It’s been a controversial strategy for more than a decade: giving estrogen hormone replacement therapy (HRT) to women to treat hot flashes, depression, and menopause-induced dementia. Although the therapy often works, it can also cause cancer, heart disease, and stroke. Now, scientists have found a way to boost estrogen only in the brain, a success in rats that may translate to safer treatments for people.
“This could be very applicable for women suffering from hot flashes or depression for whom estrogen therapy is really counter-indicated,” says neuropharmacologist Roberta Brinton of the University of Southern California in Los Angeles, who was not involved in the new work.
When a woman naturally reaches menopause—most often in her 50s—or does so prematurely, for reasons such as a hysterectomy or cancer treatment, levels of estrogen in her body begin to plummet. The hormonal changes can cause hot flashes, depression, and, over time, contribute to women’s risk of developing dementia and osteoporosis. Throughout the latter half of the 20th century, physicians commonly prescribed estrogen HRT to women going through menopause to help ease this transition as well as prevent the long-term effects of estrogen deprivation. Around the turn of the century, though, researchers noticed that women on HRT had an increased risk of heart disease, uterine and breast cancers, and strokes, and doctors generally stopped prescribing the drugs. Even pills that combined estrogen with other hormones meant to alleviate those problems didn’t fare any better when it came to dangerous side effects.
Researchers led by biochemist Laszlo Prokai of the University of North Texas Health Science Center in Fort Worth were studying the production of estrogen in the body when they realized that one estrogen-generating pathway was only active in the brain. A compound called 10β,17β-dihydroxyestra 1,4 dien-3-one (DHED), they found, relies on an enzyme in the brain to be converted from its “prodrug” form into the active form of estrogen; other organs in the body use different starting blocks to generate the hormone. That means that, theoretically, treating animals with DHED would only result in an estrogen increase in the brain, not in the heart, uterus, or breast tissue, where it can cause unwanted side effects.
And indeed, when the researchers gave rats doses of DHED, estrogen levels in their brains increased, whereas levels elsewhere in the body remained stable. What’s more, in female rats lacking ovaries—prone to hot flashes, depression, memory problems, and stroke—DHED reversed these nervous system–linked menopause symptoms without any detectable impacts on the rest of the body, the scientists report online today in Science Translational Medicine.
“Because this prodrug remains completely inactive everywhere else in the body, you can remedy the neurological and psychiatric symptoms associated with estrogen deficiency while avoiding side effects in the rest of the body,” Prokai says. DHED could be particularly useful in treating women who prematurely enter menopause after surgery, because they have the most drastic changes in hormone levels and often deal with symptoms for the longest, he points out. Prokai’s group has already launched nonhuman primate studies of the therapy.
But although the drug holds promise for helping some women, such as those who have specific risk factors for cancer, Brinton says, it may not be an ideal first-line treatment for estrogen-deficiency in many others. “Specifically targeting the brain might have some potential advantages but you aren’t protecting against osteoporosis and other conditions associated with the loss of hormones,” Brinton says. “There are certainly organ systems other than the brain which benefit from estrogen.” Prodrugs specific to those other organs—such as bones—would have to be developed to boost estrogen elsewhere in the body, she says.