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Studying Sex Differences in Health and Disease

In the first session of the workshop, experts from four academic institutions and the National Institutes of Health (NIH) discussed the public health importance of studying sex differences in the nervous system, particularly the potential application of a stronger understanding of these differences to healthcare delivery. Participants discussed the design of preclinical experiments and clinical studies, and the need to bridge between them. Knowing when sex differences should be considered is as important as knowing when they should not.

SCIENTIFIC PRINCIPLES FOR STUDYING SEX DIFFERENCES IN HEALTH AND DISEASE

Arthur Arnold, professor and chair of the Department of Physiological Science at the University of California–Los Angeles, stressed that basic science is the foundation for translation of knowledge about sex differences into clinical practice. Sex differences exist in the susceptibility to and progression of diseases. Identifying the sex-specific factors that protect one sex from a particular disease can guide development of therapies to protect both sexes from the disease.

Why Compare the Sexes?

A physician does not treat a sex difference, but rather treats one patient at a time, male or female. So why not simply study what works in each sex? Because knowledge of the physiology of one sex can provide fresh



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2 Studying Sex Differences in Health and Disease In the first session of the workshop, experts from four academic insti- tutions and the National Institutes of Health (NIH) discussed the public health importance of studying sex differences in the nervous system, par- ticularly the potential application of a stronger understanding of these differences to healthcare delivery. Participants discussed the design of pre- clinical experiments and clinical studies, and the need to bridge between them. Knowing when sex differences should be considered is as important as knowing when they should not. SCIENTIFIC PRINCIPLES FOR STuDyING SEx DIFFERENCES IN HEALTH AND DISEASE Arthur Arnold, professor and chair of the Department of Physiologi- cal Science at the University of California–Los Angeles, stressed that basic science is the foundation for translation of knowledge about sex differ- ences into clinical practice. Sex differences exist in the susceptibility to and progression of diseases. Identifying the sex-specific factors that protect one sex from a particular disease can guide development of therapies to protect both sexes from the disease. Why Compare the Sexes? A physician does not treat a sex difference, but rather treats one patient at a time, male or female. So why not simply study what works in each sex? Because knowledge of the physiology of one sex can provide fresh 

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 SEX DIFFERENCES AND IMPLICATIONS perspective on the physiology of the other sex, Arnold said. One example of how studying sex differences can provide a new perspective is differential susceptibility. In humans, males die at a greater rate at every life stage than females, except at the oldest ages. This comparison leads to the question of how to lower mortality of males to match that of females. What protective factors exist in females that could be used to lower male mortality? Without comparison of the sexes, this question would not occur. Another example is X-inactivation, a female-specific physiological pro- cess. Females inherit two copies of every gene on the X chromosome while males inherit only one copy of the X chromosome in addition to the Y chromosome. For normal female development to occur one X chromosome must be inactivated resulting in equivalent X chromosome gene product levels between males and females. This mechanism of dosage compensa- tion (X-inactivation) can be understood through direct comparison between male and female gene product levels. Investigators often only study sex-specific factors in one sex. Although this approach provides helpful information, it is also important to compare identical treatments in males and females to determine if responses are similar or different. Our Evolving understanding of Sex Differentiation Ten years have passed since the publication of the Institute of Medicine (IOM) report on sex and gender differences in health, Arnold reminded participants (IOM, 2001). During that time, there has been a shift in the conceptual framework for explaining the proximate signals that cause sex differences, and increased consideration of the concept of compensation (the notion that some sex-specific factors make the sexes more equal, e.g., X-inactivation). According to the traditional model for the physiologic basis of sex dif- ferences, the Sry gene on the Y chromosome causes testes to develop; and testicular secretions, such as testosterone, influence masculine body and brain development. In the absence of Sry, ovaries develop, testosterone is lacking, and a feminine body and brain develop. There are two major classes of gonadal hormone action. Organizational (differentiating) effects are permanent, such as the testosterone-induced irreversible commitment of a tissue to a masculine rather than a feminine phenotype. Organizational effects impact external and internal genitals, and brain circuits. Actiational effects are reversible; the resulting sex differences in traits are caused by differences in secretion of sex steroids at the time of measurement and can be abolished by gonadectomy in adulthood. Most sex differences, Arnold said, might actually be caused by acti- vational effects. He cited a microarray study of sexually dimorphic gene

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 STuDYING SEX DIFFERENCES IN HEALTH AND DISEASE expression in mouse livers that found that expression of about 2,600 genes were sex biased in mice with gonads, but only 12 genes remained sex biased after gonadectomy (van Nas et al., 2009). Most genes therefore appear to be sexually differentiated or sexually dimorphic because of the action of hormones in adulthood. All sex differences result from the imbalance of X and Y genes. These are the only genes in the fertilized egg cell and the zygote that are not sexu- ally dimorphic. As noted above, gonadal asymmetry and gonadal hormone secretion as a result of Sry action in males leads to organizational and acti- vational effects of hormones. Over the past decade, however, new evidence has emerged that sex chromosome genes act in non-gonadal tissues to cause sex differences in traits and disease. These non-hormonal actions lead to what are called sex chromosome effects. Arnold presented the “unified model” of sex differentiation, outlining these three classes of proximate factors causing sex differences in phenotype (Figure 2-1). Some of these sex chromosome effects can be quite significant. To study these effects, researchers have developed a “four-core genotypes” mouse model in which the gene determining gonadal sex (Sry) was spontaneously deleted from the Y chromosome and through transgenic technology inserted into an autosome, so that the gonadal sex of the animal is no longer related to the chromosome complement. XX and XY no longer effect the gonads the animal develops, and four core genotypes result: XY gonadal males, XX XY vs. XX Genetic level: All sex differences result from X and Y imbalance Gonadal Non-gonadal Sry in male Unequal expression of X and Y genes including Sry Hormonal Hormonal “Sex “Activational Chromosome “Organizational Effects” Effects” Effects” Three classes of proximate factors causing sex differences in phenotype FIGuRE 2-1 The unified model of sex differentiation. Sex Diff fig 2-1.eps SOURCE: Arnold (2009).

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 SEX DIFFERENCES AND IMPLICATIONS gonadal males, XX gonadal females, and XY gonadal females. This allows for separation of the sex chromosome and gonadal hormone effects. One example of direct sex chromosome effects demonstrated using this model is that XX mice show a faster response to thermal nociceptive stimuli than XY mice, regardless of their gonadal sex. Another study sug- gests that the number of X chromosomes influences susceptibility to neural tube closure defects in a mouse model. Still other studies have shown that the sex chromosome complement contributes to sex differences in a mouse model of multiple sclerosis. The Sry gene itself is expressed in the brain, in the substania nigra, and influences the control of movement. As this gene is on the Y chromosome and only found in males, this effect can only be male specific. Sometimes males and females express a similar phenotype because of different processes within the sexes. These sex-specific mechanisms cancel each other out and make the sexes more similar, such as X-inactivation. To understand the differences between males and females, we also have to understand that some of the similarities are actually based on differences that cancel out, Arnold said. Clinical Implications of Hormonal versus Sex Chromosomal Differences In the search for factors in one sex that protect that sex from a disease, it is critical to understand whether the sex difference is caused by organi- zational, activational, or direct sex chromosome effects. Therapies directed toward genes will be different from therapies directed toward hormonal effect. If the difference is a genetic effect of X and Y genes, the gene needs to be identified and the mechanism of action targeted. If the sex-specific protection is caused by hormones, then therapies need to be targeted to- ward hormone-driven molecular pathways. Next Steps Although progress has been made, not only in the past 10 years but over the past 60 years, most animal models of disease-related phenotypes remain poorly studied with regard to sex differences. It is important to understand which of the three factors—organizational, activational, or direct chromosome effects—are important in causing observed sex dif - ferences. Animal studies are quite important because in humans, of those three factors, researchers can only ethically address activational effects by manipulation of gonadal hormones in adults. There are relatively few hu- man models in which one can observe organizational effects of hormones, and almost no models in which one can separate the direct sex chromosome effects from endocrine effects.

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 STuDYING SEX DIFFERENCES IN HEALTH AND DISEASE To facilitate translation, more preclinical studies are needed to under- stand the basic biology of sex differences. For example, identify in animal models the X chromosome genes that cause sex differences, and then hy- pothesize studies in humans to see if those same X genes have an association with disease phenotypes. Arnold also stressed the importance of educating both scientific grant program review staff and researchers about the importance of sex differ- ences and how to study sex differences. STuDyING SEx DIFFERENCES IN DRuG RESPONSE Jeffrey Mogil, E. P. Taylor Chair in Pain Studies at McGill University, used pain and analgesia as a case example to illustrate when, how, and why sex differences in drug response should be studied. Even if one is not specifi- cally studying sex differences, Mogil said, both sexes should be included in basic science experiments from the beginning. Adding to Arnold’s review of how sex differences should be considered, Mogil referred participants to a consensus report for sex differences research specific to the domain of pain and analgesia (Greenspan et al., 2007). Why Study Sex Differences? One reason to study sex differences is that they are an important and known factor contributing to individual differences. Assessing pain in more than 8,000 mice using the tail-withdrawal test, researchers found an overall 0.4-second difference in tail withdrawal latency between males and females. The data could be thought of in one of two ways, Mogil said. One could be impressed by the nearly half-second difference in the overall range of about 8 seconds as explained by sex differences. A second way would be to attribute the difference to genetics and be unimpressed. Genes are certainly responsible for much of this observed difference, but which genes these are is still unknown. Instead, questions can be addressed within the context of explaining individual differences because the two variants (male and female) are known and there are methods to study them. Another reason to study sex differences is that for many disease states, including pain, there is a sex difference in prevalence. Many common pain- ful disorders are more prevalent in females than in males (Berkley, 1997). However, this epidemiological difference has not been fully utilized by basic scientists when experimental protocols are designed, Mogil said. As a consequence the biological underpinnings of this difference are not en- tirely known. Reviewing reports of rodent animal model studies published in the journal PAIN over a 10-year period, Mogil found that 79 percent of all papers used male subjects only (Mogil and Chanda, 2005). Another

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0 SEX DIFFERENCES AND IMPLICATIONS 5 percent of them used both male and female animals, but did not discuss whether there was a sex difference (presumably because no sex-based analysis was done). An additional 3 percent simply did not report the sex of the subjects (which likely means they were male). In total, 87 percent of these studies simply ignored sex differences, he said. A few pain research- ers specifically study sex differences, but most in the pain field are not contributing to knowledge about sex differences at all because they only study male animals. One reason for the lack of studies in female animals is the misconcep- tion that data from female mice are more variable than data from male mice. The variability is the same in males and females, and this is an empiri- cal fact, Mogil said (Mogil and Chanda, 2005). Females do have an estrus cycle that adds a source of variability that males do not have. But there are male-specific sources of variability as well, such as dominance hierarchies and fighting among males. Sex Differences in Pain Sensitivity Sex differences in sensitivity to pain are not always reported in studies, but when they are, they almost always show that females are more sensitive to and less tolerant of pain, and better able to discriminate among different levels of pain (although the magnitude of the difference depends on the type of pain). In addition to these differences in sensitivity, there are important differences in pain processing mechanisms. One evidence-based example is the male-specific involvement of the N-methyl-d-aspartate (NMDA) receptor and the apparently analogous female-specific involvement of the melanocortin-1 receptor (MC1R) in pain and analgesia. MC1R is involved in regulating skin and hair pigmenta- tion. Mogil and colleagues (2003) compared female and male redheads to brunettes and found a female-specific genetic effect associated with kappa- opioid (pentazocine) analgesia. The same sexual dimorphism has recently been demonstrated in mice for opioid hyperalgesia (Juni et al., 2010). After chronic opioid treatments, instead of producing analgesia, morphine and other opiates start to produce hyperalgesia that can actually make chronic pain worse in both sexes, Mogil explained. However, in mice lacking a functional MC1R (essentially redhead mice), nothing changed in males while females experienced analgesia, but not hyperalgesia, suggesting that hyperalgesia in female mice was due to MC1R. The Impact of Sex Differences in Pain Treatment Dextromethorphan, the active ingredient in cough medicine and an NMDA receptor antagonist, potentiates morphine analgesia at low doses,

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 STuDYING SEX DIFFERENCES IN HEALTH AND DISEASE and attenuates it at high doses. To capitalize on this effect, a Phase II clini- cal trial of a drug called MorphiDex, a 1:1 combination of morphine and dextromethorphan, was conducted, but was an undeniable failure, Mogil said. As it turns out, the interaction between morphine and dextrometh- orphan cannot be demonstrated in females, at any dose of morphine or dex- tromethorphan. This information was unknown until this clinical trial was conducted because not one of the nearly 100 animal studies conducted over the prior 10 years had included females. In a subsequent conversation with the drug developer, Mogil was told that while women were included in the study, they did not analyze the clinical trial data by sex and did not intend to as they had become focused on other priorities. Mogil postulated that it is possible this clinical trial in humans failed because the drug worked in men, but not in women, and the results cancelled each other out. As a result, a drug that might have potential use for men will not be developed further. As another example, the Toll-like receptor 4 (TLR4) is involved in neuropathic pain development. Male C3H/HeJ mice without functional TLR4 receptors have reduced mechanical allodynia, which is a symptom of chronic pain, but females have normal mechanical allodynia. Current stud- ies suggest that the role of TLR4 in pain is, in fact, entirely male specific. This will be very important to elucidate as TLR4 antagonism is currently of great interest in analgesic drug development. STuDyING SEx DIFFERENCES IN DISEASE SuSCEPTIBILITy Kathryn Sandberg, director of the Center for Study of Sex Differences at Georgetown University Medical Center, discussed when and how sex differ- ences in disease susceptibility should be studied (summarized in Box 2-1). When to Study Sex Differences An obvious situation in which sex differences should be studied is when there is a difference in anatomy, Sandberg said. Even though there are no disparities in general intelligence, when differences in brain size are taken into account, women have ten times more white matter while men have almost 7 times more gray matter as related to intellectual skill. This sug- gests a significant sex difference where intelligence is manifested. Because function often follows structure, these sex differences in neuroanatomy need to be understood. Better understanding of known sex differences in nervous system physi- ology may improve care after injury. For example, functional magnetic resonance imaging conducted while participants listened to a book being read aloud showed that in women, both sides of the brain were active, while in men, only one side was active. Both were listening, but through different

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 SEX DIFFERENCES AND IMPLICATIONS BOX 2-1 When and How to Study Sex Differences Study the impact of sex differences when they exist in • Anatomy • Physiology • Incidence and age of disease onset • Symptoms impacting diagnosis of disease • Disease severity, progression, and outcome • Response to treatment Study sex differences across the lifespan by expanding the number of experimen- tal models that can address • Aging • Disease susceptibility • Sex chromosome dosage NOTE: This box summarizes remarks made by workshop participants. physiological mechanisms. Other studies show that men and women use different mechanisms to navigate; women rely more on landmarks whereas men prefer compass directions. Furthermore, while men use both the right and left hippocampi when navigating, women only use the right hippocam- pus. Instead of using the left, women invoke the aid of the right prefrontal cortex. The disease implications of these functional brain differences are significant. It is easy to see how a stroke in a sexually differentiated brain region could result in very different outcomes for each sex. Differences in disease prevalence or age of disease onset are another in- stance when sex differences should be studied, Sandberg said. Using stroke as an example again, males have a higher incidence of stroke across much of their lifespan; however, after age 80, women have a higher incidence of stroke. A better understanding of what makes men in their 40s more sus- ceptible to stroke while women are protected may lead to better therapies or preventive measures for both sexes. Studying sex differences may provide an important health benefit when there sex-specific symptoms. The commonly known symptoms of stroke, for example, include sudden numbness of one side of the body (face, arm, or leg), difficulty speaking or understanding, inability to see out of one or both eyes, difficulty walking including dizziness or loss of balance, and a severe headache. But these symptoms do not present equally in males and females. Women have less loss of balance and coordination, and more

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 STuDYING SEX DIFFERENCES IN HEALTH AND DISEASE changes in mental status (confusion, unconsciousness) than men. Women also have more nausea and heart attack-like symptoms, and tend to present with more severe headaches. These symptoms are not unique to women, Sandberg clarified, but they are experienced more often by women than men. These sex differences have the potential to negatively impact diagnosis and consequently recovery if emergency room personnel are not trained to recognize sex-specific symptoms. Sex differences in the type of stroke also occur. Men have more athero- sclerotic strokes (68 percent of men versus 19 percent of women), which is perhaps related to the fact men have a higher prevalence or an earlier onset of atherosclerosis than women, whereas women have more cardioembolic type of strokes. Clearly, there are underlying mechanistic differences behind these sex differences that need to be studied that may lead to better targeted preventive therapies. Studying sex differences may also shed light on disease severity, pro- gression, and/or outcome. Following a stroke, women are institutionalized for longer periods of time, and have lower functional recovery. Although increases in length of institutionalization could be related to the fact that women live longer than men, when the age difference is ruled out of the analysis, there remains something inherently different between the sexes that does not explain the lower functional recovery observed in women. We must learn why this is the case. Potential differences in responses to therapeutic intervention provides another important reason to study sex differences. Aspirin has been shown to be cardioprotective in men, but it does not reduce the incidence of myo- cardial infarction in women; however, aspirin does decrease the incidence of stroke in women. At a basic science level, with the majority of studies still conducted only in male animal models, drug development is inherently biased toward what works well in males, suggested Sandberg. Furthermore, because Phase I and II clinical trials do not require sufficient numbers of women to assess sex differences in safety and efficacy, sex differences in treatment responses only become obvious when large clinical trials take place. Thus research bias may, in turn, bias drug development leading to better treatments in men and obscuring potential adverse drug side effects in women. How to Study Sex Differences in Disease Susceptibility Sex differences must be studied across the entire lifespan, Sandberg said. Recall that women appear protected from stroke until their mid-80s, when their incidence of stroke surpasses that of men. As another example, asthma peaks early on, between ages 2 and 10 in boys, and is more preva- lent in boys than girls. However, adult women have a higher incidence of

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 SEX DIFFERENCES AND IMPLICATIONS asthma than adult men. These age-specific differences suggest the need to study asthma across the lifespan instead of during a single time point to better understand the mechanisms. Experimental models need to be expanded and improved, as most do not take into account the significant hormonal differences between males and females, and the changes over the lifespan of each. Aging can also af- fect the processes of disease and should be considered in animal models, as most experimental models focus only on young animals. Better models for disease susceptibility are also needed. For example, to study stroke us- ing the Dahl salt-sensitive rat model, animals are kept on a low-salt diet for one year and then ovariectomized after which blood pressure rises and the animals start to have strokes. Gonadally intact young animals are not hypertensive and do not have strokes on the low-salt diet. Waiting a year before experiments can be done in this model is expensive. Finally, the impact of sex chromosome dosage should be studied. Sandberg referred to her recent study results using the four-core genotype model, described by Arnold (above), in which she found sex chromosome effects on blood pres- sure that were independent of the sex of the animal (Ji et al., 2010). In Sandberg’s conclusion, she noted that just because a sex difference is not apparent does not mean it is not there. Analysis of sex differences should always be done, and sex differences should be studied across the lifespan by developing and expanding experimental models. OFFICE OF RESEARCH ON WOMEN’S HEALTH AT NIH Federal attention to the issues of sex differences in health began in the late 1980s with a focus on the inclusion women in clinical studies, ex- plained Vivian Pinn, director of the Office of Research on Women’s Health (ORWH) at the NIH. Advocates raised concerns that clinical research on conditions that affect both women and men was being conducted primar- ily in a homogeneous white male population, but results were then applied in medical practice to both men and women of all races. This drew the attention of the Congressional Caucus for Women’s Issues and led to the establishment of the ORWH, which was charged with ensuring that women were included in clinical studies in a way that the results of the research could compare the effects of the intervention on both men and women. The NIH instituted policies on inclusion that were subsequently incorporated into public law.1 As a result, all clinical studies funded by NIH, with rare exceptions, must include women and minorities, and Phase III (see http:// www.nlm.nih.gov/services/ctphases.html) clinical trials must be designed to 1 The NIH Reitalization Act of  (Public Law 103-43), section on “Clinical Research Equity Regarding Women and Minorities.”

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 STuDYING SEX DIFFERENCES IN HEALTH AND DISEASE facilitate “gender analysis,” that is, to be powered so that valid analysis of potential sex differences can be accomplished. The intent of the law and associated policies was to determine whether the outcomes studied would apply equally to both males and females. However, some of the language of the law has raised issues, Pinn noted. For example, as originally drafted, the law said that a “statistically significant difference” must be demonstrated by the research. This raised the concern that demonstration of statistically significant results pertaining to women and members of minority groups and their subpopulations would present difficult challenges in defining and enrolling study populations. Eventually the terminology that was agreed on called for a “valid analysis” to be con- ducted to determine whether or not there might be a significant difference, defined as a difference that is of clinical or public health importance based on substantial scientific data. Pharmacokinetics and pharmacodynamics have known and suspected sex-specific aspects, Pinn said, that can influence absorption, metabolism, and excretion of drugs. Following the establishment of the Food and Drug Administration (FDA) Guideline for the Study and Ealuation of Gender Differences in Clinical Ealuation of Drugs (FDA, 1993), the Office of Women’s Health at the FDA and the NIH ORWH developed an online course on the science of sex and gender in human health, which was made available at no charge.2 The course was designed to provide a basic scien- tific understanding of the major physiological differences between the sexes, the influence of these differences on health, and the policy, research, and healthcare implications. Early on, one of the major areas that ushered in the establishment of analysis of research results by sex was cardiovascular research. Despite the fact that heart disease is the leading cause of death for U.S. women, a 2003 report from the Agency for Healthcare Research and Quality (AHRQ), sup- ported by the NIH ORWH, found that only about 20 percent of evidence- based articles reporting coronary heart disease studies that included women actually provided separate findings for women (AHRQ, 2003). The report recommended that, in addition to requiring the inclusion of women and minorities in research, the results of that research should be published or made easily available. A subsequent review of the literature for publication of sex-specific results in 2007 recommended that journal editors require authors to provide sex-specific data; the review found that 51 percent of NIH-funded trials, and only 22 percent of non-NIH trials, reported out- comes analyses by sex (Blauwet et al., 2007). Although NIH could require analysis by sex in final progress reports of the studies it funded, it had no role in journal editorial policies. The Journal of the National Cancer Insti- 2 See http://sexandgendercourse.od.nih.gov/.

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 SEX DIFFERENCES AND IMPLICATIONS tute, however, has incorporated into its editorial policy a recommendation that clinical and epidemiologic studies should be analyzed to see if sex has an effect, and if not, that should be stated in the results. Furthermore, as discussed in Chapter 4, some neuroscience journals are considering similar changes to their editorial policies. Basic Research: Sex at the Cellular Level A significant barrier to the progress of research on sex difference in health, Pinn said, is that many in the scientific and policy communities and funding agencies still think of sex-specific research as being exclusive to clinical research. In fact, research on sex differences at the molecular and the cellular levels is very much needed. A 2001 IOM consensus study called Exploring the Biological Contributions to Human Health: Does Sex Mat- ter? helped draw attention to this issue (IOM, 2001). This report discussed the need for new knowledge about biological differences or similarities between the sexes, and the translation of information on sex differences into preventive diagnostic and therapeutic practices to improve healthcare and patient outcomes. Before addressing sex differences in basic research, the IOM commit- tee defined the use of the terms sex and gender. These terms are often used interchangeably, but to be scientifically correct, Pinn said, sex should be used to refer to those biological functions assigned by one’s chromosomes. In contrast, gender is a social construct—how people represent themselves, influenced by biology and shaped by their environment and experience (IOM, 2001). The report concluded that being male or female is an important, basic human variable, and that sound medical research and treatment must ac- count for sex and gender differences and similarities. Not all sex differences are due to differences in the hormonal milieu. Every cell has a sex and sex- ual genotype (i.e., XX for females and XY for males), which can effect the pathophysiology and prevalence of some diseases. Sex also affects behavior and perception. Without question, sex clearly affects health. Thus, expand- ing the understanding of sex differences at the cellular level will offer key insights into underlying biological mechanisms of health and disease. Challenges Pinn highlighted some of the challenges to progress in sex differences research that she has observed across NIH programs and working groups (Box 2-2). She noted that even though the NIH has an inclusion policy in place, the ORWH sees a need for continued emphasis on the importance of conducting clinical analyses by sex. She also pointed out that the law man-

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 STuDYING SEX DIFFERENCES IN HEALTH AND DISEASE BOX 2-2 Challenges to Future Progress in Sex Differences Research • linical trials: Getting sex differences research accomplished and results C reported. • Basic research: Many researchers are not aware of the pervasiveness of sex differences. There are concerns that trying to control for all variables (e.g., hormonal cycles) may result in impractically large experiments. Experimental standards and phenotypes historically have been defined using male animals. • ranslational research: Facilitating collaboration and awareness among ba- T sic, clinical, and industry researchers about the needs of each and improving understanding about the relevance of sex differences research. • nterdisciplinary research: Bridging basic and clinical science, interdisciplin- I ary work is translational by nature, but is complex, may be expensive, and does not fit into typical academic silos: New models of collaboration, institutional support, and metrics are needed. • ducation, communication, and public engagement: Making the case for E the importance of sex differences research to health without stigma. • esearch resources and emerging technologies: How best to collect, ana- R lyze, and apply knowledge about sex differences. dating inclusion is applicable only to studies funded by the NIH, and not to those funded by industry, foundations, or patient advocacy organizations. NIH Funding Initiatives The NIH has numerous funding initiatives, and one in particular that has helped to make a difference in the area of women’s health research is the funding of Specialized Centers of Research (SCOR) on sex and gender factors affecting women’s health. These interdisciplinary centers must cover the span of basic, translational, and clinical projects. Pinn highlighted sev- eral examples of SCOR research areas, such as the role of sex differences on stress responses and addiction (Goldstein et al., 2010; Quinn et al., 2007). Another recently implemented funding mechanism is Advancing Novel Science in Women’s Health Research, which is designed to fund new areas of sex and gender research (e.g., sex differences in complications in diabetic

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 SEX DIFFERENCES AND IMPLICATIONS neuropathy; acute pain and analgesic responses; myocardial ischemia; and expression and function of regulatory T-cells in lupus). As important as these initiatives are, Pinn stressed the need for more investigator-initiated research and engagement by the private sector to also integrate sex differ- ences into their research and development portfolios. Pinn also highlighted findings from a technologies bioengineering and imaging working group, which noted that many technologies are not applicable to women because the technologies were developed and standardized based on studies con- ducted primarily in male subjects, including male animals. MOvING INTO THE FuTuRE: NEW DIMENSIONS AND STRATEGIES FOR WOMEN’S HEALTH RESEARCH: NEuROSCIENCE WORKING GROuP In planning its research agenda for the next decade, the ORWH held a series of national conferences entitled Moving into the Future: New Dimen- sions and Strategies for Women’s Health Research. In October 2009 Jon Levine of the Department of Neurobiology and Physiology at Northwestern University cochaired a working group on neurosciences, which focused on the need to better understand sex differences in brain development, struc- ture, and function.3 Levine provided an overview of the working group’s findings on sex differences in the brain, and translational research in neuroscience. The working group focused on two core issues: (1) translation of findings in basic neuroscience research to clinical research in practice, and (2) absence of focus on sex differences in brain function and dysfunction in basic and clinical neuroscience research. Barriers to Progress The working group identified three basic areas that are fundamental to translation—the scientific process, administration of science, and social and cultural aspects of the enterprise—and sought to understand the barriers to successful translation. Many scientists entering graduate and medical school programs often do not have a basic understanding about the role sex has in the biology of disease states. In the neurosciences this is often perpetuated due to the absence of sex differences in brain function as an integral topic in neurosci- ence graduate programs and medical school neuroscience courses. There is also a lack of recognition of the importance of sex differences in brain func- 3 Discussed further by Levine, below.

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 STuDYING SEX DIFFERENCES IN HEALTH AND DISEASE tion and disease within the scientific community at large, and as it relates to grant reviews and funding decisions. Furthermore, basic scientists, clinical researchers, and industry find themselves working in parallel universes. Although progress is being made on understanding sex differences in all three spheres, cross-talk is limited. In addition, often some basic science researchers focus on the study of sex differences in general, and others study diseases that are sexually dimor- phic in either presentation or responsiveness to drug therapies. Ultimately, better communication and collaboration is needed between those who are specifically investigating sex differences in brain function and those who are not. The limitations of current animal models present another challenge. Great progress has been made using animal models, for example, in under- standing how genes and hormones direct sexually differentiated function in adulthood. But, Levine said, there has been limited feedback from clinical and basic science studies in humans to validate the current animal models of human brain diseases. It is not at all clear if some of the same basic sexual dimorphisms studied in animal models parallel those in humans. Neuroscience Working Group Recommendations Levine reviewed the set of six recommendations that the neuroscience working group provided the NIH ORWH following the October 2009 ses- sion (Box 2-3). PuBLIC HEALTH IMPORTANCE OF STuDyING SEx DIFFERENCES This session emphasized the significant impact that increasing basic scientific knowledge and examination of sex differences would have on public health initiatives. Critical to these efforts is the need for closer evalu- ation of underlying causes of sex differences in disease prevalence, age at onset, severity of progression and symptom presentation. Participants highlighted several potential outcomes that would have a direct influence on public health including identification of better drug targets. In addi- tion, greater awareness of sex-specific symptoms would decrease incidents of emergency room misdiagnosis and improve standards of care. Overall, targeted inclusion of both sexes in current research programs will directly improve public health.

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0 SEX DIFFERENCES AND IMPLICATIONS BOX 2-3 Office of Research on Women’s Health Neuroscience Working Group Recommendations 1. Promote recognition and understanding of sex differences in brain function and brain disorders in neuroscience graduate and medical school training curriculums. 2. Convene a panel of experts to make recommendations to the National Insti- tutes of Health Peer Review administration on the inclusion of female subjects and/or focus on sexually differentiated brain function and disease in basic neuroscience research. 3. Develop new paradigms to study the epigenetic influences impacting de- velopment of neurological and psychiatric disorders. What determines sex- specific or sex-biased brain disease vulnerability, course, and/or response to therapeutics? • evelop experimental paradigms that model sex-specific or sex-biased D experiential, hormonal, and psychosocial effects on gene expression, and intra- and intercellular signaling properties in the brain. • evelop and use high-throughput epigenomic approaches to character- D ize the large-scale epigenetic alterations associated with experience and related to sexually differentiated brain function and disease. 4. Develop new paradigms and molecular genetic approaches to study the impact of experience, hormones, developmental stage, and aging on sex differences in steroid hormone signaling in vivo; these could include new generations of transgenic and gene targeting approaches. 5. Develop and support new approaches to define similarities and differences in sexually differentiated brain function and disease in human and animal models, for example, through the use of comparative imaging of sexually differentiated brain function. 6. Develop new methodologies for targeted imaging and application of pharma- cological agents to sexually differentiated cell populations in the brain.