Resistance to bromocriptine in prolactinomas.
Bromocriptine therapy normalizes PRL secretion in most, but not all, patients with prolactinomas. This study was undertaken to determine the mechanism(s) responsible for bromocriptine resistance in patients with a PRL-secreting macroadenomas (n = 5) or microadenomas (n = 3). Their mean basal plasma PRL value was 807 +/- 220 (+/- SE) micrograms/L before treatment, and their nadir mean value was 354 +/- 129 micrograms/L during chronic therapy with 15-30 mg bromocriptine daily; four of the eight patients had an increase in tumor size during therapy. In cultures of prolactinoma cells from patients normally responsive to bromocriptine therapy (n = 10), considered as controls, 10(-9) mol/L bromocriptine inhibited PRL release by 71 +/- 6% (+/- SE), and the half-inhibitory dose was 7 x 10(-11) mol/L. In contrast, in cultures of prolactinoma cells from five patients resistant to bromocriptine, PRL release was inhibited by only 3-42% at 10(-9) mol/L bromocriptine. This partial inhibition was reversed by a 100-fold excess of haloperidol. In contrast, the effects of other inhibitors of PRL release (10(-8) mol/L T3 and 10(-8) mol/L somatostatin) or of a stimulator (10(-8) mol/L angiotensin-II) on cells from resistant and normally responsive patients were similar. In cell membranes from five bromocriptine-responsive adenomas the density of dopaminergic binding sites, labeled by [3H] spiroperidol was 243 +/- 65 (+/- SE) fmol/mg protein. In adenomas from the eight patients resistant to bromocriptine therapy the density of [3H]spiroperidol-binding sites lower (145 +/- 31 fmol/mg protein). In adenomas from five resistant patients whose tumor had grown during therapy the density of binding sites was 25 +/- 3 fmol/mg protein, 10% of that in normally responsive patients. The effects of dopamine on adenylate cyclase activity also were different in the three groups of adenomas. Dopamine inhibited adenylate cyclase activity by 28.8 +/- 5.6% in five bromocriptine-responsive tumors and by 16.5 +/- 4.3% in adenomas from eight resistant patients. In contrast, in the five patients whose tumors grew during therapy dopamine paradoxically stimulated adenylate cyclase activity (+26.4 +/- 9.8%). There was a very good correlation between the density of dopaminergic binding sites and maximal inhibition of adenylate cyclase activity in bromocriptine-responsive prolactinoma patients (r = 0.90) and resistant patients who had no tumor growth during therapy (r = 0.94).(ABSTRACT TRUNCATED AT 400 WORDS)
Laboratoire de Neuroendocrinologie Expérimentale, INSERM U. 297, Marseille, France.
I
I
Pellegrini
R
R
Rasolonjanahary
G
G
Gunz
P
P
Bertrand
S
S
Delivet
C P
CP
Jedynak
C
C
Kordon
F
F
Peillon
P
P
Jaquet
A
A
Enjalbert
D015065:17-Hydroxycorticosteroids / Q000097:blood; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D001971:Bromocriptine / Q000627:therapeutic use*; D002462:Cell Membrane / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D013006:Growth Hormone / Q000097:blood; D006801:Humans; D007700:Kinetics; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008875:Middle Aged; D010911:Pituitary Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D011388:Prolactin / Q000097:blood; D015175:Prolactinoma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D014407:Tumor Cells, Cultured / Q000378:metabolism
D015065:17-Hydroxycorticosteroids; D000067956:Adenylyl Cyclase Inhibitors; D011954:Receptors, Dopamine; C031611:spiroperidol receptor; D001971:Bromocriptine; D013134:Spiperone; D011388:Prolactin; D007986:Luteinizing Hormone; D013972:Thyrotropin; D013006:Growth Hormone; D000262:Adenylyl Cyclases; D013974:Thyroxine; D004298:Dopamine