Highlights
- •The risk of VTE was increased in users of oral hormone therapy versus non-users.
- •Non-oral hormone therapy did not affect the risk of venous thromboembolism.
- •New trials are needed to sort out the impact of different progestins, estrogen doses and administration routes on VTE risk.
Abstract
Introduction
Hormone therapy (HT) is an effective treatment for climacteric symptoms. Nevertheless,
combined estrogen-progestin therapy and the oral route seem to entail higher risk
of venous thromboembolism (VTE) than estrogen-only therapy and transdermal administration.
The present study aimed to investigate the risk of thromboembolic events in postmenopausal
women using non-oral estrogen compared to women using oral estrogen and control groups
(women receiving placebo or non-users of HT), as well as to assess the thrombotic
impact of estrogens alone vs. combined estrogen-progestin therapy.
Materials and methods
Systematic review of MEDLINE, Cochrane CENTRAL, EMBASE, and ClinicalTrials.gov according to PRISMA guidelines.
Results
Twenty-two studies were included in the meta-analyses (9 case-control studies, 9 cohort
studies, and 4 randomized controlled trials). As compared to control groups, VTE risk
was not increased with non-oral HT, including users of estrogens and estrogens plus
progestins (OR 0.97 [0.9–1.06]), non-oral estrogen therapy (ET)-only (OR 0.95 [0.81–1.10]),
and non-oral combined estrogen-progestin therapy (OR 0.92 [0.77–1.09]). Conversely,
increased risk of VTE was observed as compared with control groups in users of oral
HT, including users of estrogens and estrogens plus progestins HT (OR 1.72 [1.47–2.01]),
oral ET-only (OR 1.43 [1.34–1.53]), and combined oral estrogen-progestin HT (OR 2.35
[1.9–2.9]). The comparison of non-oral vs. oral HT showed increased VTE risk with
oral HT (OR 1.66 [1.39–1.98]).
Conclusions
VTE risk was increased in postmenopausal women with no previous thromboembolic events
using oral HT. Non-oral HT did not significantly affect this risk. The quality of
the evidence produced in our meta-analyses is low to moderate, and further clinical
trials are needed to sort out the impact of different types of progestin and different
estrogen doses and administration routes on VTE risk.
Abbreviations:
APC (Activated protein C), BMI (body mass index), CBG (cortisol-binding globulin), CRP (C-reactive protein), CEE (conjugated equine estrogens), CVD (Cardiovascular disease), ET (estrogen therapy), HDL-C (high-density lipoprotein cholesterol), HR (Hazard ratio), HT (Hormone therapy), IGF-1 (Insulin-like growth factor 1), LDL-C (low-density lipoprotein cholesterol), NOS (Newcastle-Ottawa Scale), OR (odds ratio), PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis), RCT (randomized controlled trials), SHBG (Sex hormone-binding globulin), TBG (thyroxine-binding globulin), TFPI (tissue factor pathway inhibitor), VTE (venous thromboembolism)Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Thrombosis ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: a comprehensive review.Health Qual. Life Outcomes. 2005; 3: 47
- Menopausal vasomotor symptoms: a review of causes, effects and evidence-based treatment options.J Reprod Med. 2005; 50: 155-165
- Trends of postmenopausal estrogen plus progestin prevalence in the United States between 1970 and 2010.Obstet. Gynecol. 2014; 124: 27-733
- 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: 321-333
- Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial.JAMA. 2011; 305: 1305-1314
- Does the type of hormone replacement therapy influence the risk of deep vein thrombosis? A prospective case-control study.J. Thromb. Haemost. 2005; 3: 943-948
- Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk.Lancet. 2003; 362: 428-432
- Estrogen and thromboembolism risk (ESTHER) study group. Hormone therapy and venous thromboembolism among postmenopausal women impact of the route of estrogen administration and progestogens: the ESTHER study.Circulation. 2007; 115: 840-845
- Effects of nonoral estradiol–micronized progesterone or low-dose oral estradiol drospirenone therapy on metabolic variables and markers of endothelial function in early postmenopause.Fertil. Steril. 2009; 92: 605-612
- Mazer NA.A comparison of the short-term effects of oral conjugated equine estrogens versus transdermal estradiol on C-reactive protein, other serum markers of inflammation, and other hepatic proteins in naturally menopausal women.J. Clin. Endocrinol. Metab. 2008; 93: 1702-1710
- Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review.Maturitas. 2008; 60: 185-201
- New evidence regarding hormone replacement therapies is urgently required transdermal postmenopausal hormone therapy differs from oral hormone therapy in risks and benefits.Maturitas. 2005; 52: 1-10
- Activated protein C resistance among postmenopausal women using transdermal estrogens: importance of progestogen.Menopause. 2010; 17: 1122-1127
Stanczyk FZ, Hapgood JP, Winer S, Mishell DR Jr. Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects. Endocr. Rev. 2013; 34: 171–208.
Vandenbroucke JP1, Rosing J, Bloemenkamp KW, Middeldorp S, Helmerhorst FM, Bouma BN, Rosendaal FR. Oral contraceptives and the risk of venous thrombosis. N. Engl. J. Med. 2001;344: 1527–35.
- Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study.Lancet. 1999; 354: 2036-2040
- Hormone therapies and venous thromboembolism: where are we now?.J. Thromb. Haemost. 2011; 9: 257-266
- Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001-10.BMJ. 2012; 344e2990
- Hormone replacement therapy and risk of venous thromboembolism in post-menopausal women: systematic review and meta-analysis.BMJ. 2008; 336: 1227-1231
- Association between hormone replacement therapy and subsequent arterial and venous vascular events: a meta-analysis.Eur. Heart J. 2008; 29: 2031-2041
- Oral vs transdermal estrogen therapy and vascular events: a systematic review and meta-analysis.J. Clin. Endocrinol. Metab. 2015; 100: 4012-4020
- PRISMA statement.Epidemiology. 2011; 22 (author reply 128): 128
- Conducting meta-analyses in R with the metafor package.J. Stat. Softw. 2010; 36: 1-48
- Meta-analysis in clinical trials.Control. Clin. Trials. 1986; 7: 177-188
- Measuring inconsistency in meta-analyses.BMJ. 2003; 327: 557-560
- Bias in meta-analysis detected by a simple, graphical test.BMJ. 1997; 315: 629-634
- Risk of venous thromboembolism in users of hormone replacement therapy.Lancet. 1996; 348: 977-980
- Risk of hospital admission for idiopatic venous thromboembolism among users of postmenopausal oestrogens.Lancet. 1996; 348: 981-983
- Hormone replacement therapy and risk of venous thromboembolism: population based casecontrol study.BMJ. 1997; 314: 796-800
- Hormone replacement therapy and the risk of venous thromboembolism: a population-based study.J. Thromb. Haemost. 2010; 8: 979-986
- The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy.J. Thromb. Haemost. 2013; 11: 124-131
- Risk of venous thromboembolism associated with local and systemic use of hormone therapy in peri- and postmenopausal women and in relation to type and route of administration.Menopause. 2016; 23: 593-599
- Prospective study of exogenous hormones and risk of pulmonary embolism in women.Lancet. 1996; 348: 983-987
- Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The WHI randomized controlled trial.JAMA. 2004; 14: 1701-1712
- Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women.BMJ. 2007; 335: 239
- Risk of cardiovascular outcomes in users of estradioldydrogesterone or other HRT preparations.Climacteric. 2009; 12: 445-453
- Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism. Results from E3N cohort study.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 340-345
- Reproductive history, hormone replacement therapy and the incidence of venous thromboembolism: the longitudinal investigation of thromboembolism etiology.Br. J. Haematol. 2010; 149: 606-612
- Does route of administration for estrogen hormone therapy impact risk of venous thromboembolism? Estradiol transdermal system vs. oral estrogen-only hormone therapy.Menopause. 2011; 18: 1052-1059
- Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study.J Thromb Haematol. 2012; 10: 2277-2286
- Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial.BMJ (Online). 2012; e6409: 345
- Hormone therapy and risk of venous thromboembolism in among postmenopausal women in Taiwan.Circ. J. 2015; 79: 1107-1114
- Drospirenone plus estradiol and the risk of serious cardiovascular events in postmenopausal women.Climacteric. 2016; 19: 349-356
- Venous thromboembolism and cardiovascular disease complications in menopausal women using transdermal versus oral estrogen therapy.Menopause. 2016; 23: 600-610
- Hormone therapy and venous thromboembolism among postmenopausal women.Front. Horm. Res. 2014; 43: 21-32
- Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.JAMA. 1998; 280: 605-613
- Increased risk of recurrent venous thromboembolism during hormone replacement therapy—results of the randomized, double-blind, placebo-controlled estrogen in venous thromboembolism trial (EVTET).Thromb. Haemost. 2000; 84: 961-967
- Hormone therapy and recurrence of venous thromboembolism among postmenopausal women.Menopause. 2011; 18: 488-493
- Treatment of symptoms of the menopause: an Endocrine Society clinical practice guideline.J. Clin. Endocrinol. Metab. 2015; 100: 3975-4011
- Guideline development group for menopause: diagnosis and management (NICE clinical guideline no. 23). Diagnosis and management of menopause. The National Institute of Health and Care Excellence (NICE) guideline.JAMA Intern. Med. 2016; 176: 1205-1206
- EStrogen and THromboEmbolism Risk (ESTHER) Study Group. Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study.J. Thromb. Haemost. 2006; 4: 1259-1265
Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3rd. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch. Intern. Med. 2002; 162: 1245–8.
- Lipid biomarkers, hormone therapy and the risk of venous thromboembolism in women.J. Thromb. Haemost. 2009; 7: 588-596
- Menopause. 2012; 19: 257-271
- Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1116-1121
- Differential effects of oral and transdermal estrogen/progesterone regimens on sensitivity to activated protein C among postmenopausal women: a randomized trial.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1671-1676
- Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women.Curr. Opin. Hematol. 2010; 17: 457-463
- Progestogens and venous thromboembolism among postmenopausal women using hormone therapy.Maturitas. 2011; 70: 354-360
- Activated protein C resistance among postmenopausal women using transdermal estrogen: importance of progestogen.Menopause. 2010; 17: 1122-1127
- Effects of low-dose versus placebo or conventional dose postmenopausal hormone therapy on variables related to cardiovascular risk: a systematic review and meta-analyses of randomized clinical trials.J. Clin. Endocrinol. Metab. 2015; 100: 1028-1037
Article info
Publication history
Published online: June 18, 2018
Accepted:
June 16,
2018
Received in revised form:
May 22,
2018
Received:
November 29,
2017
Identification
Copyright
© 2018 Elsevier Ltd. All rights reserved.
