Download PDF
Semin Reprod Med 2014; 32(06): 419-425
DOI: 10.1055/s-0034-1384624
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Postmenopausal Hormone Therapy and the Risks of Coronary Heart Disease, Breast Cancer, and Stroke

Ross L. Prentice
1   Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
› Author Affiliations
Further Information

Publication History

Publication Date:
16 October 2014 (online)

    Permissions and Reprints

Abstract

The principal findings are briefly reviewed from the Women's Health Initiative trials of the most commonly used postmenopausal hormone regimens in the United States—conjugated equine estrogens and these same estrogens plus medroxyprogesterone acetate. A more detailed review is presented for three major clinical outcomes: coronary heart disease (CHD), the primary trial outcome for which a major benefit was hypothesized; invasive breast cancer, the primary safety outcome for which some adverse effect was expected; and stroke which surfaced as an important adverse effect with both regimens, and one that is influential in decisions concerning the continued use of postmenopausal estrogens alone. The review for these outcomes includes an update on interactions of treatment effects with study subject characteristics and exposures and with prerandomization biomarker levels. It also includes a focus on timing issues that are important to the understanding of treatment effects. Specifically, with combined estrogen plus progestin, CHD risk was elevated early with the elevation dissipating after a few years of treatment, whereas breast cancer elevations increased during the treatment period, and climbed to about a threefold increase following 5 years of adherence. Importantly, breast cancer risk elevations appear to be higher among women who initiate treatment at the menopause, or soon thereafter, compared with women having a longer gap time. Stroke effects, on the contrary, did not seem to vary appreciably with these timing issues. The adverse effect was evidently localized to ischemic strokes, for which there was an approximate 50% increase with either regimen. The rather limited knowledge concerning the biomarkers and biological pathways that mediate the hormone therapy effects on these diseases is also briefly reviewed.

Keywords

breast cancer - coronary heart disease - postmenopausal hormone therapy - randomized controlled trial - stroke

Note

Since the time of completion of this article, WHI investigators have presented[35] a rather comprehensive analysis of data from both HT trials with extended poststopping trial follow-up. The reader is referred to this article for additional data analyses, especially for outcomes other than the three focused on here.


 

  • References

  • 1 Rossouw JE, Anderson GL, Prentice RL , et al; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002; 288 (3) 321-333
    CrossrefPubMedGoogle Scholar
  • 2 Anderson GL, Limacher M, Assaf AR , et al; Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004; 291 (14) 1701-1712
    CrossrefPubMedGoogle Scholar
  • 3 The Women's Health Initiative Study Group. Design of the Women's Health Initiative clinical trial and observational study. Control Clin Trials 1998; 19 (1) 61-109
    CrossrefPubMedGoogle Scholar
  • 4 Prentice RL, Anderson GL. The women's health initiative: lessons learned. Annu Rev Public Health 2008; 29: 131-150
    CrossrefPubMedGoogle Scholar
  • 5 Heiss G, Wallace R, Anderson GL , et al; WHI Investigators. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA 2008; 299 (9) 1036-1045
    CrossrefPubMedGoogle Scholar
  • 6 LaCroix AZ, Chlebowski RT, Manson JE , et al; WHI Investigators. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 2011; 305 (13) 1305-1314
    CrossrefPubMedGoogle Scholar
  • 7 Chlebowski RT, Anderson GL, Gass M , et al; WHI Investigators. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2010; 304 (15) 1684-1692
    CrossrefPubMedGoogle Scholar
  • 8 Simon MS, Chlebowski RT, Wactawski-Wende J , et al. Estrogen plus progestin and colorectal cancer incidence and mortality. J Clin Oncol 2012; 30 (32) 3983-3990
    CrossrefPubMedGoogle Scholar
  • 9 Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med 1991; 20 (1) 47-63
    CrossrefPubMedGoogle Scholar
  • 10 The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995; 273 (3) 199-208
    CrossrefPubMedGoogle Scholar
  • 11 Beral V ; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003; 362 (9382) 419-427
    CrossrefPubMedGoogle Scholar
  • 12 Manson JE, Hsia J, Johnson KC , et al; Women's Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003; 349 (6) 523-534
    CrossrefPubMedGoogle Scholar
  • 13 Hsia J, Langer RD, Manson JE , et al. Conjugated equine estrogens and the risk of coronary heart disease. Arch Intern Med 2006; 166: 357-365
    CrossrefPubMedGoogle Scholar
  • 14 Rossouw JE, Cushman M, Greenland P , et al. Inflammatory, lipid, thrombotic, and genetic markers of coronary heart disease risk in the women's health initiative trials of hormone therapy. Arch Intern Med 2008; 168 (20) 2245-2253
    CrossrefPubMedGoogle Scholar
  • 15 Prentice RL, Langer R, Stefanick M , et al; for the Women's Health Initiative Investigators. Combined postmenopausal hormone therapy and cardiovascular disease: toward resolving the discrepancy between Women's Health Initiative Clinical Trial and Observational Study Results. Am J Epidemiol 2005; 162 (5) 404-414
    CrossrefPubMedGoogle Scholar
  • 16 Prentice RL, Langer RD, Stefanick ML , et al; Women's Health Initiative Investigators. Combined analysis of Women's Health Initiative observational and clinical trial data on postmenopausal hormone treatment and cardiovascular disease. Am J Epidemiol 2006; 163 (7) 589-599
    CrossrefPubMedGoogle Scholar
  • 17 Chlebowski RT, Hendrix SL, Langer RD , et al; WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 2003; 289 (24) 3243-3253
    CrossrefPubMedGoogle Scholar
  • 18 Stefanick ML, Anderson GL, Margolis KL , et al; WHI Investigators. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006; 295 (14) 1647-1657
    CrossrefPubMedGoogle Scholar
  • 19 Chlebowski RT, Kuller LH, Prentice RL , et al; WHI Investigators. Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med 2009; 360 (6) 573-587
    CrossrefPubMedGoogle Scholar
  • 20 Ravdin PM, Cronin KA, Howlader N , et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med 2007; 356 (16) 1670-1674
    CrossrefPubMedGoogle Scholar
  • 21 Prentice RL, Chlebowski RT, Stefanick ML , et al. Estrogen plus progestin therapy and breast cancer in recently postmenopausal women. Am J Epidemiol 2008; 167 (10) 1207-1216
    CrossrefPubMedGoogle Scholar
  • 22 Prentice RL, Chlebowski RT, Stefanick ML , et al. Conjugated equine estrogens and breast cancer risk in the Women's Health Initiative clinical trial and observational study. Am J Epidemiol 2008; 167 (12) 1407-1415
    CrossrefPubMedGoogle Scholar
  • 23 Prentice RL, Manson JE, Langer RD , et al. Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Am J Epidemiol 2009; 170 (1) 12-23
    CrossrefPubMedGoogle Scholar
  • 24 Beral V, Reeves G, Bull D, Green J ; Million Women Study Collaborators. Breast cancer risk in relation to the interval between menopause and starting hormone therapy. J Natl Cancer Inst 2011; 103 (4) 296-305
    CrossrefPubMedGoogle Scholar
  • 25 Wassertheil-Smoller S, Hendrix SL, Limacher M , et al. A randomized trial of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiaitive. JAMA 2003; 289: 2673-2684
    CrossrefPubMedGoogle Scholar
  • 26 Hendrix SL, Wassertheil-Smoller S, Johnson KC , et al; WHI Investigators. Effects of conjugated equine estrogen on stroke in the Women's Health Initiative. Circulation 2006; 113 (20) 2425-2434
    CrossrefPubMedGoogle Scholar
  • 27 Kooperberg C, Cushman M, Hsia J , et al. Can biomarkers identify women at increased stroke risk? The Women's Health Initiative Hormone Trials. PLoS Clin Trials 2007; 2 (6) e28
    CrossrefPubMedGoogle Scholar
  • 28 Prentice RL, Huang Y, Hinds DA , et al. Variation in the FGFR2 gene and the effects of postmenopausal hormone therapy on invasive breast cancer. Cancer Epidemiol Biomarkers Prev 2009; 18 (11) 3079-3085
    CrossrefPubMedGoogle Scholar
  • 29 Huang Y, Ballinger DG, Dai JY , et al. Genetic variants in the MRPS30 region and postmenopausal breast cancer risk. Genome Med 2011; 3 (6) 42
    CrossrefPubMedGoogle Scholar
  • 30 Huang Y, Ballinger DG, Stokowski R , et al. Exploring the interaction between SNP genotype and postmenopausal hormone therapy effects on stroke risk. Genome Med 2012; 4 (7) 57
    CrossrefPubMedGoogle Scholar
  • 31 Zhao S, Chlebowski RT, Anderson GL , et al. Sex hormone associations with breast cancer risk and the mediation of randomized trial postmenopausal hormone therapy effects. Breast Cancer Res 2014; 16 (2) R30
    CrossrefPubMedGoogle Scholar
  • 32 Katayama H, Paczesny S, Prentice R , et al. Application of serum proteomics to the Women's Health Initiative conjugated equine estrogens trial reveals a multitude of effects relevant to clinical findings. Genome Med 2009; 1 (4) 47
    CrossrefPubMedGoogle Scholar
  • 33 Pitteri SJ, Hanash SM, Aragaki A , et al. Postmenopausal estrogen and progestin effects on the serum proteome. Genome Med 2009; 1 (12) 121
    CrossrefPubMedGoogle Scholar
  • 34 Prentice RL, Paczesny S, Aragaki A , et al. Novel proteins associated with risk for coronary heart disease or stroke among postmenopausal women identified by in-depth plasma proteome profiling. Genome Med 2010; 2 (7) 48-60
    CrossrefPubMedGoogle Scholar
  • 35 Manson JE, Chlebowski RT, Stefanick ML , et al. The Women's Health Initiative hormone therapy trials: Overview of health outcomes during the intervention and post-stopping phases. JAMA 2013; 310: 1353-1368
    CrossrefPubMedGoogle Scholar
  • 36 Curb JD, Prentice RL, Bray PF , et al. Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med 2006; 166 (7) 772-780
    CrossrefPubMedGoogle Scholar
  • 37 Cushman M, Kuller LH, Prentice R , et al; Women's Health Initiative Investigators. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004; 292 (13) 1573-1580
    CrossrefPubMedGoogle Scholar
  • 38 Chlebowski RT, Wactawski-Wende J, Ritenbaugh C , et al; Women's Health Initiative Investigators. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med 2004; 350 (10) 991-1004
    CrossrefPubMedGoogle Scholar
  • 39 Ritenbaugh C, Stanford JL, Wu L , et al; Women's Health Initiative Investigators. Conjugated equine estrogens and colorectal cancer incidence and survival: the Women's Health Initiative randomized clinical trial. Cancer Epidemiol Biomarkers Prev 2008; 17 (10) 2609-2618
    CrossrefPubMedGoogle Scholar
  • 40 Anderson GL, Judd HL, Kaunitz AM , et al; Women's Health Initiative Investigators. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA 2003; 290 (13) 1739-1748
    CrossrefPubMedGoogle Scholar
  • 41 Cauley JA, Robbins J, Chen Z , et al; Women's Health Initiative Investigators. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. JAMA 2003; 290 (13) 1729-1738
    CrossrefPubMedGoogle Scholar
  • 42 Jackson RD, Wactawski-Wende J, LaCroix AZ , et al; Women's Health Initiative Investigators. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the women's health initiative randomized trial. J Bone Miner Res 2006; 21 (6) 817-828
    CrossrefPubMedGoogle Scholar
  • 43 Bonds DE, Lasser N, Qi L , et al. The effect of conjugated equine oestrogen on diabetes incidence: the Women's Health Initiative randomised trial. Diabetologia 2006; 49 (3) 459-468
    CrossrefPubMedGoogle Scholar
  • 44 Margolis KL, Bonds DE, Rodabough RJ , et al; Women's Health Initiative Investigators. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women's Health Initiative Hormone Trial. Diabetologia 2004; 47 (7) 1175-1187
    PubMedGoogle Scholar
  • 45 Cirillo DJ, Wallace RB, Rodabough RJ , et al. Effect of estrogen therapy on gallbladder disease. JAMA 2005; 293 (3) 330-339
    CrossrefPubMedGoogle Scholar
  • 46 Hendrix SL, Cochrane BB, Nygaard IE , et al. Effects of estrogen with and without progestin on urinary incontinence. JAMA 2005; 293 (8) 935-948
    CrossrefPubMedGoogle Scholar
  • 47 Hsia J, Criqui MH, Rodabough RJ , et al; Women's Health Initiative Investigators. Estrogen plus progestin and the risk of peripheral arterial disease: the Women's Health Initiative. Circulation 2004; 109 (5) 620-626
    CrossrefPubMedGoogle Scholar
  • 48 Shumaker SA, Legault C, Kuller L , et al; Women's Health Initiative Memory Study. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA 2004; 291 (24) 2947-2958
    CrossrefPubMedGoogle Scholar
  • 49 Shumaker SA, Legault C, Rapp SR , et al; WHIMS Investigators. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003; 289 (20) 2651-2662
    CrossrefPubMedGoogle Scholar
  • 50 Manson JE, Chlebowski RT, Stefanick ML , et al. The Women's Health Initiative hormone therapy trials: Overview of health outcomes during the intervention and post-stopping phases. JAMA 2013; 310: 1353-1368
    CrossrefPubMedGoogle Scholar