Why Sickness and Health Can Look Different for Women Than Men
May 2016—A man and a woman in their 30s both receive a flu shot. While the man notices a little soreness in his arm and feels off for a few hours, the woman’s arm aches, and she feels nauseated and shaky for days. New research by Sabra Klein
, a biologist in the Bloomberg School of Public Health at The Johns Hopkins University, could explain why.
Sex differences in health and medicine have been recognized for years — in 2004, the American Heart Association’s Go Red For Women campaign, for instance, highlighted that men and women experience heart attacks differently — but researchers have only recently begun to elucidate the underlying hormonal and genetic factors at play. Their findings have implications for diagnosis, public health messages and treatment.
The X Factor
Johns Hopkins has long been a leader in researching the interplay between gender and health. Barbara Migeon
, a pediatrician and geneticist in the school of medicine, has intensively researched a phenomenon known as mosaicism
. While males have only one X chromosome, which makes them more susceptible to effects of mutation, females have two. A process called X inactivation turns off most of the second X so that a baby girl has a mix of her mother’s and father’s genetic material; the mix of parental genes provides a biological advantage to females and contributes to their surviving better at every age. "It is also a source of greater diversity for females," says Migeon. She and others have shown that about 15 percent of a girl’s genes escape X inactivation and continue to be active at low levels. Migeon hypothesizes that the extra activity is responsible for the congenital abnormalities in people who have too few or too many X chromosomes (conditions known as Turner and Klinefelter syndromes).
Male and Female Vaccinations?
While Migeon’s focus has always been on genetics, Klein has focused on sex hormones and how they influence response to infections and vaccinations. In a typical study, Klein first observes the antibody response to a vaccine or pathogen to see if male and female mice respond differently. If they do, she removes the mice’s genitalia to eliminate any hormonal differences. Then she adds sex hormones back in and tests whether the sex differences in the immune response reappear. Her work, and that of others working with animals and humans, has revealed a strange paradox: While women show a higher inflammatory immune response to pathogens during their reproductive years, that response decreases as they age. Conversely, men’s inflammatory immune response increases with age. Testosterone is anti-inflammatory, so its lower levels in older men could explain this phenomenon, speculates Klein.
She is now putting that and other theories to the test with the launch of a seven-year longitudinal study in people over 65. Her goal is to observe how men and women respond differently to vaccines. All the residents are in assisted living, so she is able to study the effects of a vaccine without much of the background noise that has muddied outcomes of similar studies. “We all live in different environments that contribute to differences in how well a vaccine works,” she says. "Now, we get to eliminate the environmental variables because everybody is living in the same place.”
Women-Specific Health Risks
As researchers sort out the unique interplay between gender and health, the work could have important implications for public health campaigns. For instance, Rita Kalyani
, an endocrinologist in the school of medicine, and Pamela Ouyang
, a cardiologist in the school of medicine, recently published an analysis of data from 10,000 participants in three studies. While it had been believed that women under 60 are generally at much lower risk of developing heart disease than men, their study revealed that the difference disappears in young women with diabetes. (Heart disease risk does not appear to go up as much for men with diabetes.) That’s crucial information for doctors and patients alike, Kalyani says. “We need to focus more of our heart health efforts on reaching young women with diabetes.”
While that effort is still in the works, Ouyang has launched a pilot study on how to get obese women at risk of developing heart disease to exercise more. Women suffer from higher rates of obesity than men and are much more likely to avoid physical exercise, Ouyang notes. She adds that in focus groups with obese women, she has found that many feel too self-conscious to go to the gym. So Ouyang recently launched a pilot study with 30 obese women, each of whom was given a Fitbit to track daily activity. Whenever the women were sedentary for more than an hour, they received a text message reminding them to get moving. The women then had to respond by walking at least a few steps. The study showed that when the text messaging started immediately at the beginning the study, the women reduced the time they were sedentary. However, if the start of messaging was delayed by a few weeks, women didn’t change their activity. This suggests that women can be encouraged to change behavior by messaging, Ouyang says, but more work needs to be done to find out how to keep women interested and responsive to the messaging.
Ouyang also directs a new American Heart Association-funded center that aims to advance prevention, diagnosis and treatment of a form of heart failure that’s more common in women than in men. Known as heart failure with preserved ejection fraction, the condition is distinguished by heart muscle that doesn’t relax properly between pumps, Ouyang says. In one planned study, researchers will examine heart tissue biopsies to learn more about the biochemical pathways at fault in this type of heart failure. In another, they’ll look for biomarkers that could flag the condition early through a blood test. They will also test the effects of exercise and estrogen replacement therapy. And they will train fellows in how to conduct research on women’s health and cardiovascular disease. “We think that by looking at this disease from basic, clinical and population angles, as well as training fellows to become future leaders in the field, we can make a big difference in the toll it takes,” Ouyang says.
Besides developing targeted public health campaigns, research into gender and disease could also influence treatment. The flu, again, is a case in point. Studies have shown that women in their reproductive years mount two to four times the antibody response to the flu vaccine as men. In theory, this is good, as the greater the antibody response, the greater one’s resistance to the flu. “Should you ever get infected, those antibodies are in place to bind to and neutralize the virus,” Klein explains. However, the stronger response also explains why women experience more headaches, swelling, achiness and general malaise in response to the vaccine than men. It could also explain why women are considerably less likely to get vaccinated than men. And because women are known to make the majority of health-related decisions in a given household, the effects could mean that entire families skip out on the vaccine. “You can see how this can spiral throughout the household,” Klein says. One possible solution she would like to look into? Giving women smaller doses of the vaccine.