As gender equality took root in the U.S. some decades ago, why didn't feminist political correctitude insist on retooling the word menopause to womenopause?

On average, age 51 signals the shutdown of a woman's child-bearing years. Hot flashes (politically "power surges") are usually the first sign of postmenopausal symptoms. They coincide with the gradual turnoff of the sex steroid hormone estrogen. Untreated, this loss may lead to osteoporosis - bone fragility. Its treatment, replacement estrogen, fends off this malady, and lowers the risk of heart disease by half. But estrogen replacement augments the risk of breast cancer and uterine cancer - the female body's two main genotropic (reproductive) organs.

A large federal study of these risks, called the Women's Health Initiative, enrolled l6,000 postmenopausal women, half given estrogen replacement, half a placebo. The trial was abruptly terminated last July, after scientists noted that the estrogen-receiving cohort had a slightly increased incidence of breast cancer, heart attacks, strokes and blood clots, which outweighed the benefits of the hormone. Conversely, estrogen slightly diminished hip fractures - a hazard of postmenopause.

Today's issue of Science, dated Oct. 25, 2002, heralds a possible breakout from this double trap of estrogen replacement. Its title: "Reversal of bone loss in mice by nongenotropic signaling of sex steroids." The paper's senior author, Stavros Manolagas, is professor and director of endocrinology at the University of Arkansas Medical School. Its first author is molecular and cellular biologist Stavroula Kousteni, an assistant professor at the university.

"The major message of this paper," Kousteni told BioWorld Today, "is that the actions of estrogen on bone can be dissociated from its action on reproductive tissues. If you activate the nongenotropic mechanism of estrogen, you can have the protective effect of estrogen on bone. However, you do not have all the harmful effects that are mediated by the genotropic mechanism. But if you have a way of selectively activating nongenotropic estrogen, you can have the hormone's protective effects on bone. This effect," she added, "can be completely dissociated from those of estrogen on reproductive tissues - like uterus or breast. They are exerted by the classical genotropic mechanism of action, which everybody knows up until now."

Putting Quietus On Big, Outdated Assumptions

"Heretofore," she recalled, "there was a big assumption that the beneficial effects of replacement estrogen on reproductive and nonreproductive tissues both result from similar mechanisms of action. We have silenced that big assumption by showing that these actions can be dissociated.

"The second finding we report," Kousteni continued, "is a compound that actually achieves this effect. It can selectively activate only the nongenotropic mechanism of action. This synthetic molecule, named estren, is already commercially available, though not yet marketed. It's the invention of Dr. Manolagas, our paper's senior author, whose patent has been licensed by the university to Abonix Inc., a biotech company he founded on the campus. We have given estren to male and female mice in preclinical experiments.

"These have shown that not only were the animals protected from bone loss, but estren had an effect that was even better than estrogen in female mice, and at least as good as testosterone, which is a normal androgen in male mice. And what is very important is that estren had no effect either in the uterus of those female mice or in the seminal vesicles of the male mice. It did not activate the proliferation of breast cancer, which is a very well-known and highly topical property of estrogen. So estren dissociated the effects on bone from reproductive tissues. It had an even better effect on bone than estrogen itself, and could act on both females and males, which means it can be used as gender-neutral drugs."

Kousteni summed up how she and her co-authors conducted their in vivo experiments. "In female mice," she recounted, "we sham-operated a group of control animals. We just opened them, did a simulated surgical procedure, then closed them up again without taking out any of their tissues. Next, we removed the ovaries from two cohorts of mice, one of which received a replacement dose of estrogen, because when we ovariectomize mice, their uterine weight is decreased. Replacement estrogen restored the uterine weight up to the sham controls. Then we ovariectomized a third group, which received estren and was observed for six weeks. At the end of that period, we measured bone mineral density [BMD] and other bone parameters, as well as the influence on uterine weight. We obtained the estren from its developer," Steraloids Inc., of Newport, R.I., Kousteni noted, "and administered it in the form of pellets."

Female, Male Mice Testify To Estren Efficacy

"We found that in the case of BMD, estren had an anabolic effect better than estradiol and above the level of the sham-operated controls. Again, when we measured random vertebrae, not only did estren prevent loss of bone strength - which occurs with ovariectomy, and what estrogen usually does - but also increased strength to levels higher than some control mice. It did not affect the uterine weight of the ovariectomized animal at all.

"In males, our experiments were along the same lines. We had the sham-operated mice - two orchidectomized groups, one that received testosterone and another estrogen. When we castrated those males, that decreased the weight of their seminal vesicles - the counterparts of ovaries. Again, in the case of BMD, the estren prevented bone loss by orchidectomy, in terms of bone strength, and [had] no effect on seminal vesicle weight increase.

"We're now replicating these experiments in other animal species, such as the rat," Kousteni continued. "And we're interested to see the effect in other nonreproductive tissues, such as the CNS or cardiovascular systems. This work is part of a biotech company. That will probably follow the usual line of preclinicals, going into the hands of biotechnologists," she pointed out. "Trying this in humans is behind the whole idea and our big hope that we can have similar effects in patients. I trust that these studies can answer a lot of the basic problems," she concluded, "that have been highlighted with the result of the Women's Health Initiative."