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Estrogen and Progesterone Cardiac Protection:
A Review of the Bidding 2004 (V)

Dr. Tim Bilash MD OBGYN
June 18, 2004

(see also:)
Experts: WHI study flawed (June 28, 2004)
WHI - Better Survival with HRT? (Oct 27, 2004)

This is a compilation from a number of studies, including randomized trials,
whose findings differ from the conclusions in the WHI trials about Cardiovascular Risk.

based on the excellent review article
"Rise and Fall" of hormone therapy in postmenopausal women with cardiovascular disease
Angela HEM Maas MD, Yvonne T Van der Schouw PhD,
Diederick E Grobbee MD PHD, Yolanda van der Graaf MD PhD,
Menopause, Vol.11, No. 2, 2004, p228-235

  1. Effects of Hormones on Lipid and Vascular Physiology

    1. Estrogens (ET)
      1. Oral ET inhibits cholesterol synthesis in the liver
      2. Oral ET inhibits LDL cholesterol oxidation and penetration into the vessel wall (necessary for plaque formation)
      3. Oral ET increases Triglycerides and VLDL cholesterol, with unclear clinical significance
      4. Oral ET causes a two-fold rise in CRP, but the clinical significance of this is unclear
        1. assumed that CRP levels promote vascular inflammation and plaque instability
        2. Progestin has no affect on CRP level increase with estrogen (PEPI)
      5. Transdermal estrogens improves lipoprotein parameters less than than oral (first pass effect)
      6. Estrogen causes vasodilation by rapid activation (5-20min) of nitric oxide synthesis in endothelial cells
        1. IV estrogen causes this in healthy women as well as women with atherosclerotic disease
        2. PO estrogen appears to have same effect in animal models, but some trials fail to show an effect in women (see HERS, PHOREA trials)

  2. Animal Studies (ET)

    1. in monkeys ET inhibits vascular plaques after oopohorectomy (loss of hormones)
    2. in monkeys, ET started after two years gave no vascular protection
    3. in rats, with carotid intima damage, estrogen inhibits intima hyperplasia and smooth muscle proliferation (parts of plaque formation) only when given in the early stages of endothelial damage. After 3 days there was no benefit.
    4. in pigs, percutaneous cardiac stents had lower rates of re-stenosis with decreased neointima proliferation when coated with 17beta estradiol
    5. animal studies show protective effects of estrogen against the development of cardiac hypertrophy, which is increased in older women

  3. Observational Studies of Hormone Therapy (HT)

    1. generally indicate HT reduces cardiac risks by 35-50%
      1. different preparations were used in the different studies with different dosing, so hard to compare
      2. studies used different age groups, so hard to compare
      3. support the hypothesis that estrogen has a beneficial effect in the early stages of atherosclerotic disease and vascular wall repair
      4. support the hypothesis that longer exposure to endogenous estrogens protect against cardiovascular disease (CVD)
      5. for each year's delay in the onset of menopause, the cardiovascular mortality decreases by 2%.
      6. appear mediated by estrogen alpha and beta receptors

    2. Framingham Heart Study (1976) and Nurses' Health Study (1987)
      1. increase in cardiovascular disease in young women after bilateral oophorectomy (removal of ovaries which produce estrogen and progesterone), a risk that did not occur in women using hormone therapy (HT) after surgery.

    3. Nurses' Health Study (HT 2001)
      1. subgroup analysis shows a cardiac risk reduction of (-35%) among current HT users with up to 20 years of followup
      2. subgroup analysis shows a cardiac risk increase in the first year only (+25%) , however no increase in mortality

    4. After PTCA, elective percutaneous transluminal coronary angioplasty (1997)
      1. current users of HT show fewer cardiovascular events (12% vs 35%)
      2. current users of HT show better survival (93% vs 75%)

    5. After Coronary Bypass surgery (1997)
      1. chronic HT use was associated with significantly improved 5-year survival compared to never users

    6. After Recent MI (2001)
      1. starting Estrogen(ET) increased the incidence of unstable angina, death and reinfarction
      2. compared to chronic or never users
      3. attributed to proinflammatory and thrombogenic effects of ET
      4. [ISLT] Dont start ERT until heart damage has been stabilized.

    7. After First MI (2002), unopposed 17beta-estradiol had no effect on the frequency of reinfarction or cardiac death after two years of treatment, but the study had low power due to non-compliance.

  4. Randomized Trials

    1. CVHS trial
      1. Cardiovascular Health Study (2001)
      2. HT affected only arteries of healthy women
      3. over age 80 had no effect on brachial artery flow
      4. suggests that healthy endothelium responds to estrogens, damaged endothelium does not
      5. suggests that estrogen may be more important in maintaing vascular health than in treating damage

    2. EPAT trial
      1. Estrogen and Prevention of Atherosclerosis Trial (2001)
      2. showed that 17beta-estradiol slowed vascular intima thickening
      3. Statins and Estrogens had equal, non-additive beneficial effects

    3. ERA trial
      1. Estrogen Replacement and atherosclerosis Trial (2000)
      2. continuous CEE0.625mg with and without MPA2.5mg
      3. no differences in coronary vessel diameter or clinical outcomes
      4. postmenopausal for average 20 years

    4. HERS trial
      1. Heart and Estrogen/progestin Replacement Study (1998)
        1. advanced mean age (67 years)
        2. 83% of participants were receiving aspirin or other antiplatelet agents at entry
          1. 33% were receiving beta-blockers, and 53% were receiving lipid-lowering drugs.
          2. 18% were receiving angiotensin-converting enzyme inhibitors
          3. Women in the studywith more risk factors were less likely to be taking aspirin (P<0.001) and lipid-lowering drugs (P=0.006).
      2. Coronary Events
        1. No benefit of combined continuous CEE0.625mg/2.5mgMPA in preventing CHD after 4.1 years nor when extended to 6.7 years of follow-up (HERSII)
        2. Increase of coronary events in the first year of treatment by 50%
          1. Statins
            1. No increase risk for women who were on Statin therapy (note EPAT trial results for Statins)
            2. Statin baseline use reduced risk to no statistical significance (HR=1.34, 95%CI=0.63-2.86, p=0.45)
            3. Statins prevent the rise in CRP levels caused by estrogen monotherapy
            4. Statins decreased Myocardial Infarction/Fatal CHD (HR=0.78, 95%CI=0.61-0.99, p=0.044)
            5. Statins lowered all cause mortality (-30%)

          2. Aspirin (see EPAT trial)
            1. Aspirin had equal improvement to Estradiol for vascular intima in EPAT, so if on Aspirin might expect a reduced effect of Estrogen (non-additive) in HERS
            2. Role of Aspirin not well defined in HERS
          3. Assumption is that HT destabilizes plaques (increased lysis), and Statins stabilize plaques

      3. Venous thromoboembolism (VTE)
        1. VTE risk was higher in the hormone group (HR=2.7, CI=1.4-5.1, p= 0.003)
          1. Statin or Aspirin
            1. use wiped out increased VTE risk equally
            2. Statins lowered rates of VTE by 50% with or without HT(HR=0.40, 95%CI=0.18-0.91 multivariate)
            3. Aspirin lowered rates of VTE by 50%
          2. VTE risk decreased over time (from HERSI to HERSII)
            1. HERSI (years 1.0-4.7) HR=2.66 (95%CI=1.41-5.04)
            2. HERSII (years 4.7-6.8) HR=1.40 (95%CI=0.64-3.05)
            3. HERSI&II (years 1.0-6.8) HR=2.08 overall (95%CI=1.28-3.40)
            4. so non-significant difference in later years after more exposure
        2. Other factors increased VTE risk more:
          1. VTE was increased by lower-extremity fractures (HR=18.1,CI=5.4 to 60.4)
          2. VTE was increased after nonsurgical hospitalization (HR=5.7, CI=3.0 to 10.8)
          3. VTE was increased in the first 90 days after inpatient surgery (HR=4.9, CI=2.4 to 9.8)
          4. VTE was increased by a diagnosis of cancer (HR=3.9, CI= 1.6 to 9.4)
      4. [ISLT] need to control HRT studies for Aspirin, Statin and Estrogen exposure

    5. PEPI trial
      1. Postmenopausal Estrogen/Progestin Interventions Study (1999)
      2. *****Oral Estrogen alone or in combination with Progestin normalized lipoprotein levels to premenopausal levels
        1. Medroxyprogesterone acetate (MPA) attenuated the improved lipid levels with estrogen (-75%)
          1. but there were no detrimental effects from this attenuation
          2. micronized progesterone also attenuated but less (-30%)
          3. LDL levels decreased in all treatment groups
          4. both continuous or cyclic therapy
      3. Oral Estrogen increases CRP serum levels
        1. MPA (medroxyprogesterone acetate) and micronized progesterone had no effect on CRP (continous or cyclic)
      4. there were no changes in BP or insulin level between the groups
      5. fibrinogen was slightly decreased in treatment groups
      6. two-hour post challenge glucose increased in the CEE plus medroxyprogesterone acetate (cyclic and continuous) groups but was unchanged in CEE alone and CEE plus MP groups
      7. Estrogen, with or without progestogen, was associated with a lower weight gain

    6. PHOREA trial
      1. Postmenopausal Hormone Replacement Against Atherosclerosis (2001)
      2. 48 week treatment with 17beta-estradiol with and without progestin
      3. progressive increase of carotid intima was not slowed with any hormone treatment
      4. Estrogen with or without progestin decreased LDL and Fibrinogen serum levels however (improvement)

    7. WEST trial
      1. Women's Estrogen for Stroke Trial (2001)
      2. oral estrogen only (no progestin) given after ischemic stroke or TIA
      3. mean age 71 years
      4. mean follow-up of 2.8 years (short term study)
      5. oral 17beta estradiol did not have a beneficial effect on transient ischemic attack or stroke
      6. increase in recurrent stroke or mortality in first 6 months only (HR 2.3, 95%CI=1.1-5.0, with poorer outcomes)
      7. findings at 2.8 years lost statistical significance
        1. Stroke or Death (HR=1.1, CI=0.8-1.4 NS)
        2. Death alone (HR=1.2, CI=0.8-1.8 NS)
        3. Non-fatal stroke (HR=1.0, CI=0.7-1.4 NS)
        4. Fatal stroke (HR=2.9, CI=0.9-9.0 NS)

    8. WHI trial
      1. Women's Health Initiative (2002, 2004)
      2. Women in this study were older, well past menopause, without hormones for many years before entering the study
      3. showed a two fold increase in thromboembolic events
        1. thromboembolic events for both PE and DVT combined
        2. PE (Pulmonary Embolism) increase is non-significant leaving only DVT (Deep Vein Thrombosis) contribution when corrected for multiple testing
        3. increase is in non-fatal events
          1. would expect to see an increase in mortality with such an increase incidence of thromboembolic events
        4. not controlled for Statin and Aspirin use, believed to counter VTE risk (more use in Placebo group identified)
        5. contrast the Estrogen+Progestin and Estrogen Arms; note problems with statistical significance
      4. indicates that early intervention is a factor in the prevention of atherosclerosis and endothelial damage
      5. randomized initially to treatment group, but not well controlled as to actual treatment exposure and outcome group

    9. WHI-OS trial
      1. Women's Health Initiative Observational Study (nested case-control, still on-going)
      2. HT significantly elevates CRP
      3. HT does not elevate other inflammatory markers (interleukin-6)
        1. Total levels of inflammatory biomarkers (not just CRP) seem to be important in predicting coronary risk
        2. Suggests that other factors than HT are involved in inflammatory states that increase risk of early cardiovascualr events

  5. Other Data

    1. SERMS (Selective Estrogen Receptor Modulators)
      1. treats osteoporosis
      2. may reduce the incidence of breast cancer
      3. decrease LDL, but no change in HDL, TRIG
      4. decreased LipoproteinA, fibrinogen, homocysteine
      5. no change in plasminogenactivator inhibitor-1, CRP
      6. venous thromboembolism risk similar to oral estrogen

    2. MORE trial
      1. Multiple Outcomes of Raloxifene Evaluation trial (retrospective)
      2. no early increase in first year, 40% reduction after 4 years of treatment
      3. older population

    3. RUH trial
      1. Raloxifene Use for the Heart Randomization trial (randomized)
      2. currently underway

  6. References

    1. "Rise and Fall" of hormone therapy in postmenopausal women with cardivascular disease,
      Angela HEM Maas MD, Yvonne T. Van der Schouw PhD, Diederick E Grobbee MD PHD, Yolanda van der Graaf MD PhD,
      Menopause, Vol.11, No. 2, 2004 p228-235

    2. Postmenopausal Hormone Therapy Increases Risk for Venous Thomboembolic Disease
      The Heart and Estrogen/progestin Replacement Study,
      Deborah Grady, MD, MPH; Nanette K. Wenger, MD; David Herrington, MD, MHS; Steven Khan, MD; Curt Furberg, MD; Donald Hunninghake, MD; Eric Vittinghoff, PhD; and Stephen Hulley, MD, MPH, for the Heart and Estrogen/progestin replacement Study Research Group,
      Annals of Internal Medicine, 2 May 2000, Vol 32, Issue 9, p689-696

    3. Risk Factors and Secondary Prevention in Women with Heart Disease: The Heart and Estrogen/progestin Replacement Study,
      Eric Vittinghoff, PhD; Michael G. Shlipak, MD, MPH; Paul D. Varosy, MD; Curt D. Furberg, MD, PhD; Christine C. Ireland, MPH; Steven S. Khan, MD; Roger Blumenthal, MD; Elizabeth Barrett-Connor, MD; and Stephen Hulley, MD, MPH, for the Heart and Estrogen/progestin Replacement Study Research Group
      Annals of Internal Medicine, 21 January 2003, Vol 138, Issue 2, p81-89

    4. (link to review article, David Derbyshire, June 28, 2004, Chicago Sun-Times )
      The Women's Health Initiative could not have detected cardioprotective effects of starting hormone therapy during the menopausal transition
      Naftolin F et al, Fertility and Sterility, June 2004, 1498-1501
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