Advancing Research on Chronic Conditions in Women (2024)

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Advancing Research on Chronic Conditions in Women Eve J. Higginbotham, Aisha Bhimla, Zarah Batulan, Editors Committee on a Framework for the Consideration of Chronic Debilitating Conditions in Women Board of Population Health and Public Health Practice Health and Medicine Division PREPUBLICATION COPY: UNCORRECTED PROOFS Consensus Study Report 

NATIONAL ACADEMIES PRESS 500 Fifth Street, NW, Washington, DC 20001 This activity was supported by contracts between the National Academy of Sciences and the National Institute of Health, Department of Health and Human Services, under Contract Number HHSN263201800029I (task order 75N98022F00013). Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project. International Standard Book Number-13: 978-0-309-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X Digital Object Identifier: https://doi.org/10.17226/27757 This publication is available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2024 by the National Academy of Sciences. National Academies of Sciences, Engineering, and Medicine and National Academies Press and the graphical logos for each are all trademarks of the National Academy of Sciences. All rights reserved. Printed in the United States of America. Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2024. Advancing research on chronic conditions in women. Washington, DC: The National Academies Press. https://doi.org/10.17226/27757. PREPUBLICATION COPY: UNCORRECTED PROOFS 

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org. PREPUBLICATION COPY: UNCORRECTED PROOFS 

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. Rapid Expert Consultations published by the National Academies of Sciences, Engineering, and Medicine are authored by subject-matter experts on narrowly focused topics that can be supported by a body of evidence. The discussions contained in rapid expert consultations are considered those of the authors and do not contain policy recommendations. Rapid expert consultations are reviewed by the institution before release. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo. PREPUBLICATION COPY: UNCORRECTED PROOFS 

COMMITTEE ON A FRAMEWORK FOR THE CONSIDERATION OF CHRONIC DEBILITATING CONDITIONS IN WOMEN EVE J. HIGGINBOTHAM (Chair), Vice Dean, Inclusion, Diversity and Equity; Senior Fellow, Leonard Davis Institute of Health Economics; Professor of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania ARTHUR P. ARNOLD, Distinguished Research Professor, Department of Integrative Biology & Physiology, University of California, Los Angeles CYNTHIA M. BOYD, Director, Division of Geriatric Medicine and Gerontology; Professor of Medicine, Johns Hopkins Bloomberg School of Public Health NKECHI T. CONTEH, Attending Psychiatrist, Department of Psychiatry, Boston University Medical Center; Program Director, Boston University Medical Center Psychiatry Residency Program; Assistant Professor, Boston University School of Medicine KRISTINE Y. DELEON-PENNELL, Associate Professor, Department of Medicine, Division of Cardiology, Medical University of South Carolina; Research Health Scientist, Research Service, Ralph H. Johnson VA Medical Systems ERICA E. MARSH, Professor and Vice Chair, Department of Obstetrics and Gynecology; S. Jan Behrman Collegiate Professor of Reproductive Medicine; Chief, Division of Reproductive Endocrinology and Infertility, University of Michigan STACEY A. MISSMER, Professor of Obstetrics and Gynecology, University of Michigan, and Adjunct Professor of Epidemiology, Harvard T.H. Chan School of Public Health, and Lecturer Harvard Medical School. ANNA CAMILLE J. MORENO, Medical Director, Midlife Women’s Health and Menopause Medicine Program; Assistant Professor, Department of Obstetrics and Gynecology, University of Utah WALTER A. ROCCA, Professor of Epidemiology and Neurology; Ralph S. and Beverley E. Caulkins Professor of Neurodegenerative Diseases Research, Departments of Quantitative Health Science and Neurology, Mayo Clinic College of Medicine and Science JULIA FRIDMAN SIMARD, Associate Professor, Department of Epidemiology and Population Health, Division of Immunology and Rheumatology, Department of Medicine, Department of Obstetrics and Gynecology, Stanford University School of Medicine FARIDA SOHRABJI, Distinguished Professor & Department Head, John and Maurine Cox Endowed Chair, Department of Neuroscience and Experimental Therapeutics, Texas A&M University; Director, Women's Health in Neuroscience Program, Texas A&M University SANDRA SPRINGER, Professor of Medicine, Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine; Director of the Infectious Disease Clinic, VA Connecticut Healthcare System PREPUBLICATION COPY: UNCORRECTED PROOFS v 

Study Staff AISHA BHIMLA, Study Director ZARAH BATULAN, Associate Program Officer GRACE READING, Senior Program Assistant DONNA ALMARIO DOEBLER, Senior Program Officer AMY B. GELLER, Senior Program Officer MIA SALTRELLI, Senior Program Assistant MISRAK DABI, Senior Finance Business Partner SHARYL NASS, Senior Director, Board on Health Care Services ROSE MARIE MARTINEZ, Senior Director, Board on Population Health and Public Health Practice National Academy of Medicine Fellow in Emergency Medicine TRACY MADSEN, Associate Professor of Emergency Medicine and Epidemiology, Brown University Consultants JOE ALPER, Science Writer JILL BECKER, Patricia Y Gurin Collegiate Professor of Psychology; Research Professor, Michigan Neuroscience Institute, University of Michigan CAROLYN CRANDALL, Professor, Department of Medicine, General Internal Medicine and Health Services Research, Ronald Reagan UCLA Medical Center JOHN DELANCEY, Professor, Obstetrics and Gynecology, Female Pelvic Medicine and Reconstructive Surgery, University of Michigan Medicine Von Voigtlander Women’s Clinic JANE GAGLIARDI, Professor, Psychiatry and Behavioral Sciences, and Medicine, Duke University School of Medicine BERNARD HARLOW, Professor of Epidemiology; Professor of Medicine, Boston University School of Public Health JEFFREY MOGIL, Professor of Psychology, McGill University SENIHA OZUDOGRU, Assistant Professor of Neurology; Program Director, Headache and Facial Pain Fellowship, Perelman School of Medicine, University of Pennsylvania KAREN REUE, Professor, Human Genetics and Medicine, University of California Los Angeles VISHNU SUNDARESH, Associate Professor of Medicine; Director, The Osteoporosis and Metabolic Bone Health Program, University of Utah School of Medicine, MACY ZARDENETA, MD-PhD Candidate, Texas A&M University School of Medicine, Department of Neuroscience and Experimental Therapeutics PREPUBLICATION COPY: UNCORRECTED PROOFS vi 

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Reviewers This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We thank the following individuals for their review of this report: MONTSERRAT C. ANGUERA, University of Pennsylvania C. NOEL BAIREY MERZ, Cedars-Sinai Medical Center C. NEILL EPPERSON, University of Colorado School of Medicine, Anschutz Medical Campus LIISA GALEA, The Centre for Addiction and Mental Health LOUISE D. MCCULLOUGH, UTHealth Houston PAULA A. ROCHON, University of Toronto MARIA I RODRIGUEZ, Oregon Health and Science University NANETTE F. SANTORO, University of Colorado School of Medicine ANANDI SHETH, Emory University ELIZABETH A. STEWART, Mayo Clinic KIMBERLY J. TEMPLETON, University of Kansas Medical Center NICOLE C. WRIGHT, The University of Alabama at Birmingham Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report nor did they see the final draft before its release. The review of this report was overseen by SUSAN C. SCRIMSHAW, International Nutrition Foundation and LISA I. IEZZONI, Massachusetts General Hospital. They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies. PREPUBLICATION COPY: UNCORRECTED PROOFS vii 

Acknowledgements The committee wishes to thank and acknowledge the many individuals and organizations that contributed to the study process and this report. To begin, we give special thanks to the National Institutes of Health, the study sponsor. The committee and staff are grateful for the support provided by the Health and Medicine Division (HMD) and National Academies of Sciences, Engineering, and Medicine staff who contributed to producing this report. The committee thank Lori Brenig, Samantha Chao, Monica Feit, Annalee Gonzalez, Leslie Sim, and Taryn Young (HMD Executive Office); Will Andersen, Ellen Kimmel, Christopher Lao-Scott, Rebecca Morgan, and Khiara Reed (National Academies Research Center); Benjamin Hubbert and Amber McLaughlin (Office of the Chief Communications Officer); Megan Lowry (Office of News and Public Information); Julie Eubank (Office of Congressional and Government Affairs); Patsy Powell, Dempsey Price, Ahmir Robinson, and Amechi Ukpabi (Office of Conference Management); and Burgess Manobah (HMD). The committee found the perspectives of many individuals helpful in informing its deliberations through presentations and discussions at the public meetings. The following speakers provided their expertise and perspective: Drs. Janine Clayton, Holly Moore, Marjorie Jenkins, Charles Nemeroff, Nadine Burke Harris, Bess Dawson-Hughes, Arthur Mirin and Ms. Denise Hyater-Lindenmuth, Kathryn Schubert, Carolee Lee, Diana Falzone, Annika Ehrlich, Ayesha Patrick, Wendy Rodgers, The Honorable Donna F. Edwards, Ann DeVelasco, and Evelyn Kelly. Finally, the committee offers special thanks to Dr. Naoko Sasamoto for assisting in the design of a report figure. PREPUBLICATION COPY: UNCORRECTED PROOFS viii 

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Contents PREFACE ACRONYMS AND ABBREVIATIONS KEY TERMS SUMMARY S-1 1 INTRODUCTION 1-1 Reports on Women’s Health, 1-2 Current Landscape and Background, 1-4 Charge to the Committee and Approach, 1-7 References, 1-14 2 WHY WOMEN DEVELOP CHRONIC CONDITIONS DIFFERENTLY THAN MEN 2-1 Biological Factors, 2-3 Epigenetics: Environmental Regulation of Gene Expression, 2-11 Structural and Social Determinants of Health, 2-13 Summary, 2-26 References, 2-27 3 METHODOLOGICAL CONSIDERATIONS FOR STUDIES OF CHRONIC CONDITIONS IN WOMEN 3-1 Population and Non-Population Based Studies, 3-2 Studies of Frequency and Distribution (Disease), 3-5 Observational Studies, 3-11 Experimental Studies of Interventions, 3-16 Summary, 3-17 References 3-18 4 IMPACT OF SELECT CHRONIC CONDITIONS IN WOMEN 4-1 Impact of Female-Specific and Gynecologic Conditions, 4-3 Impact of Chronic Conditions that Predominantly Impact or Affect Women Differently, 4-7 Economic Burden, 4-18 Quality of Life, 4-22 Summary, 4-25 PREPUBLICATION COPY: UNCORRECTED PROOFS x 

References, 4-25 5 FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 5-1 Introduction, 5-1 Endometriosis, 5-2 Uterine Fibroids, 5-12 Female Infertility, 5-16 Vulvodynia, 5-22 Pelvic Floor Disorders, 5-28 Pregnancy and Chronic Conditions, 5-32 Menopausal Symptoms and Transition, 5-34 Summary, 5-42 References, 5-42 6 CHRONIC CONDITIONS THAT PREDOMINANTLY IMPACT OR AFFECT WOMEN DIFFERENTLY 6-1 Depression, 6-1 Substance Use Disorder, 6-9 HIV/AIDS, 6-14 Migraines/Headaches, 6-19 Cardiometabolic Conditions, 6-24 Multiple Sclerosis, 6-39 Chronic Pain, 6-43 Fibromyalgia, 6-52 Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 6-57 Alzheimer’s Disease, 6-61 Osteoporosis, 6-69 Sarcopenia, 6-79 Summary, 6-85 References, 6-86 7 CHRONIC CONDITIONS IN WOMEN AND THE STRUCTURAL AND SOCIAL DETERMINANTS OF HEALTH 7-1 Structural and Social Determinants of Health, 7-1 Research Gaps, 7-13 References, 7-15 8 MULTIPLE CHRONIC CONDITIONS 8-1 Definition of Multiple Chronic Conditions, 8-1 Measurement Tools, 8-2 Prevalence of Multiple Chronic Conditions, 8-5 Gender Differences in Multiple Chronic Conditions, 8-5 Economic Effect of Multiple Chronic Conditions in the United States, 8-6 Multiple Chronic Conditions Across the Life Course, 8-6 Biological Mechanisms of Multiple Chronic Conditions, 8-8 Examples of Multiple Chronic Conditions Clusters, 8-15 PREPUBLICATION COPY: UNCORRECTED PROOFS x 

Biomarkers for Multiple Chronic Conditions, 8-21 Disparities and Structural/Social Contexts, 8-21 Treatment and Management of Multiple Chronic Conditions, 8-23 Research Gaps, 8-24 Summary, 8-26 References, 8-26 9 IMPROVING PREVENTION AND CARE FOR CHRONIC CONDITIONS IN WOMEN 9-1 Translating Research: Opportunities and Challenges, 9-2 Additional Opportunities to Enhance the Translation of Research to Clinical Practice, 9-11 Summary, 9-18 References, 9-18 10 AN AGENDA TO ADVANCE RESEARCH ON CHRONIC CONDITIONS IN WOMEN 10-1 A Research Agenda for the Future, 10-2 APPENDIXES A COMMITTEE MEMBER BIOGRAPHIES A-1 B OPEN SESSION AGENDAS B-1 C PATIENT PERSPECTIVES AND LIVED EXPERIENCE C-1 PREPUBLICATION COPY: UNCORRECTED PROOFS xi 

Preface Women’s Health Deserves Greater Attention and Clearer Focus Women’s health deserves greater attention from policy makers, health systems, researchers, and clinicians. While continued attention is needed to address the high rates of maternal morbidity and mortality as well as reproductive health, the chronic diseases that affect women require just as much attention. At a global level, the evidence shows that medical progress was negatively impacted by the coronavirus disease 2019 pandemic, particularly related to women’s health. Seventeen United Nations Sustainable Development Goals (SDGs) are slated to be achieved by the year 2030 and agreed upon by more than 190 countries, including the United States in 2015. Pertinent to this National Academies of Sciences, Engineering, and Medicine (NASEM) Consensus Study, SDG 3 centers on the health and well-being of populations, and gender equity is the focus of SDG 5. Both SDG goals may not be achieved by 2030. For example, progress toward SDG 3 has slowed, as evidenced by the minimal progress (0.04 percent) in reducing maternal morbidity in 2016-2020, significantly lower than the 2.7 percent in 2000-2015. To achieve the target for 2030, this annual rate would have to increase to 11 percent. None of the Goal 5’s 18 metrics have been achieved as of 2023, indicating many missed opportunities to make gains toward full gender equity. Thus, we not only have a sense of urgency now but also clearly recognize that the rate of progress has slowed, and significant action is needed to change that. Human costs, of course, persist not only during pregnancy, but also across the entire life course of women across the globe driven by the costs of caring for individuals with chronic diseases, many of which start, or at least for which they are risk factors, in childhood or early adulthood. We live in an aging society, and the cost of health care is driven by the cost of caring for individuals with chronic conditions. A recent report from the World Economic Forum (WEF) noted that enhanced investment in women’s health may result in an increase of $1 trillion dollars annually to the global economy. Pertinent to this consensus study, the WEF report highlights four areas with opportunities for a greater focus on women’s health: (1) science, because the science on the conditions impacting women is largely based on studies that primarily involve men; (2) data shortfalls, where the estimates of the health burdens of chronic conditions for women are not fully understood; (3) care delivery, where women experience diagnostic delays in treatment and often less than optimal treatment; and (4) lower investment and fewer resources allocated toward women’s research versus the conditions that primarily impact men. The WEF report further indicates that social determinants, such as income and geography, can amplify the variations in health and care globally between women and men. PREPUBLICATION COPY: UNCORRECTED PROOFS xii 

Clearly, the toll of chronic conditions on the lives of women is likely underestimated, given such factors as shortfalls in data and an underrepresentation of women in clinical research studies. Women comprise 50.4 percent of the U.S. population and are the primary caregivers of others in their families, and often significant contributors to the financial security of their loved ones. At times, their own health needs thus become secondary to those for whom they are providing care, so they minimize their symptoms and delay necessary interventions that can resolve the impacts of their medical conditions early in their life course. Women from minoritized communities also carry the additional burden of not receiving full and required attention to their care and may also not trust the health care system to provide the necessary information to make the most informed decisions. The impact of this allostatic load, the cumulative burden of chronic stress and demands on the body, given years of discrimination is unknown. Therefore, the intersection of the social determinants of health, behavior, provider knowledge, and health system policies and practices are critically important to clearly grasp the full impact of these and other different contributors to the health and well-being of individuals and especially women. Over the life course, such delays in diagnosis and intervention only intensify the adverse impacts on quality of life, resulting in prolonged periods of additional negative impacts from extended stretches of disability. The consensus committee that was convened to develop a “Framework for the Consideration of Chronic Debilitating Conditions in Women” has thus crafted this report entitled, “Advancing Research on Chronic Conditions in Women.” This report offers a proactive strategic approach for better addressing the chronic conditions that adversely impact the quality of life for women, who may be living longer but are still experiencing years of suboptimal quality of life. The committee also consciously eliminated “debilitating” to better capture the resilience exemplified by the lived experiences of individuals who shared their narratives. The Statement of Task charges the committee to review the literature and consider what is known about the epidemiology, diagnosis, and treatment of female-specific gynecologic conditions and conditions that occur mostly in women and assess the social and economic impact of those chronic conditions on women. The committee was further requested to include separate considerations related to gender, race, ethnicity, socioeconomic status, gender minorities, and underserved rural populations. Finally, the committee was asked to propose a research agenda to advance the progress and deepen our understanding of chronic conditions in women and thereby significantly increase the pace of achieving optimal sex- and gender-based health overall. Once the consensus committee began its work, it was clear that knowledge and research gaps persist. Imprecise diagnostic criteria, inadequate assessment of the burden of conditions impacting women, and lack of representation of female-specific conditions on national surveys were among the challenges identified in crafting a new framework. Moreover, the health impacts in the lived experiences of individuals whom we each personally knew, who shared their experiences with us on conditions such as endometriosis and multiple sclerosis, were compelling. The extensive review of the literature underscored the social and economic contributors to health and well-being of women over their life span that have not been robustly integrated into studies focused on topics such as pathophysiology, access to care, and disease management. After thoughtful deliberation, the committee reconsidered its approach assessing chronic diseases and chose a life course perspective. This model offers an opportunity to consider chronic diseases within all structural, social, and cultural contexts. The following summary of the conclusions highlight what was learned, all of which align with the findings of the WEF: PREPUBLICATION COPY: UNCORRECTED PROOFS xiii 

o Uncertainty related to the actual burden that specific chronic conditions have on women; o Absence of pertinent data on female-specific conditions in national databases; o Lack of a deep understanding of the etiology of specific chronic conditions and the impact of reproductive milestones on those chronic conditions; o Impact of structural and social determinants, early-life experiences, and lifestyle behaviors on the overall health of women. Given the challenges clearly noted related to the science, data integrity, care delivery, and historical patterns of underinvestment, the committee was motivated to proceed with its process and delineate a clear research plan that would address the gaps in research outlined in the report. Sharing reflections on the lived experiences of women with chronic conditions provided an even deeper understanding of why this proposed research plan is so critical. This lived experience of one woman offered below clearly exemplifies the key elements that were considered in this report. One Woman’s Lived Experience: Ms. R first became aware of a change in her health status while she was attending a program at a downtown theater in Boston. She had traveled there for the graduation of her daughter from medical school. Ms. R left her seat before intermission due to bilateral knee pain from the cramped seating. This incident was particularly notable, as it was the first time Ms. R experienced moderate pain in her knees. As she reflected on her observations of her change in functional status, she recalled the repeated periods in her life when she was always active. She considered herself a highly functional individual who walked every day to her teaching job in New Orleans. However, now, she realized that simple physical actions were becoming a challenge. She also had successfully navigated three pregnancies despite having a diagnosis of uterine fibroids. Otherwise, her adult life was largely punctuated by periodic attempts at managing weight gain following the onset of menopause. Ms. R’s mobility declined with the gradual increase of her knee pain, so by the time she had surgery more than 15 years later, she had lost much of her mobility. Perhaps if she had decided on knee replacement before a decline in muscle strength, the outcome of her surgical intervention in her late 80s would have been different. If clinicians caring for her throughout her life course had guided her decision making more proactively, perhaps an earlier intervention would have been possible. She passed away 2 days short of her 99th birthday, having spent the last part of her life largely in a wheelchair and unable to fully function physically during her final years. One may ask why Ms. R waited so long to undergo knee replacement surgery. As a woman of color, living in the Deep South, she faced considerable adversity throughout her entire life. She lost her mother at the age of 12, navigated childhood and adulthood through the Jim Crow era in New Orleans, and balanced a professional career with the responsibilities of raising three daughters when women were generally expected not to work outside the home. She taught at a school that was farther away from her home than the one for White students due to segregation, and sometimes she had to teach twice as many students because of segregation-induced infrastructure issues exacerbated by a PREPUBLICATION COPY: UNCORRECTED PROOFS xiv 

construction project at another African American school, which consolidated the student bodies of two schools into one for nearly a year. Her interactions with the health care system were not always positive. She experienced instances of disrespect when staff members addressed her using her first name rather than more formal terms. For years, she was also assigned to segregated waiting rooms for her doctor’s appointments. Perhaps the stress and disrespect she endured because of societal attitudes compounded the health challenges in her life. Other medical conditions also compounded the impact of the osteoarthritis: hypothyroidism, atrial fibrillation, and irritable bowel syndrome. Fortunately, her personal attentiveness to changes in her own health led to the timely detection and complete surgical removal of a modest size malignancy without any sequelae. She also developed Parkinson’s disease in her early 90s. Because discussions about mental health did not often occur in this post-Depression generation, no challenges related to mental health throughout her life course were noted. She always projected a level of confidence and well-being as she navigated her societal stresses. She and her loving husband passed that attitude on to their daughters. This narrative is the story of my mother. She spent approximately a third of her life with less than ideal physical functioning. Thus, my incentive for advancing the work of this consensus committee is both personal and professional in its intent and strong purpose. Her narrative exemplifies a number of the topics raised in this preface and highlighted in this report. Uterine fibroids remain a major challenge for women during their reproductive stage of life, and yet only marginal progress has been made on etiology and effective management. Perimenopausal cardiometabolic syndrome and musculoskeletal challenges also impact women more than men, and both of these conditions played a significant role in my mother’s life. Atrial fibrillation is one of the conditions that impacts women differently than men. Certain lifestyle changes, which should have been recommended by her providers, might also have modified the trajectory of her mobility challenges in the later stages of life. Thus, much greater study is needed to understand the relationship between lifestyle and the chronic conditions found in women. My mother’s observance of her own bowel habits further underscores the importance of health literacy and personal agency. The nonbiological contributors to the development of Parkinson’s disease are also unknown. Last, at least a third of my mother’s life was negatively affected by delays in appropriate counseling and intervention that could have helped her better address her emerging and evolving conditions. The WEF estimate of 9 more years of disability for women compared to men experienced is generally shorter than what my mother experienced but nevertheless still too long to be considered acceptable for one of the wealthiest nations in the world. We are likely making some improvements. Women are undergoing knee replacement surgery earlier, at an average age of 65, whereas my mother made that choice in her 80s. Thus, the art of medicine appears to be catching up, but still not fast enough, given the burden many of these conditions still force on women. Many readers of this report, including members of the committee, may have similar examples of these lived experiences, whether that person is a grandmother, mother, or older PREPUBLICATION COPY: UNCORRECTED PROOFS xv 

sister who also struggles to receive the correct diagnosis and gain effective treatment that provides meaningful, patient-centered outcomes. These observations underscore the major importance of this report. In closing, I want to thank all of my fellow committee members for the remarkable contributions they shared in voice, mind, and script: Drs. Arthur Arnold, Cynthia Boyd, Nkechi Conteh, Kristine Deleon-Pennell, Erica Marsh, Stacey Missmer, Camille Moreno, Walter Rocca, Julia Simard, Farida Sohrabji, and Sandra Springer. We are also grateful for the hard work of the staff members of the National Academies of Sciences, Engineering, and Medicine: Drs. Aisha Bhimla, Zarah Batulan, Donna Almario Doebler, Rose Marie Martinez and Ms. Grace Reading, Ms. Crysti Park, and Ms. Mia Saltrelli. The work of this committee was carefully reviewed by both internal and external reviewers, a coordinator, and monitor, all listed in the introductory pages of this text. We appreciate their thoughtful feedback before the release of this report. We also want to thank Dr. Janine Clayton and her colleagues at the National Institutes of Health Office of Research on Women’s Health, our sponsor for this important study. Now, the work begins for all of us. We want to create a future anchored in enhanced knowledge and strategies. Such an approach will mitigate the adverse impact of chronic conditions, improve health, and drastically reduce the number of years when women are totally dependent on others to carry out the vital functions of daily living and experience life to its fullest. The award-winning author Malcom Gladwell captures the spirit of the moment in which we find ourselves today as a research community: “People who bring transformative change have courage, know how to re-frame the problem, and have a sense of urgency.” This is not the first National Academies report on women’s health, and it will not be last. The time has come to better define our respective roles for identifying better and operationalizing more effective strategies that can address chronic conditions in women. Eve J. Higginbotham, M.D., S.M., Chair, Committee on Framework for the Consideration of Chronic Debilitating Conditions in Women PREPUBLICATION COPY: UNCORRECTED PROOFS xvi 

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Acronyms and Abbreviations 3D three-dimensional ACA Affordable Care Act ACEs adverse childhood experiences ACOG American College of Obstetrics and Gynecology ACR American College of Rheumatology AD Alzheimer’s disease AHA American Heart Association AMH Anti-Mullerian hormone ANA antinuclear antibodies AIDS acquired immunodeficiency syndrome APA American Psychology Association ApoE Apolipoprotein E ART antiretroviral therapy ASRM American Society for Reproductive Medicine ATCC American Type Culture Collection AUB/HMB abnormal uterine bleeding/heavy menstrual bleeding BCT biomechanical computed tomography BHOF Bone Health and Osteoporosis Foundation BMD bone mineral density BMI body mass index BRFSS Behavioral Risk Factor Surveillance System CAR chimeric antigen receptor CBPR community-based participatory research CCER comparative clinical effectiveness research CDC Centers for Disease Control and Prevention CES-D Center for Epidemiology Studies–Depression Scale CFS chronic fatigue syndrome CGRP calcitonin gene-related peptide CHD coronary heart disease CHF congestive heart failure CHI chronic histiocytic intervillositis CMS Centers for Medicare and Medicaid Services CNS central nervous system PREPUBLICATION COPY: UNCORRECTED PROOFS xviii 

COMPARE-UF Comparing Options for Management: Patient-Centered Results for Uterine Fibroids COPD chronic obstructive pulmonary disease COVID-19 coronavirus disease 2019 CPP chronic pelvic pain CT Computed Tomography CVD cardiovascular disease D+Q Dasatinib and Quercetin DALYs disability-adjusted life years DNA deoxyribonucleic acid DSM Diagnostic and Statistical Manual DXA dual-energy X-ray absorptiometry EAE experimental autoimmune encephalomyelitis EHR electronic health record ELP early-life programming ER estrogen receptor EWGSOP European Working Group on Sarcopenia in Older People FCG Four Core Genotypes FDA Food and Drug Administration FNIH Foundation for the National Institutes of Health FY fiscal year GABA gamma-aminobutyric acid GnRH Gonadotropin Releasing Hormone GWAS genome-wide association studies HCHS/SOL Hispanic Community Health Study/Study of Latinos HIV human immunodeficiency virus HIV/AIDS human immunodeficiency virus/acquired immunodeficiency syndrome HRS Health and Retirement Study IASP International Association for the Study of Pain ICHD-3 International Classification of Headache Disorder, 3rd edition IHME Institute for Health Metrics and Evaluation IL interleukin INOCA ischemia with no obstructive coronary artery disease IOM Institute of Medicine IPV intimate partner violence IRB Institutional Review Board PREPUBLICATION COPY: UNCORRECTED PROOFS xix 

IVF in vitro fertilization IWGS International Working Group on Sarcopenia LDL low-density lipoprotein LGBTQIA+ lesbian, gay, bisexual, transgender, queer, intersex, asexual LUTS lower urinary track symptoms MASALA Mediators of Atherosclerosis in South Asians Living in America MBSR mindfulness-based stress reduction MCC multiple chronic conditions MDD major depressive disorder MDE major depressive episode ME myalgic encephalomyelitis ME/CFS myalgic encephalomyelitis/chronic fatigue syndrome MEPS Medical Expenditure Panel Survey MINOCA myocardial infarction with no obstructive coronary artery disease miRNA microRNA MMR maternal mortality rate MRI magnetic resonance imaging mRNA messenger RNA MS multiple sclerosis NASEM National Academies of Sciences, Engineering, and Medicine NCD noncommunicable disease NCHS National Center for Health Statistics NHANES National Health and Nutrition Examination Survey NHIS National Health Interview Survey NHS Nurses’ Health Study NIA National Institute on Aging NIH National Institutes of Health NK3R neurokinin 3 receptor NSAID nonsteroidal inflammatory drugs NSDUH National Survey on Drug Use and Health OADR Office of Autoimmune Disease Research ORWH Office of Research on Women’s Health OUD opioid use disorder PCORI Patient-Centered Outcomes Research Institute PCOS Polycystic Ovary Syndrome PDS postpartum depressive symptom PET positron emission tomography PFD pelvic floor disorder PREPUBLICATION COPY: UNCORRECTED PROOFS xx 

PMDD premenstrual dysphoric disorder PMS premenstrual syndrome POL Popular Opinion Leader PPD postpartum depression PrEP pre-exposure prophylaxis PRO patient-reported outcome PROM patient-reported outcome measure PTSD posttraumatic stress disorder QCT quantitative computed tomography RA rheumatoid arthritis RCDC Research, Condition, and Disease Categorization RCT randomized controlled trial RNA ribonucleic acid RRMS Relapse-remitting Multiple sclerosis SAMHSA Substance Abuse and Mental Health Services Administration SCAD spontaneous coronary artery dissection SDOH social determinants of health SEER Surveillance, Epidemiology, and End Results SLE systemic lupus erythematosus SNP single nucleotide polymorphism SOT Statement of Task SPAN Stroke Pre-Clinical-Clinical Assessment Network SS symptom severity SSRI selective serotonin reuptake inhibitor STAIR Stroke Therapy Academic Industry Roundtable SUD substance use disorder SWAN Study of Women’s Health Across the Nation TBS Trabecular Bone Score TCR3 Tachykinin receptor 3 gene TLR toll-like receptor tPA tissue plasminogen activator UAE uterine artery embolization USPSTF U.S. Preventive Services Task Force VFA vertebral fracture assessment VMS vasomotor symptoms WHI Women’s Health Initiative PREPUBLICATION COPY: UNCORRECTED PROOFS xxi 

WHO World Health Organization WISE Women’s Ischemia Syndrome Evaluation WPI widespread pain index YLD years lived with disability PREPUBLICATION COPY: UNCORRECTED PROOFS xxii 

Key Terms Related to Sex, Gender, Race, and Ethnicity Several terms are used in the report to denote sex, gender, race, and ethnicity. The committee used inclusive terms where possible; however, when discussing results of cited literature, the committee was considerate of the terms used by researchers. The various terms in the report are below: Sex and Gender: throughout the report, when citing research findings and study results, the committee used “female” to refer to biological factors related to animal research and “women” in human research when describing sex and gender differences. If the researchers misclassified or incorrectly used sex when referring to gender or vice versa, the term “woman” was used. In specific cases where a researcher referred to sex as “assigned female at birth”; that terminology was used in those instances. Gender Identity and Sexual Orientation: the committee referred to various groups based on what was cited in the literature. These included: ‘LGBTQIA+,’ ‘transgender,’ ‘cisgender,’ ‘bisexual’ Race and Ethnicity: the committee referred to various racial and ethnic groups based on what was cited in the literature wherever possible. These included: “American Indian,” “Alaska Native,” “American Indian and Alaska Native” “Asian,” “Asian American” “Black,” “African American,” “Non-Hispanic Black,” “Black and African American” “Hispanic,” “Latina,” “Latina/o,” “Hispanic/Latino,” “Hispanic/Latina,” “Native Hawaiian and Pacific Islander” “White,” “Non-Hispanic White” Sexism and racism: these are described as structural determinants of health, such as institutional discrimination, evident in laws, policies, or rules and occurring at the interpersonal, societal, and structural levels. PREPUBLICATION COPY: UNCORRECTED PROOFS xxiii