Estrogen Inhibitors Can Prevent and Treat PAH in Mice, Vanderbilt Study Finds

Estrogen inhibitors may treat pulmonary vascular disease by correcting metabolic defects in women with pulmonary arterial hypertension (PAH), say researchers at Nashville’s Vanderbilt University.

Their study,“Oestrogen inhibition reverses pulmonary arterial hypertension and associated metabolic defects,” appeared in the European Respiratory Journal.

Most people with hereditary PAH have mutations in the protein BMPR2 (bone morphogenetic protein receptor type II). However, 43 percent of women — and only 14 percent of males — with BMPR2 mutations will develop PAH.

In addition, women who metabolize their estrogen into a 16-estrogen molecule (16αOHE1) are more likely to get PAH than those who metabolize estrogen into 2- or 4-ostrogen molecules. Previous research has shown this may be because 16αOHE1 causes metabolic problems linked to the development of PAH.

Since estrogen clearly plays a role in PAH, researchers set out to determine whether estrogen inhibitors could prevent the disease from developing.

The Vanderbilt team used mouse models of PAH that had BMPR2 mutations, and treated the animals with the estrogen inhibitors anastrozole, fulvestrant and tamoxifen. Researchers evaluated anastrozole and fulvestrant for prevention of PAH, and tamoxifen for treatment of the disease.

Results indicated that inhibiting estrogen both prevented and treated PAH in BMPR2 mutants; it also decreased metabolic defects such as insulin resistance and oxidized lipid formation.

Researchers also conducted experiments to see which estrogen receptor causes this positive effect. They learned that such effects are mediated primarily through ESR2 (estrogen receptor 2), and somewhat through ESR1.

They concluded by suggesting further research on the use of estrogen receptors to treat PAH, since they seem to be able to ameliorate pulmonary vascular disease by fixing metabolic defects. Recently, the National Institutes of Health approved and funded the launch of U.S. clinical trials assessing estrogen inhibition in patients with PAH.

“Our data suggest that trials of estrogen inhibition in human PAH are warranted, and may improve pulmonary vascular disease through amelioration of metabolic defects,” researchers wrote. “Although fulvestrant and anastrozole were more effective than tamoxifen, tamoxifen may be useful in premenopausal females, because of a reduced risk of induction of menopause.”