Keeping sex under control.

Keeping sex under control

When is a hormone not a hormone? When it looks like an important sex-related hormone but is biologically impotent, say the first scientists to report finding such a substance in human blood. These "antihormones" may play a role in the timing of puberty, as well as in changes in sex-organ function during aging. The discovery could also have implications for future contraceptives, treatments for hormonal dysfunction and methods to pinpoint ovulation, say the scientists.

Researchers at the University of California at San Diego reported results last week from a study where women with below-normal ovarian function were given an "antagonist" of gonadotropin-releasing hormone (GnRH). This regulatory hormone prompts secretion of gonadotropins, hormones that affect functions like gonadal (sex organ) growth and the release of other sex-related hormones. Treating women with a GnRH antagonist--which closely mimics GnRH but lacks its gonad-stimulating activity -- is a standard clinical protocol to help evaluate different segments of an individual's complex hormone-release cycles.

Of particular interest to the researchers was the gonadotropin called follicle-stimulating hormone (FSH). "There's a feedback loop [involved in hormone-secretion cycles], says Aaron J.W. Hsueh, who helped conduct the study. "However, if the ovaries or testes are removed or are not functioning normally, the FSH levels are very high because the feedback mechanism is lost." As reported in the Jan. 1 SCIENCE, Hsueh, Kristine D. Dahl and Thomas A. Bicsak -- dissatisfied with current commercial assays for FSH--developed more sensitive methods capable of separating several chemical forms of FSH and then tested blood from the GnRH-antagonist-treated women.

What they found was "something very strange," according to Hsueh, who says the results are the first proof that "anti-hormones" circulate naturally in the body. Other scientists had reported that when sugars are experimentally removed from purified FSH in the laboratory, the gonadotropin still binds to its receptors on gonadal cells but loses its bioactivity: It no longer stimulates estrogen production, for example.

But the new data go beyond the laboratory situation, showing that FSH-like molecules without biological activity also circulate through the body. The researchers confirmed this lack of biological activity, says Hsueh, by adding the newly discovered FSH-like substance to cultured ovary cells, which failed to secrete estrogen.

By binding to gonadal cells, these antagonistic antihormones block activity by well-known forms of FSH, thereby disrupting normal hormone secretion. Whether they occur in the general population has not been determined, says Hsueh. To answer that question, the scientists are now studying a group of older men. During aging, the FSH levels are relatively high, but the biological activity of the gonadotropin is low, says Hsueh, adding that circulating antihormones could explain the discrepancy. Antihormones also may be active in children, "just to make sure puberty comes at the right time," says Hsueh.

In another study underway, Dahl is using the new FSH assays on urine samples, including specimens from killer whales and endangered species like the gorilla. Better timing of the animals' sexual cycles could improve success in zoo breeding, says Hsueh.