Correspondence: Professor A. Pines, Department of Medicine ‘ T ’ , Ichilov Hospital, Tel-Aviv, Israel

CLIMACTERIC 2011;14:535–536

SHORT REVIEW © 2011 International Menopause Society Received 9-05-2011DOI: 10.3109/13697137.2011.599058 Accepted 16-05-2011

no evidence for interaction between hormone use and VMS at either menopause onset or at WHI enrollment in predicting cardiovascular events or all-cause mortality.

OVERVIEW

The exact pathophysiological mechanisms of VMS are still unclear. A hormonal etiology seems likely in view of the asso-ciation of fl ushing with the climacteric, and the well-proven clinical value of estrogen therapy in this respect. The estab-lished effects of estrogen on cardiovascular risk parameters and clinical events led to studies which examined possible associations between VMS and cardiovascular endpoints. VMS appear to be associated with lower antioxidant plasma levels and a higher degree of oxidative stress 2 , higher body mass index, blood pressure and total cholesterol levels, lower HDL cholesterol and higher intercellular-adhesion-molecule-1 (ICAM-1) levels 3,4 , all indicating an adverse cardiovascular risk profi le.

Vascular responses seem to be related to VMS as well: bra-chial artery fl ow-mediated diameter demonstrated a smaller post-occlusion magnitude of changes in women with moder-ate to severe hot fl ushes, when compared to premenopausal women or women with no or only mild hot fl ushes 5 . Since a reduced vascular reaction indicates endothelial dysfunction,

Based on previous data from other studies, possible associ-ations between vasomotor symptoms (VMS) and clinical cardio-vascular events and all-cause mortality were investigated in the Women ’ s Health Initiative (WHI) Observational Study 1 . The cohort included about 60 000 postmenopausal women (mean age 63 years, mean time since menopause 14 years), who were followed for a mean period of 9.7 years. According to informa-tion provided by self-fi lled questionnaires, participants were divided into those who had never suffered VMS (31%), those who experienced early VMS (at onset of menopause but not at enrollment to the WHI study, 41%), those who reported per-sistent VMS (early + late, 25%) and those who reported late VMS (only at enrollment to the WHI study, 2%). Women with early VMS compared with no VMS had a modest, yet signifi -cant decreased risk of stroke (hazard ratio (HR) 0.84), total cardiovascular disease events (HR 0.89), and all-cause mortal-ity (HR 0.93), in the fully adjusted model. For women with persistent VMS, there was no signifi cant increase or decrease in risk of major coronary events, stroke, total cardiovascular disease, or all-cause mortality compared with women with no VMS. However, for women with late VMS compared with no VMS, there was an increased risk of major coronary events, stroke, total cardiovascular events, and all-cause mortality in the minimally adjusted model. It is noteworthy that only the signifi cantly increased risk of major coronary event and all-cause mortality persisted in the fully adjusted model. There was

Vasomotor symptoms and cardiovascular disease risk A. Pines

Department of Medicine ‘ T ’ , Ichilov Hospital, Tel-Aviv, Israel

ABSTRACT

Although the exact etiology of hot fl ushes and night sweats has not been fully clarifi ed, the intriguing ques-tion whether vasomotor symptoms (VMS) are markers of coronary artery disease risk has been evaluated in several studies. Surrogate metabolic and hemodynamic parameters point at adverse alterations in fl ushers, but the results related to clinical endpoints are not unidirectional. Recent relevant data come from the Women ’ s Health Initiative (WHI) observational study (60 000 women, mean age 63 years, mean follow-up period 10 years). Women with VMS only at onset of menopause but not at enrollment to the WHI study had a modest, yet signifi cant decreased risk of stroke, total cardiovascular disease events, and all-cause mortality, compared with women having no VMS. Contrarily, women with late VMS (reported at enrollment to the study but not at onset of menopause) had an increased risk in the above-mentioned parameters. There was no interaction between hormone use and VMS in this respect. This mini-review, which summarizes the rel-evant data, shows that hot fl ushes seem to be a marker for physiological alterations that could be associated with cardiovascular disease.

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Vasomotor symptoms and cardiovascular disease risk Pines

536 Climacteric

Thurston RC, Sutton-Tyrrell K, Everson-Rose SA, Hess R, Powell 7. LH, Matthews KA. Hot fl ashes and carotid intima media thick-ness among midlife women. Menopause 2011. Epub ahead of print Allison MA, Manson JE, Aragaki A, 8. et al . Vasomotor symptoms and coronary artery calcium in postmenopausal women. Meno-pause 2010;17:1136 – 45 Thurston RC, Sutton-Tyrrell K, Everson-Rose SA, Hess R, 9. Matthews KA. Hot fl ashes and subclinical cardiovascular disease: fi ndings from the Study of Women’s Health Across the Nation Heart Study. Circulation 2008;118:1234 – 40 Rossouw JE, Prentice RL, Manson JE, 10. et al . Postmenopausal hor-mone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:1465 – 77 Huang AJ, Sawaya GF, Vittinghoff E, Lin F, Grady D. Hot fl ushes, 11. coronary heart disease, and hormone therapy in postmenopausal women. Menopause 2009;16:639 – 43

References

Szmuilowicz ED, Manson JE, Rossouw JE, 1. et al . Vasomotor symptoms and cardiovascular events in postmenopausal women. Menopause 2011 Feb 19. Epub ahead of print Leal M, D í az J, Serrano E, Abell á n J, Carbonell LF. Hormone re-2. placement therapy for oxidative stress in postmenopausal women with hot fl ushes. Obstet Gynecol 2000;95:804 – 9 Gast GC, Grobbee DE, Pop VJ, 3. et al . Menopausal complaints are asso-ciated with cardiovascular risk factors. Hypertension 2008;51:1492 – 8 Sassarini J, Fox H, Ferrell W, Sattar N, Lumsden MA. Vascular 4. function and cardiovascular risk factors in women with severe fl ushing. Clin Endocrinol (Oxf) 2011;74:97 – 103 Bechlioulis A, Kalantaridou SN, Naka KK, 5. et al . Endothelial function, but not carotid intima-media thickness, is affected early in menopause and is associated with severity of hot fl ushes. J Clin Endocrinol Metab 2010;95:1199 – 206 Tuomikoski P, Ylikorkala O, Mikkola TS. Menopausal hot fl ushes 6. and vascular health. Ann Med 2011 Jan 24. Epub ahead of print

these results mark an increase in cardiovascular risk in women with VMS. Contrarily, another study recorded a better endothelial function in fl ushers compared to non-fl ushers 4 . A Finish group published several studies on VMS and vascular health. They recently summarized their data in a review, stat-ing that hot fl ushes were accompanied by a vasodilatory effect during endothelial testing, and this reaction was related to the severity of hot fl ushes 6 . They also found that hot fl ushes seem to be associated with a possibly increased sympathetic pre-ponderance without an effect on parasympathetic activity in cardiovascular autonomic responses, pointing at a potentially negative impact on cardiovascular health in women experienc-ing hot fl ushes.

Thurston and colleagues used carotid intima-media thick-ness (IMT) as a marker for coronary atherosclerosis 7 . IMT was higher in women suffering from VMS, especially in overweight or obese women. The more sophisticated, yet non-invasive way of measuring coronary artery plaques involves coronary CT scans. In the WHI estrogen-alone trial, a history of any VMS was signifi cantly associated with reduced odds for coronary calcium, independent of traditional cardiovascular risk factors and other relevant covariates 8 . The severity of VMS did not affect the results, but a shorter duration of symptoms was associated with lower odds for having any calcifi cations. In contrast to the WHI results, the SWAN study, which recruited pre-, peri-, and young postmenopausal women, demonstrated greater coronary artery and aortic calcifi cations in fl ushers in mod-els adjusted for age, race, cardiovascular risk factors and estradiol 9 .

Obviously, the most important endpoint would be the asso-ciation between VMS and cardiovascular events. The relevant data from both the clinical and the observational WHI trials were summarized as follows:

(1) Risk factors for coronary heart disease tended to be more adverse in the women with vasomotor symptoms;

(2) Early VMS were associated with decreased risk of stroke, total cardiovascular events, and all-cause mortality, but late VMS were associated with increased coronary events and all-cause mortality. The higher risks for coronary heart disease events in women more distant from meno-pause appeared to be concentrated in the small subset of women with moderate or severe vasomotor symp-toms 1,10 . This trend was also recorded in the HERS study, a coronary heart disease secondary prevention trial, where a signifi cant increase in risk was seen only in the fi rst year of hormone use in women with signifi -cant hot fl ushes 11 .

TAKE-HOME MESSAGES

• Hot fl ushes may be a marker for physiological alterations that associate with cardiovascular disease.

• Cardiovascular risk is probably different in symptomatic compared to asymptomatic women.

• Having vasomotor symptoms only in early menopause or only in late menopause probably carries different implica-tions in this respect.

• The whole issue needs further research since so far the data are not uniform.

Confl ict of interest The author reports no confl icts of interest. The author alone is responsible for the contents and writing of this paper.

Source of funding Nil.

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