Estrogen Reversed PH in Rat Study, Offering Clues to Disease Mechanisms

Estrogen Reversed PH in Rat Study, Offering Clues to Disease Mechanisms
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The female sex hormone estrogen may prevent disease progression of pulmonary hypertension — at least if results in rats can be translated to human patients.

Researchers at the University of California, Los Angeles (UCLA) showed that estrogen reversed progression from pulmonary hypertension (PH) to right heart failure, and restored lung and heart structure and function in a rat model of the condition.

The findings, published in the American Journal of Respiratory and Critical Care Medicine in a study titled Estrogen Rescues Pre-existing Severe Pulmonary Hypertension in Rats,” suggest that the hormone’s benefits on the diseased rats were mediated mainly through the estrogen receptor beta.

“Unfortunately, up until now, there hasn’t been an ideal pharmacological therapy to treat advanced pulmonary hypertension,” Mansoureh Eghbali, PhD, an assistant professor of anesthesiology at the David Geffen School of Medicine at UCLA, and senior study author, said in a press release.

“We hope that this early study may offer insight into new therapies,” he added.

Eghbali, who has been studying the role of sex and estrogen in cardiovascular diseases, decided to take a look at the female sex hormone in male rats that were in advanced stages of pulmonary hypertension.

Giving the rats low doses of the hormone for 10 days prevented the animals from developing heart failure. Right heart failure results when the right side of the heart becomes dilated as it constantly pumps blood against the increased pressure in the lung artery.

Other disease aspects — such as systolic blood pressure and the amount of blood pumped from the heart to the lungs in each heartbeat, called ejection fraction — also improved. Meanwhile, abnormally high lung weight, a sign of fibrosis, became normal, and estrogen restored the loss of blood vessels in the lungs and right ventricle of the heart.

While many aspects improved after this short treatment course, researchers continued monitoring the animals for another 12 days. To their astonishment, improvements had continued during this time — systolic blood pressure and ejection fraction were back to normal.

“We were surprised to find this continued benefit, even after we stopped the estrogen treatment,” said Soban Umar, first author of the study and a researcher in Eghbali’s lab. “These findings suggest that even short-term estrogen therapy may suffice to reverse the disease.”

Researchers also noted that all rats treated with estrogen survived throughout the 42-day study. In contrast, only 25 percent of untreated rats (control group) were still alive in the same time period.

But the research team did not settle there. They also wanted to know more about the mechanisms through which the hormone controlled the disease.

The team noted that the hormone treatment prevented the presence of high numbers of inflammatory cells and reduced the activity in pro-inflammatory genes. Importantly, they could conclude that the effects were mediated mainly by one estrogen receptor, called estrogen receptor beta.

“Estrogen appears to work through an interplay of several factors, including suppression of lung inflammation and fibrosis, as well as reversal of ventricle enlargement,” Eghbali said. “We may be able to utilize estrogen receptor beta in the development of future therapies to stimulate estrogen activity to treat pulmonary hypertension.”

The beta form, compared to estrogen receptor alpha, is less involved in the hormone’s effects on breasts and the uterus, researchers said.

Since pulmonary hypertension often affects young women — who should have enough female sex hormones to protect them from the disease — the team believes that these women might have a genetic flaw that interrupts normal estrogen signaling.

The research team will now focus on identifying potential genetic mutations that could be involved in the disease.

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