To alleviate vaginal dyspareunia or dryness, a painful symptom of menopause that causes sexual dysfunction, Yale researchers have created a topical estrogen that eliminates side effects of conventional estrogen and that in the future could also alleviate some symptoms of aging skin. "The topical estrogen we've created confines itself to a specific region of the body and helps eliminate the side effects associated with estrogen found in hormone replacement therapies (HRT)," said Richard B. Hochberg, M.D., professor of obstetrics and gynecology at Yale School of Medicine and lead investigator on the study.
Scheduled for publication in a recent issue of the Journal of Medicinal Chemistry, the study showed that the newly-created estrogen does not act systemically and does not stimulate the growth of the uterus in female rats, making it much less likely to cause the common side effects associated with HRT, according to Hochberg.
HRT has long been prescribed to relieve menopausal symptoms like hot flashes, heart disease, bone loss associated with osteoporosis and vaginal dryness, which affects about 40 percent of women within 10 years of the onset of menopause. But fear of side effects such as breast and edometrial cancer and stroke cause many women to steer clear of HRT.
Hochberg said the risks associated with HRT outweigh the benefits for many women. "The risks of side effects are small, but they are real," he said. "Although they happen in only a small percentage of women, because these side effects involve cancer and stroke, a general fear of HRT exists."
There are topical estrogen creams now available on the market to treat vaginal dryness that are given intravaginally, but these estrogens are absorbed in the vaginal walls and enter the blood, resulting in significant blood levels of estrogen. "The cream we've developed contains a powerful but local estrogen that metabolizes quickly in the tissues and the blood stream," Hochberg said.
"Since topically applied estrogen is absorbed into the blood, its purpose is defeated," Hochberg added. "A potent estrogen whose range is limited to the tissue to which it is applied is ideal for the treatment of menopausal disorders."
Using a derivative of estradiol, the major estrogen, that, because of its charge, was no longer estrogenic, Hochberg and his team masked this group-derivative by another substitution, resulting in a compound that was highly estrogenic, meaning it could bind the estrogen receptor protein that mediates the action of estrogen.
"This compound had high estrogenic potential and at the same time, it was designed to be metabolically labile, so it could be metabolized by an enzyme called esterase that converts this compound very rapidly back to the inactive parent," Hochberg said. "The consequence is that the estrogen could be metabolized extremely quickly in the bloodstream. Tests in female rats showed that there was very little systemic activity."
Hochberg and his team then tested the estrogen for vaginal activity. "We placed the material directly into the vaginas of mice where it was extremely estrogenic," he said. "In this test, we measured the production of a protein that is a marker for estrogen simulation of vaginal growth."
The new topical estrogen also includes anti-aging properties. Hochberg said that because the skin contains estrogen receptors, it is an estrogen target organ that can respond to estrogen replacement. "This new topical estrogen has some anti-aging properties and may alleviate some of the symptoms of aging skin," he said.
