Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) is characterized by an increase in mean pulmonary artery pressure due to pulmonary vascular remodeling, resulting in right ventricular failure.¹ Pulmonary arterial hypertension is defined hemodynamically by the presence of a mean pulmonary artery pressure of ≥25 mmHg with a pulmonary capillary wedge pressure or left ventricular end-diastolic pressure of ≤15 mmHg. The pathophysiology of PAH is complex and originates from an imbalance between mediators of vasodilation (such as prostacyclin or nitric oxide) and vasoconstriction (such as endothelin-1) in favor of vasoconstrictive forces and the promotion of vascular remodeling in small pulmonary arteries.^2,3 Before the availability of specific therapies, PAH was considered to be a rapidly fatal illness with a median survival time of 2.8 years.¹ Despite recent advances in the treatment of PAH, the prognosis remains poor.

It has been recognized since the early 1980s that PAH predominantly affects women of childbearing age. During the 1980s, a National Institutes of Health registry was instrumental in defining PAH as a predominantly (64%) female disease, and the mean age was 36 years among the enrolled patients. Data from the recent Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL) suggest that almost 80% of enrolled patients were female, with a mean age of 47 years.⁴ The female predominance has actually increased over time, and this could be because men have a higher mortality rate from PAH, and it is possible that men do not survive to be enrolled in these registries. In fact, the risk calculator created from the REVEAL registry data suggests that being male carries a worse prognosis. French registry data indicate that 65% of the enrolled PAH subjects were female, and the Scottish registry showed that 66% of those enrolled were female. It can be argued that the enrollment criteria were not uniform across these registries; nevertheless, it seems that PAH predominantly affects women, the worse prognosis among men notwithstanding.

The Estrogen Paradox

Estrogen has a multitude of effects on the pulmonary vasculature. These include decreased expression of endothelin-1 (a potent vasoactive and mitogen mediator), increased production of nitric oxide and prostacyclin release (both have vasodilatory properties), alteration in mitogen-activated protein kinase and extracellular-regulated kinase signaling pathways, and anti-inflammatory properties.⁵ On the other hand, the effects of testosterone include proinflammatory and proapoptotic effects in the myocardium and vasodilator properties in the coronary and pulmonary vasculature. In an isolated pulmonary artery model, the acute administration of estrogen or testosterone caused vasorelaxation under normoxic conditions.⁶ In chronic hypoxia, females exhibit less severe pulmonary hypertension than do their male counterparts. However, chronically hypoxic ovariectomized rats develop more severe pulmonary arterial remodeling and right ventricular hypertrophy than do chronically hypoxic rats with intact ovaries.

Estradiol (E2) is the predominant form of estrogen in non-pregnant females. Polymorphism of the cytochrome P450 1B1 (CYP1B1), an important modifier, predisposes female bone morphongenetic protein receptor type II (BMPR2) carriers to develop PAH. The function of CYP1B1 is to metabolize estrogen and regulate the production of estrogen metabolites within tissues. A CYP1B1 variant increases the conversion of estradiol into 16α-hydroxyestrone, a metabolite whose mitogenic properties might help promote pulmonary vascular remodeling by inducing excessive cell growth. One study that explored the development of portopulmonary hypertension in females with cirrhosis identified high aromatase activity as an important risk factor.

The protective effects of estrogen could be linked to the stimulation of pulmonary and myocardial angiogenesis through the activation of the estrogen receptor-β. Estrogen receptor-β activation could promote angiogenesis by increasing the production of angiogenic factors such as vascular endothelial growth factor and nitric oxide. An imbalance favoring the accumulation of “bad” estrogen metabolites such as 16α-hydroxyestrone over “good” metabolites such as 2-hydroxyestrogen might increase the susceptibility to PAH in BMPR2 carriers.

Conclusion

Pulmonary arterial hypertension is a female-predominant disease. Estrogen seems to be protective in animals but causative in human beings. Estrogen and estrogen receptor-based therapies have shown promise in reversing preexisting pulmonary hypertension in animals. However, the role of such therapies in human beings is not yet defined, and further studies are needed.