Project Summary From the earliest modern description, pulmonary arterial hypertension (PAH) has been recognized as a “female” disease. Female sex is the strongest risk factor for idiopathic and heritable PAH. Despite the decades-old recognition of this sex predilection, surprisingly few human and experimental studies have focused on the mechanism of female sex in causing PAH and the use of treatment targeting sex hormones. While estrogen has been traditionally been considered protective from cardiovascular disease, the strong female sex predominance in PAH implicates estrogen in the pathophysiology of the disease. Aromatase converts androgens to estradiol (E2) in the periphery and is responsible for most of the E2 production in post- menopausal women and men. Our research group and others have performed several studies which suggest that aromatase and estrogen production may play an important role in the risk of PAH. Anastrozole is a generic aromatase inhibitor which is has been FDA-approved for breast cancer for 20 years and has an excellent safety profile. In these clustered Clinical Coordinating and Data Coordinating Center applications, we propose a Phase II randomized, double-blind, placebo-controlled trial in 84 post-menopausal women and men with PAH for one year to determine if anastrozole increases the six minute walk distance, improves right ventricular function, improves quality of life, and has an acceptable side effect and safety profile.