Estrogen has a key role in the pathogenesis of pituitary adenomas (PAs). The study was to evaluate the estrogen receptor alpha (ESR1) level in 289 PAs cases, its association with clinicopathologic features and serving as a target of cancer treatment. In this study, the ESR1 level was evaluated by tissue microarray (TMA). The effect of fulvestrant was determined by an animal model of prolactinoma established by subcutaneous injection of 17 beta-estradiol in F344 rats. The volume and weight of the pituitary were assessed in the different groups. The effects of fulvestrant on cell proliferation and cell invasion were explored in the pituitary adenoma cell lines GH3 and JT1-1. The ESR1-positive cells rates of 191/289 cases were more than 50%. And ESR1 high level cases (age >= 50) were 103/133, and 88/156 in cases (age<50) (X-2 = 14.17, p = 0.0001). The average weight of the pituitary gland in F344 rat tumor model induced by 17-beta-estradiol was 38.6 +/- 11.2 mg, almost 6 times higher than control group (6.2 +/- 1.7 mg). Fulvestrant significantly reduced the weight of the pituitary and its inhibition rate was 68.4 +/- 8.3%. TUNEL assay and Western blotting showed that fulvestrant induced apoptotic cell death in vivo and in vitro. PTEN/MAPK signaling pathways were activated in response to fulvestrant treatment in GH3 cells. U0126 partly rescued cell viability of GH3 cells after fulvestrant exposure. ESR1 can be a potential target for PAs, especially for elder GHomas and NFPAs. Fulvestrant may be a new choice for the treatment of PAs. (C) 2016 Elsevier Ireland Ltd. All rights reserved.