Invasive　prolactinomas　are　more　likely　to　be　resistant　to　drug　therapy　but　the　mechanism　of　this　is　still　unknown.　The　objective　of　this　study　was　to　analyze　the　different　expression　of　ERmRNA　and　D2RmRNA　isoforms　in　prolactinomas　responsive　and　resistant　to　dopamine　agonist　(DA),　and　to　discuss　the　correlation　of　such　gene　expression　with　tumor　biological　behavior.　A　prospective　study　of　20　consecutive　patients　who　harbored　prolactinomas　was　designed.　Patients　were　classified　as　responsive　(14　cases)　or　resistant　(six　cases)　according　to　their　clinical　and　biochemical　response　to　bromocriptine.　Tumor　tissue　samples　were　examined　by　means　of　QRT-PCR　analysis.　Median　D2SmRNA　expression　in　responsive　patients　was　about　2.5-fold　that　in　resistant　ones　(13.5　+/-　A　10.4　and　5.4　+/-　A　2.4,　respectively,　P　=　0.09).　No　significant　difference　was　found　between　D2LmRNA　expression　levels　(P　=　0.77).　However,　there　was　a　significant　difference　between　D2S/D2LmRNA　ratios　for　responsive　and　resistant　tumors　(P　=　0.012).　A　significant　difference　was　not　found　between　these　two　groups　in　levels　of　ER　alpha　mRNA　and　ER　beta　mRNA　expression　(P　=　0.20　and　0.06,　respectively).　D2SmRNA　expression　was　significantly　different　for　invasive　and　noninvasive　tumors　(6.2　+/-　A　3.6　vs.　17.0　+/-　A　11.2,　respectively,　P　=　0.02).　The　D2S/D2L　ratio　is　related　to　the　responsiveness　of　prolactinomas　to　DA　medication,　in　which　D2SmRNA　plays　an　important　role.　Lower　expression　of　D2SmRNA　in　invasive　tumor　patients　suggests　that　invasive　prolactinomas　may　be　more　likely　to　be　resistant　to　DA　medication.