"We are developing a new class of pharmaceutical agents with the potential for bone-building, sex-neutral hormone replacement therapy," said lead investigator Stavros C. Manolagas, MD, PhD, an endocrinologist with the Central Arkansas Veterans Health Care System and the University of Arkansas for Medical Sciences. He also directs the Osteoporosis and Metabolic Bone Diseases Center in Little Rock, a research laboratory established jointly by VA and UAMS.
Manolagas' team reported last year in the journal Cell that sex hormones exert their bone-protecting and reproductive effects through separate cellular mechanisms--one fast-acting and non-sex-specific, the other long-term and sex-specific. The researchers also identified a synthetic estrogen-like hormone--"estren"--to work in one pathway but not the other. This earlier study, conducted with mouse bone cells, suggested the possibility of gender-neutral hormone replacements that could produce benefits to the bone without reproductive side effects.
The new study is the first time scientists have demonstrated in animals how synthetic hormones can build bone without affecting reproductive organs.
Manolagas and colleagues tested the effects of estren, compared to conventional estrogen and testosterone, in male and female mice. Some of the mice had their ovaries or testis removed, to halt the production of their natural sex hormones. These mice showed a 6-percent loss in bone density, a 23-percent loss in bone strength, and, in the female mice, a 71-percent loss in the weight of the uterus.
The researchers then gave back a naturally occurring form of estrogen, for females, or testosterone, for males, to one group of sex-organ-deficient mice. Another group received the synthetic hormone estren, regardless of sex.
Remarkably, estren was even more effective than estrogen for females, and just as effective as testosterone for males, in helping bone. In fact, while estrogen only prevented bone loss, the estren actually increased bone density and strength, even to levels above those of the female mice with their ovaries intact. Most important, the estren--unlike the estrogen or testosterone--had no effect on the weight of the uterus or seminal vesicle. Moreover, the estren, unlike estrogen, did not trigger the growth of breast-cancer cells in a Petri dish. While estrogen preserves the mass and function of female sex organs, it has also been shown to cause tumors with prolonged use as a therapy.
Manolagas said the results of the study show that synthetic hormones such as estren may provide a safe form of hormone replacement therapy that preserves and even builds bone, without affecting the reproductive system. He added that estren may even provide other anti-aging benefits, such as protecting blood vessels and nerve cells, since these tissues appear to respond to sex steroids through the same mechanism as does bone tissue--without involvement of the reproductive organs.
Hormone replacement therapy (HRT), using estrogen and progestin, was the treatment of choice until very recently for millions of menopausal women seeking to halt the bone loss that causes osteoporosis, and to help with other symptoms, such as hot flashes and mood swings. The therapy was also thought to cut the risk of heart disease. The therapy was associated with a small increase in the risk for uterine and breast cancer, but the benefits were thought to outweigh the risks.
This belief was challenged in July when the National Heart, Lung and Blood Institute stopped a major clinical trial after finding significantly increased rates of breast cancer and cardiovascular disease in women taking HRT, compared to women on placebo. Soon after, a report in the British journal The Lancet showed an increased risk of breast cancer, stroke and blood clots for women on HRT.
Osteoporosis is a debilitating disease in which bones become weak and brittle and more likely to break. Fractures of the hip, spine, wrist and ribs are most common. Of the 10 million Americans estimated to have osteoporosis, 80 percent are women. The sex hormones--namely estrogen in women, and testosterone in men--help build and preserve bone throughout early and middle adulthood; as their levels decrease with age, the risk of osteoporosis increases. In fact, in the five to seven years following menopause, women can lose up to 20 percent of their bone mass.
Funding for Manolagas' study was provided by the Department of Veterans Affairs and the National Institutes of Health.
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