HELP VIA HORMONES: A new "designer estrogen" therapy, combining a variety of the hormone with an anti-inflammatory medication, may offer a new, effective therapy for multiple sclerosis. Image: © GIDEON MENDEL/CORBIS
Researchers have proposed a new treatment for multiple sclerosis (MS) that utilizes the hormone estrogen to stave off and even reverse some of the mysterious disease's debilitating symptoms without the dangerous side effects of some other hormone therapies.
MS is largely believed to be an autoimmune disease in which the immune system turns on healthy tissue—in this case in the brain and nervous system. Current treatments include medicines designed to suppress an overactive immune system and reduce inflammation, a first-line response of the immune system. Whereas Copaxone and other such drugs often improve some of the muscle weakness and movement issues associated with the condition, they do little to combat the accompanying neurodegeneration.
In recent years, researchers began focusing on the potential of estrogen in battling MS after observing that the disease went into remission during pregnancy. "Pregnant women had this beautiful effect their estrogen levels went skyrocketing," says Seema Tiwari-Woodruff, an assistant professor of neurology at the University of California, Los Angeles, and lead author of a study on estrogen as a potential MS treatment published in Proceedings of the National Academy of Sciences USA. "As soon as they had the baby, the MS came back, and more drastically."
In the body, estrogen binds to two types of receptor proteins in cells: estrogen receptor α and estrogen receptor β. The former—often referred to as estradiol—is known to play a role in mediating the effects of tumor-causing agents—and a major risk of estrogen treatments is the increased risk for breast and uterine cancer in women. Estrogen receptor β has no known connection to tumor cell proliferation and, thusly, the research team believed it may present a better treatment option.
The U.C.L.A. team was able to target specific receptor proteins in a mouse model of multiple sclerosis by attaching receptor-specific compounds to estrogen. Young adult female mice (five to six weeks old) were given a compound that induced encephalomyelitis, an autoimmune condition similar to MS. Some of the infected animals immediately received estrogen targeted to the α receptor, whereas others received the β receptor–specific hormone.
The α group did not develop any MS symptoms; the animals did not display any movement effects or damage to nerves or to the myelin (protective sheath) on the cells' axons, which transmit information—in the form of electrical impulses—away from neurons. Tiwari-Woodruff notes that despite the heartening result, researchers are not sure exactly why it works. "We don't know if it was stopping inflammation," she says, "or directly stopping the degeneration of neurons and axons."
The mice that received estrogen targeted to the β receptor initially developed signs of MS, including difficulty maintaining balance and a generally slower gait. The scientists say there was inflammation throughout these animals' central nervous systems. But some 20 days later, these mice began to show improvements in motor control, eventually regaining the ability to walk normally—and despite inflammation there was no neurodegeneration, which typically occurs at this stage of the disease. "This is the first time," she says, "a hormone treatment has been described [that works] without touching the inflammation part" of the equation.
Targeting the α receptor may provide a more thorough treatment, but researchers say it is not clear that its benefits outweigh the increased cancer risk that accompanies it. The gradual β receptor treatment offers the opportunity to protect an MS patient from neurodegeneration; supplementing it with an anti-inflammatory drug could counter swelling, yielding an all-around safer therapeutic option for women as well as for men.
"The β receptor is not one of the receptors that causes breast growth and all the feminine side effects" Tiwari-Woodruff says, "so this could potentially be given to men, too." She adds that the U.C.L.A. team will now try out the β receptor–targeted estrogen in a male mouse model. Next up: human trials if those go well.