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APPENDIX B Physiological and Pharmacological Differences Between the Sexes Physiological and pharmacological differences between the sexes are discussed in Chapter 5 (see Table 5-3~. Additional examples are presented here in Table B-1, which is a continuation of Table 5-3, as the purpose of understanding sex differences is to achieve better health and health care, and understanding the differences between the sexes in response to thera- peutic agents is particularly important in that regard. TABLE B-1 Receptor, Enzyme, and Structural Differences Between Males and Females Sex Difference Clinical Relevance The dopamine D2 receptor gene has a TaqIA restriction fragment length polymorphism that yields two alleles, A1 and A2. Individuals with the A1 allele have a D2 receptor with a lower density and diminished function. Nemonapride, a potent D2 receptor antagonist with antipsychotic activity, increases the plasma prolactin concentration more in females with the A1 allele than males with this polymorphism (Mihara et al., 2000~. 233 Females may be at higher risk than males of adverse events associated with nemonapride-induced hyperprolactinemia. continued on next page

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234 TABLE B-1 Continued EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH Sex Difference Clinical Relevance The levels of androgen and progesterone May explain why men have deeper voices receptors present in vocal cords are than women and why women treated greater in males than females. with testosterone may develop a deep Progesterone receptor levels decrease voice. with age (Newman et al., 2000~. Inorganic phosphate pi-class glutathione S-transferase (pI 4.8) is approximately 1.6 times more abundant in the female colon than in the male colon. There are also significant differences between males and females in substrate specificities and inhibition kinetics (Singhal et al., 1992~. Atrial natriuretic peptide (ANP) levels are twofold greater in young women than young men. Levels do not vary during the menstrual cycle. ANP levels are not different in age-matched men and menopausal women. Aldosterone levels are higher in women than men during the luteal phase but not during the preovulatory phase of menses (Clark et al., 1990~. Clearance of methylprednisolone is greater in men than women during the late luteal phase of the menstrual cycle. The 50 percent inhibitory concentration for suppression of cortisol secretion is significantly lower in females. No sex differences in net cortisol or helper T-lymphocyte suppression exist. Males had greater net suppression of blood basophil weight (tow et al., 1993~. Blood samples from more men than women (89 versus 48 percent) with stage B-type lymphatic leukemia test positive for the MDR1 (multiple drug resistance) phenotype (Monteleone et al., 1997~. Male and female colons may metabolize small organic molecules differently. When women are infused with hypertonic saline, ANP levels are increased more during the luteal phase than the follicular phase of the menstrual cycle. Investigators conclude that intra- vascular volumes were decreased during the luteal phase compared with those during the follicular phase (Trigoso et al., 1996~. More rapid elimination of methyl- prednisolone by women compensates for their increased sensitivity to methyl- prednisolone-induced cortisol suppression. The doses given to patients were based on lean body mass. Women have a more benign course of disease, suggesting that sex-dependent differences in drug resistance gene activity may be responsible for at least some of the disease course (Monteleone et al., 1997~. In deciding on a treatment for untreated patients, sex and determination of marl gene expression should be considered in selecting appropriate treatment, including the need to use P-glycoprotein inhibitors.

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APPENDIX B TABLE B-1 Continued 235 Sex Difference Clinical Relevance d-Fenfluramine is used as a probe for central serotonin activity, such as in patients with obsessive-compulsive disease. In healthy subjects the secretion of a plasma cortisol response to d-fenfluramine was blunted in females but not males. The blunted response was more pronounced in female patients than healthy female subjects (Gilmore et al., 1992~. Young adults generally discriminate lower concentrations of citric acid and caffeine from water than elderly subjects. Younger subjects also detected suprathreshold concentrations of caffeine significantly more intense than those judged by young males and the elderly (Hyde and Feller, 1981) Young ovulating females excrete more kallikrein in their urine than males and menopausal females. During the follicular phase of the menstrual cycle the levels are similar to those in males and the levels rise during the luteal phase. These sex differences are present in white subjects but not African- American subjects (Kailasam et al., 1998~. Suggests serotonin dysfunction in female patients with some psychiatric disorders. These differences may influence the types and quantities of food and drink that people consume. The level of renal kallikrein excretion is diminished in essential hypertension. Results suggest that renal kallikrein biosynthesis responses are decreased in African Americans, a group at increased risk for development of hypertension. Estrogen receptors are higher in varicose It has not been determined if these segments than nonvaricose segments of the same vein, especially in females. Progesterone receptor levels are denser in the nonvaricose segments of females than in those of males (Mashiah et al., 1999~. Estrogen and progesterone receptor transcripts are expressed in arterial cruciate ligaments of males and females (Sciore et al., 1998~. Males have significantly larger knee cartilage than females, independent of body and bone size (Cicuttini et al 1999~. differences are age related or are associated with an increased incidence of varicosities in females. The rate of injury to ligaments in female athletes is greater than that to ligaments in male athletes. continued on next page

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236 TABLE B-1 Continued EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH Sex Difference Clinical Relevance Platelet phenolsulfotransferase levels Investigators recommend research into have different seasonal profiles in males sex-dependent metabolism of the and females (Marazziti et al., 1998b). endogenous and exogenous substrates for the enzyme. A positive relationship between occurrence of buccal mucosa ridging and tongue indentation (signs of bruxism) and sex and age was found, with the relationship found to be more common in females than males (Piquero et al., 1999~. Peroxidase activity in tears is higher during the preovulatory and luteal phases of the menstrual cycle. The activity correlates with plasma estradiol levels (Marcozzi et al., 2000~. May be associated with a variety of illnesses, e.g., headache and neck stiffness. Is a possible cause for the greater incidence of some ocular diseases, e.g., keratoconjunctivitis sicca (dry eyes), in females The dissociation constant (Kd) for These observations suggest that paroxetine binding to human platelets modifications in the serotonin is lower in young females than males; transporter might provide the basis for the opposite is found in elderly females. the increased susceptibility of females to The Kd was negatively correlated with depression. age in males (Marazziti et al., 1998a). The ratio of the incidence of irritable bowel syndrome in females:males is 2:1 (Mayer et al., 1999~. Obstructive sleep apnea is more prevalent in males than females, but the incidence increases in postmeno- pausal women, suggesting that pro- gesterone may provide protection against the disorder. Jordan et al. (2000) tested this hypothesis and found that one potential mechanism, the poststimulus ventilatory decline, is not different in males and females or in females during the follicular and luteal phases of their menstrual cycles. Males receiving a 21-milligram nicotine patch take significantly longer to relapse to smoking than females (Swan et al., 1997~. Positron emission tomography scans after rectosigmoid balloon distension show differences and may help elucidate the reason for the sex differences. The biological basis for this difference is unknown.

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APPENDIX B TABLE B-1 Continued 237 Sex Difference Clinical Relevance Elderly people metabolize the verapamil An example of a pharmacokinetic, not a enantiomer more slowly than young pharmacodynamic, difference. people. Mean arterial pressure and PR interval (an electrocardiogram variable) reduction correlated with S- and R-verapamil levels in blood and are not affected by sex or age (Gupta et al., 1995~. The endothelial synthesis of nitric oxide from L-arginine is stimulated by acetylcholine. The vasodilating effect of the brachial artery administration of acetylcholine was markedly impaired in hypercholesterolemic males but not hypercholesterolemic females compared with the effect in eucholesterolemic controls. The responses to acetylcholine were normalized by L-arginine in hyper- cholesterolemic males, whereas the effects were similar in hyper- cholesterolemic and control women (Chowienczyk et al., 1994~. Administration of 6 milligrams of bromperidol raises plasma prolactin levels more in females than males and correlates with the levels of brom- peridol and its reduced metabolite in plasma (Yasui et al., 1998~. In healthy subjects a plasma cortisol response to d-fenfluramine is present in females but not males. The response did not differ between patients with obsessive-compulsive disease and control subjects but was significantly reduced in female patients compared with that in female controls (Monteleone et al., 1997~. These responses may account for why hypercholesterolemic females appear to be protected from the adverse effects of nitric oxide production. Serum prolactin level increases in males receiving haloperidol have been correlated with the clinical response to this antipsychosis drug (Van Putten et al., 1991~. Assuming that the mechanism for the prolactin increases for these drugs is similar in males and females, a smaller dose for females than males may be appropriate. These results suggest a dysfunction of serotonin transmission in female patients with obsessive-compulsive disease. continued on next page

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238 TABLE B-1 Continued EXPLORING THE BIOLOGICAL CONTRIBUTIONS TO HUMAN HEALTH Sex Difference Clinical Relevance Estrogen binds to the dopamine receptor, providing an explanation of why postmenopausal women are more likely than younger women to experience the dopamine-related side effects of drugs (Dawkins and Potter, 1991; Yonkers et al., 1992~. Apolipoprotein E genotype differences had no effect on the response to tacrine in patients with mild to moderate Alzheimer's disease, although there was a clear sex difference. Treatment effect size was not different between epsilon 2-3 and epsilon 4 in men but was larger for epsilon 2-3 than epsilon 4 in women (Farlow et al., 1998~. To satisfactorily dose patients with growth hormone, a dose adjustment method provides the best results since females were less sensitive to growth hormone and larger doses are required to achieve in females the same levels achieved in males (Drake et al., 1998~. The incidence of vascular thromboses varies between the sexes. Estrogen beta and androgen receptors are expressed on human megakaryocytes; they are upregulated by 1.5 and 10 nanomoles of testosterone per liter and are down- regulated by 100 nanomoles of testosterone per liter (Khetawat et al., 2000~. Binding to receptor probably has an antidopaminergic effect. Could significantly improve drug selection for each patient if the effect is substantiated for other drugs. Serum insulin-like growth factor type 1 level measurements provide the surrogate endpoint for the appropriate dose. The ability of megakaryocytes to respond to testosterone provides a possible mechanism by which sex hormones may mediate sex differences in platelet activity and thrombotic diseases.