Clinical practice
Post Reproductive Health
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Menopause and cardiovascular disease Reprints and permissions:
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DOI: 10.1177/2053369117749675
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Louise Newson1,2
Abstract
Cardiovascular disease is very common in women. It is still under diagnosed and under treated. Many women are not
having their risk factors for cardiovascular disease properly addressed. Many healthcare professionals are uncertain about
the role of hormones in cardiovascular disease. This article gives an overview of the most important risk factors for
cardiovascular disease and how to manage those risk factors appropriately, based on the available evidence.
Keywords
Estrogen, heart disease, hormone replacement therapy, menopause
Cardiovascular disease (CVD) is the leading cause of Risk factors
morbidity and mortality in postmenopausal women.1
Cardiovascular disease causes 26% of all deaths in
Hypertension
the UK; an average of 435 people each day. Around Hypertension is a very important risk factor for heart
42,000 people under the age of 75 in the UK die from disease in women and it is generally under-diagnosed
CVD each year.2 and under-treated. In developed countries, 30% of
Healthcare costs relating to cardiovascular disease adult women have hypertension, and this prevalence
are estimated at £9 billion each year. The cost of is even higher in low–middle-income countries, reach-
CVD to the UK economy (including premature ing up to 53%.6,7
death, disability and informal costs) is estimated to be For every 20 mmHg systolic and 10 mmHg dia-
£19 billion each year.2 stolic blood pressure increase, there is a doubling
There are differences between men and women of mortality both from coronary heart disease and
regarding clinical presentation of cardiovascular dis- stroke for women aged 40–89 years.8 Although younger
ease as well as regarding pathophysiology and women are at lower absolute cardiovascular risk than
response to treatment. CVD in women is fre- older women, this should not impede the detection and
quently underdiagnosed. Women often have a lower effective management of hypertension at any age.
perception of risk which can result in a delayed diag- The prevalence of hypertension in postmenopausal
nosis and failure to recognise their symptoms. Women women is more than twice the prevalence in premeno-
are more likely to have stable plaques and a greater pausal women.9 Even moderate or borderline hyperten-
occurrence of microvascular lesions compared sion (<140/90 mmHg) causes more endothelial
to men.3 dysfunction and cardiovascular complications in
women than in men.10
Cardiovascular disease and menopause
Cholesterol
The risk of CVD greatly increases after the menopause
when estrogen levels reduce. Typically, women are The incidence of raised total cholesterol concentration
around 10 years older than men at first presentation >6.5 mmol/L is equivalent or greater in women
of atherosclerotic coronary heart disease and this can
be related to decline in ovarian hormone concentrations
1
during the menopausal transition and beyond.4 2
Shirley Medical Centre, Solihull, West Midlands, UK
Primary Care Women’s Health Forum: www.pcwhf.co.uk
Estrogens and also testosterone are involved in the
development of CVD in women, and these hormones Corresponding author:
have a role in endothelial function, vascular tone and Louise Newson, Shirley Medical Centre, Solihull, West Midlands, UK.
also in cardiac function.5 Email:
[email protected] 2 Post Reproductive Health 0(0)
compared to men aged 50 years and older in the UK.11
Cholesterol
Raised cholesterol is a risk factor for CVD. Current guidelines on the management of dyslipidemias
recommend considering statin use for primary preven-
tion in women who have an elevated CVD risk.24,25
Early menopause
In addition, they should be prescribed to women for
The average age of the menopause is approximately 51 secondary prevention of cardiovascular events; the rec-
years. Women with premature menopause (aged < 40 ommendations and targets are the same for women as
years), either natural or surgical, have an increased for men.
risk of CVD risk.12–15 HRT can improve lipid profiles and lead to a reduc-
tion in low-density lipoprotein cholesterol.26 In
addition, HRT can produce significant increases
Menopause
in high-density lipoprotein cholesterol and decreases
Low estrogen levels can be associated with a greater in lipoprotein(a) compared to statins which actually
future risk of heart disease and osteoporosis, and it have little effect on these levels.27
is important that women know that there are bene-
ficial health effects of taking estrogen in addition
to hormone replacement therapy (HRT) improving
Early menopause
their symptoms.16–18 Estrogens can modulate vascular In women with premature surgical menopause, estro-
function by targeting estrogen receptors in endothelial gen treatment has been shown to be associated with
cells and also in vascular smooth muscle cells. significant protection against ischaemic heart disease.28
Estrogens can also lead to the release of nitric oxide The benefit from estrogen has been shown to be the
and prostacyclin, which are both vasodilators. In add- most pronounced for current users and for women
ition, they can lead to a reduction in the production who started treatment within 1 year after their surgery.
of endothelin and angiotensin II which are All women with premature ovarian insufficiency
vasoconstrictors. (POI) should receive hormone therapy at least until
Ageing and atherosclerosis can lead to damage of the age of the natural menopause (51 years) unless
the vascular wall with loss of estrogen receptors. In there are contraindications.17,18,29,30
addition, a reduction in circulating estrogen leads to a
reduction in estrogen receptors in both the vascular
Menopause and HRT
endothelium and also the vascular smooth cells.
Estrogens also reduce inflammation and can reduce The benefits and risks of HRT vary by dosage, route of
the secretion of pro-atherogenic cytokines such as administration and timing of initiation.31 Estrogen in
tumour necrosis factor alpha (TNF-a) and can HRT can have a protective effective in early atherogen-
increased prostaglandin I2, which reduces oxidative esis compared to a potentially harmful effect in estab-
stress and also platelet activation. lished atherosclerosis.32 In early atherogenesis, estrogen
There is evidence that women of any age with vaso- has beneficial effects by improving plasma lipids, main-
motor symptoms have a worse cardiovascular risk pro- taining endothelial cell integrity and promoting nitric
file (increased risk of CVD, CHD, or ischaemic stroke) oxide production. Conversely, in established athero-
compared with women without vasomotor symptoms. sclerosis, estrogen can increase matrix metalloprotei-
Women experiencing vasomotor symptom have signifi- nase (MMP) expression which can lead to instability
cantly higher systolic and diastolic blood pressures, of the fibrous cap and rupture of the atheromatous
higher circulating total cholesterol levels and a higher plaque (Figure 1).
body mass index than their counterparts with no HRT with estrogens in older postmenopausal
symptoms.19,20 women has not shown to be associated with a reduction
in CVD events.16,33 However, data accumulated
from numerous studies have shown that, in women
Management of CVD risk factors in under the age of 60 years with symptoms or other indi-
women cations, initiating HRT near their menopause provides
a favourable benefit:risk ratio. This is reflected in
Hypertension current National Institute for Health and Care
Current guidelines are available regarding managing Excellence (NICE) and International Menopause
hypertension in women and it is important that these Society guideline recommendations.17,18 This means
are followed.21,22 However, the rate of hypertensive that the cardioprotective effect of estrogen replacement
women detected, treated and subsequently well con- therapy is seen in postmenopausal women in a time-
trolled is estimated to be only 10%.23 dependent manner.
Newson 3
Figure 1. Differential protective effects of estrogens in hormone replacement therapy in early atherogenesis and harmful effects in
established atherosclerosis. Differential protective effects of estrogenic HRT in early atherogenesis and harmful effects in established
atherosclerosis. In early atherogenesis, cardiovascular risk factors, haemodynamic forces and circulating inflammatory factors cause
endothelial cell injury resulting in decreased NO production and increased EC permeability. Once injured, the endothelium increases
the expression of leukocyte adhesion molecules, which increases the adherence of macrophages and other leukocytes. The increased
EC permeability allows entry of leukocytes and lipoproteins into the subendothelial space. Oxidized lipoproteins are taken up by
macrophages and SMCs to form foam cells (fatty streak). E2 has beneficial effects on early atherosclerotic lesions by changing the
plasma lipid profile, maintaining EC integrity and promoting NO production. In established atherosclerosis foam cells at the central-
most position of the developing atheroma become necrotic and form the central lipid core, whereas the shoulder regions contain
SMCs, macrophages and other leukocytes. Platelet-derived growth factor and transforming growth factor-b stimulate SMC migration
and collagen formation in the subendothelial space, as well as formation of the fibrous cap. E2 increases MMP expression in established
atherosclerosis, causing instability of the fibrous cap and rupture of the plaque.
CAM: cell adhesion molecule; EC: endothelial cell; ET-1: endothelin-1; LDL: low density lipoprotein; MCP-1: monocyte chemotactic
protein-1; MMP: matrix metalloproteinase; NO: nitric oxide; PGI2: prostacyclin; TNF-a: tumour necrosis factor-a; VSMC: vascular
smooth muscle cell.
Source: Picture from Rev Recent Clin Trials. 2012 Feb 1; 7(1): 47–70.
Studies have shown that there is a lower incidence of with 19 fewer CHD deaths and 7 fewer stroke deaths
CVD in women taking HRT within 10 years of their per 1000 women.37 This concept is often referred to
menopause.34,35 A Cochrane meta-analysis showed that as the ‘timing hypothesis’ as the cardiovascular effects
for women taking HRT within 10 years of their meno- of HRT strongly depend on individual vascular
pause, there is a 0.70 relative risk reduction of all-cause health and the time since their menopause before start-
mortality and a 0.52 relative risk reduction of coronary ing HRT.
heart disease mortality.36 The Danish Osteoporosis Prevention Study was
The CVD benefit of taking HRT is greatest the ear- undertaken to investigate the long-term effect of HRT
lier a woman starts HRT with respect to her perimeno- on cardiovascular outcomes in recently postmenopau-
pause or menopause. A Finnish study has shown that sal women.38 This study found that after 10 years of
using any HRT for at least 10 years is associated randomised treatments, women receiving HRT which
4 Post Reproductive Health 0(0)
started early after the menopause had a significant effect of aldosterone, causing natriuresis and also a
reduction in risk of cardiovascular mortality, heart fail- reduction in blood pressure.45
ure or myocardial infarction.
In the Early versus Late Intervention Trial with
Summary
Estradiol, postmenopausal women free from cardiovas-
cular disease were stratified according to time since Prevention of cardiovascular disease in women, as for
menopause and were randomly assigned to receive men, should be started early. Consultations with peri-
either 17b-estradiol plus micronised progesterone vagi- menopausal and menopausal woman are perfect oppor-
nal gel or placebo over a median of 5 years.39 tunities to assess cardiovascular risk. More women
Compared with placebo, estrogen treatment resulted should ideally be considered for HRT at an earlier
in a significantly slower progression of coronary stage in order to gain maximum cardiovascular protec-
artery intima media thickness among women who tion. Women with POI, early menopause and women
initiated HRT less than 6 years after menopause. within 10 years of their menopause can potentially gain
NICE state that women should be informed that significant improvements in their cardiovascular health,
the presence of cardiovascular risk factors is not a as well as their general health, by being offered HRT.
contra-indication to HRT and also that it is essential The education of healthcare professionals is paramount
to optimally manage any underlying cardiovascular when reflecting on the potential health benefits to be
risk factors (e.g. hypertension, high cholesterol).17 gained by taking HRT.
This means that having raised blood pressure is not
a contra-indication to taking HRT nor a reason to Declaration of conflicting interests
stop prescribing HRT. Elevated blood pressure
I have lectured and acted in an advisory capacity for a
should be addressed and promptly managed in number of pharma companies.
women as it should be for women who are not
taking HRT.
Avoiding HRT in menopausal women can actually Funding
be detrimental to their future health in terms of cardio- The author(s) received no financial support for the research,
vascular disease and also osteoporosis. Some experts authorship, and/or publication of this article.
are now recommending that HRT should now be con-
sidered as part of a general prevention strategy for References
women at the onset of the menopause.40 1. Tandon VR, Mahajan A, Sharma S, et al. Prevalence of
There is some evidence that cardiovascular morbid- cardiovascular risk factors in postmenopausal women: a
ity and mortality can increase in the first year after rural study. J Midlife Health 2010; 1: 26–29.
HRT is stopped, although it is unclear whether tapering 2. www.bhf.org.uk/research/heart-statistics.
the dose reduces this risk.41 This risk was actually 3. Harvey RE, Coffman KE and Miller VM. Women-specific
greater in women who were under 60 years at the initi- factors to consider in risk, diagnosis and treatment of car-
ation or discontinuation of HRT use. diovascular disease. Womens Health (Lond) 2015; 11:
239–257.
The MMPs and their tissue inhibitors are important
4. Anand SS, Islam S, Rosengren A, et al. Risk factors for
for vascular remodelling. Estradiol can increase the
myocardial infarction in women and men: insights from
release of MMPs in a dose-dependent manner. Low- the INTERHEART study. Eur Heart J 2008; 29: 932–940.
dose estrogen may lead to increases in MMPs which 5. Mendelsohn ME and Karas RH. Molecular and cellular
can normalise vascular remodelling, whereas high basis of cardiovascular gender differences. Science 2005;
doses of estrogen may produce large increases in 308: 1583–1587.
MMPs and lead excessive remodelling.42 This means 6. Kearney PM, Whelton M, Reynolds K, et al. Global
that the starting dose of estrogen in women with estab- burden of hypertension: analysis of worldwide data.
lished atheroma should be as low as possible to Lancet 2005; 365: 217–223.
improve symptoms. Low doses of estrogen are unlikely 7. Lloyd-Sherlock P, Beard J, Minicuci N, et al.
to be harmful in this respect. Hypertension among older adults in low- and middle-
Progestogens have differing effects on cardiovascular income countries: prevalence, awareness and control. Int
J Epidemiol 2014; 43: 116–128.
risk. In general, those progestogens more like proges-
8. Lewington S, Clarke R, Qizilbash N, et al. Age-specific
terone have been associated with a lower effect on car- relevance of usual blood pressure to vascular mortality: a
diovascular disease compared to the more androgenic metaanalysis of individual data for one million adults in 61
progestogens.43 Micronised progesterone seems to have prospective studies. Lancet 2002; 360: 1903–1913.
a neutral or beneficial effect on blood pressure in post- 9. Staessen J, Bulpitt CJ, Fagard R, et al. The influence of
menopausal women.44 In contrast to other progesto- menopause on blood pressure. J Hum Hypertens 1989; 3:
gens, progesterone has been shown to antagonise the 427–433.
Newson 5
10. Vasan RS, Larson MG, Leip EP, et al. Impact of high- 26. Maclaren K and Stevenson JC. Primary prevention of
normal blood pressure on the risk of cardiovascular dis- cardiovascular disease with HRT. Women’s Health
ease. N Engl J Med 2001; 345: 1291–1297. 2012; 8: 63–74.
11. WHO Global Infobase, https://apps.who.int/infobase/ 27. Collins P, Webb CM, de Villiers TJ, et al. 2016)
Indicators.aspx (accessed 13 December 2017). Cardiovascular risk assessment in women – an update.
12. Ossewaarde ME, Bots ML, Verbeek AL, et al. Age at Climacteric 2016; 19: 329–336.
menopause, cause-specific mortality and total life expect- 28. Lokkegaard E, Jovanovic Z, Heitmann BL, et al. The
ancy. Epidemiology 2005; 16: 556–562. association between early menopause and risk of ischae-
13. van der Schouw YT, van der Graaf Y, Steyerberg EW, mic heart disease: influence of hormone therapy.
et al. Age at menopause as a risk factor for cardiovascu- Maturitas 2006; 53: 226–233.
lar mortality. Lancet 1996; 347: 714–718. 29. POI Guideline Development Group. Management of
14. Lokkegaard E, Jovanovic Z, Heitmann BL, et al. The women with premature ovarian insufficiency. 2015, www.
association between early menopause and risk of ischae- eshre.eu/Guidelines-and-Legal/Guidelines/Management-
mic heart disease: influence of hormone therapy. of-premature-ovarian-insufficiency.aspx.
Maturitas 2006; 53: 226–233. 30. Hamoda H British Menopause Society and Women’s
15. Atsma F, Bartelink ML, Grobbee DE, et al. Health Concern. The British Menopause Society and
Postmenopausal status and early menopause as inde- Women’s Health Concern recommendations on the man-
pendent risk factors for cardiovascular disease: a meta- agement of women with premature ovarian insufficiency.
analysis. Menopause 2006; 13: 265–279. Post Reprod Health 2017; 23: 22–35.
16. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and 31. L’Hermite M. HRT optimization, using transdermal
benefits of estrogen plus progestin in healthy postmeno- estradiol plus micronize progesterone, a safer HRT.
pausal women: principal results from the Women’s Climacteric 2013; 16(Suppl. 1): 44–53.
Health Initiative randomized controlled trial. JAMA 32. Santen RJ. Use of cardiovascular age for assessing risks
2002; 288: 321–333. and benefits of menopausal hormone therapy. Menopause
17. Menopause: diagnosis and management. NICE, 2015. 2017; 24: 589–595.
www.nice.org.uk/guidance/ng23. 33. Hulley S, Grady D, Bush T, et al. Randomized trial of
18. Baber RJ, Panay N and Fenton A. The IMS Writing estrogen plus progestin for secondary prevention of cor-
onary heart disease in postmenopausal women. Heart
Group 2016 IMS Recommendations on women’s midlife
and Estrogen/progestin Replacement Study (HERS)
health and menopause hormone therapy, Climacteric
Research Group. JAMA 1998; 280: 605–613.
2016; 19(2): 109–150.
34. Rossouw JE, Prentice RL, Manson JE, et al.
19. Biglia N, Cagnacci A, Gambacciani M, et al. Vasomotor
Postmenopausal hormone therapy and risk of cardiovas-
symptoms in menopause: a biomarker of cardiovascular
cular disease by age and years since menopause. JAMA
disease risk and other chronic diseases? Climacteric 2017;
2007; 297: 1465–1477.
20(4): 306–312.
35. Vitale C, Mercuro G, Cerquetani E, et al. Time since
20. Franco OH, Muka T, Colpani V, et al. Vasomotor symp-
menopause influences the acute and chronic effect of
toms in women and cardiovascular risk markers: system-
estrogens on endothelial function. Arterioscler Thromb
atic review and meta-analysis. Maturitas 2015; 81: Vasc Biol 2008; 28: 348–352.
353–361. 36. Boardman HM, Hartley L, Eisinga A, et al. Hormone
21. Hypertension: management of hypertension in adults in pri- therapy for preventing cardiovascular disease in post-
mary care. NICE Clinical Guideline (August 2011), www. menopausal women. Cochrane Database Syst Rev 2015;
nice.org.uk/guidance/cg127. 3: CD002229.
22. Mancia G, Fagard R, Narkiewicz K, et al. Task Force 37. Mikkola TS, Tuomikoski P, Lyytinen H, et al. Estradiol-
for the Management of Arterial Hypertension of based postmenopausal hormone therapy and risk of car-
the European Society of Hypertension and the diovascular and all-cause mortality. Menopause 2015; 22:
European Society of Cardiology. Blood Press 2014; 976–983.
23(1): 3–16. 38. Schierbeck LL, Rejnmark L, Tofteng CL, et al. Effect of
23. Lloyd-Sherlock P, Beard J, Minicuci N, et al. hormone replacement therapy on cardiovascular events
Hypertension among older adults in low- and middle- in recently postmenopausal women: randomised trial.
income countries: prevalence, awareness and control. BMJ 2012; 345: e6409.
Int J Epidemiol 2014; 43: 116–128. 39. Hodis HN, Mack WJ, Henderson VW, et al. Vascular
24. Reiner Z, Catapano AL, De BG, et al. ESC/EAS effects of early versus late postmenopausal treatment
Guidelines for the management of dyslipidaemias: the with estradiol. N Engl J Med 2016; 374: 1221–1231.
Task Force for the management of dyslipidaemias of 40. Lobo RA, Pickar JH, Stevenson JC, et al. Back to the
the European Society of Cardiology (ESC) and the future: hormone replacement therapy as part of a preven-
European Atherosclerosis Society (EAS). Eur Heart J tion strategy for women at the onset of menopause.
2011; 32: 1769–1818. Atherosclerosis 2016; 254: 282–290.
25. Cardiovascular disease: risk assessment and reduction, 41. Mikkola TS, et al. Increased cardiovascular mortality
including lipid modification. NICE 2016, www.nice.org. risk in women discontinuing postmenopausal hormone
uk/guidance/cg181. therapy. J Clin Endocrinol Metab 2015; 100: 4588–4594.
6 Post Reproductive Health 0(0)
42. Wingrove CS, Garr E, Godsland IF, et al. 17beta- 44. Honisett SY, Pang B, Stojanovska L, et al. Progesterone
oestradiol enhances release of matrix metalloproteinase-2 does not influence vascular function in postmenopausal
from human vascular smooth muscle cells. Biochim women. J Hypertens 2003; 21: 1145–1149.
Biophys Acta 1998; 1406: 169–174. 45. Boschitsch E, Mayerhofer S and Magometschnigg D.
43. Stanczyk FZ, Hapgood JP, Winer S, et al. Progestogens Hypertension in women: the role of progesterone and
used in postmenopausal hormone therapy: differences in aldosterone. Climacteric 2010; 13: 307–313.
their pharmacological properties, intracellular actions,
and clinical effects. Endocr Rev 2013; 34: 171–208.
