Menopause-related changes in vascular signaling by sex hormones.

CVD is more common in adult men and postmenopausal women than in premenopausal women.

• Women during menopausal transition show marked increase in the incidence of CVD and associated vascular dysfunction.
• The increased CVD risk is associated with declining ovarian function and reduced production of estrogen (E2) and progesterone.
• Conditions such as hypertension and coronary artery disease involve pathological changes in vascular signaling, function, and structure.

Estrogen (E2) and E2 receptor signaling have beneficial effects on vascular function.

• Mechanistic research suggests E2 and E2 receptor signaling promote vasodilation and decreased blood pressure.
• E2 signaling is associated with cardiovascular protection.
• These effects are mediated through influences on endothelial cells, vascular smooth muscle, and extracellular matrix.

Clinical trials of menopausal hormone therapy (MHT) in CVD have produced inconsistent results despite tangible benefits of E2 supplementation on menopausal symptoms.

• The benefits of E2 supplementation in improving menopausal symptoms prompted clinical trials of MHT in CVD.
• The results of these clinical trials have been characterized as 'inconsistent.'
• Earlier observations of vascular benefits of MHT 'did not materialize in randomized clinical trials.'

Multiple factors related to E2 administration may account for the inadequate cardiovascular benefits of MHT.

• Inadequate benefits could be attributed to the E2 type, dose, formulation, route, timing, and duration of therapy.
• Menopausal changes in E2/E2 receptor vascular signaling may also reduce MHT responsiveness.
• The integrated hormonal milieu including gonadotropins, progesterone, and testosterone may affect responsiveness to MHT.

Vascular health status and systemic factors beyond the cardiovascular system influence MHT responsiveness in postmenopausal women.

• Preexisting cardiovascular conditions may affect MHT responsiveness.
• Menopause-related dysfunction in the renal, gastrointestinal, endocrine, immune, and nervous systems are identified as additional factors affecting MHT outcomes.
• Vascular function is also influenced by environmental factors including diet, exercise, and stress, as well as genetic background, sex differences, and age.

Further analysis of menopausal changes in vascular signaling by sex hormones is needed to improve CVD management in postmenopausal women.

• The authors state that 'further analysis of these factors should enhance our understanding of menopause-related changes in vascular signaling by sex hormones.'
• Such analysis should 'provide better guidance for management of CVD in postmenopausal women.'
• Adjusting MHT protocols based on this understanding is proposed to 'enhance their effectiveness in reducing the risk and the management of cardiovascular disease in postmenopausal women.'