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Menopause and Cardiovascular Implication
  JOHTN
REVIEW ARTICLE
Menopause and Cardiovascular Implication
Mayur Agrawal, Subhash Yadav
Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road Lucknow, Uttar Pradesh, India
Address for correspondence: Mayur Agrawal, Professor, Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli RoadLucknow, Uttar Pradesh, India
Received: 02-11-2017; Accepted: 20-12-2017
 
ABSTRACT
Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality in postmenopausal women.[1] Estrogendeficiency has a negative impact on cardiovascular function and metabolism.
Keywords: Menopause, cardiovascular, amenorrhea
How to cite this article: Agrawal M, Yadav S. Menopause andcardiovascular implication. Hypertens 2018;4(1): 13-17.
Source of support: Nil
Conflict of interest: None
 
 

Cardiovascular risk factors increase with age, and in women,menopause aggravates these risk factors. Cardiovasculardisease (CVD) is one of the leading causes of morbidity andmortality in postmenopausal women.[1] Estrogen deficiencyhas a negative impact on cardiovascular function andmetabolism.

Menopause

Menopause is diagnosed after 12 months of amenorrhea due to theloss of ovarian function. It is a physiological change, not a disease.The stages of reproductive aging workshop (STRAW) classificationseparate a woman's life into seven segments, with segments -2, -1,and 0 denoting the early menopausal transition, the late menopausaltransition, and the final menstrual period, respectively.[2]

Levels of follicle-stimulating hormone (FSH) >10 IU/L areindicative of declining ovarian function. FSH levels > 20 IU/Lare diagnostic of ovarian failure in the peri-menopausal age groupwith vasomotor symptoms (VMS) even in the absence of thecessation of menstruation. FSH levels >40 IU/L done 2 monthsapart are diagnostic of menopause.[3] While peri-menopause isdefined as the period of 1 year after the last menstrual period.It may last for 2-8 years. It is associated with irregular menses,and fertility decreases in this period. The estimated mean age ofmenopause is 46.2 years in India.[4]

Anti-Mullerian hormone (AMH), which is produced bygranulosa cell of ovarian follicle, can be used to predict the age of menopause. AMH decreases with increasing age andbecomes undetectable before menopause in females. 257 normalovulatory women, AMH, antral follicle count, and FSH wereassessed and followed for 11 years. It was found that using ageand AMH, the age range in which menopause will subsequentlyoccur can be calculated.[5] With menopause, the FSH levelraises reflecting decrease in ovarian reserve and estradiol leveldecreases. Estrone is the major estrogen produced, which is dueto peripheral aromatization of androgen produced from adrenaland ovary.

 
Menopausal woman may be asymptomatic or may havetroublesome climacteric symptoms such as hot flashes,insomnia, headache, body ache, depression, mood changes,and weight gain. Hot flush indicates the sensation of heat,maybe associated with sweating, and sometimes followed by achill. Onset, duration, progression, and severity of symptomsvary. The Greene Climacteric Scale, Kupperman Index, andMenopause-specific Quality of Life Questionnaire are some ofthe commonly used scores for menopausal symptoms. Studieson the quality of life after menopause are conflicting: Somereveal decline, while some studies show improvement, andothers have no association.[6] As the life expectancy is increasing,the duration of life spend in menopausal state is increasing, soit becomes important to address the problem associated withmenopause.

There may be a link between menopausal symptoms andCVD risk. In a population-based study of 5523 women aged46-57 years, flushing and night sweating were associatedwith higher cholesterol level, higher body mass index (BMI),and higher systolic and diastolic blood pressure comparedwith asymptomatic women.[7] In wise (Women's IschemiaSyndrome Evaluation) study, 254 postmenopausal womenaged more than 50 years, not taking hormone therapy, wereevaluated. It was found that women with VMS < 42 years hadlower FMD (flow-mediated dilation), reduced endothelialfunction, and higher CVD mortality relative to women withlater onset symptoms.[8]

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Estrogen has pleiotropic effects. It has both nuclear, slowresponse through regulating transcription factor and rapid nonnucleareffects through membrane-associated estrogen receptor(ER). It has a protective effect and signals through PI3K, Akt, andERK 1/2. Estrogen decreases pathologic cardiac hypertrophyand has an anti-inflammatory property.[9] The anti-inflammatoryand antioxidant mechanism prevents plaque rupture. Estrogenincreases expression of genes involved in prostacyclin synthetaseand nitric oxide synthetase, increasing endothelial-derived nitricoxide and which increases in cyclic guanosine monophosphate,thereby leading to relaxation of vascular smooth-muscle cells.[10]Estrogen therapy in postmenopausal women decreases serumtotal cholesterol (TC) and low-density lipoprotein (LDL)cholesterol concentrations, increases serum high-densitylipoprotein (HDL) cholesterol and triglyceride concentrations,and decreases serum Lp(a) lipoprotein concentrations.

Menopause and Cardiovascular Risk Factors

Hypertension (HTN), dyslipidemia, obesity, glucoseintolerance, cigarette smoking, diabetes, and sedentary lifestyleare considered as modified risk factors, whereas age, gender, andhereditary are the non-modifiable risk factors of CVDs.

Women are about 10 years older as compared to men whenthey develop CVDs.[11] Menopause greatly increases the risk forcoronary diseases by 3-4-fold. Women should follow a healthylifestyle to reduce the conventional risk factors.

Age of Woman

In the wise study, the incidence of obstructive coronary arterydisease in women with angina increases dramatically after theage of 50, with a prevalence of 48% in the 55-64 age group and79% for women >75 years of age.[8]

In population-based LifeLines Cohort Study, 63,466 women,aged between 18 and 65 years, were grouped into premenopausal,perimenopausal, naturally postmenopausal, and surgicallypostmenopausal. Postmenopausal women aged 45 years hadhigher TC and low-density lipoprotein cholesterol (LDL-c) andsystolic and diastolic blood pressure than in postmenopausalwomen aged 50. Chronological age and menopausal status areboth independently associated with CVD risk factors.[12]

Age at Menopause

In the nurse's health study cohort, 354,326 person-yearsfollow-up was done to access the age of menopause and impac on cardiovascular mortality. A total of 757 incident cases ofcoronary heart disease (CHD) occurred with a significantassociation between younger age at menopause and higher riskof CHD among women who experienced natural menopauseand never used hormone therapy. This increased risk was seenonly with women who were current smokers but not amongnon-smokers and past smokers. A possible explanation isthat smoking is a strong risk factor for early menopause anda strong independent risk factor for CHD and therefore aconfounder.[13]

 
In ladies ACS Study, 373 women with acute myocardialinfarction, who underwent angiography, were askedmenopause questionnaires to specifically evaluate whetherthe age at menopause is linked to the extent of coronary arterydisease. Patients with early menopause had no differences inthe extent of coronary disease at angiography, but womenwith late menopause had significantly better outcomeduring 1-year follow-up as compared with those with earlymenopause. With each year's delay in the menopause, theadjusted risk decreased by 12%. This study revealed thatextent of the coronary disease shows a correlation withabsolute age after 55 years but no correlation with the age ofmenopause.[14]

Dyslipidemia

Low plasma estrogen levels may explain unfavorable lipid andcarbohydrate metabolism changes rapidly occurring duringmenopausal transition and soon after menopause. No differencewas observed in HDL, LDL, HDL:TC ratio, fasting insulin,and the ratio of fasting insulin to fasting blood glucose betweenwomen with premature ovarian failure with a mean age of32.8 years and in those during natural menopausal transitionwith a mean age of 52.[15]

HTN

Relationship between sex and prevalence of HTN is varied byworld region. During earlier ages, men have a higher prevalenceof HTN than women, whereas in older people, they were higherin women than in men.[16] For every 20 mmHg systolic and10 mmHg diastolic blood pressure increase, there is a doubling ofmortality both from CHD and stroke for women and men aged40-89 years.[17] As compared with optimal blood pressure, highnormalblood pressure is associated with a risk factor-adjustedhazard ratio of 2.5 in women and 1.6 in men for CVD.[18]

Obesity

It is a preventable cause of cardiovascular event. Weight gainis related to aging, menopause, lifestyle changes, and geneticfactors. In both gender, central obesity increases with aging.Menopause leads to an increase of total body fat along withthe redistribution of body fat from the periphery to the trunk,causing central adiposity.[19] This is associated with insulinresistance, diabetes, and dyslipidemia.

 
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Diabetes Mellitus

Diabetes mellitus increases the risk of CVD and its prevalenceincreases with aging. Diabetics mellitus (DM) prevalence ishigher in older woman than man.[20] High testosterone levelsare associated with higher risk of type 2 diabetes in women butwith lower risk in men, while both women and men with highersex hormone-binding globulin (SHBG) levels have a lower riskof type 2 diabetes.[21] There is a greater relative risk for CVDevents and death from CVD in women with DM as comparedto men.[22]

Whether menopausal status independently affects therisk of developing diabetes is controversial, data fromlarge clinical trials suggest that postmenopausal hormonetherapy decreases the risk of developing diabetes mellitus.Some studies suggest that women with diabetes undergomenopause earlier than non-diabetic women,[23] but thesefindings are not consistent.

A longitudinal study of 9 years in 949 participating womenacross the Nation SWAN (Study of Women's Health Acrossthe Nation) revealed an increased incidence of the metabolicsyndrome among perimenopausal women. Odds of developingthe MetS per year in perimenopause was 1.45.[24]

A recent study of 3639 postmenopausal women from theRotterdam Study, a prospective cohort study, showed thatwomen with late menopause had a significantly lower riskof type 2 diabetes. Early onset of natural menopause is anindependent marker for type 2 diabetes. For each 1-year delayin the onset of menopause, the risk of type 2 diabetes decreasedby 4% independent of potential risk factors for type 2 diabetes(including BMI, glucose, and insulin levels) and levels ofendogenous sex hormones and SHBG.[25]

Management of CVD Risk Factors

It is important to realize that, other than family history, manyrisk factors such as lifestyle, smoking diabetes, HTN, anddyslipidemia are modifiable. By stopping smoking, your risk ofCVD will diminish over time. Improve in diet pattern also helpsin improving the CVD risk factors.[26] Postmenopausal femalesare also advised to reduce weight and performing exercise at least30 min most days.[27,28]

Hormone Replacement Therapy (HRT)

HRT used in menopause reduces VMS, dyspareunia, andosteoporosis. It also probably decreases the risk of type 2diabetes and colorectal cancer. However, the use of HRTfor the prevention of CHD still remains controversial.Observational studies of menopausal women taking HRTshowed a reduction in the occurrence of CVD events andCHD death.

One of the largest randomized trials, Women's HealthInitiative (WHI) hormone trial, a placebo-controlled studyexamined the effects of HRT (conjugated equine estrogens[CEE] + medroxyprogesterone acetate (MPA), or CEE alone) on primary CVD prevention, osteoporotic fractures,and breast cancer risk. It was stopped early due to an excessof invasive breast cancer in women taking CEE plus MPA.Increased risk of CHD, stroke, and thromboembolismoutweighs the benefit achieved by colorectal cancer andhip fracture reduction. All-cause mortality with hormonereplacement was found to be lower when HRT was begunduring the fifth decade but higher when begun after 60 yearsof age.[29]

 
In Estrogen Replacement and Atherosclerosis (ERA) trial,309 postmenopausal women who had angiographically verifiedcoronary disease received either conjugated estrogen alone orconjugated estrogen plus MPA. Significant reductions in LDL-clevels and significant increases in HDL-c levels were observed;however, no change was seen in the progression of coronaryatherosclerosis.[30]

In a recent trial, Early versus Late Intervention Trial withEstradiol Trial, 643 postmenopausal women were groupedinto early and late menopause according to time sincemenopause. After a median of 5 years, estradiol, with or withoutprogesterone, and CIMT progression were significantly lessin early postmenopause strata but not in late postmenopausestrata when compared to placebo. However, no significant effecton cardiac CT measures of atherosclerosis was found in eitherpostmenopause group.[31]

Non-hysterectomized postmenopausal women are atincreased risk of endometrium cancer if they are on estrogenonlyHRT. Similarly, there is an increased risk of ovarian cancerirrespective of estrogen-only or combined estrogen-progestogenHRT.

HTN

HTN in postmenopausal female is treated in accordance tovarious available guidelines. While treating these patients forHTN, we should also consider for other comorbidities such asdiabetes and stroke.[32] However, the rate of hypertensive womendetected, treated, and subsequently well controlled is estimatedto be only 10%.[33]

Dyslipidemias

Statin is recommended as per the current guidelines for primaryprevention in women who have an elevated CVD risk.[34] Inaddition, they should be prescribed to women for secondaryprevention of cardiovascular events; the recommendationsand targets are the same for women as for men. As mentionedpreviously, HRT can improve lipid profiles and lead to areduction in LDL-c, significant increases in HDL-c, anddecreases in lipoprotein(a).[35,36]

Conclusion

The take-home message is that risk factor increases at thetime of menopause and menopausal transition, some of themare due to aging and some are due to menopausal changes itself. Doctors should be aware of these and should counselthe perimenopausal woman for screening for risk factors andcardiovascular events and for lifestyle changes and treatmentif required.

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References
  1. Tandon VR, Mahajan A, Sharma S, Sharma A. Prevalence ofcardiovascular risk factors in postmenopausal women: A ruralstudy. J Midlife Health 2010;1:26-9.
  2. Soules MR, Sherman S, Parrott E, Rebar R, Santoro N, Utian W,et al. Executive summary: Stages of reproductive aging workshop(STRAW). Fertil Steril 2001;76:874-8.
  3. Meeta, Digumarti L, Agarwal N, Vaze N, Shah R, Malik S,et al. Clinical practice guidelines on menopause: Anexecutive summary and recommendations. J Midlife Health2013;4:77-106.
  4. Ahuja M. Age of menopause and determinants of menopauseage: A PAN India survey by IMS. J Midlife Health2016;7:126-31.
  5. Broer SL, Eijkemans MJ, Scheffer GJ, van Rooij IA, de Vet A,Themmen AP, et al. Anti-mullerian hormone predictsmenopause: A long-term follow-up study in normoovulatorywomen. J Clin Endocrinol Metab 2011;96:2532-9.
  6. Nelson HD, Haney E, Humphrey L, Miller J, Nedrow A,Nicolaidis C, et al. Management of menopause-relatedsymptoms: Summary, evidence report/technology assessment.Prep Oregon Evidence Based Pract Cent 2005;120:1-6.
  7. Gast GC, Grobbee DE, Pop VJ, Keyzer JJ, Wijnands-van Gent CJ,Samsioe GN, et al. Menopausal complaints are associated withcardiovascular risk factors. Hypertension 2008;54:1492-8.
  8. Thurston RC, Johnson BD, Shufelt CL, Braunstein GD, Berga SL,Stanczyk FZ, et al. Menopausal symptoms and cardiovasculardisease mortality in the women's ischemia syndrome evaluation(WISE). Menopause 2017;24:126-32.
  9. Galloway DA, Laimins LA, Division B, Hutchinson F. HHSPublic Access. New York: Raven Press; 2016. p. 87-92.
  10. Mendelsohn ME, Karas RH. The protective effects of estrogenon the cardiovascular system. N Engl J Med 1999;340:1801-11.
  11. Kannel WB, Wilson PW. Risk factors that attenuate the femalecoronary disease advantage. Arch Intern Med 1995;155:57-61.
  12. de Kat AC, Dam V, Onland-Moret NC, Eijkemans MJ,Broekmans FJ, van der Schouw YT, et al. Unraveling theassociations of age and menopause with cardiovascular riskfactors in a large population-based study. BMC Med 2017;15:2.
  13. Hu FB, Grodstein F, Hennekens CH, Colditz GA, Johnson M,Manson JE, et al. Age at natural menopause and risk ofcardiovascular disease. Arch Intern Med 1999;159:1061-6.
  14. Savonitto S, Colombo D, Franco N, Misuraca L, Lenatti L,Romano IJ, et al. Age at menopause and extent of coronaryartery disease among postmenopausal women with acutecoronary syndromes. Am J Med 2016;129:1205-12.
  15. Senoz S, Direm B, Gulekli B, Gokmen O. Estrogen deprivation,rather than age, is responsible for the poor lipid profile andcarbohydrate metabolism in women. Maturitas 1996;25:107-14.
  16. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK,He J, et al. Global burden of hypertension: Analysis of worldwidedata. Lancet 2005;365:217-23.
  17. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R, Prospective Studies Collaboration., et al. Age-specific relevanceof usual blood pressure to vascular mortality: A meta-analysis ofindividual data for one million adults in 61 prospective studies.Lancet 2002;360:1903-13.

 
  1. Vasan RS, Larson MG, Leip EP, Evans JC, O'Donnell CJ,Kannel WB, et al. Impact of high-normal blood pressure on therisk of cardiovascular disease. N Engl J Med 2001;345:1291-7.
  2. Davis SR, Castelo-Branco C, Chedraui P, Lumsden MA,Nappi RE, Shah D, et al. Understanding weight gain atmenopause. Climacteric 2012;15:419-29.
  3. Forouhi NG, Merrick D, Goyder E, Ferguson BA, Abbas J,Lachowycz K, et al. Diabetes prevalence in england,2001--estimates from an epidemiological model. Diabet Med2006;23:189-97.
  4. Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenoussex hormones and risk of type 2 diabetes: A systematic reviewand meta-analysis. JAMA 2006;295:1288-99.
  5. Anagnostis p, Majeed A, Johnston DG, Godsland IF.Cardiovascular risk in women with type 2 diabetes mellitus andprediabetes: Is it indeed higher than men?. Eur J Endocrinol2014;171:R245-55.
  6. Malacara JM, Huerta R, Rivera B, Esparza S, Fajardo ME.Menopause in normal and uncomplicated NIDDM women:Physical and emotional symptoms and hormone profile.Maturitas 1997;28:35-45.
  7. Janssen I, Powell LH, Crawford S, Lasley B, Sutton-TyrrellK. Menopause and the metabolic syndrome: The studyof women's health across the nation. Arch Intern Med2008;168:1568-75.
  8. Muka T, Asllanaj E, Avazverdi N, Jaspers L, Stringa N, Milic J,et al. Age at natural menopause and risk of type 2 diabetes:A prospective cohort study. Diabetologia 2017;60:1951-60.
  9. Willett WC, Green A, Stampfer MJ, Speizer FE, Colditz GA,Rosner B, et al. Relative and absolute excess risks of coronaryheart disease among women who smoke cigarettes. N Engl JMed 1987;317:1303-9.
  10. Gorodeski GI. Impact of the menopause on the epidemiologyand risk factors of coronary artery heart disease in women. ExpGerontol 1994;29:357-75.
  11. Eaker ED, Chesebro JH, Sacks FM, Wenger NKL, Whisnant JP,Winston M. Cardiovascular disease in women. Circulation1993;88:1999-2009.
  12. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ,Kooperberg C, Stefanick ML, et al. Risks and benefits ofestrogen plus progestin in healthy postmenopausal women:Principal results from the women's health initiative randomizedcontrolled trial. JAMA 2002;288:321-33.
  13. Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC,Shumaker SA, Snyder TE, et al. Effects of estrogen replacementon the progression of coronary-artery atherosclerosis. N Engl JMed 2000;343:522-9.
  14. Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ,Hwang-Levine J, et al. Vascular effects of early versus latepostmenopausal treatment with estradiol. N Engl J Med2016;374:1221-31.
  15. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A,Bohm M, et al. 2013 ESH/ESC practice guidelines for themanagement of arterial hypertension. Blood Press 2014;23:3-16.
  16. Lloyd-Sherlock P, Beard J, Minicuci N, Ebrahim S, Chatterji S.Hypertension among older adults in low- and middle-income countries: Prevalence, awareness and control. Int J Epidemiol2014;43:116-28.

 
16 Hypertension Journal, January-March, Vol 4, 2018

Menopause and cardiovascular implication Agrawal and Yadav

  1. European Association for Cardiovascular Prevention &Rehabilitation, Reiner Z, Catapano AL, De Backer G, Graham I,Taskinen MR, et al. ESC/EAS guidelines for the managementof dyslipidaemias: The task force for the management ofdyslipidaemias of the european society of cardiology (ESC)and the european atherosclerosis society (EAS). Eur Heart J2011;32:1769-818.

 
  1. Maclaran K, Stevenson JC. Primary prevention of cardiovascular disease with HRT. Womens Health (Lond) 2012;8:63-74.
  2. Collins P, Webb CM, de Villiers TJ, Stevenson JC, Panay N,Baber RJ, et al. Cardiovascular risk assessment in women - anupdate. Climacteric 2016;19:329-36.

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