Gender, menopause and nonmodulation

Angiotensinogen is one of the few genes related by linkage analysis to human hypertension -- but only among males. Polymorphisms in this gene also predict abnormal renal responsiveness to angiotensin II, a feature of nonmodulation (NM). To explore this bridge between genetics and physiology, we evaluated the effects of gender on NM. The NM phenotype, characterized by defective adaptation to changes in sodium intake, was assessed by either the aldosterone response on a low sodium diet or the renal plasma flow response on a high sodium diet to a 3 ng/kg/min infusion of angiotensin II. Identical protocols were conducted on 202 hypertensive inpatients (64 women, 138 men) in Boston, Mass. and Rome, Italy. Overall, the frequency of NM was lower among women (30%; 95% confidence interval 19-42%) than among men (47%;38-56) (p=0.02). We tested the hypothesis that sex steroids play a role by comparing women under 45 (premenopausal, mean age 34) with those over 55 (postmenopausal, mean age 60). Among younger women, the frequency of NM was only 14% (C.I. 5-30%), less than half that of younger men (38%;25-52);p=0.02. This difference disappeared among older patients: 60% of females were NM, similar to 50% of men. We conclude that the premenopausal state protects against expression of the NM phenotype, and speculate that this phenomenon participates in the known protection against cardiovascular disease in younger women.