Sex Differences and Implications for Translational Neuroscience Research Workshop Summary (2011) / Chapter Skim
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2 Studying Sex Differences in Health and Disease
2 Studying Sex Differences in Health and Disease
Pages 5-20
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From page 5... ...
SCIENTIFIC PRINCIPLES FOR STuDyING SEx DIFFERENCES IN HEALTH AND DISEASE Arthur Arnold, professor and chair of the Department of Physiological Science at the University of California–Los Angeles, stressed that basic science is the foundation for translation of knowledge about sex differences into clinical practice. Sex differences exist in the susceptibility to and progression of diseases.
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. According to the traditional model for the physiologic basis of sex differences, the Sry gene on the Y chromosome causes testes to develop; and testicular secretions, such as testosterone, influence masculine body and brain development.
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These non-hormonal actions lead to what are called sex chromosome effects. Arnold presented the "unified model" of sex differentiation, outlining these three classes of proximate factors causing sex differences in phenotype (Figure 2-1)
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Animal studies are quite important because in humans, of those three factors, researchers can only ethically address activational effects by manipulation of gonadal hormones in adults. There are relatively few human models in which one can observe organizational effects of hormones, and almost no models in which one can separate the direct sex chromosome effects from endocrine effects.
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Arnold also stressed the importance of educating both scientific grant program review staff and researchers about the importance of sex differences and how to study sex differences. STuDyING SEx DIFFERENCES IN DRuG RESPONSE Jeffrey Mogil, E
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A few pain researchers specifically study sex differences, but most in the pain field are not contributing to knowledge about sex differences at all because they only study male animals. One reason for the lack of studies in female animals is the misconception that data from female mice are more variable than data from male mice.
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STuDyING SEx DIFFERENCES IN DISEASE SuSCEPTIBILITy Kathryn Sandberg, director of the Center for Study of Sex Differences at Georgetown University Medical Center, discussed when and how sex differences in disease susceptibility should be studied (summarized in Box 2-1)
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It is easy to see how a stroke in a sexually differentiated brain region could result in very different outcomes for each sex. Differences in disease prevalence or age of disease onset are another instance when sex differences should be studied, Sandberg said.
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Furthermore, because Phase I and II clinical trials do not require sufficient numbers of women to assess sex differences in safety and efficacy, sex differences in treatment responses only become obvious when large clinical trials take place. Thus research bias may, in turn, bias drug development leading to better treatments in men and obscuring potential adverse drug side effects in women.
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Finally, the impact of sex chromosome dosage should be studied. Sandberg referred to her recent study results using the four-core genotype model, described by Arnold (above)
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women, a 2003 report from the Agency for Healthcare Research and Quality (AHRQ) , supported by the NIH ORWH, found that only about 20 percent of evidencebased articles reporting coronary heart disease studies that included women actually provided separate findings for women (AHRQ, 2003)
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Challenges Pinn highlighted some of the challenges to progress in sex differences research that she has observed across NIH programs and working groups (Box 2-2)
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. Another recently implemented funding mechanism is Advancing Novel Science in Women's Health Research, which is designed to fund new areas of sex and gender research (e.g., sex differences in complications in diabetic
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translation of findings in basic neuroscience research to clinical research in practice, and (2) absence of focus on sex differences in brain function and dysfunction in basic and clinical neuroscience research.
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Great progress has been made using animal models, for example, in understanding how genes and hormones direct sexually differentiated function in adulthood. But, Levine said, there has been limited feedback from clinical and basic science studies in humans to validate the current animal models of human brain diseases.
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5. Develop and support new approaches to define similarities and differences in sexually differentiated brain function and disease in human and animal models, for example, through the use of comparative imaging of sexually differentiated brain function.
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