Estrogen, SERMS reduce asthma impact by halting constriction

Apr 3 2005

For years, anecdotal evidence suggested that ovulating or pregnant women or post-menopausal women taking estrogen supplements, experienced fewer asthma attacks and less severe asthma symptoms, strongly suggesting that perhaps estrogen affects airway smooth muscle function by preventing the hyperresponsiveness characteristic of asthma and other chronic lung diseases.

Now, scientists at the Medical College of Georgia have shown that elevated estrogen levels may reduce the severity of asthma and perhaps of other chronic lung diseases involving airway constriction. Christiana Dimitropoulou and her team at the Department of Pharmacology and Toxicology report that estrogen, as well as selective estrogen receptor modifiers (SERMs), completely abolished abnormal tracheal constriction in a carbachol test.

Carbachol is often used to stimulate, or mimic, contractions of airway and other muscles. The Georgia researchers found that hyperresponsiveness of mouse tracheal rings to carbachol was completely prevented with only 30 minutes of estrogen treatment. Then they repeated the tests with SERMs, such as tamoxifen, and found they were equally able prevent the exaggerated constriction to allergen seen in asthmatic-induced airways.

“This could represent a new and potentially important role for estrogen, SERMs, or both,” Dimitropoulou said. She is presenting the research at the 35th Congress of the International Union of Physiological Sciences in San Diego, March 31 - April 5.

The full team includes: Christiana Dimitropoulou, Shu Zhu, Richard E. White and John D. Catravas of the Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta, and Dennis Ownby of the Department of Pedatrics; Catravas also is with the MCG Vascular Biology Center.

Estrogen receptor inhibitors abolish protective effect

To confirm that the dramatic results weren’t a non-specific effect of estrogen, experiments were repeated in the presence of an inhibitor of estrogen receptors, the cell proteins that are responsible for binding estrogen and mediating their pharmacologic effects. Estrogen receptor inhibitors abolished the protective effect of estrogen.

In the experiments, researchers removed airways from adult male mice, cut them into rings and placed them in an apparatus that measures their contractility to external stimuli. To simulate asthmatic conditions, the rings were exposed for 24 hours to sera drawn from severely asthmatic patients (IgE over 1,000) and then challenged to constrict, by exposing them to carbachol.

Carbachol is a stable congener of the neurotransmitter acetylcholine traditionally used to stimulate contractions of airway and other muscle. Each ring was exposed to a range of carbachol concentrations and the magnitude of the constrictor responses was measured. Rings that were exposed to sera from asthmatic patients constricted more than twice as much and at lower carbachol concentrations than rings exposed to sera from normal human subjects (IgE under 70).

When airway rings that were exposed to sera from normal subjects were treated with estrogen, their response to carbachol was not affected. But when airway rings that were exposed to sera from asthmatic patients were treated with estrogen for only 30 minutes before exposing them to carbachol, the normally observed hypersensitivity to carbachol was abolished; instead, they constricted no more than normal airway rings.

Next steps. In future studies, Dimitropoulou will test her hypothesis in live asthmatic mice, to confirm the current findings. If these new studies prove successful, they will be followed by “studies examining whether low estrogen or SERM concentrations given by inhalation can improve our current, standard treatment of asthma,” she said.

“Taken together, the results to date offer new molecular targets for the pharmacological management of both asthma and chronic obstructive pulmonary disease,” Dimitropoulou concluded.