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5 Sex Affects Health ABSTRACT Males andfemales have different patterns of illness and different life spans, raising questions about the relative roles of biology and environment in these disparities. Dissimilar exposures, susceptibilities, and responses to initiating agents and differences in energy storage and metabolism result in variable responses to pharmacological agents and the initiation and mani- festation of diseases such as obesity, autoimmune disorders, and coronary heart disease, to name a few. Understanding the bases of these sex-based differences is important to developing new approaches to prevention, diag- nosis, and treatment. Sex should be considered as a variable in all biomedi- cal and health-related research. Studies should be designed to control for exposure, susceptibility, metabolism, physiology (cycles), and immune re- sponse variables. Males and females have different patterns of illness and different life spans, which leads to important questions about how these differences might be biologically determined. Diseases other than those of the repro- ductive system affect both sexes, often with different frequencies or presentations, or they may require different treatments. This chapter explores how these differences result from differences in exposures, sus- ceptibilities, and responses to disease-initiating agents, differences in en- ergy storage and metabolism, and disparate diagnostic and therapeutic interventions. Because it is not possible to explore all diseases, disorders, and condi- 117

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118 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH lions with sex differences, the committee chose several illustrative ex- amples. The committee first briefly describes the complexities of sex dif- ferences in response to therapeutic agents and energy metabolism. The subsequent section focuses on differences in energy metabolism, obesity, and physical performance and then uses two illustrations melanoma and osteoporosis to describe sex differences. The chapter then focuses on the complexities of a normal immune response that has gone awry or that has spontaneously lost its normal immune regulation system (au- toimmune diseases). These diseases in particular demonstrate variable susceptibilities between human males and human females, as well as differential exposures to environmental factors. The chapter concludes by describing a disease whose etiology occurs from conception to the grave but that affects both sexes differently, coronary heart disease. SEX DIFFERENCES IN RESPONSE TO THERAPEUTIC AGENTS: DIAGNOSTIC AND THERAPEUTIC INTERVENTIONS Background Pharmacological agents can be used as probes to diagnose, prevent, and treat human illnesses. How much of an agent one encounters de- pends on the route of entry into the body (see Figure 5-7), absorption, distribution, metabolism, and excretion and is a major factor in the body's response, whether it is a therapeutic or an adverse response. The follow- ing discussion uses the definitions provided in Box 5-1 and the schema presented in Figure 5-1.

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SEX AFFECTS HEALTH D= Drug UD = Unbound drug (free) PP = Plasma proteins T = Tissue R= Receptor Absorption - UD R Sitters) of Action 119 Sites of Tissue Storage ~ =: (3 j/ Circulation ~ UD , \ \ Excretion Metabolites ~ rev \ | Phase I Phase 11 \ + UD' Biotransformation (metabolism) ~ Excretion FIGURE 5-1 Schematic representation of the absorption, distribution, metabo- lism, and excretion of drugs. Pharmacokinetic and pharmacodynamic variables can be measured and can demonstrate differences between males and females. Pharmaco- kinetic and pharmacodynamic differences between males and females exposed to the same compound and dose do not necessarily result in different health outcomes. Outcome data that can be used, however, to establish whether differences between the sexes are clinically meaningful are sparse. The methods used to study sex differences in the effects of drugs can serve as a template for the study of the relative effects of any foreign chemical, including volatile organic chemicals. For example, most stan- dards for the human carcinogen benzene have been based on studies involving males, even though physiologically based pharmacokinetic modeling shows that females have higher levels of metabolism of ben- zene (Brown et al., 1998~. Greater appreciation of these methods will yield significant clinical data regarding the importance of sex both in drug development, prescription, and dosing and in assessments of environ- mental exposures.

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20 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH In reviewing the examples described below, the committee was cog- nizant of the small numbers of subjects involved in some of the studies, the sometimes conflicting results of studies, and the significant variations observed in the results of many of the studies that purport to evaluate sex and age differences. It will be essential in future studies to define the stages of a woman's menstrual cycle, use protocols with sufficient power to detect statistically significant differences, and determine whether dem- onstrated differences deemed to be sex relevant affect clinical outcomes. Although many studies are designed to demonstrate sex differences in pharmacokinetics, few look at pharmacodynamics, and even fewer deter- mine clinical outcomes. Processes of Drug Absorption and Metabolism Absorption of Pharmacological Agents Through Different Routes of Entry Absorption of small organic molecules is usually passive, but it may involve a facilitated process or an active process that requires energy. The factors that affect the absorption of chemicals from the gastrointestinal tract are listed in Table 5-1. TABLE 5-1 Factors Affecting Absorption of Chemicals Physical characteristics Dosage form Gastrointestinal characteristics pKa Aqueous solubility Lipid solubility Disintegration Dissolution Enteric coating Controlled-release properties Presence of food and type of food in the gastrointestinal tract Rate of gastric emptying pH of the different segments of the gastrointestinal tract Intestinal microorganisms Intestinal transit time Gastrointestinal blood flow Gastrointestinal enzymes Alcohol dehydrogenase Cytochrome P450 Glucuronosyltransferase Sulfotransferase Gastrointestinal transport systems P glycoprotein Effects of other drugs

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SEX AFFECTS HEALTH 121 The venous blood supply of the entire gastrointestinal tract except the rectum goes directly to the liver, where absorbed compounds may be metabolized (first-pass metabolism). This observation may be explained by the high prevalence of CYP3A4 in the upper part of the intestine and its absence from the colon and rectum. Drugs given through the rectum (suppositories) and urinary bladder do not go through significant first- pass metabolism (Buyse et al., 1998~. Interestingly, drugs applied to the vagina accumulate to a greater extent in the uterus than when adminis- tered by other routes; that is, they have a "first-uterine-pass effect" (Bulletti et al., 1997; Mizutam et al., 1995~. Gastrointestinal Tract Absorption of drugs from the stomach is affected by a variety of factors (Table 5-1~. (For a general review of the effect of gastrointestinal motility on the absorption of drugs, see Hebbard et al. [1995~.) Gastric emptying (Malagelada et al., 1993) can be measured by several techniques, of which transit times determined with a radiolabeled liquid or solid meals provide the best-validated and clinically meaningful measurements (Camilleri et al., 1998~. Differences in age, sex, body mass index, phase of menstrual cycle, and type of meal consumed lead to large inter- and intrasubject variabili- ties. The preponderance of evidence (Bennink et al., 1999; Datz et al., 1987; Gryback et al., 1996; Hermansson and Silvertsson, 1996; Hutson et al., 1989; Knight et al., 1997; Tucci et al., 1992) supports the conclusion that females empty solids more slowly than men; however, others have found that all transit variables are unaffected by sex (Madsen, 1992~. The gastric emptying of liquids has also been reported to be slower in women than men (Datz et al., 1987; Mohiuddin et al., 1999~; however, others have found no differences (Bennink et al., 1998~. In addition, young people empty their stomachs faster than elderly people do (Jane et al., 1998; Moore et al., 1983; Teff et al., 1999~. The small-bowel transit time of solids and liquids do not differ between the sexes (Horowitz et al., 1984; Madsen, 1992), but differences are seen between old and young subjects (Bennink et al., 1999; Madsen, 1992~. Slower gastric emptying in females does not likely affect the absorp- tion of most solid drugs since most absorption takes place in the small intestine. The rate of absorption of enteric coated forms is delayed (Mojaverian et al., 1987~. Drugs with narrow therapeutic indices are most likely to be harmful (Greiff and Rowbotham, 1994) or lack efficacy in persons with slow rates of gastric emptying. A slow rate of gastric empty- ing also decreases the level of absorption of alcohol. Progesterone may be responsible for the slower rate of gastric empty- ing in women (Gill et al., 1985, 1987; Hutson et al., 1989; Mathias and Clench, 1998; Riezzo et al., 1998~. Females are less sensitive than males to muscarinic blockade of stomach motility, possibly because of differences

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22 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH in autonomic tone (Teff et al., 1999~. It is of interest that 80 to 90 percent of diabetic patients with gastroparesis (paralysis of the stomach) are females (Bennink et al., 1998~. Basal acid output, pH, and gastrin secretion are independent of sex (Bernard) et al., 1990; Dressman et al., 1990; Straus and Raufman, 1989) and age (Russell et al., 1993~. In patients with gastroesophageal reflux, however, the mean basal level of acid output is greater in males than females (Collen et al., 1994~. Transport systems within the gastrointestinal tract may have signifi- cant effects on drug absorption. For example, a component of the intestine and liver, P glycoprotein (Pgp), is a transmembrane efflux protein that actively transports many compounds including drugs out of cells. The livers of males express twofold larger amounts of Pgp than the livers of females (Schuetz et al., 1995~. This suggests that males transport drugs out of hepatocytes more rapidly than females, decreasing the time for biotransformation, although further studies are needed. The absorption of many drugs might be affected if a sex difference in intestinal Pgp activity also exists, and it is important to determine whether such a sex difference exists. Drug absorption rates from the rectum may also be sex dependent. Females absorbed one of the two specially prepared ondansetron suppositories (an antiemetic) differently than males (Jane et al., 1998), although this could be attributed to normal variability. The menstrual cycle has no effect on motility in the esophagus (Mohiuddin et al., 1999) or on whole-gut transport (Kamm et al., 1989~. However, evidence for a menstrual cycle effect on gastric emptying is conflicting (Gill et al., 1987; Horowitz et al., 1985; Mones et al., 1993; Parkman et al., 1996; Petring and Flachs, 1990~. Skin Gels, ointments, creams, or patches deliver small organic com- pounds through the skin (Brown and Langer, 1988; Xu and Chien, 1991~. Transit through the stratum corneum (outer skin) barrier often requires the use of absorption enhancers (Kanikkannan et al., 2000~. The level of transepidermal water loss, a measure of epidermal bar- rier permeability following injury to and recovery of the stratum cor- neum, does not differ between males and females or between Caucasians and Asians (Reed et al., 1995~. Dark skin recovers from an injury more quickly than lightly pigmented skin. In a clinical trial of transdermal clonidine for the treatment of hypertension, blood pressure reduction was independent of race, ethnicity, sex, and age (Dies et al., 1999~. In vitro, transdermal absorption of fentanyl and sufentanil (analgesics) was neither age nor sex dependent (Roy and Flynn, 1990~. Pulmonary tract Absorption of drugs via the pulmonary tract varies with breathing rate and depth (ventilation) (Gonda, 2000~. Progesterone

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SEX AFFECTS HEALTH 123 may be a ventilatory stimulant. Females have greater minute ventilations and lower tidal volumes than males, and the ventilatory response to high carbon dioxide levels is greater in males (White et al., 1983~. A drug, ethionamide, given orally to healthy and ill men and women appeared in equal concentrations in alveolar cells of both sexes (Conte et al., 2000~. Women have higher ventilatory responses in the luteal phase than in the follicular phase of the menstrual cycle. Protein Binding Most small organic compounds bind to albumin or oc~-acid glycopro- tein (AAG) and less frequently to alpha, beta, and gamma globulins, lipo- proteins, or erythrocytes. AAG binds with a high affinity to basic drugs. Albumin binds to acidic drugs in a complex in which the drug readily dissociates to maintain an equilibrium between the bound and unbound (free) fractions. The unbound fraction is in equilibrium with the receptor (Anton, 1960; Shoeman and Azarnoff, 1975~. Thus, the degree of binding of drugs to plasma proteins can influence their dispositions (Gillette, 1973~. The plasma protein binding of enantiomers (mirror-image com- pounds) in racemic mixtures (containing both enantiomers) may differ, and selective binding of the enantiomers does occur (Gross et al., 1988; Waite et al., 1983~. The level of AGG, an acute-phase reactant, increases in patients with infections, cancer, and rheumatoid arthritis. Decreased albumin levels or increased AAG levels occur in patients with renal, liver, and thyroid Crohn's disease, myocardial infarction, cancer, and burns (Reidenberg and Affrime, 1973~. Increased levels of unbound drug occur in patients with uremia (Garland, 1998; Reidenberg and Affrime, 1973) and cirrhosis (Goldstein et al., 1969~. It is not known whether sex differences exist in these circumstances. In a very small study (nine women each examined through one men- strual cycle), the concentration of AGG was higher on day 4 of the men- strual cycle than on days 12, 20, and 28 (Parish and Spivey, 1991), but the study had very significant inter- and intrapatient variabilities. The level of sex hormone binding globulin has also been found to increase during the luteal phase of the menstrual cycle (Plymate et al., 1985~. The concentration of a drug in the fetus is a function of the concentra- tion in the mother, placental permeability, fetal drug clearance, and dif- ferences in the levels of protein binding between maternal and fetal plasma (Boulos et al., 1971~. The placental transfer of lipophilic drugs is good, but the transfer of hydrophilic drugs is slow. The concentration of protein is significantly lower in the fetal circula-

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24 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH TABLE 5-2 Differences in Drug Concentrations Between the Mother and Fetus and Between Males and Females Mother-fetus comparisons Male-female comparisons Binding of propranolol and verapamil is lower in fetal serum Propranolol R/S enantiomer ratio is larger in maternal serum Verapamil R/S enantiomer ratio is similar in maternal and fetal serum AAG levels are higher in maternal serum Albumin levels are slightly lower in maternal serum (Belpaire et al., 1995; Notarianni, 1990) Unbound concentrations of chlordiazepoxide, diazepam, imipramine, and nitrazepam are higher in women (MacKichan, 1992) The level of the unbound fraction of S-propranolol but not R-propranolol is decreased in older women (Walle et al., 1983) lion than in the maternal circulation during early pregnancy, but the concentration in the fetus exceeds that in the mother at term. The mater- nal AAG level is very low before 16 weeks of gestation and thereafter increases at a constant rate to a fetal concentration-maternal concentra- tion ratio of 0.37 near term (Perucca and Crema, 1982~. Examples of cir- cumstances in which plasma protein variables affect drug concentrations are shown in Table 5-2. Body Composition Male-female differences in body fatness may account for the increased volumes of distribution for lipophilic drugs (such as benzodiazepines) in females (Parker, 1984; Sciore et al., 1998) and for alcohol in males (Loebstein et al., 1997; Parker, 1984; Petring and Flachs, 1990~. The level of total body water decreases with age because of a dispro- portionate decrease in intracellular water levels (Kashuba and Nafziger, 1998; Phipps et al., 1998~. It is important to adjust body composition mod- els not only for sex but also for age and body size (Kasuba and Nafziger 1998; Phipps et al., 1998~. (It is important to note, however, that some sex differences in pharmacokinetics reported in the literature are a result of differences in weights between males and females receiving the same fixed dose of the drug. Thus, pharmacokinetic parameters should be cor- rected by weight before concluding that a sex difference exists. The effects of differences in body fat, as noted above, can confound weight issues and should also be considered.)

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SEX AFFECTS HEALTH Biotransformation 125 Sex has a complex effect on the pharmacokinetics of drugs metabo- lized in the liver (Harris et al., 1995; Yonkers et al., 1992~. Temazepam and oxazepam, benzodiazepines that are metabolized through conjugation, are cleared faster by males (Divoll et al., 1981; Greenblatt et al., 1980; Smith et al., 1983~. Alprazolam (Kristjansson and Thorsteinsson, 1991) and diazepam (Greenblatt et al., 1980) are metabolized via an oxidative mechanism and are cleared faster by females. Nitrazepam (Iochemsen et al., 1982) is metabolized via reduction of its nitro group, and its metabo- lism shows no sex differences. Thus, sex affects differently even drugs within the same pharmacological class and drugs with the same structures. Cytochromes P450 The cytochromes P450 (CYPs) are a superfamily of at least 17 isozymes that modulate the oxidative metabolism of drugs in the liver (Wrighton and Stevens, 1992~. CYP1, CYP2, and CYP3 are thought to be responsible for most hepatic metabolism of drugs. The CYP3A4 subfamily is the most abundant of the CYPs in the human liver and is responsible for the metabolism of cyclosporine, quinidine, erythro- mycin, dapsone, and lidocaine (Harris et al., 1995; Wing et al., 1984~. The major CYP isoform found in the human embryonic, fetal, and newborn liver is CYP3A7. The activity of CYP3A4 is very low before birth but increases rapidly at birth and reaches 50 percent of the level in adults between 6 and 12 months of age. This maturation of drug-metabolizing enzymes is the main factor for age-associated changes in nonrenal drug clearance (de Wildt et al., 1999~. Studies with tirilazad (an antioxidant) (Hurst et al., 1994), erythromy- cin (Watkins et al., 1985), and diazepam (Greenblatt et al., 1980) suggest that females have greater CYP3A4 activity, but studies with other probe drugs yield conflicting results. Drugs metabolized by CYP3A4 are exten- sively cleared by females, whereas drugs cleared by other isozymes are usually cleared faster by males (Harris et al., 1995~. The sex-specific differ- ences in CYP3A4 activity are related to estrogen and progesterone, which regulate the activity of CYP3A4 at the gene level (Harris et al., 1995~. However, the metabolism of ranitidine, also metabolized by CYPs, shows no sex difference (Abad-Santos et al., 1996~. The metabolism of some drugs eliminated through conjugation shows sex differences (Divoll et al., 1981; Greenblatt et al., 1980, 1984; Macdonald et al., 1990; Miners et al., 1983, 1984~. Excretion The kidney is the major organ of drug excretion. Drugs diffuse in their un-ionized form across the kidney glomeruli and tubules or are

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26 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH secreted and reabsorbed by active tubular transport systems. Drugs are also excreted in the feces if either the drug has not been absorbed from the gastrointestinal tract or it is excreted from the liver into the bile in the intestinal tract. Reabsorption (enterohepatic circulation) may occur as the excreted drug travels through the intestines. Males have higher levels of creatinine in serum and urine and higher rates of creatinine clearance (CLCR) than females. The difference is related to the greater lean body mass of males (lames et al., 1988~. In a three-way crossover study with young and elderly men and women, the renal clear- ance of amantadine was significantly inhibited by quinine and quinidine only in the male subjects. There were no age-related effects (Gaudry et al., 1993~. The mechanism of this interaction is probably related to the differ- ential effects of quinine and quinidine on the tubular excretion rate of cations (Charney et al., 1992~. A physician would not need to consider this interaction when treating an elderly woman with quinidine for muscle cramps who developed influenza and was prescribed amantadine; a lack of attention to this drug-drug interaction in a male, however, could lead to a significant adverse reaction. CLCR is lower during the first week of menses and increases by week 4 by 20 percent. Overnight CLCR measured three times a week during 11 menstrual cycles found the median CLCR to be 7.3 percent higher during the luteal phase than during the follicular phase. Similar changes were found when intravenous chromium 51-labeled EDTA was used, a more accurate measure of the glomerular filtration rate (Paaby et al., 1987a,b). Estradiol and estriol do not affect the glomerular filtration rate, urine flow, renal plasma flow, or tubular reabsorption in humans (Christy and Shaver, 1974; Davison, 1987~. CLCR was found to be slightly increased only in the midluteal phase in another study (Phipps et al., 1998~. How- ever, the changes were attributable to changes in creatinine excretion and are not considered clinically important. It is surprising that investigators are still attempting to determine the effect of the menstrual cycle on CLCR. The renal clearance of the aminoglycoside antibiotics tobramycin (Nafziger et al., 1989) and amikacin (Matsuki et al., 1999) are not signifi- cantly altered during the menstrual cycle. In a recent review, Kashuba and Nafziger (1998) reported that most published studies have been con- ducted with small numbers of women and limited numbers of menstrual cycle phases within one menstrual cycle. In addition, studies of the effects of estrogen or progesterone on renal clearance are limited and their re- sults are contradictory. They further conclude, "there are no demonstrated clinically significant changes that occur in the absorption, distribution or elimination of drugs" during a normal menstrual cycle (Kashuba and Nafziger, 1998, p. 204~. Beierle et al. (1999) concluded that sex-related differences in the renal clearance of drugs is generally only of minor importance. However, a meta-analysis of 10 studies with 172 healthy vol-

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SEX AFFECTS HEALTH 127 unteers administered an oral therapeutic dose of the antibiotic fleroxacin provided evidence that the volume of distribution/systemic availability ratio (V/F) is 20.4 liters greater in males than females and that the clear- ance/systemic availability ratio is 10.8 milliliters per minute (ml/min) greater in males than females (Reigner and Welker, 1996~. Pharmacodynamics Receptors are macromolecules on or in cells to which a drug binds to initiate its effect. Continued stimulation of a receptor may lead to its downregulation or desensitization (refractoriness). Hyperreactivity may also occur and may result from long-term administration of antagonists or the synthesis of additional receptors. Drugs may also act as substrates for enzymes or may inhibit enzymes competitively or noncompetitively. Although there is marked interindividual variation (Levy, 1998), phar- macodynamic differences between the sexes do occur. Several examples are shown in Table 5-3. (For additional examples, see Table B-1 in Appendix B.) Clinical Implications Some pharmacokinetic and pharmacodynamic sex differences may affect drug efficacy or make serious adverse events more likely. A sex difference will more likely affect drugs with narrow therapeutic indices than those with wide therapeutic indices. Adjustment of the dose or dos- ing interval of the drug may be sufficient to correct the difference, or it may be necessary to use a different drug or treatment modality. Given the amount of resources being dedicated to drug development worldwide, it is especially important to consider sex-specific issues relat- ing to clinical trials research, the effects of drugs on receptors (or sexual dimorphisms of receptors and neurotransmitters), and the sexual dimor- phism of treatment responses. Sex-related variables should be specifically and comprehensively included in all diagnostic, longitudinal, and treat- ment research studies (i.e., all clinical studies involving humans) when- ever feasible. Studies should be designed to determine the relative effects of covariables to clearly establish the contributions of sex to outcome data. Analyses should be planned a priori (even if they are secondary or exploratory analyses) that address sex-related hypotheses (i.e., they should not rely primarily on post hoc analyses). In addition, at least some diagnostic, longitudinal, and treatment studies should be powered spe- cifically to permit the appropriate analysis of sex-related variables (post hoc analyses are usually conducted with sample sizes that are too small, making it likely that type II errors [the assumption that no relationship exists when in, fact, it does] will occur). The Office of Research on

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162 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH al., 2000) reexamined 3,000 middle-aged women and men in Norway 15 years after an initial examination. Hypertension, total cholesterol levels, high-density lipoprotein (HDL) cholesterol levels, and body mass index independently predicted increased carotid intimal thickness in both women and men. However, triglyceride levels were an independent risk factor in women but not men, whereas physical activity and smoking were independent risk factors in men but not women. The National Health and Nutrition Examination Survey is a federal epidemiological follow-up study that has collected national data on U.S. residents since the 1960s and that provides evidence of the incidence and prevalence of a variety of health indicators by age, race, and sex (National Center for Health Statistics, 2000b). These data again show differences in cardiovascular disease incidence between the sexes and among racial and ethnic groups. For example, the age-adjusted risk for incident coronary heart disease is higher in African-American women ages 20 to 54 years than in Caucasian women of the same age and lower in African-American men than in Caucasian men of the same age (Gillum et al., 1997~. In terms of risk factors, men have higher prevalences of hypertension, cigarette smoking (until age 65), and excess weight, whereas women have higher prevalences of elevated serum cholesterol levels and obesity (Na- tional Center for Health Statistics, 2000a). Regarding the age-specific prevalences of hypertension and serum cholesterol levels greater than 240 mg/dl, men have a higher prevalence than women until about their late 40s and early 50s. After that, the prevalence is higher in women. These studies underscore the fact that coronary heart disease begins early in life, that it continues across the life span, and that sex differences exist. What they do not demonstrate is why such differences exist. Cigarette Smoking Many airborne toxins that are absorbed through the respiratory sys- tem predispose an individual to the development of coronary heart dis- ease. One of the most pervasive and lethal of these agents is cigarette smoke. Cigarette smoking is more frequent among men than women, espe- cially in African Americans (National Center for Health Statistics, 1999) (Table 5-14~. Data from the Centers for Disease Control and Prevention indicate that both men and women who smoke have three times the risk of dying from heart disease as individuals who do not smoke. In women, smoking (Baron et al., 1988; Michnovicz et al., 1986) promotes susceptibility to early menopause and to a number of diseases, including coronary heart disease.

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SEX AFFECTS HEALTH 30 - 25 - o . _ In ~ 20 - Q o Q o C' 15 - 10 - 5 - 0 - 163 TABLE 5-14 Smoking Prevalence by Race and Sex, 1998 Percent African American Caucasian Males 29 26 Females 21 23 SOURCE: National Center for Health Statistics (1999~. Males Females White African American White, African American, non-Hispanic non-Hispanic FIGURE 5-4 Age-adjusted high serum cholesterol levels (> 240 mg/dl) among individuals ages 20 to 74 years, by sex and race, 1988-1994. Source: National Center for Health Statistics (1999~. Cholesterol Sex differences exist in the levels of lipoprotein subfractions of choles- terol: LDL cholesterol, HDL cholesterol, and very-low-density lipopro- tein (VLDL) cholesterol (Figure 5-4 and 5-5~. Before menopause, women have higher HDL cholesterol ("good cho- lesterol") levels and lower LDL cholesterol ("bad cholesterol") levels. During the pert- and postmenopausal periods, however, LDL cholesterol levels rise and HDL cholesterol levels drop. Rates of death from heart disease rise with age in both men and women, but the rate of ascent rises more sharply in women as menopause ensues.

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64 60 - 50 - o . _ ~ 40 - Q o o ~ 30 - a' C' a' 20 - 10 - O- EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH Males Females 20-34 35-44 45-54 55-64 65-74 Age (years) FIGURE 5-5 Non-age-adjusted high serum cholesterol levels (>240 mg/dl) by sex and age. Source: National Center for Health Statistics (1999~. Estrogen affords women a protective advantage against coronary heart disease before menopause. 17-~-Estradiol increases HDL choles- terol levels and decreases LDL cholesterol levels, stimulates nitric oxide, and inhibits vasoconstricting factors (Collins, 2000~. These factors may operate independently or synergistically (Collins, 2000~. Estrogen also prevents calcium influx through ion channels in the membranes of vascu- lar smooth muscle cells, preventing vessel contraction. During perimenopause estrogen levels begin to decline and continue to do so through menopause, and HDL cholesterol levels fall as LDL cholesterol levels rise. Hepatic LDL cholesterol receptor activity may ex- plain these changes (Semenkovich and Ostlund, 1987~. Another explana- tion for the increased incidence of cardiovascular disease after meno- pause is that the LDL cholesterol particles may become denser and therefore less protective (Campos et al., 1988; Haffner et al., 1993~. High triglyceride levels present a greater risk to women than to men. HDL cholesterol levels may be a better predictor than LDL cholesterol levels of coronary heart disease risk in women (Gordon et al., 1989; lacobs et al., 1990~.

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SEX AFFECTS HEALTH 165 As noted above, endogenous estrogen present in premenopausal women appears to have a cardioprotective effect. Observational studies of postmenopausal women taking hormone replacement therapy, and experimental studies with animals, demonstrate that unopposed estrogen has a strong effect in preventing atherosclerosis and its clinical sequelae (Barrett-Connor, 1998a; Barrett-Connor and Grady, 1998~. These studies however have not been supported in two large clinical trials of estrogen combined with progestin in women with established coronary disease (Hulley et al., 1998; Herrington et al., 2000~. Other clinical trials including women both with and without established coronary disease are currently in progress. As a result, the issue of whether hormone replacement therapy has cardioprotective effects must be considered unresolved. Hypertension The causes of hypertension are unknown (Williams, 1991), yet studies suggest multiple factors, polygenetic and environmental. Essential hyper- tension is the most common form, and it affects a substantial portion of the U.S. population. Risk factors for hypertension include age, sex, smok- ing, diet, elevated blood cholesterol levels, obesity, diabetes, sedentary lifestyle, and family history. Hypertension is both a risk factor for coronary heart disease and a disease itself. As a result of hypertension, the heart wall thickens and its function declines. There are differences in the association of hypertension and coronary heart disease by sex (Fiebach et al., 1989; Kannel et al., 1976; Sigurdsson et al., 1984) and race (Johnson et al., 1986~. Men have higher blood pressure levels than women (National Center for Health Statistics, 2000a, p. 245~. Height differences as well as differ- ences in mass contribute to differences in blood pressure between men and women. The genesis of hypertension in adulthood often occurs in childhood, and weight is a greater predictor for hypertension in girls than in boys (Cook et al., 1997~. Blood pressure is higher during the follicular phase than during the luteal phase of the menstrual cycle in both normotensive and hyperten- sive women (Dunne et al., 1991~. African-American women respond to stress with a higher diastolic pressure and higher plasma epinephrine levels during the follicular phase than during the luteal phase, but Cauca- sian women (and men of all ethnicities) do not exhibit any significant change in blood pressure over the course of a month (Ahwal et al., 1997; Mills et al., 1996~. These results have been disputed by investigators (Litschauer et al., 1998), who believe that the differences may be caused by an interaction of sex and task characteristics (cause of stress). The angiotensin-converting enzyme deletion-insertion polymorphism appears to be associated with systemic hypertension in Caucasian men

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166 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH (O'Donnell et al., 1998~. In Japanese men but not Japanese women there is a similar association between angiotensin-converting enzyme gene poly- morphism and hypertension (Higaki et al., 2000~. Two hypertension-associated conditions are sex specific: preeclamp- sia and hypertension of pregnancy. Both conditions are characterized by increasing levels of hypertension as pregnancy progresses and are most common in the last trimester. Both are serious and can be fatal. Whether either of these conditions progresses to coronary heart disease is not un- derstood, although two studies have shown that such a relationship exists (Croft and Hannaford, 1989; Rosenberg et al., 1983~. Diabetes Mellitus Diabetes mellitus is a risk factor for coronary heart disease and is an example of the sex differences in the risk for coronary heart disease. Pre- menopausal women, who are not typically at risk for coronary heart dis- ease, are at risk if they have type I (juvenile) or type II (adult-onset, non- insulin-dependent) diabetes mellitus (Figure 5-6~. Rates of mortality from coronary heart disease are two to four times greater in diabetic men than nondiabetic men and three to seven times greater in diabetic women than nondiabetic women (Barrett-Connor and Wingard, 1983; Kannel and Abbott, 1987; Manson et al., 1991; Pan et al., 1986~. Diabetes may negate estrogen receptor binding and thereby miti- gate the positive estrogenic effect (Ruderman and Haudenschild, 1984~. O 70- o 60- <,, 50- <,, 40- 30 - ~a 20- 0 10- o ,$ ~ ,,~ Diabetic Men ,, ~ , ___-~ =~~~ ~ Diabetic Women Men ~ ,, ~ ~_-~~~ ~ ~ _ Women 0-3 4-7 8-11 12-15 Duration of follow-up (years) 16-19 20-23 FIGURE 5-6 Mortality from coronary heart disease and diabetes in men and women ages 25 to 64. Source: Krolewski et al. (1991~. Reprinted, with permission, from A. S. Krolewski, l. H. Warram, P. Valsania, B. C. Martin, L. M. Laffel, and A. R. Christlieb. 1991. Evolving natural history of coronary artery disease in diabetes mellitus. American journal of Medicine 90:56S-61S. Copyright 1991 by Elsevier Sci- ence Ltd.

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SEX AFFECTS HEALTH 167 Diabetes of pregnancy may represent a risk for the development of non-insulin-dependent diabetes mellitus after pregnancy. Current evi- dence suggests that gestational diabetes is a risk factor for coronary heart disease (Mestman, 1988; O'Sullivan, 1984; Stowers, 1984~. Differences in Presentation of Coronary Heart Disease The manifestations of coronary heart disease vary in presentation and intensity between women and men (Table 5-15~. Coronary heart disease presents in women 10 to 15 years later than it does in men. Women often have comorbidities, such as congestive heart failure, hypertension, diabetes, and others. Diabetic women are particularly vul- nerable to complications after a myocardial infarction (Greenland et al., 1991~. More men present with myocardial infarction as the initial manifesta- tion of the disease, but the event is more often fatal in women (Greenland et al., 1991; Kannel and Abbott, 1987; Lerner and Kannel, 1986; Murabito et al., 1993; Wenger, 1985~. Women admitted with acute myocardial in- farction are more likely, on average, to be older than men being admitted and therefore have more severe coronary artery disease. However, in the Framingham study, nearly 66 percent of sudden deaths due to coronary heart disease in women occurred in those with no previous symptoms of disease (Mosca et al., 1999~. TABLE 5-15 Complications of Acute Myocardial Infarctions, by Sex Percent Females Males Complication (N = 1,524) (N = 4,315) P value Mechanical complications Angina in hospital 8.2 8.8 NSa Congestive heart failure on admission 26.8 24.4 0.02 Cardiogenic shock 11.1 7.4 <0.002 Arrhythmic complications Sinus tachycardia 3.2 3.1 NS Supraventricular arrhythmia 12.1 13.0 NS Atrioventricular block 12.6 10.0 NS Ventricular tachycardia 12.9 19.0 <0.005 Ventricular fibrillation 5.8 7.4 0.11 Cardiac arrest 9.8 6.6 <0.0005 aNS, not significant. SOURCE: Greenland et al. (1991~.

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168 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH Among individuals with myocardial infarction, men more often present with ventricular tachycardia and women more often present with cardiogenic shock and cardiac arrest (Greenland et al., 1991; Milner et al., 1999). Although many women present with "classical" signs and symptoms, some do not. Women are less likely to present with severe chest pain than men and at the time of diagnosis are more likely to be experiencing con- gestive heart failure (events that may be age rather than sex related). Sex Differences in Treatment of Coronary Heart Disease (Myocardial Infarction) Women do not fare as well as men after a myocardial infarction for the following reasons: Women with myocardial infarctions are older. Women have more "silent" myocardial infarctions. Men have larger collateral circulations. After a myocardial infarction, women younger than 65 years of age are more than twice as likely to die as men of the same age (Vaccarino et al. 1999~. Possible explanations include the following: -Diabetes, heart failure, and stroke are more prevalent in younger women. die. -Plaque erosions are more common in premenopausal women who -Arterial narrowing is less and reactive platelets levels are higher in younger women. -Women are less likely to be given effective interventions, such as aspirin, beta-blockers, and thrombolytic agents. Differences also extend to the use of different diagnostic and thera- peutic procedures, in that women have fewer diagnostic procedures (O'Farrel et al., 2000; Shaw et al., 1994; Steingart et al., 1991; Vaccarino et al., 2001; Wong et al., 2001~. A great deal has been posited about whether women are discriminated against or whether mitigating factors account for the differences in assessment of women for coronary heart disease. Certainly, tests for coronary heart disease are more frequently conducted for men. Women have less obstructive disease at earlier ages than men, and thus, the noninvasive tests have less predictive value for women (Wenger, 1994~.

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SEX AFFECTS HEALTH 169 Subclinical disease, which occurs in younger women, is two to three times more likely to be myocardial infarction or stroke (Kuller et al., 1995~. Women have a smaller coronary artery size (lumen). This reduces the possibility of angiography or angioplasty and bypass surgery and thus of diagnosis and a better outcome (Sheifer et al., 2000~. However, the technology is gradually changing to accommodate this need. A 1991 study examined such differences in Massachusetts and Mary- land (Ayanian and Epstein, 1991~. The findings confirm that women are less likely than men to undergo diagnostic and therapeutic procedures (Table 5-16~. Men were between 15 and 45 percent more likely to undergo selected procedures. The investigators (Ayanian and Epstein, 1991) sug- gest several reasons for such discrepancies: physician perception of the severity of the disease in men versus women; physician perception of the risks and efficacies of diagnostic and therapeutic procedures between men and women (women have higher rates of mortality after the use of procedures); higher rates of admission for women with an absence of true coro- nary heart disease versus the rates for women with ischemic symptoms; patient's perceptions and preferences (women may be more will- ing to adhere to a lifestyle of medications and limitations than to face surgery); and bias in health care delivery. TABLE 5-16 Male: Female Odds Ratios for Use of Diagnostic Procedures for Coronary Heart Disease Mean (Range) Odds Ratio Massachusetts Disease Angiography Maryland Revascularization Angiography Revascularization Any coronary 1.28 heart disease (1.22-1.35) Myocardial 1.39 infarction (1.23-1.58) (1.10-1.51) 1.45 (1.35-1.55) 1.31 1.15 (1.08-1.22) 1.29 (1.10-1.51) 1.27 (1.16-1.40) 1.40 (1.02-1.91) NOTE: Odds ratios were calculated by multiple logistic regression, with adjustment for principal diagnosis, age, secondary diagnosis of congestive heart failure or diabetes melli- tus, race, and insurance status. SOURCE: Ayanian and Epstein (1991).

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170 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH Racial and ethnic differences exist between the sexes. A surveillance of hospital admissions for myocardial infarction and of in-hospital and out-of-hospital deaths due to coronary heart disease between 1987 and 1994, showed that Caucasian men had the greatest average annual de- crease in rates of mortality from coronary heart disease and myocardial infarction, followed by Caucasian women, African-American women, and African-American men. No differences in rates of hospitalization for a first myocardial infarction were evident between men and women over the time studied. Furthermore, over the time period studied, the rate of reinfarction decreased and the rate of survival increased (Rosamond et al., 1998~. Summary Sex differences in the development, recognition, and treatment of coronary heart disease exist across the life span. There is mounting evi- dence that these differences are not solely related to hormones. Scientists and clinicians have just begun to appreciate and address these differences by studying the earliest stages of development and the subsequent effects of the internal and external environments. Research to date, however, has posed as many questions as it has answered. FINDINGS AND RECOMMENDATIONS Findings Many diseases affect both sexes, and the diseases often have different frequencies or presentations in males and females; therefore, different preventive, diagnostic, and treatment approaches may be required for males and females. Exposures, susceptibilities, responses to initiating agents, energy metabolism, genetic predisposition, and responses to thera- peutic agents are important factors in understanding how each sex re- sponds to insult, injury, disease progression, and treatment (Figure 5-7) Compounds that may be differentially internalized by males and fe- males include . . poses; foods for energy and nutrients, including vitamins and minerals; drugs for diagnostic, prophylactic, therapeutic, or recreational pur- environmental compounds to which exposure is either purposeful (preservatives in foods) or inadvertent (pollutants or secondhand ciga- rette smoke); and microorganisms that act as pathogens or commensals.

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SEX AFFECTS HEALTH Physical: Sounds, light, heat, vibrations, gravity, radiation Chemical: Drugs, food and supplements, environmental compounds Infectious: Bacteria, mycobacteria, viruses, fungi, parasites - ~_ \ / Entry Gastrointestinal tract, respiratory tract, skin, eyes, urogenital tract, parenteral routes, transplacental :~v~> 1 ,\W Responses Genetic, molecular, cellular, organ, organ system, whole organism (dependent or independent of environment) Factors That Affect Responses Genotype, growth and development, life stage, hormone cycles, pregnancy, chronobiology, prior exposures and responses, current health status FIGURE 5-7 External agents. 17 ,/ These compounds can enter the body via the placenta, gastrointesti- nal tract, respiratory tract, eyes, urogenital tract, the transdermal route, or the parenteral route. Portals of entry can differ between the sexes, affect- ing types and incidences of disease. In addition, individuals are exposed to environmental factors such as sensory stimuli (sounds, light, heat), forces (vibration, gravity), and radiation.

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72 EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH Exposures and responses to exogenous agents may be influenced by growth and development; other aging processes; reproductive events; body size and composition; cumulative exposures, prior responses, and current health status; and genotype. Some exogenous factors (e.g., vitamins) are essential, whereas others are of no apparent consequence and some (e.g., cigarette smoke) are det- rimental. Some factors are beneficial at low doses but harmful at high doses (e.g., ultraviolet radiation). It is essential to understand whether males and females respond differently to these various substances, whether they do so at various stages in their life spans, and if so, how and with what implications. A continuing challenge is the identification of sex differences in health and illness that are methodologically robust, hereafter referred to (pro- vocatively) as "true" sex differences. Different biological, lifestyle, and social structural contexts for males and females can lead to spurious infer- ences about sex. Even the most methodologically valid comparisons are potentially susceptible to biased interpretations, intentional or not. Exposure, susceptibility, responses to initiating agents, energy me- tabolism, and responses to therapeutic agents matter and must be consid- ered in any consideration of sex differences in health and disease. How- ever, in many instances these differences in disease manifestations and health outcomes cannot be explained by the obvious anatomical or sex hormone differences between males and females. In some instances, soci- etal practices and beliefs, independent of biological sex, account for the differences, but in other instances, the differences remain unexplained. The following recommendation is presented as a result of these consider- ations. Recommendation RECOMMENDATION 6: Monitor sex differences and similarities for all human diseases that affect both sexes. Investigators should consider sex as a biological variable in all biomedical and health- related research; and design studies that will -control for exposure, susceptibility, metabolism, physiology (cycles), and immune response variables; -consider how ethical concerns (e.g., risk of fetal injury) con- strain study designs and affect outcomes; and -detect sex differences across the life span. Also see Recommendation 3 (in Chapter 3) for a discussion of the need to mine cross-species information.