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  • Oestrogen therapy increased stroke risk and decreased hip fracture risk but did not affect coronary heart disease risk in postmenopausal women with prior hysterectomy

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Therapeutics
Oestrogen therapy increased stroke risk and decreased hip fracture risk but did not affect coronary heart disease risk in postmenopausal women with prior hysterectomy
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  1. Holly L Thacker, MD, FACP
  1. Cleveland Clinic Foundation Women’s Health Center
 Cleveland, Ohio, USA

    http://dx.doi.org/10.1136/ebm.9.6.184

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      Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004;291:1701–12.
      OpenUrlCrossRefPubMedWeb of Science

      
 
 Q In postmenopausal women with prior hysterectomy, what is the effect of conjugated equine oestrogen (CEE) on major disease rates?

      Clinical impact ratings GP/FP/Primary care ★★★★★☆☆ IM/Ambulatory care ★★★★★★☆ Endocrine ★★★★★★☆ Gynaecology ★★★★★☆☆

      METHODS

      Embedded ImageDesign:

      randomised placebo controlled trial (Women’s Health Initiative [WHI]).

      Embedded ImageAllocation:

      {concealed*}†.

      Embedded ImageBlinding:

      blinded {participants, clinicians, data collectors, and outcome assessors}†.*

      Embedded ImageFollow up period:

      mean 6.8 years.

      Embedded ImageSetting:

      40 US clinical centres.

      Embedded ImageParticipants:

      10 739 postmenopausal women aged 50–79 years (mean age 64 y, 75% white) with prior hysterectomy. Exclusion criteria included probable survival <3 years and breast cancer.

      Embedded ImageIntervention:

      CEE, 0.625 mg/day (n = 5310); or matching placebo (n = 5429).

      Embedded ImageOutcomes:

      incidences of coronary heart disease (CHD) (defined as CHD death or non-fatal myocardial infarction), stroke, venous thromboembolic disease, invasive breast cancer, colorectal cancer, and hip fracture.

      Embedded ImagePatient follow up:

      95% (intention to treat analysis).

      MAIN RESULTS

      Women who received CEE had a greater incidence of stroke (number needed to harm 120) and a decreased incidence of hip fracture (number needed to treat 219) than did those who received placebo; no differences were seen for incidences of CHD, venous thromboembolic disease, invasive breast cancer, or colorectal cancer (table).

      View this table:

      Oestrogen v placebo for incidences of major diseases in postmenopausal women with prior hysterectomy at mean 6.8 years*

      CONCLUSION

      In postmenopausal women with prior hysterectomy, oestrogen increased the risk of stroke and decreased the risk of hip fracture but did not affect the risks of coronary heart disease, venous thromboembolic disease, breast cancer, or colorectal cancer.

      Commentary

      Results of the oestrogen CEE only arm of the WHI contrasts with those of the oestrogen progestin (CEE medroxyprogesterone acetate [MPA]) arm in that no increased risk of breast cancer was seen in 6.8 years.1 This is reassuring for the women who have had hysterectomy and whose main concern has been the risk of breast cancer. The lack of benefit for CHD is disappointing but not surprising. The only risk seen with 0.625 mg CEE was an increased risk of stroke. The WHI was a preventive trial in older postmenopausal women, and thus the intent was not therapeutic. Hormone therapy (HT) remains the only US Food and Drug Administration approved treatment for menopausal symptoms.2

      Many questions remain unanswered. Is the increased risk of breast cancer related to all progestins or just MPA? Is the neutral breast effect related to equine oestrogens or is this translatable to all oestrogens? Is the risk of stroke (and deep vein thrombosis) more of a risk with oral than with transdermal oestrogen? Further information about the characteristics of women sustaining stroke while on CEE and CEE MPA will be important, and studying lower doses of oestrogen will also be useful.

      We can now reassure women who have had a hysterectomy and take CEE that no increased risk of breast cancer exists in 6.8 years of use. Extrapolation of risks of the oestrogen and CEE MPA preventive arm of the WHI with respect to early and late cardiovascular effects and to cerebral aging in younger women remains to be studied. The International Menopause Society’s recent statement was that, in addition to lifestyle management, HT remains a principal tool in preventing bone wasting, fractures, and atrophy of connective tissue and in influencing the quality of life in women who are symptomatic.3

      References

      1. ↵
        Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA 2003;289:3243–53.
        OpenUrlCrossRefPubMedWeb of Science
      2. ↵
        Sikon A, Thacker HL. Treatment options for menopausal hot flashes. Cleve Clin J Med 2004;71:578–82.
        OpenUrlAbstract/FREE Full Text
      3. ↵
        Wright J, Naftolin F, Schneider HP, et al. Guidelines for the hormone treatment of women in the menopausal transition and beyond. Position statement by the Executive Committee of the International Menopause Society. Maturitas 2004;48:27–31.
        OpenUrlCrossRefPubMedWeb of Science
      View Abstract

      Footnotes

      • ↵* See glossary.

      • ↵† Information provided by author.

      • For correspondence: Dr G L Anderson, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. garnetwhi.org

      • Source of funding: National Heart, Lung, and Blood Institute.