Jill Goldstein

Sex differences—differences between men and women in physiology, disease progression, response to treatment and more—are pervasive in medicine. And yet, for decades, there’s been a strong tilt toward over-representing men in basic, translational and clinical research. In 1993, new regulations by the National Institutes of Health requiring the participation of female subjects in clinical trials helped re-balance the clinical research scales, but the disproportionate number of male animals and cells derived from male subjects has meant that preclinical research may not tell the full story.

In January of 2016, the NIH issued requirements that all NIH-funded research involving animals with spines must include both male and female subjects. In light of these new requirements, in May, the Connors-BRI Center for Research on Women’s Health and Gender Biology held a workshop to explore sex differences methodologies to help investigators inform themselves about how to design studies to include female animals in preclinical research and female participants in clinical trials and to also consider the importance of differences between male and female cells. The event featured a keynote speaker and talks by BWH experts who addressed the importance of sex differences in population research as well as basic research.

“Men and women differ in the frequency of so many disorders that affect the brain, the body or both. It’s absolutely critical for us to think about the impact of the nature of one’s sex on the nature of these disorders—the causes, the timing of onset, the course of the disease and the therapeutic response,” said Jill Goldstein, PhD, director of Research at BWH’s Connors Center and chair, Connors- BRI Center. “Different fields have been studying this in fits and starts, but the goal of the Connors-BRI Center is to bring together senior and junior investigators from across disciplines and methodologies to focus on the importance of sex differences in medicine.”

Goldstein, a clinical neuroscientist who is internationally renowned for her expertise in sex differences in health and diseases that affect the central nervous system, introduced the workshop and offered an example of sex differences in the fetal programming of the brain. In the second trimester, as male fetal gonads begin producing testosterone, this drives the gonadal hormone regulation of masculinizing the male brain enhancing the direct effect of genes on sexual differentiation which occurs in first trimester. This means that depending on timing in gestation, there will be differences in the sex differences in the brain that researchers studying development may uncover.

“Sex influences every level of analysis,” said Goldstein.

Goldstein also introduced the workshop’s keynote speaker, Doris Taylor, PhD, FAHA, FACC, the director of Regenerative Medicine Research and the Center for Cell & Organ Biotechnology at the Texas Heart Institute. Taylor is a leading expert in cardiac repair and replacement, and spoke about sex differences in cardiovascular regenerative medicine.

Taylor described differences in the onset of heart disease in men and women as well as differences in the events—particularly, inflammation—leading to heart disease. In experiments carried out in mouse models, Taylor and her colleagues found that bone marrow stem cell transplants from older female mice helped fight inflammation and protected against the development of heart disease; bone marrow stem cell transplants from older male mice, however, did not.

“Biology of sex really does matter,” said Taylor. “Cell therapy is based on the assumption that certain cells are capable of responding to and helping repair an injury, but what we’re seeing is that this may not be the same for cells from males and females.”

Julie Buring, ScD, of the Department of Medicine at BWH, shared insights from her firsthand experiences with two clinical trials: the Women’s Health Study and the Physicians’ Health Study. The latter study, which began in the early 1980s, enrolled only male physicians. When researchers tested the effects of aspirin on risk of heart attack and stroke, they stopped the trial prematurely after finding that aspirin significantly decreased heart attack risk. It did not, however, protect against stroke.

“We then asked, ‘What about for women?’” Buring said. “We didn’t expect our findings would be any different.”

But when the research team carried out the same trial in female health professionals, they found that aspirin offered no protection against heart attacks but did protect against stroke.

“I would’ve put down money that this wouldn’t have happened. The only way to see it was to look at women and compare the results to men,” said Buring.

Ursula Kaiser, MD, chief of the Division of Endocrinology in the Department of Medicine, presented on basic research. Kaiser, who studies the neuroendocrine circuitry involved in reproduction, noted that even though some advancements have been made in clinical trials, “we’re just beginning to address these issues in preclinical research.”

“Sex matters in preclinical research,” said Kaiser. “There are hormone-dependent responses, the female menstrual cycle, exposure to sex differences and intrinsic chromosomal differences, all of which can influence outcomes.”

The workshop concluded with a networking event that allowed junior investigators interested in incorporating sex differences into their research to seek advice from BWH experts.