Chloe Bird, Ph.D., on Advancing Understanding of Sex & Gender Influences on Health & Disease

Chloe Bird, Ph.D., on Advancing Understanding of Sex & Gender Influences on Health & Disease


>>Chloe Bird:
Hello, I’m Dr. Chloe Bird, Senior Advisor to the Director of the Office of Research
on Women’s Health at the National Institutes of Health. Today, I’m speaking to you about increasing
knowledge about the health of women by advancing understanding of sex and gender influences
on health and disease. Let’s talk about sex, and gender, and health. The Mission of the NIH is to seek fundamental
knowledge about the nature and behavior of living systems and the application of that
knowledge to enhance health, lengthen life, and reduce illness and disability. How are we doing with regard to the health
and longevity of women? A few pieces of data highlight the challenge. First, while U.S. men have continued to make
gains in longevity, including survival to age 50, U.S. women’s chances of surviving
to age 50 have fallen far behind other high-income peer countries, literally dropping off the
tail of the distribution, as the chances for women in other high-income countries have
continued to improve. Moreover, in many U.S. counties life expectancy
plateaued for women, even as it continued to increase for men. Wang and colleagues estimated life expectancy
at the county level from 1985 to 2010. During this period, the life expectancy of
men remained stagnant or decreased in fewer than 5% of U.S. counties. By contrast, in 45% of counties the researchers
found no significant change or a significant decrease in the life expectancy of women over
the same period. Life expectancy improved for men in a much
larger share of the country than for women between 1985 and 2010. Even if the differences between men’s and
women’s survival trends narrow, it will be important to keep monitoring these trends
– both within the United States and among peer countries – using the most recently available
data. In light of the trends, there is a larger
debate taking place about why US women’s life expectancy is not improving, or more so, what
can we do to change the trajectory of women’s health in the United States? The large variation in women’s life expectancy
that occurs among counties in the United States is also accompanied by state-to-state variation
in average mortality rate for women. In the map shown here, Jennifer Montez and
colleagues estimated state-level mortality rates for U.S.-born women aged 45 to 89 years,
using data collected in the 1980s and 90s, with mortality follow-up through 2002. The researchers tested a number of possible
explanations for the variation in women’s mortality rate across states. They tested the contribution of women’s characteristics,
such as age, race, ethnicity, education, income, and marital status, and contextual characteristics
of the state in which they lived, such as economic conditions, social cohesion, physical
infrastructure, and tobacco environment. Not surprisingly, when they only used age
to adjust the variation in women’s mortality, they found a substantial amount of residual
variation in mortality across states. When they added the other individual-level
characteristics of women, their model explained 30% of the variation in women’s mortality. Note the decrease in the variation across
states when these factors are taken into account. When they also included state-level characteristics,
their model accounted for an additional 32% of variation in mortality rate. In other words, 62% of the variation in women’s
mortality across states is accounted for by the individual-level and the state-level factors
that Montez and colleagues examined. These results nicely illustrate how factors
beyond age, race, and other individual-level characteristics have important influences
on women’s mortality rate. Context and environment seem to be at least
as important as the individual-level factors. Clearly, a multilevel approach is needed to
“raise the bar” on the health of women. Today I’m going to discuss three ways we can
advance research to “raise the bar” for the health of women: improving our conceptual
model of sex and gender influences on health and disease; recognizing what we do and don’t
know; and asking better research questions. Let’s start with the conceptual model. When we study animals, it is simpler. The differences between males and females
are sex differences; they are biological. When we study humans, there are sex differences,
and there are also gender differences, which are associated with the social and environmental
contexts in which people live. Both sex and gender influence health. In some cases, we know that differences in
health and disease are biological in origin. These include cancers in sex-specific organs
and sex-linked diseases, such as most forms of hemophilia, which are more common in males
than females. At the other end of the spectrum, there are
likely some conditions or events we might be able to categorize as purely gendered,
meaning entirely socially created and not biological. But it’s difficult to point to specific examples. For instance, we could discuss or debate whether
some forms of violence against women are, or are not, solely social phenomenon, but
we are not going to do that today. In most cases, when we study human health,
we are studying sex and gender, not sex or gender, because humans live in a world with
a myriad of life-long gendered expectations and socialization, which overlay inherent
biological differences. In fact, these have been shown to impact how
we perceive and interact with newborns and infants on the basis of their presumed sex. In the simplest case here, both sex and gender
are treated as dichotomous. In reality, we recognize that there is more
variation all the way down to the genetic level, which determines sex in humans and
other mammals. Individuals who are intersexed (including
those who are not XX or XY genetically) and those who are transgender have additional
complexity to their health and medical care. Similarly, some societies have recognized
three or more genders, and those categories and related life experience likely shape health
in complex ways as well. To understand the influences of sex and gender
on health, we need to consider the levels at which they operate – internally from the
genome to the individual and externally from the individual to the national or even global
social and environmental context. In short, internal biological factors and
external social and environmental factors and contexts shape our lives and our health. Almost all aspects of health are influenced
by exposures to external and internal factors. These exposures occur across the life course
and contribute to differences in health, such as the risk of type 2 diabetes in adolescents,
which is higher among girls, or rates of autism, which like heart disease, has been defined
and understood as a disease of males and is now thought to include previously unrecognized
expressions in females. Let’s look at some specific examples where
sex and gender play important roles in disease outcome and severity. Let’s start with lung cancer, the leading
cause of cancer death in the United States. Prohibitions against women smoking protected
women from lung cancer for many decades. However, as these norms gave way, women’s
smoking rates and eventually their lung cancer rates grew. After smoking was linked to cancer, smoking
rates began to decline, but rates decreased more rapidly in men than women. Consequently, lung cancer rates peaked among
men in 1984, but did not peak among women until 1998. Only after smoking rates declined did it become
clear that women are at higher risk of lung cancer than men when they are not smokers. In fact, 20% of women with lung cancer are
nonsmokers compared to less than 15% of men. For decades, gendered social and behavioral
patterns masked differences in men’s and women’s cancer risk among nonsmokers. Coronary heart disease is the leading cause
of death and disability in the United States. Though rates of coronary heart disease mortality
have decreased, they declined sooner and faster in men than women. We now know that biology influences men’s
and women’s cardiovascular disease risk, as Noel Bairey Merz has shown in her work on
microvascular disease, which demonstrates that plaque tends to accrue in the smallest
vessels of the heart for women, whereas men have higher rates of developing acute blockages. In terms of social and environmental context,
Mark Hayward and colleagues have shown strong gender differences in the relationship between
marital biography and cardiovascular risk. You can think of marital biography as exposure
to being married over the adult life course. For example, Zhang and Hayward found that
women who experienced marital loss had a higher cardiovascular disease risk in midlife compared
to continuously married women, whereas marital loss was not associated with men’s cardiovascular
disease risk. Emotional distress and socioeconomic status
account for divorced women’s higher cardiovascular disease risk. McFarland and colleagues also found that marital
exposure was protective for cardiovascular disease risk in women but not men. They also found that early age at first marriage
was associated with chronic inflammation among men but not women. Health behaviors did not explain these associations. As you can see, the influences of sex and
gender are complex. Women’s lifetime risk of Alzheimer’s Disease
(one in six) is higher than their risk of breast cancer. Almost two-thirds of individuals diagnosed
with Alzheimer’s Disease are women, due in part to their greater longevity. Whether and to what extent women are otherwise
at greater risk of Alzheimer’s Disease compared to men remains unclear, and the findings are
mixed. Genetic research has found a number of genes
and single nucleotide polymorphisms (or SNPs) that increase risk and progression of Alzheimer’s
Disease in women but not men, and some with greater impact in men. Most but not all of the studies finding sex
differences link the association to sex hormones, but not always in the expected directions. Thus, the biological mechanisms are not fully
understood. Changing epidemiologic patterns for Alzheimer’s
Disease among women compared to men also appear to have been influenced by decades of changes
in men’s and women’s comparative levels of education, their intellectual lifestyles,
and physical activity patterns, all of which are protective against Alzheimer’s Disease,
as well as in their smoking behavior, which is associated with increased risk of Alzheimer’s
Disease in some studies (especially for men and especially in late life). Of note, women are also more likely than men
to be impacted by Alzheimer’s Disease as unpaid family caregivers, clinicians, and other healthcare
workers. Women are also more likely to lack a caregiver
spouse, due to the combination of longevity, gender roles, and the marriage patterns I’ve
mentioned. As these examples have begun to illustrate,
the influences of sex and gender on health are complex. They are not only additive, they can interact
in ways that amplify or confound health effects. One’s sex can contribute to exposure to, and
impact of, social factors and contexts. For example, women’s greater longevity exposes
them to greater risk of widowhood and poverty in old age, which in turn impact health, and
this hazard is exacerbated by social norms of marrying men who are on average two years
older. Similarly, gendered social exposures can also
influence exposure to, or impact of, biological factors on health. Consider the case of the impact of workplace
on-site childcare on men’s and women’s health. There are many reasons we might expect a stronger
exposure and impact on women’s health, but for women, on-site childcare can support extended
breastfeeding and in so doing lower a woman’s risk of breast cancer. Workplace childcare will not have the same
impact on men’s health. Consequently, understanding women’s health
and the influences of sex and gender on health requires both a clear conceptual model encompassing
both types of exposures and impacts, and rigorous methodology and research. Scientific advances arise from a clear understanding
of, and appreciation for, the limits of our knowledge. In other words, knowing what we don’t know
is as, or perhaps even more important than what we do know. So, how clear are we about the limits of our
knowledge on women’s health? The process for building a knowledge base
on health – from basic science research, through preclinical research and clinical trials,
to regulatory review and clinical practice – has been developed and refined over decades,
with the goal of applying new knowledge to enhance health, lengthen life, and reduce
illness and disability. However, there are some lingering gaps in
the research continuum, which can impact our knowledge of the health of women. To understand what we know and don’t know
about women’s health, we need to be clear on the extent to which research to date has
included and examined data on women and female laboratory animals, rather than generalized
from men and male animals. However, the extent to which findings are
based on predominantly or exclusively male samples is not transparent, in part because
until very recently, many studies did not report the sex of animals or tissues studied. And even all-male studies were published with
titles suggesting that they were studies of a disease or disease process, without qualifying
that they were studies of the disease or disease process exclusively among males. Although some disciplines moved more rapidly
to include females, others have been slower to do so, and as late as 2009, many articles
did not even report the sex of the research subjects. In contrast, it would be unfathomable to have
a significant proportion of studies not reporting the age of research subjects. Another part of what we don’t know involves
recognizing where there are untested assumptions that findings from men or male animals can
be, or have been generalized to females. In some areas, the assumptions of generalizability
of findings on men to women are so strongly held or accepted that they are no longer questioned. We forget that these are, in fact, testable
hypotheses. Objective data on women’s representation in
research and on the extent to which findings are consistent for women with those of men
are valuable. In some instances, this exploration may begin
with systematic reviews of the literature or reanalysis of data from studies that did
not assess whether the findings held for women (or females) as well as for men (or males). Such exploratory work may then provide the
necessary basis for subsequent studies designed and powered to test for possible sex and gender
influences, and if found, to evaluate why they occur and the implications for research
and for prevention of disease as well as treatment. Such efforts can help us begin asking better
questions. In some cases, the way we do research may
inadvertently provide less complete answers to questions about women’s health than men’s
health. The practice in clinical trials of studying
younger patients with a disease may not provide as generalizable information on women’s health
as it does on men’s, particularly for diseases with later onset in women. Consider, for example, clinical trials investigating
cardiovascular disease, which generally arises at an earlier age in men. Wherever investigators place the age cut-off
for excluding the enrollment of older individuals, if the same age threshold is used for all
trial participants, men in the study population will be more representative of men with cardiovascular
disease in the general population, compared to the trial’s representation of women, who
typically experience later onset of cardiovascular disease. Even for interventions found to work in women
as well as men, when the gap between the average age of the research participants and those
in the disease population is much larger for women than men, additional research may be
needed to provide a comparable level of evidence on the health of women to take the work from
clinical trials to clinical practice and community health. Here, the problems arise in assuming answers
and generalizability of findings that involve extrapolating beyond the data. A related issue involves the extent to which
the population studied is representative of the health of men and of women in the population
with the disease or condition studied, with regard to comorbidities. This becomes particularly important in clinical
trials research, where rigor is thought to be improved when the subjects do not have
other diseases or health conditions. As a result, randomized trials often focus
on somewhat healthier study samples than the population which experiences the disease or
condition. As with age, women’s higher rates of comorbidity
result in trial data based on women who are less representative of the population of women
with the disease than is the case in studies among men. To overcome this knowledge gap, research on
women may require additional pragmatic trials to assure that we understand that the specific
treatments work in women. These additional trials may also be needed
so that we understand the types and frequencies of specific complications due to comorbidities
or to the related issue of polypharmacy, in which a treatment is impacted by other medications
commonly used to treat the conditions that are more prevalent in women than men, such
as rheumatoid arthritis or other autoimmune disorders, or anxiety and other mood disorders. Clearly, sex and gender are fundamental considerations
in clinical research, regulatory review, and clinical practice. However, because preclinical research informs
clinical research, sex should be regarded as a key biological variable at all preclinical
stages of research as well. For the past couple of years, Dr. Janine Clayton,
Director of the Office of Research on Women’s Health at the NIH, has spearheaded efforts
to shape and implement a new policy for NIH-funded research, which is referred to as the Sex
as A Biological Variable Policy. According to this policy, the NIH expects
that sex as a biological variable (or SABV) will be factored into research designs, analyses,
and reporting in all vertebrate animal and human studies. In studies on human populations, it is important
to supplement the consideration of SABV with the consideration of gender as well. The consideration of SABV, and gender at appropriate
stages of research, is essential to connecting the dots all the way from bench to bedside,
to make the biomedical research as useful as possible for enhancing health, lengthening
life, and reducing illness and disability for everyone. Advancing science on the health of women requires
several things. Above all, the extent and complexity of sex
and gender influences on health and disease need to be better recognized. It is clear that the influences of sex and
gender operate to some extent at every level of analysis. Simply controlling statistically for these
influences is insufficient. Instead, the conceptual model I have described
provides a framework that brings together the relevant scientific perspectives and disciplines. This approach can provide a much better understanding
of the health of women and men than is possible from the sum of sex and gender influences
at various different levels of analysis. Science on the health of women will be advanced
by systematically assessing what we know and what we don’t know regarding the health of
women, and using this knowledge to help us all ask better research questions. In so doing, we can increase the transparency
and improve the rigor and reproducibility of research, which will both increase the
value and usefulness of the research and help us to close the knowledge gaps regarding the
health of women. In multiple research areas, we are already
beginning to see the benefits in new breakthrough science on the health of women as a result
of this approach. To learn more about how the NIH Office of
Research on Women’s Health is “putting science to work for the health of women” and working
to “raise the bar for the health of women”, I encourage you to explore the ORWH website
at NIH.gov/women. Thank you for working to improve research
on the health of women.

2 comments

  1. AAh "Knowing what we don't know"…that sounds familiar. Great educational, with my thoughts going to "GROOVIN IT" so it is palatable for your young women (school age), before they meet the world of 'breastfeeding', smoking etc and then widowhood and poverty's impact etc. Great work Chloe, you rock! #OCEANSHORESTV#WORLDPEACEBY2020#WP2020#SHARETHEDREAM#BADGEMEUP#CHARLESCRAWSHAW#CAUSINGCAUSING#LANDMARKWORLDWIDE#WISDOMCOURSE#RABBITS1963#birminghamcg22 #Birmingham2022

  2. 22 minutes of awesome. Dr. Bird lays out a convincing case for understanding the roles that sex and gender play in both health and in healthcare. Well worth a careful listen.

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