Bromocriptine treatment of macroprolactinomas: studies on the time course of tumor shrinkage and morphology

The effects of Bromocriptine (Brc) (7.5 2 - 15 mg/day for 45 days) on serum PRL levels and tumor size and morphology were investigated in 7 patients with macroprolactinomas (mean PRL ± SE = 4957 ± 920 ng/ml). Serial controls of serum PRL levels, CAT scan and visual field examination were carried out at the 5th, 10th, 20th and 45th day of Brc treatment. A rapid lowering in PRL concentrations (mean PRL ± SE = 23.1 ± 5.8 ng/ml) and a dramatic shrinkage of tumor mass were observed in 4 cases already at the 5th day of therapy. In 3 patients Brc was then withdrawn and a rapid rise of serum PRL concentration (mean PRL ± SE = 2618 ± 683 ng/ml) along with a reexpansion of the adenomas was documented within 15 days. These patients were then restarted on Brc and tumor regression was noticed again. In the remaining 3 cases no CAT scan variations occurred, though 2 of them had serum PRL in the normal range. Transsphenoidal adenomectomy was then performed in 4 patients upon Brc (1 with a marked reduction of the adenoma size and 3 with unmodified tumor mass) and tumor tissue examined. The histological picture of the 4 Brc-treated tumors was homogeneous and no relevant changes were seen in comparison with fragments of prolactinomas obtained from patients never treated with Brc. Though PRL cells appeared somewhat more closely associated, neither the tissue architecture, not the distribution of necrotic and hemorragic areas, nor the mitosis rate appeared modified by the treatment. At electron microscopy all the Brc-treated adenomas showed an increase of PRL secretory granules and a decrease of RER and Golgi apparatus. The morphometric analysis revealed in all cases a marked reduction of the cell size in comparison with the untreated tumors (73.56 μm2 ± 6.90 SE vs 148.41 μm2 ± 11.29 SE in untreated patients; p < 0.0001). In conclusion: i) the prolactinoma regression induced by Brc occurred only in patients whose serum PRL levels were markedly suppressed; however the PRL normalization was not constantly associated with tumor shrinkage; ii) all the Brc-treated adenomas showed a marked reduction in cell size and a decrease of the cytoplasmic structures responsible for PRL production; iii) cell size reduction was observed also in 3 patients who did not reduce their tumor size. This suggests that additional mechanisms should have been operating in the Brc-induced tumor shrinkage.