Exploring the Biological Contributions to Human Health Does Sex Matter? (2001) / Chapter Skim
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5 Sex Affects Health
5 Sex Affects Health
Pages 117-172
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From page 117... ...
Studies should be designed to control for exposure, susceptibility, metabolism, physiology (cycles) , and immune response variables.
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From page 118... ...
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 (autoimmune diseases)
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From page 119... ...
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.
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From page 120... ...
Although many studies are designed to demonstrate sex differences in pharmacokinetics, few look at pharmacodynamics, and even fewer determine 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.
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From page 121... ...
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 variabilities.
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From page 122... ...
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~.
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From page 123... ...
It is not known whether sex differences exist in these circumstances. In a very small study (nine women each examined through one menstrual cycle)
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From page 124... ...
It is important to adjust body composition models 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.
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From page 125... ...
is metabolized via reduction of its nitro group, and its metabolism shows no sex differences. Thus, sex affects differently even drugs within the same pharmacological class and drugs with the same structures.
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From page 126... ...
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)
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From page 127... ...
A sex difference will more likely affect drugs with narrow therapeutic indices than those with wide therapeutic indices. Adjustment of the dose or dosing interval of the drug may be sufficient to correct the difference, or it may be necessary to use a different drug or treatment modality.
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From page 128... ...
Sex Differences in Adverse Events Drugs from classes as diverse as antihistamines (terfenadine) , antibiotics (erythromycin)
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From page 129... ...
Furthermore, in animal models, estrogen has been found to prolong the QTC interval, affecting cardiac repolarization (Drici et al., 1996~. Recent studies with women suggest that drug-induced QT interval prolongation may be affected by the phase of the menstrual cycle (Rodriguez et al., 2001~.
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From page 130... ...
METABOLISM, LIFESTYLE, AND PHYSICAL PERFORMANCE Male-female differences are very striking in terms of body size and composition (Bjorntorp, 1989; Legato, 1997; National Center for Health Statistics, 1987~. These sex differences are closely linked to reproductive variables (Bjorntorp, 1989; Legato, 1997~.
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From page 131... ...
Males also typically have relatively more abdominal fat and less gluteal-femoral fat than females. Energy Metabolism and Body Composition Foods and beverages contain substances that can be oxidized to energy (heat, measured in calories)
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From page 132... ...
Energy intake in excess of energy requirements is stored preferentially and primarily as fat (Figure 5-2~. Sex differences in energy requirements derive from sex differences in body size, body composition, and activity levels (Goran, 2000~.
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From page 133... ...
· Given that many obesity-related health risks are specifically linked to abdominal fat, is a given level of overall obesity less problematic for females than for males? · Can the study of sex differences in energy balance facilitate understanding of the etiology of obesity?
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From page 134... ...
From an epidemiological perspective, exploration of these possibilities might include comparisons by ethnicity and socioeconomic status to determine whether one or more are particularly applicable or inapplicable to subgroups of females. For example, assuming that the underlying biological sex differences in obesity determinants are relatively similar, the higher level of obesity in non-Hispanic African-American females compared with that in non-Hispanic white females might be due to higher levels of occurrence of the behavioral risk factors implied above in the African-American female population (overeating, low levels of activity, less effective weight control)
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From page 135... ...
b Obesitv was defined as a body mass index of >27.8 kilograms ner sauare meter for J J — (A 1 1 males and a body mass index of 2 27.3 kilograms per square meter for females. c Obesity was defined as a body mass index of 225 kilograms per square meter.
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From page 136... ...
Current approaches to the study of sex differences in energy metabolism and obesity are compatible with the general view that there are physiologically mediated differences in energy regulation, storage, and utilization. Many differences appear to be mediated by male-female differences in fat patterning, for example, the amounts, types, and metabolic characteristics of fat in the abdominal and gluteal-femoral regions (Bjorntorp, 1989~.
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From page 137... ...
Physical Performance Studies of physical performance and energy metabolism during exercise and physical work suggest intriguing sex differences that may be qualitatively different from the sex differences in energy regulation that are observed under resting conditions (Bjorntorp, 1989~. From an evolutionary perspective, in keeping with sex role differentiation, males may be more adapted than females for brief spurts of intense energy expenditure, whereas females may be more adapted than males for sustained but less intense energy expenditure (Hoyenga and Hoyenga, 1982~.
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From page 138... ...
cited the earlier recommendation of the 1992 Committee (Institute of Medicine, 1992) that "body composition standards be based on considerations of task performance and health and be validated with regard to the ethnic diversity of the military" (Institute of Medicine, 1998, p.
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From page 139... ...
Many factors contribute to bone health. Regarding the whole organism, both body size and frailty are important factors in clinical osteoporosis: large people have large bones and are less likely than small people to suffer a fracture.
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From page 140... ...
The major risk factors for osteoporosis are positive family history, weight less than 127 pounds and current tobacco use. Lesser risk factors are white race, female sex, age more than 65 years, postmenopausal status, low levels of calcium intake, alcoholism, sedentary life style, and chronic illness (Huopio et al., 2000~.
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From page 141... ...
, and melanoma cells have been reported to express estrogen receptors (Piepkorn, 2000~. Melanoma is also influenced by immune factors.
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From page 142... ...
In humans, exposure and other extrinsic factors explain most sex differences in the incidence of infectious diseases. If infections induce autoimmune diseases, differences in exposure may likely explain the sex differences.
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From page 143... ...
Gonadal hormones partly control these normal defense systems. The literature on the nonhormonal effects of sex on mechanisms of innate and adaptive immunities is sparse, however.
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From page 144... ...
The adaptive immune response varies during the menstrual cycle. However, most experiments on immune cells examine specific questions (e.g., does estradiol upregulate expression of a certain substance without considering physiological age, menstrual cycle, or other
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From page 145... ...
Exercise, stress, and depression all downregulate immune function (Irwin, 1999; Nehlsen-Cannarella et al., 1997~. Since each of these differs between the sexes, sex differences in the resultant illness may occur.
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From page 146... ...
Changes differ at different stages of pregnancy, with no apparent general pattern. Cutaneous and humoral immune responses to specific microbial antigens are selectively depressed, as are leukocyte chemotaxis and adhesion.
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From page 147... ...
· Portal of entry. Differences in genitourinary anatomies and local immune responses cause different clinical phenotypes of gonorrhea and herpes genitalia.
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From page 148... ...
Even in the conversion of acute to chronic Lyme disease (an illness that closely resembles autoimmune disease) , the incidence and severity in males and females are similar (Pena and Strickland, 1999~.
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From page 149... ...
Autoimmunity characterizes the prototypical diseases whose occurrences differ by sex. Autoimmune diseases pose the central question for the study of such sex differences: what mechanisms explain discrepancies in disease occurrences by sex?
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From page 150... ...
rheumatic diseases are autoimmune diseases; they differ about inflammatory bowel disease, multiple sclerosis, some skin diseases, and juvenileonset diabetes. Some autoimmune diseases are strikingly predominant in females, others are not predominant in either sex, and still others are predominant in males.
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From page 151... ...
Chronic Lyme disease is a self-perpetuating autoimmune illness that is initiated by but that does not require the persistence of live Borrelia burgdorferi organisms (Carlson et al., 2000~. Its incidence has no sex difference, yet it closely resembles rheumatoid arthritis, whose incidence does have a sex difference.
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From page 152... ...
Although experimental feminization worsens autoimmune diseases in animal models and experimental masculinization ameliorates autoimmune diseases in animal models, variations in both severity and incidence are found. Rheumatoid arthritis goes into remission during pregnancy, contradicting the theory of estrogen-enhanced immunological activity.
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From page 153... ...
Life Stage Causes of Autoimmunity Most diseases that are predominant in females cluster in the young-adult years, whereas autoimmune diseases that affect younger or older patients are more evenly divided between the sexes (Table 5-11~. Characteristics of young adulthood that may explain the predominance of a disease in females include the chronobiological effects of menstrual cycles, gonadal hormones, threshold effects, vascular responses, immune responses, vaginal flora, and other as yet unknown variables.
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From page 154... ...
0 9 8 6 6 3 3 2.5 2.3 2 1 0.5 0.4 0.3 0.3 0.2 30-50 30-75 30-50 30-50 10-30 15-45 20-30 20-30 30-50 20-40 1-15 5-15 20-35 2-5 2-5 2-15 15-40 30-65 40-60 40-80 50-70 50-80 60-75 50-90 10-30 20-50 40-70 15-35 Animal Models of Autoimmunity Animal models of autoimmune disease give mixed messages about the causes of sex differences in autoimmunity. Table 5-12 displays some relevant data for three animal models of human autoimmune diseases, two of which are predominant in females and one of which is dominant in males.
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From page 155... ...
In summary, animal models suggest that autoimmune diseases have specific genetic, hormonal, life stage, and environmental causes. The human sex differences are not reproduced in many of the animal models, but no attempt has been made to understand why.
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From page 156... ...
, chromo (Lillehc 1981) Lupus Spontaneous disease Mouse F > M Inbred st MHC, c meet; 0 mmunl are rele Spontaneous disease Mouse F = M Inbred st MHC, meet; 0 immunl are rele
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From page 157... ...
Inbred strains MHC, comple ment; other immune genes are relevant Disease develops Germfree; no in young difference in adulthood incidence or severity between males and females or conventionally raised controls (Unni et al., 1975) ; germfree, ant i g en fre e males but not females have lower lymph node weights than conven tional controls; the rate of glo merulonephritis .
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From page 158... ...
A long period of latency between exposure and clinical disease is possible, complicating the search for etiologies that differ by sex. A SPECTRUM OF SEX DIFFERENCES ACROSS A DISEASE: CORONARY HEART DISEASE Coronary heart disease begins in utero, evolves through childhood, and emerges in middle and old age as a devastating and crippling problem.
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From page 159... ...
Sex Differences in Development of Coronary Heart Disease The etiologies of coronary heart disease encompass the environment, genetics, age, and lifestyle. Environment The most important environmental agents influencing coronary heart disease are diet, drugs, airborne toxins, and, possibly, infectious agents;
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From page 160... ...
In the FH heterozygote population, the age differences in incidence between the sexes are comparable to those for the general population. Age Sex differences in heart disease mortality occur over the life span TABLE 5-13 Estimated Risk of Symptoms of Coronary Heart Disease and Death from Myocardial Infarction in Heterozygotes at Different Ages Percent Male Heterozygotes Female Heterozygotes Age (years)
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From page 161... ...
The Bogalusa Heart Study followed African-American and Caucasian children over time, beginning in the 1960s, demonstrating that sex differences in risks for coronary heart disease begin at an early age. The longitudinal Tromso Heart Study (Norway)
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From page 162... ...
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.
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From page 163... ...
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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From page 164... ...
Estrogen affords women a protective advantage against coronary heart disease before menopause. 17-~-Estradiol increases HDL cholesterol levels and decreases LDL cholesterol levels, stimulates nitric oxide, and inhibits vasoconstricting factors (Collins, 2000~.
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From page 165... ...
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.
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From page 166... ...
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. Premenopausal women, who are not typically at risk for coronary heart disease, are at risk if they have type I (juvenile)
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From page 167... ...
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)
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From page 168... ...
. Sex Differences in Treatment of Coronary Heart Disease (Myocardial Infarction)
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From page 169... ...
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)
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From page 170... ...
Summary Sex differences in the development, recognition, and treatment of coronary heart disease exist across the life span. There is mounting evidence that these differences are not solely related to hormones.
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From page 171... ...
17 ,/ These compounds can enter the body via the placenta, gastrointestinal tract, respiratory tract, eyes, urogenital tract, the transdermal route, or the parenteral route. Portals of entry can differ between the sexes, affecting types and incidences of disease.
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From page 172... ...
, and immune response variables; -consider how ethical concerns (e.g., risk of fetal injury) constrain study designs and affect outcomes; and -detect sex differences across the life span.
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