F. Massara

Prolactin-Releasing Effect of Domperidone in Normoprolactinemic and Hyperprolactinemic Subjects

The prolactin (PRL)-releasing effect of domperidone (DOM), a novel antidopaminergic drug which does not cross the blood-brain barrier, was investigated in normoprolactinemic subjects, in subjects with physiologic puerperal hyperprolactinemia or pathological hyperprolactinemia. DOM (4 mg i.v.), administered to 8 normoprolactinemic women, induced a clear-cut and sustained rise in plasma PRL, with peak levels occurring 15-30 min postinjection; the effect of the drug was also evident in 3 normoprolactinemic women at the dose of 0.25 mg i.v. Also in 8 puerperal women (postpartum day 2) intravenous administration of 4 mg DOM was followed by an increase in plasma PRL (51-517% of baseline levels, 15-45 min postinjection). Administration of DOM (4 mg i.v.) to 16 subjects with pathological hyperprolactinemia, evidenced the presence of 14 DOM-nonresponder (maximum percent increase of baseline PRL 48%) and 2 DOM-responder subjects. In 8 of the DOM-nonresponder subjects the existence of a pituitary tumor was established at surgery by selective removal of an adenoma (7 subjects) or a teratoma (1 subject): of the 6 subjects who did not undergo surgery, 3 had biochemical and/or radiologic evidence suggestive of a PRL-secreting tumor and 1 was acromegalic. These results indicate that DOM is capable of releasing PRL both in normoprolactinemic subjects and subjects with puerperal hyperprolactinemia. In contrast, DOM is unable to modify PRL levels in most subjects with pathological hyperprolactinemia, with proven or suspected pituitary tumors.

GROWTH HORMONE RESPONSES TO PYRIDOSTIGMINE IN NORMAL ADULTS AND IN NORMAL AND SHORT CHILDREN

There is evidence indicating that the cholinergic system positively modulates GH release probably by inhibiting somatostatinergic tone. In the present study, the effects of cholinergic enhancement by pyridostigmine, (PD), a cholin‐esterases inhibitor, on GH release in normal adults (n= 14) (NA) and in both normal (n = 5) (NC) and short children (n = 19) (SC) with familial short stature (n =7) or constitutional growth delay (n= 12) were studied. In SC the insulin hypoglycaemia (IH)‐induced GH increase was also studied. In both NC and SC 60 mg orally PD induced a significant GH increase with mean peak at 90 min (mean ± SEM 11.0 ± 2.2 ng/ml in NC and 11.2 ± 2.3 ng/ml in SC). The GH areas under response curve (AUC) were 379.3 ± 76.6 and 327.8 ±43.2 ng/ml/h in NC and SC respectively. In NA 120 mg orally PD induced a significant GH increase with mean peak at 120 min (5.1 ± 11 ng/ml) which was significantly lower (P < 0.05) than that observed in both NC and SC. This statistical difference was strengthened by evaluating AUC (NA: 205.6 ± 33.7 ng/ml/h, P < 0.05 vs NC and SC). The correlation of drug dosage with body area ruled out that this difference could be related to the different PD dose in adults and children. In SC, IH induced a GH increase significantly lower than that observed after PD (GH peak 7.8 ± 0.6 vs 16.4 ± 1.9 ng/ml P<0.001). Our data show that cholinergic enhancement by PD induces a higher GH increase in both normal and short children than that observed in adults. This could be related to a variation of somatostatinergic tone. The higher PD‐induced GH response compared to the IH‐induced one indicates that PD test may be considered a more potent GH provocative stimulus than insulin hypoglycaemia.

INCREASED THYROTROPHIN SECRETION INDUCED BY SULPIRIDE IN MAN

100 mg i.m. sulpiride (a dopamine‐receptor‐blocking drug) led to a significant rise in plasma TSH in normal women, in female patients with galactorrhoea, and, to a much more marked degree, in male and female patients with primary hypothyroidism. In the hypothyroid patients, there was a significant positive correlation between basal TSH and its maximum increment after sulpiride. The drug proved to be an even more potent stimulator of PRL, at least in subjects with normal blood PRL. Normal males, on the other hand, displayed no significant changes in TSH after sulpiride. Continuous administration (150 mg/day per os for 15 days) also resulted in enhancement of TSH in normal women. These results suggest that TSH release is controlled by a dopaminergic mechanism in man. The more accentuated TSH response in hypothyroid patients may perhaps be attributable to the absence of negative‐feedback on the part of thyroid hormones.

Influence of glucagon on plasma levels of potassium in man

SummaryTo investigate the role played by glucagon in the regulation of plasma potassium, we have examined the behaviour of this ion during four 2 h infusions of saline, glucagon (200 ng/min), cyclic somatostatin (priming dose of 50 μg followed by 5.8 μg/min) and somatostatin plus glucagon in 6 normal volunteers. Glucagon alone produced no change in potassium, despite an increase in insulin. Somatostatin, in addition to depressing insulin, produced a slight but significant (p < 0.01) increase in potassium (Δ max: 0.2–0.8 mmol/l: mean ± SEM, 0.4±0.1). Infusion of somatostatin together with glucagon suppressed the glucagon-induced increase in insulin and greatly augmented the increase in blood glucose. Potassium rose significantly more (p < 0.02) than after somatostatin alone (Δ max: 0.5–1.3 mmol/l; mean 0.9±0.1), indicating that hyperkalaemia results from hyperglucagonaemia in the absence of insulin. Evidence is presented that this last phenomenon is not mediated by hyperglycaemia or by a reduction in aldosterone secretion. It is suggested that low blood insulin and increased glucagon could be one of the mechanisms that underlie or magnify the hyperkalaemia observed in cases of serious stress or decompensated diabetes.

Long term treatment with oral single administration of bromocriptine in patients with hyperprolactinemia

In the treatment of hyperprolactinemia bromocriptine is generally administered in 3 daily doses during the day. Due to the limited compliance of patients under this long term regimen, in 16 hyperprolactinemic patients we investigated the efficacy and tolerability of the treatment with this dopaminergic drug administered as a single evening dose. This dose was the same which the patients had been assuming previously on a tid basis. Chronic treatment (4–12 months) with an oral single evening dose of bromocriptine is able to control plasma PRL at least as well as the traditional tid regimen (2.8–21.6 ng/ml vs 1.2–31.8 ng/ml). Furthermore, during this single dose regimen the side effects were of lesser intensity and extent. Since the compliance of the patients with the single dose regimen was very good and the efficacy the same in reducing plasma PRL and controlling the clinical manifestations with a lower rate of side effects, we suggest to extend this regimen to all patients with hyperprolactinemia treated with bromocriptine after successful reduction of plasma PRL levels is obtained.

Prolactin releasing effect of sulpiride isomers in rats and man

Sulpiride, an antipsychotic drug of the benzamide class, reportedly displaces stereospecifically [3H]-butyrophenones from putative dopamine (DA) binding sites in rat striatum. To evaluate if sulpiride displays the same stereospecificity in the inhibition of pituitary DA receptors, the effect of the two (-)- and (+)-sulpiride isomers was tested with regard to their ability to stimulate prolactin (PRL) secretion in rats and man and to displace [3H]-spiroperidol bound to rat anterior pituitary receptors. In male rats, (−)-sulpiride at doses of 0.1 and 1.0 mg/kg i.p., induced a maximum PRL-releasing effect, not different from that evoked by a dose of 10 mg/kg of the compound. (+)-Sulpiride was active only at the dose of 10 mg/kg i.p., and its PRL-releasing effect was superimposable to that evoked by the same dose of (−)-sulpiride. Similarly, in 8 normal subjects (4 men and 4 women) only (−)-sulpiride was active as PRL releaser when the low dose of 0.25 mg i.v. was used; when the higher dose of sulpiride was used (4.0 mg i.v.), it induced a rise in plasma PRL of the same entity for both isomers at early post-injection times (15–30 min) but greater with the (−)-isomer at the following time intervals (45–120 min). (−)-Sulpiride displaced [3H]-spiroperidol bound to rat anterior pituitary homogenates with a potency about 100 times as greater as that showed by (+)-sulpiride. In all, these data indicate that sulpiride isomers display at the level of pituitary DA receptors for PRL control the same stereospecificity exhibited on a population of striatal DA receptors.

Prolactin and TSH responses to both domperidone and TRH in normal and hyperprolactinaemic women after dopamine synthesis blockade.

A study of the effect of α‐methyl‐1‐tryosine (metyrosine) blockade (2 g/d for 2 d) of dopamine (DA) synthesis on the PRL and TSH response to domperidone (DOM) and TRH in normal women and subjects with pathological hyperpro‐lactinaemia is reported.

Impaired prolactin responsiveness to dopamine antagonists in acromegaly

Prolactin (PRL) and growth hormone (GH) secretion have been evaluated in 17 acromegalic patients following acute administration of two dopamine (DA) receptor antagonists, i.e. sulpiride (SULP) and domperidone (DOM). Six patients had persistent hyperprolactinemia. In 8 normoprolactinemic patients, i.m. injection of 100 mg SULP elicited only a slight rise iN plasma PRL, which was strikingly lower than that SULP induced in control subjects. Likewise, an i.v. bolus injection of DOM (4 mg) was barely effective to raise plasma PRL in the 11 normoprolactinemic and the 6 hyperprolactinemic patients. DOM was instead capable of inducing a clear-cut rise in plasma PRL in normoprolactinemic controls and in a group of subjects with puerperal hyperprolactinemia. Neither drug affected GH secretion in acromegalic patients. It is proposed that a defective tuberoinfundibular DA function or, alternatively, a diminished PRL reserve due to a decrease pituitary lactotroph mass may be responsible for the blunted PRL responsiveness of acromegalics. However, standing the paucity of present knowledge on the pituitary PRL secretory pool in acromegalics, neither hypothesis seems capable to account satisfactory for the reported results.

Effects of a new long-acting form of bromocriptine on tumorous hyperprolactinemia

Recently, a new long-acting form of bromocriptine (Parlodel LA, Sandoz) has been developed and it has already been found to be effective in lowering plasma PRL levels in normal volunteers and postpartum women. This work reports the clinical, hormonal and radiological effects of a single 50 mg dose of long-acting bromocriptine in 10 patients with tumorous hyperprolactinemia (2 microprolactinomas, 6 macroprolactinomas, 1 acromegaly and 1 nonsecreting macroadenoma). A rapid and long-lasting (28 days) normalization of PRL levels was observed in patients with microprolactinoma, acromegaly and nonsecreting adenoma. None of the 6 patients with macroprolactinoma underwent normalization of plasma PRL, but the latter was markedly reduced (61–80% of basal levels). A second injection of the drug in 5 macroprolactinoma patients induced a further reduction of plasma PRL levels in 2 of them. No changes in the tumor size were observed either after the first or the second injection of long-acting bromocriptine in any of the patients. This injectable form of bromocriptine induced nausea and/or mild hypotension Jasting a few h in 4 of the 10 patients and was better tolerated than the oral form as regards both the duration and intensity of the side effects. Thus, as this drug has proved to be efficacious and well tolerated by the patients, this long-acting form of bromocriptine may be a valid therapeutical approach for initiating medical treatment of patients with prolactinoma.

Glucagon-induced increase in plasma potassium levels in Type 1 (insulin-dependent) diabetic subjects

SummaryTo investigate the hypothesis that in Type 1 (insulin-dependent) diabetes the increase in plasma potassium during decompensation may be due to a rise in glucagon concentrations, we have measured plasma glucose, potassium and glucagon levels in five diabetic patients during two tests with 0.154 mol/l saline or somatostatin (500 μg/h) performed on two successive days. The patients were maintained normoglycaemic overnight by means of a continuous insulin infusion. After insulin withdrawal during the saline infusion, glucose and potassium levels rose markedly (A maximum: glucose, 12.0±1.5 mmol/l; potassium, 0.73±0.12 mmol/l), while glucagon showed a slight, but significant increment (Δ maximum: 10.6±1.0 pmol/ml, p < 0.05). The potassium increment was not mediated by a reduction in blood pH. Somatostatin abolished the rise in glucagon concentration and simultaneously markedly inhibited the rise in potassium and glucose levels. It is concluded that in acute insulin deficiency, glucagon could be one of the factors that contributes to hyperkalaemia.