BA4 - Proteomics and the Health Effects of Postmenopausal Hormone Therapy

This page provides study documentation for BA04.  For description of the specimen results, see Specimen Results Description (open to public). Data sets of the specimen results are included in the existing WHI datasets located on the WHI Data on this site (sign in and a completed Data Distribution Agreement are required; see details on the Data site).

Investigator Names and Contact Information

Ross Prentice, PhD, FHCRC,


This project builds upon the findings from the WHI hormone therapy randomized controlled trials.  E+P findings1 include an unexpected early elevation in CHD,2 a more sustained elevation in stroke,3 a later developing elevation in breast cancer,4 a reduction in colorectal cancer,5 and a reduction in hip fracture.6  For E-alone there was no overall effect on CHD,7 but evidence for an effect that differs from E+P.8  E-alone had an adverse effect on stroke and a benefit for hip fracture, each of a similar magnitude to that for E+P.7  In contrast there was no evidence for a colorectal cancer benefit from E-alone, while there was a surprising borderline significant evidence of a breast cancer benefit.9  For both breast and colorectal cancer, there was evidence of difference in effects (hazard ratios) between the two preparations.

To a large extent the important findings just summarized remain unexplained in relation to underlying biological processes and mechanisms.  Some insights are provided by a detailed study of interactions of treatment effects with known risk factors, as described in the papers already cited.  Efforts of this type continue, including analyses that combine the two trials to examine interactions of hormone therapy effects with age and years since menopause.  Additionally, WHI investigators have completed a substantial nested case-control study of carefully selected cardiovascular disease biomarkers, and companion biomarker case-control studies have been planned, or are being planned, for breast cancer, colorectal cancer, and hip fracture.  For example, the ‘CVD Biomarker Study’ (which Dr. Prentice helped to design) focused on plasma markers of inflammation, coagulation, lipids and lipoproteins, and on related DNA polymorphisms, including polymorphisms pertinent to hormone metabolism.  While these studies (yet to be reported) do include some useful leads (e.g., changes in some inflammatory markers from baseline to 1 year, and noteworthy changes in blood lipids and lipoproteins), they do not seem to provide much explanation for the early elevation in CHD with E+P, the sustained elevation in stroke with either E+P or E-alone, or into the reasons for differences in findings between E+P and E-alone in respect to CHD and venous thromboembolism.10,11
The principal aim of this project is:
1)   To develop a list of candidate proteins that contribute to elucidate the effects of combined conjugated equine estrogen plus medroxyprogesterone acetate (E+P) or conjugated equine estrogen alone (E-alone) on each of coronary heart disease (CHD), stroke, breast cancer, colorectal cancer, hip fracture, and candidate proteins to explain differences in such health effects between the two hormone therapy preparations.
Equally important additional aims include:
2)   To provide an assessment of the association between the concentrations of a large number (>1,000) of plasma proteins (including variants thereof that alter their chromatographic migration properties) and the risk of CHD, stroke, and (invasive) breast cancer over a subsequent 8-year average follow-up period, among postmenopausal women in the age range 50-79.
3)   To provide an early assessment of the potential of changes in the plasma proteome as a result of a preventive intervention, in conjunction with information on protein-disease risk information to usefully project intervention health benefits and risks.


1.    Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy post-menopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-333.
2.   Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, Trevisan M, Black HR, Heckbert SR, Detrano R, Strickland OL, Wong ND, Crouse JR, Stein E, Cushman M; Women’s Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523-534.
3.   Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G, Kooperberg C, Baird A, Kotchen T, Curb JD, Black H, Rossouw JE, Aragaki A, Safford M, Stein E, Laowattana S, Mysiw WJ; Women’s Health Initiative Investigators. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. JAMA 2003;289:2673-2684.
4.   Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovich H, McTiernan A; Women’s Health Initiative Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative randomized trial. JAMA 2003;289:3243-3253.
5.   Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, Hubbell FA, Ascensao J, Rodabough RJ, Rosenberg CA, Taylor VM, Harris R, Chen C, Adams-Campbell LL, White E; Women’s Health Initiative Investigators. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med 2004;350:991-1004.
6.   Cauley JA, Robbins J, Chen Z, Cummings SR, Jackson RD, LaCroix AZ, LeBoff M, Lewis CE, McGowan J, Neuner J, Pettinger M, Stefanick ML, Wactawski-Wende J, Watts NB; 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;290:1729-1738.
7.   Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J, Margolis K, Ockene J, O'Sullivan MJ, Phillips L, Prentice RL, Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefanick ML, Van Horn L, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S; 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;291:1701-1712.
8.   Hsia J, Langer RD, Manson JE, Kuller L, Johnson KC, Hendrix SL, Pettinger M, Heckbert SR, Greep N, Crawford S, Eaton CB, Kostis JB, Caralis P, Prentice R. Conjugated equine estrogens and coronary heart disease: the Women's Health Initiative. Arch Intern Med 2006;166:357-365.
9.   Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Roudabough RJ, Paskett ED, Lane DS, Hubbell FA, Assaf AR, Sarto GE, Schenken RS, Yasmeen S, Lessin L, Chelbowski RT; Women’s Health Initiative Investigators. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy.  In press, JAMA, 2006.
10.  Cushman M, Kuller LH, Prentice R, Rodabough RJ, Psaty BM, Stafford RS, Sidney S, Rosendaal FR; Women’s Health Initiative Investigators. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004;292:1573-1580.
11.  Curb D, Prentice R, Barnabei V, Bray P, Cyr M, Gass M, Langer R, Mattox J, Rodabough R, Sidney S, Van H. Hormone therapy and risk of venous thrombosis in the Women’s Health Initiative trial of estrogen alone in women without a uterus. In press, Arch Intern Med, 2006.



Some of the publications related to this ancillary study are: 1065.
For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Bibliography section of this website. To search for papers by study number, access the Simple Search, and enter the study number in the “Related Studies” field.