Advancing Research on Chronic Conditions in Women (2024)

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5 Female-Specific and Gynecologic Conditions INTRODUCTION Diagnosing and treating female-specific and gynecologic 1 chronic conditions is complex given the physiological systems involved and their variation across the life course and the influence of gender, social, and psychologically relevant factors (Sarría-Santamera et al., 2022). Women’s health has been reduced to or employed as a euphemism for reproductive or gynecologic health, with women’s health research or women’s health clinics often focusing specifically on and providing obstetrics and gynecologic care (Hoffman et al., 2020). Although women’s health is not strictly related to the reproductive system or gynecologic conditions, gynecologic health is essential to women’s health throughout the life course. Despite high prevalence and impact, lack of curiosity about and inadequate prioritization of female- specific physiology and pathophysiologic discovery has resulted in persistent knowledge gaps that directly impede advancements toward prevention, more rapid diagnosis, and more effective treatment of chronic gynecologic conditions and their associated multiple chronic conditions (MCC) (Steinberg et al., 2022; Temkin et al., 2022). The consequence is that clinicians treat far too many girls and women with a mindset of ignorance, inattention, dismissal, and stigma for life- impacting symptoms. The consequences are also field defining and self-fulfilling. This lack of curiosity and prioritization results in investigators publishing few original research articles on these conditions in the highest-impact general journals. Rather, they end up in gynecology subject-specific journals with lower impact factors (Sinha et al., 2023). In addition, the lack of prioritization results in substantially fewer funding opportunities from federal sources and few if any opportunities for nongovernmental funding (Sinha et al., 2023). As a result, fewer scientists and clinician investigators choose to cultivate and sustain a career focusing on female-specific gynecologic discovery (IOM, 1992). 1 In this report, the committee chose to refer to female-specific and gynecologic conditions. Female- specific conditions include infertility and urinary incontinence associated with female organs and systems. Gynecologic conditions are those related to the reproductive organs and systems. PREPUBLICATION COPY: UNCORRECTED PROOFS 

2 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Given the breadth of chronic conditions affecting women, the committee chose to restrict its analysis to the following conditions that are all important contributors to morbidity in women: endometriosis (including dysmenorrhea, or pain during menstruation, and chronic pelvic pain (CPP), uterine fibroids, infertility, vulvodynia, pelvic floor disorders (PFD), chronic conditions associated with pregnancy, and menopausal symptoms and transition. This order was chosen based on the typical age of onset, prevalence based on available evidence, and population impact. These conditions have documented, life-altering symptoms that reveal the fascinating complexities of gynecologic organs and systems that interact and affect women’s entire bodies across their whole lives. They also raise foundational questions and deserve greater attention. The field of women’s health research is at the precipice of a grand leap forward, with many technologies and methods available to swiftly apply to these and all female-specific and gynecologic conditions. What is needed is enthusiastic curiosity, creative thought, and resources. ENDOMETRIOSIS “I have had [endometriosis] symptoms since I was about 12 years old. I was told numerous times, here, here is a birth control pack. Take it. That will help you get through the month…They did not know what it was. I never heard the word endometriosis, not until I was 33 years old. That was also a whole experience trying to be taken seriously, getting listened to, getting seen by the right experts. The barriers came in the form of years and years of thinking that this was just part of my journey as a woman, that everyone who had a period suffered just like me.” –Presenter at Committee Open Session Endometriosis is a gynecologic condition that causes significant morbidity and mortality and is linked to various other chronic conditions. This review focuses on highlighting the pathophysiology, risk factors, diagnosis, treatment, and management as well as dysmenorrhea and CPP as conditions associated with endometriosis. Pathophysiology/Biological Mechanisms and Risk Factors An understanding of the etiology and longitudinal trajectory of endometriosis remains limited. One hypothesis proposes that retrograde menstruation (when blood flows backward into the peritoneal cavity instead of out of the vagina and implants on peritoneal surfaces and pelvic organs (Sampson, 1927) causes endometriosis. However, over 90 percent of women have retrograde menstruation, but only about 10 percent develop endometriosis (Halme et al., 1984). This suggests that the peritoneal angiogenic and immunologic milieu in the latter is more hospitable to the survival, implantation, and growth of ectopic endometrial tissue. It also supports the idea that other mechanisms, such as coelomic metaplasia and stem cell pathogenesis spread through the vascular or lymphatic systems (Sampson, 1927; Zondervan et al., 2020). Endometriosis has been associated with elevated cytokines in the peritoneal environment, upregulated inflammatory genes, reduced cytotoxicity of natural killer cells, and abnormal antibody production (Harada et al., 2001; Mathur et al., 1982; Podgaec et al., 2007). Suppression of cellular immunity is evident in both Rhesus monkeys and women with endometriosis, including impaired natural killer cell activity and apoptosis of cytotoxic lymphocytes (Dmowski PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 3 et al., 1981; Oosterlynck et al., 1991). In addition, dysregulated B-cell activity leading to tissue damage, elevated autoantibodies, elevated inflammatory and immune markers, and associations with other autoimmune diseases suggest that endometriosis may arise from or be sustained by autoimmune-like pathways (Eisenberg et al., 2012; Mathur et al., 1990; Nothnick, 2001; Oosterlynck et al., 1991; Sinaii et al., 2002). Explorations of the causal pathways have largely ignored the heterogenous phenotypic presentation of the disease, including surgically visualized subtypes such as superficial and deep lesions and ovarian endometriomas; presenting symptoms; and gynecologic and pain-associated comorbidities (Becker et al., 2022; Zondervan et al., 2020). The assumption has been that superficial peritoneal lesions eventually progress to deep endometriosis affecting pelvic organs, but differential genetic associations suggest instead that these are independent subtypes (Rahmioglu et al., 2023). Symptom Heterogeneity and Genetic Subtypes Symptoms range from no symptoms to severe pelvic and widespread pain, fatigue, and infertility (see Figure 5-1) (Horne and Missmer, 2022; Zondervan et al., 2020). The extent of disease in the pelvis varies and can be classified using the revised American Society for Reproductive Medicine (ASRM) staging system (ASRM, 1997) based on surgical visualization of lesions and adhesions. Stage I indicates minimal disease and Stage IV indicates severe disease with many deep endometrial implants and many deep adhesions. However, the correlation between revised ASRM stage and patient-reported pelvic pain is weak (International working group of AAGL et al., 2021). FIGURE 5-1 Symptom heterogeneity for endometriosis. SOURCE: Horne and Missmer, 2022. PREPUBLICATION COPY: UNCORRECTED PROOFS 

4 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN The largest endometriosis genome-wide association study (GWAS) meta-analysis revealed that revised ASRM stage III/IV disease has a different genetic basis than stage I/II, likely indicating there is a difference between ovarian and peritoneal disease (Rahmioglu et al., 2023). The effect sizes of established genetic risk variants varied with different patient-reported pelvic pain types. GWAS results also identified sizeable genetic correlations between endometriosis and various inflammatory and chronic pain conditions (Rahmioglu et al., 2023) supporting the idea that pelvic inflammation and chronic stimulation and sensitization of the central nervous system (CNS) are likely sources of pain in endometriosis and pain comorbidities (As-Sanie et al., 2016; Berkley et al., 2005; Carey et al., 2017; Laux-Biehlmann et al., 2015). Research has yet to identify genetic drivers for the varied pain experiences seen in women with endometriosis that are important for understanding the underlying biology and identifying novel treatment targets. Risk Factors and Prediction Although research has identified individual risk factors, including low birthweight, earlier age at menarche, low body mass index (BMI), shorter menstrual cycle length, and lower parity— the number of pregnancies that reached a viable gestational age (Shafrir et al., 2018)— no risk prediction models for endometriosis exist for clinicians to use to identify those at high risk. Many studies of risk factors have been small or used varying control groups, leading to inconsistent results for many risk factors (Missmer, 2019). However, a few risk factors are strongly and consistently associated with endometriosis (see Figure 5-2) (Shafrir et al., 2018). FIGURE 5-2 Risk Factors Associated with Endometriosis. SOURCE: Shafrir et al., 2018 PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 5 Early age at menarche is one of the most consistent factors associated with higher risk. In the first prospective cohort study of risk factors, the investigators observed that women who reported menarche before age 10 had a 30 percent higher risk compared to those with menarche at age 12 (Missmer et al., 2004). A large meta-analysis of 18 studies supported this finding (Nnoaham et al., 2012). The cohort study also found a menstrual cycle length of less than 26 days during late adolescence (18–22 years old) was associated with a significant increase in risk compared to those with a cycle length between 26 and 31 days (Missmer et al., 2004). Low BMI is associated with increased risk from birth to adulthood. Women born full term and who reported a birthweight of less than 5.5 pounds had a significantly increased risk of developing endometriosis as an adult compared to those with a healthy full-term birthweight of 7.0–8.4 pounds (Missmer et al., 2004). Similarly, women who reported they had a lean body shape at ages 5 through 18 had an increased risk of endometriosis (Farland et al., 2017; Vitonis et al., 2010). The relationship between parity 2 and endometriosis has proven difficult to study because reference groups in endometriosis case-control studies often include those who are more likely to have given birth. Furthermore, pregnancy and infertility involve a closer evaluation of the reproductive tract, which can lead to biased detection of endometriosis, as many instances are not found and documented as diagnosed cases despite symptoms. However, well-designed prospective and case-control studies report an inverse association between parity and risk (Parazzini et al., 1995; Peterson et al., 2013; Sangi-Haghpeykar and Poindexter, 1995). Clinical Presentation and Diagnosis Common symptoms include dysmenorrhea, acyclic pelvic pain, painful intercourse, and pain while defecating, all of which contribute to chronic general pelvic and lower abdominal pain. These symptoms can continue from menarche through menopause (Zondervan et al., 2020). The absence of risk profiles and diagnostic biomarkers contributes to an estimated 7-year delay in diagnosis (Fryer et al., 2024). To shorten the time to diagnosis, the European Society of Human Reproduction and Embryology recently recommended beginning treatment without a definitive surgical diagnosis (Becker et al., 2022). However, specific guidelines regarding who should be evaluated and may be at high risk are lacking. Treatment and Management Treatment strategies focus on the endometriosis lesions and include surgical therapies to excise them or medical therapies to hormonally suppress them (As-Sanie et al., 2019). The standard of care for the primary symptom of persistent pelvic and lower abdominal pain consists of surgery, either excision or ablation of any lesions; hormonal medication; and over-the-counter pain medications (Horne and Missmer, 2022). Although these therapies are effective for some patients, they are not always sufficient to eliminate pain and can exacerbate some symptoms (Allaire et al., 2024; Aredo et al., 2017), especially among younger women (Carey et al., 2014; MacDonald et al., 1999). In addition, all three treatments have varying degrees of accompanying risks or side effects that can vary with age. Approximately 50 percent of women with endometriosis remain symptomatic and experience persistent pain despite these treatments 2 Defined as the number of live born children PREPUBLICATION COPY: UNCORRECTED PROOFS 

6 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN (Becker et al., 2017). A longitudinal study of adolescents and young adults found that among those with endometriosis, 35 percent will have persistent, severe symptoms despite surgical excision and standard medical care for 2 years (Sasamoto et al., 2023). Endometriosis and Multimorbidity The life course of endometriosis, including the risk of lifelong health outcomes, is poorly understood. Women with endometriosis have a greater risk of other morbidities, including non- malignant gynecologic diseases (Gallagher et al., 2019), malignancies (Kvaskoff et al., 2021), autoimmune diseases (Shigesi et al., 2019), cardiovascular (Mu et al., 2016), and cardiometabolic conditions (Mu et al., 2017). Of critical importance is discovering lifestyle and behavioral predictors that modify and mediate these lifelong health outcomes. However, little is known about mediating factors and the underlying biologic mechanisms that may influence risk. Studies that investigated a wide range of lifelong health outcomes among women with endometriosis, including cancers and cardiovascular disease (CVD), have not considered how factors related to endometriosis treatments, lifestyle characteristics, and behaviors modified by individuals to cope with symptoms, such as reducing physical activity, may affect these outcomes. Incorporating these factors, including biologic markers of the mediating physiologic milieu (Figure 5-3), is critical to fully understand pathways through which these health outcomes may occur and establish personalized, patient-centered targets for intervention across the life course. FIGURE 5-3 Conceptual framework of potential modifiers and mediators leading to lifelong health outcomes in women with endometriosis. PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 7 Dysmenorrhea and CPP Dysmenorrhea and CPP are often associated with endometriosis. Dysmenorrhea is the most common gynecologic condition (Macgregor et al., 2023). Primary dysmenorrhea is pain during menstruation that has no diagnosed underlying presumed causal condition; women with endometriosis experience secondary dysmenorrhea. Although pain is a known warning sign warranting attention, painful menstruation is the only type of pain deemed “normal,” and is even considered a part of being a woman. These persistent, dismissive beliefs have negatively affected attention to, funding for, and relief of what can be life-altering pain. Dysmenorrhea can appear at menarche with the first menstruation, but it most commonly presents within 6–12 months after first menstruation, thus affecting girls in early adolescence. This results in school absenteeism, diminished engagement with social activities, and a negative effect on family relationships and work success (Figure 5-4). FIGURE 5-4 The effect of dysmenorrhea. SOURCE: Macgregor et al., 2023. PREPUBLICATION COPY: UNCORRECTED PROOFS 

8 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Although research on dysmenorrhea has been inadequate, pathophysiology suggests that the fall in progesterone levels in the late luteal and early follicular phases catalyzes an endometrial inflammatory response that increases the level of prostaglandins that play a role in sensitizing nerve endings, enhancing endometrial vascular ischemia, and inducing uterine contractions. Other inflammatory pathways may be involved, along with changes in pain arising from tissue damage and being susceptible to normally subthreshold stimuli, that may lead to hypersensitivity to pain (Tu et al., 2020). CPP, which can include dysmenorrhea, is a common condition in women with endometriosis. It is a multifactorial condition that affects up to 20 percent of U.S. women and comes with serious economic, personal, and professional costs (Jones et al., 2004; Mathias et al., 1996). In clinical practice, poor treatment outcomes have persisted for decades, in part because the underlying pain mechanisms are heterogeneous and complex, leading to a trial and error approach that includes analgesics, hormonal treatment, and surgery (Allaire et al., 2024). Most women with CPP receive hormone-suppressive therapies—the only medical treatment for endometriosis approved by the Food and Drug Administration (FDA)—despite little guidance to predict who will respond. The established view is that it provides pain relief by suppressing an estrogen-mediated complex of pelvic inflammation and neuroangiogenesis in common gynecologic CPP conditions (Krikun et al., 2005; Nirgianakis et al., 2013). This disease model is incomplete, though, because the severity of pelvic inflammation is only weakly associated with the severity of pain (Overton et al., 1996; Scholl et al., 2009; Vercellini et al., 2007), and pain relief following hormonal suppression is not predicted by baseline disease severity (e.g., stage of disease) (Al-Hendy et al., 2021; Winzenborg et al., 2020). Furthermore, hormonal suppression improves pain in conditions without comorbid endometriosis, such as irritable bowel syndrome and migraine (Mathias et al., 1994, 1998; Murray and Muse, 1997; Palomba et al., 2005). These issues underscore the need to approach the study of endometriosis-associated pelvic pain from a broader systemic perspective (Horne and Missmer, 2022; Taylor et al., 2021). Risk factors beyond those directly related to the pelvis, such as low-grade systemic inflammation and widespread pain, significantly shape the manifestation and trajectory of CPP. Heightened systemic inflammation is associated with increased brain connectivity in pain-promoting pathways, increased sensitivity to experimental pain, and symptoms associated with CNS sensitization such as widespread pain in women who have interstitial cystitis or awaiting hysterectomy (removal of the uterus) for CPP (Schrepf et al., 2014, 2015). Women with endometriosis pain often seek strategies to augment or supplement standard surgical, hormonal, and analgesic treatments. Acyclic pelvic pain, which occurs at times other than with menses, can be challenging because it is associated with flares that are much less predictable than other symptoms. Some patients seek recommendations from their health care providers, but no established pelvic pain management protocols or decision trees exist (Huntington and Gilmour, 2005). Numerous studies investigating alternative approaches to alleviate endometriosis pain have focused solely on individual or similar strategies, often with a limited number of cases (Carlyle et al., 2020; Samy et al., 2021), underscoring the need for a more comprehensive evaluation of strategies and including larger cohorts with endometriosis. Adolescents and young adults may manage chronic pain differently, and pain management plans for adults may not be appropriate for younger age groups (Anastas et al., 2018). Data confirm that women with endometriosis are at 3–4 times greater risk of chronic opioid use, dependence, and overdose compared to women without endometriosis (Chiuve et al., 2021). Adolescents and young women with endometriosis (under 25 years of age) have a higher PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 9 risk of chronic opioid use compared to adults with endometriosis (Chiuve et al., 2021). Therefore, optimal pain management, especially for adolescents, is critical to achieve a significant positive effect on clinical outcomes. Cancers Women with endometriosis have an increased risk of certain cancers, particularly ovarian cancer. A 2016 pooled analysis of six cohort studies observed a 35 percent increased risk of ovarian cancer among women with endometriosis compared to those without (Wentzensen et al., 2016). This increased risk was most prominent among women with clear cell and endometrioid ovarian cancers. A pooled analysis of 13 ovarian cancer case-control studies yielded similar results (Pearce et al., 2012). In addition, studies have shown consistently that women with endometriosis have an increased risk of thyroid cancer and may have a small increased risk of breast and melanoma cancers (Kvaskoff et al., 2021). However, research has yet to elucidate the pathways through which these increased risks occur, particularly in relation to how dynamic, modifiable behaviors and characteristics may influence the development of particular cancers. A recent review of Mendelian randomization studies noted a potential causal association between genetically predicted endometriosis and ovarian cancer, specifically for clear cell carcinoma, endometrioid, and high-grade serous ovarian tumors (McGrath et al., 2023). In addition, GWAS have reported multiple loci common to endometriosis and these types of ovarian cancer (Lee et al., 2016; Lu et al., 2015). Limited research has investigated how changes in hormonal and inflammatory markers resulting from either endometriosis or its treatments may affect cancer development. A few studies have assessed how endometriosis status may modify traditional ovarian cancer risk factors and have shown that hysterectomy (Harris et al., 2023; Ring et al., 2023) and frequent aspirin use (Sasamoto et al., 2021) were associated with a decreased risk of ovarian cancer among participants with endometriosis but not among those without endometriosis. Similarly, estrogen-only hormone therapy was associated with an increased risk of ovarian cancer among postmenopausal women with endometriosis but not among those without (Lee et al., 2023). Although these studies suggest that hysterectomy, hormone therapy, and aspirin may be important in ovarian cancer among those with endometriosis, they have been examined as modifiers, not mediators. No studies have assessed whether behavioral characteristics and any changes in them after endometriosis diagnosis may influence cancer risk. Cardiovascular, Cerebrovascular, and Metabolic Disease Women with endometriosis are at increased risk of CVD, including ischemic heart disease, myocardial infarction (Mu et al., 2016), and stroke (Farland et al., 2022). They are also at increased risk of hypertension and hypercholesterolemia (Madika et al., 2021; Mu et al., 2017), suggesting pathways through which endometriosis may influence cardiovascular and cerebrovascular disease risk. Evidence also shows that endometriosis increases the risk of developing type 2 diabetes, although this only occurs among women who are lean or never experienced infertility (Farland et al., 2021). A 2023 meta-analysis of three cohort studies identified a 50 percent increased risk of ischemic heart disease in women with endometriosis compared to those without (Poeta do Couto et al., 2023); preliminary studies suggest that systemic inflammation and potential underlying genetic susceptibility may play a role. PREPUBLICATION COPY: UNCORRECTED PROOFS 

10 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Endometriosis is an inflammatory condition with dysregulation of immune cells and increases in proinflammatory cytokines (Zondervan et al., 2018). These alterations may directly affect risk of CVD. GWAS of populations of Japanese and European ancestry identified multiple independent loci in a chromosomal region that regulates central mechanisms for atherosclerotic plaque and endometriosis, including cell proliferation, adhesion, and apoptosis (Holdt et al., 2013; Motterle et al., 2012). Research has also found this region is associated with coronary heart disease outcomes and endometriosis, suggesting a shared genetic susceptibility (McPherson et al., 2007; Rahmioglu et al., 2014; Samani et al., 2007; Uno et al., 2010). Furthermore, research has suggested that for both coronary heart disease and stroke, the higher rate of hysterectomy among women with endometriosis explained 40–45 percent of the observed associations (Mu et al., 2016, 2017). Autoimmune and Immune-Mediated Conditions Autoimmune disorders, which are more common among women, share features of immunologic and hormonal abnormalities with endometriosis. Epidemiologic evidence has shown an increased risk of autoimmune disorders, including systemic lupus erythematous (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), Sjogren’s syndrome, allergies, and asthma among women with endometriosis (McGrath et al., 2023; Shigesi et al., 2019). In a recent meta- analysis, albeit of low-quality studies, researchers observed a 40–100 percent increased risk of SLE among those with endometriosis, with similar associations observed for RA (Shigesi et al., 2019). One study observed an increased risk of inflammatory or autoimmune-related disorder among mostly adolescent and young adults, suggesting that even at a younger age those with endometriosis may be at an increased risk of comorbid autoimmune disorders (Shafrir et al., 2021). Few studies have investigated potential mediators of endometriosis and autoimmune diseases. Shared genetic pathways relating to steroid hormones may link endometriosis and asthma (McGrath et al., 2023). The Nurses’ Health Study II found a potential mediating effect of hysterectomy and oophorectomy on associations with SLE, RA, and psoriatic arthritis (Harris et al., 2016, 2022). Accounting for hysterectomy and oophorectomy slightly reduced the associations for each of these, suggesting that these surgeries play a role in developing at least some autoimmune disorders. Given the evidence of immune dysregulation, perhaps it is not surprising that endometriosis has emerged as a condition that places women at greater risk of long-COVID, with a suggestion of greater risk among younger women (Wang et al., 2023a). Early Natural Menopause Early natural menopause, defined as occurring at age 45 and younger, is associated with CVD risk and early mortality. One study found that laparoscopically confirmed endometriosis was associated with a 51 percent greater risk of early natural menopause, even after adjusting for various reproductive factors, the risk was greatest among those who never used oral contraceptives (Thombre Kulkarni et al., 2022). PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 11 Mental Health Endometriosis is frequently associated with an increased risk for depression and anxiety. A systematic qualitative review of 17 studies identified factors in addition to pelvic pain that contribute to depression or anxiety. These include poorer quality of sleep, lower self-esteem, and lower confidence to express one’s feelings (van Barneveld et al., 2022). Although this is robust evidence of reduced quality of life and increased rates of depression and anxiety, data are sparse on lifestyle and behavioral interventions that may improve these outcomes. Disparities A systematic review and meta-analyses of 20 studies to examine the prevalence of endometriosis by race and ethnicity in women found that Black women had lower odds and Asian women had higher odds of endometriosis than White women. Hispanic women had lower odds, but it was not a significant association. The authors noted that although the results suggest an association with race and ethnicity, the studies they reviewed were of limited quality (Bougie et al., 2019). Another literature review concluded that it is difficult to obtain an accurate measure of endometriosis and that variation in access to the diagnostic surgical procedures for endometriosis affect racial and ethnic differences (Giudice et al., 2023). For example, women with a lower income or who belong to minority populations excluded from research have less access to minimally invasive laparoscopic surgery and robotic surgery, leading to underestimating their endometriosis prevalence (Giudice et al., 2023). In addition, as with many other chronic conditions affecting women, endometriosis studies seldom include American Indian and Alaska Native women, Asian Americans and Pacific Island women, transgender men, and adolescents (Giudice et al., 2023). Those underserved populations defined by race and ethnicity, socioeconomic status, and/or various gender and sexual identity groups may experience the effects of dysmenorrhea differently. Research Gaps Although prevalent and with well-documented individual, public health, and economic effects, endometriosis remains largely misunderstood, unprioritized, and underfunded, with numerous research needs (As-Sanie et al., 2019; Giudice et al., 2023; Zondervan et al., 2023). Research focused on the basic pathophysiology of endometriosis and underlying physiology of dysmenorrhea and of non-menstrual CPP arising in those with and without endometriosis is essential. In addition, given the pain symptoms of women with endometriosis, additional research is needed. Key areas of investigation include examining the nociceptive role of endometriosis in pelvic pain and the risk of pain from altered nociception despite no clear evidence of tissue damage (Allaire et al., 2024). Improving measures that capture pain expression, severity, and triggers of flares (especially distinguishing between acute/short-lived and long-lasting flares) can improve the understanding of the role pain plays in endometriosis, can affect patient-provider communication by reducing skepticism and stigma that many with pelvic pain experience when seeking successful treatment (As-Sanie et al., 2019; Missmer et al., 2021; Sims et al., 2021). In addition, improved, standardized, and widely implemented symptom quantification may improve diagnosis, reduce biases to treatment, and improve the accuracy of prevalence estimates (Shafrir et al., 2018). PREPUBLICATION COPY: UNCORRECTED PROOFS 

12 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Establishing a biologically and clinically informative classification of endometriosis subtypes is also critically needed (International working group of AAGL et al., 2021). Women experience varied symptoms, some of which are localized to the pelvis and others that are widespread or include MCC (Horne and Missmer, 2022). One finding, for example, suggests that the genetic loci associated with endometriosis are also associated primarily with endometriotic ovarian cysts and not superficial peritoneal disease, the most prevalent presentation of the lesions (Rahmioglu et al., 2023). As Chapter 9 discusses in more detail, researchers need to develop new experimental models for endometriosis, menstruation, and CPP that better represent the human diversity in biologic, anatomic, and cellular presentation of the uterine and extrauterine three- dimensional dynamic environment. A more detailed picture of the pathophysiology driving these varied manifestations and improved prediction of who will exhibit these symptoms and comorbid conditions will revolutionize the understanding of endometriosis, CPP, and the symptoms and conditions associated with them. The goal is to catalyze developing more sensitive and specific diagnostics and more personalized therapeutics for endometriosis. Research is also needed to compare the manifestation of endometriosis-associated symptoms, especially among adolescent, perimenopausal, and postmenopausal women to develop novel treatments across the life course. Given that women with endometriosis are at a greater risk of presenting with other chronic conditions, further research is needed to understand the risk of subsequent lifelong health outcomes and how to mitigate these consequences across the life course. Additional research is needed focused on underserved populations, including adolescents, women of color, and those in medically underserved areas to help reduce delays in care (Farland and Horne, 2019). UTERINE FIBROIDS Uterine fibroids, also known as leiomyomas, are highly prevalent, non-malignant tumors that develop in the muscular layer of the uterine wall and are only present in individuals assigned female sex at birth and born with a uterus. They are commonly referred to as “fibroids” because of they have a fibrous appearance and consist largely of collagen fibers. It is estimated that uterine fibroids are clinically evident in 25 percent of women of reproductive age. Of women with uterine fibroids, about 25 percent require treatment (Stewart et al., 2017). Although benign, fibroids are the leading cause of hysterectomy in the U.S. (Cardozo et al., 2012; Wu et al., 2007). Pathophysiology/Biological Mechanisms Fibroids are known to be sex steroid sensitive and require estradiol and progesterone for growth (Bulun, 2013). The Fibroid Growth Study found that although they have a median growth rate of 9 percent over 6 months, fibroids in the same uterus can grow, shrink, remain unchanged, or regress, with a growth rate range of 89–138 percent (Peddada et al., 2008). Uterine fibroids may increase in size and number during pregnancy. The increased number and size can enhance the risk for preterm birth, cesarean delivery, placenta previa and other adverse outcomes (Li et al., 2024). During menopause, uterine fibroids may reduce in size and associated symptoms lessen. However, shrinkage may not occur and uterine fibroids continue to be present. Moreover, new uterine fibroids may continue to appear during menopause (Ulin et al., 2020). PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 13 Risk Factors Systematic reviews on uterine fibroids have identified a number of risk factors, including race and age (Katon et al., 2023; Laughlin-Tommaso et al., 2017; Stewart et al., 2017). A 2023 systematic review highlighted consistent evidence of higher prevalence of uterine fibroids among Black women compared to White women. Racial differences in levels of gene expression and differences in micro-ribonucleic acid (RNA) expression in fibroid tissue have been observed, potentially contributing to racial disparities (Katon et al., 2023). A 2017 systematic review indicated that age, followed by race, had the highest impact on uterine fibroids risk–women in their 50s or 60s had a 10 fold higher risk, compared to women in their 30s (Stewart et al., 2017). In addition, other factors may increase the risk of developing uterine fibroids. For example, results from clinical studies suggest a correlation between low vitamin D levels and development of uterine fibroids in women. However, clinical studies demonstrating the effectiveness of vitamin D supplementation in reducing the need for surgery or other medical treatments are inconclusive. Other dietary factors that may increase the risk for developing uterine fibroids include low intake of fruits and vegetables as well as the ingestion of pollutants in food, such as phenolic environmental estrogens. However, further research is needed to understand the exact mechanisms contributing to this potential risk (Tinelli et al., 2021). Other notable risk factors include family history for uterine fibroids, reproductive factors including premenopausal stage and time since last birth, hypertension, and dietary factors including food additives and soybean milk consumption (Stewart et al., 2017). Factors which were noted to be potentially protective included smoking (Wesselink et al., 2023), parity, and oral contraceptive use. The authors noted the limitations of these findings, based on available data, with greater variability in studies involving only a single center. No effective primary or secondary prevention strategies for fibroids have been identified. Clinical Presentation and Diagnosis Many individuals with fibroids are asymptomatic, but 30–40 percent have symptoms. The location of fibroids in the uterine wall and their size largely drive symptoms, which most commonly include abnormal uterine bleeding and heavy menstrual bleeding (AUB/HMB), dysmenorrhea, pelvic pressure, and pain arising from the bulk and volume of the fibroids (Donnez and Dolmans, 2016). Other symptoms may include fatigue, shortness of breath, and palpitations from AUB/HMB-related anemia; increased urinary frequency, particularly at night, or urinary retention from pressure on the bladder; and back pain and constipation from fibroid pressure from the posterior uterus. Fibroids may be found or suspected incidentally, such as in an annual exam, from imaging for pregnancy, or based on symptom presentation. The findings of an enlarged uterus or an irregular uterine contour on bimanual exam are suggestive of fibroids. Pelvic ultrasound is acceptable for diagnosis given its relatively low cost and accessibility. Magnetic resonance imaging (MRI) is helpful when precise fibroid mapping within the uterine wall is needed, a question about fibroid viability arises, many or large fibroids exist, or it is important to assess blood flow to the fibroids (Levens et al., 2009; Yang and Navuluri, 2021). Pathological histology, however, remains the gold standard for diagnosis because of the very low but present risk of leiomyosarcoma, a rare type of cancer that grows in smooth muscle (Chen et al., 2018). Evaluation may also include assessment of anemia and iron stores depending on the patient’s PREPUBLICATION COPY: UNCORRECTED PROOFS 

14 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN history and symptom profile. Given how little is known about normal menses parameters and the normalization of abnormal menses for some patients, it is important to probe beyond “are your periods normal” in patients with suspected fibroids (Ghant et al., 2016; Marsh et al., 2014). Lastly, studies have shown significant intersections between fibroid symptoms and mental and emotional well-being: patients with fibroids have significantly higher rates of depression, anxiety, and self-harm than matched patients without fibroids (Chiuve et al., 2022). A recent systematic review found significant improvement in quality of life and mental health parameters after treatment (Neumann et al., 2024). Treatment and Management The current treatment options for uterine fibroids include medication, surgery, and uterine artery embolization. Fibroids or fibroid symptoms can be managed medically through hormonal or nonhormonal options, using interventional radiological techniques or surgery. Each of these options carry their own level of risk and thus, shared decision-making between patient and provider is critically important. Watchful waiting may be appropriate for the asymptomatic patient with no evidence of (AUB/HMB)-related anemia or iron deficiency, mild symptoms who and close to menopause, or who is unwilling or not ready to engage in treatment. Treatment choice should involve shared decision making and be based on the symptoms; the individual’s life goals, including the desire for pregnancy, retention of uterus independent of pregnancy, risk factors, and availability of appropriate medical expertise. Medical treatments, which include hormonal and nonhormonal options, largely treat AUB/HMB- and dysmenorrhea-related symptoms (De La Cruz and Buchanan, 2017). Nonhormonal treatments include nonsteroidal inflammatory drugs (NSAIDs) and tranexamic acid (De La Cruz and Buchanan, 2017). NSAIDs reduce HMB by decreasing prostaglandin activity in the endometrial cavity, and tranexamic acid is an antifibrinolytic. Hormonal agents include combined oral contraceptives, levonorgestrel-releasing intrauterine systems, and progestin-only oral and injectable agents, patches, and vaginal rings (De La Cruz and Buchanan, 2017); they work largely by thinning the endometrium and suppressing ovulation, resulting in less AUB/HMB. Despite the known role of estrogens and progestins on fibroid pathophysiology, research has not identified an association between endogenous hormones and an increased risk of fibroids (Marsh et al., 2024). Medications, such as tibolone, aromatase inhibitors, selective estrogen receptor modulators, and selective progesterone receptor modulators, are still in the early stages of clinical trials, but show promise (Ulin et al., 2020). Gonadotropin-releasing hormone (GnRH) analogues have been shown to be an effective treatment for fibroids. Depot leuprolide acetate, which is a GnRH agonist given intramuscularly, is FDA approved to treat fibroid related anemia prior to surgical procedures and found to decrease fibroid size preoperatively. Oral GnRH- antagonists, a newer class of GnRH analogues have proven to be effective in mitigating HMB and uterine fibroid associated pain. They block GnRH receptors in the pituitary gland, which lowers levels of gonadotropins, and subsequent reduction of sex steroid levels of estradiol and progesterone. This then leads to a thin endometrium and less bleeding. Oral GnRH agents currently approved for the treatment of uterine fibroids are elagolix and relugolix. Patients may be prescribed either once daily relugolix with estradiol and norethindrone acetate or twice daily elagolix for a period up to 24 months. Linzagolix, is another oral GnRH antagonist, which has not yet received FDA approval in the U.S. but has also been shown to significantly reduce fibroid related bleeding symptoms (Donnez et al., 2022; Neblett and Stewart, 2023). This class of PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 15 treatment holds great promise for improving the quality of life of patients with uterine fibroids. (Neblett and Stewart, 2023; Stewart et al., 2021). Interventional radiological approaches include uterine artery embolization, high-intensity focused ultrasound, and MRI-guided focused ultrasound (Fischer et al., 2015). The latter is the only interventional radiological procedure that the FDA has approved for patients who want to become pregnant. Surgical options include myomectomy (removing the fibroids), hysterectomy, radiofrequency ablation, and endometrial resection and ablation. The former is the only appropriate option for patients who desire childbearing. Surgeons can remove fibroids or perform a hysterectomy using one of several approaches. with the ideal being to select the least invasive option. Uterine artery embolization is another option. During this procedure, an embolic agent is injected into both uterine arteries, resulting in devascularization of the uterine fibroids and reduction in size. This reduction may last up to 5 years or more depending on the age of the patient at the time of the procedure. However, data are limited regarding the impact of uterine artery embolization on fertility and pregnancies (Stewart et al., 2021). Quality of life measures were similar among patients receiving uterine artery embolization, hysterectomy, and/or myomectomy. Selecting the appropriate treatment approach should be based on the individual patient's needs, stage of life course, risk, and the impact of continued growth of uterine fibroids (Ulin et al., 2020). Disparities Significant racial disparities exist in in gene expression, incidence and prevalence, and treatment choices outcomes. Racial differences in levels of aromatase gene expression and estradiol levels have been observed, and may contribute to racial disparities given that fibroids are known to be sex steroid responsive (Ishikawa et al., 2009; Marsh et al., 2011). In addition, asymptomatic Black women presented with fibroids at a younger age, compared to White women: of women between 18 and 30 years of age, 26 percent of Black women had fibroids compared to 7 percent of White women (Marsh et al., 2013). More so, Black women had a higher age-specific cumulative incidence than White women: by age 50, Black women had an estimated cumulative incidence of more than 80 percent, compared to 70 percent for White women (Baird et al., 2003). A prospective ultrasound-based study of more than 1,600 Black women found a higher age specific incidence of fibroids, which was higher than previous figures based on self-report in cohort studies (Wegienka et al., 2022). The vast majority of data on fibroid prevalence and incidence comes from studies of White and Black women, which is a significant limitation. Differences in lived experience suggest that Black women are exposed to other risk factors for uterine fibroids, including stress, interpersonal and structural discrimination, behavioral factors related to diet and physical activity, use of certain beauty products, and harmful environmental and occupational exposures (Katon et al., 2023). In addition, social exposures early on in life, including adverse childhood experiences and chronic psychological stress were associated with increased odds of uterine fibroids and may interact with other lifestyle behavioral factors such as alcohol use, poor diet, and physical inactivity among women (Katon et al., 2023). Nonetheless, Black women represented only 15 percent of participants in fibroid-related clinical l trials as of 2010 (Taran et al., 2010). They disproportionately have hysterectomies or undergo surgical removal and are less likely to have a minimally invasive option for PREPUBLICATION COPY: UNCORRECTED PROOFS 

16 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN hysterectomy, even when controlling for uterine size. One recent study found that when given the choice, Black patients opt for uterine-sparing procedures more than White patients (Wegienka et al., 2021). Research Gaps Despite the high prevalence and morbidity of fibroids, several gaps exist. These include the underrepresentation examining Hispanic/Latina, Asian, Middle eastern/North African, and other racial/ethnic groups of women and the lack of prevalence and incidence data. In addition, there are gaps in the understanding differences in disease presentation and health care access, such as, the variation in the number of fibroids women experience, disease recurrence, impact on fertility and pregnancy, specialty referrals, including counseling. Furthermore, significant research gaps exist in what is known about the condition across the full spectrum of the disease, especially around established strategies to prevent, diagnose and treat fibroids. Research gaps include the following areas: prediction tools, longitudinal studies that include imaging-based screening of uterine fibroids (versus self-report), and biological markers. In addition, research is needed that incorporate diverse racial and ethnic groups and other groups to improve understanding of factors, especially structural sand social determinants of health, that contribute to the pathophysiology and disparities in fibroids. For example, although some studies suggest worse symptoms in Hispanic compared to Black and White women, and higher incidence in Asian and Pacific Islander women, compared to White women, and lower risk in American Indian and Alaska Native women, compared to White women, there is an overall underrepresentation of women from racial and ethnic groups. The existing studies are poorly designed and underpowered to look at racial/ethnic groups beyond Black and White women (Armed Forces Health Surveillance Center, 2011; Aninye and Laitner, 2021; Marsh et al., 2018). Research is needed that look into treatments that go beyond symptom management and focus on primary and secondary prevention (Aninye and Laitner, 2021), as is research beyond basic and mechanistic research of cells that should include behavioral, patient- and person-centered, community-based participatory, and health services research on fibroids. FEMALE INFERTILITY The World Health Organization classifies infertility as a disease. Historically, it has been defined as the inability to conceive after 12 months of unprotected sexual intercourse if less than 35 years old or trying to conceive for 6 months if older than (CDC, 2023). Acknowledging the limitations of this definition, ASRM recently expanded the definition of infertility to the following: • The inability to achieve a successful pregnancy based on a patient’s medical, sexual, and reproductive history, age, physical findings, diagnostic testing, or any combination of those factors; • The need for medical intervention, including, but not limited to, using donor gametes or donor embryos to achieve a successful pregnancy either as an individual or with a partner; • In patients having regular, unprotected intercourse and with no known etiology for either partner suggestive of impaired reproductive ability, evaluation should be initiated at 12 PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 17 months when the female partner is under 35 years of age and at 6 months when the female partner is 35 years of age or older; • Nothing in this definition shall be used to deny or delay treatment to any individual, regardless of relationship status or sexual orientation (Practice Committee of the ASRM, 2023). Infertility is further defined as primary or secondary and by etiology, which is important because it affects treatment options and success rates. Under the new definition, primary infertility means that pregnancy has never been achieved. Secondary infertility arises after having conceived at least once, regardless of the outcome, but then being unable to conceive. The 12-month criteria derives from the biologic and clinical observations that 85–90 percent of non-contracepting couples of normal fertility will conceive within a year (Cramer et al., 1979; Guttmacher, 1956). Pathophysiology/Biological Mechanisms and Risk Factors Infertility is classified into etiological categories that include ovulatory dysfunction, diminished ovarian reserve, tubal factors, uterine factors, endometriosis, and male factors (Carson et al., 2021). “Unexplained” infertility is a diagnosis reached by exclusion, found in 15– 30 percent of couples (Gelbaya et al., 2014). It refers to the absence of identifiable abnormalities following a standard evaluation that yields evidence of regular ovulation, normal sperm parameters, and tubal patency. Male factor infertility, which includes disorders of sperm production and function, is beyond the scope of this report. However, regardless of factors involved, women require infertility treatment that can often be more invasive. In a review of 8 published reports that included more than 5,129 infertile couples, investigators reported that the primary diagnoses were disorders of oocyte production, including not ovulating or ovulating irregularly (27 percent); disorders of sperm production, such as low sperm concentration or motility (23 percent); tubal defects (19 percent); endometriosis (4 percent); uterine, cervical, and other factors (4 percent); and unexplained infertility (16 percent) (Collins and Crosignani, 1992). Male factors are the primary diagnosis in 30 percent of couples and a contributing factor in an additional 20 percent (Howards, 1995). In many couples, more than one factor is present (Brugo-Olmedo et al., 2001;White et al., 2006). Diminished Ovarian Reserve Ovarian reserve refers to a woman’s store of oocytes with the potential for a future pregnancy. Although research has shown that a number of environmental and genetic factors affect it, the most consistent risk factor for diminished ovarian reserve is increasing age. The follicular pool has been shown to peak at mid-gestation at 5–7 million primordial follicles. This number decreases to one million by birth and less than 50,000 by the mid- to late- 30s. Fertility studies in populations that reproduce freely and do not use contraception demonstrate a clear decline in fertility with advancing age (Tietze, 1957). Beyond infertility rates, little is known about drivers of and physiology underlying the human variation in onset, duration, and symptoms of perimenopause (O’Reilly et al., 2023). In addition to the decreasing oocytes with age, cytogenetic analysis of retrieved oocytes that failed to fertilize during in vitro fertilization (IVF) reveals a marked increase in oocytes with fewer than the normal 46 human chromosomes as age increases (Kuliev et al., 2003; Pellestor et al., 2003). As women grow older, the number of conceptions ending in spontaneous abortion PREPUBLICATION COPY: UNCORRECTED PROOFS 

18 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN increases, a trend almost entirely explained by increasing rates of chromosome abnormalities. One research team observed that the probability of a chromosomally abnormal, spontaneously aborted fetus rose from less than 40 percent at 20 years old to nearly 80 percent at older than 42 (Hassold and Chiu, 1985). Ovulation Disorders Regular menstrual cycles, defined as menstruation every 21–35 days with less than 7 days of variability between cycles (ACOG, 2012), are a signal of regular ovulation. Irregular or absent cycles (secondary amenorrhea) require evaluation and most often reflect irregular or absent ovulation. Potential etiologies include pregnancy, hypothalamic dysfunction, hyperprolactinemia, thyroid disorders, polycystic ovarian syndrome, or primary ovarian insufficiency. Uterine and Tubal Factor Infertility Abnormalities in the uterus may lead to infertility or an increased risk of pregnancy loss. Congenital uterine malformations are not associated with infertility but do increase the risk of pregnancy loss. Uterine fibroids affect both fertility and pregnancy loss. Asherman’s syndrome, or intrauterine adhesions, presents another acquired cause of infertility and most commonly results from dilation and curettage, either postpartum for retained placenta or after a missed or incomplete abortion (Klatsky et al., 2008; Pritts et al., 2009; Smikle et al., 2024). A major contributor to tubal factor infertility is inflammation of the epithelial surfaces of the fallopian tubes caused by infections, including sexually transmitted infections (Tsevat et al., 2017). Clinical Presentation and Diagnosis The evaluation for the female components of infertility includes a history and physical exam and diagnostic evaluation of an ovary’s store of oocytes, confirmation of ovulatory function, confirmation that the fallopian tubes are not blocked, and evaluation for uterine abnormalities (Walker and Tobler, 2024). The causes underlying a significant portion of infertility cases remain unexplained. The 2010 National Survey of Family Growth found that of the women experiencing infertility, 17 percent aged 25-44 or their partners had ever used fertility services (Chandra et al., 2014). This was more common among older, non-Hispanic White women who had never given birth and women of all races and ethnicities with higher levels of education and household income (Chandra et al., 2014). In addition, women using fertility services are more likely to be lean, have never smoked, and report more regular exercise and more multivitamin use (Farland et al., 2014, 2016). One study found that 50 percent of women with primary infertility sought help from a general practitioner, whereas only 34 percent of those with secondary infertility did (Gunnell and Ewings, 1994). Treatment and Management Treatment of female infertility depends on the etiology, if one is identified, and includes ovulation induction with either oral or injectable agents and IVF. Additional treatment options include correction of certain hormonal abnormalities (e.g., hyperprolactinemia, thyroid dysfunction, improved diabetes control), surgery (e.g., Asherman’s syndrome, some fibroids, PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 19 septums) and intrauterine insemination (Carson and Kallen, 2021; Unuane et al., 2011). Preventing primary and secondary infertility includes lifestyle and behavior changes to reduce exposure to factors that negatively affect fertility, along with education and increasing the general awareness of windows of fertility and indications of subfertility. Moderators of successful prevention including disparities and structural and social contexts (see Figure 5-5) (Fauser et al., 2024). FIGURE 5-5 Conceptual model of infertility prevention. SOURCE: Fauser et al., (2024). PREPUBLICATION COPY: UNCORRECTED PROOFS 

20 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Disparities Treatment costs, racial and ethnic disparities, and geographic distance affect access to care and use of fertility services (Feinberg et al., 2006). Although state-mandated insurance coverage of fertility services, available in 19 states, increases their use (Jain et al., 2002), disparities in use and outcomes persist (Feinberg et al., 2006; McQueen et al., 2015). In a study of those starting assisted reproductive therapy, Black and Hispanic women had been attempting to conceive for 1.5 years longer than White women and reported that it was difficult to get an appointment, take time off from work, and pay for treatment (Galic et al., 2021). The distribution of specific types of infertility varies by population and study, depending on the methods used for diagnosing, classifying, and treating patients. Although older studies found disparities in prevalence among different racial and ethnic populations, more recent studies have shown that it is not associated with race or ethnicity (Kelley et al., 2019). One study found that in low-cost settings, African American women’s use of IVF exceeded African American representation in the general population (Feinberg et al., 2006). Hispanic women, however, remained significantly underrepresented, even in low-cost Department of Defense settings (Feinberg et al., 2006). Disparities exist along the full spectrum of the infertility journey, including who is asked about their desire to become pregnant, is diagnosed, and receives a referral through treatment and live birth (Figure 5-6) (Weiss and Marsh, 2023). People seeking infertility treatments are a small subset and not representative of all such individuals or couples (Farland et al., 2014; 2016). Referral bias must be considered when interpreting prevalence statistics or the results of descriptive, associative, and causal inference studies, including basic science discoveries using biologic samples collected from those undergoing treatment, particularly IVF. In addition, the extent to which each couple undergoes evaluation, the selection of patients for treatment, couples’ decisions to seek and pay for infertility therapies, length of patient follow-up all differ. PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 21 FIGURE 5-6 The infertility journey. SOURCE: Weiss and Marsh (2023). Research Gaps Delaying, minimizing, or altering education on reproductive anatomy and sexual health increases the risk of infertility. In addition to improving awareness, research to better understand sexual dysfunction and the yet unknown pathophysiology driving what is simply defined as idiopathic or “unknown” cause or infertility would improve livebirth rates and may inform pathways for preventing secondary and even primary infertility. However, infertility is difficult to study in humans, as it is only identified when women are intentionally attempting to conceive and aware that months have passed without successful pregnancy (Pérez Capotosto et al., 2023; Wang et al., 2023b). The length of infertility remains unknown, which masks biological indicators of the earliest states of infertility. For this reason, developing experimental models in myriad species has been essential to understanding the roots of infertility. Researchers need to continue using these models to identify possible causes and improve translation of research to clinical treatment and preventive protocols. Although infertility affects individuals from all socioeconomic statuses, and to some degree may be inversely associated with affluence, clinical evaluation and treatment are strongly skewed toward those with higher educational attainment and greater financial resources. Thus, the diagnosis is largely dependent on those who seek care and treatment, so unbiased prevalence estimates are needed (Fauser et al., 2024). Research is needed to address these barriers to care and treatment especially among those groups who experience disparities, through improving evaluation and implementing earlier interventions that will lead to successful care. PREPUBLICATION COPY: UNCORRECTED PROOFS 

22 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN VULVODYNIA Vulvodynia is chronic vulvar burning or pain that leads to major physical and psychological distress. It has no known cause, persists for 3 or more months, and negatively impacts quality of life, especially sexual functioning. In 2015, a consensus panel of experts defined vulvodynia as a chronic condition of vulvar pain in which no known clinical pathology can explain its origin (Bornstein et al., 2016). Its classification is based on the site of the pain— whether it affects the entire vulva or is localized to one or more specific areas—and triggers, such as whether it is provoked by touch or spontaneous. It is well documented that women with vulvodynia, compared to women with no history of vulvar pain, report a greater number of chronic comorbid medical conditions; functional somatic syndromes such as chronic pain, fibromyalgia, irritable bowel syndrome, and interstitial cystitis are significantly more common in women with vulvodynia (Reed et al., 2012). However, the temporal relationships between these conditions are not well understood, raising question of whether these conditions have similar etiological underpinnings. Pathophysiology/Biological Mechanisms Although the mechanism behind vulvodynia is unknown, it may result from an altered immune-inflammatory response to biopsychosocial or environmental exposures (Reed et al., 2019; Torres-Cueco and Nohales-Alfonso, 2021). However, it is unclear whether immune- inflammatory processes influence it. Upon clinical examination, some women exhibit skin irritation, but many do not. Histopathology studies in women with and without clinically confirmed vulvodynia do not consistently show differences in inflammatory markers such as TNF-α, IL-1α, and IL-1β (Eva et al., 2007). However, studies have found a significant correlation between inflammation, the presence of mast cells, and the density of nerve bundles in vaginal tissue specimens from women with vulvodynia (Awad-Igbaria et al., 2022; Bornstein et al., 2004). Inflammation may therefore serve as an intermediate step in the activation of sensory receptors, triggering nerve proliferation that results in vulvar pain, but by that point, clinical signs of inflammation may no longer be present (Awad-Igbaria et al., 2022; Bornstein et al., 2004). Studies in animal models have shown that female mice exposed to a chemical allergen directly on the labia (anatomically similar to vulvar tissue) developed an inflammatory reaction, histological evidence of nerve growth proliferation (Falsetta and Wood, 2020). Consistent with this finding in mice, a study of women found that self-reported history of hives, allergic reactions to insect bites, and seasonal allergies were more commonly observed in women with vulvodynia relative to controls (Harlow et al., 2009). Additional support for the role a compromised immune-inflammatory process plays in vulvodynia comes from a large, nationwide, Swedish register-based study (Harlow et al., 2023). The authors showed that women with localized provoked vulvodynia, involuntary vaginal muscle spasms, or both were more likely to experience a wide spectrum of other immune-related conditions compared to women who had never been diagnosed with a vulvar pain syndrome. This association became stronger with increasing numbers of unique immune-related conditions relative to women with no vulvar pain history (Harlow et al., 2023). However, more research is needed to understand why certain women exposed to events that lead to hyperimmune-activated responses develop vulvodynia yet many who experience the same exposures do not. PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 23 Risk Factors Although the cause of vulvodynia remains unknown, research has found evidence of several factors that may increase the risk (see Figure 5-7). FIGURE 5-7 Risk factors for vulvodynia. SOURCE: Bernie Harlow, unpublished. PREPUBLICATION COPY: UNCORRECTED PROOFS 

24 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Oral Contraceptives It is plausible that oral contraceptives may increase the risk of vulvodynia. They are known to affect serum estradiol, free testosterone levels, and hormonal receptors, and alter the morphological pattern of the vulvar vestibular mucosa, which may induce atrophic changes in the mucosa (Johannesson et al., 2007a, 2007b; Liao and Smith, 2014; Ting et al., 2004). Although observational studies have shown that oral contraceptives use increases the risk of vulvodynia (Bazin et al., 1994; Bouchard et al., 2002; Goldstein et al., 2010; Harlow et al., 2008; O’Reilly et al., 2023), many of the studies selected cases from clinic-based populations, a self- selected group of women with vulvodynia, and exposure to oral contraceptives in women with vulvodynia differs in those who seek treatment (Bond et al., 2022). In addition, women selected as controls from clinic-based FDA populations differ in their patterns of oral contraceptives use compared to those selected from the general population. Thus, whether oral contraceptives affects the risk has become highly debated, with better research needed to address these methodological limitations (Johannesson et al., 2007a, 2007b; Liao and Smith, 2014; Ting et al., 2004). Infectious Diseases and the Vaginal Microbiome Altered inflammatory mechanisms triggered by urinary tract or genital infections may play a role. However, disentangling the temporal relation between them and the onset of vulvodynia is challenging. Yeast infections have consistently been shown to be associated with vulvodynia for decades (Bohm-Starke, 2010), and several studies have explored the relationship with sexually transmitted infections (Graziottin and Serafini, 2009; Nguyen et al., 2009). A 2017 study sought to identify the temporal relation between yeast infections and vulvar pain onset. The authors studied 200 population-based and clinically confirmed cases of vulvodynia and a similar number of general population controls. They separated yeast infections that occurred before and after vulvar pain onset and observed strong associations suggesting that yeast infections are an antecedent risk factor for vulvodynia, and that vulvodynia is an antecedent risk factor for new or recurrent yeast infections (Harlow et al., 2017). This is consistent with studies of vaginal fibroblasts isolated from vulvodynia patients that indicate higher levels of inflammatory cytokines, compared to those isolated from controls, when challenged with yeast antigens (Farmer et al., 2011; Foster et al., 2015). Thus, the immune profiles of women at risk of vulvar pain may predispose them to yeast infections (Farmer et al., 2011; Foster et al., 2015). Their immune profiles may also lead to recurrent yeast infections in women with a vulvodynia diagnosis. Changes in the vaginal microbiome may affect the development of vulvodynia (Panzarella et al., 2022; Park et al., 2021; Sacinti et al., 2024). Preliminary evidence indicates that such changes can lead to vaginal nerve ending injury and mast cell overproduction. However, only a handful of studies have explored this association, with mixed results (Panzarella et al., 2022; Park et al., 2021; Sacinti et al., 2024). A recent case-control study showed no overall association but did show that women with low diversity of vaginal lactobacillus were more prone to vulvodynia as a consequence of exposure to yeast infections, childhood trauma, and mood or anxiety disorders (Bedford et al., 2020). PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 25 Trauma and Mental Disorders Mechanistic evidence links psychological stressors to physiological changes in the central nervous, endocrine, and immune systems (Agorastos and Chrousos, 2022; Segerstrom, 2007), suggesting that abnormal stress immune responses may affect vulvodynia onset. As illustrated in Figure 5-8, trauma and psychiatric conditions stimulate a response that may be short lived and well tolerated or prolonged, leading to a state of perseverative cognition or rumination in response to the stressors. The prolonged response can affect immune-inflammatory response mechanisms that may precede vulvodynia. As vulvodynia itself is a stressor, it may feed into a cycle of rumination (Khandker et al., 2019). FIGURE 5-8 The biological rationale for the effect of stressors on vulvodynia. PREPUBLICATION COPY: UNCORRECTED PROOFS 

26 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Victimization One case-control study to assess the association between victimization and vulvodynia found that women who never or rarely received family support as children were 2–3 times more likely to report vulvar pain compared to women who sometimes or more often received support (Harlow and Stewart, 2005). Women who reported feeling danger in their home, neighborhood, or school as children were also 2–3 times more likely than women who did not to experience vulvodynia symptoms, and those with severe physical or sexual abuse in childhood were significantly more likely to report vulvodynia symptoms than women who did not. The association with physical abuse was in women who lived in fear of physical abuse or were physically or sexually harmed by an immediate family member rather than strangers (Harlow and Stewart, 2005). These findings are consistent with the biological rationale for the effect of stressors (see Figure 5-8). However, additional population-based studies of clinically confirmed cases of vulvodynia are needed to replicate this association (Charbonneau-Lefebvre et al., 2022; Cohen-Sacher et al., 2015; Edwards et al., 1997; Jackowich et al., 2021). Selection bias associated with case ascertainment and differential reporting bias between clinic- and population-based cases and controls may partially explain the inconsistent findings in the few studies reported on the relationship (Charbonneau-Lefebvre et al., 2022; Cohen-Sacher et al., 2015; Edwards et al., 1997; Jackowich et al., 2021). Psychiatric Morbidity Studies assessing the association between psychiatric morbidity and vulvodynia have not considered the temporal relationship between them. Clearly, women who experience vulvodynia endure a significant psychological impact resulting from a lack of intimacy, discomfort that affects physical and social functioning, and the stigma attached to this condition. However, few studies have been able to assess the influence of prior psychiatric morbidity. One nested case- control study of 100 women with vulvodynia and 325 matched community-based controls reported that cases were significantly more likely to self-identify with depressive symptoms prior to onset of vulvar pain compared to a similar period in controls (Arnold et al., 2007). In another study, researchers interviewed 82 women with vulvodynia and 82 without and found that along with depression and anxiety, abnormal behavioral traits such as obsessive- compulsive disorder and phobia were significantly higher in women with vulvodynia (Wylie et al., 2004). Unfortunately, each study relied upon self-reported symptoms rather than diagnosis of psychological disorders. However, findings from a study that used the Structured Clinical Interview for the Diagnostic and Statistical Manual-IV Axis I Disorders suggested that in relation to the first onset of vulvar pain, women with clinically assessed prior mood or anxiety had four times the odds of vulvodynia compared to women without (Khandker et al., 2011). Investigators have observed substantial associations with a mood disorder only, anxiety disorder only, or both mood and anxiety disorder as a consequence of vulvodynia (Arnold et al., 2007; Khandker et al., 2011; Wylie et al., 2004). Clinical Presentation and Diagnosis A true diagnosis requires clinical confirmation to rule out other known, such as dermatological conditions or gynecologic infections. Ruling out vulvovaginal yeast infections and other gynecologic conditions as the source of pain is essential for an accurate diagnosis (Bergeron et al., 2020). A major limitation in vulvodynia research is applying consistent PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 27 diagnostic criteria to. Thus, diagnostic misclassification will likely bias research aimed at identifying the cause. However, as a large proportion of women fail to seek treatment, studies that identify women from the general population will likely minimize selection bias and allow for more accurate prevalence and valid exposure assessments. The challenge with this approach is that confirming vulvodynia in the clinic is somewhat labor intensive and requires resources that are not always available in population-based research. Treatment and Management No standardized treatment exists for vulvodynia, leaving women frustrated and anxious after seeing multiple physicians and trying multiple treatments with no relief. Well-conducted studies on proposed treatments are few, and the level of evidence is low (Bohm-Starke et al., 2022). A multidisciplinary approach to patient care, delivered by a team that may include gynecology, dermatology, physiotherapy, clinical psychology, sexual counseling, and pain specialists, is needed to address the physical and psychological aspects (Santangelo et al., 2023). Treatment choices should be individualized, include the partner when appropriate, and consider cost and the local health care system (Andrews, 2010; Danby and Margesson, 2010; Mandal et al., 2010). Recent vulvodynia treatment guidelines endorsed by the National Vulvodynia Association recommend education and support as part of any care plan (Brotto et al., 2010). Because women have many caregivers and are often confused and frustrated, they need precise, clear, reliable information about their diagnosis and prescribed treatments that help them set realistic expectations. Researchers have developed self-management programs that can be effective in helping a woman understand and take control of her condition (Brown et al., 2009). Disparities A recent scoping review highlighted that studies on disparities in vulvodynia outcomes by race and ethnicity are limited due to studies lacking diversity, with a large percentage of participants being White women and highly educated (Niedenfuehr et al., 2023). These limited studies suggest that Black women experienced greater functional and psychological impairment compared to White women. In addition, cultural differences suggest that the reporting of vulvar pain is lower in Black and Latina women compared to White women. Research Gaps Significant research gaps exist regarding the pathogenic mechanisms underlying vulvodynia, especially related to immune-inflammatory responses to biopsychosocial and environmental exposures. Research is needed to further elucidate the role of oral contraceptives, urogenital infections, exposure to trauma, and psychiatric conditions, and establish better diagnostic criteria. A major gap in the research is applying consistent diagnostic criteria to rule out other explanations, which presents major issues in diagnostic misclassification and bias in etiological research. Ruling out vulvovaginal yeast infections and other gynecological conditions is also essential for an accurate diagnosis. Considering the lack of standardized treatment, more research is needed on treatment options and their effectiveness to either alleviate or prevent pain. Research is also lacking on disparities experienced by racial and ethnic groups of women and how they intersect with the influence of structural and social determinants of health. PREPUBLICATION COPY: UNCORRECTED PROOFS 

28 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN PELVIC FLOOR DISORDERS People have known for millennia that women experience chronic and debilitating problems arising from childbirth (Emge and Durfee, 1966). These include urinary and fecal incontinence and prolapse of the pelvic organs and are collectively referred to as pelvic floor disorders (PFD). PFD affect one in four women in the U.S., become more common as women age, and result from several primary factors (Nygaard et al., 2008), including the unique anatomical accommodations in a woman’s body required to allow the large head of a newborn to pass through the pelvis during vaginal birth. Other factors include the damage that can occur during delivery and the deterioration that occurs with age. These factors interact in various combinations to cause different types of PFD. Understanding of the functional and structural failures responsible for PFD in women lags behind conditions that affect both sexes and those that primarily afflict men. Women suffer significant stigmatization for incontinence and prolapse and report diminished self-esteem, altered body image, and ability to enjoy sexual relations. PFD are commonly associated with depression and hopelessness as well (Rantell, 2023; Robinson et al., 2022). Incontinence, for example, can leave women feeling anxious about leaving their homes, which can result in lost connections with friends and family. It can also affect employment for women whose workplace does not allow them free access to bathrooms (Linder and Nygaard, 1998; Harlow et al., 2018). PFD can be severe enough that 15 percent of American U.S. women require surgery to treat them. Because these problems are not discussed widely, many people are unaware of how commonly treatment is needed (DeLancey, 2004). For example, surgery for PFD is four times more common than inguinal hernia repair in women and three times more common than removal of the entire prostate gland in men (Lowrance et al., 2012). However, the belief that PFD are inevitable can lead to women, clinicians, and researchers dismissing this as “normal” and not something to focus to develop treatment options. This attitude can also deter women from seeking care and cause clinicians to feel uncomfortable evaluating for PFD. Many women avoid admitting to these problems and often do not seek treatment because the psychological cost is greater if they are medically diagnosed (Nicolson et al., 2008). The rapidly growing adult incontinence products industry is evidence that women are living with these problems. Emphasis on privacy and home shipment signify the stigma of being seen purchasing these products, which, like menstrual products and most female-dominant products, are still subject to sales tax and not defined as essential in state-specific or federal legislation. Pathophysiology An understanding of the disease mechanisms responsible for PFD lags behind other fields. Clinicians classify PFD as symptom complexes—stress versus urge urinary incontinence, for example—rather than understanding the mechanistic failures underling them, such as urethral failure, sensory dysfunction, or abnormally strong contractions of the detrusor muscles surrounding the bladder (Aoki et al., 2017; Hastings and Machek, 2020). Understanding functional and structural failures in the neuromuscular and fascial structures is necessary to develop personalized approaches that target each condition. Such research has been undertaken recently, but lags behind other fields, such as cardiology, where the causes of congestive heart failure (CHF), are determined (e.g., mitral stenosis, ventricular dysfunction, cardiac arrhythmias) and treatment is based causes. The lack of understanding of the basic mechanisms that cause PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 29 PFD is a major contributor to the lack of evidence-based treatments and treatments’ suboptimal success. Urinary Incontinence Urinary incontinence results from damage that occurs from vaginal birth, obesity, hysterectomy, and genetic predisposition. It involves the complex interplay among the bladder’s detrusor muscle stability, urethral sphincter’s striated and smooth muscles competence, integrity of connection between the levator ani muscle—the largest component of the pelvic floor—and urethra (Aoki et al., 2017; DeLancey et al., 2008a) and complex neural control mechanisms. The classical categorization divides the common forms into stress incontinence, urge incontinence, and mixed incontinence associated with exertion, effort, sneezing, or coughing. Stress incontinence, for example, occurs during a cough, where abdominal pressure causes leakage because of poor urethral support; urge incontinence is caused by detrusor contraction at inappropriate times. Recent evidence shows that failure of the urethral sphincter is present in in both stress and urge incontinence (Pipitone et al., 2021). This finding may help explain why the standard treatments that only target detrusor suppression and not the urethral sphincter are rated by reduced rather than completely eliminated incontinence (Lukacz et al., 2017). Fecal Incontinence Fecal continence relies on intact and innervated internal and external muscle and the puborectal muscle. Older women with fecal incontinence often exhibit reduced anal resting or squeeze pressures, indicating sphincter weakness. Neurogenic injury, common in obstetric trauma or neuropathies, contributes to anal weakness, and impaired sensation can play a role as well. The pathogenesis of a smaller rectal reservoir remains unknown, particularly when associated with anal weakness (Hayden and Weiss, 2011). Pelvic Organ Prolapse Unlike urinary and fecal incontinence, which have specific terms that are generally understood to describe symptoms, prolapse symptoms are challenging to describe, which makes population-based studies based on questionnaires difficult. Although the need for surgery is the most objective parameter available to assess prolapse occurrence, it certainly underestimates the number of women with prolapse because those who choose surgery do not seek treatment. Data regarding the number of surgeries required to treat pelvic organ prolapse each year show that the lifetime risk increases with advancing age. The lifetime risk of prolapse surgery for women who give birth is 11–19 percent (Milsom et al., 2013). Research is just now beginning to establish the specific structural and functional failures that cause pelvic organ prolapse. Impairments of levator ani muscle, its motor control mechanisms, and interaction with several specific fascial connections from the pelvic organs and the pelvic walls occur in varying complex patterns to result in a single clinical condition (Hong et al., 2023). Women with prolapse have 7.3 greater odds of damage to the levator ani muscle compared with women without (DeLancey et al., 2007). Menopause is often mentioned as a causal factor, but when age is factored into the analysis, it is no longer an independent factor (Zhang et al., 2024). Research has identified four deoxyribonucleic acid polymorphisms associated with prolapse, but the relative importance of genetic factors, childbirth, and advancing age is not yet PREPUBLICATION COPY: UNCORRECTED PROOFS 

30 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN known (Deprest et al., 2022). Vaginal childbirth is the primary causal life event due to damage to the muscles, nerves, and connective tissue that control the urogenital hiatus (Handa et al., 2021; Memon and Handa, 2013). However, the advantages of cesarean section deliveries in preventing PFD and identifying women most at risk for PFD are still unclear, especially given the unintended harms that can result from cesarean delivery if widely used. Changes with advancing age cause further deterioration in pelvic organ support, resulting in most women developing prolapse after childbearing (Delancey et al., 2008b). Prevention Women with higher BMI, more comorbid conditions, a hysterectomy, and higher parity have higher odds of one or more PFD (Wu et al., 2014). Similar findings from other studies demonstrate a significant association between increasing age and higher BMI and PFD (Kenne et al., 2022). Given the chronic nature of these conditions and the limited ability to cure them, prevention is a key strategy to improving overall women’s health. Because childbirth is so prominent in all PFD and occurs most often under medical supervision in the U.S., acting then may provide the most promising avenue for prevention strategies. Overall, work has been limited on preventing PFD, except for clinical trials for anal sphincter injury, in part due to the difficulty of assessing outcomes over decades. However, multiple longitudinal cohorts of U.S. women exist with varied population sampling, and a few included data collection on PFD incidence or treatments (Baker et al., 2015). Pelvic muscle training near birth has been advocated for prevention, and yet it is unclear whether the beneficial effects in reducing postpartum urinary incontinence result from therapeutic effects or actual prevention. Evidence is limited that reducing obesity by 8 percent of body weight can decrease the number of incontinence episodes by 20 percent compared to controls (Subak et al., 2009). Diagnosis and Treatment Diagnostic strategies lag far behind those in other fields. In general, PFD diagnosis focuses primarily on documenting symptom complexes and has not advanced to establishing causal mechanisms. Diagnosis is primarily based on physical examination with limited physiological testing. Ultrasound and MRI can determine structural defects but are not widespread because training regarding PFD remains based on decades-old paradigms and evaluation strategies. Urodynamic testing of bladder function and anorectal manometry are used widely, but with significant disagreement in the literature regarding what constitutes a positive diagnosis for many tests (Swavely et al., 2021), and minor changes in testing equipment can yield significantly different measurements. Tests typically use decades-old technology and are significantly limited given the artificial nature of testing in a clinical laboratory, the limited period of observation that may miss the actual events, which occur a few times a day, and significant measurement artifacts. Overall, treatments for PFD reduce the symptoms, but cures are uncommon and rare for urge incontinence. Mid-urethral tape surgery for stress incontinence is highly effective in the short, medium, and long term in eliminating it and improving quality of life (Ford et al., 2015). It has an objective success rate of 80 percent, but 38 percent of women continue to report incontinence symptoms because of coexistent urge incontinence that this surgery does not eliminate (Richter et al., 2010). PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 31 Anticholinergic drugs for urge urinary incontinence result in modest improvements in symptoms compared with placebo (Gandi and Sacco, 2021), but these drugs only eliminate the problem in about 25 percent of individuals, often leaving women with enough incontinence that they would still qualify for treatment trials. Recent studies show only modest improvement in quality of life, and adverse effects were higher with all anticholinergics compared with placebo (Stoniute et al., 2023). For conservative interventions in urinary incontinence, evidence shows better results with pelvic floor muscle training, electrical stimulation, and weight loss compared to controls, along with high evidence of improved quality of life with pelvic floor muscle training compared to controls (Todhunter-Brown et al., 2022). When sufficiently severe to require surgery, pelvic organ prolapse can be managed surgically or with intravaginal pessaries. These are both effective in eliminating prolapse in 75 percent of women, yet long-term success is lower (Bugge et al., 2020; Maher et al., 2023). Pessaries offer relief without surgery but are often associated with vaginal discharge and the need for repeated visits to monitor for complications (Bugge et al., 2020). Treatments for fecal incontinence include pelvic floor muscle training, electrical stimulation, dietary manipulations, drugs, and surgery (Brown et al., 2013) in selected groups of people, particularly when the defects in the muscles surrounding the anal canal can be corrected mechanically. Unfortunately, none of these treatments have high success rates, although improvement is welcome (Bugge et al., 2020; Maher et al., 2023; Stoniute et al., 2023). Disparities Women of color continue to be significantly underrepresented in research focused on PFD despite a comparable prevalence across different groups (Northington and Minaglia, 2023). Observational studies spanning the last 2 decades reveal treatment outcome disparities, with women of color experiencing differences in the rate of surgical interventions. For example, a 2023 review of data from the American College of Surgeons National Surgical Quality Improvement Program found that Black women were more likely to undergo pelvic organ prolapse apical repair procedures or surgery with hysterectomy than White women. Women from other racial and ethnic groups, including Hispanic women, were more likely to undergo surgery to remove or close off all or a portion of the vaginal canal than either Black or White women (Rodríguez et al., 2023). One study found that 20 percent of non-Hispanic Black women experienced complications after surgery compared to 16 percent for White women, 11 for Hispanic women, and 13 percent for women of other racial and ethnic groups (Brown et al., 2022). Discrepancies in outcomes may stem from variations in symptom assessment tools, originally designed in largely homogeneous White, non-Hispanic populations. Understanding these disparities is crucial for uncovering potential underlying causes. Much of the population-based epidemiological data are from Scandinavian countries with populations that are dissimilar to that of many people in the U.S. Research Gaps A major barrier to advancing treatment of PFD has been the misconception that they are somehow a “normal” aspect of being a woman and of aging, an attitude that is changing slowly. However, population-based research has now documented how these chronic conditions are common and deserving of the attention of researchers and clinicians. PREPUBLICATION COPY: UNCORRECTED PROOFS 

32 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Perhaps the greatest barrier is the lack of a robust scientific community conducting mechanistic research. Basic science work focused on elucidating the causal mechanisms and identifying the specific anatomical and physiological impairments responsible for each PFD has begun but lacks evidence-based disease models to organize various research findings and spur a coordinated effort to address important knowledge gaps. Further research is needed at the cellular, molecular, genetic, anatomical, and physiological levels that would aid in developing of new treatment strategies to address impairments not yet discovered as important causal factors for PFD. New diagnostic testing strategies that identify specific failures in individual women are needed so that treatment can address the underlying causes rather than symptom complexes. PREGNANCY AND CHRONIC CONDITIONS Although not considered a chronic condition, pregnancy is a complex physiological process and one of the most critical physiological disrupters in the life course, which is why two chapters in this report consider its effect on women. Chapter 6 discusses it as a reproductive milestone that may influence conditions such as cardiometabolic conditions; this section focuses on the specific conditions associated with it that can affect future pregnancies and the interface between chronic conditions and pregnancy. A brief review of both areas underscores the importance of this life stage. The rates of U.S. maternal morbidity, and it usually can be prevented. As many as 60,000 women each year experience complications categorized as severe maternal morbidity, defined as “unexpected outcomes of labor or delivery resulting in significant short- or long-term consequences to health” (Declercq and Zephyrin, 2021). This does not include prenatal and postpartum conditions such as prenatal depression, miscarriage, intractable vomiting during pregnancy, postpartum pulmonary edema, congestive heart failure, sepsis, inflammation of the inner uterine lining, and depression (Declercq and Zephyrin, 2021). Based on the maternal mortality ratio (MMR), defined as the number of maternal deaths per 100,000 live births, where maternal death is the death of a woman while pregnant or within 42 days of termination of pregnancy, the U.S. has documented an increase in MMR (Declercq and Zephyrin, 2020; World Health Organization, 2024). The U.S. leads industrialized countries in MMR, and women of color are affected disproportionately. Non-Hispanic Black women have three- to fourfold higher rates compared to non-Hispanic White women (Callaghan, 2012). In addition, developed countries have observed an increase in the average age of conception and a greater birth rate among women of advanced maternal age (Glick et al., 2021). Advanced maternal age has been identified as a risk for greater adverse maternal complications such as gestational diabetes, hypertension, and cesarean delivery (Glick et al., 2021). Thus, greater focus on the contributors to maternal morbidity will provide an opportunity to decrease MMR. Reviewing this topic in detail is beyond the scope of this report, but it highlights areas of research that would benefit from additional work on chronic conditions affecting women. Chronic Inflammatory Placental Disorders One group reviewed three conditions that may recur in women and lead to adverse outcomes in future pregnancies: inflammation of the tiny projections of placental tissue, chorionic villi, of unknown etiology; infiltration of maternal macrophages into the space between the villi of the placenta, chronic histiocytic intervillositis (CHI); and extensive deposition of PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 33 fibrin in the space between placental villi (Cornish et al., 2022). The primary finding in these conditions is the disruption of the space between the villi and infiltration of the placenta by maternal immune cells. Severe inflammation of the villi is associated with recurrent pregnancy loss and severe constriction of fetal growth. Women who experience recurrent CHI may be at higher risk for autoimmune diseases. Extensive deposition of fibrin in the space between placental villi can ultimately lead to atrophy and sclerosis. Excluding an infectious cause is critical to the diagnosis. Researchers estimate that inflammation of the villi occurs in 5–15 percent of placentas, with infiltration of maternal macrophages into the space between the villi occurring in 0.2 percent and extensive deposition of fibrin in 0.5 percent. Investigators have studied these conditions in small cohorts and unrandomized studies engaging homogenous populations, limiting their applicability. Research gaps to consider in designing studies include the reliability of the screening methods for placental infection, the mechanism of recurring disease, and the role of immunosuppression in preventing these inflammatory conditions of the placenta. Systemic Chronic Diseases Among Pregnant Women Given the physiological changes during pregnancy, a deepened understanding of its interaction with systemic chronic diseases is paramount. One group assessed the prevalence of chronic diseases among U.S. women with chronic disabilities (Iezzoni et al., 2014). Within a cohort of 6,043 women aged 18—49, 2.0 percent were pregnant, 20.8 percent reported two conditions associated with their self-reported disabled status, and 12.7 percent reported three or more conditions. The most common were back or neck problems, musculoskeletal conditions, and arthritis. In another study, musculoskeletal and pelvic pain were most often noted among delivering women with anxiety or depression (Dalton et al., 2023). The association of pain, anxiety, and depression, and the prevalence of musculoskeletal conditions among pregnant women underscores the importance of diagnostic precision, interdisciplinary care, and safe therapeutic interventions. Pregnant women who are living with chronic conditions, such as human immunodeficiency virus, substance use disorder, cardiometabolic diseases, and autoimmune disorders, may experience greater risk of adverse pregnancy outcomes, and there is a lack of research on the management of these conditions during and after pregnancy (Arab et al., 2017; Daly et al., 2021; Mehta et al., 2020; Singh et al., 2024). Given the increasing prevalence of chronic kidney disease, the need is growing to assess the effect of renal conditions on pregnancy. Coupled with systemic hypertension and elevated protein levels in urine, affected women are at higher risk for complications during pregnancy (Koratala et al., 2017). Other comorbidities such as vitamin D deficiency and anemia, can also worsen during pregnancy, potentially creating a postpregnancy change in the course in these conditions (Wiles et al., 2018). Pregnant women requiring dialysis have a greater risk of premature births and high rates of neonatal intensive care (Oliverio and Hladunewich, 2020). A pregnant woman with MCC requires close surveillance by an interdisciplinary health care team, in addition to better diagnostic tools and safer interventions. Nevertheless, it is critical that she herself understands the risks. One study examined the knowledge and attitudes related to pregnancy and preconception health among women with chronic conditions. In general, women with hypertension and diabetes were aware of potential related complications related if they became pregnant but not the specific complications. Recognizing their risks, participants did not necessarily see the need to seek out preconception health promotion or planning (Chuang et al., PREPUBLICATION COPY: UNCORRECTED PROOFS 

34 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN 2010). These findings point to the need for health promotion strategies focused on women who are considering conception to convey the risks associated with chronic conditions and pregnancy. Research Gaps Effective health communication is needed to ensure that women who are pregnant or considering conception and report chronic conditions are aware of the specific risk to their pregnancies and their own health. Better predictors of complications are needed to implement enhanced risk stratification of pregnant women with chronic conditions, deepen the understanding regarding the etiology of chronic inflammatory placental disorders, and enhance understanding regarding the role of intersectionality and risk for complications related to pregnancy and amplification of risk of chronic diseases following pregnancy. Clinical trial exclusion of pregnant women historically has impaired the ability to provide data-driven recommendations on safe and effective management of these conditions during pregnancy and should be further explored (Denne and the Pediatric Policy, 2019). MENOPAUSAL SYMPTOMS AND TRANSITION Menopause is a reproductive phase at midlife that is characterized by the changes in and decline of ovarian hormone levels and cessation of ovulation and menstruation. It is diagnosed the menstrual cycle ceases for at least 1 year (Peacock et al., 2023). The transition preceding the final period is referred to as perimenopause, which is associated with physiological changes that vary among women (Santoro et al., 2020), with little investigation into that variation in terms of symptom experience, onset, duration, severity, and response to treatments. Post-menopause is the final stage of the menopause process. Perimenopause begins with mostly regular cycles that gradually transition to longer time between menstruation until the final period (McCarthy and Raval, 2020). Menopause can be divided into spontaneous or natural and induced, most commonly via surgical removal of both ovaries, radiation, or chemotherapy. Although data are sparse and have not adequately included underserved populations, hot flashes, night sweats, and cold sweats—collectively termed vasomotor symptoms (VMS)—are classic menopausal symptoms that an estimated 80 percent of midlife women experience, with about one-third having frequent or severe VMS (El Khoudary et al., 2020; Gold et al., 2006). Women experience features of other conditions linked to the transition, including weight gain, and increased rate of diabetes, CVD, cognitive decline, osteoporosis, and depression (El Khoudary et al., 2020; Jeong and Park, 2022; Lobo and Gompel, 2022; Sochocka et al., 2023). VMS affect quality of life over an average of 7–10 years and are one of the main reasons for midlife women to seek care (Avis et al., 2015; Freeman et al., 2011; Williams et al., 2007). Increased anxiety has also been reported. Bromberger and colleagues (2013) found women with low levels of anxiety at study baseline had significantly higher odds of high anxiety at early perimenopause, later perimenopause, and post-menopause compared to the premenopause stage, after controlling for other risk factors. Pathophysiology/Biological Mechanisms and Risk Factors PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 35 Menopause is a natural physiologic process that results in the reduction of primary ovarian follicles which lead to a cessation of ovulation and decline in estrogen production. The changes in levels of ovarian hormones during menopause, particularly estrogens, trigger a multitude of physiological effects. Estrogens mediate its effects via binding to receptors that many cell types throughout the body express. The reduction of estrogen levels will inevitably affect the functioning of virtually all physiological systems and contribute to developing menopausal symptoms (Peacock et al., 2023). Furthermore, studies have suggested that levels of follicle stimulating hormone may contribute to VMS, specifically hot flashes (Jiang et al., 2015). Genetic Factors Related to VMS It is widely known that the reduction in estrogens contributes to hot flashes; however, the precise, underlying mechanisms are unclear. Estrogens have effects on brain structure and function, with the hippocampal and prefrontal cortical regions expressing a high density of estrogen receptors (ER) (Ishunina et al., 2007; Osterlund et al., 2000). Researchers have postulated that signaling originating in the brainstem triggers hot flashes, with different brain regions—the insular cortex, prefrontal cortex, and anterior cingulate—mediating the perception (Diwadkar et al., 2014). Other brain regions that research has implicated in hot flashes include those, such as the hippocampus, that are activated without external stimuli (Thurston et al., 2015). Although the genetic basis of VMS is largely unexplored, researchers have proposed associations with genetic variants. These include single nucleotide polymorphisms (SNPs) in ER genes and genes involved in estrogen metabolism (Butts et al., 2012; Crandall et al., 2006; Rebbeck et al., 2010; Visvanathan et al., 2005); serotonin transport (Montasser et al., 2015); and angiogenesis (Schneider et al., 2009). A meta-analysis of GWAS data from the Women’s Health Initiative (WHI) study, which collected information on genetic variants and VMS in several independent U.S. cohorts of postmenopausal women (n=17,695; 12,276 with VMS) from multiple ethnic groups identified an association between several SNPs in the tachykinin receptor 3 gene (TCR3) with higher odds of VMS (Crandall et al., 2017). GWAS using data from the U.K. Biobank, a population-based cohort, corroborated the association (Ruth et al., 2023). Based on data from studies in animal models, TCR3—also known as neurokinin β or neurokinin 3 receptor—encodes a receptor for neurokinin β, a protein expressed in neural populations of the infundibular nucleus and hypothalamus (Rance et al., 2010; Topaloglu et al., 2009). In animal models, NK3R-mediated neuronal signaling affects thermoregulatory mechanisms controlled by the hypothalamus and the autonomic nervous system in response to lower levels of circulating estradiol, which leads to VMS (Rance et al., 2013). Menopause results in marked alterations in hypothalamic kisspeptin/neurokinin B/dynorphin neurons, and it has been suggested that these neurons could contribute to the generation of flashes through cutaneous vasodilatation (Mittelman-Smith et al., 2015). These findings, in both animal models and large-scale, population-based GWAS, suggest that variants in TCR3 may influence the susceptibility to severe or prolonged VMS and may account for the variability in reporting of hot flashes (Crandall et al., 2017). PREPUBLICATION COPY: UNCORRECTED PROOFS 

36 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Physiologic Impact of Menopause Researchers use in vivo animal models to study menopause and its role in developing other conditions. However, as most mammals in experimentation do not experience natural menopause and therefore cannot capture all aspects of it, their value as models of menopause is limited. Two common methods study the effects of the loss of female hormones are removing the ovaries, which mimics surgically induced menopause, and using an ovarian toxin (Brooks et al., 2016; Chen et al., 2014; Li et al., 2014). The toxin model chemically induces follicular loss, resulting in longer menstrual cycles, erratic hormonal fluctuations, an eventual drop in estrogen levels, and increased follicular stimulating hormone, mimicking perimenopause in humans (Brooks et al., 2016; Chen et al., 2014; Van Kempen et al., 2011). Toxin-induced ovarian failure triggers clinically relevant bone disorders observed in women after menopause (Wright et al., 2008). Similarly, researchers using the ovary removal model have shown that the loss of estrogens accelerates cartilage and bone turnover and significantly suppresses cartilage regeneration (Høegh-Andersen et al., 2004; Xu et al., 2019). Estrogens and selective ER modulation inhibited these detrimental effects (Høegh-Andersen et al., 2004). One potential mechanism driving these changes following a sudden drop in estrogens, as seen in the ovary removal model, involves dysregulated metabolic activity of chondrocytes— cells that produce cartilage—that favor breakdown rather than build-up pathways. One study found that female mice that had both ovaries surgically removed and were fed a Western diet exhibited left ventricle hypertrophy without fibrosis or aortic valve stenosis (Joll et al., 2022). These results suggest possible mechanistic explanations for how the loss of estrogens may influence developing chronic conditions such as CVD, osteoporosis, and other skeletomuscular disorders that often affect postmenopausal women. Aside from estrogens, changes in other hormones after menopause appear to influence the development of chronic conditions in women. Illustrative examples include how rising levels of follicular stimulating hormone (released by the hypothalamus in response to low levels of estrogens) in late perimenopause contribute to visceral adiposity and bone loss (Liu et al., 2017); how reductions in progesterone and its metabolite, allopregnanolone, lead to neuroinflammation, an etiological mechanism for Alzheimer’s disease (AD) and multiple sclerosis (MS) (Noorbakhsh et al., 2014; Yilmaz et al., 2019); and how reductions in the non-steroidal ovarian hormones, anti-mullerian hormone and relaxin, heighten risks of atherosclerosis and CVD (Appt et al., 2012; Aragón-Herrera et al., 2022; Brecht et al., 2011; Lambrinoudaki et al., 2020; Verdiesen et al., 2022) (see Chapter 2). Generally, however, these surgical and toxin menopause models do not mimic the perimenopausal window, so no model addresses a transition in which women experience highly varied age at onset, duration, and symptoms about which little is known (see Chapter 9). Stress and Trauma Factors Numerous studies have reported significant associations between traumatic experiences, such as military sexual trauma (Travis et al., 2024), intimate partner violence (Gibson et al., 2019), adverse childhood events (Doucette et al., 2023; Kapoor et al., 2021) and menopausal symptoms. In a recent cross-sectional study, sexual trauma during military service in a cohort of 232 mid-life women veterans aged 45–64 was associated with a greater than twofold odds of VMS after adjusting for sociodemographic variables, BMI, and menopause status (Travis et al., 2024). A history of military sexual trauma was also associated with depressive symptoms and anxiety (Travis et al., 2024). PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 37 A history of trauma may precipitate alterations in the body’s stress response that influence a woman’s hormonal changes across the life span (Travis et al., 2024). Residual effects from trauma may result in autonomic nervous system dysfunction, higher symptom sensitivity, and behavioral changes such as interpersonal avoidance, substance use, and an inability to seek care, that worsen the menopausal experience (Travis et al., 2024) The inflammatory process is another mechanism by which traumatic experiences lead to physiological alterations that aggravate menopausal symptoms. One clinical study of 186 peri- or postmenopausal women aged 45–60 showed that self-reported bothersome VMS characteristics correlated with higher levels of interleukin-6, an inflammatory marker; cortisol, a stress marker reflecting activation of the hypothalamus-pituitary-adrenal axis; and norepinephrine, an indicator of sympathetic nervous system activation. These findings suggest a role for proinflammatory and stress pathways in mediating the severity of VMS (Gordon et al., 2016). However, recent analyses of longitudinal data from the Study in Women’s Health Across the Nation (SWAN) showed no significant associations between inflammatory markers and initial appearance of VMS (Gold et al., 2022); this study did not assess correlations with persistent or increasing severity of VMS. Pre-Existing and Pregnancy-Related Conditions Research has shown that conditions related to pregnancy such as hypertensive disorders of pregnancy and gestational diabetes, as well as never giving birth (Cortes et al., 2020) can influence menopausal symptoms. Other cross-sectional studies have indicated that migraine can predict risk of VMS (Faubion et al., 2023) and that depression is associated with VMS (Ziv-Gal et al., 2017). However, whether depression is a risk factor for VMS remains unclear, as indicated by longitudinal analysis of data from SWAN showing that inflammatory biomarkers associated with depression were not associated with onset of VMS (Gold et al., 2022). Treatment and Management Evidence points to the menopausal transition as an important life stage in a woman’s life during which certain metabolic and CVD risks emerge (Lobo and Gompel, 2022). An increased propensity for cancer; cardiometabolic conditions, such as obesity, metabolic syndrome, diabetes, CVD, and stroke; and autoimmune disorders, including arthritis; and cognitive dysfunction, including AD; have been attributed to the menopausal physiological changes (see Chapter 6). The transition should therefore be considered a critical time during which preventive strategies that reduce disease risks could determine health outcomes, improving quality of life and decreasing mortality in postmenopausal women (Lobo and Gompel, 2022). Two general approaches exist for treating VMS: hormone therapy and NK3R antagonists. Hormone Therapy Hormone therapy if administered at the onset of menopause, can alleviate VMS (Manson et al., 2024), and improve bone, metabolic, and cardiovascular health (Manson and Martin, 2001), The evidence and beliefs about its benefits versus on the pace of aging and risk of chronic diseases in women have changed dramatically in the last few decades. Observational studies and randomized clinical trials illustrated that hormone treatment after menopause was associated with a reduced risk of several chronic diseases, including CVD, osteoporosis, cognitive decline, PREPUBLICATION COPY: UNCORRECTED PROOFS 

38 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN and dementia, and clinician-initiated hormone therapy in post-menopausal women (Manson et al., 2020). Women were normally prescribed estrogen, alone or with a progestin, to treat symptoms during the perimenopausal or early postmenopausal phase (Manson et al., 2020). However, from 2002–2004, results from the Women’s Health Initiative (WHI) clinical trial agreed with most observational study findings but contradicted observations regarding coronary heart disease (CHD) by showing an increased risk in women who initiated estrogen alone or in combination with a progestin at ages 50–79 years (Anderson et al., 2004; Manson et al., 2020; Rossouw et al., 2002). The trial of estrogen-progestin was stopped in 2002 after a median of 5.2 years to follow-up because the global index which summarized the balance of risks and benefits of major clinical outcomes showed that the harms exceeded benefits and should not be continued or initiated for primary prevention of CHD (Writing Group for the WHI Investigators, 2002). The trial of estrogens only was stopped for futility, after a median follow-up of 7.2 years, as no cardiovascular risk outcome was likely to become statistically significant by continuing the trial and the risk of stroke was elevated (Manson et al., 2020). To reconcile the observational data with the clinical trial data for CVD, several research groups introduced “the timing hypothesis”: the effects of hormone therapy are beneficial for cardiovascular health when initiated early after menopause but may become neutral or even detrimental when initiated later in life, when the vascular lesions of atherosclerosis and degenerative processes in other tissues have already developed. Detrimental effects, primarily thrombotic or inflammatory, may predominate if older women start hormone therapy several years after menstruation ends. Although researchers initially proposed the timing hypothesis to explain the effects of hormone therapy on cardiovascular outcomes, they later applied it to cerebrovascular diseases and dementia (Rocca et al., 2011). In a 2020 review of the findings from WHI, investigators concluded that the evidence supporting the timing hypothesis was convincing. Women in WHI who started estrogen-progestin therapy at ages 50–59, or within 10 years of the onset of menopause, had a more favorable risk-benefit balance (North American Menopause Society, 2022) (see Figure 5-9), and it was even more favorable for women who initiated estrogen-only therapy at ages 50–59 (Manson et al., 2017, 2020; North American Menopause Society, 2022). PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 39 FIGURE 5-9 Overall Mortality Outcomes in the Women’s Health Initiative Hormone Therapy Trials During the Intervention Phase. 3 SOURCE: Manson et al. (2017). Researchers designed two clinical trials to test the timing hypothesis. The Early vs. Late Intervention Trial with Estradiol (ELITE) compared an oral estrogen and micronized progesterone vaginal gel to placebo. It included two groups by average at randomization: 56 years and 65 years. Women in the early group but not the late group showed a beneficial effect on atherosclerosis, but neither group had a difference in cognition after approximately 5 years of follow-up (Henderson et al., 2016). The Kronos Early Estrogen Prevention Study (KEEPS) trial compared an oral equine estrogen or transdermal estrogen with placebo in women with an intact uterus and average age of 53 at randomization, with both groups also receiving micronized progesterone. The trial did not find a beneficial effect on atherosclerosis or cognition after approximately 3 years of follow-up (Gleason et al., 2015; Harman et al., 2014). A cohort of women in the KEEPS trial were evaluated at follow-up of 14 years from baseline, and there was no evidence of cardiovascular and/or metabolic benefits or adverse effects associated with 4 years of oral or transdermal hormone therapy by menopausal women who had good cardiovascular health (Kantarci et al., 2024). In summary, the answer to the simple question of whether hormone therapy is protective or harmful for chronic diseases related to aging is quite complex and may vary across groups of women and depend on if menopause is spontaneous or induced. Investigators have suggested that a better understanding of the effects of hormone therapy on the risk of chronic conditions may come from considering the age of onset and type of menopause (Rocca et al., 2023). 3 CEE indicates conjugated equine estrogens; MPA, medroxyprogesterone acetate; HR, hazard ratio; CI, confidence interval; CVD, cardiovascular disease; CHD, coronary heart disease; COPD, chronic obstructive pulmonary disease; N/E, not estimable; N/R, not reported; and IQR, interquartile range (Manson et al., 2017). PREPUBLICATION COPY: UNCORRECTED PROOFS 

40 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN NK3R Receptor Antagonists A more recent treatment approach for VMS targets the NK3R protein, and in May 2023, FDA approved Veozah (fezolinetant), an NK3R antagonist, as the second nonhormonal medication to treat VMS and help regulate body temperature (FDA, 2023). Studies in in vivo animal models have shown that NK3R activation and signaling resulting from lower circulating estradiol levels alters the brain’s thermoregulatory systems, resulting in VMS (Krajewski-Hall et al., 2019; Rance et al., 2013). Given these promising findings, several clinical studies tested whether antagonists to NK3R improve VMS. Four phase 2 clinical trials have shown that NK3R antagonists significantly reduced VMS, similar to what was observed after hormone therapy (Depypere et al., 2019; Fraser et al., 2020; Prague et al., 2017; Rance et al., 2013; Trower et al., 2020). Several NK3R antagonists are in phase 3 clinical trials (Prague, 2021). Identifying NK3R as an important player in thermoregulation and VMS in menopausal women has provided an important proof of principle regarding the power of GWAS (see above section on “Genetic Factors Related to VMS”). Future identification of genes using GWAS experimental approaches should therefore be encouraged to uncover other VMS biological mechanisms, as this could lead to new therapies. Treatment of VMS to Prevent Future Chronic Conditions Menopausal symptoms have been associated with other chronic conditions, including CVD, osteoporosis, and AD (Thurston, 2018, 2024; Thurston et al., 2021; Zhu et al., 2020). VMS has been associated with subclinical atherosclerosis and increased CVD risk and outcomes (Carson and Thurston, 2023; Uijen and Van De Lisdonk, 2008). The MsBrain Study, which enrolled 248 late perimenopausal or postmenopausal women aged 45 and 67, found a significant correlation between nighttime VMS and AD biomarkers. These findings suggest an association between the severity of VMS during sleep and AD risk (Thurston et al., 2023). However, additional research is needed to determine if nighttime VMS could be used to predict AD risk or if treating could affect that risk. Non-Medical Interventions Many women navigate menopause without requiring medical intervention (Hickey et al., 2024a). An empowerment model, such as the My MenoPlan, 4 emphasizes providing evidence- based information to women about both medical and non-medical treatments for managing symptoms (Hickey et al., 2024a). Shared decision making is an essential aspect of treatment and management of menopausal symptoms in women (Hickey et al., 2024a). Other non-medical interventions include cognitive behavior therapy, mindfulness-based stress reduction (MBSR), acupuncture, and lifestyle/behavioral interventions such as physical activity (Dodin et al., 2013; Hickey et al., 2024a; Samami et al., 2021). MBSR has been shown to be associated with stress and lowered menopausal symptoms including psychological symptoms (e.g., anxiety, depression, irritability) and VMS (Sood et al., 2019). A systematic review of five RCTs showed that those in the MSBR intervention groups showed improvements in improved quality of life and reductions in VMS among menopausal women (Chen et al., 2021). A recent, U.S. observational study suggested that cold water swimming may improve menopausal symptoms and findings are in 4 Available at https://mymenoplan.org/ PREPUBLICATION COPY: UNCORRECTED PROOFS 

FEMALE-SPECIFIC AND GYNECOLOGIC CONDITIONS 41 line with the purported beneficial effects of cold water exposures on other conditions, such as depression (Burlingham et al., 2022; van Tulleken et al., 2018), anxiety (Burlingham et al., 2022), negative mood (Kelly and Bird, 2022; Massey et al., 2020; Yankouskaya et al., 2023), and post-operative pain (Mole and Mackeith, 2018). Further research is needed to verify cold water effects on menopausal symptoms in larger cohorts of women representative of different racial and ethnic group, and determine the underlying mechanisms that lead to the alleviation of symptoms. Disparities Cross-sectional analyses have shown that race, ethnicity, and adverse social determinants of health (SDOH) appear to influence the characteristics of VMS (Avis et al., 2001; De Mello et al., 2021; Gold et al., 2000). A longitudinal analysis of VMS in a multiethnic cohort of women in SWAN evaluated possible associations with race and ethnicity and showed that regardless of racial and ethnic background, reporting of VMS increased over time during perimenopause, although the rate of change differed among the groups (Gold et al., 2006). Black women reported the highest rates of change across all stages of the transition, whereas Asian women exhibited the lowest. Compared to White women, significantly more Black women reported VMS; insignificant decreases in reporting were noted in Hispanic and Chinese or Japanese women (Gold et al., 2006). The Penn Ovarian Aging Study cohort compared VMS in Black and White women and women who were premenopausal with follow-up assessments conducted annually (Freeman et al., 2005; Freeman et al., 2011). Follow-up data at 13 and 16 years showed that Black women experienced a longer duration of VMS, specifically moderate-to-severe hot flushes compared to White women (Freeman et al., 2011; Freeman et al., 2014). Compared to White women, Black women tended to experience persistent and increasing VMS (Kim et al., 2024). Large-scale studies support the findings that Black women are susceptible to persistent VMS (Freeman et al., 2011; Gold et al., 2006; Kim et al., 2024; Freeman et al., 2011). Recent GWAS may provide clues that explain this. For example, GWAS identified 3 SNPs located on chromosomes 3 and 11 that were associated with VMS in Black women in the SNP Health Association Resource cohort in WHI (Crandall et al., 2017). In addition, specific changes in a gene involved in thermoregulation occurred more frequently in Black women (Small et al., 2000, 2002). However, GWAS analysis of data from SWAN did not find a significant association between this genetic change and the frequency of VMS during perimenopause (Aharon et al., 2019). Research Gaps The primary needs for research on menopause are to identify the triggers that define at what age women enter perimenopause, what underlies the symptoms during it, and what defines its (until menstruation has completely ceased for more than 12 months and menopause has occurred). It is important to determine the pathways catalyzed by surgical menopause, or radiation or chemotherapy (Hickey et al., 2024b), compare them to the physiology of natural menopause, and identify effective preventive interventions to diminish the impact on health, which may or may not be applicable to preventive strategies effective in those with natural menopause. Furthermore, research is needed to understand how premature and early menopause influence developing chronic conditions and on effective strategies to reduce that risk. Future research focusing on how the diminution of other ovarian hormones (aside from estrogens) and PREPUBLICATION COPY: UNCORRECTED PROOFS 

42 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN compensatory increases in gonadotropin hormones during the perimenopause contribute to chronic conditions in mid-life women is encouraged. Research is also needed to determine why so much variation in menopausal symptoms occurs and the biological mechanisms underlying them. As perimenopause often coincides with multiple midlife stressors and role transitions, research is needed to explore and define attribution of symptoms, particularly mental health changes, to hormonal or other physiologic changes versus other complementary and independent causal factors (Brown et al., 2024). It is also important to consider the effect of symptoms on quality of life, including work functioning, and devise methods for improving awareness and tactics to diminish adverse effects (Alzueta et al., 2024). Understanding these factors may also lead to a broader range of effective management and treatment options, including pharmacological and nonpharmacological interventions related to lifestyle behaviors and therapies. Further development of decision tools to guide shared decision making about the use and selection of menopause symptom treatments are needed. Advancing such research would provide a more nuanced and detailed understanding of the transition from pre- to peri- to post-menopause, and effective strategies to assist women through each life stage so that they can thrive for decades in health and well-being. SUMMARY The female reproductive system, female-specific physiology, and female-specific and gynecologic conditions have received inadequate attention, curiosity, and prioritization. Research, and consequently foundational knowledge, has lagged significantly in understanding preventive measures and risk factors for and life course consequences of these conditions. In addition to a lack of funding, there is a poorly developed workforce to address research on female specific and gynecologic conditions which is reflective of lower concentrations of research activities and capabilities within obstetrics and gynecologic departments (Institute of Medicine, 1992). Furthermore, diagnoses are still delayed, at significant personal and societal costs. These delays are driven by not only knowledge gaps but also stigma, dismissal, and conditioning of women to expect that little can or will be done to help these prevalent, life- affecting symptoms. Essential foundational knowledge is lacking on biologic norms and natural human variation, let alone the etiological mechanisms involved in developing these conditions. Female- specific and gynecologic conditions have significant effects on developing MCC across the life course, including mental health and other chronic conditions such as CVD and diseases of immune dysregulation. Women’s health is not gynecologic health, but prioritizing female- specific and gynecologic health is essential to overall health at each life stage. REFERENCES ACOG (American College of Obstetricians and Gynecologists). 2012. Practice bulletin no. 128: Diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstetrics and Gynecology 120(1):197–206. AFHSC. 2011. Uterine fibroids, active component females, U.S. Armed Forces, 2001–2010. MSMR 18(12):10–13. Agorastos, A., and G. P. Chrousos. 2022. The neuroendocrinology of stress: The stress-related continuum of chronic disease development. Molecular Psychiatry 27(1):502–513. PREPUBLICATION COPY: UNCORRECTED PROOFS 

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