Estrogen, hormonal replacement therapy and cardiovascular disease

Abstract

Purpose of review: Premenopausal women have a lower risk and incidence of hypertension and cardiovascular disease (CVD) compared to age-matched men and this sex advantage for women gradually disappears after menopause, suggesting that sexual hormones play a cardioprotective role in women. However, randomized prospective primary or secondary prevention trials failed to confirm that hormone replacement therapy (HRT) affords cardioprotection. This review highlights the factors that may contribute to this divergent outcome and could reveal why young or premenopausal women are protected from CVD and yet postmenopausal women do not benefit from HRT.

Recent findings: In addition to the two classical estrogen receptors, ERα and ERβ, a third, G-protein-coupled estrogen receptor GPR30, has been identified. New intracellular signaling pathways and actions for the cardiovascular protective properties of estrogen have been proposed. In addition, recent Women's Health Initiative (WHI) studies restricted to younger postmenopausal women showed that initiation of HRT closer to menopause reduced the risk of CVD. Moreover, dosage, duration, the type of estrogen and route of administration all merit consideration when determining the outcome of HRT.

Summary: HRT has become one of the most controversial topics related to women's health. Future studies are necessary if we are to understand the divergent published findings regarding HRT and develop new therapeutic strategies to improve the quality of life for women.

Figure 1. Possible mechanisms responsible for estrogen-mediated vasodilatation, renal and cardiovascular protection

The multifaceted mechanisms of estrogen involve (a) acting on estrogen receptor-α (ERα) and ERβ to reduce synthesis of NADPH oxidase and increase synthesis of endothelial nitric oxide synthase (eNOS) and superoxide dismutase (SOD), thereby decreasing superoxide and increasing NO production and bioavailability (genomic effect); (b) rapidly activating eNOS via a calcium-mediated mechanism(s) without altering gene expression (nongenomic effect), leading to NO/cGMP release and vascular relaxation; (c) activating Akt via MAP kinase (MAPK)–PI3 kinase (PI3K) pathways, reducing apoptosis and enhancing cell survival and (d) reducing NF-κB activation/translocation via p38α-mediated p53 phosphorylation and JNK1/2-mediated signaling pathways, inhibiting chemokine/cytokine transcription and decreasing inflammation. In addition, estrogen acts on the membrane-bound and G-protein-coupled estrogen receptor (GPER) GPR30 associated with transactivation of epidermal growth factor receptors, which induces rapid signal transduction, including activation of MAPK, protein kinase A (PKA) and PI3K, leading to cardiovascular protection.