Vasomotor symptoms andcardiovascular riskM. Gambacciani and A. Pepe

Department of Obstetrics and Gynecology, Menopause and Osteoporosis Center, Pisa UniversityHospital, Pisa, Italy

Key words: MENOPAUSE, VASOMOTOR SYMPTOMS, CARDIOVASCULAR RISK

ABSTRACT

Climacteric complaints are the main indication for hormone replacement therapy (HRT)in the clinical practice. Observational studies demonstrating a protective effect of HRTon cardiovascular disease (CVD) were conducted in early menopausal, young,symptomatic women. Vasomotor symptoms correlate with lower level of plasmaantioxidant activity, an increased cardiovascular reactivity to stressful situations,elevated cholesterol, higher sympathetic nerve activity, impaired flow-mediated dilation,hypertension and a higher risk of aortic calcification. All the available findings indicatethat hot flushes can be seen as a marker for underlying vascular changes among mid-life,otherwise healthy, climacteric women. Thus, young, healthy symptomatic postmeno-pausal women differ from those without vasomotor symptoms with regard tocardiovascular risk factors. Therefore, responses to HRT can change in terms ofcardiovascular outcomes according to the baseline vasomotor complaints. Thispoint may explain, at least in part, the negative/null effects of HRT on cardiovasculardisease observed in the trials where HRT was given to largely asymptomatic, elderlywomen.

INTRODUCTION

A number of observational studies have demon-strated a protective effect of hormone replacementtherapy (HRT) on cardiovascular disease with riskreductions up to 30–50%1–3. Conversely, placebo-controlled, randomized trials did not confirm acardioprotective effect and showed no overallbenefit of HRT on the risk of cardiovascularevents4,5. This evident discrepancy between theobservational studies and the trials has differentexplanations. An important difference is that, inthe observational studies, the most commonreason to initiate HRT was to relieve menopausalcomplaints. In contrast, in the randomized,

controlled trials, the vast majority of women wereelderly, up to 20 years since the last menstrualperiod. In addition, subjects reporting menopausalsymptoms were either excluded or were a minor-ity of the total population. Recent re-analysis ofthe combined Women’s Health Initiative trialsshowed that younger women who initiatedHRT closer to menopause had lower coronarycalcium scores6 and a reduced coronary heartdisease risk than in those assigned to placebo7. Ayounger age is likely to be accompanied by ahigher frequency of menopausal complaints. Thepresence of climacteric complaints may decide the

Correspondence: Professor M. Gambacciani, Department of Obstetrics and Gynecology, Menopause and Osteoporosis

Center, Pisa University Hospital, Via Roma 67, 56100 Pisa, Italy

CLIMACTERIC 2009;12(Suppl 1):32–35

ª 2009 International Menopause SocietyDOI: 10.1080/13697130903013445

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susceptibility to HRT. Climacteric complaints arethe main indication for HRT in clinical practice8

and in the populations of observational trials.

MENOPAUSAL SYMPTOMS

Women with climacteric symptoms appear tohave a lower level of plasma antioxidant activ-ity9,10. Vasomotor symptoms correlate not onlywith higher oxidative stress, but also with anincreased cardiovascular reactivity to stressfulsituations9,10. Symptomatic postmenopausal wo-men who have hot flushes show lower total basalantioxidant status in plasma, lower concentra-tions of reduced sulfhydryl groups, and higherconcentrations of lipoperoxides than womenwithout hot flushes10. Thus, hot flushes in post-menopausal women are associated with theoxidative process. HRT decreases not only hotflushes but also the oxidative stress in sympto-matic women10. Because oxidative stress is asso-ciated with a high risk for cardiovascular diseases,HRT might protect women with hot flushes.

Gast and colleagues11 recently evaluated theassociation between menopausal complaints andcardiovascular risk. They reported on 5523women (age range 46–57 years) in whom vaso-motor symptoms were associated with elevatedcholesterol (odds ratio (OR) 1.52; 95% confi-dence interval (CI) 1.25–1.84) and hypertension(OR 1.20; 95% CI 1.07–1.34), suggesting anadverse cardiovascular risk profile in symptomaticwomen in comparison to asymptomatic women.In the Study of Women’s Health Across theNation (SWAN), a significant association betweenhot flushes and flow-mediated dilation (b¼70.97; standard error 0.44; p¼ 0.03) was de-monstrated12. In addition, vasomotor symptomsare associated with a higher risk of aorticcalcification (OR 1.63; 95% CI 1.07–2.49), afteradjusting for other cardiovascular disease riskfactors and estradiol levels. In the SWAN study,women with hot flushes were more likely to haveevidence of subclinical disease (i.e. endothelialdysfunction, aortic calcification) than womenwithout hot flushes. In addition, hot flushes areassociated with increased blood pressure13,14.Symptomatic postmenopausal subjects show ahigher systolic blood pressure level in comparisonwith age-matched asymptomatic women. Thedifference is significant and clinically relevantnot only during the day time when women areawake, but also during sleep. Elevated bloodpressure is one of the major risk factors for

cardiovascular disease15,16. Menopause is asso-ciated with a rise in blood pressure in many17–20

but not all21–23 studies. The inconsistencies inthese findings can, at least in part, be explained byvariations in the rate of symptomatic womenincluded in the populations studied.

The activation of sympathetic tone may under-line both blood pressure changes and hotflushes24–26. The most likely explanation for thehigher blood pressure in women with hot flushes isan increase of sympathetic nerve activity. Severalstudies have shown that the main metabolite ofcentral norepinephrine, 3-methoxy-4-hydroxy-phenylglycol, is increased in women with hotflushes compared with women without hotflushes27. While the a-antagonist yohimbine in-creases hot flushes in menopausal women25,clonidine, an a-blocker, which reduces norepi-nephrine release, may reduce hot flushes insymptomatic women26. There may be a relation-ship between hot flushes and blood pressure viathe autonomic nervous system, not in the sensethat hot flushes provoke increased blood pressureor vice versa, but that the same factor, involved inchanges of sympathetic stimulation, is responsiblefor both.

During the climacteric transition and in theearly postmenopausal period, changes in bothsymptoms and in blood pressure at the time ofmenopause may be mediated by changes insympathetic activation. Systolic blood pressure issignificantly higher in women who reported hotflushes while awake and during periods of sleep14.At present, it is not known whether womenexperiencing hot flushes have an increased riskof hypertension and the development of cardio-vascular disease.

CONCLUSIONS

All the available findings indicate that hot flushesmay be seen as a marker for underlying vascularchanges in mid-life, otherwise healthy, climactericwomen. Thus, young, healthy symptomatic post-menopausal women differ from those withoutvasomotor symptoms with regard to cardiovascu-lar risk factors. Therefore, responses to HRT canchange in terms of cardiovascular outcomesaccording to the baseline vasomotor complaints.This may explain, at least in part, the findings onthe effects of HRT on cardiovascular disease thatwere negative/null in the trials where hormoneswere given to largely asymptomatic, elderlywomen, while they were positive (significantreduction in the number of events) in observational

Vasomotor symptoms and cardiovascular risk Gambacciani and Pepe

Climacteric 33

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studies where HRT was prescribed for healthy,symptomatic, perimenopausal women.

Updated guidelines and more recent recommen-dations on HRT issued by American and Eur-opean Societies28–32 now indicate similarconclusions to the 2007 recommendations of theInternational Menopause Society33, in that estro-gen is the best and most effective option to treatvasomotor symptoms and there should not beconcern for safety in healthy, young postmeno-pausal women during the first years of use33.According to the individual risk profile, theseverity of menopausal symptoms and their effecton quality of life may be seen as a marker for thefuture risk of cardiovascular disease and shouldalso be included in the benefit–risk equation in thesetting of a primary-care clinic.

The current data suggest that declining ovarianreserve in early menopause might identify a groupof women who are at increased risk, not only for

decreased quality of life but also for long-termbone health and cardiovascular risk. Implicationsfor perimenopausal women include the possibilitythat women suffering from hot flushes will haveadverse vascular changes and subclinical cardio-vascular disease indicators for a significantlyhigher lifetime risk for cardiovascular and boneevents. The list of risk factors for coronary heartdisease, breast cancer and osteoporosis is wellknown, and several popular scoring systems forrisk evaluation are being used. However, inclinical practice, we need a simple, integrativealgorithm for initiation of HRT in the earlymenopause, including the presence of vasomotorsymptoms as a marker of susceptibility tocardiovascular disease.

Conflict of interest Nil.

Source of funding Nil.

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