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Home / Equine Research Bank / JAMA / Esterified estrogens and conjugated equine estrogens and the...
JAMA2004; 292(13); 1581-1587; doi: 10.1001/jama.292.13.1581

Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis.

Abstract: Clinical trial evidence indicates that estrogen therapy with or without progestins increases venous thrombotic risk. The findings from these trials, which used oral conjugated equine estrogens, may not be generalizable to other estrogen compounds. Objective: To compare risk of venous thrombosis among esterified estrogen users, conjugated equine estrogen users, and nonusers. Methods: This population-based, case-control study was conducted at a large health maintenance organization in Washington State. Cases were perimenopausal and postmenopausal women aged 30 to 89 years who sustained a first venous thrombosis between January 1995 and December 2001 and controls were matched on age, hypertension status, and calendar year. Methods: Risk of first venous thrombosis in relation to current use of esterified or conjugated equine estrogens, with or without concomitant progestin. Current use was defined as use at thrombotic event for cases and a comparable reference date for controls. Results: Five hundred eighty-six incident venous thrombosis cases and 2268 controls were identified. Compared with women not currently using hormones, current users of esterified estrogen had no increase in venous thrombotic risk (odds ratio [OR], 0.92; 95% confidence interval [CI], 0.69-1.22). In contrast, women currently taking conjugated equine estrogen had an elevated risk (OR, 1.65; 95% CI, 1.24-2.19). When analyses were restricted to estrogen users, current users of conjugated equine estrogen had a higher risk than current users of esterified estrogen (OR, 1.78; 95% CI, 1.11-2.84). Among conjugated equine estrogen users, increasing daily dose was associated with increased risk (trend P value = .02). Among all estrogen users, concomitant progestin use was associated with increased risk compared with use of estrogen alone (OR, 1.60; 95% CI, 1.13-2.26). Conclusions: Our finding that conjugated equine estrogen but not esterified estrogen was associated with venous thrombotic risk needs to be replicated and may have implications for the choice of hormones in perimenopausal and postmenopausal women.
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Publication Date: 2004-10-07 PubMed ID: 15467060DOI: 10.1001/jama.292.13.1581Google Scholar: Lookup
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  • Comparative Study
  • Journal Article
  • Research Support
  • U.S. Gov't
  • P.H.S.

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research article investigates the risk of venous thrombosis among users of esterified estrogen, conjugated equine estrogen, and nonusers. Findings indicate that conjugated equine estrogen users have a higher risk of venous thrombotic risk compared to esterified estrogen users, suggesting important considerations for the choice of hormones in perimenopausal and postmenopausal women.

Objectives of the Study

  • The article’s primary objective was to explore the risk of venous thrombosis among users of esterified estrogen, conjugated equine estrogen, and nonusers.
  • The research aimed to determine whether all types of estrogen therapies bring the same level of risk of venous thrombosis, or if some are safer than others.

Methodology

  • This was a population-based, case-control study conducted at a large health maintenance organization in Washington State.
  • The subjects of the study were perimenopausal and postmenopausal women aged 30-89 who had their first venous thrombosis between January 1995 and December 2001.
  • The controls were women matched on age, hypertension status, and the calendar year.
  • Risks were calculated in relation to current use of either esterified or conjugated equine estrogens, with or without progestins.
  • Current use was defined as use at the time of the thrombotic event for cases and a comparable reference date for controls.

Results

  • The study identified 586 incident venous thrombosis cases and 2268 controls.
  • Compared to non-users, current users of esterified estrogen showed no increased in venous thrombotic risk.
  • In contrast, women currently on conjugated equine estrogen had a higher risk.
  • Among conjugated equine estrogen users, increasing the daily dosage escalated the risk.
  • For all estrogen users, the risk was even higher for those who also used progestin.

Conclusions

  • The researchers concluded that only conjugated equine estrogen was associated with a heightened risk of venous thrombosis, and not esterified estrogen.
  • The study highlights the need for further research to confirm these findings and the necessity of considering them when choosing hormones for perimenopausal and postmenopausal women.

Cite This Article

APA
Smith NL, Heckbert SR, Lemaitre RN, Reiner AP, Lumley T, Weiss NS, Larson EB, Rosendaal FR, Psaty BM. (2004). Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis. JAMA, 292(13), 1581-1587. https://doi.org/10.1001/jama.292.13.1581

Publication

JAMA
ISSN: 1538-3598
NlmUniqueID: 7501160
Country: United States
Language: English
Volume: 292
Issue: 13
Pages: 1581-1587

Researcher Affiliations

Smith, Nicholas L
  • Department of Epidemiology, University of Washington, Seattle, USA. nlsmith@u.washington.edu
Heckbert, Susan R
    Lemaitre, Rozenn N
      Reiner, Alex P
        Lumley, Thomas
          Weiss, Noel S
            Larson, Eric B
              Rosendaal, Frits R
                Psaty, Bruce M

                  MeSH Terms

                  • Adult
                  • Aged
                  • Aged, 80 and over
                  • Case-Control Studies
                  • Climacteric
                  • Estrogen Replacement Therapy / adverse effects
                  • Estrogens, Conjugated (USP) / adverse effects
                  • Estrogens, Conjugated (USP) / therapeutic use
                  • Estrogens, Esterified (USP) / adverse effects
                  • Estrogens, Esterified (USP) / therapeutic use
                  • Female
                  • Humans
                  • Logistic Models
                  • Middle Aged
                  • Postmenopause
                  • Progestins / therapeutic use
                  • Risk
                  • Venous Thrombosis / epidemiology
                  • Venous Thrombosis / etiology

                  Grant Funding

                  • AG09556 / NIA NIH HHS
                  • HL43201 / NHLBI NIH HHS
                  • HL60739 / NHLBI NIH HHS
                  • HL68639 / NHLBI NIH HHS
                  • HL68986 / NHLBI NIH HHS
                  • HL73410 / NHLBI NIH HHS
                  • HL74745 / NHLBI NIH HHS

                  Citations

                  This article has been cited 45 times.
                  1. Weller SC, Davis JW, Porterfield L, Chen L, Wilkinson G. Hormone exposure and venous thromboembolism in commercially insured women aged 50 to 64 years. Res Pract Thromb Haemost 2023 Mar;7(3):100135.
                    doi: 10.1016/j.rpth.2023.100135pubmed: 37193125google scholar: lookup
                  2. Thibord F, Klarin D, Brody JA, Chen MH, Levin MG, Chasman DI, Goode EL, Hveem K, Teder-Laving M, Martinez-Perez A, Aïssi D, Daian-Bacq D, Ito K, Natarajan P, Lutsey PL, Nadkarni GN, de Vries PS, Cuellar-Partida G, Wolford BN, Pattee JW, Kooperberg C, Braekkan SK, Li-Gao R, Saut N, Sept C, Germain M, Judy RL, Wiggins KL, Ko D, O'Donnell CJ, Taylor KD, Giulianini F, De Andrade M, Nøst TH, Boland A, Empana JP, Koyama S, Gilliland T, Do R, Huffman JE, Wang X, Zhou W, Manuel Soria J, Carlos Souto J, Pankratz N, Haessler J, Hindberg K, Rosendaal FR, Turman C, Olaso R, Kember RL, Bartz TM, Lynch JA, Heckbert SR, Armasu SM, Brumpton B, Smadja DM, Jouven X, Komuro I, Clapham KR, Loos RJF, Willer CJ, Sabater-Lleal M, Pankow JS, Reiner AP, Morelli VM, Ridker PM, Vlieg AVH, Deleuze JF, Kraft P, Rader DJ, Min Lee K, Psaty BM, Heidi Skogholt A, Emmerich J, Suchon P, Rich SS, Vy HMT, Tang W, Jackson RD, Hansen JB, Morange PE, Kabrhel C, Trégouët DA, Damrauer SM, Johnson AD, Smith NL. Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors. Circulation 2022 Oct 18;146(16):1225-1242.
                    doi: 10.1161/CIRCULATIONAHA.122.059675pubmed: 36154123google scholar: lookup
                  3. Lidstrom SC, Wiggins KL, Harrington LB, McKnight B, Blondon M, Smith NL. Incident thrombus location and predicting risk of recurrent venous thromboembolism. Res Pract Thromb Haemost 2022 Jul;6(5):e12762.
                    doi: 10.1002/rth2.12762pubmed: 35910943google scholar: lookup
                  4. Blondon M, Timmons AK, Baraff AJ, Floyd JS, Harrington LB, Korpak AM, Smith NL. Comparative venous thromboembolic safety of oral and transdermal postmenopausal hormone therapies among women Veterans. Menopause 2021 Jul 26;28(10):1125-1129.
                    doi: 10.1097/GME.0000000000001823pubmed: 34313612google scholar: lookup
                  5. Edimo CO, Wajsberg JR, Wong S, Nahmias ZP, Riley BA. The dermatological aspects of hEDS in women. Int J Womens Dermatol 2021 Jun;7(3):285-289.
                    doi: 10.1016/j.ijwd.2021.01.020pubmed: 34222585google scholar: lookup
                  6. Sammaritano LR. Which Hormones and Contraception for Women with APS? Exogenous Hormone Use in Women with APS. Curr Rheumatol Rep 2021 Apr 30;23(6):44.
                    doi: 10.1007/s11926-021-01006-wpubmed: 33939022google scholar: lookup
                  7. Villa P, Amar ID, Shachor M, Cipolla C, Ingravalle F, Scambia G. Cardiovascular Risk/Benefit Profile of MHT. Medicina (Kaunas) 2019 Sep 6;55(9).
                    doi: 10.3390/medicina55090571pubmed: 31500138google scholar: lookup
                  8. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ 2019 Jan 9;364:k4810.
                    doi: 10.1136/bmj.k4810pubmed: 30626577google scholar: lookup
                  9. Levin VA, Jiang X, Kagan R. Estrogen therapy for osteoporosis in the modern era. Osteoporos Int 2018 May;29(5):1049-1055.
                    doi: 10.1007/s00198-018-4414-zpubmed: 29520604google scholar: lookup
                  10. Ko JKY, King TFJ, Williams L, Creighton SM, Conway GS. Hormone replacement treatment choices in complete androgen insensitivity syndrome: an audit of an adult clinic. Endocr Connect 2017 Aug;6(6):375-379.
                    doi: 10.1530/EC-17-0083pubmed: 28615185google scholar: lookup
                  11. Gialeraki A, Valsami S, Pittaras T, Panayiotakopoulos G, Politou M. Oral Contraceptives and HRT Risk of Thrombosis. Clin Appl Thromb Hemost 2018 Mar;24(2):217-225.
                    doi: 10.1177/1076029616683802pubmed: 28049361google scholar: lookup
                  12. Harrington LB, Marck BT, Wiggins KL, McKnight B, Heckbert SR, Woods NF, LaCroix AZ, Blondon M, Psaty BM, Rosendaal FR, Matsumoto AM, Smith NL. Cross-sectional association of endogenous steroid hormone, sex hormone-binding globulin, and precursor steroid levels with hemostatic factor levels in postmenopausal women. J Thromb Haemost 2017 Jan;15(1):80-90.
                    doi: 10.1111/jth.13554pubmed: 27797446google scholar: lookup
                  13. Heit JA, Spencer FA, White RH. The epidemiology of venous thromboembolism. J Thromb Thrombolysis 2016 Jan;41(1):3-14.
                    doi: 10.1007/s11239-015-1311-6pubmed: 26780736google scholar: lookup
                  14. Harrington LB, Weiss NS, Wiggins KL, Heckbert SR, McKnight B, Blondon M, Woods NF, LaCroix AZ, Psaty BM, Smith NL. Prior hysterectomy and oophorectomy and incident venous thrombosis risk among postmenopausal women: a population-based, case-control study. Menopause 2016 Feb;23(2):143-9.
                    doi: 10.1097/GME.0000000000000591pubmed: 26757272google scholar: lookup
                  15. Harrington LB, Wiggins KL, Sitlani CM, Blondon M, van Hylckama Vlieg A, Rosendaal FR, Heckbert SR, Psaty BM, Smith NL. The association of F11 genetic variants with the risk of incident venous thrombosis among women, by statin use. Thromb Haemost 2016 Mar;115(3):682-4.
                    doi: 10.1160/TH15-08-0683pubmed: 26631918google scholar: lookup
                  16. Chubak J, Bowles EJ, Yu O, Buist DS, Fujii M, Boudreau DM. Breast cancer recurrence in relation to antidepressant use. Cancer Causes Control 2016 Jan;27(1):125-36.
                    doi: 10.1007/s10552-015-0689-ypubmed: 26518198google scholar: lookup
                  17. Baratloo A, Safari S, Rouhipour A, Hashemi B, Rahmati F, Motamedi M, Forouzanfar M, Haroutunian P. The Risk of Venous Thromboembolism with Different Generation of Oral Contraceptives; a Systematic Review and Meta-Analysis. Emerg (Tehran) 2014 Winter;2(1):1-11.
                    pubmed: 26495334
                  18. Bińkowska M. Menopausal hormone therapy and venous thromboembolism. Prz Menopauzalny 2014 Oct;13(5):267-72.
                    doi: 10.5114/pm.2014.46468pubmed: 26327865google scholar: lookup
                  19. Heit JA. Epidemiology of venous thromboembolism. Nat Rev Cardiol 2015 Aug;12(8):464-74.
                    doi: 10.1038/nrcardio.2015.83pubmed: 26076949google scholar: lookup
                  20. Lundin JI, Ton TG, LaCroix AZ, Longstreth WT, Franklin GM, Swanson PD, Smith-Weller T, Racette BA, Checkoway H. Formulations of hormone therapy and risk of Parkinson's disease. Mov Disord 2014 Nov;29(13):1631-6.
                    doi: 10.1002/mds.26037pubmed: 25255692google scholar: lookup
                  21. Rott H. Prevention and treatment of venous thromboembolism during HRT: current perspectives. Int J Gen Med 2014;7:433-40.
                    doi: 10.2147/IJGM.S46310pubmed: 25210472google scholar: lookup
                  22. Khalil RA. Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease. Biochem Pharmacol 2013 Dec 15;86(12):1627-42.
                    doi: 10.1016/j.bcp.2013.09.024pubmed: 24099797google scholar: lookup
                  23. Smith NL, Blondon M, Wiggins KL, Harrington LB, van Hylckama Vlieg A, Floyd JS, Hwang M, Bis JC, McKnight B, Rice KM, Lumley T, Rosendaal FR, Heckbert SR, Psaty BM. Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens. JAMA Intern Med 2014 Jan;174(1):25-31.
                    doi: 10.1001/jamainternmed.2013.11074pubmed: 24081194google scholar: lookup
                  24. Westra HJ, Peters MJ, Esko T, Yaghootkar H, Schurmann C, Kettunen J, Christiansen MW, Fairfax BP, Schramm K, Powell JE, Zhernakova A, Zhernakova DV, Veldink JH, Van den Berg LH, Karjalainen J, Withoff S, Uitterlinden AG, Hofman A, Rivadeneira F, Hoen PAC', Reinmaa E, Fischer K, Nelis M, Milani L, Melzer D, Ferrucci L, Singleton AB, Hernandez DG, Nalls MA, Homuth G, Nauck M, Radke D, Völker U, Perola M, Salomaa V, Brody J, Suchy-Dicey A, Gharib SA, Enquobahrie DA, Lumley T, Montgomery GW, Makino S, Prokisch H, Herder C, Roden M, Grallert H, Meitinger T, Strauch K, Li Y, Jansen RC, Visscher PM, Knight JC, Psaty BM, Ripatti S, Teumer A, Frayling TM, Metspalu A, van Meurs JBJ, Franke L. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet 2013 Oct;45(10):1238-1243.
                    doi: 10.1038/ng.2756pubmed: 24013639google scholar: lookup
                  25. Blondon M, Wiggins KL, Van Hylckama Vlieg A, McKnight B, Psaty BM, Rice KM, Heckbert SR, Smith NL. Smoking, postmenopausal hormone therapy and the risk of venous thrombosis: a population-based, case-control study. Br J Haematol 2013 Nov;163(3):418-20.
                    doi: 10.1111/bjh.12508pubmed: 23927442google scholar: lookup
                  26. Canonico M, Plu-Bureau G, O'Sullivan MJ, Stefanick ML, Cochrane B, Scarabin PY, Manson JE. Age at menopause, reproductive history, and venous thromboembolism risk among postmenopausal women: the Women's Health Initiative Hormone Therapy clinical trials. Menopause 2014 Mar;21(3):214-20.
                    doi: 10.1097/GME.0b013e31829752e0pubmed: 23760439google scholar: lookup
                  27. Blondon M, Wiggins KL, Harrington LB, Psaty BM, Smith NL. Lack of strong effect modification by NFE2L2/CYP3A5/ABO of the risk of venous thrombosis associated with oral hormone therapy. J Thromb Haemost 2013 Aug;11(8):1617-9.
                    doi: 10.1111/jth.12309pubmed: 23734777google scholar: lookup
                  28. Blondon M, Wiggins KL, McKnight B, Psaty BM, Rice KM, Heckbert SR, Smith NL. The association of smoking with venous thrombosis in women. A population-based, case-control study. Thromb Haemost 2013 May;109(5):891-6.
                    doi: 10.1160/TH12-10-0732pubmed: 23467568google scholar: lookup
                  29. Reslan OM, Khalil RA. Vascular effects of estrogenic menopausal hormone therapy. Rev Recent Clin Trials 2012 Feb;7(1):47-70.
                    doi: 10.2174/157488712799363253pubmed: 21864249google scholar: lookup
                  30. Hippisley-Cox J, Coupland C. Development and validation of risk prediction algorithm (QThrombosis) to estimate future risk of venous thromboembolism: prospective cohort study. BMJ 2011 Aug 16;343:d4656.
                    doi: 10.1136/bmj.d4656pubmed: 21846713google scholar: lookup
                  31. Smith NL, Rice KM, Bovill EG, Cushman M, Bis JC, McKnight B, Lumley T, Glazer NL, van Hylckama Vlieg A, Tang W, Dehghan A, Strachan DP, O'Donnell CJ, Rotter JI, Heckbert SR, Psaty BM, Rosendaal FR. Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis. Blood 2011 Jun 2;117(22):6007-11.
                    doi: 10.1182/blood-2010-10-315473pubmed: 21163921google scholar: lookup
                  32. Barsoum MK, Heit JA, Ashrani AA, Leibson CL, Petterson TM, Bailey KR. Is progestin an independent risk factor for incident venous thromboembolism? A population-based case-control study. Thromb Res 2010 Nov;126(5):373-8.
                    doi: 10.1016/j.thromres.2010.08.010pubmed: 20833412google scholar: lookup
                  33. Dublin S, Glazer NL, Smith NL, Psaty BM, Lumley T, Wiggins KL, Page RL, Heckbert SR. Diabetes mellitus, glycemic control, and risk of atrial fibrillation. J Gen Intern Med 2010 Aug;25(8):853-8.
                    doi: 10.1007/s11606-010-1340-ypubmed: 20405332google scholar: lookup
                  34. Heckbert SR, Wiggins KL, Glazer NL, Dublin S, Psaty BM, Smith NL, Longstreth WT Jr, Lumley T. Antihypertensive treatment with ACE inhibitors or beta-blockers and risk of incident atrial fibrillation in a general hypertensive population. Am J Hypertens 2009 May;22(5):538-44.
                    doi: 10.1038/ajh.2009.33pubmed: 19265792google scholar: lookup
                  35. Lamon-Fava S, Herrington DM, Reboussin DM, Sherman M, Horvath K, Schaefer EJ, Asztalos BF. Changes in remnant and high-density lipoproteins associated with hormone therapy and progression of coronary artery disease in postmenopausal women. Atherosclerosis 2009 Jul;205(1):325-30.
                    doi: 10.1016/j.atherosclerosis.2008.12.020pubmed: 19155011google scholar: lookup
                  36. Wiggins KL, Smith NL, Glazer NL, Rosendaal FR, Heckbert SR, Psaty BM, Rice KM, Lumley T. ABO genotype and risk of thrombotic events and hemorrhagic stroke. J Thromb Haemost 2009 Feb;7(2):263-9.
                    doi: 10.1111/j.1538-7836.2008.03243.xpubmed: 19036074google scholar: lookup
                  37. Utian WH, Archer DF, Bachmann GA, Gallagher C, Grodstein Fn, Heiman JR, Henderson VW, Hodis HN, Karas RH, Lobo RA, Manson JE, Reid RL, Schmidt PJ, Stuenkel CA. Estrogen and progestogen use in postmenopausal women: July 2008 position statement of The North American Menopause Society. Menopause 2008 Jul-Aug;15(4 Pt 1):584-602.
                    doi: 10.1097/gme.0b013e31817b076apubmed: 18580541google scholar: lookup
                  38. Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol 2008 Mar;28(3):370-2.
                    doi: 10.1161/ATVBAHA.108.162545pubmed: 18296591google scholar: lookup
                  39. Chubak J, Buist DS, Boudreau DM, Rossing MA, Lumley T, Weiss NS. Breast cancer recurrence risk in relation to antidepressant use after diagnosis. Breast Cancer Res Treat 2008 Nov;112(1):123-32.
                    doi: 10.1007/s10549-007-9828-9pubmed: 18058227google scholar: lookup
                  40. Notelovitz M. Clinical opinion: the biologic and pharmacologic principles for age-adjusted long-term estrogen therapy. MedGenMed 2006 Mar 28;8(1):84.
                    pubmed: 16915214
                  41. Xia W, Khalil RA. Hormone Replacement Therapy and Cardiovascular Health in Postmenopausal Women. Int J Mol Sci 2025 May 24;26(11).
                    doi: 10.3390/ijms26115078pubmed: 40507889google scholar: lookup
                  42. Burggraaf-van Delft JLI, Wiggins KL, van Rein N, le Cessie S, Smith NL, Cannegieter SC. External validation of the Leiden Thrombosis Recurrence Risk Prediction models (L-TRRiP) for the prediction of recurrence after a first venous thrombosis in the Heart and Vascular Health study. Res Pract Thromb Haemost 2024 Nov;8(8):102610.
                    doi: 10.1016/j.rpth.2024.102610pubmed: 39640909google scholar: lookup
                  43. Hasser EK, Brody JA, Bartz TM, Thibord F, Li-Gao R, Kauko A, Wiggins KL, Teder-Laving M, Kim J, Munsch G, Haile HG, Deleuze JF, van Hylckama Vlieg A, Wolberg AS, Boland A, Morange PE, Kraft P, Lowenstein CJ, Emmerich J, Sitlani CM, Suchon P, Rosendaal FR, Niiranen T, Kabrhel C, Trégouët DA, Smith NL. Genome-wide investigation of exogenous female hormones, genetic variation, and venous thromboembolism risk. J Thromb Haemost 2024 Aug;22(8):2261-2269.
                    doi: 10.1016/j.jtha.2024.05.011pubmed: 38782299google scholar: lookup
                  44. Bernstein SR, Kelleher C, Khalil RA. Gender-based research underscores sex differences in biological processes, clinical disorders and pharmacological interventions. Biochem Pharmacol 2023 Sep;215:115737.
                    doi: 10.1016/j.bcp.2023.115737pubmed: 37549793google scholar: lookup
                  45. Machin N, Ragni MV. Hormones and thrombosis: risk across the reproductive years and beyond. Transl Res 2020 Nov;225:9-19.
                    doi: 10.1016/j.trsl.2020.06.011pubmed: 32599096google scholar: lookup
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