Rationale: Recent studies have focused on the role of female sex and estradiol (E2) in pulmonary arterial hypertension (PAH), but it is not known whether sex hormones are risk factors for PAH in men.Objectives: We performed a case-control study to determine whether hormone levels (E2, dehydroepiandrosterone-sulfate [DHEA-S], and testosterone) are associated with PAH in men.Methods: Plasma sex hormone levels in men with idiopathic, heritable, or connective tissue disease-associated PAH were compared with those from age-and body mass index-matched men without clinical cardiovascular disease.Measurements and Main Results: There were 23 cases with PAH (70% had idiopathic PAH, 65% were functional class III/IV) and 67 control subjects. Higher E2 and E2/testosterone levels were associated with the risk of PAH (odds ratio per 1 ln[E2:testosterone], 6.0; 95% confidence interval, 2.2-16.4; P = 0.001), whereas higher levels of DHEA-S were associated with a reduced risk (odds ratio per 1 ln[DHEA-S], 0.1; 95% confidence interval, 0.0-0.3; P = 0.001). E2 and DHEA-S levels were strong predictors of case status (C statistic for both, 0.82) but testosterone was not (C statistic, 0.53). Higher levels of E2 were associated with shorter 6-minute-walk distances (P = 0.03), whereas higher levels of DHEA-S were associated with lower right atrial pressure (P = 0.02) and pulmonary vascular resistance (P = 0.01) in men with PAH.Conclusions: Higher levels of E2 and lower levels of DHEA-S were associated with PAH in men. Sex-based differences in sex hormone processing and signaling may contribute to unique phenotypes in pulmonary vascular disease.

Rationale: The aromatase inhibitor anastrozole blocks the conversion of androgens to estrogen and blunts pulmonary hypertension in animals, but its efficacy in treating patients with pulmonary arterial hypertension (PAH) is unknown.Objectives: We aimed to determine the safety and efficacy of anastrozole in PAH.Methods: We performed a randomized, double-blind, placebocontrolled trial of anastrozole in patients with PAH who received background therapy at two centers. Measurements and Main Results:A total of 18 patients with PAH were randomized to anastrozole 1 mg or matching placebo in a 2:1 ratio. The two co-primary outcomes were percent change from baseline in 17b-estradiol levels (E2) and tricuspid annular plane systolic excursion (TAPSE) at 3 months. Anastrozole significantly reduced E2 levels compared with placebo (percent change: 240%; interquartile range [IQR], 261 to 226% vs. 24%; IQR, 214 to 14%; P = 0.003), but there was no difference in TAPSE. Anastrozole significantly increased the 6-minute-walk distance (median change = 126 m) compared with placebo (median change = 212 m) (median percent change: anastrozole group, 8%; IQR, 2 to 17% vs. placebo 22%; IQR, 27 to 11%; P = 0.042). Anastrozole had no effect on circulating biomarkers, functional class, or health-related quality of life. There was no difference in adverse events.Conclusions: Anastrozole significantly reduced E2 levels in patients with PAH but had no effect on TAPSE. Anastrozole was safe, well tolerated, and improved 6-minute-walk distance in this small "proof-of-principle" study. Larger and longer phase II clinical trials of anastrozole may be warranted in patients with PAH.Clinical trial registered with www.clinicaltrials.gov (NCT 1545336).

6MWD and BNP values at baseline or week 12 identifi ed a population with an elevated risk of death at 2 years. A repeat assessment of 6MWD or BNP after 12 weeks of ambrisentan therapy did not provide additional prognostic information beyond that obtained from baseline values.

Hepatopulmonary syndrome and portopulmonary hypertension are two pulmonary vascular complications of liver disease. The pathophysiology underlying each disorder is distinct, but patients with either condition may be limited by dyspnea. A careful evaluation of concomitant symptoms, the physical examination, pulmonary function testing and arterial blood gas analysis, and echocardiographic, imaging, and hemodynamic studies is crucial to establishing (and distinguishing) these diagnoses. Our understanding of the pathobiology, natural history, and treatment of these disorders has advanced considerably over the past decade; however, the presence of either still increases the risk of morbidity and mortality in patients with underlying liver disease. There is no effective medical treatment for hepatopulmonary syndrome. Although liver transplantation can resolve hepatopulmonary syndrome, there appears to be worse survival even with transplantation. Liver transplantation poses a very high risk of death in those with significant portopulmonary hypertension, where targeted medical therapies may improve functional status and allow successful transplantation in a small number of select patients.Keywords: hepatopulmonary syndrome; hypertension; pulmonary; liver cirrhosis; pulmonary circulationThe pulmonary circulation may be affected by pathogenic processes arising within the liver and portal venous system. Reports of abnormalities of the pulmonary vasculature found in association with coexisting chronic liver disease were first published in the 1950s (1, 2). Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PoPH) are both associated with portal hypertension and/or liver disease and in simplest terms are related to excessive pulmonary microvascular dilation (in HPS) or vasoconstriction/vascular obstruction in pulmonary resistance vessels (in PoPH). The fact that these seemingly disparate conditions can occur within the same patient population (and even simultaneously or sequentially in the same patient) suggests the role of disease modifiers that determine the particular pulmonary vascular phenotype. These important pulmonary complications both commonly present with dyspnea, yet have unique pathophysiologies, diagnostic modalities, approaches to treatment, and distinct implications regarding liver transplantation (LT). A thorough understanding of the approach to evaluation and treatment of patients with cirrhosis and possible pulmonary vascular disease is imperative to minimize sequelae and to ensure appropriate management of the underlying liver disease.HEPATOPULMONARY SYNDROME Definition HPS is a disorder of altered gas exchange due to abnormal capillary dilatation and/or arteriovenous fistulae within the pulmonary vascular bed (3). The European Respiratory Society Task Force on Pulmonary-Hepatic Vascular Disorders has defined HPS by the presence of (1) Use of the A-a gradient criterion for abnormal gas exchange captures cases of HPS that would not otherwise meet the Pa O 2 criterion (e.g., due to cirrhosis-in...

High oestradiol (E2) and low dehydroepiandrosterone-sulfate (DHEA-S) levels are risk factors for pulmonary arterial hypertension (PAH) in men, but whether sex hormones are related to PAH in women is unknown.Post-menopausal women aged ≥55 years with PAH were matched by age and body mass index to women without cardiovascular disease. Plasma sex hormone levels were measured by immunoassay.Lower levels of DHEA-S (p<0.001) and higher levels of E2 (p=0.02) were associated with PAH. In PAH cases (n=112), lower DHEA-S levels were associated with worse haemodynamics (all p<0.01) and more right ventricular dilatation and dysfunction (both p=0.001). Lower DHEA-S levels were associated with shorter 6-min walking distance (6MWD) (p=0.01) and worse functional class (p=0.004). Each Ln(1 µg·dL) decrease in DHEA-S was associated with a doubling in the risk of death (hazard ratio 2.0, 95% CI 1.5-2.7; p<0.001). Higher levels of E2 were associated with shorter 6MWD (p=0.03) and worse functional class (p=0.01).High E2 and low DHEA-S levels are associated with the risk and severity of PAH in post-menopausal women. Hormonal modulation should be studied as a treatment strategy in PAH.