Con(tra)ception: hormonal coin toss.

Con(tra)ception: Hormonal coin toss

Two research teams at the Salk Institute in La Jolla, Calif., have discovered a reproductive hormone that may one day be useful in the treatment of certain kinds of infertility. Another reproductive hormone, also recently isolated by one of the same research groups, may have potential as a contraceptive. In an unusual demonstration of the body's thriftiness, the hormones are a matched set: Although opposite in activity, they are largely rearrangements of the same components.

The newly discovered hormones are intriguing because they act specifically on the production of follicle-stimulating hormone (FSH), which triggers the development of ova and the production of sperm. Inhibin, one of the recently isolated hormones, acts on the pituitary gland to decrease FSH secretion without affecting levels of other hormones that are often released in tandem. Because of that specificity, says Kenneth Klivington, spokesperson for the research groups, "inhibin provides a potential ideal contraceptive for both men and women."

Unexpected findings during the research on inhibin led to the discovery of a substance that works in the opposite direction, stimulating release of FSH. That substance was reported in the June 19 NATURE. Two forms were isolated at Salk -- one named follicle-stimulating hormone releasing protein (FRP) by a group led by Wylie Vale, and the other called activin by a group led by Roger Guillemin. Klivington says it may someday lead to a "choice treatment" for infertility.

Modern contraceptive technology is prone to problems. Even though birth control pills succeed in blocking fertility in women, there are side effects that ripple throughout the hormonal system; and there is no male hormonal contraceptive available at all. The problem for researchers has been the body's intricate dovetailing of the hormones that orchestrate reprodductive events.

Scientists have long known that much of the regulation occurs in a hypothalamus-pituitary-gonad hormonal loop: The hypothalamus in the brain stimulates the pituitary to secrete two hormones, FSH and lutenizing hormone (LH), which, among other things, stimulates the production of sex steroids like estrogen and testosterone. Most birth control pills for women use estrogens and other steroids, which can disturb the rest of the hormonal balance. When researchers have attempted to use FSH-inhibiting substances as male birth control, they have been unable to block the release of FSH without also inhibiting LH. That meant that while production of sperm stopped, levels of sex steroids dropped as well -- and so did the steroid-controlled sex drive.

But a contraceptive based on inhibin might block production of sperm or ova without "fouling up background levels of sex steroids," Klivington says. In using it, "you wouldn't mess up the psychological aspects of reproductive behavior."

The activating compounds may turn out to be valuable treatments for men and women who are infertile because of low levels of FSH, Klivington says. Currently, hypothalamic hormone is used to treat some of these cases of infertility, but that hormone is a blunt tool, raising levels of LH along with FSH. That can be a particular problem for women, because inappropriately high levels of LH at the end of the menstrual cycle may actually inhibit follicle selection and egg development.

Applications of the newly discovered hormones are still very much in the realm of the theoretical, researchers warn. For one thing, the work at Salk has used inhibin from animals and has so far been done only in test tubes. But inhibin in humans is very similar to that from animals, according to Anthony Mason at the San Francisco-based biotechnology firm Genentech. Mason worked with Guillemin on the isolation of inhibin. Another recent announcement, in the May 31 LANCET, is encouraging to the researchers: The paper confirms that inhibin can be found circulating in the blood in humans. (According to the researchers, led by Robert McLachlan at Prince Henry's Hospital in Melbourne, Australia, blood levels of inhibin may eventually be used to signal the best time for in vitro fertilization.)

One of the most striking aspects of the discoveries has nothing to do with the function of the hormones, according to the Salk Institute researchers, but with the way they are put together. Inhibin is made up of an alpha subunit and one of two possible beta subunits. The activating hormones consist of two of the beta subunits linked together.

The rearrangement to produce different proteins seems to occur at the level of the subunits, the researchers say, rather than at the level of the genes which code for them. Examples of such rearrangements of several gene products are the norm, rather than the exception," Guillemin's team writes, "this proces clearly extends the diversity of the final products (and their biological activity) derived from a limited number of genes."