Diagnosis And Drug Resistance Mechanism Of Prolactinoma

Backgroud:Prolactinoma is the most common functional pituitary tumor that accounts for 40%-50% of all pituitary tumor in adults. The most common presentation of prolactinoma is hyperprolactinemia, and dopamine receptor agonists (DA) as first-line treatment could normalise PRL levels in 90% patients. Guidelines suggest that most patients with prolactin levels higher than 200-250ng/mL will harbor a prolactinoma. Howerver, values between normal high range and 200ng/mL are a grey area and are currently associated with diagnostic uncertainty. Forward fields focusing on studying the mechanisms of resistance to dopamine agonist therapy and discuss strategies for managing DA-resistant prolactinomas; among which, increased angiogenesis and microvascular density maybe underlying mechanism of drug resistance. Besides, statins as inhibitors of HMG-CoA reductase, exhibit effects beyond cholesterol reduction, especially anticancer activity. Whether statins could be possible molecular anticancer treatments for prolactinomas is still unknown.Objectives:1) Investigate the serum PRL lower limits to differentiate prolactinoma from non-functioning pituitary adenomas with hyperprolactinemia.2) To examine the expression of angiogenesis associated factors between dopamine agonist resistant and sensitive prolactinomas.3) To evaluate the impact of statins on dopamine agonist resistant and sensitive prolactinoma cell lines, respectively GH3 and MMQ.Methods:1) Prolactin expression in pituitary tumors with different serum prolactin levels was examined by immunohistochemical methos and Image Pro-Plus software. The relativities of serum prolactin levels and pathological parameters will be analyzed by statistical methods.2) Angiogenesis related factors expressions, such as VEGF, CD31 were analyzed between dopamine agonist resistant prolactinoma and sensitive ones, using immunohistochemical methods. So did extracellular materials including MMP2 and MMP9.3) Rat prolactinoma cell line GH3 and MMQ were cultured in Simvastatin solutions with different concentrations. Different methods will be used to determine simvastatin’s impact on cell proliferation, apoptosis and secretion of PRL; including Cell Counting Kit 8(CCK8), Flow Cytometry, Western blotting and Elisa.Results:1) The expression of prolactin was significantly upregulated in pituitary tumor patients with serum prolactin levels above 100 ng/mL, compared with those with serum prolactin levels above normal and below 100 ng/mL.2) VEGF expression levels in dopamine agonist resistant prolactinomas are higher than that of sensitive ones; no significant differences are found on MMP2, MMP9 and CD31 expressions.3) VEGF expression levels in dopamine agonist resistant prolactinomas associated with Ki67 values, but not with tumor size nor serum prolactin levels.4) Statins can effectively inhibit cell proliferation, induce apoptosis and downregulated expression of PRL and VEGF in rat prolactinoma GH3 and MMQ cell lines.Conclusions:1) Prolactinoma should be the first considered diagnose among pituitary tumor patients with serum prolactin level higher than 100ng/mL.2) Dopamine agonist resistant prolactinoma may generate strong angiogenesis than sensitive ones, which maybe related with more aggressive prolactinomas.3) Statins could be one of the potential treatment for dopamine agonist resistant prolactinoma and the detailed mechanism should be studied.