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.

Dopamine agonist medications are effective as a first-line therapy for invasive giant prolactinomas, because they can significantly shrink tumor volume and control the PRL level. Tumor mass vanishes in some patients after bromocriptine treatment; in other patients with localized residual tumor, stereotactic radiosurgery is a viable option so that unnecessary surgery can be avoided. The application of radiotherapy does not reliably shrink tumor volume.

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.

No abstract

About three-fourths of prolactinomas with CS invasion can be effectively controlled not only with regard to tumor volume disappearance but also in serum PRL normalization. Residual tumor in the CS areas with PRL normalization and no pressure symptoms can be treated with low-dose of bromocriptine so as to achieve long-term tumor volume control and endocrine control. Great attention should be paid to CS residual tumors accompanying the empty sella, especially in cases with optic chiasmal herniation.

Dopamine agonists (DAs) are the first-line treatment of prolactinomas. They function through the dopamine 2 receptor (D2R) in the tumor cells. Endocan, also called endothelial cell-specific molecule-1 (ESM1), has been described as a marker of neoangiogenesis. However, whether ESM1 promotes the resistance of prolactinomas to DA therapy is largely unknown. In our study, 25 patients with prolactinomas were divided into resistant- and sensitive- groups according to the clinical response to bromocriptine. We found that ESM1-microvessel density of resistant prolactinomas was significantly higher than that of sensitive prolactinomas (47.9 ± 11.6, n = 8, vs 13.1 ± 2.8, n = 17, p = 0.0006), indicating that ESM1 was a DA resistance-related gene. Immunostaining showed that ESM1 was expressed in tumor vessels and sporadic tumor cells, and ESM1 was overlapped with the Smooth Muscle Actin (SMA) and von Willebrand Factor (VWF) in the tumor vessels. Silencing of ESM1 markedly suppressed the viability of GH3 and MMQ cells in vitro, and furthermore, significantly increased the sensitivity of GH3 and MMQ cells to DA treatment. Additionally, silencing of ESM1 down-regulated the angiogenesis-associated genes, such as VEGFR2, FGF2, CD34, CD31, VWF, and EGFR. Knockdown of ESM1 decreased endothelial tube formation of HUVECs, and significantly increased the sensitivity of HUVECs to Avastin treatment. Therefore, we first demonstrate that DA resistance-related ESM1 promotes the angiogenesis and tumor cells growth of prolactinomas, suggesting that ESM1 may be a novel therapeutic target for prolactinomas.

Objective. The aim of this study is to observe clinical outcomes after more than ten years of followup in a group of patients with invasive giant prolactinomas (IGPs) treated with dopamine agonists (DAs). Methods. Twenty-five patients met the criteria of IGPs, among which 16 patients primarily received bromocriptine (BRC) and the other nine had undergone unsuccessful microsurgery prior to BRC treatment. Results. After a mean follow-up period of 135.5 ± 4.7 months, the clinical symptoms in all patients improved by different degrees. Tumor volume was decreased by a mean of 98.6%, and the tumors of 19 patients had almost completely disappeared. The mean duration of treatment at maximal doses of BRC was 48.5 months. At the last follow-up visit, nineteen patients had normal PRL levels, and 14 of these patients had received the low-dose BRC treatment (at an average of 2.9 ± 0.3 mg/d). Younger patients < 25 years had a significantly higher rate of persistent hyperprolactinemia after long-term BRC treatment (p = 0.043). Conclusion. DAs are a first-line therapy for IGPs because they can effectively achieve long-term control in both shrinking tumor volume and normalizing the PRL level, and majority of patients need low-dose DA maintenance. Younger patients are prone to persistent hyperprolactinemia despite long-term DA treatment.

This study for the first time shows a good correlation between expression of ER and D2R isoforms in prolactinomas and gonadotrope tumors. Reducing the amount of the ERalpha in neoplasm cells can alter the ratio of D2L/D2S, which may increase the drug sensitivity of pituitary adenomas.