Exercise as an Alternative to Oral Estrogen for Amelioration
Background: Both exercise and postmenopausal estrogen therapy augment endothelial function. We hypothesized that their interaction would be additive. The study objectives were to determine in postmenopausal women (1) the effects of an acute bout of exercise on brachial artery endothelium-dependent flow-mediated vasodilation (FMD), (2) whether these responses to exercise are augmented by concurrent estrogen treatment, and (3) whether these 2 interventions, independently or together, achieve FMD values observed in premenopausal women.
Methods: In postmenopausal women (n = 13; age 54 ± 2 [mean ± SE] years), FMD was quantified during supine rest and again 60 minutes after treadmill exercise for 45 minutes at 60%




O ₂max. Subjects were studied twice: before and after 4 weeks of oral estradiol. To obtain reference normal values, FMD was determined concurrently in 14 premenopausal (28 ± 1 years) women under identical basal conditions.
Results: Flow-mediated vasodilation in postmenopausal women, markedly impaired when compared with premenopausal women (5.3% ± 0.5% vs 12.1% ± 1.5%, P < .01), was significantly increased by exercise (to 9.9% ± 0.6%, P < .01). In contrast, after estrogen, FMD was augmented at rest ( P < .01) but was not further enhanced after exercise (11.5% ± 0.6% vs 9.9% ± 0.5%, P = .3). Both interventions increased, independently, FMD to values in premenopausal women ( P > .05).
Conclusions: In postmenopausal women, both acute exercise and estrogen therapy normalize FMD. However, their effects are not additive, possibly because of redundancy of nitric oxide signaling pathways activated by these 2 interventions. When considered in the context of recent trials with adverse cardiovascular outcomes, these results reinforce the therapeutic potential of exercise as an alternative nonpharmacological intervention to estrogen in postmenopausal women with endothelial dysfunction.


The endothelium plays a fundamental role in the regulation of vascular homeostasis. Endothelial dysfunction is considered to be an important permissive factor for the development of atherosclerosis. The normal endothelium releases the potent vasodilator nitric oxide (NO) in response to physiological stimuli such as increased flow. NO diffuses to smooth muscle, where it elicits vasodilation. Patients with endothelial dysfunction in the coronary arteries also have impaired brachial artery flow-mediated vasodilation (FMD). Moreover, brachial artery FMD is blunted in patients with documented coronary artery disease and with cardiovascular risk factors and improves in response to interventions known to reduce cardiovascular risk.

In animal studies, estrogen deficiency leads to increased production of vascular free radicals that scavenge NO. This leads to impaired NO bioavailability and, as a consequence, endothelial dysfunction and predisposition to atherogenesis. Conversely, administration of exogenous estrogen has been shown to increase NO bioavailability through genomic and nongenomic mechanisms. Brachial artery FMD is impaired in postmenopausal women; administration of estrogen significantly improves this response. Because combination estrogen and progestin hormone replacement therapy, in large clinical trials, has been suggested to increase cardiovascular events early in the course of treatment, whether such improvement in endothelial responsiveness translates into cardiovascular protection is controversial. Consequently, alternative approaches to primary and secondary cardiovascular prophylaxis in postmenopausal women need to be explored.

Two recent large observational studies in women have found that regular dynamic exercise is associated with a significant reduction in cardiovascular events. Several potential mechanisms for exercise-induced cardioprotection have been identified. Exercise-induced increases in blood flow and vascular shear stress may contribute to the cardioprotective vascular adaptations of exercise training through enhanced generation and bioavailability of NO. Indeed, studies predominantly in men have demonstrated increased plasma and urinary concentrations of the major stable NO metabolites nitrate and nitrite after an aerobic exercise training program. Furthermore, exercise training has been shown to improve forearm endothelium-dependent vasodilation and coronary artery endothelial function in patients with coronary disease when these responses are measured at rest, between training sessions. In contrast, little is known of the immediate after-effects of acute exercise on endothelial function in healthy subjects or subjects at increased risk of cardiovascular disease or of the interaction between exercise and estrogen replacement therapy in postmenopausal women.

If an acute bout of exercise enhances endothelial function by increasing synthesis or bioavailability of NO, postmenopausal women, a population at significant risk of morbidity and mortality from cardiovascular disease, may be particularly responsive to this intervention. In addition, because exogenous estrogen and acute dynamic exercise enhance independently the bioavailability of endothelial NO, we hypothesized that these 2 interventions, when implemented concurrently, would act synergistically to normalize endothelium-dependent vasodilation.

The objectives of this study in healthy normotensive postmenopausal women were to determine; (1) the effects of an acute bout of exercise on brachial artery endothelium-dependent (postischemic flow-mediated) vasodilation; (2) whether these responses to exercise are augmented by concurrent treatment with chronic oral estrogen replacement therapy, and (3) whether these 2 interventions, independently or together, restore or normalize FMD to achieve values observed in healthy premenopausal women.