Effects of nomifensine on growth hormone and prolactin secretion in normal subjects and in pathological hyperprolactinemia.

We have studied the effect of the oral administration of 200 mg nomifensine (nom), a drug which activates the dopaminergic system, on GH and PRL secretion in 15 normal subjects, 18 patients with idiopathic hyperprolactinemia, and 17 patients with tumoral hyperprolactinemia. GH levels increased significantly after nom in normal subjects (basal, 0.96 +/- 0.76 ng/ml; peak 4.6 +/- 0.61 ng/ml; P less than 0.01) and patients with hyperprolactinemia, both idiopathic (basal, 1.0 +/- 0.38 ng/ml; peak, 4.2 +/- 1.0 ng/ml; P less than 0.05) and tumoral (basal 0.88 +/- 0.3 ng/ml, peak 6.68 +/- 1.2 ng/ml; P less than 0.01). Peak GH levels higher than 5 ng/ml were observed in 8 of 15 normal subjects, 6 of 18 patients with idiopathic hyperprolactinemia, and 8 of 17 patients with tumoral hyperprolactinemia. PRL levels decreased in response to nom in normal subjects, but not in patients with idiopathic or tumoral hyperprolactinemia. A reduction in plasma PRL levels of at least 30% below the baseline was observed only in two patients with idiopathic hyperprolactinemia and in none of the patients with tumoral hyperprolactinemia. These results demonstrate that nom does not discriminate between idiopathic and tumoral hyperprolactinemia. Since nom probably requires a hypothalamic pool of dopamine to bring about its GH stimulatory effect, the suggestion that the lack of a PRL-lowering effect of the drug is attributable to a dopamine deficiency is not supported by our data.

Effectiveness of the dopamine agonist lisuride in the treatment of acromegaly and pathological hyperprolactinemic states.

We have studied the effects of the chronic administration of the dopamine agonist lisuride (L) in 21 acromegalics (group 1) and in 25 patients with pathological hyperprolactinemia (group 2). Before starting the treatment levels of PRL and/or GH were determined during acute tests with L (0.3 mg po) or TRH (0.2 mg iv). L was given in doses ranging between 0.4 and 2.4 mg/day. GH and/or PRL were determined at monthly intervals, TRH (6 patients of group 1 and 10 of group 2) was repeated during L therapy. In 10 patients of group 1 GH levels were reduced below 10 ng/ml by L therapy; in the remaining patients GH levels were reduced by 50% of the pretreatment values or they were unchanged. The correlation (p less than 0.01) found between GH levels during acute and chronic L administration indicates that GH changes after acute test are predictive of the outcome of the treatment. In all patients PRL was reduced during the therapy to at least 50% of the basal values and in most patients PRL fell to the normal range. No correlation was found between PRL levels during acute and chronic L administration. During the therapy TRH still increased GH levels in most patients whereas it failed to raise PRL. The withdrawal of L was followed by a rapid return of GH to the pretreatment values whereas PRL showed a slower increase. In acromegalics whose GH was lowered by L there was also a marked amelioration of clinical and metabolic parameters. The lowering of PRL was accompanied by the resumption of ovulatory menses even in patients with tumoral hyperprolactinemia. Males reported improvement in sexual performance. An improvement of visual field occurred in 1 patient. In 1 patient with a large prolactinoma serial computerized tomography scans performed during 2 yr of treatment showed a marked reduction of the tumor size.

Homogeneity in the growth hormone-lowering effect of dopamine and somatostatin in acromegaly.

We have studied the effect of maximally inhibiting doses of dopamine (DA) or somatostatin on GH levels in 39 acromegalic patients. The GH-lowering effects of the two drugs were highly variable in different patients. A significant correlation (r = 0.45; P < 0.01) was found between the percent changes obtained during the infusions of DA (500 microgram/min) and somatostatin (3.33 microgram/min). Pretreatment with L-sulpiride markedly blunted the inhibitory effect of DA but did not affect the response to somatostatin. We conclude that the GH-secreting cells of acromegalic patients contain separate receptors for DA and somatostatin. We hypothesize that the partial or total lack of responsiveness to DA or somatostatin may be due to the loss of receptors for these agents on the GH-secreting neoplastic cells.

Effects of sulpiride induced hyperprolactinaemia in patients with Turner's syndrome.

In order to evaluate the interference of prolactin (PRL) on some aspects of pituitary-gonadal derangement observed in patients with hyperprolactinaemic amenorrhoea (HA), a GnRH stimulation test (100 micrograms i.v.) was performed on twenty-one patients with hyperprolactinaemia without evidence of pituitary tumour and in nine subjects with Turner's syndrome (TS) before and after sulpiride administration (200 mg/day orally, for 3 months). In patients with HA an enhanced response of gonadotrophins to GnRH was observed. In patients with TS a further increase of the gonadotrophin hyper-responsiveness to the releasing hormone occurred when hyperprolactinaemia was induced by chronic sulpiride administration. Since, in these patients, appreciable ovarian steroidogenesis is lacking, a direct effect of the increased plasma PRL at the hypothalamo-pituitary level is likely. In hyperprolactinaemic amenorrhoea pituitary hyper-responsiveness may not be due to PRL effects on ovarian steroidogenesis.

Lisuride hydrogen maleate: evidence for a long lasting dopaminergic activity in humans.

In 12 acromegalics a single oral dose of 0.2 mg lisuride, an ergoline derivative, significantly reduced plasma PRL but not GH concentrations. Three-tenths milligram of the drug significantly reduced plasma levels of the two hormones. Four-tenths milligram of lisuride did not augment this inhibitory effect. Plasma PRL levels were suppressed in all patients, whereas GH levels were reduced by more than 50% of the base-line values in only seven patients who also responded to the administration of 2.5 mg bromocriptine (CB154). In the patients unresponsive to lisuride, CB154 also failed to change GH levels. The suppressive effect of lisuride started at 60 min (at 150 min for CB154) and plasma GH and PRL levels were still markedly suppressed at 300 min. Plasma GH and PRL concentrations were consistently reduced in two acromegalic patients during 2 weeks of chronic treatment with 0.3 mg lisuride four times a day. In six normal subjects, TRH-induced PRL release was significantly inhibited by pretreatment with 0.3 mg of the drug. The similarity in the effects of lisuride and CB154 suggests that the observed effects of lisuride on GH and PRL are attributable to the known dopaminergic activity of the drug. This conclusion is supported by the data showing that pimozide effectively counteracted the inhibitory action of lisuride on GH and PRL release. We suggest that lisuride may be of value in the medical treatment of acromegaly and hyperprolactinemic states.

Evidence for a dopaminergic activity of methysergide in humans.

The acute administration of 2 mg of methysergide significantly reduced plasma prolactin levels in nine normal subjects and in seven hyperprolactinaemic patients. The prolactin lowering effect of this drug was abolished by sulpiride. Morever methysergide lowered plasma GH levels in four out of nine acromegalic patients, who were also responsive to a dopaminergic drug such as bromocriptine. Although methysergide did not significantly blunt the TRH-induced prolactin release, our data suggest that this drug may affect GH and prolactin release through a dopaminergic mechanism of action. This effect should be taken into account when methysergide is employed as antiserotoninergic drug in neuroendocrinological studies.

Inhibitory effect of an ergoline derivative, methergoline, on growth hormone and prolactin levels in acromegalic patients.

Plasma levels of growth hormone (GH) and prolactin (PRL) were measured in twelve acromegalic patients after acute administration of an ergoline derivative (methergoline) which has been proposed as a specific serotoninergic blocking agent. The administration of methergoline (4 mg p.o.) was followed by a significant decrease in plasma GH and PRL concentrations. The administration to the same subjects of CB 154 (2.5 mg p.o.), a known stimulator of dopaminergic receptors, led to results almost superimposable to those obtained with methergoline although the suppressive effect of CB 154 on GH and PRL levels was more sustained. Also on the ground of results obtained in these patients with the use of cyproheptadine, phentolamine, or pimozide, we have concluded that methergoline inhibition of GH and PRL release is, in acromegalic patients, most probably due to a dopaminergic mechanism of action.

Effect of dopamine infusion on plasma levels of growth hormone in normal subjects and in agromegalic patients.

In ten normal subjects and in twenty acromegalic patients plasma levels of growth hormone were studied after administration of L-dopa and a dopamine infusion. In the ten normal subjects L-dopa, but not dopamine, increased plasma levels of GH. In the acromegalic patients both L-dopa and dopamine were followed by an inhibition of GH release. Since dopamine does not cross the blood-brain barrier, these results, although not excluding a site of action at median eminence level, support the thesis that the inhibitory effect of dopaminergic stimulation on GH release in acromegaly possibly involves receptors present on GH-secreting cells.

Stable reduction of plasma growth hormone (hGH) levels during chronic administration of 2-Br-alpha-ergocryptine (CB-154) in acromegalic patients.

In 7 acromegalic patients in whom plasma hGH concentrations had dropped acutely after a single dose of 2-B r-alpha-ergocryptine (CB-154, 2.5 mg orally) chronic CB-154 treatment (10 mg orally for 30 days) was also accompanied by a significant and stable reduction of hGH. Withdrawal of the drug was followed by a rapid return of hGH to pretreatment values. Reinstatement of oral CB-154 treatment resulted again in suppression of hGH levels measured 30 and 60 days later. In 5 patients, unresponsive to acute administration of CB-154, no appreciable variation in hGH levels was present after 30 days of treatment. These results suggest that 2-Br-alpha-ergocryptine offers a new approach to the medical treatment of acromegaly.