25 - 410 Women’s Health

410 Women’s Health

treatments due to health concerns or are unable to use them due to a history of breast cancer or endometrial cancer. Hyaluronic acid vaginal gel has been found to be efficacious in treating atrophic vaginitis. ORAL AGENTS Flibanserin, originally developed as an antidepressant, is approved by the FDA as a treatment for low sexual desire in premenopausal women. Flibanserin, a postsynaptic agonist of serotonin recep­ tor 1A and antagonist of serotonin receptor 2A, increases sexual desire and reduces resultant stress in women with hyposexual desire disorder (HSDD) with few adverse effects. Flibanserin has two principal pharmacologic actions in neural microcircuits: it acts as a full agonist at postsynaptic 5-HT1A receptors and an antagonist at postsynaptic 5-HT2A receptors. Exclusive binding at these receptors differentiates flibanserin from buspirone and bupropion. This action in the prefrontal cortex causes the down­ stream release of dopamine and norepinephrine and reduction of serotonin. Flibanserin acts selectively on pyramidal neurons that excite brainstem 5-HT neurons yet also selectively on pyramidal neurons that inhibit brainstem norepinephrine and dopamine neurons.

PART 12 Endocrinology and Metabolism Flibanserin may boost sex drive in women who experience low sexual desire and who find the experience distressing. The drug should be discontinued if there is no improvement in sex drive after 8 weeks. Potentially serious side effects include low blood pressure and dizziness, particularly if it is mixed with alcohol. Other common adverse events include nausea, fatigue, sleepiness, and insomnia. Health care professionals and pharmacies dealing with flibanserin have to undergo a certification (risk evaluation and mitigation strategy [REMS]) process, and patients need to submit a written agreement to abstain from alcohol. The goal of the flibanse­ rin REMS is to inform patients about the increased risk of hypoten­ sion and syncope due to an interaction with alcohol. Bremelanotide, a melanocortin 4 receptor agonist, is also approved for HSDD. It demonstrates significant improvement in desire and a significant decrease in distress related to lack of desire. The most common adverse effects include nausea (40%), facial flushing (20%), and headache (10%). Bremelanotide’s place in ther­ apy is unclear, as the trials met statistical significance for change in sexual desire elements and distress related to sexual desire, yet the clinical benefit may only be modest. It is a subcutaneous injection given 45 min prior to sexual activity. Bremelanotide has no clini­ cally significant interactions with ethanol. Prescribing guidelines recommend no more than one dose in 24 h and no more than eight doses per month. Individuals should discontinue use after 8 weeks without benefit. There is no role for PDE-5is in FDS and should be discouraged. CLITORAL VACUUM DEVICE In patients with arousal and orgasmic difficulties, the option of using a clitoral vacuum device may be explored. This handheld battery-operated device has a small soft plastic cup that applies a vacuum over the stimulated clitoris. This causes increased caverno­ sal blood flow, engorgement, and vaginal lubrication. ■ ■FURTHER READING Burnett AL et al: Erectile dysfunction: AUA Guideline. J Urol 200:633, 2018. Geerkens MJM et al: Sexual dysfunction and bother due to erectile dysfunction in the healthy elderly male population: Prevalence from a systematic review. Eur Urol Focus 6:776, 2020. Kloner RA et al: Effect of phosphodiesterase type 5 inhibitors on major adverse cardiovascular events and overall mortality in a large nationwide cohort of men with erectile dysfunction and cardiovascular risk factors: A retrospective, observational study based on healthcare claims and national death index data. J Sex Med 20:38, 2023. McVary KT: Clinical practice. Erectile dysfunction. N Engl J Med 357:2472, 2007.

Mulhall JP et al: Evaluation and management of testosterone deficiency: AUA guideline. J Urol 200:423, 2018. Nappi RE et al: Medical treatment of female sexual dysfunction. Urol Clin North Am 49:299, 2022. Zhao B et al: Erectile dysfunction predicts cardiovascular events as an independent risk factor: A systematic review and meta-analysis. J Sex Med 16:1005, 2019. Emily Nosova, Andrea Dunaif

Women’s Health The clinical discipline of women’s health is well established. Indeed, its emphasis on greater attention to patient education and medical decision-making is a paradigm for what has become known as patientcentered health care. Moreover, the recognition of sex differences in gene expression, disease processes, and health outcomes is an impor­ tant example of precision medicine. Sex difference refers to the biologic differences conferred by sex chromosomes and hormones. In contrast, gender differences are related to psychosocial roles and cultural expec­ tations. The study of sex differences continues to grow as a scientific discipline. In 2016, the National Institutes of Health recognized its importance by implementing the expectation that sex should be con­ sidered as a biologic variable in study designs, analyses, and reporting in not only human but also vertebrate animal research. Strong scientific justification must be provided to limit research to only one sex. DISEASE RISK: REALITY AND PERCEPTION The leading causes of death are the same in women and men: (1) heart disease and (2) cancer (Fig. 410-1). In 2020, COVID-19 emerged as the third leading cause of death, representing >10% of all deaths that year. Mortality rates due to COVID-19 were slightly lower in women (9.8%) than in men (10.9%). The leading cause of cancer death, lung cancer, is the same in both sexes. Breast cancer is the second leading cause of cancer death in women. Men are more likely than women to die from suicide and accidents. Maternal mortality continues to be higher in the United States than in other industrialized nations and is associated with substantial health disparities in maternal deaths. U.S. maternal mortality rates declined for the majority of the twentieth century given improvements in maternity care and safer surgical techniques; however, the rates began to rise again in 2000. Over the past decade, the mortality rate has remained relatively stable with the exception of a slight rise in 2021–2022, followed by a decline to typical rates again in 2023. In June 2022, an historic Supreme Court decision overturned Roe v. Wade after nearly 50 years, declaring that women no longer had the constitutional right to abortion in the United States. In the year that fol­ lowed this landmark ruling, more than a dozen states banned abortion, while several enacted abortion protection laws, and at least 70 clinics ceased offering abortion-related services. These changes were projected to affect nearly 30% of women of reproductive age in the United States. A 2022 study found that maternal mortality in states that restricted abortion was 62% higher compared to that of states with more wide­ spread access (28.8 compared to 17.8 per 100,000 live births). Further longitudinal observation is needed to assess the impact of changes in abortion access on maternal and fetal mortality and outcomes. Women’s risk for many diseases increases at menopause. The median age of menopause in Caucasian women from industrialized countries is between 50 and 52 years, where women spend one-third of their lives in the postmenopausal period. Menopause occurs at earlier ages in Hispanic and African-American women as well as in women of lower socioeconomic status. Estrogen levels fall abruptly at menopause,

Septicemia, 2% Kidney Disease, 2% Influenza & Pneumonia, 2% Diabetes, 3% Accidents, 4% Stroke, 6% CLRD, 5% A Liver Disease & Cirrhosis, 1.8% Intentional Self-Harm (Suicide), 2.1% AD, 2.3% Diabetes, 3.3% COVID-19, 10.9% Accidents, 7.5% CVD, 3.9% CLRD, 4.1% B FIGURE 410-1  Percent distribution of 10 leading causes of death in (A) women compared to (B) men in the United States in 2020. In both women and men, the first, second, and third leading causes of death are the same: heart disease, cancer, and COVID-19, respectively. Causes of death then diverge by sex. Chronic lower respiratory disease (CLRD), stroke, and Alzheimer’s disease (AD) cause a larger percentage of deaths in women than in men. Suicide is among the 10 leading causes of death in men but not in women. CVD, cardiovascular disease. (Data from https://www.cdc.gov/nchs/data/nvsr/nvsr72/nvsr72-14.pdf.) inducing a variety of physiologic and metabolic responses. Rates of cardiovascular disease (CVD) increase, and bone density decreases rapidly after menopause. In the United States, women live on average 5.9 years longer than men, with a life expectancy at birth in 2021 of 79.1 years in women compared with 73.2 years in men of all races. Notably, these estimates represent a decrease in life expectancy from prior years related to the COVID-19 pandemic. Life expectancy is lower in African Americans of both sexes and higher in Hispanics of both sexes than their Cau­ casian counterparts. Accordingly, elderly women outnumber elderly men, so that age-related conditions, such as hypertension, have a female preponderance. SEX DIFFERENCES IN HEALTH AND DISEASE ■ ■ALZHEIMER’S DISEASE (See also Chap. 442) Alzheimer’s disease (AD) affects approximately twice as many women as men. Because the risk for AD increases with age, part of this sex difference is accounted for by the fact that women live longer than men. However, even in relatively younger groups (60–70 years of age), there is still a higher incidence of AD among

Women Heart Disease, 20% All Other, 26% Women’s Health CHAPTER 410 Cancer, 18% COVID-19, 10% AD, 6% Men Heart Disease, 22% All Other, 26.9% Cancer, 18.0% women. Additional factors may contribute to the increased risk for AD in women, including sex differences in brain size, structure, and func­ tional organization. Multimodal neuroimaging has demonstrated that certain biomarkers of the preclinical phase of AD, including a decline in neuronal mitochondrial function and impaired cerebral glucose metabolism, are evident earlier in women and are even distinguishable during the perimenopausal endocrine transition. There is emerging evidence for sex-specific differences in gene expression, not only for genes on the X and Y chromosomes but also for some autosomal genes. These genetic differences may translate into variable severity of AD, with women experiencing greater deficits in cognition. The ε4 allele of the apolipoprotein E gene (APOε4), a cholesterol carrier integral for lipid transport in the brain, is a major risk factor for AD. Recent studies show that the APOε4 genotype is strongly linked to develop­ ment of sporadic AD in women. Women who carry either the APOε4 homo- or heterozygous isoform have an increased risk of progressing from healthy aging patterns to cognitive impairment or AD, whereas men who carry either isoform experience marginal impact on their memory or cognition. Estrogens have pleiotropic genomic and nongenomic effects on the central nervous system, including neurotrophic actions in key areas involved in cognition and memory. Women with AD have lower

endogenous estrogen levels than do women without AD. These obser­ vations have led to the hypothesis that estrogen is neuroprotective. The Women’s Health Initiative Memory Study (WHIMS), an ancillary study in the Women’s Health Initiative (WHI) in women aged ≥65 years, found significantly increased risk for both dementia and mild cognitive impairment in women receiving estrogen alone or estrogen with pro­ gestin compared to placebo. However, the Kronos Early Estrogen Pre­ vention Study (KEEPS), a randomized clinical trial of early hormone therapy (HT) initiation after menopause that compared conjugated equine estrogen (CEE), transdermal estradiol (both estrogen arms included cyclic oral micronized progesterone), and placebo, found no adverse effect of HT on cognitive function. In summary, there is no evidence from placebo-controlled trials that HT improves cognitive function.

PART 12 Endocrinology and Metabolism While studies have shown a link between female sex and AD, other neurodegenerative disorders, including Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), exhibit a stronger association with male sex. Men are 1.5 times more likely to develop PD than women across all age groups. A possible explanation for the male predilection may be the effect of Y-chromosome exclusive gene sex-determining region Y (SRY) on nigrostriatal dopaminergic (NSDA) neurons: the SRY upregulates neuronal numbers, synthesis of dopamine, and metabolism of neurons. ■ ■CVD AND STROKE (See also Chap. 284) There are major sex differences in CVD, the leading cause of death in developed countries. However, there are also major gender differences because of perceptions by both women and their health care providers that women are at lower risk for CVD. As a result of these misconceptions, women are less likely to seek medical help when they experience symptoms of CVD. Health care providers are less likely to suspect CVD, so women receive fewer interventions for modifiable risk factors as well as fewer acute interventions than do men. Women and their health care providers are also less aware that prodromal symptoms of cardiac disease differ in women compared to men. Women are less likely than men to present with chest pain and more likely to present with fatigue, shortness of breath, indigestion/ nausea, and anxiety. Sex steroids have major effects on the cardiovascular system and lipid metabolism. Estrogen increases high-density lipoprotein (HDL) and lowers low-density lipoprotein (LDL), whereas androgens have the opposite effect. Estrogen has direct vasodilatory effects on the vascular endothelium, enhances insulin sensitivity, and has antioxidant and anti-inflammatory properties. There is a striking increase in CVD after both natural and surgical menopause, suggesting that endogenous estrogens are cardioprotective. Women also have longer QT intervals on electrocardiograms, and this increases their susceptibility to certain arrhythmias. CVD presents differently in women, who are usually 10–15 years older than their male counterparts and are more likely to have comor­ bidities such as hypertension, congestive heart failure, and diabetes mellitus (DM). In the Framingham study, angina was the most com­ mon initial symptom of CVD in women, whereas myocardial infarc­ tion (MI) was the most common initial presentation in men. Women more often have atypical symptoms such as fatigue, anxiety, nausea, indigestion, and upper back pain. Although awareness that heart dis­ ease is the leading cause of death in women has nearly doubled over the past 15 years, women remain less aware that its symptoms are often atypical and are less likely to contact 9-1-1 when they experience such symptoms. A type of acute coronary syndrome (ACS) termed takotsubo syn­ drome, initially described in 1990 and characterized as a transient and reversible stress cardiomyopathy, disproportionately affects women. National cohort studies demonstrate that ~2% of all patients present­ ing to acute care centers with symptoms of ACS are diagnosed with takotsubo, and importantly, 80–90% are postmenopausal women. If stratified by sex, ~10% of patients with suspected ACS are ultimately diagnosed with takotsubo syndrome. Recurrence of this condition is also more common among women. Interestingly, morbidity and

mortality rates are higher in men, with cardiogenic shock, cardiac arrest, and mortality occurring more frequently than in women. The pathophysiology that leads to takotsubo is complex: potential inciting mechanisms involve microvascular dysfunction and impaired vascular reactivity, followed by reversible abnormalities in the coronary flow reserve and microvascular resistance. One potential explanation for the striking sex difference is that postmenopausal women have age- and estrogen deficiency–related coronary vasomotor dysfunction. Estrogen improves coronary blood flow through endothelium-dependent and -independent mechanisms; however, its deficiency results in increased sympathetic drive and endothelial dysfunction. An animal study suggested that estrogen supplementation may partially attenuate an excessive cardiovascular response to stress; however, this has not been studied clinically. Furthermore, hypotheses related to estrogen do not explain why takotsubo occurs in men and also appears to be associated with higher mortality rates in men. The specific mechanisms underly­ ing these sex differences in disease prevalence and outcomes remain unknown and require further study. Deaths from CVD have decreased markedly in men since 1980, whereas CVD deaths only started to decrease substantially in women beginning in 2000. After 2010, death rates from CVD among both sexes stabilized and even began to increase slightly in men. Women with MI are more likely to present with cardiac arrest or cardiogenic shock, whereas men are more likely to present with ventricular tachy­ cardia. Further, younger women with MI are more likely to die than are men of similar age. However, this mortality gap has decreased in recent years because younger women have experienced greater improvements in survival after MI than men. The improvement in survival is due largely to a reduction in comorbidities, suggesting a greater attention to modifiable risk factors in women. Sex differences account for more variable short-term outcomes observed among women with CVD who receive therapeutic interven­ tion, as compared to men. Women undergoing coronary artery bypass graft surgery have more advanced disease, a higher perioperative mortality rate, less relief of angina, and less graft patency; however, 5- and 10-year survival rates are similar. Women undergoing percu­ taneous transluminal coronary angioplasty have lower rates of initial angiographic and clinical success than men, but they also have a lower rate of re-stenosis and a better long-term outcome. Women may ben­ efit less and have more frequent serious bleeding complications from thrombolytic therapy compared with men. Factors such as older age, more comorbid conditions, smaller body size, and more severe CVD in women at the time of events or procedures account in part for the observed sex differences. Important risk factors for CVD in both men and women include elevated cholesterol levels, hypertension, smoking, obesity, low HDL cholesterol levels, DM, and lack of physical activity (Fig. 410-2). Total triglyceride levels are an independent risk factor for CVD in women but not in men. Low HDL cholesterol and DM are more important risk factors for CVD in women than in men. Several disorders conferring increased CVD risk affect women exclusively, such as pregnancyassociated hypertension, preeclampsia, gestational DM, and polycystic ovary syndrome, or predominantly, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Cholesterol-lowering drugs are equally effective in men and women for primary and secondary prevention of CVD. In contrast to men, randomized trials showed that aspirin was not effective in the primary prevention of CVD in women; it did significantly reduce the risk of ischemic stroke. Psychosocial stressors and loneliness may also be important risk factors for the development of CVD in women. A recent cohort study of nearly 60,000 women older than 65 years showed that loneliness and social isolation were associated with a 5% and 8% higher risk of CVD, respectively, even after adjusting for health behaviors and outcomes. Women with greater loneliness and social isolation had a 13–27% higher risk of incident CVD compared with women with relatively less social isolation and less loneliness. Sex-specific factors related to reproductive and pregnancy history are now recognized as important risk-enhancing factors for CVD in women. Recent studies demonstrate that the greatest risk for CVD

FIGURE 410-2  Traditional and nontraditional risk factors for atherosclerotic cardiovascular disease (ASCVD) in women. (Reproduced with permission from M Garcia et al: Cardiovascular disease in women: Clinical perspectives. Circ Res 118:1273, 2016.) (at least twofold) was conferred by adverse pregnancy outcomes (APO), including a history of stillbirth, preterm birth, or preeclampsia, followed by a 1.5- to 1.9-fold risk with gestational diabetes and hyper­ tension, premature ovarian insufficiency, and placental abruption; the lowest risk (<1.5 fold) was associated with early menarche, early menopause, parity, and polycystic ovary syndrome. Given these strong associations, targeted counseling and increased surveillance of CVD risk factors is warranted for women in high-risk groups. Accordingly, the 2019 American Heart Association (AHA) guidelines included a recommendation to assess for pregnancy complications as a part of routine cardiovascular risk assessment for primary prevention. The sex differences in CVD prevalence, beneficial biologic effects of estrogen on the cardiovascular system, and reduced risk for CVD in observational studies led to the hypothesis that HT was cardioprotec­ tive. However, the WHI, which studied >16,000 women on CEE plus medroxyprogesterone acetate (MPA) or placebo and >10,000 women with hysterectomy on CEE alone or placebo, did not demonstrate a benefit of HT for the primary or secondary prevention of CVD. In addition, CEE plus MPA was associated with an increased risk for CVD, particularly in the first year of therapy, whereas CEE alone nei­ ther increased nor decreased CVD risk. Both HT groups were associ­ ated with an increased risk for ischemic stroke. In a subgroup analysis of the WHI estrogen-alone trial, a relatively younger age (50–59 years) combined with a history of bilateral salpingo-oophorectomy (BSO) was associated with a >30% CEE treatment–associated reduction in all-cause mortality, whereas CEE-treated older women with prior BSO did not see a significant reduction in any other outcomes, including incidence of coronary artery disease, invasive breast cancer, all-cause mortality, and a composite index of the aforementioned outcomes plus stroke, hip fracture, pulmonary embolism, and colorectal cancer. These results suggest that postmenopausal women younger than 60 with prior BSO may have mortality benefit from HT, while women older than 60 with BSO may suffer consequences associated with HT. More recent data from KEEPS indicate that even if estrogen therapy is initiated shortly after the menopausal transition, it does not reduce atherosclerotic progression or impact CVD outcomes. Additionally, HT and placebo groups have similar outcomes with respect to venous thromboembolism and breast cancer. Although HT does not slow CVD development as previously thought, findings from KEEPS sug­ gest that treated women experience significant improvements in vaso­ motor symptoms, mood, sexual function, and bone density, especially when therapy is started sooner after menopause onset. HT is discussed further in Chap. 407. ■ ■DIABETES MELLITUS (See also Chap. 415) Women are more sensitive to insulin than men. Despite this, the prevalence of type 2 DM is similar in men and women. There is a sex difference in the relationship between endogenous

Women’s Health CHAPTER 410 androgen levels and DM risk. Higher bioavailable testosterone levels are associated with increased risk in women, whereas lower bioavail­ able testosterone levels are associated with increased risk in men. This observation has been confirmed in a recent Mendelian randomization that found that genetically determined higher testosterone increases risk for DM in women but reduces risk in men. Polycystic ovary syndrome, preeclampsia, pregnancy-associated hypertension, and ges­ tational DM—common conditions in premenopausal women—are associated with a significantly increased risk for type 2 DM. Among individuals with DM, women have a greater risk for MI than do men. Women with DM have a sixfold greater risk of dying of CVD compared to women without DM. Premenopausal women with DM lose the car­ dioprotective effect of female sex and have rates of CVD identical to those in males. These women have impaired endothelial function and reduced coronary vasodilatory responses, which may predispose to cardiovascular complications. Women with DM are more likely to have left ventricular hypertrophy. Women with DM receive less aggressive treatment for modifiable CVD risk factors than men with DM. ■ ■HYPERTENSION (See also Chap. 288) After age 60, hypertension is more common in U.S. women than in men, largely because of the high prevalence of hypertension in older age groups and the longer survival of women. Isolated systolic hypertension is present in 30% of women >60 years old. Sex hormones affect blood pressure. Both normotensive and hypertensive women have higher blood pressure levels during the fol­ licular phase than during the luteal phase. In the Nurses’ Health Study, the relative risk of hypertension was 1.8 in current users of oral contra­ ceptives, but this risk is lower with the newer low-dose contraceptive preparations. Long-term data from this cohort also demonstrate that having gestational hypertension or preeclampsia during a first preg­ nancy doubled the rate of developing chronic hypertension. HT is not associated with hypertension. Among secondary causes of hyperten­ sion, there is a female preponderance of renal artery fibromuscular dysplasia. The benefits of treatment for hypertension have been dramatic in both women and men. A meta-analysis of the effects of hypertension treatment, the Individual Data Analysis of Antihypertensive Interven­ tion Trial, found a reduction of risk for stroke and major cardiovascular events in women. The effectiveness of various antihypertensive drugs appears to be comparable in women and men; however, women may experience more side effects, such as cough with angiotensin-converting enzyme inhibitors. ■ ■AUTOIMMUNE DISORDERS (See also Chap. 367) Most autoimmune disorders occur more com­ monly in women than in men; they include autoimmune thyroid and liver diseases, Hashimoto’s hypothyroidism, Graves’ disease (GD), SLE,

RA, scleroderma, multiple sclerosis (MS), and idiopathic thrombocy­ topenic purpura. However, there is no sex difference in the incidence of type 1 DM, and ankylosing spondylitis occurs more commonly in men. Sex differences in both immune responses and adverse reactions to vaccines have been reported. For example, there is a female prepon­ derance of postvaccination arthritis.

Adaptive immune responses are more robust in women than in men; this may be explained by the stimulatory actions of estrogens and the inhibitory actions of androgens on the cellular mediators of immunity. Consistent with an important role for sex hormones, there is variation in immune responses during the menstrual cycle, and the activity of certain autoimmune disorders is altered by castra­ tion or pregnancy (e.g., RA and MS may remit during pregnancy). Nevertheless, the majority of studies show that exogenous estrogens and progestins in the form of HT or oral contraceptives do not alter autoimmune disease incidence or activity. Exposure to fetal antigens, including circulating fetal cells that persist in certain tissues, has been speculated to increase the risk of autoimmune responses. There is clearly an important genetic component to autoimmunity, as indicated by the familial clustering and HLA association of many such disorders. X chromosome genes also contribute to sex differences in immunity. Indeed, nonrandom X chromosome inactivation may be a risk factor for autoimmune diseases. PART 12 Endocrinology and Metabolism ■ ■HIV INFECTION (See also Chap. 208) Women (sex assigned at birth) accounted for 18% (6600) of the ~36,100 new HIV diagnoses in the United States in 2021. This represents a similar incidence observed in recent years. Black/ African-American women accounted for 54% of new diagnoses among people assigned as female at birth, as compared to white women, who accounted for 23%, and Hispanic/Latino women, who represented about 18% of the newly diagnosed. AIDS remains an important cause of death in younger women, particularly African-American women aged 25–44 years. Heterosexual contact with an at-risk partner is the fastest-growing transmission category, and women are more suscep­ tible to HIV infection during vaginal sex than men. This increased susceptibility is accounted for in part by an increased prevalence of sexually transmitted diseases, i.e., gonorrhea and syphilis, in women. Some studies have suggested that hormonal contraceptives may increase the risk of HIV transmission. Progesterone has been shown to increase susceptibility to infection in nonhuman primate models of HIV. Women are also more likely to be infected by multiple variants of the virus than men. Women with HIV have more rapid decreases in their CD4 cell counts than do men. Compared with men, HIVinfected women more frequently develop candidiasis, but Kaposi’s sarcoma is less common than it is in men. Women have more adverse reactions, such as lipodystrophy, dyslipidemia, and rash, with antiret­ roviral therapy than do men. This observation is explained in part by sex differences in the pharmacokinetics of certain antiretroviral drugs, resulting in higher plasma concentrations in women. ■ ■OBESITY (See also Chap. 414) The prevalence of both obesity (body mass index ≥30 kg/m2) and abdominal obesity (waist circumference ≥88 cm in women) are similar in U.S. women and men. According to the most recent National Health and Nutrition Examination Survey data span­ ning 2017 until prepandemic March 2020, the age-adjusted prevalence of obesity among U.S. adults was 41.8%, and there were no significant differences observed between women and men, even across different age groups. However, some sex-specific differences were observed: the prevalence of obesity was highest among non-Hispanic black women (57.9%) as compared with non-Hispanic white (39.6%), Hispanic (45.7%), and non-Hispanic Asian women (14.5%). NonHispanic black women had a higher prevalence of obesity compared to non-Hispanic black men. There were no significant differences in prevalence between men and women among non-Hispanic white, non-Hispanic Asian, or Hispanic adults. More than 80% of patients who undergo bariatric surgery are women. Pregnancy and menopause are risk factors for obesity.

There are major sex differences in body fat distribution. Women characteristically have a gluteal and femoral or gynoid pattern of fat distribution, whereas men typically have a central or android pattern. Women have more subcutaneous fat than men. In women, endogenous androgen levels are positively associated with abdominal obesity, and androgen administration increases visceral fat. In contrast, there is an inverse relationship between endogenous androgen levels and abdominal obesity in men. Further, androgen administration decreases visceral fat in these obese men. The reasons for these sex differences in the relationship between visceral fat and androgens are unknown; however, emerging evidence suggests that there is a contribution of genetic variation. Studies in humans also suggest that sex steroids play a role in modulating food intake and energy expenditure. In men and women, abdominal obesity characterized by increased visceral fat is associated with an increased risk for CVD and DM. Obesity increases a woman’s risk for certain cancers, in particular post­ menopausal breast and endometrial cancer, in part because adipose tis­ sue provides an extragonadal source of estrogen through aromatization of circulating adrenal and ovarian androgens, especially the conversion of androstenedione to estrone. Obesity increases the risk of infertility, miscarriage, and complications of pregnancy. In addition to sex-specific epidemiologic differences in obesity, notable patterns have emerged with the advent and rising popular­ ity of the novel obesity pharmacotherapies, namely the glucagon-like 1 peptide (GLP1) receptor agonists and the combined GLP1/gastric inhibitory polypeptide (GIP) receptor agonists (Chap. 414). In the recent Semaglutide Treatment Effect in People with Obesity (STEP 1–4) studies from 2021, in which weekly semaglutide was compared to placebo for weight management, women comprised 55–80% of the study populations. Subgroup analyses evaluating the efficacy of sema­ glutide by sex have demonstrated a greater average weight reduction in women participants compared to men. Possible explanations for these findings include a lower average baseline body weight in women, potential differences in eating behavior that may be regulated by dif­ ferences in sex hormones, and differential rates of gastric emptying. Sex-related differences in gastrointestinal side effects may also play a role. A possible connection may exist at the neurologic level: a recent study in mice demonstrated sex-specific dynamics in GLP1 recep­ tor and GIP receptor expression patterns in metabolically responsive areas of the hypothalamus and the amygdala induced by exposure to a high-fat diet. It remains unclear whether mechanistic differences may explain the differential outcomes in women compared to men who use these medications. ■ ■OSTEOPOROSIS (See also Chap. 423) Osteoporosis is about five times more common in postmenopausal women than in age-matched men, and osteopo­ rotic hip fractures are a major cause of morbidity in elderly women. Men accumulate more bone mass and lose bone more slowly than do women. Sex differences in bone mass are found as early as infancy. Calcium intake, vitamin D, and estrogen all play important roles in bone formation and bone loss. Particularly during adolescence, calcium intake is an important determinant of peak bone mass. Vitamin D deficiency is surprisingly common in elderly women, occurring in

40% of women living in northern latitudes. Receptors for estrogens and androgens have been identified in bone. Estrogen deficiency is associated with increased osteoclast activity and a decreased number of bone-forming units, leading to net bone loss. The aromatase enzyme, which converts androgens to estrogens, is also present in bone. Estrogen is an important determinant of bone mass in men (derived from the aromatization of androgens) as well as in women. ■ ■PHARMACOLOGY On average, women have lower body weights, smaller organs, a higher percentage of body fat, and lower total-body water than men. There are also important sex differences in drug action and metabolism that are not accounted for by these differences in body size and composition. Sex steroids alter the binding and metabolism of a number of drugs. Further, menstrual cycle phase and pregnancy can alter drug action.

Women also take more medications than men, including over-thecounter formulations and supplements. The greater use of medications combined with these biologic differences may account for the reported higher frequency of adverse drug reactions in women than in men. Two-thirds of cases of drug-induced torsades des pointes, a rare, life-threatening ventricular arrhythmia, occur in women because they have a longer, more vulnerable QT interval. These drugs, which include certain antihistamines, antibiotics, antiarrhythmics, and antipsychot­ ics, can prolong cardiac repolarization by blocking cardiac voltagegated potassium channels. ■ ■PSYCHOLOGICAL DISORDERS (See also Chap. 463) Depression, anxiety, and affective and eating disorders (bulimia and anorexia nervosa) are more common in women than in men. Epidemiologic studies from both developed and develop­ ing nations consistently find major depression to be twice as common in women as in men, with the sex difference becoming evident in early adolescence. Depression occurs in 10% of women during pregnancy and in 10–15% of women during the postpartum period. There is a high likelihood of recurrence of postpartum depression with subse­ quent pregnancies. The incidence of major depression diminishes after the age of 45 years and does not increase with the onset of menopause. Depression in women appears to have a worse prognosis than does depression in men; episodes last longer, and there is a lower rate of spontaneous remission. Schizophrenia and bipolar disorders occur at equal rates in men and women, although there may be sex differences in symptoms. Both biologic and social factors account for the greater prevalence of depressive disorders in women. Men have higher levels of the neurotransmitter serotonin. Sex steroids also affect mood, and fluc­ tuations during the menstrual cycle have been linked to symptoms of premenstrual syndrome. Sex hormones differentially affect the hypo­ thalamic-pituitary-adrenal responses to stress. Testosterone appears to blunt cortisol responses to corticotropin-releasing hormone. Both low SARS-CoV2 SARS-CoV2 Attachment Activation Testosterone Attachment Activation TMPRSS2 ACE2 Cytosol HSP HSP AR AR Activated Virus entry Virus entry Translocation Nucleus TMPRSS2 mRNA ? TMPRSS2 ARE TMPRSS2 ARE FIGURE 410-3  Proposed sex hormone differences in TMPRSS2-mediated SARS-CoV-2 host cell entry. The virus entry point into cells is the membrane-bound angiotensin-converting enzyme 2 (ACE2) receptor. The cell-membrane protease, TMPRSS2, is also vital for host cell entry. Circulating levels of ACE2, expressed abundantly in the lung, heart, and kidney tissues, have been reported to be relatively higher in men. Upregulation of the ACE2 receptor in men may provide greater opportunity for cellular entry, viral replication, symptom development, and multiorgan involvement. (Adapted from C Gebhard et al: Impact of sex and gender on COVID-19 outcomes in Europe. Biol Sex Differ 11:29, 2020.)

and high levels of estrogen can activate the hypothalamic-pituitaryadrenal axis.

■ ■COVID-19 INFECTION (See also Chap. 205) Soon after the discovery of COVID-19, which was identified in November 2019 in Wuhan, China, as being caused by the novel coronavirus SARS-CoV-2, it was evident that there were appreciable sex differences in severity and outcomes. Indeed, observa­ tional data from the early pandemic, spanning late 2019 to early 2020, demonstrated a higher overall incidence of infectious cases, hospital­ izations, intensive care unit admissions, and case-fatality rates among men as compared to women. More pronounced sex differences were observed with advanced age, with a higher overall incidence in older male age groups. These sex differences have persisted among different racial, ethnic, and socioeconomic groups and across all continents, as SARS-CoV-2 became a global pandemic. Women’s Health CHAPTER 410 There are several potential mechanisms for these sex-specific effects of SARS-CoV-2 infection (Fig. 410-3). The virus’s entry point into cells is the membrane-bound angiotensin-converting enzyme 2 (ACE2) receptor, and it also harnesses the primer TMPRSS2, a cellular serine protease. Circulating levels of ACE2, which is expressed in a variety of tissues including the lung, heart, and kidneys, have been reported to be relatively higher in men who have diabetes and/or kidney disease, as well as in healthy men; however, not all studies have reported similar sex differences. One hypothesis is that upregulation of the ACE2 receptor in men may provide greater opportunity for cellular entry, viral replication, and development of symptoms and deleterious sequelae. ACE2 plays a critical role in bronchial transient secretory cells/type II alveolar cells as well as the renin-angiotensin-aldosterone system (RAAS). In the RAAS, ACE2 opposes angiotensin II’s vasoconstrictive actions by converting angiotensin II to the vasodilatory angiotensin 1-7 in critical tissues, including cardiac myocytes, cardiac fibroblasts, and coronary endothelial cells. Importantly, recent evidence has shown the impact of sex and sex hormones on the RAAS and ACE2: estrogen downregulates angiotensin II receptor type 1 and regulates renin activity, as well as modulates local RAAS in the atrial myocardium. Furthermore, it has been shown that ovariectomized females have increased ACE2 activity and expression in their kidney and adipose tissue and that estradiol replacement reduces ACE2 expression. On the contrary, orchiecto­ mized males have decreased ACE2 activ­ ity. Estrogen appears to reduce ACE2 expression in the heart and kidney in both rodent and human studies. SARS-CoV2 ACE2 TMPRSS2 TMPRSS2, a vital contributor to SARSCoV-2 cellular invasion, is a protein that is most abundantly expressed in prostate epithelial tissue, including high-grade prostate cancers and metastases. Accord­ ingly, the protein’s involvement in viral priming is thought to be an important reason for the higher case-fatality rate observed in men; however, the associa­ tion has not yet been proven. TMPRSS2 is also expressed in airway epithelia, where its physiologic function is not entirely clear. Transcription of the cellular protein is regulated by androgenic ligands and androgen receptor binding element; it is unknown whether estrogen plays a role in its regulation. Emerging in vitro stud­ ies have demonstrated that a TMPRSS2 inhibitor blocks viral entry into cells. These data may serve as an important foundation for sex-specific and personal­ ized therapeutic approaches in the future. TMPRSS2 mRNA