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Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases

BMJ 2019; 364 doi: (Published 09 January 2019) Cite this as: BMJ 2019;364:k4810

Rapid Response:

Postmenopausal hormone therapy and risk of venous thromboembolism: what about progesterone?

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

15 January 2019
Pierre-Yves Scarabin
Inserm Research Director Emeritus
Inserm and Paris-Sud University
Inserm, CESP, Villejuif. France