Women Are Not Just Small Men! Sex Differences in Blood Pressure Control

Hypertension is a common condition that is a significant risk factor for development of other cardiovascular diseases. The prevalence of hypertension is higher in men than women until after menopause, when the prevalence reverses and is higher in women. In addition, more women die of cardiovascular disease each year than do men.

There is mounting evidence that blood pressure in women is less well controlled than in age-matched men, despite the facts that women see their physicians more frequently and are often more compliant with their medications than men. This statistic makes one consider that either physicians are not as aggressive in treating hypertension in women, which is possibility, or that what causes hypertension in women may not be the same as what causes hypertension in men. Yet the guidelines for treatment for hypertension are the same for men and women based on data mostly collected in men, or if women were included in the studies, there were no analyses of the data to separate responses to antihypertensive therapy in men and women.

This leads to the notion in hypertension treatment that “women are just small men”—we treat their hypertension the same, even the doses of drugs are the same despite significant body weight differences between men and women that may suggest that kinetics and utilization of drugs may also be different.

The reason I think this is important is based on our animal experiments. We have studied aged male and female spontaneously hypertensive rats and found that the blood pressure in old males can be well controlled to normotensive levels by angiotensin receptor blockers (ARBs) or angiotensin I converting enzyme (ACE) inhibitors, suggesting that the renin-angiotensin system is the major system that affects blood pressure in the males.

In the old females, however, ARBs or ACE inhibitors reduce blood pressure but don’t normalize it. Also, endothelin ETA receptor antagonists reduce blood pressure but don’t normalize it. 20-hydroxyeicosatetraeonic acid (20-HETE) synthesis inhibitors reduce blood pressure but don’t normalize it. The combination of ARBs, endothelin ETA receptor antagonists, and 20-HETE inhibitors given together significantly reduce blood pressure in the old females, but still doesn’t normalize it (their blood pressure remains at 110 mm Hg mean blood pressure, measured by 24-hour telemetry, where the definition of “normal” is 100 mm Hg). These old females are no longer estrous cycling, which is similar to menopause in women. Also, bear in mind that these rats are inbred and raised in barriers, and so have little genetic variation or environmental confounding effects compared to humans. Based on these data, it’s not surprising that blood pressure control in women, especially postmenopausal women, confounded by genetics and environmental conditions may be difficult to manage! It also surprising that very few human studies have been done in which gender differences in responses to antihypertensive therapies have even been evaluated!

So what can we do as clinicians and scientists? First of all, make the NIH put teeth into their rules for human subject studies and require that all studies be powered to evaluate gender-specific differences. This is as important for men as for women, and the finding that there is no gender difference in responses is as important as finding them. The second thing is to advocate that women are not just “little men,” with different genetics and environmental conditions that may differentially affect their incidence of diseases, disease progression, treatment, and responses to that treatment. Finally, as new drug therapies for hypertension, or any other disease for that matter, come on the market we should advocate for gender differences studies in responses to make certain we are treating women and men with the best available therapies for their “differences” or “similarities.”