After the end of the Second World War, thalidomide was introduced in Europe as a safe and effective new sedative, an alternative to the highly addictive barbiturates that had been rising in use since the tail end of conflict. It was soon marketed for scores of other uses, from anxiety to the common cold. Handed out like candy to doctors and available without a prescription, thalidomide quickly made its way into households across the globe, including the United States. Its most notorious off-label use, though, was as a treatment for morning sickness. At the time, little was understood about how drugs passed from patient to fetus. When tens of thousands of babies were subsequently born with severe developmental anomalies, the FDA made a sweeping judgment call that would profoundly affect female reproductive health for decades. Instead of investing research effort into drug safety during pregnancy, it opted to simply exclude all women of “child-bearing potential” from early clinical trials.
Almost half a century later, we still lack adequate data on female subjects, and it’s a problem that reaches beyond the clinic and back to the research labs, where promising new treatments are discovered and developed in animal models. Guidelines handed down by organizations that fund basic research, such as the NIH and FDA, are slowly catching up to this need for experimental equity. New research initiatives are also starting to bridge this gap—such as the Global Consortium for Reproductive Longevity and Equality at the Buck Institute for Research on Aging, where efforts are underway to look beyond “child-bearing potential” in order to understand how changes in female reproductive physiology affect health across the whole lifespan.
Before a drug makes it to clinical trials, its biochemical properties are first studied in animal models such as mice and rats. Even at this early stage, sample bias toward male subjects has been just as pernicious as it is in the clinic. After a few experiments conducted in the early 1960s and 1970s suggested that data collected from female rodents might be unreliable due to cyclical fluctuations in estrogen, researchers tended to avoid the headache of an extra variable and used only male animals in experiments. Dozens of independent studies done over the past decade, however, have revealed no such variability due to the estrous cycle.
One major problem in biomedical research is not just that these studies are conducted in unfairly biased ways, but that many aspects of female reproductive health simply aren’t studied in the first place. Dr. Judith Campisi, a professor at the Buck Institute who studies the basic cellular mechanisms of aging, explains that the reasons why male fertility persists throughout the lifespan while female reproductive capacity ends in middle age remain unclear to scientists. “Menopause is quite rare among mammals,” Dr. Campisi says in an interview for Lady Science. A gradual lifelong decrease in fertility is common in many species, she notes, “but this precipitous loss of reproductive ability is peculiar to humans.” A fundamental goal that unifies the work of the different labs who make up the consortium is to understand the basic molecular and chemical drivers of this difference.
Berenice Benayoun and her team at the University of Southern California are working to take some of the mystery out of this basic biological question. Her lab is developing mouse models of menopause, which until now have mostly been studied by removing the ovaries from mice who are 2-3 months old—the equivalent, Dr. Benayoun says, of throwing a 15-year-old human directly into menopause with none of the gradual hormonal shifts normally experienced by older women. By using models that more closely approximate human timelines and transitions, her work will pave the way for more thorough investigations of the basics of female physiology throughout the lifespan, beyond the mechanics of pregnancy and childbirth.
“There’s always been a lot of interest in trying to rescue the fertility or preserve the fertility of women who are undergoing premature ovarian failures,” Dr. Benayoun explains, speaking to Lady Science. “The ovary does a lot of things that are not related to reproduction.”
Work by Dr. Benayoun and others has revealed cyclical changes in immune function that correlate to estrogen levels, and links estrogen to susceptibility for Alzheimer’s disease and a variety of other age-related pathologies. Estrogen-dependent variations in the biochemical processes involved in these diseases can lead to variations in drug metabolism, which can translate to major differences in how a patient responds to a drug, how much of it is needed to be of any therapeutic value, and the potential toxicity of these compounds.
While intended to prevent unforeseen effects on prenatal development, the FDA’s guidance in response to the thalidomide crisis stymied progress on drug development for diseases that affect women in greater numbers than men. This response also failed to account for potential sex differences in adverse side effects. Several common sleeping medications were prescribed in equal doses to men and women, until women began reporting a higher incidence of serious cognitive side effects. Studies revealed differences between male and female patients in the rate certain sleep drugs clear the blood, prompting the FDA to adjust their dosage suggestions. Doctor Benayoun says she sees differences like these regularly when her lab compares the effects of common anti-aging interventions in either male or female mice. “Most of what works does not work the same in females and males,” she points out.
Because sex differences have been viewed in research for so long as an experimental confound rather than a critical area of further study, we’ve lost valuable insight into how these fundamental differences work. From the exclusion of women from clinical trials over concerns for the health of their fetuses, to the dearth of research into what happens after fertility declines, the inseparability of female physiology from fertility in the minds of clinicians and basic researchers has limited women’s health. “There’s so much we still don’t know,” says Dr. Benayoun, “that we can’t estimate how much we’ve lost.” But as her lab and others like it begin to expand our basic knowledge of this field, the research climate has begun to shift—and the attitude and approach of the larger medical community will shift with it.