Short-term morphologic and functional effects of bromocriptine on pituitary prolactin cell adenomas in vitro

Bromocriptine, a dopamine agonist, rapidly reduces profactin (PRL) blood levels in vivo; it also causes a marked reduction in tumor size in patients with lactotroph adenomas within 2 weeks of initiation of therapy. The effects are direct, as shown in vitro, and are thought to be due to inhibition of gene transcription that causes alteration in tumor cell morphology. However, the morphologic changes that account for a functional response within hours of administration have not been elucidated. We report the functional and morphologic changes in 7 pituitary lactotroph adenomas studied in vitro after 2, 24, and 48 hours of incubation with bromocriptine. In 2-hour incubations, PRL release rapidly fell to 46% to 74% of control; morphologic analysis revealed an increase in the cytoplasmic volume density (CVD) of secretory granules. After 24 hours of treatment, PRL release was maximally suppressed at 18% to 32 % of control; at 24 hours, the CVDs of secretory granules and lysosomes were increased, and they remained higher than in control cells at 48 hours. The CVD of rough endoplasmic reticulum was reduced at 2 hours in some tumors, but that of Golgi complexes was reduced only at 48 hours. Cell size was altered only to slightly below 80% of control and only after 48 hours of exposure in 2 or 3 tumors. This study indicates that inhibition of PRL secretion occurs within 2 hours of exposure to bromocriptine; the initial morphologic correlates are an increase in the CVD of secretory granules, suggesting inhibition of hormone release, and a decrease in rough endoplasmic reticulum, suggesting reduction of hormone synthesis. Lysosomal accumulation occurs within 24 hours, most likely reflecting degradation of the stored hormone. Subsequently, Golgi complexes involute as the next step in reduced hormone synthesis occurs, and cell shrinkage occurs relatively later. These findings correlate well with the rapid reduction in PRL blood levels and the slower tumor shrinkage documented clinically in patients with PRL cell adenomas.