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2Why Women Develop Chronic Conditions Differently than Men This chapter introduces important multidimensional factors that aid in understanding thedifferential development of chronic conditions in women compared to men, encompassingbiological, social, and environmental factors, including the structural and social determinants ofhealth. The chapter concludes with a discussion on the potential impact of enhancing research invarious domains related to chronic conditions in women. Sex and gender are multidimensional concepts that influence health and the developmentand outcomes associated with chronic conditions in women. Biological (sex) andsocial/environmental (gender) factors define two major classes of relevant variables differentiallyinfluencing women and men. Sex factors, comprising sex chromosomes, gonadal hormones 1, andother factors they influence, lead to male and female differences in morphology, physiology, andbehavior—a concept also known as “sexual differentiation” (Cabrera Zapata et al., 2022).Gender is a social construct that defines women and men differently and then differentiallydistributes power, status, and resources (Barr et al., 2023; Heise et al., 2019). Health outcomesattributed to one's sex or gender are due to biological or environmental differences, in partbecause of social inequities associated with gender (Heise et al., 2019). Sex and gender differences occur in most types of cells and most diseases. Someconditions are specific to women or may be more prevalent or progress faster in women, andothers are more predominant in men. For conditions affecting both men and women, the sexdifferences may be quite large. Thus, explaining chronic conditions in women requires anunderstanding of how they differ from men and identifying the biological, social, andenvironmental forces that cause this. Determining whether sex-specific or -biased molecularagents and cellular processes elevate or reduce risk of disease requires studying both men andwomen to identify which therapeutic strategies are optimal in both; better understanding chronicconditions in women can lead to better understanding disease in men and improve therapies for 1 Although the term “gonadal hormones” theoretically includes all hormones produced by the gonads (e.g., femaleovaries produce the steroid-derived hormones, estrogens, progesterone, and androgens, as well as others derived fromother substrates, including anti-Mullerian hormone and relaxin), in most instances throughout this report, it is equatedwith the terms “sex steroid hormones” and “reproductive hormones.” Together, these terms will refer to the majorclasses of reproductive hormones produced by the gonads: estrogens, progesterone, and androgens. PREPUBLICATION COPY: UNCORRECTED PROOFS

2 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMENall individuals. Moreover, understanding disease regulation under diverse conditions (such as indiverse sexes/genders) leads to improved concepts of the full spectrum of it. Discovering biological factors and social/environmental factors involves quite differentmethodologies. Although strict experimental control of individual biological factors can beachieved in studies of animals or humans, investigating social factors involves epidemiologicalstudies in human populations that convincingly implicate gendered variables as criticallyimportant in diseases influencing women. One major challenge is that biological and socialfactors covary (sex chromosomes are strongly correlated with gendered patterns of rearing),making their specific effects difficult to separate. A second challenge is that the two set offactors have profound effects on each other. Many biological factors are thought to havedifferent effects depending on the environment, and changes in the social or physicalenvironment have powerful effects on gene expression and disease course. Further investigationis necessary to understand the complex interaction, or intersection, of sex and gender, as well ashow these interactions can be explained by epigenetics. As animals share many genes and physiological mechanisms with humans, theunderstanding of sex differences is greatly increased by studies of animal species in whichspecific sex-biasing factors can be manipulated in isolation from each other, to understand theirindividual effects. It is difficult to perform this research in humans, given the interplay ofbiological and nonbiological factors that influence trajectory of conditions, so animal researchgives rise to invaluable novel concepts of cell and tissue organization, which suggest noveldiagnostic and therapeutic approaches in humans that would not be uncovered if only humanswere studied. Animal research is therefore an essential incubator of concepts about basic biologyof chronic conditions in women. Animals often do not model the complex social andenvironmental factors that cause gender differences in disease and thus are not typically used toinvestigate them. Ultimately, processes discovered in animals may be similar or different inhumans, and thus further research in humans establishes which concepts are helpful inunderstanding human disease. When discussing animal research, the discussion of femalesfocuses predominantly on XX animals with ovaries, compared to males as XY animals withtestes. That comparison not only illuminates factors that cause differences between the twogroups, but also provides a foundation for contrasting variation among individuals that are notmembers of those groups. In specific cases, differences among other groups with othercomplements of sex chromosomes, including XO, XX, XY, XXY, and XYY individuals witheither ovaries or testes, are discussed. This chapter discusses essential factors necessary for understanding chronic conditions inwomen throughout their lives (see Figure 2-1). These include the major life course stages ofchildhood, adolescence, adulthood, and older adulthood that are associated with importantreproductive stages, such as prepuberty, puberty, menopause, and post-menopause. This chapteralso identifies the interplay of biology and social and environmental factors in the manifestationand course of chronic conditions. Finally, factors specifically related to aspects of the health caresystem, such as access to care, are noted because they play a significant role in women’sexperiences from diagnosis through treatment and the management of these conditions. PREPUBLICATION COPY: UNCORRECTED PROOFS

WHY WOMEN DEVELOP CHRONIC CONDITIONS DIFFERENTLY THAN MEN 3FIGURE 2-1 Factors that contribute to chronic conditions in women over the life course that this reportshighlights. BIOLOGICAL FACTORS Effects of Sex Chromosomes and Gonadal Hormones All sex differences in mammals originate from the molecular differences encoded by theX and Y sex chromosomes (Arnold, 2012, 2022). Typical females have two X chromosomes,and typical males have one X and one Y chromosome. By midgestation in most placentalmammals, the undifferentiated XX gonad begins to express genes that cause an ovary to developand suppress testicular development. In XY gonads, genes on the Y chromosome trigger testesdevelopment and suppress ovary development (Capel, 2017; Eggers et al., 2014). The two typesof gonads secrete different levels of hormones at many stages of life, especially estrogens,progestogens, and androgens, that act directly on specific receptors in many different types ofcells in the body to cause sex differences in basic physiology and disease. In this report, the phrase ‘gonadal hormones’ refers to sex steroid hormones considered asthe primary hormonal drivers of sexual differentiation—estrogens and progesterone in females,and androgens (notably, testosterone) in males. Although these sex steroid hormones mayindividually and collectively influence the development of chronic conditions in women, thisreport mainly focuses on estrogens. This is primarily because of their role in sexualdifferentiation, reproduction, homeostasis, and maintenance of physiologic function over the life-span. When appropriate, findings related to progesterone in the development of chronicconditions are included. The role of testosterone is highlighted in some sections of the reportwhich often contrasts with the functional effects of estrogens (see Chapter 6 on chronic pain).Assigning estrogens and progesterone as female-specific sex steroids and testosterone as a male-specific sex steroid may be overly simplistic, given that the ovaries are also a source oftestosterone and the testes are a source of estrogens, although at much lower levels. However, theeffects of these low levels of sex steroid hormones emerges when considering how the overallratios of these hormones impact men and women differently. For example, during the menstrual PREPUBLICATION COPY: UNCORRECTED PROOFS

4 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMENcycle and perimenopause, as well as post-menopause, the effects of testosterone are moreapparent when estrogen levels are low or in flux. Another pathway that leads to such sex differences involves molecules encoded by geneson the X and Y chromosomes, other than those that control gonadal hormone production. Thesemolecules act in virtually all cell types to make XX and XY cells different, via mechanismsunlike those responsible for the effects of gonadal hormones (Arnold, 2019, 2022). Research hasshown that both of these pathways influence the incidence or progression of diseases in animals.Thus, when examining diseases that affect women more than men, investigators look to bothtypes of sex-biasing agents (sex chromosome genes and gonadal hormones) as possible rootcauses (Arnold, 2017). Numerous events during embryogenesis can establish long-lasting sex differences evenafter the sex-biasing factors have ceased to operate. For example, differences in development ofthe external genitals (cl*tor*s vs. penis, vagin*l labia vs. scrotum) are controlled by testosteronesecreted by the embryonic testes, which acts during embryonic life to suppress the female patternand promote the male pattern (Achermann and Jameson, 2018). Sexual differentiation of thesefemale genital structures does not require specific ovarian secretions. In animals, specific sexdifferences in brain regions created near the time of birth result from the action of testosteronesecreted by the testes or by testosterone’s metabolite estradiol (Morris et al., 2004). Evidencesupports similar actions of gonadal hormones to influence sex difference in the human brains(Hines, 2020; Lombardo et al., 2020). Research has implicated estrogens secreted in female micein the typical female pattern of development of some brain regions (Bakker and Baum, 2008).These hormonal secretions in early development cause sex differences that are permanent—oftencalled “organizational” effects of gonadal hormones—leading to a sex difference in the genital orneural substrates that therefore can be differentially affected by disease, long after the sexdifferences are created (Arnold, 2009). Although diseases affecting sexually differentiatedtissues, such as the uterus or brain, are obvious examples, permanent differences in the heart,liver, and other organs likely result via this type of mechanism (Waxman and O’Connor, 2006).Long-lasting sex differences caused by sex chromosome genes may also occur but are much lesswell understood. In contrast to permanent sex differences, gonadal hormones have widespread and potenteffects that are reversible and come and go as hormone levels wax and wane, often referred to asthe “activational” effects of estrogens, progestogens, and androgens (Blencowe et al., 2022). Theonset and severity of numerous diseases correlates with increases or decreases in plasma levelsof gonadal hormones occurring at puberty; during stress; during ovulatory cycles, pregnancy,menopause; or in aging. In animal studies, many sex differences in the transcriptome areeliminated or reduced after gonads are removed in adults, testifying to the dominant reversibleeffects of circulating gonadal hormones in the causation of sex differences in adult phenotypes(Blencowe et al., 2022; van Nas et al., 2009). The numerous factors acting independently to make women different from men can alsohave synergistic or antagonistic effects, creating a complex web. An emerging concept in the last20 years is that some phenotypes may be similar in the two sexes, but that masks an underlyingsexual inequality of mechanism (Arnold, 2022; De Vries, 2004). For example, one factorprevalent in women may reduce the effect of another factor, making women more like men; theapparent similarity of the two sexes occurs via differing underlying molecular mechanisms. Animportant ramification is that any environmental factor, such as a pathological agent, candifferentially disrupt the dissimilar mechanisms operating in the two sexes. A tissue that PREPUBLICATION COPY: UNCORRECTED PROOFS

WHY WOMEN DEVELOP CHRONIC CONDITIONS DIFFERENTLY THAN MEN 5functions similarly in the two sexes may thus respond differently to the disease, leading to achronic condition affecting one sex and not the other. A prime example of this effect involves the XIST gene, which is expressed at high levelsin differentiated XX but not XY cells. In XX cells, XIST noncoding ribonucleic acid (RNA)reduces the expression of most genes on one X chromosome in each cell, bringing expressioninto the range typically found in XY cells (Carrel and Willard, 2005; Disteche, 2016; Fang et al.,2021; Syrett and Anguera, 2019; Tukiainen et al., 2017). Thus, XIST has long been heralded as afactor enhancing similarity of XX and XY cells and individuals. Its function is variable and hasbeen associated with sex differences in autoimmune diseases (Syrett et al., 2019). However, thebalance in X gene expression is achieved because X genes are regulated by XIST in XX but notXY cells. When a disease process interferes with the action of XIST or other components of theX inactivation system, the disease can cause a condition that is more prevalent in females thanmales (Delbridge et al., 2019; Forsyth et al., 2024; Yang et al., 2020; Yildirim et al., 2013).Moreover, XIST is now thought to have effects other than regulation of expression of X genes. Inhuman pluripotent stem cells, XIST downregulates some autosomal genes to create a sexdifference in expression (Dror et al., 2024). XIST is implicated as a female-specific contributor toautoimmune diseases such as Systemic Lupus Erythematosus (SLE), based on two mechanisms.XIST is a rich female-specific source of ligands of toll like receptor (TLR) 7, which activatesinterferon-alpha production in plasmacytoid dendritic cells, increasing inflammation andcontributing to SLE pathogenesis (Crawford et al., 2023). XIST also interacts withribonucleoprotein partners which are attacked during autoimmune disease, perhaps contributingto their higher incidence in women (Crawford et al., 2023; Dou et al., 2024). The central positionof XIST in the biology of XX cells, and its widespread expression in XX but not XY cells,warrants further research into its role in regulating chronic conditions in women. The hormonal and sex chromosomal mechanisms discussed so far operate at the level ofthe cells, making XX and XY cells different in each individual. Sex differences may also arisebecause of biological factors that operate at the level of populations, increasing or decreasingdisease incidence in groups of women compared to men (Arnold, 2017). The best examples ofthese protect women from disease. For example, X-chromosome-linked alleles causing diseaseaffect more men because women have a second X chromosome, usually with a different allelethat reduces the deleterious impact of the disease allele (Migeon, 2007). Another example is thatthe maternal inheritance of mitochondria is thought to allow the evolutionary emergence ofmitochondrial alleles that have a negative impact in males. Because males do not pass the allelesto their offspring, selection against the alleles does not occur. The resulting mitochondrialgenetic diseases influence populations of males more than females (Dowling and Adrian, 2019). Animal Models for Studying Sex Differences in Physiology and Disease As discussed, sex differences in any trait are caused ultimately by the unequal effects ofXX versus XY sex chromosomes, which lead to a different genetic makeup of every cell andcause organizational (long-lasting) or activational (reversible) sex differences via gonadalhormone action. The emergent sex differences in tissue physiology or disease are the result ofsex differences in gene pathways that are influenced by one or more of these inherent sex-biasingfactors. A primary goal is to identify which of these mechanisms is operating to cause sexdifferences in phenotype and then to study the downstream gene pathways altered by the sex-biasing factors to affect disease. Animal models that measure hormonal and/or sex chromosomeeffects are discussed next. PREPUBLICATION COPY: UNCORRECTED PROOFS

6 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Many of the methods used in animal research are not possible in human research. Animalresearch provides a rich source of information about molecular and cellular mechanisms causingsex differences in disease, generating many hypotheses about disease mechanisms that could notderive from studies of humans. These ideas can then be tested for validity in noninvasive humanresearch, leading to advances in understanding of basic human physiology and disease.Conceptual and Practical Animal Models for Detecting Gonadal Hormone Effects Several experiments can be performed in animals to test if a sex difference is caused bygonadal hormones. In general, the approach is to manipulate the level or action of one or morehormones at specific times of life or in specific cells and measure effects on phenotypes ofinterest. Because it is primarily gonadal hormones (rather than hormones from other organs) thatare known to be sexually differentiated by sex chromosome effects, the hormones most oftenmanipulated in experimental settings are the steroid-derived, reproductive hormones, estrogens,progestogens, or androgens. A detailed review of methods used to investigate hormone effects is beyond the scope ofthis chapter. One informative method, for example, involves removing the gonads surgically inadulthood to determine whether the sex difference in a trait is reduced or abolished. If so, thatsuggests that the reversible, activational effects of gonadal hormones cause it. Furtherexperiments—measuring the trait after replacing specific testicular or ovarian hormones, forexample—can define which hormone(s) contribute to the sex difference and uncoverdownstream molecular mechanisms regulated by the hormone(s) (Craft et al., 2004). Removing all gonadal hormones in adulthood may not eliminate a sex difference, such asthe morphology of internal or external genitals or of some brain regions and in behaviors (Blochand Gorski, 1988; Breedlove and Arnold, 1981). A second hypothesis is that these persistent sexdifferences could result from the organizational effects of gonadal hormones, typically exertedjust before or after birth. To test that hypothesis, gonads can be removed prenatally or at birthand the trait measured in adulthood. Alternatively, the action of gonadal hormones can beincreased or decreased perinatally using drugs that block the hormonal action or mimic it. Thesemethods have proven that prenatal and perinatal secretions of the testes cause permanentmasculine development of external and internal genitalia and of specific brain regions.Alternatively, injecting testosterone into females, pre- or postnatally, has been shown to causepermanent masculinization of genitalia and brain (Arnold and Gorski, 1984; Jost, 1970; Morris etal., 2004). Further experiments then identify receptors that mediate the hormonal effect, cellularsites of hormone synthesis and action, and molecular pathways regulated by hormones to inducesex differences. Although gonadectomy and hormone therapy have been used since before the 20thcentury, they continue to be used because they are convenient and informative. Other approachesinclude blocking hormone action with drugs that block hormonal receptors or inhibit gonadalhormone synthesis. Hormone action is also studied with whole-animal or conditional knockoutsof genes required for hormone synthesis, or of receptors mediating hormone actions on cells. Forexample, the Cre-lox system allows fine control of genes encoding receptors or syntheticenzymes required for sex steroid hormone action (Kim et al., 2018). Depending on the promoterused to activate the Cre recombinase, these genes can be turned off in specific molecularlydefined cell types or at different times of development. In other genetically engineered mice,reporter genes are driven by promoters of genes encoding steroid synthetic enzymes or receptors,allowing finer observation of cell types and drug or environmental control of steroid hormone PREPUBLICATION COPY: UNCORRECTED PROOFS

WHY WOMEN DEVELOP CHRONIC CONDITIONS DIFFERENTLY THAN MEN 7action (Shah et al., 2004; Wu et al., 2009). These and other modern methods will continue torevolutionize the understanding of when and where gonadal hormones act to cause sexdifferences and the molecular mechanisms downstream of hormone action. An important caveat is that the discovery of potent gonadal hormone effects on tissuesdoes not disprove the existence of sex chromosome effects that also contribute to sexualdifferentiation (Smith-Bouvier et al., 2008). Early evidence of sex differences due to sexchromosomes involved in vitro models (Beyer et al., 1991, 1992; Carruth et al., 2002), which areexperimental systems involving biological molecules, cells, or microorganisms to test scientifichypotheses. These studies demonstrated the early development of mesencephalic cells reflected asex difference induced by sex chromosome complement, not hormones. However, most sexchromosome effects are found in tissue systems that also show sex-biasing effects of gonadalhormones. The interaction of hormonal and sex chromosome effects in sexual differentiation hasreceived little attention. Future studies in animals will help define the nature of theseinteractions, as a model for such interactions in humans.Conceptual and Practical Animal Models for Detecting Sex Chromosome Effects When testing the differential effects of XX versus XY sex chromosomes on cellular,tissue, and whole-animal traits, the goal is to compare the phenotypes of animals that have eitherXX or XY. However, because the sex chromosomes typically determine the type of gonad andpatterns of gonadal secretions, which themselves cause profound phenotypic sex differences, it isimportant to compare XX and XY animals while keeping gonadal hormones as constant aspossible, starting well before birth. The most favorable model is the Four Core Genotypes (FCG)mouse model, in which the Y chromosome lacks the testis-determining gene Sry and is called the“Y–” chromosome (De Vries et al., 2002). An XY– mouse is a gonadal female because ovariesdevelop in the absence of Sry. The model thus allows comparing XX and XY– gonadal females,to detect the effects of sex chromosome complement throughout the body, in two groups withovarian hormones. Inserting an Sry transgene (a gene added to the genome by molecular geneticmethods) into an autosome causes testes formation and allows the comparison of XY–(Sry+) andXX(Sry+) mice, contrasting the effects of XX versus XY in two groups with testes. The FCGmodel answers three questions. Do XX and XY tissues (an effect of sex chromosomes differ inmice that have the same type of? Is there an effect of gonadal hormones, measured in both XXand in XY mice? Is there an interaction of the effects of sex chromosomes and gonadal hormoneson phenotypes, such that one type of factor influences the effect of the other type? Thus, theFCG model provides a good first step to detect cell-autonomous sex chromosome effects innongonadal tissues. It allows classification of any sex difference as induced hormonally versussex chromosomally, which is critical in choosing experimental strategies for uncovering cellularand molecular mechanisms causing any sex difference (Arnold, 2020, 2022). If a sex chromosome effect is discovered using FCG mice (inequality of XX and XYmice with the same type of gonad), the XY* mouse model can replicate the effect in animalslacking a transgene and determine if it is caused by X or Y genes or chromatin (Arnold, 2020;Burgoyne and Arnold, 2016; Cox et al., 2014). The Y* chromosome pairs in an unusual mannerwith the X chromosome during meiosis in an XY* gonadal male, producing several differenttypes of progeny with different numbers of X and Y chromosomes. The XY* model comparesfour genotypes that are very similar to XO, XX, XY, and XXY. Comparisons of XO versus XX,and XY versus XXY determine if the sex chromosome effect is caused by the different numbersof X chromosome. Comparison of XO versus XY, and XX versus XXY, determines if the PREPUBLICATION COPY: UNCORRECTED PROOFS

8 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMENphenotype is altered by presence/absence of the Y chromosome. The Y effect could be caused byY genes within nongonadal cells or because Y-bearing mice have testes in this model (Burgoyneand Arnold, 2016). The FCG and XY* models have been used in dozens of studies to demonstrate that thesex chromosome complement—the specific XX or XY pairing—contributes to sex differences ina wide variety of tissues and disease models, including brain and behavior, autoimmune diseases,Alzheimer disease (AD), metabolic diseases, neural tube closure defects, bladder cancer, andcardiovascular disease (CVD), including ischemia-reperfusion injury, stroke, hypertension, andatherosclerosis (Arnold, 2020). Most sex chromosome effects discovered using these models have been attributed to Xchromosome genes (Arnold, 2022). In one case, however, a protective Y chromosome gene wasfound to explain a female preponderance of experimental pulmonary hypertension in a mousemodel (Cunningham et al., 2022). Various studies have suggested that some classes of X genesare more likely than others to cause sex differences in disease models, including genes thatescape X inactivation or have an ancestral hom*olog on the Y chromosome (Arnold, 2022). The mouse models discussed so far allow discovery of physiological and diseasephenotypes in which a sex difference is attributed to sex chromosome effects, gonadal hormoneeffects, or their interaction. If sex chromosome complement is implicated as a cause of sexdifferences in disease, further research identifies the X or Y genes responsible and thedownstream molecular mechanisms. Use of the FCG and XY* mouse models has uncoveredcontributions of sex chromosome effects on sex differences in behavior and disease that areunaffected by the influence of gonadal hormones; however, biological processes are usuallyinfluenced by both (Arnold, 2020). Examples of sex chromosome effects on phenotype involveKdm6a and Kdm5c, two X chromosome genes encoding histone demethylases that escape Xinactivation and are therefore expressed at higher levels in XX cells than in XY cells. Kdm6a hasbeen linked to sex differences in mouse models of multiple sclerosis, AD, CVD, and cancer, andKdm5c has been implicated in sex differences in metabolism (see Chapter 6) (Arnold, 2020;Davis et al., 2020; Fazazi et al., 2023; Itoh et al., 2019; Kaneko and Li, 2018; Link et al., 2020). Discovering specific X or Y genes in mice and the autosomal genes that they regulatedifferently in females and males is a strategy for defining unknown gene pathways accountingfor factors influencing women more than men that represent potential targets for therapy toalleviate disease in all individuals. Translation to humans will most likely occur after theproximal gene pathways affecting disease have been studied, because regulatory pathways inanimals and humans overlap. For example, some sex chromosome genes are conserved inmammals, including mice and humans, and may show common sex-biasing properties. However,the discovery of sex-biasing X and Y genes is new and requires further study. Are sex differences caused predominantly by one of the mechanisms discussed? Analysesof sex differences in the transcriptome in various organs suggest that a large majority of sexdifferences are caused by gonadal hormone effects (Blencowe et al., 2022; van Nas et al., 2009).On the other hand, a structural magnetic resonance imaging study of FCG mouse braindiscovered that 37 percent of sex-biased brain regions were the result of sex chromosome effects,compared to 53 percent caused exclusively by gonadal hormones (Corre et al., 2016). As theeffects of sex chromosomes or gonadal hormones vary as a function of disease or otherenvironmental variables (Arnold, 2022), the relative importance of each may be difficult tomeasure in any one study. PREPUBLICATION COPY: UNCORRECTED PROOFS

WHY WOMEN DEVELOP CHRONIC CONDITIONS DIFFERENTLY THAN MEN 9Which X and Y Genes Cause Differences Within XX and XY Cells The X and Y chromosome are an ancient autosomal pair that diverged when thedeveloping Y chromosome evolved a testis-determining gene, SRY (Graves, 2006; Hughes andPage, 2016). They began to diverge in their deoxyribonucleic acid (DNA) sequences and ceasedto recombine along most of their length. The Y chromosome lost virtually all of its ancestralgenes (Bachtrog, 2013; Bellott et al., 2014; Charlesworth and Charlesworth, 2000). The genesremaining on the present-day X and Y chromosomes are specialized (Graves, 2006). Differencesin effects of XX and XY somatic cells are due to effects of Y genes that are not mimicked by thesecond X chromosome and various effects of two X chromosomes compared to one (Arnold,2022). Studies have compared X and Y chromosome genes in different mammalian species togarner information about their evolution (Bellott and Page, 2021; Naqvi et al., 2019). The sexchromosomes have been subjected to selection pressure to make XX and XY cells similar,including the evolution of X inactivation that transcriptionally silences one X chromosome andbrings the dosage of most X genes into a similar range in XX and XY cells (Carrel and Brown,2017; Disteche, 2016). Nearly a quarter of human X genes escape inactivation and are expressedhigher at the messenger RNA (mRNA) level in females than males, which focuses attention onthese genes as possible agents that cause sex differences (Tukiainen et al., 2017). However, thegenome-wide downstream transcriptional effects of a second (inactive) X chromosome in humanXX cells in vitro are similar to the genes regulated by the Y chromosome in XY cells, suggestingfurther selection pressures that operated to balance function of XX and XY cells (San Roman etal., 2024). As an example, a second sex chromosome of either type prevents the lethality causedby monosomy X (45, X or Turner’s syndrome), implying common actions of a second X or Y.Thus, evaluating whether an X or Y gene causes sex differences in disease involves comparingthe effect of each to the effects of genes on the other sex chromosome. Thousands of genes areexpressed differently in XX and XY cells harvested from diverse tissues of animals and humans,which indicates that sexual imbalance is widespread, contributing to sex differences inphysiology and many diseases (Oliva et al., 2020; Yang et al., 2006). Significant additionalresearch is required to uncover the cellular mechanisms leading to sex differences in chronicconditions.Genome-Wide Assessments of Sex Differences in Gene Expression Patterns and Networks Systems genetics approaches have been developed to analyze the complex interactions ofmany genes and gene products that work in combination to produce sex differences in humanand animal traits (Khramtsova et al., 2019; Lopes-Ramos et al., 2020a, 2020b; Seldin et al.,2019). The advent of numerous high-throughput technologies for measuring DNA sequences,expression of RNA and proteins, chromatin configurations, protein-protein interactions,transcription factor binding sites, and others, enable integrating multi-omic information toconstruct gene networks and correlate genetic variation at specific locations in the genome withvariation in physiological or disease traits of interest. Investigators use diverse quantitative methods to integrate mechanistic information andmake inferences about gene regulatory mechanisms and how they differ in the two sexes. Thesemethods can be applied to humans and model organisms, with greater control available inlaboratory animals to manipulate the environment (diet, disease, etc.) to understand the geneticarchitecture (gene–gene and gene–environment interactions) regulating disease outcome.Although many laboratory studies in model species use the reductionist approach, for example, PREPUBLICATION COPY: UNCORRECTED PROOFS

10 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMENmanipulating one gene or hormone at a time, systems approaches have the advantage ofexamining variation across the entire genome in large datasets, enabling unbiased detection ofgenes and networks of interest in which genetic variation is associated with sex-specific variationin a trait. Combining systems and reductionist approaches in animal models is particularlypowerful for uncovering and proving novel genetic regulatory mechanisms that cause sexdifferences in disease. Similar analyses of data from humans are critical for application. A review of systems genetics approaches is outside of the scope of this report. However,a large-scale analysis of the transcriptomes of 44 human tissues from over 800 individuals in theGenotype Tissue Expression project showed that 37 percent of all genes showed sex differencesin expression in at least one tissue (Oliva et al., 2020). This is no doubt an underestimate becausetissue samples were not available from many human diseases or environmental conditions.Although the effect size of sex differences is typically not large—less than twofold in expressionof individual genes—the impressive number of genes influenced by sex suggests a largeaggregate influence on many gene regulatory pathways. By integrating quantitative trait loci—genetic regions showing variation that correlate with variation in important clinical or geneexpression traits—studies using gene expression patterns have identified dozens of sex-specificassociations between genes and traits. The result of this analytical approach forms the foundationfor many studies to determine which genes are most effective as causal agents in conditionsaffecting women specifically and which gene products might be targets of. Investigators haveapplied similar systems analyses in specific tissues or diseases to uncover genes important in sexdifferences in cardiac function (Shi et al., 2021), mitochondrial networks regulating cardio-metabolism (Norheim et al., 2019), brain regions related to neurological and psychiatric disease(Wingo et al., 2023), and cancer (Lopes-Ramos et al., 2020b). The systems genetics approacheswill be a major component of research into conditions affecting women. Female Hormonal Effects Over the Life-Span The general outline of major life changes in ovarian hormonal levels includes relativehormonal quiescence during pre- and postnatal life until puberty, when menstrual cycles begin.During the typical reproductive, the ovarian steroid hormones, estrogens, androgens, andprogesterone, influence the incidence, severity, and clinical presentation of certain chronicconditions affecting women. These effects arise from the fluctuations in hormonal levels and theneuroendocrine feedback mechanisms involved in menstrual cycles and perimenopause and theeventual end of ovarian function with menopause. Non-steroidal ovarian hormones play animportant role in exerting systemic effects throughout the life-span and may contribute tosusceptibilities of women to chronic conditions. Anti-Mullerian hormone (AMH), which belongsto the transforming growth factor-beta protein family and is secreted by ovarian follicles isknown to play important functions in sexual differentiation during fetal development. Whileknown as a surrogate marker of ovarian reserve (Lambrinoudaki et al., 2020), low circulatinglevels of AMH have been associated with subclinical atherosclerosis in women and men(Lambrinoudaki et al., 2020; Verdiesen et al., 2022), and is supported by studies conducted infemale primates (Appt et al., 2012). Another non-steroidal ovarian hormone, relaxin-2, secretedby the corpus luteum of the ovary, is a cardioprotective factor, exerting vasodilatory and anti-inflammatory effects on the vasculature (Aragón-Herrera et al., 2022; Brecht et al., 2011). Howthe reductions in these hormones, because of a decline in ovarian function over the life-span,influence the development of chronic conditions is further discussed throughout the report. PREPUBLICATION COPY: UNCORRECTED PROOFS

WHY WOMEN DEVELOP CHRONIC CONDITIONS DIFFERENTLY THAN MEN 11 Sex-specific molecular and clinical studies have identified puberty, pregnancy, andmenopause as three windows of vulnerability. High testosterone and estradiol and low sexhormone–binding globulin levels are associated with conditions characterized by low-gradeinflammation including insulin resistance and diabetes (Horstman et al., 2012). Thus, age-relatedchanges in sex hormones contribute to the development of a proinflammatory state which mayaffect many chronic conditions (Horstman et al., 2012). Estrogen receptors (ERs) such as ERα and ERβ, and G-protein coupled estrogenreceptor 2, are distributed ubiquitously throughout the body in many cells and tissues andinvolved in complex physiologic mechanisms in women (Paterni et al., 2014; Prossnitz andBarton, 2023), and estrogens play a key role in women across the life-span. They influence manyorgan systems, including the musculoskeletal and cardiovascular systems and the urinary tract,reproductive tract, brain, hair, and skin, and the reduction in estrogen hormones at menopauseaffects various cells and tissues (Wend et al., 2012). Estrogens play a key role across the lifecourse: puberty, menstrual cycles, pregnancy, perimenopause, and menopause. For example,women lose on average 80 percent per year of their estrogens during the first year of menopause,which can lead to an accelerated decline in bone mass, muscle mass, and muscle strength(Horstman et al., 2012). Overall, the process of aging is influenced by hormone levels becausethe endocrine system plays a major role in cellular interactions, metabolism, and growth(Horstman et al., 2012). EPIGENETICS: ENVIRONMENTAL REGULATION OF GENE EXPRESSION The development of chronic conditions in women is determined by genetic predispositionand the various stressors and environments throughout the life-span. Genetic mutations accountfor many disease etiologies, but many chronic conditions may not have clear genetic linkages.Instead, an array of genetic and environmental modifying factors exert additive or multiplicativeeffects that ultimately lead to one or more chronic conditions. The field of epigenetics offers a biochemical mechanism to explain how social and otherenvironmental variables (e.g., toxins) can influence the readout of the genome and thus diseaseincidence and progression. Classical genetics points to the DNA sequence of genes and theiralleles, inherited from an individual’s parents, as a major cause of variations among individuals,including differences between women and men. However, both biological (e.g., hormones, sexchromosome genes) and environmental factors can also modify DNA, by altering not its DNAsequence but its chemical attributes or its associated chromatin (Figure 2-2), a process known as“epigenetics.” Epigenetic alterations change gene expression, which can alter cellular functions.Epigenetic modifications include DNA methylation and numerous types of modifications (e.g.,acetylation and methylation) of histone proteins around which the DNA is wrapped. Both longand small noncoding RNAs (which includes miRNAs) function to regulate gene expression,through a variety of different mechanisms, occurring in the cytoplasm or nucleus or both.Histone modifications can open up or close down specific regions of the genome, making themmore or less available to a host of signaling molecules such as transcription factors that increaseor decrease expression of specific genes. Environmental events can cause changes in DNAmethylation and histone modifications that last a lifetime and may even be passed to subsequent 2 G-protein coupled estrogen receptor was first named GPR30, for “G-protein coupled receptor 30” (Carmeci etal., 1997). PREPUBLICATION COPY: UNCORRECTED PROOFS

12 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMENgenerations. Although this causal link between environmental events and activity of biologicalpathways could explain the influence of social and other environmental events on incidence andprogression of diseases, the field of epigenetics is in its infancy. More research is needed tounderstand how specific environmental experiences affect specific biological pathways.Moreover, agents that modify histones are sometimes sex biased (Arnold, 2022; Kundakovic andTickerhoof, 2023).FIGURE 2–2 Sex and gender: modifiers of health, disease, and medicine.SOURCE: Reprinted from The Lancet, Vol. 396, Franck Mauvais-Jarvis et al., Sex and gender: modifiersof health, disease, and medicine, 565-82, Copyright (2020), with permission from Elsevier. PREPUBLICATION COPY: UNCORRECTED PROOFS

WHY WOMEN DEVELOP CHRONIC CONDITIONS DIFFERENTLY THAN MEN 13 STRUCTURAL AND SOCIAL DETERMINANTS OF HEALTH This section discusses social and cultural factors tied to gender that can produce variedexposures and experiences within the structural and social determinants of health (Figure 2-3).Through various mechanisms, these experiences influence preventive behavior and the onset,characteristics, and progression of conditions. Women also encounter distinct experiences in thehealth care system with clinical and patient-centered care. These concepts are shown in Figure 2-3 and discussed next in further detail.FIGURE 2–3 A bio-socio-cultural model for understanding chronic conditions and experiences inwomen. PREPUBLICATION COPY: UNCORRECTED PROOFS

14 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN An important consideration is intersectionality, or how an individual’s experiencescombine, interact, and are shaped by their multiple identities and therefore influence their health(Cooper, 2016; Crenshaw, 1994). Intersectionality, developed by Kimberlé Crenshaw, is atheoretical framework to describe how multiple social identities—including race, ethnicity,gender identity, sexual orientation, socioeconomic status, age, and disability—intersect at microlevels of an individual’s experience to represent various interlocking systems of oppression andprivilege at the macro social-structural level, including racism, sexism, heterosexism, and ageism(Bowleg, 2012; Bowleg, 2021; Crenshaw, 1994). A central tenet is that social categories at themicro level, including race, gender, socioeconomic status, and sexual orientation, are notindependent but intersect and create complex pathways to health inequities (Bowleg, 2012). Social and Cultural IdentitiesGender Identity A 2022 National Academies report defined gender as “a multidimensional construct thatlinks gender identity, gender expression, and social and cultural expectations about status,characteristics, and behavior that are associated with sex traits” (NASEM, 2022). Gender isfurther conceptualized to characterize one’s identity, which is a core element of one’s individualsense of self. Gender identities include but are not exclusive to, transgender, in which a person’scurrent gender identity is different from the sex they were assigned at birth; cisgender, in which aperson whose current gender identity corresponds to the sex they were assigned at birth, andnonbinary, which is an umbrella term for gender identities that lie outside of the gender binary(NASEM, 2022).Gender Roles Gender roles and sociocultural expectations shape the health of girls and women throughassociated behaviors and societal expectations. Even before birth, they are exposed to genderedcultural norms and roles that hold together the gender system (Heise et al., 2019). Sexism, whichis based on gender, is linked to social determinants of health (SDOH), such as educationalattainment, occupation, and socioeconomic status. Inequities in the SDOH contribute toconditions that promote poor health (Fleming and Agnew-Brune, 2015). One example is unpaid caregiving (emotional, instrumental, and informational support orcare) (Maragh-Bass et al., 2021). This disproportionately falls on women, who care for familymembers, including children, spouses, parents, and older relatives. This role often interferes withwomen’s ability to care for themselves, leading to delays in seeking care or not receiving care atall (Maragh-Bass et al., 2021). Caregiving can also impact women’s health behaviors andincrease stress. Studies have shown that women caregivers had higher rates of depression andanxiety and lower levels of well-being and were less likely to engage in health behaviors, such asphysical activity (Bauer and Sousa-Poza, 2015; Zan and Shin, 2022). Some evidence shows thatwomen, especially racially and ethnically minoritized women such as Black and AfricanAmerican women, experience a greater disparity from unpaid caregiving for family membersliving with chronic conditions (Maragh-Bass et al., 2021). Conforming to or challenging gender norms have implications for behaviors associatedwith health outcomes. For example, female gender norms associated with thinness and body PREPUBLICATION COPY: UNCORRECTED PROOFS

WHY WOMEN DEVELOP CHRONIC CONDITIONS DIFFERENTLY THAN MEN 15image may have implications for diet and physical activity. Challenging gender norms caninfluence women’s use of tobacco and other substances (Fleming and Agnew-Brune, 2015).Sexual Orientation Sexual orientation is defined as a “multidimensional construct encompassing emotional,romantic, and sexual attraction, identity, and behavior” (NASEM, 2022). It is based on thepattern of emotional attraction to others (the same gender, a different gender, or multiplegenders). Sexual orientation identities include heterosexual, gay, lesbian, bisexual, queer,pansexual, and two-spirit (NASEM, 2022). Sexual minority populations experience greaterhealth disparities than their cisgender heterosexual counterparts because of stigma,discrimination, and stress (NASEM, 2020). These external influences are particularly amplifiedgiven the increased legislative pressures placed on gender-affirming therapy and other policiesrestricting free expression. Research has shown that sexual and gender minority populations have varying odds ofvarious chronic conditions compared to nonminority groups (Tran et al., 2023), which may bethe result of structural and environmental stressors, including prejudice and stigma (Baptiste-Roberts et al., 2017). Several studies, for example, have shown that women identifying as lesbianwere more likely to report moderate psychological distress, poor or fair health, multiple chronicconditions (MCC), heavy drinking, and heavy smoking compared to women who identified asheterosexual (Baptiste-Roberts et al., 2017; Simoni et al., 2017; Trinh et al., 2017). Similarly,bisexual women were more likely to report MCC, poorer overall physical health, severepsychological distress, heavy drinking, greater body mass index, and moderate smoking thanheterosexual women (Baptiste-Roberts et al., 2017; Simoni et al., 2017). Members of the lesbian,gay, bisexual, transgender, queer, intersex, and asexual community were also more likely toreport mental health conditions, especially depression and postpartum depression. Stressors suchas stigma associated with accessing sexual health resources can lead to undiagnosed or untreatedHIV and other sexually transmitted infections in this population (Baptiste-Roberts et al., 2017). Sexual and gender minority populations also report unmet health care needs thatcontribute to increases in chronic conditions, including a lack of health insurance coverage,providers lacking cultural proficiency, and the failure to treat same-sex partners as family, whichcan lead to delays in accessing health care (Alencar Albuquerque et al., 2016; Baptiste-Roberts etal., 2017; Bowen et al., 2004; Diamant et al., 2000; Gonzales et al., 2016). A study withtransgender women found that they, too, faced high risks of adverse mental health outcomes 3because of experiences of stigma, and social and structural vulnerabilities, including foodinsecurity, social support, housing insecurity, employment, and sex work (Sherman et al., 2024).Race and Ethnicity Two concepts that are sometimes used interchangeably and inaccurately are ancestry andrace. Ancestry describes the biological makeup and line of descent, whereas race categorizes“populations into an arbitrary, hierarchical classification framework, largely based on phenotypiccharacteristics, such as skin color” (NASEM, 2023). Race is not a valid biological construct; it isa social construct and linked to racism, which is a structural determinant of health and a driver of 3 Mental health outcomes were measured using the Primary Care PTSD Screen for DSM-5 and theKessler Psychological Distress Scale 6-item that assesses psychological distress, capturing DSM-5 anxietyand depressive symptom severity in the most recent 30 days. PREPUBLICATION COPY: UNCORRECTED PROOFS

16 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMENinequities within SDOH. Racism is driven by discriminatory, biased behavior at the interpersonallevel and restrictive policies and practices at the societal level. The American Indian and Alaska Native population’s history is shaped by structuraldisadvantage and extermination, removal, and assimilation (Moss, 2019). American Indian andAlaska Native is a racial categorization but also distinct due to the “legally enforceableobligations and responsibilities of the federal government to provide certain services and benefitsto members or citizens (and, in some cases, descendants) of federally recognized Tribal Nations”(NASEM, 2023). More than 500 federally recognized tribes exist, and federal and state policiescan influence their health and well-being (NASEM, 2023). Ample evidence shows that Black, Hispanic/Latina, American Indian and Alaska Native,Asian, and Native Hawaiian and Pacific Islander women have worse health outcomes than theirWhite heterosexual counterparts, especially regarding chronic conditions; heart disease; diabetes;hypertension; cancer; mental health conditions; autoimmune diseases such as SLE; andsubstance use (Henning-Smith et al., 2019; Reid et al., 2023; Whitman et al., 2022). Inequitiesexperienced by racially and ethnically minoritized women are discussed in more detail next. Structural Determinants of Health Chapter 1 defined structural determinants of health as “macrolevel factors, such as laws,policies, institutional practices, governance processes, and social norms that shape thedistribution (or maldistribution) of the SDOH (e.g., housing, income, employment, exposure toenvironmental toxins, interpersonal discrimination) across and within social groups” (NASEM,2023). The following section provides examples of how the structural determinants of health leadto health inequities in women.Sexism Beyond gender norms, evidence shows that sexism, which refers to systematic genderinequalities for women, leads to negative impacts on health, including a higher prevalence ofchronic conditions (Dore et al., 2023). Structural sexism refers to institutional discriminationenacted by laws, policies, or rules (Krieger, 2014). Research on gender discrimination hasexplored women’s experiences of perceived discrimination and its link to mental and physicalhealth (Homan, 2019). Research examining bias in the health care system, by both professionalsand medical institutions, found that women are less likely to be diagnosed accurately or receiveadvance or multidisciplinary treatment (Hoffmann et al., 2022; Homan, 2019). Despite cleargender differences in health outcomes, epidemiological and health services research issignificantly lacking on structural sexism and discriminatory gender structures that exist withinthe health care system and at other organizational levels. Most research focuses on interpersonallevels of discrimination and perceptions of treatment (Homan, 2019; Krieger, 2014). Structuralsexism is discussed further in Chapter 7.hom*ophobia/Heterosexism hom*ophobia is “an irrational fear, prejudice, and hatred of gay individuals” (Weinberg,1972). Significant evidence shows that exposure to verbal harassment, discrimination, andoutright physical violence because of gender identity and sexual orientation can produce severenegative effects on health that lead to chronic conditions such as mental health conditions,substance use disorders (SUD), and chronic medical conditions. Individuals who identify as PREPUBLICATION COPY: UNCORRECTED PROOFS

WHY WOMEN DEVELOP CHRONIC CONDITIONS DIFFERENTLY THAN MEN 17women and gay are more likely to experience acts of discrimination; this is particularly true forracial and ethnically minoritized individuals. hom*ophobic acts lead to significant levels of stressthat increase cortisol production and proinflammatory cytokine activation (Mays et al., 2018).Research has shown that higher cortisol leads to elevations in blood pressure and heart rate thatcan increase the chance of developing chronic CVD and earlier death among women (Inoue etal., 2021). These acts of discrimination create increased stress and chronic inflammatory statesleading to chronic conditions that are different than in heterosexual men (Huebner et al., 2021).Inequities and the Effects of Racism Black and African American, Hispanic/Latina, American Indian and Alaska Native,Asian, and Native Hawaiian and Pacific Islander women face an increased risk and prevalence ofchronic conditions. Although Black women are on average younger than the general U.S. femalepopulation, they have a higher prevalence of many chronic health conditions, such as CVD,stroke, obesity, cancer, and diabetes, resulting in part from structural inequities within andoutside of the health system they experience across the life course (Chinn et al., 2021).Furthermore, the intersectionality of gender and race creates synergistic effects that subjectBlack women to high levels of racism, sexism, and discrimination not experienced by Black menor White women (Chinn et al., 2021). This phenomenon, known as “gendered racism,” has led topoorer reproductive and sexual health outcomes, including adverse pregnancy outcomes (Mehraet al., 2020; Miller et al., 2022). Black women also experience significant mental and physicalhealth inequities (Chinn et al., 2021). As a result of historical and current racist policies, such as segregation and redlining,Black Americans experience significant socioeconomic inequalities, such as poorer-quality andmore socioeconomically disadvantaged neighborhoods (Anderson et al., 2023; Bailey et al.,2021; Bethea et al., 2016; NASEM, 2017). In the Black Women’s Health Study, neighborhoodsocioeconomic status was associated with higher mortality from CVD and cancer (Bethea et al.,2016). The authors state that the potential mechanisms of this relationship stem from socialaspects, including reduced access to health care, increased exposure to crime and social disorder,residential segregation, higher psychosocial stress, and therefore a higher allostatic load (Betheaet al., 2016). Black and African American populations have not been well delineated in theliterature. These groups are heterogenous and may include individuals who are from U.S.populations that have significant mixture with other populations, from the Caribbean, which mayhave higher levels of consanguinity, or recently immigrated from continental Africa. Each ofthese populations is impacted differently by racism. How stress affects the physiology of women,particularly certain racial and ethnic groups, is discussed later in this report. Hispanic/Latina women are significantly impacted by chronic conditions. Research inthis area has focused on chronic diseases, such as obesity, CVD, and other metabolic conditions.The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) examined genderdifferences in chronic conditions (NIH, 2006) and found that Hispanic women experience a highprevalence, including of obesity, hypercholesterolemia, and hypertension, with greater inequitieswhen the data are disaggregated by country of origin (Daviglus et al., 2012). Hispanic womenreported higher levels of negative pregnancy outcomes, including preeclampsia and gestationaldiabetes (Gomez et al., 2022). Contributing factors included the effect of immigration and PREPUBLICATION COPY: UNCORRECTED PROOFS

18 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMENacculturation 4 on health and health care access (Paz and Massey, 2016). In general, greateracculturation has been associated with higher levels of obesity and poor dietary and physicalactivity behaviors in Latinas in epidemiological studies such as the Women’s Health Initiativeand HCHS/SOL (Camplain et al., 2020; Lopez-Pentecost et al., 2022; Santiago-Torres et al.,2022). Undocumented immigrants face greater inequities, report poorer self-rated health, andhave added challenges in accessing health care (Cabral and Cuevas, 2020; Ortega et al., 2018).Undocumented Latinas reported being diagnosed with diseases such as HIV and breast cancer atlater stages and having babies with lower birth weight (Cabral and Cuevas, 2020). Given the within-group inequities among Latinas, they cannot be viewed as an aggregategroup (Errisuriz et al., 2024). For example, some studies have found that Puerto Rican andCuban women face greater mortality from ischemic heart disease than non-Latina and Mexicanwomen and that Mexican women experience greater mortality from cerebrovascular disease thanCuban and Puerto Rican women (Errisuriz et al., 2024). Reported associations betweenacculturation and other cultural measures, such as ethnic enclaves, that are sometimes found tobe protective are complex, and failing to disaggregate data may hinder research on understandinghealth outcomes in Latinas (Errisuriz et al., 2024). This can lead to generalized narratives thatLatinas are healthier, even though they have lower income, education, and lack of access to otherSDOH, and that needs to be examined critically (Errisuriz et al., 2024). Understanding the factors unique to American Indian and Alaska Native women livingwith chronic conditions is challenging given the lack of research. American Indian and AlaskaNative people face violence, historical oppression, and trauma resulting from colonization(Burnette and Figley, 2016). Poor mental health outcomes are significant, with a higher rate ofposttraumatic stress disorder (PTSD) and alcohol use disorder. American Indian and AlaskaNative women are more likely to be exposed to trauma (e.g., intimate partner violence (IPV) andchild sexual abuse) than other racial and ethnic populations (Ka'apu and Burnette, 2019). To describe the resilience and various protective and harmful factors that affect thedevelopment of chronic conditions in American Indian and Alaska Native people, the culturallyrelevant Framework of Historical Oppression, Resilience and Transcendence was developed(Burnette and Figley, 2016). American Indian and Alaska Native women experience a significantburden of chronic conditions, including severe morbidity and mortality, CVD, obesity, anddiabetes (Breathett et al., 2020; Kozhimannil et al., 2020). Furthermore, stress from trauma,violence, discrimination, and health issues is a risk factor for chronic conditions (Burnette et al.,2020). American Indian and Alaska Native women with higher levels of enculturation(identification with native culture) perceived a supportive neighborhood environment as beingassociated with engaging in healthy behaviors and lower risk of chronic conditions. In contrast,exposure to violence, trauma, and discrimination were associated with less engaging in healthybehaviors and a higher risk of chronic conditions (Burnette et al., 2020). More research is neededto understand sex and gender differences in risk factors for chronic conditions among thispopulation (Burnette et al., 2020). Asian American women have experienced discrimination in multiple ways including,fetishization, being viewed as passive, and being invalidated through lack of representation, andthrough pervasive White beauty ideals (Forbes et al., 2023; Mukkamala and Suyemoto, 2018). Acculturation is the process by which individuals adopt attitudes, values, customs, beliefs and 4behaviors of another culture and is often associated with health outcomes (Santiago-Torres et al., 2022;Velasco-Mondragon et al., 2016). PREPUBLICATION COPY: UNCORRECTED PROOFS

WHY WOMEN DEVELOP CHRONIC CONDITIONS DIFFERENTLY THAN MEN 19The coronavirus disease 2019 pandemic exacerbated these experiences with the rise inxenophobia and anti-Asian hate (Le et al., 2020). A study measured Asian American women’sexperiences of discrimination and found that 1 in 3 experienced discriminatory practices by theirhealth care provider and that this was related to higher reporting of physical and mental healthimpairment (Do et al., 2023). More intersectional frameworks are needed to study chronicconditions in Asian American women. The Asian American population is heterogeneous, comprising 24 groups with varioussocial and economic characteristics that affect health outcomes and development of chronicconditions. Most research on this population, however, has focused on six major groups (Yomand Lor, 2022). Knowledge gaps about the health of Asian American populations have persistedin part because of the problematic practice of aggregating the broad and diverse populations forresearch purposes (Waitzfelder et al., 2023). The majority of research on chronic conditions inAsian American women has focused on CVD, diabetes, metabolic syndrome; fewer studies havefocused on female-specific and gynecologic conditions and mental health (Yom and Lor, 2022). Research has made progress in unmasking inequities in various Asian American groups.For example, Filipino women had 1.66 higher odds of CVD compared to non-Hispanic Whitewomen (Holland et al., 2011). National data show that Filipino and Korean women had a higherprevalence of diabetes and mental health conditions, such as SUD and depression (Choi et al.,2013; Wang et al., 2023). Native Hawaiian and Pacific Islander groups are often aggregated with the AsianAmerican population, creating challenges in measuring the impact of chronic conditions for eachgroup (Kanaya et al., 2022; Morey et al., 2022). Limited data on Native Hawaiian and PacificIslander groups suggest they experience higher levels of heart disease, hypertension, and diabetesand difficulty maintaining a healthy body weight. Key factors contributing to these disparities inhealth include poverty, low levels of high school completion, poor physical environments,limited access to care, and experiences with racial segregation and physical displacement(NASEM, 2023).Ageism Structural age discrimination, also known as ageism, is a contributor to the developmentof chronic conditions (Allen, 2016). Ageism refers to the “inequitable historic, cultural,institutional, political, and interpersonal conditions, structures, practices, and norms embeddedwithin our society that routinely privilege some age groups, such as younger adults, whilesimultaneously disadvantaging other groups, including older adults” (Allen, 2016). Ageism isexperienced during a portion of the life course and may lead to repeated exposure to chronicstressors which increase the progression of physical deterioration and associated chronicconditions (Allen, 2016). A nationally representative survey of U.S. adults between the ages of50–80 showed that women reported greater levels of everyday ageism than men (Allen et al.,2022). Gendered ageism is experienced by women where they face discrimination based on bothsex/gender and age, which create greater disparities in health and well-being (Rochon et al.,2021). More specifically, the combined impact of sexism and ageism are detrimental to olderwomen, who live longer than men, and may face greater exposure to physical and sexualviolence, trauma, poverty, and thus greater health inequities (Hand and Ihara, 2024). PREPUBLICATION COPY: UNCORRECTED PROOFS

20 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Social Determinants of Health The last 2 decades have seen immense strides in recognizing that the factors thatinfluence the risk of developing and outcomes associated with chronic conditions go beyondindividual biological and genetic factors and can be affected by the surroundings andenvironment. SDOH are fundamental factors that can influence susceptibility to chronicconditions and disease outcomes negatively and affect overall well-being and quality of life(Girardi et al., 2023). SDOH can promote health and reduce disease risk or contribute to the development ofchronic conditions, affect diagnosis, and exacerbate disease. They can affect molecular processesimplicated in the biology of chronic disease development, but these mechanisms are poorlyunderstood. However, some research has shown that stress-causing SDOH may promoteinflammation—a major contributor to developing chronic conditions—and epigenetically altergene regulation (Simons et al., 2016). The concept of transgenerational epigenetics demonstratesthat changes in regulation of gene expression are passed on to subsequent generations and couldaccount for why certain groups demonstrate increased susceptibility to chronic conditions (Fitz-James and Cavalli, 2022; Pembrey et al., 2014). SDOH can lead to biological changes that can initiate chronic conditions (co*ckerham etal., 2017; Vennu et al., 2020). According to the Office of Health Policy, SDOH affect as much as50 percent of county-level variation in health outcomes, whereas clinical care affects only 20percent (Whitman et al., 2022). Furthermore, national data show that unfavorable SDOH, such asunemployment, lower family income, food insecurity, low education, lack of private healthinsurance, and living alone, are associated with premature mortality and that this association wasstronger for Black adults compared to White adults (Bundy et al., 2023). Healthy People 2030 categorizes SDOH into five main groupings: (1) economic stability,such as poverty and employment; (2) education access and quality; (3) health care access andquality; (4) neighborhood and built environment, such as accessible housing, food and nutrition,and transportation; and (5) social and community context (HHS, n.d.). SDOH play a major rolein contributing to women’s health inequities, including chronic conditions. At the individuallevel, lower socioeconomic status, including lower income, poverty, marital status, lack of accessto health insurance, lower educational attainment, and interpersonal experiences of sexism,racism, and discrimination, are prevalent in and disadvantage women more, especially raciallyand ethnically minoritized women (CDC, 2023; Temkin et al., 2023). At the community level, poverty, neighborhood crime, exposure to pollutants andcontaminants, and the physical and built environment can affect the development andmanagement of chronic conditions and the ability to engage in actions associated with preventingthem (Koehler et al., 2018). These community-level conditions can adversely affect the healthand well-being of pregnant women and lead to adverse outcomes, such as preeclampsia (Girardiet al., 2023). Structural determinants of health affecting opportunities and life position that resultin advantages or disadvantages, such as racism, sexism, and hom*ophobia/heterosexism, influenceindividual-level SDOH, such as poverty, access to housing, income level, and access toeducation (Chetty, 2016; Emlet, 2016; Homan, 2019, 2021; Quiñones, 2019). Greatersocioeconomic advantage can be protective. For example, a higher level of education isassociated with lower risks for cognitive decline and AD (Larsson et al., 2017) (see Chapter 7). PREPUBLICATION COPY: UNCORRECTED PROOFS

WHY WOMEN DEVELOP CHRONIC CONDITIONS DIFFERENTLY THAN MEN 21The Neighborhood and Built Environment The neighborhood and built environment influences health behaviors that may preventchronic conditions and also affect outcomes associated with them (Pinter-Wollman et al., 2018).The built environment can affect the ability to manage health behaviors for individuals who arediagnosed and living with chronic conditions. Much of the research on its effects on chronicconditions has focused on physical activity and recreational activities as a means of reducingmorbidity and mortality from CVD and obesity (Sallis et al., 2012). Few studies have beenconducted in women or explore gender differences (De La Fuente et al., 2020). Among women,accessibility to public transport, safety for cycling, housing density, and distance to dailydestinations were more salient as predictors of physical activity than the built environment(Tcymbal et al., 2020). Neighborhood context also has an important relationship with health behaviors andchronic conditions. Studies have shown that factors such as socioeconomic disadvantage andneighborhood deprivation have negative outcomes for health and chronic disease. For example, apopulation-based study in Minnesota found that an area deprivation index was more stronglyassociated with cardiovascular conditions in women versus men (Chamberlain et al., 2020,2022). Rurality is another SDOH that requires attention. Rural populations are more likely thanurban populations to have lower levels of education, employment, and economic status. Theyalso face shortages of physicians and difficulties accessing specialty care—over half of U.S.counties have no obstetricians and gynecologists (Rayburn et al., 2012), for example—andtherefore are more likely to experience chronic medical and mental health conditions than theirurban counterparts (co*ckerham et al., 2017; Havranek et al., 2015). These social factors mayinclude or influence lifestyle factors, such as exposure to smoking, environmental pollution,nutrition, and physical activity, that research has linked to chronic conditions in women, such asheart and autoimmune diseases.Access to Quality Health Care Access to quality health care is essential to prevent and treat chronic conditions,especially for women. Despite substantial clinical research on chronic conditions, populationhealth studies are needed to advance equitable awareness and treatment, including transportationto health care, cultural norms, and environmental influences (Aninye et al., 2021; Butler et al.,2016). Black women and Latinas and their multiple intersecting identities are significantlyaffected by health care access for reproductive and sexual health (Small et al., 2023). In general,childcare duties and lack of insurance, financial security, access to clinicians based ongeographic location, and transportation serve as barriers to proper care for women living withchronic conditions. Women experience negative judgment, discrimination, and stigma in healthcare settings related to their sexual behavior and sexuality compared to men. Black women inparticular have more negative health care interactions than White women; their reproductivedesires are minimized or undervalued in care decisions (Fletcher et al., 2021; Prather et al.,2016). The lack of access to quality health care can have negative consequences resulting inpoorly treated or untreated chronic conditions and progression to more severe symptoms thatimpact quality of life and morbidity in women. PREPUBLICATION COPY: UNCORRECTED PROOFS

22 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Exposures and ResourcesAdverse Childhood Experiences Early adverse life events after birth, during childhood, and until adolescence canpredispose individuals to higher risks for chronic conditions as adults. Adverse childhoodexperiences (ACEs) refer to exposure to childhood emotional, physical or sexual abuse, andhousehold dysfunction and have been linked to higher mortality at younger ages and higher risksfor a host of chronic conditions and severe, debilitating illness later in life (Felitti et al., 1998). Limited research has shown that in women, exposure to ACEs is linked to mental healthconditions, including depression and other mood disorders, anxiety, SUD, PTSD, and chronichealth conditions, such as migraines, cancer, diabetes, heart disease, lung disease, stroke,autoimmunity, endometriosis, fibroids, and chronic pain (Alcalá et al., 2017; Dong et al., 2004;Moussaoui et al., 2023; Nelson et al., 2020; Norman et al., 2012; Rich-Edwards et al., 2010;Simon and Admon, 2023; Springer et al., 2007). 5 Studies have shown that women mayexperience more ACEs than men, with gender differences in the frequency and type of exposures(Alcalá et al., 2017; Haahr-Pedersen et al., 2020). For example, women are more likely to reportchildhood sexual abuse, physical and emotional neglect, and household drug or alcohol abuse.One study found the prevalence of ACEs was 39 percent in women compared to 21 percent inmen (Haahr-Pedersen et al., 2020). One area of study has focused on the relationship between ACEs and gynecologicsurgeries. Studies have found that women who underwent bilateral oophorectomy before age 46were more likely to have experienced ACEs. These associations were stronger when the surgerywas done at younger age and with no ovarian pathology to support it (Gazzuola Rocca et al.,2017a; Ryan et al., 2016). Psychological mechanisms may contribute to a higher risk ofgynecologic pathology or symptoms among patients with ACEs or may cause them to experiencegynecologic symptoms more severely, prompting them to choose a more definitive surgicaltreatment rather than more conservative strategies. Subjective differences in pain perception mayalso help explain the frequency of surgery among patients with ACEs who have no identifiedgynecologic pathology (Gazzuola Rocca et al., 2017b; Rocca et al., 2021). ACEs may causestress-related epigenetic modification, endocrine dysregulation, or alteration of the immuneresponse, which may lead to gynecologic pathology or symptoms (Demakakos et al., 2022).Mechanisms of Adverse Childhood Experiences Inflammation could be one mechanism underlying the effects of ACEs on developmentof chronic conditions (Baumeister et al., 2016; Egger et al., 2022; Iob et al., 2020; Lacey et al.,2020; Pinto Pereira et al., 2019; Rasmussen et al., 2020). Animal studies in rodents show thatbehavioral changes associated with early-life adversity were linked to increased microglialactivation—a marker of inflammation in the brain—that reduced neurogenesis and proliferationof neural stem cells, and altered neuronal networks (Johnson and Kaffman, 2018; Waters andGould, 2022). Clinical studies support this, showing that ACEs related to abuse, householddysfunction, parental absence, and poor parent–child relationships are associated with heightenedinflammation in mid- and later life, with adults exhibiting higher levels of the inflammatory5 Earlier ACEs studies have limitations, as the initial CDC and Kaiser epidemiological study was primarily conductedin White, insured, middle-class adults and other studies investigating ACES in women have been mainly based oncertain geographical locations. PREPUBLICATION COPY: UNCORRECTED PROOFS

WHY WOMEN DEVELOP CHRONIC CONDITIONS DIFFERENTLY THAN MEN 23marker C-reactive protein and interleukin-6 (Baumeister et al., 2016; Iob et al., 2022, 2022;Lacey et al., 2020). Other clinical and population-based studies support the idea that chronicsystemic inflammation is associated with depression in adults (Haapakoski et al., 2015; Iob et al.,2022; Osimo et al., 2020). Sleep disturbances are a maladaptive response to ACEs resulting in anelevated stress vulnerability during adulthood, which is most likely a secondary effect stemmingfrom dysfunction in the hypothalamus-pituitary-adrenal axis altered by ACE-related stresses(Simon and Admon, 2023). Another possible explanation for the enduring effects of early-life stress involvesmolecular epigenetic mechanisms that regulate gene expression, such as DNA methylation orhistone modifications. Epigenetic studies in animal models implicate several genes whoseexpression is altered in response to early-life adversity (SLC6A4 serotonin transporter NR3C1and FKBP5 genes 6 involved in glucocorticoid activity) (Waters and Gould, 2022). One clinicalstudy found an association between lower expression levels of a specific X chromosome-linkedgene, Methyl-CpG binding protein 2 (MECP2) with early life stress and anxiety/depression(Cosentino et al., 2022), suggesting that X chromosome genes may mediate the long-termdetrimental effects of early-life stressors. Interestingly, other clinical studies have revealed thatthe response to or impact of ACEs depends on the individual’s inherent genetic susceptibility orreceptivity to stress (Waters and Gould, 2022). These findings suggest that genetic susceptibilitymay influence health outcomes in adults who have experienced ACEs and that the developmentof chronic conditions may be mediated by epigenetic mechanisms.Trauma and Intimate Partner Violence Violence against women is defined as "any act of gender-based violence that results in, oris likely to result in, physical, sexual, or mental harm or suffering to women, including threats ofsuch acts, coercion or arbitrary deprivation of liberty, whether occurring in public or in privatelife" (WHO, 2024). Violence against women includes IPV, which has been reported in over athird of U.S. women and is one of the most common types of trauma experienced (Smith et al.,2018). IPV has been linked to poorer physical health and the development of chronic conditionsincluding CVD, depression, bladder pain, and chronic pain (El‐Serag and Thurston, 2020;Humphreys and Lee, 2009; Raphael et al., 2022; Walker et al., 2022). Both lifetime and recentexperiences of violence, including IPV, can significantly affect health. In the Nurses’ HealthStudy II, women who had recently experienced severe emotional abuse by an intimate partnerhad a 24 percent increased rate of hypertension (Mason et al., 2012). A community-based studyon midlife to older women found that lifetime exposure to IPV had greater odds of bladder pain(Raphael et al., 2022). Experience of lifetime emotional and physical IPV was associated with agreater odds of menopausal symptoms in midlife and older women (Gibson et al., 2019). Olderwomen are more likely to experience other forms of violence, including from other familymembers and caregivers, which may be related to their physical and mental health and livingwith chronic conditions (Meyer et al., 2020). Exposure to trauma and IPV are also discussed asfactors that contribute to chronic conditions (see Chapters 5 and 6), intersect with structural andsocial determinants of health (see Chapter 7), and MCC (see Chapter 8). 6 NR3C1 refers to Nuclear Receptor Subfamily 3 Group C Member 1 and FKBP5 to FK506 Binding Protein 5genes. PREPUBLICATION COPY: UNCORRECTED PROOFS

24 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMENCoping Mechanisms and Resilience Coping and resilience are critical strategies women use to adapt, enhance positiveoutcomes, and grow from adversity (Bowling et al., 2019a). Resilience has been bound to theexperience of stress and defined as “a dynamic process encompassing positive adaptation in thecontext of past or present adversity” (Luthar et al., 2000). It is a protective factor influenced byvarious internal and external factors (Bowling et al., 2019b). Key components include self-efficacy, hope, coping, competence capability, resistance, and adaptation (Woods-Giscombe etal., 2023). The inability to overcome adversity may be linked to women developing chronicconditions, and interventions to address resilience are needed for women living with chronicconditions (Kim et al., 2019; Kim et al., 2021).Inflammation Many chronic health conditions are related to chronic, prolonged inflammation. Researchhas shown that chronically elevated inflammation contributes directly to the pathophysiology ofchronic conditions, such as CVD, Type II diabetes, osteoporosis, osteoarthritis, rheumatoidarthritis, AD, and certain cancers (Liu et al., 2017; Paalani et al., 2011; Simons et al., 2021;Sokolove and Lepus, 2013). A proinflammatory state is typically characterized by highcirculating levels of a number of different cytokines, such as the interleukins (IL1, IL2, IL6, andIL17), tumor necrosis factor, and macrophage inflammatory protein (Simons et al., 2021). Increases in proinflammatory cytokines are protective during an infection or tissue injury,but sustained inflammation can lead to significant tissue damage and thus chronic healthconditions. Women often tend to have more associated stress leading to protracted states ofinflammation that cause chronic conditions that are different from men (Liu et al., 2017). SDOH, such as social disadvantage, socioeconomic status, racism, sexism, andhom*ophobia, produce chronic stress and influence health by increasing inflammation via severalbiological pathways. Exposure to chronic stress and the resulting inflammation negatively affectmultiple organ systems via neuroendocrine, developmental, immunologic, and vascularmechanisms that might damage key physiologic systems and can lead to more rapid onset orprogression of chronic conditions (Notterman and Mitchell, 2015; Simons et al., 2021). Researchers have proposed that social environments that pose a persistent threat ofhostility, denigration, and disrespect promote chronically high levels of inflammation. Theassociation of adverse consequences that women experience differently than men related tosocial and structural determinants of health, gender and sex discrimination, hom*ophobia, ACEs,and other factors can be better understood in this context of protracted stress and inflammation(Powell et al., 2013; Simons et al., 2021; Wardecker et al., 2021).Embodiment/Weathering/Allostatic Load Embodiment is defined as “outside physical and social world becomes embedded into ourbiology—that is, how daily interactions with our social and physical environments ‘get under ourskin’ to affect our physical, psychological, and emotional well-being by altering how our bodyfunctions” (Krieger, 2001). Allostatic load is understood as the physical embodiment of repeatedor chronic exposure to stress-inducing social and living conditions over time and a physiologicexpression of weathering (Petteway et al., 2019). Studies on neighborhood context (e.g., poverty,deprivation, violence, disorder, cohesion) have explored whether these factors are related togreater allostatic load and biological markers of aging, which include telomere length PREPUBLICATION COPY: UNCORRECTED PROOFS

WHY WOMEN DEVELOP CHRONIC CONDITIONS DIFFERENTLY THAN MEN 25(Gustafsson et al., 2014; Petteway et al., 2019). The mechanistic pathways in which places,experiences, and exposures become embedded biologically are through stress and inflammation. The accumulation of stress due to exposure to racism and sexism, which drives poverty,socioeconomic disadvantage, exposure to poor built and neighborhood environment, and otherstressful environments, leads to wider health disparities for Black women as they age(Geronimus, 1992; Geronimus et al., 2006), known as the “weathering hypothesis” (see Figure 2-4).FIGURE 2–4 Impact of structural inequalities on SDOH and chronic disease disparities in Black women. Health Care System Figure 2-3 illustrates how different exposures, and structural and social determinants ofhealth influence the experience of women in the health care system. SDOH are tied to a health-care-related social needs and include access to the required care. The patient experience includesthe interactions with their care team (including health care facility staff), care administration, andthe complexity of their insurance. One conceptual framework of the patient experience considersthree perspectives: person, patient, and user (Oben, 2020). Studying it fully requires consideringall three, as they influence the ability and opportunity to access care and the patient’s experience.Trust and patient activation—active involvement and investment in managing their chroniccondition—influences their health and clinical interactions (Venechuk et al., 2023). Although trust is frequently cited as critical to the patient–physician relationship (Murrayand McCrone, 2015), literature is growing on the dismissal and minimization of women’s painand symptoms. This not only erodes trust in the health care setting and the specific providers butcan lead to misdiagnosis, missed diagnosis, and poorer outcomes because of deferring or beingdenied appropriate care. A recent cohort study indicated that diagnostic error is the greatestsource of medical-error-related death across care settings, and this may be pronounced in womenand various racial and ethnic groups (Newman-Toker et al., 2024). The invalidation of women’sexperiences can be traced back to the diagnosis of hysteria, an exclusively female disease ofunknown origins presenting with a wide range of manifestations. Although it was dismissed as avalid psychological condition in the 1980s (Tasca et al., 2012), ongoing first-person accounts andthe scientific literature report sex- and gender-based discrepancy in care arising from theinvalidation of women's experiences and symptoms. Qualitative studies have highlighted the pervasiveness of communicativedisenfranchisem*nt (Thompson et al., 2023; Venechuk et al., 2023), described as “the process bywhich individuals’ identities, relationships, and experiences are treated as not ‘real’ or of value”(Hintz and Wilson, 2021). Dismissal, minimization of pain, and psychologizing were noted asways providers invalidated women’s concerns (Venechuk et al., 2023). Relatedly, medicalgaslighting, where providers dismiss or trivialize symptoms or health concerns, leading patients PREPUBLICATION COPY: UNCORRECTED PROOFS

26 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMENto doubt their own experiences or believe their conditions are imagined rather than real, mayextend beyond the interpersonal relationships and be a result of the health care system (Sebring,2021). The unintended consequences of this include not only a growing mistrust in the healthcare system, but delayed diagnosis and treatment (Au et al., 2022). SUMMARY Separating the effects of biology (sex) and social environment (gender) is difficult. Somestudies fail to discriminate between the two, promoting a long-standing tradition of confusing thecausal origins of sex and gender differences. Many study classifications of sex and gendergroups tend to support a cis-centric worldview, marginalizing sex and gender minorities.Comparing only two sex and gender groups (women versus men) involves thousands of traitsacross only two dimensions, making it difficult to determine which factors cause the differences. The effects of biological factors can be assessed in humans by comparing groups thatdiffer primarily on some biological variable, such as genetic or hormonal, to ask if physiology ordisease is correlated with it. Similarly, it is possible to compare groups that differ along animportant social continuum, such as race or socioeconomic status, to determine whether thosevariables correlate with disease. In many studies, however, the biological and social factors maycovary, making it difficult to make precise conclusions about causality. For example, groupsdiffering in socioeconomic level may also differ in their underlying biology. Similarly, groupsdiffering in biology, such as expression of different alleles, may not be represented equally indifferent environmental situations (for example, if having a specific allele places the individualin a different environment), making it difficult to determine which factor causes groupdifferences. Nevertheless, studies of both biological and social variables are critically importantto provide basic understanding of the possible variables influencing health and access to medicalcare. Animal research continues to provide a critical perspective on biological factors thatinfluence women and men differently; the ability to manipulate only one such factor at timeoffers unparalleled analytical power to understand how each one influences physiology ordisease. Concepts developed in animal studies shape hypotheses to be tested in research onhuman conditions. Making progress and understanding the landscape of structural and social determinants ofhealth and their effect on chronic conditions in women requires a wealth of data across multiplelevels to account for individual- and community-level factors, the complex interplay between aperson and their community, the effects of policies and opportunities, and the onset of diseaseover the life-span. Research is lacking about how structural factors, including racism and sexism,affect risk factors associated with chronic conditions and lead to health disparities in variouschronic conditions in women. Many studies do not properly examine these factors, and despiteincreased use of neighborhood-level data for examining such associations, many are notinvestigated in racially, ethnically, and sexually diverse groups. Most studies have also beencross sectional, and more longitudinal studies are needed to examine causal associations,especially to understand the mechanisms that would explain why these social factors increasesusceptibility to developing chronic conditions in women from various racial and ethnicbackgrounds. Research is lacking on how gender differences exist in the relationship between thebuilt environment and lifestyle behavioral factors associated with chronic conditions. Datadisaggregation is lacking, which has further masked disparities in racial and ethnic groups. PREPUBLICATION COPY: UNCORRECTED PROOFS

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