therapy with bromocriptine. The treatment resulted in rapid tumour regression in all the women, as verified by repeated computerized tomography (CT) scans. Pronounced visual field defects were present in three of the four women before treatment. All of them had marked improvement of vision within a few days after the initiation of bromocriptine therapy and they regained normal or nearly normal visual fields during the treatment. The raised serum prolactin concentrations decreased to normal levels in all the women. Thus, medical treatment with bromocriptine can induce rapid tumour regression in patients with hyperprolactinaemia and large pituitary tumours.
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Abstract. The effect of 100 mg im sulpiride on plasma Prl levels was studied in 10 normal females, 21 patients with galactorrhoea and normal plasma Prl, 10 women with puerperal hyperprolactinaemia and 27 patients with amenorrhoea-galactorrhoea and high plasma Prl levels. The response to sulpiride in patients with galactorrhoea but normal Prl was slightly higher ( P < 0.05) than that observed in normal women, but only if expressed in per cent. Women with puerperal hyperprolactinaemia respond to the drug with a marked increase in Prl (mean ± sem : 563.0 ± 142.8%), even though their baseline values are already very high (mean ± sem : 133.6 ± 23.8 ng/ml). By contrast, there is a lower or no response to sulpiride in 13 women with pituitary tumour. The same was true in 11 patients with hyperprolactinaemia of uncertain aetiology but also 10 of these subjects presented signs suggestive of a tumour. In the last 3 patients with pathological hyperprolactinaemia in whom a consistent Prl increase after sulpiride was observed, hyperprolactinaemia was probably not of tumourous origin. On the basis of these results, the sulpiride test appears promising for discriminating between organic and 'functional' cases of enhanced Prl secretion.
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