Kathryn Sandberg: Researching Why Sex Matters in the Application of Medicine

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No question about it, says Kathryn Sandberg, PhD, women are much more complex than men – in a purely biological sense, she adds.

It may not seem that way to most people, says Sandberg, director of the GUMC Center for the Study of Sex Differences in Health, Aging, and Disease, because men have two different sex chromosomes (an X and Y) while women have just one (two copies of the X chromosome) in their cells. That suggests that men have something women don’t have when it comes to genes. And it’s true: men are men because their Y chromosome contains the all-powerful SRY gene that dictates development of male testes. Women are the “default status” - the being that develops when an SRY gene is absent.

Furthermore, each cell in a male expresses both the X and Y chromosome, while only one of the two X chromosomes is expressed in a female cell due to inactivation of the second X chromosome.

But that is not the whole story, Sandberg says. While one X chromosome is “silenced” within each female cell, such control is imperfect. “About 17 percent of genes in the quiet X chromosome escape inactivation, so these extra genes are expressed along with the active X chromosome. And because the X chromosome has about 25 times more genes than the Y chromosome, women have significantly more gene expression than men.”

And it gets even more complicated than that when you realize X-inactivation of the maternal and paternal X chromosomes is a random event in women, she says. Thus in one cell, an X chromosome from the woman’s mother is expressed, while the cell right next to it might express the X chromosome from the father. That means that, overall, a woman is a mosaic of her maternal and paternal X chromosomes. “No wonder we are such a complicated sex, biologically speaking of course,” Sandberg says.

All of this is important, Sandberg says, because “biological sex vastly influences a person’s medical experience from cradle to grave. Women and men exhibit big differences in susceptibility to various diseases. They experience symptoms like pain in different ways, and they can react differently to drugs and have very different outcomes,” she says.

In fact, Sandberg suspects that nine out of ten drugs that the FDA pulls off the market due to adverse events are because women do not tolerate the drugs as well as men. And while the National Institutes of Health has said women must be included in federally funded phase III trials, “inclusion of women in earlier phases is not mandated, and that is where efficacy and side effects are studied.”

Given this, Sandberg and her “virtual” center are dedicated to sex difference research and educating researchers nationwide about the importance of considering the role of biological sex from bench to beside, including studies of all three phases of clinical trial testing. “The concept is so easy to grasp because everyone knows sex differences exist,” she says.

Sandberg herself is fascinated by the fact that once women reach menopause, their blood pressure rises and soon exceeds levels seen in men. “Ninety percent of essential hypertension is not understood, and that includes sex differences that put older post-menopausal women at higher risk than similarly aged men,” she says.

But now Sandberg has a unique mouse model she says is pointing to “some very exciting” research avenues. She and her research team are studying mice in which the SRY gene was spontaneously deleted from the Y chromosome, thereby resulting in XY female mice. To mimic menopause, ovaries were removed from both XY and XX females, and her laboratory has discovered that XX mice developed higher blood pressure than the XY females in an induced model of hypertension. “These findings raise the possibility that gene expression in the XX sex chromosomal complement has an adverse effect on blood pressure once menopause begins. It may not be active before menopause because ovarian hormones could be blocking or masking it,” she says. “No one has ever suspected such a scenario.

“If our research leads us to a greater nuanced understanding of hypertension in women, we may be able to develop a targeted treatment approach,” Sandberg says. “And what we learn about women may be applicable to men – even if they are less complex.”

By Renee Twombly, GUMC Communications