Sex as a biological variable in renal, metabolic, and cardiovascular physiology: eighteen years of leadership by the American Physiological Society

Recent mandates from the National Institutes of Health (NIH) requiring the consideration of sex as a biological variable in NIH-funded research have resulted in an increase in the inclusion of females in experimental studies. As more investigators include animals of both sexes in their experiments and as clinicians perform studies sufficiently powered to determine whether there are sex differences, the scientific community is beginning to identify molecular, cellular, and systems-based differences between males and females that affect normal physiology, responses to pathological conditions, and responses to therapeutics. As a result, the topic of sex and gender is of growing interest to many in the scientific community. The American Physiological Society (APS) promoted the understanding of sex as a biological variable well before the NIH mandate was set. In 2001, the APS sponsored a conference entitled “Genome and Hormones: An Integrative Approach to Gender Differences in Physiology” thus establishing itself as a leader in understanding the influence of biological sex on physiology and pathophysiology. As a testament to the quality of the 2001 meeting and the strong interests of the APS membership, similarly titled conferences took place in 2007, 2009, 2011, and 2015, establishing the physiology of sex differences as one of the most important topics brought to the APS conference committee and the topic of APS-sponsored conferences that recurs the most.

This track record of leadership was continued in September 2018 with the sixth conference in the series, entitled “Cardiovascular, Renal, and Metabolic Diseases: Sex-Specific Implications in Physiology,” held in Knoxville, Tennessee. The objective of the conference was to provide a greater understanding of how sex and gender impact normal physiology and the pathophysiology of disease, and to gather a critical mass of expert clinical and basic researchers with interests in the role of sex hormones, sex chromosomes, and gender in cardiovascular-renal diseases, obesity, and metabolic syndrome. The intent of this forum was to foster an exchange of ideas and collaborations while educating, exploring, and expanding our understanding of the unique considerations for the study of physiology in males and females. Another goal of the organizing committee was to expand the scope of the meeting and encourage new participation in this important field of research. To this end, there were numerous first-time attendees and invited speakers, and the conference had good attendance with 110 registrants. Among the registrants, 69% were women and 31% were men. Trainees (graduate students and postdoctoral fellows) made up 35% of the attendees and played a central role in the meeting with many serving as session co-chairs. Thanks to the generous support of the APS, National Heart, Lung, and Blood Institute, Diabetic Complications Consortium, and the University of Mississippi Medical Center Women’s Health Center, we were able to provide travel awards to 31 trainees. Perhaps most importantly, more than 60% of the meeting attendees were new to the meeting having never attended one of the previous conferences.

Scientifically, the design of the program encompassed eight major themes (Table 1) in order to capture the breadth of work in the field. Several experts in the field were invited to talk on each theme, with the remaining presentations selected from submitted abstracts. All of the submitted abstracts were presented in one of two poster sessions held during the meeting. Marjorie Jenkins, MD, a professor at Texas Tech University Health Sciences Center, Director and Chief Scientific Officer for the Laura W. Bush Institute for Women’s Health, and Director of Medical Initiatives and Scientific Engagement for the Office of Women’s Health at the Food and Drug Administration, delivered the plenary lecture entitled “National initiatives in sex and gender-based medicine (SGBM).” We were fortunate that the program included national leaders on the study of sex differences in male and female physiology across multiple disciplines. Among them were many first-time attendees including Drs. Zdenka Pausova (University of Toronto), Alicia McDonough (University of Southern California), and Michelle Hladunewich (University of Toronto).

Table 1.

Scientific themes for the 2018 APS Conference on Cardiovascular, Renal, and Metabolic Diseases: Sex-Specific Implications in Physiology

	Theme
1	Sex and gender differences in physiology and function: the brain and  nervous system
2	Physiology and gender: aging and senescence
3	Sex and gender differences in physiology and function: the heart
4	Physiology and gender: obesity and metabolism
5	Sex and gender differences in physiology and function: the kidney
6	Female-specific cardiovascular, renal and metabolic complications
7	Sex and gender differences in physiology and function: the vasculature
8	Male-specific cardiovascular, renal and metabolic complications

Dr. Pausova spoke on “Sex difference in blood pressure hemodynamics during sexual maturation and aging” where she outlined results from the community-based Saguenay Youth Study with over 1,000 youth participants plus their parents (7). Dr. Pausova’s work suggests that there are marked differences in systemic hemodynamic responses to daily activities between men and women that become apparent at the onset of male puberty but that disappear as women transition through menopause. Dr. McDonough spoke on “Sex differences in renal sodium transporters” and described how differences in renal transporters between men and women are likely to be mechanistically responsible for the more rapid excretion of a sodium load in women, mediated in part by lower proximal tubular sodium reabsorption in women (5, 8). Dr. Hladunewich gave a clinical perspective on “Long-term sequelae of preeclampsia,” describing the central role of impaired vascular function in women with preeclampsia and the markedly increased risk for those patients to develop end-stage renal disease later in life (1, 6). Dr. Hladunewich also introduced the concept of a “renal-placental syndrome” to describe the link between preeclamptic pregnancies and chronic kidney disease.

Among the participants who have attended and supported past meetings were Drs. David Pollock and A. Kim Johnson. Dr. Pollock (University of Alabama, Birmingham) discussed “Sex differences in renal function” from the perspective of the endothelin system. In his presentation, Dr. Pollock highlighted work demonstrating that urinary endothelin 1 (ET-1) excretion is consistently higher in females than males and thus may play an important role in regulating salt and water homeostasis differences that exist between the sexes (2, 4). Dr. Johnson (University of Iowa) described the “Role of sensitization and neuroplasticity in sex differences in blood pressure and hypertension,” outlining mechanisms by which hypertensive response sensitization occurs only in males (3, 9, 10).

In addition to the outstanding scientific programming, Dr. Kelly Hyndman organized a session for the trainees entitled “Get the job you want: tips for interviewing and negotiating.” Dr. Hyndman impaneled conference faculty who have leadership roles at their respective institutions in order to facilitate open discussion and interaction about career opportunities, hiring practices, interviewing, and networking with the trainees.

Throughout the conference, several common themes were echoed by the speakers and attendants. Chief among them was the concept that the field of sex as a biological variable has advanced significantly in the past 20 years; however, in order for the field to remain relevant, investigators need to move beyond simply asking the question of whether “sex differences” exist. Reporting a phenotypic sex difference is important, but studies need to be designed to understand the mechanistic basis underlying these observations that can ultimately lead to improved treatment strategies for disease. Since the NIH mandate to consider sex as a biological variable there has been an increase in the number of females included in both clinical and basic science studies; however, the inclusion of females alone is not enough. The studies must be sufficiently powered to assess sex-specific outcomes. In addition, the data should be reported separately by sex, and studies should be designed to determine whether biological sex impacts experimental end points. Moreover, the absence of a phenotype in females should not be a valid scientific justification to exclude females from a study. Rather, the absence of a phenotype in females should be considered of interest because the mechanisms that protect against a phenotypic change may be valuable for understanding physiological processes that could lead to the design of better therapeutic strategies in both sexes. As the field continues to advance, it is important not only to identify sex and gender differences, but also to begin to translate these findings into improved overall health in both men and women. Through its conference programs, the American Physiological Society should continue to lead this effort going forward.

GRANTS

This work was supported in part by National Heart, Lung, and Blood Institute Grants R01 HL127091, P01 HL134604, and R01 HL136684; American Heart Association Grant 17EIA33410565; and VA Merit Award BX002604.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

M.J.R. and J.C.S. drafted manuscript; edited and revised manuscript; approved final version of manuscript.