Rob Oosterom

Effect of Tamoxifen Administration on Prolactin Release by Invasive Prolactin-Secreting Pituitary Adenomas

Bromocriptine treatment of patients with invasive prolactin (PRL)-secreting pituitary adenomas does not invariably result in normalization of the plasma PRL levels. We previously showed that the antiestrogenic drug tamoxifen inhibited hormone release from transplantable PRL-secreting pituitary tumors in rats. In 8 patients with invasive PRL-secreting pituitary adenomas with extrasellar extension, the effect of the administration of tamoxifen was investigated on the plasma PRL concentration and on the bromocriptine-mediated inhibition of PRL release. Treatment for 5 days with tamoxifen (20 mg/day) suppressed plasma PRL levels as measured in 5 samples over the day significantly by 20 +/- 3% (means +/- SEM; p less than 0.01). During tamoxifen administration the inhibition of PRL secretion by 2.5 mg bromocriptine was further suppressed by 36 +/- 7%, in comparison with the plasma PRL levels after bromocriptine alone (p less than 0.01). Tamoxifen administration suppressed PRL release in patients with giant invasive PRL-secreting pituitary adenomas, and it had a slight but significant additive or potentiating effect on the bromocriptine-mediated inhibition of PRL secretion. However, despite the simultaneous administration of bromocriptine and tamoxifen, normalization of the circulating PRL levels was not reached in this type of patient.

The mechanism of action of cyproheptadine on prolactin release by cultured anterior pituitary cells

The role of a direct effect of serotonin (5-HT) on PRL secretion at the pituitary level is uncertain. The present study investigated the mechanism of action of the serotonin receptor-blocking agent cyproheptadine on PRL release by normal cultured rat anterior pituitary cells. Cyproheptadine (10 nM-10 microM) and its metabolite desmethylcyproheptadine (a compound which has lost its affinity for serotonin receptors) directly inhibited PRL release, while serotonin, investigated over a wide concentration range, did not reverse this inhibition. The cyproheptadine-mediated inhibition of PRL-release could be completely prevented by 50 microM verapamil. Cyproheptadine strongly inhibited TRH-induced PRL release in the absence, but not in the presence of verapamil. Our studies suggest that cyproheptadine inhibits PRL release at the pituitary level by a blockade of calcium influx at the cell membrane, without affecting the movement of Ca2+ between intracellular compartments.

A close correlation between the amount of met-enkephalin-immunoreactivity and epinephrine in adrenal pheochromocytoma tissue from patients with sipple's syndrome

The concentration of epinephrine, norepinephrine, dopamine, met-enkephalin-, ACTH-, calcitonin- and somatostatin-like immunoreactivity (IR) were determined in the extracts of 9 adrenal pheochromocytomas from 7 patients. Six of these patients had Sipples syndrome. There was a close correlation between the amounts of met-enkephalin-IR and of epinephrine present in the tumor tissue (p less than 0.01). Such a correlation was not found between catecholamines and the other polypeptide hormones investigated. The relevance of the close parallel in the occurrence of met-enkephalin-IR and epinephrine in human adrenal pheochromocytoma tissue is unknown, but it underlines earlier observations in the normal bovine and rat adrenal medulla on a co-storage and co-release of these substances in normal circumstances.

Mechanism of action and tolerance of mesulergine

The tolerance and prolactin (PRL) release‐inhibiting action of the 8α‐aminoergoline mesulergine were investigated. In a blind crossover study in six subjects with hyperprolactinemia, 0.5 mg mesulergine induced fewer side effects than did 2.5 mg bromocriptine, while the PRL release‐inhibiting effect of the two was of the same order. Six different subjects with suspected PRL‐secreting pituitary adenomas who (repeatedly) had to discontinue bromocriptine because of nausea, vomiting, or symptoms of orthostatic hypotension were treated for 20 mo with mesulergine (1 to 2 mg/day). Mesulergine did not induce side effects and its actions resembled those of bromocriptine. Mesulergine induced cessation of galactorrhea and resumption of normal menstrual cycles in five subjects, while in one subject an insufficient luteal phase persisted. No abnormalities in routine blood parameter estimations were observed. In two of three subjects there was shrinkage of a pituitary tumor after 12 to 15 mo on mesulergine. Mesulergine did not directly inhibit PRL release by cultured normal rat pituitary cells and human prolactinoma cells and it antagonized the action of dopamine in a dose‐dependent manner. This suggests that the dopaminergic action is carried out by a metabolite of mesulergine, while the parent drug probably prevents the well‐known side effects of dop amine‐agonistic drugs by its dopamine receptor blocking activity. Because of its acceptability, mesulergine might be important in the treatment of hyperprolactinemia and perhaps also of acromegaly and Parkinsons disease.