Objective: Previous studies attempting to define the natural history of postoperative nonfunctioning pituitary adenomas (pNFPAs) were somewhat limited by selection bias and/or small numbers and/or lack of consistency among the study findings. The aim of this study was to scrutinize the literature in order to analyze the natural history of pNFPAs. Methods: Electronic database including MEDLINE, PubMed and Cochrane CENTRAL were searched. The literature relating to the patients with pNFPAs without postoperative radiotherapy and pharmacotherapy was collected. Eligible studies reported on the rate of tumor recurrence, the tumor growth-free survival rate (TGFSR) at 5 and 10 years, and/or the residual tumor volume doubling time (TVDT). Results: 19 studies met the criteria. The pNFPAs were divided into two groups: the pooled recurrence rate of group I without detectable residual tumor (371 patients) was 12% (95% CI 6–19%), the TGFSR at 5 and 10 years were 96% (95% CI 89–99%) and 82% (95% CI 65–94%), respectively. The pooled recurrence rate of group II with residual tumor (600 patients) was 46% (95% CI 36–56%), the TGFSR at 5 and 10 years were 56% (95% CI 41–71%) and 40% (95% CI 27–53%), respectively. The mean TVDT was 3.4 years (95% CI 2.4–4.5 years). Conclusions: pNFPAs, with or without detectable residual tumor, need stratification of treatment and radiological/endocrinological follow-up strategy. According to the TVDT, residual tumor regrowth is very slow, which permits an extensive and safe follow-up program for most patients.

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 +/- 10.4 and 5.4 +/- 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 ERalphamRNA and ERbetamRNA expression (P = 0.20 and 0.06, respectively). D2SmRNA expression was significantly different for invasive and noninvasive tumors (6.2 +/- 3.6 vs. 17.0 +/- 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.

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To date, the management of dopamine agonist (DA)-resistant prolactinomas remains a major clinical problem. Previously, we determined that miRNA-93 expression increases in DA-resistant prolactinomas; however, the role of miRNA-93 in the DA resistance remains largely unexplored. Hence, this study aimed to investigate the susceptibility of tumor cells to cabergoline (CAB) and the autophagy changes in MMQ and GH3 cells after miRNA-93 overexpression or inhibition. We used bioinformatics to identify the potential target of miRNA-93. Subsequently, we analyzed the correlation between miRNA-93 and autophagy-related 7 (ATG7) using protein expression analysis and luciferase assays. Furthermore, the change in the effect of miRNA-93 was measured after ATG7 overexpression. miRNA-93 expression was elevated in DA-resistant prolactinomas, whereas the expression of its identified target, ATG7, was downregulated. miRNA-93 overexpression suppressed the cytotoxic effect of CAB in MMQ and GH3 cells. In contrast, miRNA-93 downregulation enhanced CAB efficiency and promoted cell autophagy, eventually resulting in apoptosis. These results were further confirmed in in vivo xenograft models in nude mice. ATG7 overexpression could reverse the inhibitory effect of miRNA-93 on CAB treatment. Taken together, our results suggest that miRNA-93 mediates CAB resistance via autophagy downregulation by targeting ATG7 and serves as a promising therapeutic target for prolactinoma.