Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databasesBMJ 2019; 364 doi: https://doi.org/10.1136/bmj.k4810 (Published 09 January 2019) Cite this as: BMJ 2019;364:k4810
All rapid responses
The UK study by Vinogradova Y et al (BMJ 2019;364:k4810, 10 January 2019) provides further evidence that oral but not transdermal oestrogen is associated with increased risk of venous thromboembolism (VTE) among women who use postmenopausal hormone therapy (HT). The advantage of transdermal versus oral oestrogen regarding VTE risk has been shown for the first time 15 years ago (1) and several large-scale studies have fully confirmed the safety of this mode of HT delivery (2). In addition, most of these studies have highlighted the important role of concomitant progestogens in determining VTE risk in HT users.
Progestogens include progesterone and progestins (synthetic progestogens). A large variety of progestogens are used in Europe, especially in France where micronized progesterone is the most commonly used, while medroxyprogesterone acetate (MPA) is almost exclusively used in the USA. In the UK study, data are limited to MPA and some other progestins. Surprisingly, the impact of progesterone on VTE risk is not discussed and related works are not referenced. There is strong evidence that micronized progesterone has no effect on clotting factors (3) and resistance to activated protein C (4) in users of transdermal oestogen. Furthermore, an updated meta-analysis has recently shown that among transdermal oestrogen users, there was no change in VTE risk in women using micronized progesterone, whereas norpregnanes derivatives were associated with increased VTE risk. In this meta-analysis, data on other progestins including pregnane and nortestosterone derivatives were heterogeneous (5).
VTE is one of the most frequent serious adverse effects of HT and improving the risk/benefit profile of HT remains an important challenge. Despite the large body of evidence in favor of transdermal oestrogen to prevent VTE, there has been little change in the mode of HT delivery since 2003. The authors of the UK study are right to encourage women to switch oral with transdermal route of oestrogen administration. However, the choice of progestogen is also critical and the most recent clinical guides recommend transdermal oestrogen combined with micronized progesterone for women who need HT, especially for those at high VTE risk (6,7). In order to make significant changes in medical practice, health agencies should also contribute to better information of women and their doctors.
Pierre-Yves Scarabin, MD, MSc
Inserm Research Director Emeritus
1. Scarabin PY, Oger E, Plu-Bureau G for the ESTHER Study Group. Differential associations of oral and transdermal oestrogen replacement therapy with venous thromboembolism risk. Lancet 2003;362:428-32.
2. Scarabin PY. Hormone therapy and venous thromboembolism among postmenopausal women. Front Horm Res. 2014;43:21-32.
3. Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol 1997;17:3071–8.
4. Oger E, Alhenc-Gelas M, Lacut K, et al. 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;23:1671–6
5. Scarabin PY. Progestogens and venous thromboembolism in menopausal women: an updated oral versus transdermal estrogen meta-analysis. Climacteric 2018;21:341-345.
6. Stuenkel CA, Davis SR, Gompel A, et al. Treatment of symptoms of the menopause: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2015;100:3975–4011
7. Baber RJ, Panay N, Fenton A. the IMS Writing Group. 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy. Climacteric 2016;19:109–50.
Competing interests: No competing interests
Our compliments to the authors for bringing up such an important issue about hormone replacement therapy (HRT). In the last two decades, HRT has seen many ups and downs in its use. HRT came as a very effective therapy for treating vasomotor symptoms like hot flushes, night sweats and other symptoms experienced by peri & postmenopausal women due to oestrogen deficiency and was found to improve the quality of life of such women. Then a period came when prescribers stopped prescribing these after the results of Women’s Health Initiative Study started coming. Again, in the last decade, some observational studies demonstrated the benefits of HRT in reducing the risk of coronary heart disease, osteoporotic fractures and Alzheimer’s disease and they are being re-prescribed.
However, the association of risk of venous thromboembolism with the oral hormone replacement therapy is well known. It leads to a hypercoagulable state with increase in the concentration of prothrombin fragments along with a decrease in antithrombin concentration and an increase in acquired resistance to activated protein C.1
Reanalysis of data has shown that benefits and risks need to be weighed considering the factors like age, body weight and smoking, etc., which could be some of the confounding risk factors for VTE. Another important factor that needs attention is the dose and route of administration of HRT, which the authors have described in a very lucid manner. A previous French study ESTHER (Estrogen and THromboEmbolism Risk) conducted in 2003 had also concluded in its results about the safety of transdermal route of estradiol administration over oral route in relation to VTE.2
In the present study also, the authors have compared oral and transdermal HRT and concluded that oral HRT was associated with a 70% increased risk of VTE while the transdermal route was safe. The transdermal preparation of estrogen along with oral progesterone could be a right approach in decreasing problems like VTE. Another study suggests that the transdermal preparations are preferred for women who are obese or carry an increased risk of VTE.3 Other preparations with oestrogen or progestogen that are used as topical (cream) or vaginal (pessaries) treatments have also been analysed by the authors and found safe. Considering the type of oestrogen is also important, as oestrogen only preparations using conjugated equine oestrogen have been found to have a higher risk of VTE by the authors.
The authors have very beautifully explained the results indicating that the transdermal and local route of HRT administration are safe but side by side have advised preferably prescribing oral HRT, while looking carefully into the patient profile as a whole, so that factors increasing the risk of VTE may not be ignored.
1. Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women. Impact of the route of estrogen administration and progestagens: the ESTHER Study. Circulation 2007; 115: 840-845.
2. Post MS, Christella M, Thomassen LG, et al. Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis: a randomized placebo controlled study in postmenopausal women. Arterioscler Thromb Vasc Biol 2003; 23: 1116-1121.
3. Keli L. Becka, Michelle C. Andersonb and Julienne K. Kirka. Transdermal estrogens in the changing landscape of hormone replacement therapy. Postgrad med J 2017; 129: 632–636.
Thanks & Best Regards
Competing interests: No competing interests
Re: Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases
The authors are to be congratulated on a really useful contribution to the literature, highlighting how replacing postmenopausal female hypogonadism with an equine xenohormone, rather than physiological 17,beta-Estradiol (E2) is associated with a significantly greater risk of venous thromboenbolism (VTE).
However, this epidemiological signal was already evident several years ago from the Transgender literature, wherein Trans-Women taking conjugated equine estrogens had an 8-fold greater risk of VTE than those using oral oral or transdermal E2 (1).
An even stronger signal emerging from the transgender literature is the adverse cardiovascular and pro-thrombitic profile of ethinylestradiol, a synthetic oestrogen receptor modulator that is found in almost all combined oral contraceptives (COP) (2). Despite this, many younger hypogonadal women, such as those with Turner's syndrome, continue to be prescribed COPs, rather than safer and more physiological E2-plus-progesterone hormone replacement (3).
1. Seal, LJ, Franklin, S, Richards, C. Predictive markers for mammoplasty and a comparison of side effect profiles in transwomen taking various hormonal regimens. J Clin Endocrinol Metab 2012; 97: 4422–4428.
2. van Kesteren, PJ, Asscheman, H, Megens, JA. Mortality and morbidity in transsexual subjects treated with cross-sex hormones. Clin Endocrinol (Oxf) 1997; 47: 337–342.
3. MacCauley M & Quinton R. 2017 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 T. Menopause. 24: 232.
Competing interests: No competing interests