Portal de Periódicos da CAPES

Gender Medicine: “In a Perfect World …”

2014; Elsevier BV; Volume: 36; Issue: 12 Linguagem: Inglês

10.1016/j.clinthera.2014.10.020

1879-114X

Jane F. Reckelhoff,

Diversity and Career in Medicine

This focus group of papers for the Women's Health/Gender Medicine section highlights a topic that is near and dear to my heart as a researcher who studies sex and gender differences in cardiovascular and renal disease and hypertension. It is also timely because the National Institutes of Health (NIH) and the Office of Research in Women's Health have recently come together to require that NIH applicants consider sex as a variable in biomedical research involving animals and cells. In a commentary published earlier this year in Nature,1Clayton J.A. Collins F.C. NIH to balance sex in cell and animal studies.Nature. 2014; 509: 282-283Crossref PubMed Scopus (1037) Google Scholar Janine Clayton, Director of the Office of Research in Women's Health, and Francis Collins, Director of the NIH, suggest that this initiative is the equivalent in animal and cell research to the NIH Revitalization Act of 1993, which required the inclusion of women in NIH-funded clinical research.2National Institutes of Health. NIH policy and guidelines on the inclusion of women and minorities as subjects in clinical research. 2001. http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. Accessed October 1, 2014.Google ScholarIn 2001, the Institute of Medicine published a white paper that defined sex as "being male or female according to reproductive organs and the functions assigned by chromosomal complement (XX for female and XY for male)."3Wizemann T.M. Pardue M.L. Exploring the Biological Contributions to Human Health: Does Sex Matter? Board on Health Sciences Policy. Institute of Medicine, Washington, DC2001Google Scholar This includes any physiological process that is directly mediated by the presence or absence of sex steroids,3Wizemann T.M. Pardue M.L. Exploring the Biological Contributions to Human Health: Does Sex Matter? Board on Health Sciences Policy. Institute of Medicine, Washington, DC2001Google Scholar and includes but is not limited to reproduction. In contrast, gender, a term that is often misused not only by the scientific community but also the lay press, includes "everything else,"3Wizemann T.M. Pardue M.L. Exploring the Biological Contributions to Human Health: Does Sex Matter? Board on Health Sciences Policy. Institute of Medicine, Washington, DC2001Google Scholar and is mainly how one sees oneself as male or female, and how society therefore responds to the person as male or female. Gender encompasses psychosocial issues and environment, which are not included in the definition of sex.It is very true that most preclinical research is done using male animal models.4Miller V.M. Why are sex and gender important to basic physiology and translational and individualized medicine?.Am J Physiol Heart Circ Physiol. 2014; 306: H781-H788Crossref PubMed Scopus (87) Google Scholar The reasons are myriad, including the notion that the cost of including females in the study doubles the cost, which can be prohibitive in these times of reduced funding levels and cutbacks at NIH. In addition, there is the misconception that the presence of the estrous cycle in the female makes them a more difficult and variable model to study. To date, there have been very few physiologic or pharmacologic effects that have been shown to vary by the day in the estrous cycle, especially in rodents, the most commonly used animal model for preclinical research. Certainly women are not treated differently for their hypertension, heart disease, or hypercholesterolemia based on whether they are in the follicular phase or the luteal phase of their menstrual cycles, or even based on the lack of a menstrual cycle after menopause. With regard to hypertension, the guidelines for treatment of women are not different than for men. Unfortunately, this is despite the fact that many studies around the world are now showing that hypertension is not as well controlled in postmenopausal women as in men,5Keyhani S. Keyhani S. Scobie J.V. et al.Gender disparities in blood pressure control and cardiovascular care in a national sample of ambulatory care visits.Hypertension. 2008; 51: 1149-1155Crossref PubMed Scopus (110) Google Scholar, 6Kim J.K. Alley D. Seeman T. et al.Recent changes in cardiovascular risk factors among women and men.J Womens Health (Larchmt). 2006; 15: 734-746Crossref PubMed Scopus (58) Google Scholar suggesting that, among other causes, the mechanisms responsible for the hypertension in women may be different than for men.Although it is also true that the NIH has required the inclusion of women in all clinical trials since the Revitalization Act, the numbers of women actually recruited for clinical trials range from 20% to 60% of the cohort.7Wenger N.K. Hayes S.N. Pepine C.J. Roberts W.C. Cardiovascular care for women: the Q-10 Report and beyond.Am J Cardiol. 2013; 112: S2Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar For example, for hypertension, the clinical trials are fairly good, with an average of 60% women, but for heart disease, the numbers are much lower, closer to 20% women. Importantly, although women are included in the trials, very few of the studies are powered statistically to find gender differences. In addition, there are no adverse consequences for investigators funded by the NIH who do not recruit enough women and men to evaluate the role of gender in their studies, whether there is a gender effect or not. It is just as important to show that there is no effect of gender on a physiologic outcome as to show there is an effect, and these data should be published.In a perfect world, we would recommend the NIH announce financial incentive programs paid for by specific percentages of the portfolios in each institute, including Requests for Applications, to perform preclinical studies to evaluate sex differences, and require documentation that this is accomplished in the yearly progress reports required of funded investigators. That, more than anything else, would change the culture of research in which only males are used. These changes would impact not only NIH then, but also other foundation-supported funding as well because, as we all know, what happens at NIH has a ripple effect throughout many other funding agencies. We would also recommend that NIH encourage training in how to perform studies using both sexes, and set aside a portion of T32 training grant funding that is directed toward and focuses on this training. Finally, both study section members and administrators will need training in how to scientifically evaluate applications that incorporate sex as a tested variable in animal studies.Finally, in a perfect world, both women and men in equal numbers would be recruited in clinical trials when appropriate, and the principal investigators would be held accountable by NIH if these equal numbers were not met and the data were not analyzed for gender.Although I have focused on the new initiatives by NIH to include sex as a variable in preclinical studies, this is a common problem being addressed by many governmental research agencies around the world.8World Health OrganizationWHO Expert Committee on Biological Standardization. Thirty-Seventh Report. WHO Health Organization Technical Report Series. WHO, Geneva1987Google Scholar, 9Caron J. Canadian Institutes of Health Research. Report on governmental health research policies promoting gender or sex differences sensitivity. http://dsp-psd.pwgsc.gc.ca/collection_2008/cihr-irsc/MR21-103-2003E.pdf. Accessed October 1, 2014.Google Scholar, 10European Commission. Vademecum. Gender Mainstreaming in the 6th Framework Programme-Reference Guide for Scientific Officers/Project Officers. 2003 ftp://ftp.cordis.europa.eu/pub/science-society/docs/gendervademecum.pdf. Accessed October 1, 2014.Google ScholarThese are exciting times for gender medicine going forward, and we hope that these proposed initiatives by NIH will improve the health of both men and women.In the current issue of Clinical Therapeutics, we have included several review articles that incorporate the use of animal models to study various diseases. Tipton and Sullivan discuss the role of T cells and the immune mechanisms responsible for hypertension.11Tipton A.J. Sullivan J.C. Sex and gender differences in T cells in hypertension.Clin Ther. 2014; 36: 1882-1900Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar This is a growing area of research based on findings several years ago that replacement of T cells but not B cells in mouse models that are null for both T cells and B cells causes them to have a hypertensive response to the vasoconstrictor angiotensin II.12Harrison D.G. Guzik T.J. Lob H.E. et al.Inflammation, immunity, and hypertension.Hypertension. 2011; 57: 132-140Crossref PubMed Scopus (599) Google ScholarAlthough heart disease is the leading cause of death among women, they are typically approximately 10 years older than men at diagnosis and, therefore, in women, the consequences of the disease are complicated by aging. Premenopausal women have been thought to be protected because the incidence of heart disease is lower in this group than in age-matched men. Garcia and colleagues13García N.H. Perez H.A. Spence J.D. Armando J.L. Premenopausal women may not be protected against early vascular disease in the presence of diabetes.Clin Ther. 2014; 36: 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar provide data to suggest that premenopausal women might not be protected against heart disease, especially in the face of diabetes.The cardiovascular disease that accompanies systemic lupus erythematosus is a focus of the review by Gilbert and Ryan.14Gilbert E.L. Ryan M.J. Estrogen in cardiovascular disease during systemic lupus erythematosus.Clin Ther. 2014; 36: 1901-1912Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Women have a 9-fold higher incidence of developing systemic lupus erythematosus, as is the case with most autoimmune disorders. This has led many investigators to propose that estradiol may promote the incidence of the disease and cardiovascular disease complications associated with the disease. This article examines the data supporting an etiologic and permissive role of estrogen in women with studies utilizing animal models that show that estradiol may be protective in females with systemic lupus erythematosus as they age.Preeclampsia is another immune-associated disease that is the focus of the review by Eric George.15George E. New approaches for managing preeclampsia: clues from clinical and basic research.Clin Ther. 2014; 36: 1873-1881Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Preeclampsia is the leading cause of morbidity and mortality of both the mother and fetus during pregnancy. In fact, the children of women who have preeclampsia are born small for gestational age and, in extreme case, might even be subjected to premature birth to save the child and the mother. Finding the mechanisms responsible for preeclampsia is a field of intense research. In his comprehensive review, George covers the diagnostics, treatment, and potential mechanisms responsible for preeclampsia based on both human studies and studies in animal models.The Barker hypothesis proposes that children born with low birth weight are at increased risk for cardiovascular disease. In her review, Barbara Alexander,16Alexander B.T. Low birth weight: impact on women's health.Clin Ther. 2014; 36: 1913-1923Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar a leader in the field of developmental programming of cardiovascular disease, describes what led Barker to this hypothesis in England in the early 1900s and the recent evidence supporting this hypothesis from both human studies and animal models. This focus group of papers for the Women's Health/Gender Medicine section highlights a topic that is near and dear to my heart as a researcher who studies sex and gender differences in cardiovascular and renal disease and hypertension. It is also timely because the National Institutes of Health (NIH) and the Office of Research in Women's Health have recently come together to require that NIH applicants consider sex as a variable in biomedical research involving animals and cells. In a commentary published earlier this year in Nature,1Clayton J.A. Collins F.C. NIH to balance sex in cell and animal studies.Nature. 2014; 509: 282-283Crossref PubMed Scopus (1037) Google Scholar Janine Clayton, Director of the Office of Research in Women's Health, and Francis Collins, Director of the NIH, suggest that this initiative is the equivalent in animal and cell research to the NIH Revitalization Act of 1993, which required the inclusion of women in NIH-funded clinical research.2National Institutes of Health. NIH policy and guidelines on the inclusion of women and minorities as subjects in clinical research. 2001. http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. Accessed October 1, 2014.Google Scholar In 2001, the Institute of Medicine published a white paper that defined sex as "being male or female according to reproductive organs and the functions assigned by chromosomal complement (XX for female and XY for male)."3Wizemann T.M. Pardue M.L. Exploring the Biological Contributions to Human Health: Does Sex Matter? Board on Health Sciences Policy. Institute of Medicine, Washington, DC2001Google Scholar This includes any physiological process that is directly mediated by the presence or absence of sex steroids,3Wizemann T.M. Pardue M.L. Exploring the Biological Contributions to Human Health: Does Sex Matter? Board on Health Sciences Policy. Institute of Medicine, Washington, DC2001Google Scholar and includes but is not limited to reproduction. In contrast, gender, a term that is often misused not only by the scientific community but also the lay press, includes "everything else,"3Wizemann T.M. Pardue M.L. Exploring the Biological Contributions to Human Health: Does Sex Matter? Board on Health Sciences Policy. Institute of Medicine, Washington, DC2001Google Scholar and is mainly how one sees oneself as male or female, and how society therefore responds to the person as male or female. Gender encompasses psychosocial issues and environment, which are not included in the definition of sex. It is very true that most preclinical research is done using male animal models.4Miller V.M. Why are sex and gender important to basic physiology and translational and individualized medicine?.Am J Physiol Heart Circ Physiol. 2014; 306: H781-H788Crossref PubMed Scopus (87) Google Scholar The reasons are myriad, including the notion that the cost of including females in the study doubles the cost, which can be prohibitive in these times of reduced funding levels and cutbacks at NIH. In addition, there is the misconception that the presence of the estrous cycle in the female makes them a more difficult and variable model to study. To date, there have been very few physiologic or pharmacologic effects that have been shown to vary by the day in the estrous cycle, especially in rodents, the most commonly used animal model for preclinical research. Certainly women are not treated differently for their hypertension, heart disease, or hypercholesterolemia based on whether they are in the follicular phase or the luteal phase of their menstrual cycles, or even based on the lack of a menstrual cycle after menopause. With regard to hypertension, the guidelines for treatment of women are not different than for men. Unfortunately, this is despite the fact that many studies around the world are now showing that hypertension is not as well controlled in postmenopausal women as in men,5Keyhani S. Keyhani S. Scobie J.V. et al.Gender disparities in blood pressure control and cardiovascular care in a national sample of ambulatory care visits.Hypertension. 2008; 51: 1149-1155Crossref PubMed Scopus (110) Google Scholar, 6Kim J.K. Alley D. Seeman T. et al.Recent changes in cardiovascular risk factors among women and men.J Womens Health (Larchmt). 2006; 15: 734-746Crossref PubMed Scopus (58) Google Scholar suggesting that, among other causes, the mechanisms responsible for the hypertension in women may be different than for men. Although it is also true that the NIH has required the inclusion of women in all clinical trials since the Revitalization Act, the numbers of women actually recruited for clinical trials range from 20% to 60% of the cohort.7Wenger N.K. Hayes S.N. Pepine C.J. Roberts W.C. Cardiovascular care for women: the Q-10 Report and beyond.Am J Cardiol. 2013; 112: S2Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar For example, for hypertension, the clinical trials are fairly good, with an average of 60% women, but for heart disease, the numbers are much lower, closer to 20% women. Importantly, although women are included in the trials, very few of the studies are powered statistically to find gender differences. In addition, there are no adverse consequences for investigators funded by the NIH who do not recruit enough women and men to evaluate the role of gender in their studies, whether there is a gender effect or not. It is just as important to show that there is no effect of gender on a physiologic outcome as to show there is an effect, and these data should be published. In a perfect world, we would recommend the NIH announce financial incentive programs paid for by specific percentages of the portfolios in each institute, including Requests for Applications, to perform preclinical studies to evaluate sex differences, and require documentation that this is accomplished in the yearly progress reports required of funded investigators. That, more than anything else, would change the culture of research in which only males are used. These changes would impact not only NIH then, but also other foundation-supported funding as well because, as we all know, what happens at NIH has a ripple effect throughout many other funding agencies. We would also recommend that NIH encourage training in how to perform studies using both sexes, and set aside a portion of T32 training grant funding that is directed toward and focuses on this training. Finally, both study section members and administrators will need training in how to scientifically evaluate applications that incorporate sex as a tested variable in animal studies. Finally, in a perfect world, both women and men in equal numbers would be recruited in clinical trials when appropriate, and the principal investigators would be held accountable by NIH if these equal numbers were not met and the data were not analyzed for gender. Although I have focused on the new initiatives by NIH to include sex as a variable in preclinical studies, this is a common problem being addressed by many governmental research agencies around the world.8World Health OrganizationWHO Expert Committee on Biological Standardization. Thirty-Seventh Report. WHO Health Organization Technical Report Series. WHO, Geneva1987Google Scholar, 9Caron J. Canadian Institutes of Health Research. Report on governmental health research policies promoting gender or sex differences sensitivity. http://dsp-psd.pwgsc.gc.ca/collection_2008/cihr-irsc/MR21-103-2003E.pdf. Accessed October 1, 2014.Google Scholar, 10European Commission. Vademecum. Gender Mainstreaming in the 6th Framework Programme-Reference Guide for Scientific Officers/Project Officers. 2003 ftp://ftp.cordis.europa.eu/pub/science-society/docs/gendervademecum.pdf. Accessed October 1, 2014.Google Scholar These are exciting times for gender medicine going forward, and we hope that these proposed initiatives by NIH will improve the health of both men and women. In the current issue of Clinical Therapeutics, we have included several review articles that incorporate the use of animal models to study various diseases. Tipton and Sullivan discuss the role of T cells and the immune mechanisms responsible for hypertension.11Tipton A.J. Sullivan J.C. Sex and gender differences in T cells in hypertension.Clin Ther. 2014; 36: 1882-1900Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar This is a growing area of research based on findings several years ago that replacement of T cells but not B cells in mouse models that are null for both T cells and B cells causes them to have a hypertensive response to the vasoconstrictor angiotensin II.12Harrison D.G. Guzik T.J. Lob H.E. et al.Inflammation, immunity, and hypertension.Hypertension. 2011; 57: 132-140Crossref PubMed Scopus (599) Google Scholar Although heart disease is the leading cause of death among women, they are typically approximately 10 years older than men at diagnosis and, therefore, in women, the consequences of the disease are complicated by aging. Premenopausal women have been thought to be protected because the incidence of heart disease is lower in this group than in age-matched men. Garcia and colleagues13García N.H. Perez H.A. Spence J.D. Armando J.L. Premenopausal women may not be protected against early vascular disease in the presence of diabetes.Clin Ther. 2014; 36: 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar provide data to suggest that premenopausal women might not be protected against heart disease, especially in the face of diabetes. The cardiovascular disease that accompanies systemic lupus erythematosus is a focus of the review by Gilbert and Ryan.14Gilbert E.L. Ryan M.J. Estrogen in cardiovascular disease during systemic lupus erythematosus.Clin Ther. 2014; 36: 1901-1912Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Women have a 9-fold higher incidence of developing systemic lupus erythematosus, as is the case with most autoimmune disorders. This has led many investigators to propose that estradiol may promote the incidence of the disease and cardiovascular disease complications associated with the disease. This article examines the data supporting an etiologic and permissive role of estrogen in women with studies utilizing animal models that show that estradiol may be protective in females with systemic lupus erythematosus as they age. Preeclampsia is another immune-associated disease that is the focus of the review by Eric George.15George E. New approaches for managing preeclampsia: clues from clinical and basic research.Clin Ther. 2014; 36: 1873-1881Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Preeclampsia is the leading cause of morbidity and mortality of both the mother and fetus during pregnancy. In fact, the children of women who have preeclampsia are born small for gestational age and, in extreme case, might even be subjected to premature birth to save the child and the mother. Finding the mechanisms responsible for preeclampsia is a field of intense research. In his comprehensive review, George covers the diagnostics, treatment, and potential mechanisms responsible for preeclampsia based on both human studies and studies in animal models. The Barker hypothesis proposes that children born with low birth weight are at increased risk for cardiovascular disease. In her review, Barbara Alexander,16Alexander B.T. Low birth weight: impact on women's health.Clin Ther. 2014; 36: 1913-1923Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar a leader in the field of developmental programming of cardiovascular disease, describes what led Barker to this hypothesis in England in the early 1900s and the recent evidence supporting this hypothesis from both human studies and animal models.