Study looks at causes, consequences of sex differences

Vandenbergh was one of 16 team members on an 18-month Institute of Medicine (IOM) study on differences between the sexes and how those differences affect health. The committee�s report, "Exploring the Biological Contributions to Human Health: Does Sex Matter?," concludes that many normal physiological functions and disease functions are influenced directly or indirectly by sex-based biological differences.

"The focus of study was on basic biology of sex determination -- how do we get to be males and females from a genetic, an endocrine and a developmental point of view," Vandenbergh said. "And the second part of this was, how do these basic differences between us cause us to look at diseases in a different way?"

Some basic differences in how men and women respond to disease are well-known but not well-understood. For instance, women clearly use both left and right hemispheres of the brain for language tasks, while men tend to use mainly the left hemisphere. Therefore, women are more likely to recover speech after a left-brain stroke, while it is much more difficult for men to recover from it. And women are nearly twice as vulnerable to diseases caused by tobacco smoke than men, which may account for an increase in the incidence of lung cancer among women.

On the other hand, males are much more likely to suffer from severe mental retardation, which may be the result of disruptions that occur in fetal development. During the complex process when a fetus is differentiated as male, minor lapses in hormone or genetic activity could lead to problems in a man later in life.

"Our finding is that significant differences are present in animals and humans as a function of sex. When investigators conduct studies of human health relevance, they should include sex as a variable wherever it makes much sense," Vandenbergh said.

One reason for the study was concern over the fact that women are often excluded from clinical studies of diseases and drugs. This practice dates to a post-World War II law excluding women for liability reasons. It also springs from the practical concern that women, at different stages of their hormonal cycles, have different biochemical reactions to tests. But tests developed in the past decade make it much easier for scientists conducting clinical studies to control for women�s cycles, Vandenbergh said.

The IOM committee recommended some changes in the way clinical studies are done. "Our committee does not recommend that all clinical studies include both men and women. What it does recommend is that investigators and funding agencies make sure they consider using both men and women and evaluate the importance of doing that," Vandenbergh said. "If you�re studying the effect of a drug on prostate cancer, it doesn�t make much sense to put women into the study. On the other hand, if you�re studying a drug for breast cancer, it might make sense to put men in some of the studies. Men do have mammary tissue, and they, at a very low rate, get breast cancer. By including men in a study of breast cancer, you might learn something about women."

Vandenbergh, whose research interests include hormonal changes during puberty and reproduction, has explored how fetal exposure to sex hormones -- the male hormone, testosterone, and the female, estradiol -- affects animals later in life. Research has shown that animals� sexual behavior, anatomy and physiology are influenced by the hormones they encounter in the womb.

Litter-born animals such as rodents and pigs are exposed to sex hormones in utero from other fetuses surrounding them, said Vandenbergh. Research has shown that in utero placement and the consequent exposure to male or female hormones have a lifetime effect on animals, although those effects vary greatly between species. For instance, female mice that lie between two males in utero (also called 2M females) experience elevated testosterone levels before birth and have shorter life periods of fertility than do females who lie in utero between two other females (called 2F females). Male mice prefer to mate with 2F female mice, and 2M female mice are more aggressive toward other females and to intruders than 2F females.

"There�s growing evidence to suggest that humans may be influenced by prenatal hormone exposure, perhaps not as dramatically as animals because most humans are born as singletons," Vandenbergh said. Human studies of fraternal twins have shown that girls with a twin brother, who were therefore exposed to testosterone in utero, show some slight masculine tendencies later in life.

"This does not mean that hormones are your destiny," he said. "But it does mean that hormones shape your choices. And genes don�t control your destiny, but they do control some of your orientations, some selections and patterns of adult characteristics."