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Hormones and the heart, (and other vascular things)!. Dr Heather Currie Associate Specialist Obstetrician & Gynaecologist MD Menopause Matters Ltd. Plan. CVD in women Menopause & CVD risk Menopause, HRT and other vascular things!. Demographics. 1850 Age of menopause - 45 yrs.

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Hormones and the heart and other vascular things

Hormones and the heart, (and other vascular things)!

Dr Heather Currie

Associate Specialist Obstetrician & Gynaecologist

MD Menopause Matters Ltd


Hormones and the heart and other vascular things

Plan

  • CVD in women

  • Menopause & CVD risk

  • Menopause, HRT and other vascular things!


Demographics

Demographics

  • 1850

  • Age of menopause - 45 yrs.

  • Life expectancy - 45 yrs.

  • 2009

  • Age of menopause - 52 yrs.

  • Life expectancy - 82 yrs.

  • Today > 30% life = postmenopausal


Physiology

Physiology


Oocytes

Oocytes

  • 5th month gestation—7 million

  • Birth—1-2 million

  • Puberty—400,000

  • 40+--rapid decline!


Types of menopause

Types of menopause

  • Spontaneous

  • Surgical

  • Drug induced


Premature ovarian failure

Premature ovarian failure

  • Special considerations

  • Symptom control

  • Bone health

  • Cardiovascular health

  • Dementia

  • Fertility


Early symptoms

Early Symptoms

  • Periods changing

  • Vasomotor

  • Insomnia

  • Mood

  • Connective tissue

  • Cognitive function

  • Coping


Intermediate symptoms

Intermediate symptoms

  • Urogenital atrophy

  • Vagina and bladder

  • Hugely under-reported and under-treated


Reporting and treatment

Reporting and Treatment

Cumming G, Currie H et al. Menopause International 2007;13:79-83


Long term health

Long term health

  • Osteoporosis

  • Cardiovascular disease

  • Dementia


Mortality rates in women

Mortality Rates in Women

6500

4500

2500

1600

1200

800

400

0

45–49

50–54

55–59

60–64

65–69

70–74

75–79

80–84

85+

At Every Age, More Women Die of Heart Disease Than Breast Cancer

Coronary Artery Disease

Stroke

Lung Cancer

Breast Cancer

Colon Cancer

Endometrial Cancer

Mortality Rate per 100,000

Age (years)

National Center for Health Statistics. 1999:164-7.


Cvd in women

CVD in women


Death from cvd

Death from CVD

  • Europe, stats from 2005

  • 43% of men

  • 57% of women


Causes of death in european women who 2004

Causes of death in European women WHO 2004


Women s perceptions of their greatest health problems

Women’s perceptions of their greatest health problems

Cardiovascular disease

7%

Don’t know/ no answer

Breast cancer

16%

34%

Other problems

16%

27%

Cancer

Mosca et al. Arch Fam Med 2000.


European survey

European survey

  • Only 1/3 women associated CVD with menopause

  • Only ¼ associated raised cholesterol with menopause

  • Only 8% women 45—65 had been advised to have cholesterol level checked

  • Only 15% hcps aware that women equal risk as men


Symptoms of cvd in women

Symptoms of CVD in women

Different from those in men

Angina can be mistaken for indigestion or heartburn

MI symptoms can include overwhelming fatigue, shortness of breath, nausea, or indigestion


Other problems

Other problems

  • Often present late

  • Other medical problems

  • Poorly represented in trials

  • Less interventions

  • Worse prognosis following MI:

  • 38% women die in 1 year, 25% men

  • In 6 years, further MI in 35% women, 18% men


Incidence of cvd relation to menopause status

Incidence of CVD: Relation to Menopause Status

The Framingham Study

Incidence

(per 1000 women)

Age (years)

n = 2873.

Kannel WB, et al. Ann Intern Med. 1976;85:447-52.


Modifiable risk factors

Modifiable risk factors

  • Smoking

  • BMI (waist – hip ratio)

  • Lack of exercise

  • Hypertension

  • Cholesterol

  • Stress

  • Diabetes—doubles risk CVD in men, trebles risk in women


Effect of estrogen lack

Effect of estrogen lack

  • Change in BMI, fat distribution

  • Inc LDL cholesterol

  • Decreased HDL

  • Increase TGs

  • Blood pressure

  • Glucose/insulin metabolism

  • 4 fold increased risk CVD

  • Prem menopause—53% inc risk CHD


Raised cholesterol

Raised cholesterol


Hormones and the heart and other vascular things

So………

  • Need for increased awareness

  • See onset of menopausal symptoms as “wake up call”

  • Think beyond symptoms

  • Long term health—heart as well as bones

  • WHO—80% CVD can be prevented by diet and lifestyle changes

  • Premature menopause


Contributory factors

Contributory factors

Obese population aged 15 and above

  • Weight

  • Dietary

  • Exercise

  • Smoking

OECD Factbook 2005 www.sourceoecd.org/factbook


What about hrt

What about HRT?

  • Should be good!

  • Favourable effects on W/H ratio, lipids, vascular function, atheroma formation

  • Conflicting findings—observational studies and randomised trials


Hrt and cardiovascular protection

HRT and Cardiovascular Protection

  • 23 good observational studies

    BUT

  • Not randomised

  • Mainly unopposed estrogen

  • Healthy cohort effect


Effect of duration of ht use on risk of nonfatal acute mi

Effect of Duration of HT Use on Risk of Nonfatal Acute MI

0.1

0.5

1.0

2.0

5.0

Odds Ratio

HT Use

n = 371

Never Used

n = 69

12 Months

n = 75

13–60 Months

n = 27

>60 Months

Chilvers CE, et al. Eur Heart J. 2003;24:2197-205.


Hers chd events by year

HERS: CHD Events by Year

HERS

HERS II

Grady D, et al. JAMA. 2002;288:49-57.


Hers lessons learned

HERS: Lessons Learned

Hulley S, et al. JAMA. 1998;280:605-13; Grady D, et al. JAMA. 2002;288:49-57; Blumenthal RS, et al. Am J Cardiol. 2000;85:1015-7.

  • The women in HERS were on average 18 years postmenopause, suggesting that years since menopause may have an important influence on the cardiovascular effects associated with initiation of CEE/MPA

  • Cardiovascular risks of CEE/MPA in this population were observed early and did not occur in individuals taking concomitant statin therapy


W omen s h ealth i nitiative whi clinical trials of ht

Women’s Health Initiative (WHI) Clinical Trials of HT

CEE = conjugated equine estrogen; MPA = medroxyprogesterone acetate; HT = hormone therapy (estrogen alone [E-alone], estrogen plus a progestin [E+P]).

The Women's Health Initiative Study Group. Control Clin Trials. 1998;19:61-109.

  • Large, parallel, NIH-sponsored, randomized, placebo-controlled, clinical trials

    • CEE alone

    • CEE plus MPA

  • Purpose: Assess long-term risks and benefits of CEE alone and CEE/MPA in chronic disease prevention

  • More than 27,000 women aged 50 to 79 years (mean age, ~63 years) randomized between 1993 and 1998; originally scheduled to conclude in 2005

10/15/2014 10:47:24 AM


Relative risk of chd nurses health study nhs versus whi

Relative Risk of CHD: Nurses’ Health Study (NHS) Versus WHI

Never Users

CEE Alone

CEE + MPA

Placebo

95% nCI

CEE + MPA

95% aCI

Placebo

95% nCI

CEE

95% aCI

NHS1

WHI

E + P2

WHI

E Alone3

Risk Estimate

1Manson JE, et al. N Engl J Med. 2003;349:523-34; 2Grodstein F, et al. Ann Intern Med. 2000;133:933-41;

3Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-12.


Whi study jama 2002 288 321 333

WHI STUDYJAMA 2002;288:321-333

Note demographics of study population

60% > 60yrs

30% had BMI >30

Pre-existing heart disease

Drop out rate 75% (active and placebo)

NOV 2009

October 14


Timing of hrt in whi

Timing of HRT in WHI


Timing of hrt in whi1

Timing of HRT in WHI


American endocrine society statement on mht june 2010

AMERICAN ENDOCRINE SOCIETY STATEMENT ON MHT JUNE 2010

  • WHI data not applicable to typical women considering MHT

  • Av age 63 yrs. Only 3.5% 50 – 54 yrs

  • No assessment of symptom relief

  • Thus review data and new studies of MHT in women 50 - 55 yrs

October 14


Does the timing of hrt matter

Does the timing of HRT matter?

  • Meta-analysis of 23 trials

  • 39,049 participants

  • Odds ratio for CHD differed with age at enrolment

    • Under 60 - 0.68—32% reduction (significant)

    • Over 60 - 1.03

Salpeter et al J Gen Int Med 2004;19:791-804


Timing of hrt for mortality

Timing of HRT for mortality

  • Meta-analysis of 30 trials

  • 27,000 participants

  • Odds ratio for mortality differed with age at enrolment

    • Under 60 - 0.61—significant 39% reduction

    • Over 60 - 1.03

  • [Nurse’s Health Study HRT within 2 years of LMP - 0.63]


Effect of ert on coronary atherosclerosis timing of initiation

Effect of ERT on Coronary Atherosclerosis : Timing of Initiation

Premenopausal Years

Postmenopausal Years

Plaque Area (% of placebo)

Ovariectomy

70%1,2

1.

Healthy diet

CEE + atherogenic diet

2.

50%3

Atherogenic diet

CEE + atherogenic diet

Atherogenic diet

Healthy diet+ CEE

3.

0%4

Healthy diet

~ 6 Year Human Equivalent

Time

1Clarkson TB, et al. J Clin Endocrinol Metab. 1998;83:721-6; 2Adams MR, et al. Arterioscler Thromb Vasc Biol. 1997;17:217-21; 3Clarkson TB, et al. J Clin Endocrinol Metab. 2001;86:41-47; 4Williams JK, et al. Arterioscler Thromb Vas Biol. 1995;15:827-36.


Effect of hormone therapy on atherosclerosis varies with stage of reproductive life

Effect of Hormone Therapy on Atherosclerosis Varies With Stage of Reproductive Life

Premenopause

Perimenopause

Postmenopause

~5%

~15%

25-35 yrs

35-45 yrs

45-55 yrs

55-65 yrs

65 yrs

15-25 yrs

Benefits of Endogenous E2

Primary Benefits of HT

No Benefits of HT

Mikkola TS, et al. Ann Med. 2004;36:402-13.


The effect of body mass on the risk of chd putting the whi results in perspective

The Effect of Body Mass on the Risk of CHD: Putting the WHI Results in Perspective

BMI (kg/m2)

RH = relative hazard.

*Mean BMI 28.5 kg/m2.

BMI data from Willett WC, et al. JAMA. 1995;273:461-5.

WHI data from Manson JE, et al. N Engl J Med. 2003;349:523-34.


Chd primary prevention

low-dose aspirin reduces CVA risk

no reduction in CHD risk with low-dose aspirin

no reduction in CHD mortality with statins

reduction in CHD risk with HRT

CHD: PRIMARY PREVENTION

CHD

Hodis and Mack. Menopause 2007; 14: 1-14


Benefits and risks women

BENEFITS AND RISKS: WOMEN

CHD

breast cancer

Hodis and Mack. Menopause 2007; 14: 1-14


Summary hrt and chd

Summary—HRT and CHD

  • Window of opportunity

  • Best if started within 6 years of menopause and/or before age 60

  • Increased benefit with longer use

  • Use for at least 5 years

  • Results of further studies on timing, types and routes awaited

  • Similar risks to other commonly used drugs


Stroke

Stroke

  • Most common cause: infarction

    • atheroma at branch points of cerebral arteries (carotid and vertebral)

  • Less common cause: ruptured aneurysm

    • primary intracerebral and subarachnoidal hemorrhage

  • Are risk factors for cerebral and myocardial infarction similar?

    • hypertension more important, lipids less so?

  • Risk factors for hemorrhagic stroke

    • hypertension


Ischaemic stroke whi

Ischaemic Stroke--WHI

  • Overall combined HRT- + 0.85/1,000/year

  • ---Only appreciable in 70-79 age group-extra 1.3 per 1,000 per year

  • Overall estrogen only- + 1.19/1,000/year

  • ---Only appreciable in 60-69 age group-extra 1.9 per 1,000 per year

  • And in 70-79 age group-extra 1.4 per 1,000 per year


Hypertension and risk of stroke danish nurse study

Hypertension and Risk of StrokeDanish Nurse Study

Lokkegaard et al Arch Neurol 2003;60:1379


Estrogen and stroke a case for low dose estrogen

Estrogen and Stroke: a case for low-dose estrogen

Low doses may confer protection while higher doses may increase risk

Risks may be lower with transdermal

Thrombogenic effects

C-reactive Protein

Birge ss Menopause 2006;13(5):719-20


Transdermal and oral hrt and the risk of stroke

TRANSDERMAL AND ORAL HRT AND THE RISK OF STROKE

Renoux et al, BMJ 2010; 340:83

UK GP Research Database

870,286 women with no prior stroke history aged 50 – 79 between 1987 and 2006 followed up for mean duration of 6.7 years

15710 cases of stroke

October 14


Transdermal and oral hrt and the risk of stroke1

TRANSDERMAL AND ORAL HRT AND THE RISK OF STROKE

Low dose transdermal ET (50 micrograms) is not associated with increase in risk of stroke

High dose transdermal ET and oral estrogen, alone or combined with progestogen, are associated with increased risk.

Use of oral (ET or EPT) had a 28% increase in risk which translates into an absolute risk of 0.8 strokes per 1000 person years of use.

October 14


Take home messages

Take Home Messages

Use of HT at the menopause will have different effects from HT started 10 to 15 years later

No data to suggest change of indications for HT at the menopause

Increasing evidence that progestogen reduces estrogen benefit / adds to risks


Hormones and the heart and other vascular things

VTE

  • Consistent finding of increased risk with HRT, randomised and observational

  • Mostly in 1st year

  • Greater risk with combined HRT cf estrogen only

  • Likely reduced risk with transdermal HRT

  • Consider other risk factors


Vte whi rate 1000 year

VTE—WHI rate/1000/year


Hrt vte meta analysis

HRT & VTE meta-analysis

  • Oral estrogen OR 2.5 obs, 2.1 rct

  • 1st year—4.0, > 1year—2.1

  • No sig. difference opposed or unopposed

  • Transdermal—no increase

  • Oral estrogen—↑ prothrombin fragment 1+2, ↓ antithrombin, acquired resistance to activated protein C

  • Transdermal—no effect

Canonico et al BMJ 2008;336:1227-1231


Overall

Overall

  • Baseline risk for VTE 1.0 per 1,000 women per year

  • Oral HRT –additional 1.5 events per 1,000 women per year

  • May be different effect from doses and progestogen types

  • No signif increase with transdermal


Risk from ert according to age

Risk from ERT according to age


Migraine and menopause

Migraine and menopause

  • Anything possible!

  • Not C/I to HRT

  • Transdermal therapy often preferred


Diabetes

Diabetes

  • Inc risk CVD

  • Not C/I to HRT

  • Type and route


Whi cee mpa study incidence of diabetes

WHI CEE/MPA Study: Incidence of Diabetes

CEE/MPA (n)

Placebo (n)

8014

7627

7894

7618

7785

7403

7675

7271

7461

7049

5418

5049

2842

2528

1252

922

Placebo

HR = 0.79

95% CI = 0.67–0.93

Incidence

CEE/MPA

Time (years)

Margolis KL, et al. Diabetologia. 2004;47:1175-87.


Benefits v risks

Benefits v Risks

  • <50, benefits>>risks, all women should be offered HRT

  • 50-60, benefits>risks for symptomatic women

  • 60-70 benefits=risks, individualise and ?change to transdermal therapy

  • >70 risks>benefits


Ims report may 2008

IMS report May 2008

  • HRT initiated in the early postmenopausal period in healthy women is safe. Like all medicines, HRT needs to be used appropriately but it is essential that women in early menopause, when suffering menopausal symptoms, should have the option of using HRT.


Taking hrt

Taking HRT

  • Initial investigations

  • Appropriate type

  • Review

  • Duration of treatment


Hrt how long

HRT—how long?

  • Symptom relief

  • 3-5 years then gradual withdrawal

  • Restart if symptoms recur, NO arbitrary limits

  • Prevention of osteoporosis

  • 5-10 years minimum?

  • Premature menopause

  • Treat to average age of menopause

  • NB Breast cancer risk applies to >51 yrs


Alternatives

“Alternatives”

  • Prescribed

  • Clonidine

  • SSRIs SSNRIs

  • Gabapentin

  • Progestogens

  • OTC

  • Techniques


Resources

Resources

  • British Menopause Society www.thebms.org.uk

  • Menopause Matters www.menopausematters.co.uk

  • Bladder Matters

    www.bladdermatters.co.uk

  • Thank-you


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