Pain gripped Victoria Ventura's chest so fiercely she couldn't climb stairs, eat—or even take a deep breath. 

It throbbed down her arm and into her jaw, common symptoms of heart disease, but the first doctors she saw dismissed cardiac trouble as the source. The next nine years were a crucible of misdiagnosis. Stress, a benign brain tumor and uterine bleeding were all blamed and treated—but the ache in her chest remained. At age 47, Ventura saw a cardiologist who found an abnormality in her electrocardiogram. 

Still, he told her, "Young lady, I've been doing this for over 30 years, and this has nothing to do with your heart." 

"I felt dismissed because I am a woman," Ventura says.

After nearly a decade of pain, she sought help from C. Noel Bairey Merz, MD, a world leader in identifying how heart disease manifests in women. From Bairey Merz, director of the Barbra Streisand Women's Heart Center at the Smidt Heart Institute, Ventura learned that she has coronary microvascular disease—a heart condition that mostly affects women and doesn't always appear the way heart disease does in men.

Her story is all too common. Women and girls are chronically misdiagnosed, underdiagnosed and mistreated—and not just for heart disease. They suffer, unrecognized, from autoimmune diseases, post-traumatic stress disorder and attention deficit hyperactivity disorder (ADHD). 

Sex and gender bias is baked into the healthcare system. Since females have been historically underrepresented in clinical trials and basic science studies, drugs are developed for male bodies and physicians often look for men's symptoms. 

"It's not necessarily willful, but people study the things they identify with and are interested in," says Nancy Sicotte, MD, chair of the Department of Neurology. "Plus, female hormones are a complicating factor, so there's been a feeling that it's easier to study medicine from a male perspective."

Often, the male perspective has confined the study of women to their breasts and reproductive organs, limiting understanding of less explicit, but impactful, sex differences in other systems of the body. 

"Women's health is often still treated as ‘bikini medicine,' but more women still die of lung cancer than breast cancer and from colon cancer than ovarian cancer," Bairey Merz says. "We can do better."

In some cases, doing better comes in the form of renewed guidelines from national regulatory bodies. In 1992, the sleeping pill Ambien flooded the market, quickly becoming the nation's most prescribed drug. In 2013, after studies showed that women wake up with more of the drug in their bodies because they metabolize it differently, the Food and Drug Administration cut the dosage guidelines for women by half. For 21 years, women had been overmedicated by nearly twice the safe amount. 

"Unfortunately, that's hardly an isolated incident," says Sarah Kilpatrick, MD, PhD, chair of the Cedars-Sinai Department of Obstetrics and Gynecology. "Some 80% of drugs withdrawn by the Food and Drug Administration between 1997 and 2000 were removed at least in part because they posed a risk to women. The pharmaceutical industry and medical practitioners treat women as if they are just smaller men. They are not."

Now, new rules from the National Institutes of Health (NIH), the country's largest biomedical research funding agency, aim to circumvent such instances of ignorance-induced harm. Traditionally, animal research studies have focused almost exclusively on males, reasoning that varying estrogen levels in female animals could muddy the results. That means female models of disease have rarely been used, making it difficult to devise clinical studies that could lead to useful discoveries about women.

In 2016, the NIH announced it expects investigators to include female animals in most studies, and collect, analyze and report how they differ from male animals—noting that female animals' estrogen fluctuations are among the many reasons that scientists need to study them.

The NIH rolled out a similar policy in 1986, demanding women be represented in human subject studies, but only in the last 10 years have women become close to half of U.S. clinical trial participants.

"Males should not be considered the default, with females an inferior or lesser research subject," says Chyren Hunter, PhD, associate director of Basic and Translational Research in the NIH Office of Research on Women's Health. "These policies are going to benefit women and men as we begin to develop more personalized care for sex and gender across many disease states and treatments." 

Roberta Gottlieb, MD, director of Molecular Cardiobiology at Cedars-Sinai, says this research rule could help create a framework for organizing sex differences. 

"Our failure to understand sex differences in how disease manifests and how treatments work means that we've been mistreating half the population," Gottlieb says. 

Ventura's arduous health journey ultimately led her to enroll in a Cedars-Sinai clinical trial for an investigational stem cell treatment for microvascular disease. Her pain has ebbed and she is happily running the printing and graphics business she owns with her husband in Lancaster, California.

"I never realized before how sometimes we settle for less," she says, reflecting on how long she hid her pain and exhaustion from friends and colleagues. "We say ‘OK,' and we let it be. And we shouldn't have to settle like that."

At Cedars-Sinai, medical pioneers are tackling sex and gender bias on multiple fronts. Research is uncovering sex differences that impact what health looks like, whether medications work, and how and when disease is most likely to strike. Investigators are advocating for major changes to every facet of healthcare—how we train doctors, how we treat patients, how we conduct medical research and how we invest in the science that reveals our differences. 

It's a challenge, even for female researchers.

"As women, we want to think we're not that different from men," says Susan Cheng, MD, MPH, MMSc, director of Public Health Research in the Smidt Heart Institute. "We're subject to the same exposures and environment, so we think we should be treated equally, which has led us to shoot ourselves in the foot, because it causes us to be analyzed and studied as a variant of male. The more carefully we look at the data, the more we realize we're not just another line on the same axis."