Estrogen plus progestin and risk of venous thrombosis
Open accessAbstract
CONTEXT: Postmenopausal hormone therapy increases the risk of venous thrombosis. It is not known whether other factors influencing thrombosis add to this risk. OBJECTIVE: To report final data on incidence of venous thrombosis in the Women's Health Initiative Estrogen Plus Progestin clinical trial and the association of hormone therapy with venous thrombosis in the setting of other thrombosis risk factors. DESIGN, SETTING, AND PARTICIPANTS: Double-blind randomized controlled trial of 16,608 postmenopausal women between the ages of 50 and 79 years, who were enrolled in 1993 through 1998 at 40 US clinical centers with 5.6 years of follow up; and a nested case-control study. Baseline gene variants related to thrombosis risk were measured in the first 147 women who developed thrombosis and in 513 controls. INTERVENTION: Random assignment to 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate, or placebo. MAIN OUTCOME MEASURES: Centrally validated deep vein thrombosis and pulmonary embolus. RESULTS: Venous thrombosis occurred in 167 women taking estrogen plus progestin (3.5 per 1000 person-years) and in 76 taking placebo (1.7 per 1000 person-years); hazard ratio (HR), 2.06 (95% confidence interval [CI], 1.57-2.70). Compared with women between the ages of 50 and 59 years who were taking placebo, the risk associated with hormone therapy was higher with age: HR of 4.28 (95% CI, 2.38-7.72) for women aged 60 to 69 years and 7.46 (95% CI, 4.32-14.38) for women aged 70 to 79 years. Compared with women who were of normal weight and taking placebo, the risk associated with taking estrogen plus progestin was increased among overweight and obese women: HR of 3.80 (95% CI, 2.08-6.94) and 5.61 (95% CI, 3.12-10.11), respectively. Factor V Leiden enhanced the hormone-associated risk of thrombosis with a 6.69-fold increased risk compared with women in the placebo group without the mutation (95% CI, 3.09-14.49). Other genetic variants (prothrombin 20210A, methylenetetrahydrofolate reductase C677T, factor XIII Val34Leu, PAI-1 4G/5G, and factor V HR2) did not modify the association of hormone therapy with venous thrombosis. CONCLUSIONS: Estrogen plus progestin was associated with doubling the risk of venous thrombosis. Estrogen plus progestin therapy increased the risks associated with age, overweight or obesity, and factor V Leiden.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Progestins with lowest possible androgenic action such as cyproterone acetate, chlormalidone, and drospirenone have been associated with increased risk of venous thrombosis.
“Ideally, a progestin with the lowest possible androgenic action such as cyproterone acetate, chlormalidone, and drospirenone should be used. However, they have been associated with increased risk of venous thrombosis [65,66,67].”
From Controversies in the Pathogenesis, Diagnosis and Treatment of PCOS: Focus on Insulin Resistance, Inflammation, and Hyperandrogenism (2022) · cites this paper as [66]
In the Women's Health Initiative study, the risk of VTE due to MHT was highest in the first year of therapy, but persisted for the five years of follow-up.
“In the Women’s Health Initiative (WHI) study, the risk of VTE due to MHT was highest in the first year of therapy, but persisted for the five years of follow-up [102].”
From Estrogen and thrombosis: a bench to bedside review (2020) · cites this paper as [102]
In the WHI trial, VTE risk was increased with a hazard ratio of 2.06 (95% CI 1.6-2.7), similar for both DVT and PE.
“In the trial, VTE risk was increased with HR of 2.06 (95% CI, 1.6–2.7), which was similar for both DVT and PE [102].”
From Estrogen and thrombosis: a bench to bedside review (2020) · cites this paper as [102]
Other genetic mutations did not affect the risk of VTE.
“Other genetic mutations did not affect the risk of VTE [102].”
From Estrogen and thrombosis: a bench to bedside review (2020) · cites this paper as [102]
The WHI trial showed a 6-fold increase in VTE (HR 6.7, 95% CI 3.1-14.5) in women with factor V Leiden mutation who were on combined hormone therapy.
“Furthermore, the trial showed a 6-fold increase in VTE (HR 6.7, 95% CI 3.1–14.5) in women with factor five leiden mutation (FVL) who were on CHC.”
From Estrogen and thrombosis: a bench to bedside review (2020) · cites this paper as [102]
The WHI trial showed a notably high risk of VTE in women with a prior thromboembolic event, with HR 3.9.
“The WHI trial showed a notably high risk of VTE in women with prior thromboembolic event, with HR of 3.9.”
From Estrogen and thrombosis: a bench to bedside review (2020) · cites this paper as [102]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Writing Group for the Women's Health Initiative Investigators (2002) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.288.3.321 · Cited by 15,889 · see citing works
Fisher, B., Costantino, J. P., Wickerham, D. L., Redmond, C. K., Kavanah, M. T., Cronin, W. M., Vogel, V. G., Robidoux, A., Dimitrov, N. S., Atkins, J. N., et al. (1998) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/90.18.1371 · Cited by 5,478 · see citing works
Design of the Women’s Health Initiative Clinical Trial and Observational Study
The Women’s Health Initiative Study Group (1998) · Controlled Clinical Trials · doi:10.1016/s0197-2456(97)00078-0 · Cited by 2,580 · see citing works
The Epidemiology of Venous Thromboembolism
White, R. H. R. (2003) · Circulation · doi:10.1161/01.cir.0000078468.11849.66 · Cited by 2,304 · see citing works
Estrogen plus Progestin and the Risk of Coronary Heart Disease
Manson, J. E., Hsia, J., Johnson, K. C., Rossouw, J. E., Assaf, A. R., Lasser, N. L., Trevisan, M., Black, H. R., Heckbert, S. R., Detrano, R., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa030808 · Cited by 2,065 · see citing works
Self-citationCardiovascular Disease Outcomes During 6.8 Years of Hormone Therapy
Grady, D. G., Herrington, D. M., Bittner, V., Blumenthal, R. S., Davidson, M., Hlatky, M. A., Hsia, J. A., Hulley, S. B., Herd, A. J., Khan, S. S., et al. (2002) · JAMA · doi:10.1001/jama.288.1.49 · Cited by 1,926 · see citing works
Chlebowski, R. T., Hendrix, S. L., Langer, R. D., Stefanick, M. L., Gass, M. L. S., Lane, D. S., Rodabough, R. J., Gilligan, M. A., Cyr, M. G., Thomson, C. A., et al. (2003) · JAMA · doi:10.1001/jama.289.24.3243 · Cited by 1,871 · see citing works
Effect of Estrogen Plus Progestin on Stroke in Postmenopausal Women
Wassertheil-Smoller, S. W., Hendrix, S. L., Limacher, M. C., HEISS, G. M., Kooperberg, C. L., Baird, A. E., Kotchen, T. A., Curb, J. D., Black, H. R., Rossouw, J. E., et al. (2003) · JAMA · doi:10.1001/jama.289.20.2673 · Cited by 1,159 · see citing works
Pulmonary Embolism Prevention (PEP) trial Collaborative Group (2000) · The Lancet · doi:10.1016/s0140-6736(00)02110-3 · Cited by 1,076 · see citing works
Risk of venous thromboembolism in users of hormone replacement therapy
Daly, E., Vessey, M. P., Hawkins, M. M., Carson, J. L., Gough, P., & Marsh, S. (1996) · The Lancet · doi:10.1016/s0140-6736(96)07113-9 · Cited by 811 · see citing works
Cuzick, J. M., Lennard, T., & Working Party and Principal Investigators IBIS (2002) · The Lancet · doi:10.1016/s0140-6736(02)09962-2 · Cited by 745 · see citing works
Grady, D. G., WENGER, N. K., Herrington, D. M., Khan, S. S., Furberg, C. D., Hunninghake, D. B., Vittinghoff, E., & Hulley, S. B. (2000) · Annals of Internal Medicine · doi:10.7326/0003-4819-132-9-200005020-00002 · Cited by 712 · see citing works
Scarabin, P., Oger, E., & Plu‐Bureau, G. (2003) · The Lancet · doi:10.1016/s0140-6736(03)14066-4 · Cited by 704 · see citing works
Outcomes ascertainment and adjudication methods in the women's health initiative
Curb, J. D., McTiernan, A., Heckbert, S. R., Kooperberg, C. L., Stanford, J. L., Nevitt, M. C., Johnson, K., Proulx-Burns, L., Pastore, L. M., Criqui, M. H., et al. (2003) · Annals of Epidemiology · doi:10.1016/s1047-2797(03)00048-6 · Cited by 700 · see citing works
Cardiovascular Risk Factors and Venous Thromboembolism Incidence
Tsai, A. W., Cushman, M., Rosamond, W. D., Heckbert, S. R., Polak, J. F., & Folsom, A. R. (2002) · Archives of Internal Medicine · doi:10.1001/archinte.162.10.1182 · Cited by 699 · see citing works
Self-citationAn Epidemiologic Study of Risk Factors for Deep Vein Thrombosis in Medical Outpatients
Samama, M.-M. (2000) · Archives of Internal Medicine · doi:10.1001/archinte.160.22.3415 · Cited by 697 · see citing works
Jick, H., Derby, L. E., Myers, M. W., Vasilakis‐Scaramozza, C., & Newton, K. M. (1996) · The Lancet · doi:10.1016/s0140-6736(96)07114-0 · Cited by 598 · see citing works
Hulley, S. B. (2002) · JAMA · Cited by 577 · see citing works
Prospective study of exogenous hormones and risk of pulmonary embolism in women
Grodstein, F., Stampfer, M. J., Goldhaber, S. Z., Manson, J. E., Colditz, G. A., Speizer, F. E., Willett, W. C., & Hennekens, C. H. (1996) · The Lancet · doi:10.1016/s0140-6736(96)07308-4 · Cited by 570 · see citing works
(1994) · Europe PMC (PubMed Central) · Cited by 563 · see citing works
Abdollahi, M., Cushman, M., & Rosendaal, F. R. (2003) · Thrombosis and Haemostasis · doi:10.1055/s-0037-1613379 · Cited by 444 · see citing works
Self-citationHulley, S. B., Furberg, C. D., & Barrett-Connor, E. L. (2002) · ACC Current Journal Review · doi:10.1016/s1062-1458(02)00920-0 · Cited by 339 · see citing works
Hormone replacement therapy and risk of venous thromboembolism: population based case-control study
Perez‐Gutthann, S., Rodriguez, L. A. G., Castellsagué, J., & Oliart, A. D. (1997) · BMJ · doi:10.1136/bmj.314.7083.796 · Cited by 336 · see citing works
Female Hormones and Thrombosis
Rosendaal, F. R., Helmerhorst, F. M., & Vandenbroucke, J. P. (2002) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/hq0202.102318 · Cited by 267 · see citing works
Høibraaten, E., Qvigstad, E., Arnesen, H., Larsen, S. U., Wickström, E., & Sandset, P. (2000) · PubMed · Cited by 264 · see citing works
(2003) · Obstetrics and Gynecology · doi:10.1097/00006250-200301000-00034 · Cited by 251 · see citing works
The Women's Health Initiative Steering Committee (2004) · ACC Current Journal Review · doi:10.1016/j.accreview.2004.06.061 · Cited by 220 · see citing works
Use of Statins and the Subsequent Development of Deep Vein Thrombosis
Ray, J. G., Mamdani, M., Tsuyuki, R. T., Anderson, D. R., Yeo, E. L., & Laupacis, A. (2001) · Archives of Internal Medicine · doi:10.1001/archinte.161.11.1405 · Cited by 206 · see citing works
Middeldorp, S., Meinardi, J. R., Koopman, M. M. W., Pampus, E. C. M. V., Hamulyák, K., van der Meer, J., Prins, M. H., & Buller, H. R. (2001) · Annals of Internal Medicine · doi:10.7326/0003-4819-135-5-200109040-00008 · Cited by 196 · see citing works
Interaction as departure from additivity in case-control studies: a cautionary note
Skrondal, A. (2003) · American Journal of Epidemiology · doi:10.1093/aje/kwg113 · Cited by 180 · see citing works
Herrington, D. M., Vittinghoff, E., Howard, T. D., Major, D. A., Owen, J. D., Reboussin, D. M., Bowden, D. W., Bittner, V., Simon, J. A., Grady, D. G., et al. (2002) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000018301.91721.94 · Cited by 154 · see citing works
Hormonal replacement therapy, prothrombotic mutations and the risk of venous thrombosis
Rosendaal, F. R., Vessey, M. P., Rumley, A., Daly, E., Woodward, M., Helmerhorst, F. M., & Lowe, G. D. O. (2002) · British Journal of Haematology · doi:10.1046/j.0007-1048.2002.03356.x · Cited by 153 · see citing works
Varas‐Lorenzo, C., guez, L. A. G. A. R., Cattaruzzi, C., Troncon, M. G., Agostinis, L., & Perez‐Gutthann, S. (1998) · American Journal of Epidemiology · doi:10.1093/oxfordjournals.aje.a009461 · Cited by 145 · see citing works
Hulley, S. B., Furberg, C. D., Barrett-Connor, E. L., Cauley, J. A., Grady, D. G., Haskell, W. L., Knopp, R. H., Lowery, M. H., Satterfield, S., Schrott, H. G., et al. (2002) · Obstetrical & Gynecological Survey · doi:10.1097/00006254-200210000-00021 · Cited by 121 · see citing works
Chlebowski, R. T., Hendrix, S. L., Langer, R. D., Stefanick, M. L., Gass, M. L. S., Lane, D. S., Rodabough, R. J., Gilligan, M. A., Cyr, M. G., Thomson, C. A., et al. (2003) · Obstetrical & Gynecological Survey · doi:10.1097/01.ogx.0000093674.44946.d6 · Cited by 119 · see citing works
Hormone Replacement Therapy with Estradiol and Risk of Venous Thromboembolism
Abdelnoor, M., Sandset, P. M., & Høibraaten, E. (1999) · Thrombosis and Haemostasis · doi:10.1055/s-0037-1614363 · Cited by 105 · see citing works
Risk of Venous Thromboembolism in Users of Hormone Replacement Therapy
Daly, E., Vessey, M. P., Hawkins, M. M., Carson, J. L., Gough, P., & Marsh, S. (1997) · Obstetrical & Gynecological Survey · doi:10.1097/00006254-199705000-00020 · Cited by 91 · see citing works
Estrogen plus progestin and the risk of coronary heart disease
Manson, J. E., Hsia, J., & Johnson, K. C. (2003) · ACC Current Journal Review · doi:10.1016/j.accreview.2003.09.012 · Cited by 87 · see citing works
HMG CoA reductase inhibitors and the risk of venous thrombosis among postmenopausal women
Doggen, C. J. M., Lemaître, R. N., Smith, N. L., Heckbert, S. R., & Psaty, B. M. (2004) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2004.00696.x · Cited by 78 · see citing works
Pistorius, M.-A. (2008) · Cited by 52 · see citing works
Wassertheil-Smoller, S. W., Hendrix, S. L., Limacher, M. C., et al. (2003) · Obstetrical & Gynecological Survey · doi:10.1097/01.ogx.0000093671.39203.32 · Cited by 52 · see citing works
University of California, Irvine
(1979) · Neurosurgery · doi:10.1227/00006123-197907010-00032 · Cited by 10 · see citing works
Oger, E., & Scarabin, P. (1999) · American Journal of Epidemiology · doi:10.1093/oxfordjournals.aje.a009808 · Cited by 5 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Epidemiology of venous thromboembolism
Heit, J. A. (2015) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2015.83 · Cited by 1,277 · see citing works
Treatment of symptoms of the menopause: an Endocrine Society Clinical Practice Guideline
Stuenkel, C. A., Davis, S. R., Gompel, A., Lumsden, M. A., Murad, M. H., Pinkerton, J. V., & Santen, R. J. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-2236 · Cited by 884 · see citing works
Hormone therapy for preventing cardiovascular disease in post-menopausal women
Boardman, H. M., Hartley, L., Eisinga, A., Main, C., Roqué i Figuls, M., Bonfill Cosp, X., Gabriel Sanchez, R., & Knight, B. (2015) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd002229.pub4 · Cited by 612 · see citing works
Canonico, M., Plu-Bureau, G., Lowe, G. D. O., & Scarabin, P.-Y. (2008) · BMJ · doi:10.1136/bmj.39555.441944.be · Cited by 569 · see citing works
Armanini, D., Boscaro, M., Bordin, L., & Sabbadin, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23084110 · Cited by 324 · see citing works
Estrogen and thrombosis: a bench to bedside review
Abou-Ismail, M. Y., Citla Sridhar, D., & Nayak, L. (2020) · Thrombosis Research · doi:10.1016/j.thromres.2020.05.008 · Cited by 261 · see citing works
Henriksson, P., Westerlund, E., Wallen, H., Brandt, L., Hovatta, O., & Ekbom, A. (2013) · BMJ · doi:10.1136/bmj.e8632 · Cited by 180 · see citing works
Cosman, F., Baz-Hecht, M., Cushman, M., Vardy, M. D., Cruz, J. D., Nieves, J. W., Zion, M., & Lindsay, R. (2005) · Thrombosis Research · doi:10.1016/j.thromres.2004.09.014 · Cited by 98 · see citing works
Self-citationBergendal, A., Kieler, H., Sundström, A., Hirschberg, A. L., & Kocoska-Maras, L. (2016) · Menopause · doi:10.1097/gme.0000000000000611 · Cited by 90 · see citing works
ASMBS position statement on preoperative patient optimization before metabolic and bariatric surgery
Carter, J., Chang, J., Birriel, T. J., Moustarah, F., Sogg, S., Goodpaster, K., Benson-Davies, S., Chapmon, K., & Eisenberg, D. (2021) · Surgery for Obesity and Related Diseases · doi:10.1016/j.soard.2021.08.024 · Cited by 86 · see citing works
Collins, P., Rosano, G., Casey, C., Daly, C., Gambacciani, M., Hadji, P., Kaaja, R., Mikkola, T., Palacios, S., Preston, R., et al. (2007) · Climacteric · doi:10.1080/13697130701755213 · Cited by 67 · see citing works
Vandenbroucke, J., & Pearce, N. (2015) · American Journal of Epidemiology · doi:10.1093/aje/kwv225 · Cited by 67 · see citing works
Ischemic enterocolitis and its differential diagnosis
Uberti, G., Goldblum, J. R., & Allende, D. S. (2014) · Seminars in Diagnostic Pathology · doi:10.1053/j.semdp.2014.02.001 · Cited by 18 · see citing works
- Authors
- Cushman, M.
- Affiliations
- University of Vermont (US)
- Corresponding author
- Cushman, Mary
- ORCID
- Cushman, Mary
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2004-10-06
- Volume
- 292
- Issue
- 13
- Pages
- 1573
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W2126595069
- Cited by
- 632
- References
- 46
- Citations by year
- 2026: 18 · 2025: 22 · 2024: 22 · 2023: 19 · 2022: 25 · 2021: 21 · 2020: 23 · 2019: 16 · 2018: 20 · 2017: 20 · 2016: 19 · 2015: 26 · 2014: 26 · 2013: 42 · 2012: 29
- FWCI
- 28.52
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Leiden Repository (Leiden University) (submittedVersion, other-oa)
- Leiden Repository (Leiden University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Women's Health Initiative
- Brigham and Women's Hospital
- Kaiser Permanente
- Brown University
- University of Miami
- Wayne State University
- Ohio State University
- Emory University
- Northwestern University
- George Washington University
- Wake Forest University
- University of Minnesota
- University of Washington
- University of Pittsburgh
- University of Cincinnati
- University of Nevada, Reno
- University of California, Los Angeles
- University of North Carolina at Chapel Hill
- University of California, San Francisco
- National Heart, Lung, and Blood Institute
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Health Sciences › Medicine › Internal Medicine › Venous Thromboembolism Diagnosis and Management
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- venous thrombosis, estrogen plus progestin, hormone replacement therapy, deep vein thrombosis, pulmonary embolism, medroxyprogesterone acetate, conjugated equine estrogens, thrombosis risk factors, factor V Leiden, obesity, age, Women's Health Initiative, risk stratification, thromboprophylaxis
- MeSH terms
- Age Factors, Aged, Blood Coagulation Factors, Double-Blind Method, Estrogens, Conjugated (USP), Factor V, Female, Follow-Up Studies, Humans, Middle Aged, Obesity, Risk, Estrogen Replacement Therapy, Body Mass Index, Incidence, Proportional Hazards Models, Case-Control Studies, Medroxyprogesterone Acetate, Postmenopause, Venous Thrombosis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
