Advancing Research on Chronic Conditions in Women (2024)

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2 Why Women Develop Chronic Conditions Differently than Men This chapter introduces important multidimensional factors that aid in understanding the differential development of chronic conditions in women compared to men, encompassing biological, social, and environmental factors, including the structural and social determinants of health. The chapter concludes with a discussion on the potential impact of enhancing research in various domains related to chronic conditions in women. Sex and gender are multidimensional concepts that influence health and the development and outcomes associated with chronic conditions in women. Biological (sex) and social/environmental (gender) factors define two major classes of relevant variables differentially influencing women and men. Sex factors, comprising sex chromosomes, gonadal hormones 1, and other factors they influence, lead to male and female differences in morphology, physiology, and behavior—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 differentially distributes power, status, and resources (Barr et al., 2023; Heise et al., 2019). Health outcomes attributed to one's sex or gender are due to biological or environmental differences, in part because of social inequities associated with gender (Heise et al., 2019). Sex and gender differences occur in most types of cells and most diseases. Some conditions are specific to women or may be more prevalent or progress faster in women, and others are more predominant in men. For conditions affecting both men and women, the sex differences may be quite large. Thus, explaining chronic conditions in women requires an understanding of how they differ from men and identifying the biological, social, and environmental forces that cause this. Determining whether sex-specific or -biased molecular agents and cellular processes elevate or reduce risk of disease requires studying both men and women to identify which therapeutic strategies are optimal in both; better understanding chronic conditions 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., female ovaries produce the steroid-derived hormones, estrogens, progesterone, and androgens, as well as others derived from other substrates, including anti-Mullerian hormone and relaxin), in most instances throughout this report, it is equated with the terms “sex steroid hormones” and “reproductive hormones.” Together, these terms will refer to the major classes of reproductive hormones produced by the gonads: estrogens, progesterone, and androgens. PREPUBLICATION COPY: UNCORRECTED PROOFS 

2 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN all individuals. Moreover, understanding disease regulation under diverse conditions (such as in diverse sexes/genders) leads to improved concepts of the full spectrum of it. Discovering biological factors and social/environmental factors involves quite different methodologies. Although strict experimental control of individual biological factors can be achieved in studies of animals or humans, investigating social factors involves epidemiological studies in human populations that convincingly implicate gendered variables as critically important in diseases influencing women. One major challenge is that biological and social factors 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 of factors have profound effects on each other. Many biological factors are thought to have different effects depending on the environment, and changes in the social or physical environment have powerful effects on gene expression and disease course. Further investigation is necessary to understand the complex interaction, or intersection, of sex and gender, as well as how these interactions can be explained by epigenetics. As animals share many genes and physiological mechanisms with humans, the understanding of sex differences is greatly increased by studies of animal species in which specific sex-biasing factors can be manipulated in isolation from each other, to understand their individual effects. It is difficult to perform this research in humans, given the interplay of biological and nonbiological factors that influence trajectory of conditions, so animal research gives rise to invaluable novel concepts of cell and tissue organization, which suggest novel diagnostic and therapeutic approaches in humans that would not be uncovered if only humans were studied. Animal research is therefore an essential incubator of concepts about basic biology of chronic conditions in women. Animals often do not model the complex social and environmental factors that cause gender differences in disease and thus are not typically used to investigate them. Ultimately, processes discovered in animals may be similar or different in humans, and thus further research in humans establishes which concepts are helpful in understanding human disease. When discussing animal research, the discussion of females focuses predominantly on XX animals with ovaries, compared to males as XY animals with testes. That comparison not only illuminates factors that cause differences between the two groups, but also provides a foundation for contrasting variation among individuals that are not members of those groups. In specific cases, differences among other groups with other complements of sex chromosomes, including XO, XX, XY, XXY, and XYY individuals with either ovaries or testes, are discussed. This chapter discusses essential factors necessary for understanding chronic conditions in women throughout their lives (see Figure 2-1). These include the major life course stages of childhood, adolescence, adulthood, and older adulthood that are associated with important reproductive stages, such as prepuberty, puberty, menopause, and post-menopause. This chapter also identifies the interplay of biology and social and environmental factors in the manifestation and course of chronic conditions. Finally, factors specifically related to aspects of the health care system, such as access to care, are noted because they play a significant role in women’s experiences from diagnosis through treatment and the management of these conditions. PREPUBLICATION COPY: UNCORRECTED PROOFS 

WHY WOMEN DEVELOP CHRONIC CONDITIONS DIFFERENTLY THAN MEN 3 FIGURE 2-1 Factors that contribute to chronic conditions in women over the life course that this reports highlights. BIOLOGICAL FACTORS Effects of Sex Chromosomes and Gonadal Hormones All sex differences in mammals originate from the molecular differences encoded by the X 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 placental mammals, the undifferentiated XX gonad begins to express genes that cause an ovary to develop and suppress testicular development. In XY gonads, genes on the Y chromosome trigger testes development and suppress ovary development (Capel, 2017; Eggers et al., 2014). The two types of 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 of cells 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 as the primary hormonal drivers of sexual differentiation—estrogens and progesterone in females, and androgens (notably, testosterone) in males. Although these sex steroid hormones may individually and collectively influence the development of chronic conditions in women, this report mainly focuses on estrogens. This is primarily because of their role in sexual differentiation, reproduction, homeostasis, and maintenance of physiologic function over the life- span. When appropriate, findings related to progesterone in the development of chronic conditions are included. The role of testosterone is highlighted in some sections of the report which 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 of testosterone and the testes are a source of estrogens, although at much lower levels. However, the effects of these low levels of sex steroid hormones emerges when considering how the overall ratios of these hormones impact men and women differently. For example, during the menstrual PREPUBLICATION COPY: UNCORRECTED PROOFS 

4 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN cycle and perimenopause, as well as post-menopause, the effects of testosterone are more apparent when estrogen levels are low or in flux. Another pathway that leads to such sex differences involves molecules encoded by genes on the X and Y chromosomes, other than those that control gonadal hormone production. These molecules act in virtually all cell types to make XX and XY cells different, via mechanisms unlike those responsible for the effects of gonadal hormones (Arnold, 2019, 2022). Research has shown 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 both types of sex-biasing agents (sex chromosome genes and gonadal hormones) as possible root causes (Arnold, 2017). Numerous events during embryogenesis can establish long-lasting sex differences even after the sex-biasing factors have ceased to operate. For example, differences in development of the external genitals (clitoris vs. penis, vaginal labia vs. scrotum) are controlled by testosterone secreted by the embryonic testes, which acts during embryonic life to suppress the female pattern and promote the male pattern (Achermann and Jameson, 2018). Sexual differentiation of these female genital structures does not require specific ovarian secretions. In animals, specific sex differences in brain regions created near the time of birth result from the action of testosterone secreted by the testes or by testosterone’s metabolite estradiol (Morris et al., 2004). Evidence supports 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 mice in 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—often called “organizational” effects of gonadal hormones—leading to a sex difference in the genital or neural substrates that therefore can be differentially affected by disease, long after the sex differences are created (Arnold, 2009). Although diseases affecting sexually differentiated tissues, 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 less well understood. In contrast to permanent sex differences, gonadal hormones have widespread and potent effects that are reversible and come and go as hormone levels wax and wane, often referred to as the “activational” effects of estrogens, progestogens, and androgens (Blencowe et al., 2022). The onset and severity of numerous diseases correlates with increases or decreases in plasma levels of gonadal hormones occurring at puberty; during stress; during ovulatory cycles, pregnancy, menopause; or in aging. In animal studies, many sex differences in the transcriptome are eliminated or reduced after gonads are removed in adults, testifying to the dominant reversible effects 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 also have synergistic or antagonistic effects, creating a complex web. An emerging concept in the last 20 years is that some phenotypes may be similar in the two sexes, but that masks an underlying sexual inequality of mechanism (Arnold, 2022; De Vries, 2004). For example, one factor prevalent in women may reduce the effect of another factor, making women more like men; the apparent similarity of the two sexes occurs via differing underlying molecular mechanisms. An important ramification is that any environmental factor, such as a pathological agent, can differentially disrupt the dissimilar mechanisms operating in the two sexes. A tissue that PREPUBLICATION COPY: UNCORRECTED PROOFS 

WHY WOMEN DEVELOP CHRONIC CONDITIONS DIFFERENTLY THAN MEN 5 functions similarly in the two sexes may thus respond differently to the disease, leading to a chronic condition affecting one sex and not the other. A prime example of this effect involves the XIST gene, which is expressed at high levels in 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 expression into 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 a factor enhancing similarity of XX and XY cells and individuals. Its function is variable and has been associated with sex differences in autoimmune diseases (Syrett et al., 2019). However, the balance in X gene expression is achieved because X genes are regulated by XIST in XX but not XY cells. When a disease process interferes with the action of XIST or other components of the X inactivation system, the disease can cause a condition that is more prevalent in females than males (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. In human pluripotent stem cells, XIST downregulates some autosomal genes to create a sex difference in expression (Dror et al., 2024). XIST is implicated as a female-specific contributor to autoimmune 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 activates interferon-alpha production in plasmacytoid dendritic cells, increasing inflammation and contributing to SLE pathogenesis (Crawford et al., 2023). XIST also interacts with ribonucleoprotein partners which are attacked during autoimmune disease, perhaps contributing to their higher incidence in women (Crawford et al., 2023; Dou et al., 2024). The central position of 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 of the cells, making XX and XY cells different in each individual. Sex differences may also arise because of biological factors that operate at the level of populations, increasing or decreasing disease incidence in groups of women compared to men (Arnold, 2017). The best examples of these protect women from disease. For example, X-chromosome-linked alleles causing disease affect more men because women have a second X chromosome, usually with a different allele that reduces the deleterious impact of the disease allele (Migeon, 2007). Another example is that the maternal inheritance of mitochondria is thought to allow the evolutionary emergence of mitochondrial alleles that have a negative impact in males. Because males do not pass the alleles to their offspring, selection against the alleles does not occur. The resulting mitochondrial genetic 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 of XX versus XY sex chromosomes, which lead to a different genetic makeup of every cell and cause organizational (long-lasting) or activational (reversible) sex differences via gonadal hormone action. The emergent sex differences in tissue physiology or disease are the result of sex differences in gene pathways that are influenced by one or more of these inherent sex-biasing factors. A primary goal is to identify which of these mechanisms is operating to cause sex differences 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 chromosome effects 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. Animal research provides a rich source of information about molecular and cellular mechanisms causing sex differences in disease, generating many hypotheses about disease mechanisms that could not derive from studies of humans. These ideas can then be tested for validity in noninvasive human research, 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 by gonadal hormones. In general, the approach is to manipulate the level or action of one or more hormones at specific times of life or in specific cells and measure effects on phenotypes of interest. Because it is primarily gonadal hormones (rather than hormones from other organs) that are known to be sexually differentiated by sex chromosome effects, the hormones most often manipulated 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 of this chapter. One informative method, for example, involves removing the gonads surgically in adulthood to determine whether the sex difference in a trait is reduced or abolished. If so, that suggests that the reversible, activational effects of gonadal hormones cause it. Further experiments—measuring the trait after replacing specific testicular or ovarian hormones, for example—can define which hormone(s) contribute to the sex difference and uncover downstream molecular mechanisms regulated by the hormone(s) (Craft et al., 2004). Removing all gonadal hormones in adulthood may not eliminate a sex difference, such as the morphology of internal or external genitals or of some brain regions and in behaviors (Bloch and Gorski, 1988; Breedlove and Arnold, 1981). A second hypothesis is that these persistent sex differences could result from the organizational effects of gonadal hormones, typically exerted just before or after birth. To test that hypothesis, gonads can be removed prenatally or at birth and the trait measured in adulthood. Alternatively, the action of gonadal hormones can be increased or decreased perinatally using drugs that block the hormonal action or mimic it. These methods have proven that prenatal and perinatal secretions of the testes cause permanent masculine development of external and internal genitalia and of specific brain regions. Alternatively, injecting testosterone into females, pre- or postnatally, has been shown to cause permanent masculinization of genitalia and brain (Arnold and Gorski, 1984; Jost, 1970; Morris et al., 2004). Further experiments then identify receptors that mediate the hormonal effect, cellular sites of hormone synthesis and action, and molecular pathways regulated by hormones to induce sex differences. Although gonadectomy and hormone therapy have been used since before the 20th century, they continue to be used because they are convenient and informative. Other approaches include blocking hormone action with drugs that block hormonal receptors or inhibit gonadal hormone synthesis. Hormone action is also studied with whole-animal or conditional knockouts of genes required for hormone synthesis, or of receptors mediating hormone actions on cells. For example, the Cre-lox system allows fine control of genes encoding receptors or synthetic enzymes required for sex steroid hormone action (Kim et al., 2018). Depending on the promoter used to activate the Cre recombinase, these genes can be turned off in specific molecularly defined 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 7 action (Shah et al., 2004; Wu et al., 2009). These and other modern methods will continue to revolutionize the understanding of when and where gonadal hormones act to cause sex differences and the molecular mechanisms downstream of hormone action. An important caveat is that the discovery of potent gonadal hormone effects on tissues does not disprove the existence of sex chromosome effects that also contribute to sexual differentiation (Smith-Bouvier et al., 2008). Early evidence of sex differences due to sex chromosomes involved in vitro models (Beyer et al., 1991, 1992; Carruth et al., 2002), which are experimental systems involving biological molecules, cells, or microorganisms to test scientific hypotheses. These studies demonstrated the early development of mesencephalic cells reflected a sex difference induced by sex chromosome complement, not hormones. However, most sex chromosome effects are found in tissue systems that also show sex-biasing effects of gonadal hormones. The interaction of hormonal and sex chromosome effects in sexual differentiation has received little attention. Future studies in animals will help define the nature of these interactions, 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 either XX or XY. However, because the sex chromosomes typically determine the type of gonad and patterns of gonadal secretions, which themselves cause profound phenotypic sex differences, it is important to compare XX and XY animals while keeping gonadal hormones as constant as possible, 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 ovaries develop 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 with ovarian hormones. Inserting an Sry transgene (a gene added to the genome by molecular genetic methods) into an autosome causes testes formation and allows the comparison of XY–(Sry+) and XX(Sry+) mice, contrasting the effects of XX versus XY in two groups with testes. The FCG model answers three questions. Do XX and XY tissues (an effect of sex chromosomes differ in mice that have the same type of? Is there an effect of gonadal hormones, measured in both XX and in XY mice? Is there an interaction of the effects of sex chromosomes and gonadal hormones on phenotypes, such that one type of factor influences the effect of the other type? Thus, the FCG model provides a good first step to detect cell-autonomous sex chromosome effects in nongonadal tissues. It allows classification of any sex difference as induced hormonally versus sex chromosomally, which is critical in choosing experimental strategies for uncovering cellular and molecular mechanisms causing any sex difference (Arnold, 2020, 2022). If a sex chromosome effect is discovered using FCG mice (inequality of XX and XY mice with the same type of gonad), the XY* mouse model can replicate the effect in animals lacking 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 manner with the X chromosome during meiosis in an XY* gonadal male, producing several different types of progeny with different numbers of X and Y chromosomes. The XY* model compares four 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 numbers of 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 WOMEN phenotype is altered by presence/absence of the Y chromosome. The Y effect could be caused by Y genes within nongonadal cells or because Y-bearing mice have testes in this model (Burgoyne and Arnold, 2016). The FCG and XY* models have been used in dozens of studies to demonstrate that the sex chromosome complement—the specific XX or XY pairing—contributes to sex differences in a wide variety of tissues and disease models, including brain and behavior, autoimmune diseases, Alzheimer disease (AD), metabolic diseases, neural tube closure defects, bladder cancer, and cardiovascular disease (CVD), including ischemia-reperfusion injury, stroke, hypertension, and atherosclerosis (Arnold, 2020). Most sex chromosome effects discovered using these models have been attributed to X chromosome genes (Arnold, 2022). In one case, however, a protective Y chromosome gene was found to explain a female preponderance of experimental pulmonary hypertension in a mouse model (Cunningham et al., 2022). Various studies have suggested that some classes of X genes are more likely than others to cause sex differences in disease models, including genes that escape X inactivation or have an ancestral homolog on the Y chromosome (Arnold, 2022). The mouse models discussed so far allow discovery of physiological and disease phenotypes in which a sex difference is attributed to sex chromosome effects, gonadal hormone effects, or their interaction. If sex chromosome complement is implicated as a cause of sex differences in disease, further research identifies the X or Y genes responsible and the downstream molecular mechanisms. Use of the FCG and XY* mouse models has uncovered contributions of sex chromosome effects on sex differences in behavior and disease that are unaffected by the influence of gonadal hormones; however, biological processes are usually influenced by both (Arnold, 2020). Examples of sex chromosome effects on phenotype involve Kdm6a and Kdm5c, two X chromosome genes encoding histone demethylases that escape X inactivation and are therefore expressed at higher levels in XX cells than in XY cells. Kdm6a has been linked to sex differences in mouse models of multiple sclerosis, AD, CVD, and cancer, and Kdm5c 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 regulate differently in females and males is a strategy for defining unknown gene pathways accounting for factors influencing women more than men that represent potential targets for therapy to alleviate disease in all individuals. Translation to humans will most likely occur after the proximal gene pathways affecting disease have been studied, because regulatory pathways in animals and humans overlap. For example, some sex chromosome genes are conserved in mammals, 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? Analyses of sex differences in the transcriptome in various organs suggest that a large majority of sex differences 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 brain discovered 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 the effects of sex chromosomes or gonadal hormones vary as a function of disease or other environmental variables (Arnold, 2022), the relative importance of each may be difficult to measure in any one study. PREPUBLICATION COPY: UNCORRECTED PROOFS 

WHY WOMEN DEVELOP CHRONIC CONDITIONS DIFFERENTLY THAN MEN 9 Which X and Y Genes Cause Differences Within XX and XY Cells The X and Y chromosome are an ancient autosomal pair that diverged when the developing Y chromosome evolved a testis-determining gene, SRY (Graves, 2006; Hughes and Page, 2016). They began to diverge in their deoxyribonucleic acid (DNA) sequences and ceased to recombine along most of their length. The Y chromosome lost virtually all of its ancestral genes (Bachtrog, 2013; Bellott et al., 2014; Charlesworth and Charlesworth, 2000). The genes remaining on the present-day X and Y chromosomes are specialized (Graves, 2006). Differences in effects of XX and XY somatic cells are due to effects of Y genes that are not mimicked by the second 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 to garner information about their evolution (Bellott and Page, 2021; Naqvi et al., 2019). The sex chromosomes 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 and brings 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 expressed higher at the messenger RNA (mRNA) level in females than males, which focuses attention on these genes as possible agents that cause sex differences (Tukiainen et al., 2017). However, the genome-wide downstream transcriptional effects of a second (inactive) X chromosome in human XX cells in vitro are similar to the genes regulated by the Y chromosome in XY cells, suggesting further selection pressures that operated to balance function of XX and XY cells (San Roman et al., 2024). As an example, a second sex chromosome of either type prevents the lethality caused by 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 comparing the effect of each to the effects of genes on the other sex chromosome. Thousands of genes are expressed 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 in physiology and many diseases (Oliva et al., 2020; Yang et al., 2006). Significant additional research is required to uncover the cellular mechanisms leading to sex differences in chronic conditions. Genome-Wide Assessments of Sex Differences in Gene Expression Patterns and Networks Systems genetics approaches have been developed to analyze the complex interactions of many genes and gene products that work in combination to produce sex differences in human and 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 to construct gene networks and correlate genetic variation at specific locations in the genome with variation in physiological or disease traits of interest. Investigators use diverse quantitative methods to integrate mechanistic information and make inferences about gene regulatory mechanisms and how they differ in the two sexes. These methods can be applied to humans and model organisms, with greater control available in laboratory animals to manipulate the environment (diet, disease, etc.) to understand the genetic architecture (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 WOMEN manipulating one gene or hormone at a time, systems approaches have the advantage of examining variation across the entire genome in large datasets, enabling unbiased detection of genes and networks of interest in which genetic variation is associated with sex-specific variation in a trait. Combining systems and reductionist approaches in animal models is particularly powerful for uncovering and proving novel genetic regulatory mechanisms that cause sex differences 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 the Genotype Tissue Expression project showed that 37 percent of all genes showed sex differences in expression in at least one tissue (Oliva et al., 2020). This is no doubt an underestimate because tissue 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 expression of individual genes—the impressive number of genes influenced by sex suggests a large aggregate influence on many gene regulatory pathways. By integrating quantitative trait loci— genetic regions showing variation that correlate with variation in important clinical or gene expression traits—studies using gene expression patterns have identified dozens of sex-specific associations between genes and traits. The result of this analytical approach forms the foundation for many studies to determine which genes are most effective as causal agents in conditions affecting women specifically and which gene products might be targets of. Investigators have applied similar systems analyses in specific tissues or diseases to uncover genes important in sex differences 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 approaches will 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 relative hormonal quiescence during pre- and postnatal life until puberty, when menstrual cycles begin. During the typical reproductive, the ovarian steroid hormones, estrogens, androgens, and progesterone, influence the incidence, severity, and clinical presentation of certain chronic conditions affecting women. These effects arise from the fluctuations in hormonal levels and the neuroendocrine feedback mechanisms involved in menstrual cycles and perimenopause and the eventual end of ovarian function with menopause. Non-steroidal ovarian hormones play an important role in exerting systemic effects throughout the life-span and may contribute to susceptibilities of women to chronic conditions. Anti-Mullerian hormone (AMH), which belongs to the transforming growth factor-beta protein family and is secreted by ovarian follicles is known to play important functions in sexual differentiation during fetal development. While known as a surrogate marker of ovarian reserve (Lambrinoudaki et al., 2020), low circulating levels 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 in female primates (Appt et al., 2012). Another non-steroidal ovarian hormone, relaxin-2, secreted by 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). How the 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, and menopause as three windows of vulnerability. High testosterone and estradiol and low sex hormone–binding globulin levels are associated with conditions characterized by low-grade inflammation including insulin resistance and diabetes (Horstman et al., 2012). Thus, age-related changes in sex hormones contribute to the development of a proinflammatory state which may affect many chronic conditions (Horstman et al., 2012). Estrogen receptors (ERs) such as ERα and ERβ, and G-protein coupled estrogen receptor 2, are distributed ubiquitously throughout the body in many cells and tissues and involved in complex physiologic mechanisms in women (Paterni et al., 2014; Prossnitz and Barton, 2023), and estrogens play a key role in women across the life-span. They influence many organ systems, including the musculoskeletal and cardiovascular systems and the urinary tract, reproductive tract, brain, hair, and skin, and the reduction in estrogen hormones at menopause affects various cells and tissues (Wend et al., 2012). Estrogens play a key role across the life course: 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 because the 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 predisposition and the various stressors and environments throughout the life-span. Genetic mutations account for 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 multiplicative effects that ultimately lead to one or more chronic conditions. The field of epigenetics offers a biochemical mechanism to explain how social and other environmental variables (e.g., toxins) can influence the readout of the genome and thus disease incidence and progression. Classical genetics points to the DNA sequence of genes and their alleles, 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, sex chromosome genes) and environmental factors can also modify DNA, by altering not its DNA sequence 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 long and 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 them more or less available to a host of signaling molecules such as transcription factors that increase or decrease expression of specific genes. Environmental events can cause changes in DNA methylation 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 et al., 1997). PREPUBLICATION COPY: UNCORRECTED PROOFS 

12 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN generations. Although this causal link between environmental events and activity of biological pathways could explain the influence of social and other environmental events on incidence and progression of diseases, the field of epigenetics is in its infancy. More research is needed to understand how specific environmental experiences affect specific biological pathways. Moreover, agents that modify histones are sometimes sex biased (Arnold, 2022; Kundakovic and Tickerhoof, 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: modifiers of 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 varied exposures 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 the health 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 in women. PREPUBLICATION COPY: UNCORRECTED PROOFS 

14 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN An important consideration is intersectionality, or how an individual’s experiences combine, interact, and are shaped by their multiple identities and therefore influence their health (Cooper, 2016; Crenshaw, 1994). Intersectionality, developed by Kimberlé Crenshaw, is a theoretical framework to describe how multiple social identities—including race, ethnicity, gender identity, sexual orientation, socioeconomic status, age, and disability—intersect at micro levels of an individual’s experience to represent various interlocking systems of oppression and privilege 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 the micro level, including race, gender, socioeconomic status, and sexual orientation, are not independent but intersect and create complex pathways to health inequities (Bowleg, 2012). Social and Cultural Identities Gender Identity A 2022 National Academies report defined gender as “a multidimensional construct that links gender identity, gender expression, and social and cultural expectations about status, characteristics, and behavior that are associated with sex traits” (NASEM, 2022). Gender is further conceptualized to characterize one’s identity, which is a core element of one’s individual sense of self. Gender identities include but are not exclusive to, transgender, in which a person’s current gender identity is different from the sex they were assigned at birth; cisgender, in which a person whose current gender identity corresponds to the sex they were assigned at birth, and nonbinary, 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 through associated behaviors and societal expectations. Even before birth, they are exposed to gendered cultural norms and roles that hold together the gender system (Heise et al., 2019). Sexism, which is based on gender, is linked to social determinants of health (SDOH), such as educational attainment, occupation, and socioeconomic status. Inequities in the SDOH contribute to conditions that promote poor health (Fleming and Agnew-Brune, 2015). One example is unpaid caregiving (emotional, instrumental, and informational support or care) (Maragh-Bass et al., 2021). This disproportionately falls on women, who care for family members, including children, spouses, parents, and older relatives. This role often interferes with women’s ability to care for themselves, leading to delays in seeking care or not receiving care at all (Maragh-Bass et al., 2021). Caregiving can also impact women’s health behaviors and increase stress. Studies have shown that women caregivers had higher rates of depression and anxiety and lower levels of well-being and were less likely to engage in health behaviors, such as physical activity (Bauer and Sousa-Poza, 2015; Zan and Shin, 2022). Some evidence shows that women, especially racially and ethnically minoritized women such as Black and African American women, experience a greater disparity from unpaid caregiving for family members living with chronic conditions (Maragh-Bass et al., 2021). Conforming to or challenging gender norms have implications for behaviors associated with health outcomes. For example, female gender norms associated with thinness and body PREPUBLICATION COPY: UNCORRECTED PROOFS 

WHY WOMEN DEVELOP CHRONIC CONDITIONS DIFFERENTLY THAN MEN 15 image may have implications for diet and physical activity. Challenging gender norms can influence 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 the pattern of emotional attraction to others (the same gender, a different gender, or multiple genders). Sexual orientation identities include heterosexual, gay, lesbian, bisexual, queer, pansexual, and two-spirit (NASEM, 2022). Sexual minority populations experience greater health disparities than their cisgender heterosexual counterparts because of stigma, discrimination, and stress (NASEM, 2020). These external influences are particularly amplified given the increased legislative pressures placed on gender-affirming therapy and other policies restricting free expression. Research has shown that sexual and gender minority populations have varying odds of various chronic conditions compared to nonminority groups (Tran et al., 2023), which may be the 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 lesbian were more likely to report moderate psychological distress, poor or fair health, multiple chronic conditions (MCC), heavy drinking, and heavy smoking compared to women who identified as heterosexual (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, severe psychological distress, heavy drinking, greater body mass index, and moderate smoking than heterosexual 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 to report mental health conditions, especially depression and postpartum depression. Stressors such as stigma associated with accessing sexual health resources can lead to undiagnosed or untreated HIV and other sexually transmitted infections in this population (Baptiste-Roberts et al., 2017). Sexual and gender minority populations also report unmet health care needs that contribute 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, which can lead to delays in accessing health care (Alencar Albuquerque et al., 2016; Baptiste-Roberts et al., 2017; Bowen et al., 2004; Diamant et al., 2000; Gonzales et al., 2016). A study with transgender women found that they, too, faced high risks of adverse mental health outcomes 3 because of experiences of stigma, and social and structural vulnerabilities, including food insecurity, 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 and race. Ancestry describes the biological makeup and line of descent, whereas race categorizes “populations into an arbitrary, hierarchical classification framework, largely based on phenotypic characteristics, such as skin color” (NASEM, 2023). Race is not a valid biological construct; it is a 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 the Kessler Psychological Distress Scale 6-item that assesses psychological distress, capturing DSM-5 anxiety and depressive symptom severity in the most recent 30 days. PREPUBLICATION COPY: UNCORRECTED PROOFS 

16 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN inequities within SDOH. Racism is driven by discriminatory, biased behavior at the interpersonal level and restrictive policies and practices at the societal level. The American Indian and Alaska Native population’s history is shaped by structural disadvantage and extermination, removal, and assimilation (Moss, 2019). American Indian and Alaska Native is a racial categorization but also distinct due to the “legally enforceable obligations and responsibilities of the federal government to provide certain services and benefits to 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 policies can 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 their White heterosexual counterparts, especially regarding chronic conditions; heart disease; diabetes; hypertension; cancer; mental health conditions; autoimmune diseases such as SLE; and substance use (Henning-Smith et al., 2019; Reid et al., 2023; Whitman et al., 2022). Inequities experienced 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 the distribution (or maldistribution) of the SDOH (e.g., housing, income, employment, exposure to environmental toxins, interpersonal discrimination) across and within social groups” (NASEM, 2023). The following section provides examples of how the structural determinants of health lead to health inequities in women. Sexism Beyond gender norms, evidence shows that sexism, which refers to systematic gender inequalities for women, leads to negative impacts on health, including a higher prevalence of chronic conditions (Dore et al., 2023). Structural sexism refers to institutional discrimination enacted by laws, policies, or rules (Krieger, 2014). Research on gender discrimination has explored women’s experiences of perceived discrimination and its link to mental and physical health (Homan, 2019). Research examining bias in the health care system, by both professionals and medical institutions, found that women are less likely to be diagnosed accurately or receive advance or multidisciplinary treatment (Hoffmann et al., 2022; Homan, 2019). Despite clear gender differences in health outcomes, epidemiological and health services research is significantly lacking on structural sexism and discriminatory gender structures that exist within the health care system and at other organizational levels. Most research focuses on interpersonal levels of discrimination and perceptions of treatment (Homan, 2019; Krieger, 2014). Structural sexism is discussed further in Chapter 7. Homophobia/Heterosexism Homophobia is “an irrational fear, prejudice, and hatred of gay individuals” (Weinberg, 1972). Significant evidence shows that exposure to verbal harassment, discrimination, and outright physical violence because of gender identity and sexual orientation can produce severe negative 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 17 women and gay are more likely to experience acts of discrimination; this is particularly true for racial and ethnically minoritized individuals. Homophobic acts lead to significant levels of stress that 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 that can increase the chance of developing chronic CVD and earlier death among women (Inoue et al., 2021). These acts of discrimination create increased stress and chronic inflammatory states leading 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 of chronic conditions. Although Black women are on average younger than the general U.S. female population, 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 and outside 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 subject Black women to high levels of racism, sexism, and discrimination not experienced by Black men or White women (Chinn et al., 2021). This phenomenon, known as “gendered racism,” has led to poorer reproductive and sexual health outcomes, including adverse pregnancy outcomes (Mehra et al., 2020; Miller et al., 2022). Black women also experience significant mental and physical health 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 and more socioeconomically disadvantaged neighborhoods (Anderson et al., 2023; Bailey et al., 2021; Bethea et al., 2016; NASEM, 2017). In the Black Women’s Health Study, neighborhood socioeconomic 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 social aspects, including reduced access to health care, increased exposure to crime and social disorder, residential segregation, higher psychosocial stress, and therefore a higher allostatic load (Bethea et al., 2016). Black and African American populations have not been well delineated in the literature. 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 may have higher levels of consanguinity, or recently immigrated from continental Africa. Each of these 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 in this 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 gender differences in chronic conditions (NIH, 2006) and found that Hispanic women experience a high prevalence, including of obesity, hypercholesterolemia, and hypertension, with greater inequities when the data are disaggregated by country of origin (Daviglus et al., 2012). Hispanic women reported higher levels of negative pregnancy outcomes, including preeclampsia and gestational diabetes (Gomez et al., 2022). Contributing factors included the effect of immigration and PREPUBLICATION COPY: UNCORRECTED PROOFS 

18 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN acculturation 4 on health and health care access (Paz and Massey, 2016). In general, greater acculturation has been associated with higher levels of obesity and poor dietary and physical activity behaviors in Latinas in epidemiological studies such as the Women’s Health Initiative and 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, and have 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 at later 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 aggregate group (Errisuriz et al., 2024). For example, some studies have found that Puerto Rican and Cuban women face greater mortality from ischemic heart disease than non-Latina and Mexican women and that Mexican women experience greater mortality from cerebrovascular disease than Cuban and Puerto Rican women (Errisuriz et al., 2024). Reported associations between acculturation and other cultural measures, such as ethnic enclaves, that are sometimes found to be protective are complex, and failing to disaggregate data may hinder research on understanding health outcomes in Latinas (Errisuriz et al., 2024). This can lead to generalized narratives that Latinas are healthier, even though they have lower income, education, and lack of access to other SDOH, and that needs to be examined critically (Errisuriz et al., 2024). Understanding the factors unique to American Indian and Alaska Native women living with chronic conditions is challenging given the lack of research. American Indian and Alaska Native people face violence, historical oppression, and trauma resulting from colonization (Burnette and Figley, 2016). Poor mental health outcomes are significant, with a higher rate of posttraumatic stress disorder (PTSD) and alcohol use disorder. American Indian and Alaska Native women are more likely to be exposed to trauma (e.g., intimate partner violence (IPV) and child 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 the development of chronic conditions in American Indian and Alaska Native people, the culturally relevant Framework of Historical Oppression, Resilience and Transcendence was developed (Burnette and Figley, 2016). American Indian and Alaska Native women experience a significant burden of chronic conditions, including severe morbidity and mortality, CVD, obesity, and diabetes (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 being associated 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 healthy behaviors and a higher risk of chronic conditions (Burnette et al., 2020). More research is needed to understand sex and gender differences in risk factors for chronic conditions among this population (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, and through 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 4 behaviors 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 19 The coronavirus disease 2019 pandemic exacerbated these experiences with the rise in xenophobia and anti-Asian hate (Le et al., 2020). A study measured Asian American women’s experiences of discrimination and found that 1 in 3 experienced discriminatory practices by their health care provider and that this was related to higher reporting of physical and mental health impairment (Do et al., 2023). More intersectional frameworks are needed to study chronic conditions in Asian American women. The Asian American population is heterogeneous, comprising 24 groups with various social and economic characteristics that affect health outcomes and development of chronic conditions. Most research on this population, however, has focused on six major groups (Yom and Lor, 2022). Knowledge gaps about the health of Asian American populations have persisted in part because of the problematic practice of aggregating the broad and diverse populations for research purposes (Waitzfelder et al., 2023). The majority of research on chronic conditions in Asian American women has focused on CVD, diabetes, metabolic syndrome; fewer studies have focused 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 White women (Holland et al., 2011). National data show that Filipino and Korean women had a higher prevalence 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 Asian American population, creating challenges in measuring the impact of chronic conditions for each group (Kanaya et al., 2022; Morey et al., 2022). Limited data on Native Hawaiian and Pacific Islander groups suggest they experience higher levels of heart disease, hypertension, and diabetes and difficulty maintaining a healthy body weight. Key factors contributing to these disparities in health 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 development of chronic conditions (Allen, 2016). Ageism refers to the “inequitable historic, cultural, institutional, political, and interpersonal conditions, structures, practices, and norms embedded within our society that routinely privilege some age groups, such as younger adults, while simultaneously disadvantaging other groups, including older adults” (Allen, 2016). Ageism is experienced during a portion of the life course and may lead to repeated exposure to chronic stressors which increase the progression of physical deterioration and associated chronic conditions (Allen, 2016). A nationally representative survey of U.S. adults between the ages of 50–80 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 both sex/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 older women, who live longer than men, and may face greater exposure to physical and sexual violence, 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 that influence the risk of developing and outcomes associated with chronic conditions go beyond individual biological and genetic factors and can be affected by the surroundings and environment. SDOH are fundamental factors that can influence susceptibility to chronic conditions 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 of chronic conditions, affect diagnosis, and exacerbate disease. They can affect molecular processes implicated in the biology of chronic disease development, but these mechanisms are poorly understood. However, some research has shown that stress-causing SDOH may promote inflammation—a major contributor to developing chronic conditions—and epigenetically alter gene regulation (Simons et al., 2016). The concept of transgenerational epigenetics demonstrates that changes in regulation of gene expression are passed on to subsequent generations and could account 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 (Cockerham et al., 2017; Vennu et al., 2020). According to the Office of Health Policy, SDOH affect as much as 50 percent of county-level variation in health outcomes, whereas clinical care affects only 20 percent (Whitman et al., 2022). Furthermore, national data show that unfavorable SDOH, such as unemployment, lower family income, food insecurity, low education, lack of private health insurance, and living alone, are associated with premature mortality and that this association was stronger 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 and quality; (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 role in contributing to women’s health inequities, including chronic conditions. At the individual level, lower socioeconomic status, including lower income, poverty, marital status, lack of access to health insurance, lower educational attainment, and interpersonal experiences of sexism, racism, and discrimination, are prevalent in and disadvantage women more, especially racially and ethnically minoritized women (CDC, 2023; Temkin et al., 2023). At the community level, poverty, neighborhood crime, exposure to pollutants and contaminants, and the physical and built environment can affect the development and management of chronic conditions and the ability to engage in actions associated with preventing them (Koehler et al., 2018). These community-level conditions can adversely affect the health and well-being of pregnant women and lead to adverse outcomes, such as preeclampsia (Girardi et al., 2023). Structural determinants of health affecting opportunities and life position that result in advantages or disadvantages, such as racism, sexism, and homophobia/heterosexism, influence individual-level SDOH, such as poverty, access to housing, income level, and access to education (Chetty, 2016; Emlet, 2016; Homan, 2019, 2021; Quiñones, 2019). Greater socioeconomic advantage can be protective. For example, a higher level of education is associated 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 21 The Neighborhood and Built Environment The neighborhood and built environment influences health behaviors that may prevent chronic 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 are diagnosed and living with chronic conditions. Much of the research on its effects on chronic conditions has focused on physical activity and recreational activities as a means of reducing morbidity and mortality from CVD and obesity (Sallis et al., 2012). Few studies have been conducted 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 daily destinations 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 and chronic conditions. Studies have shown that factors such as socioeconomic disadvantage and neighborhood deprivation have negative outcomes for health and chronic disease. For example, a population-based study in Minnesota found that an area deprivation index was more strongly associated with cardiovascular conditions in women versus men (Chamberlain et al., 2020, 2022). Rurality is another SDOH that requires attention. Rural populations are more likely than urban populations to have lower levels of education, employment, and economic status. They also 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—and therefore are more likely to experience chronic medical and mental health conditions than their urban counterparts (Cockerham et al., 2017; Havranek et al., 2015). These social factors may include 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 as heart 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, population health studies are needed to advance equitable awareness and treatment, including transportation to 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 significantly affected 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 on geographic location, and transportation serve as barriers to proper care for women living with chronic conditions. Women experience negative judgment, discrimination, and stigma in health care settings related to their sexual behavior and sexuality compared to men. Black women in particular have more negative health care interactions than White women; their reproductive desires 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 in poorly treated or untreated chronic conditions and progression to more severe symptoms that impact quality of life and morbidity in women. PREPUBLICATION COPY: UNCORRECTED PROOFS 

22 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Exposures and Resources Adverse Childhood Experiences Early adverse life events after birth, during childhood, and until adolescence can predispose individuals to higher risks for chronic conditions as adults. Adverse childhood experiences (ACEs) refer to exposure to childhood emotional, physical or sexual abuse, and household dysfunction and have been linked to higher mortality at younger ages and higher risks for 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 health conditions, including depression and other mood disorders, anxiety, SUD, PTSD, and chronic health 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 may experience 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 report childhood 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 in men (Haahr-Pedersen et al., 2020). One area of study has focused on the relationship between ACEs and gynecologic surgeries. Studies have found that women who underwent bilateral oophorectomy before age 46 were more likely to have experienced ACEs. These associations were stronger when the surgery was 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 of gynecologic pathology or symptoms among patients with ACEs or may cause them to experience gynecologic symptoms more severely, prompting them to choose a more definitive surgical treatment rather than more conservative strategies. Subjective differences in pain perception may also help explain the frequency of surgery among patients with ACEs who have no identified gynecologic pathology (Gazzuola Rocca et al., 2017b; Rocca et al., 2021). ACEs may cause stress-related epigenetic modification, endocrine dysregulation, or alteration of the immune response, 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 development of 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 that behavioral changes associated with early-life adversity were linked to increased microglial activation—a marker of inflammation in the brain—that reduced neurogenesis and proliferation of neural stem cells, and altered neuronal networks (Johnson and Kaffman, 2018; Waters and Gould, 2022). Clinical studies support this, showing that ACEs related to abuse, household dysfunction, parental absence, and poor parent–child relationships are associated with heightened inflammation in mid- and later life, with adults exhibiting higher levels of the inflammatory 5 Earlier ACEs studies have limitations, as the initial CDC and Kaiser epidemiological study was primarily conducted in White, insured, middle-class adults and other studies investigating ACES in women have been mainly based on certain geographical locations. PREPUBLICATION COPY: UNCORRECTED PROOFS 

WHY WOMEN DEVELOP CHRONIC CONDITIONS DIFFERENTLY THAN MEN 23 marker 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 chronic systemic 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 an elevated stress vulnerability during adulthood, which is most likely a secondary effect stemming from 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 involves molecular epigenetic mechanisms that regulate gene expression, such as DNA methylation or histone modifications. Epigenetic studies in animal models implicate several genes whose expression is altered in response to early-life adversity (SLC6A4 serotonin transporter NR3C1 and FKBP5 genes 6 involved in glucocorticoid activity) (Waters and Gould, 2022). One clinical study found an association between lower expression levels of a specific X chromosome-linked gene, 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-term detrimental effects of early-life stressors. Interestingly, other clinical studies have revealed that the response to or impact of ACEs depends on the individual’s inherent genetic susceptibility or receptivity to stress (Waters and Gould, 2022). These findings suggest that genetic susceptibility may influence health outcomes in adults who have experienced ACEs and that the development of 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, or is likely to result in, physical, sexual, or mental harm or suffering to women, including threats of such acts, coercion or arbitrary deprivation of liberty, whether occurring in public or in private life" (WHO, 2024). Violence against women includes IPV, which has been reported in over a third 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 conditions including 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 recent experiences of violence, including IPV, can significantly affect health. In the Nurses’ Health Study II, women who had recently experienced severe emotional abuse by an intimate partner had a 24 percent increased rate of hypertension (Mason et al., 2012). A community-based study on 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 a greater odds of menopausal symptoms in midlife and older women (Gibson et al., 2019). Older women are more likely to experience other forms of violence, including from other family members and caregivers, which may be related to their physical and mental health and living with chronic conditions (Meyer et al., 2020). Exposure to trauma and IPV are also discussed as factors that contribute to chronic conditions (see Chapters 5 and 6), intersect with structural and social 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 5 genes. PREPUBLICATION COPY: UNCORRECTED PROOFS 

24 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Coping Mechanisms and Resilience Coping and resilience are critical strategies women use to adapt, enhance positive outcomes, and grow from adversity (Bowling et al., 2019a). Resilience has been bound to the experience of stress and defined as “a dynamic process encompassing positive adaptation in the context of past or present adversity” (Luthar et al., 2000). It is a protective factor influenced by various internal and external factors (Bowling et al., 2019b). Key components include self- efficacy, hope, coping, competence capability, resistance, and adaptation (Woods-Giscombe et al., 2023). The inability to overcome adversity may be linked to women developing chronic conditions, and interventions to address resilience are needed for women living with chronic conditions (Kim et al., 2019; Kim et al., 2021). Inflammation Many chronic health conditions are related to chronic, prolonged inflammation. Research has shown that chronically elevated inflammation contributes directly to the pathophysiology of chronic conditions, such as CVD, Type II diabetes, osteoporosis, osteoarthritis, rheumatoid arthritis, 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 high circulating levels of a number of different cytokines, such as the interleukins (IL1, IL2, IL6, and IL17), 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 health conditions. Women often tend to have more associated stress leading to protracted states of inflammation that cause chronic conditions that are different from men (Liu et al., 2017). SDOH, such as social disadvantage, socioeconomic status, racism, sexism, and homophobia, produce chronic stress and influence health by increasing inflammation via several biological pathways. Exposure to chronic stress and the resulting inflammation negatively affect multiple organ systems via neuroendocrine, developmental, immunologic, and vascular mechanisms that might damage key physiologic systems and can lead to more rapid onset or progression of chronic conditions (Notterman and Mitchell, 2015; Simons et al., 2021). Researchers have proposed that social environments that pose a persistent threat of hostility, denigration, and disrespect promote chronically high levels of inflammation. The association of adverse consequences that women experience differently than men related to social and structural determinants of health, gender and sex discrimination, homophobia, 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 our biology—that is, how daily interactions with our social and physical environments ‘get under our skin’ to affect our physical, psychological, and emotional well-being by altering how our body functions” (Krieger, 2001). Allostatic load is understood as the physical embodiment of repeated or chronic exposure to stress-inducing social and living conditions over time and a physiologic expression of weathering (Petteway et al., 2019). Studies on neighborhood context (e.g., poverty, deprivation, violence, disorder, cohesion) have explored whether these factors are related to greater 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 other stressful 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 of health 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 includes the interactions with their care team (including health care facility staff), care administration, and the complexity of their insurance. One conceptual framework of the patient experience considers three perspectives: person, patient, and user (Oben, 2020). Studying it fully requires considering all 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 chronic condition—influences their health and clinical interactions (Venechuk et al., 2023). Although trust is frequently cited as critical to the patient–physician relationship (Murray and McCrone, 2015), literature is growing on the dismissal and minimization of women’s pain and symptoms. This not only erodes trust in the health care setting and the specific providers but can lead to misdiagnosis, missed diagnosis, and poorer outcomes because of deferring or being denied appropriate care. A recent cohort study indicated that diagnostic error is the greatest source of medical-error-related death across care settings, and this may be pronounced in women and various racial and ethnic groups (Newman-Toker et al., 2024). The invalidation of women’s experiences can be traced back to the diagnosis of hysteria, an exclusively female disease of unknown origins presenting with a wide range of manifestations. Although it was dismissed as a valid psychological condition in the 1980s (Tasca et al., 2012), ongoing first-person accounts and the scientific literature report sex- and gender-based discrepancy in care arising from the invalidation of women's experiences and symptoms. Qualitative studies have highlighted the pervasiveness of communicative disenfranchisement (Thompson et al., 2023; Venechuk et al., 2023), described as “the process by which 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 as ways providers invalidated women’s concerns (Venechuk et al., 2023). Relatedly, medical gaslighting, where providers dismiss or trivialize symptoms or health concerns, leading patients PREPUBLICATION COPY: UNCORRECTED PROOFS 

26 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN to doubt their own experiences or believe their conditions are imagined rather than real, may extend 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 health care system, but delayed diagnosis and treatment (Au et al., 2022). SUMMARY Separating the effects of biology (sex) and social environment (gender) is difficult. Some studies fail to discriminate between the two, promoting a long-standing tradition of confusing the causal origins of sex and gender differences. Many study classifications of sex and gender groups 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 traits across 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 that differ primarily on some biological variable, such as genetic or hormonal, to ask if physiology or disease is correlated with it. Similarly, it is possible to compare groups that differ along an important social continuum, such as race or socioeconomic status, to determine whether those variables correlate with disease. In many studies, however, the biological and social factors may covary, making it difficult to make precise conclusions about causality. For example, groups differing in socioeconomic level may also differ in their underlying biology. Similarly, groups differing in biology, such as expression of different alleles, may not be represented equally in different environmental situations (for example, if having a specific allele places the individual in a different environment), making it difficult to determine which factor causes group differences. Nevertheless, studies of both biological and social variables are critically important to provide basic understanding of the possible variables influencing health and access to medical care. Animal research continues to provide a critical perspective on biological factors that influence women and men differently; the ability to manipulate only one such factor at time offers unparalleled analytical power to understand how each one influences physiology or disease. Concepts developed in animal studies shape hypotheses to be tested in research on human conditions. Making progress and understanding the landscape of structural and social determinants of health and their effect on chronic conditions in women requires a wealth of data across multiple levels to account for individual- and community-level factors, the complex interplay between a person and their community, the effects of policies and opportunities, and the onset of disease over 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 various chronic conditions in women. Many studies do not properly examine these factors, and despite increased use of neighborhood-level data for examining such associations, many are not investigated in racially, ethnically, and sexually diverse groups. Most studies have also been cross sectional, and more longitudinal studies are needed to examine causal associations, especially to understand the mechanisms that would explain why these social factors increase susceptibility to developing chronic conditions in women from various racial and ethnic backgrounds. Research is lacking on how gender differences exist in the relationship between the built environment and lifestyle behavioral factors associated with chronic conditions. Data disaggregation is lacking, which has further masked disparities in racial and ethnic groups. PREPUBLICATION COPY: UNCORRECTED PROOFS 

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