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J Physiol. 2019 May 11. doi: 10.1113/JP277056. [Epub ahead of print]

The exercise timing hypothesis - Can exercise training compensate for the reduction in blood vessel function after menopause if timed right?

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Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark.


As women enter menopause at mid-life, estrogen production ceases and its many beneficial effects on cardiovascular health are lost whereby the age-related risk of cardiovascular disease is accelerated. Estrogen acts via estrogen receptors and can activate the estrogen response element leading to upregulation of a number of proteins of importance for vascular health, including the vasodilator and anti-atherogenic enzyme endothelial nitric oxide synthase and angiogenic factors. Hormone replacement therapy can to some extent counteract the loss of estrogen although studies have shown that such treatment may only be effective if initiated soon after menopause, the so-called timing hypothesis. An attractive alternative to hormone therapy is regular physical activity, as it is known that exercise induces many of the same cardiovascular health protective effects as estrogen. Nevertheless, results from studies on the effect of physical activity on vascular function and cardiovascular health are inconsistent, with some studies showing a lack of effect of a physical activity program and others showing a beneficial effect. The reason for this divergence is unclear but here we explore whether there may be a timing aspect also for exercise training, the exercise timing hypothesis, where initiation of exercise interventions soon after menopause may be more effective than initiation many years after. The possibility that estrogen related receptor-α and oxidative stress may play a role for such a timing effect are discussed. Exercise training initiates cellular signals that includes activation of estrogen response element which leads to increased expression and activation of endothelial nitric oxide synthase (eNOS). This improves vascular tone, increases plaque removal and arterial (re)modelling resulting in improved vascular function. Estrogen induces similar improvements to the vascular system and the exercise timing hypothesis suggest that exercise induced improvements to the vasculature is easier achieved before the menopausal transition when both estrogen and exercise can activate these pathways compared to after menopause. This article is protected by copyright. All rights reserved.


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