Sex Differences and Blood Pressure

Over the last 10 years or so, my collaborators and I have conducted a series of studies on the physiology of sex differences, aging, and blood pressure in humans. The short story is that things get especially interesting for women at and after menopause when blood pressure can rise pretty dramatically.1

Our findings raise all sorts of questions at every level of biology all the way to population health. They can also be used to generate a linear narrative about how we systematically worked through a problem suggested by the epidemiology of blood pressure, sex differences, and aging. The reality is very different and represents how an experimental jigsaw puzzle came together. I believe our jigsaw puzzle experience might be useful for people thinking about scientific inquiry and professional development at every career stage.

Pieces of the Puzzle

When we write grants we generate nice tight “if we find A, then we conclude B” story lines, but in reality… usually after about a year or so we are pursuing related but different things.

Five main elements formed the milieu in which we were able to recognize the puzzle and discern the outlines of its solution. First, in the early 2000s, Gunnar Wallin, a colleague from Sweden, asked if we could help him understand why large groups of normotensive people with vastly different levels of sympathetic vasoconstrictor nerve activity have the same blood pressure. Gunnar had evidence that those with high levels of sympathetic “tone” also produced high levels of the vasodilator nitric oxide (NO). We had the ability to make detailed measurements of heart function and we also had Food and Drug Administration approval to give humans arginine analogs that block the synthesis of NO.

Second, Nisha Charkoudian, whose lab was “next door,” was also expert at recording sympathetic activity in humans using the technique Gunnar had perfected in Sweden. She was enthusiastic about collaborating, and together the three of us decided to pursue the topic.

Third, both Nisha and I worked in a clinical research center funded by the National Institutes of Health and were encouraged to study subjects of both sexes. After we made some initial observations in men showing that those with high levels of sympathetic activity had low levels of cardiac output that kept blood pressure normal, we started to wonder if there were sex differences in these patterns.

Fourth, Emma Hart joined the team as a postdoc and started to pursue these questions with real passion. As Emma left for a faculty position in the UK at Bristol, Jill Barnes (now at the University of Wisconsin, Madison) joined us and continued to pursue the sex differences question. The success of Emma and Jill highlights the point that the drive of female trainees working on this topic has been a real force for our team.

Fifth, no matter the specific protocol, we always obtained some common baseline data in all of the subjects we studied. This approach facilitated our own studies and also allowed us to mix and match our findings with those from other labs in studies that required larger numbers of subjects. Most recently Ronee Harvey, an MD/PhD student, has taken a deep dive into why oral contraceptives raise blood pressure by about 5mmHg in women.2

So very general questions about sympathetic activity and blood pressure in humans served as the corners and edges of our puzzle, and importantly the interior of the puzzle grows and becomes more detailed as new questions emerge. Part of this is a general ethic about asking questions versus chasing answers.3 Of course when we write grants we generate nice tight “if we find A, then we conclude B” story lines, but in reality the grants have been a template, and usually after about a year or so we are pursuing related but different things.

From Puzzle to Narrative?

I would argue that if you actually deconstruct a lot of successful careers and experimental “lines of work” there is in fact a jigsaw puzzle element to most of them and that linear narratives usually emerge post hoc. Telling ourselves and those we work with (especially younger people) that these linear stories are how it really happened can be an anxiety-producing distraction. This then leads to an overly metric-driven, as opposed to a curiosity-driven, approach that is ultimately inhibitory.

To me it is important for senior members of any team to help everyone keep the big picture questions flowing and keep the anxiety at bay. I would also add that on a practical level an ecosystem in your department and institution that encourages collaboration is likely as important as the microenvironment in your own lab.

There is in fact a jigsaw puzzle element to most successful careers and lines of work, and linear narratives usually emerge post hoc.

I also wonder if we are all working “too hard.” One of the advantages of doing complex studies in humans is that logistical limitations require at least a few days a week off from data collection. These built- in breaks provide a perfect excuse for idea- generating, coffee-fueled chats with trainees, colleagues, and collaborators.

All of us have to pay attention to things like tenure clocks and checking various boxes so we can move our careers forward. We also need to tell good and mostly linear stories in our papers and grants. However, let’s all remember that some of the best linear stories are based on nonlinear experiences, and when you are in the middle of one don’t let it raise your blood pressure too much.

—Michael J. Joyner, Mayo Clinic




  1. Joyner MJ, Barnes JN, Hart EC, Waling BG, Charkoudian N (2015). Neural control of the circulation: how sex and age differences interact in humans. Compr Physiol 5, 193–215 (doi: 10.1002/cphy. c140005).
  2. Harvey RE, Hart EC, Charkoudian N, Curry TB, Carter JR, Fu Q, Minson CT, Joyner MJ, Barnes JN (2015). Oral contraceptive use, muscle sympathetic nerve activity, and systemic hemodynamics in young women. Hypertension 66, 590–597 (doi: 10.1161/ hypertensionaha.115.05179).
  3. Holmes J (August 24, 2015 ). The case for teaching ignorance. The New York Times (
Michael J. Joyner

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