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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

HRT: Are Route and Type of Oestrogen important to consider?

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.

References :
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

11 January 2019
Dr. Sangeeta Bhanwra
Rajiv Kumar, Faculty, Department of Pharmacology, Government College & Hospital, Chandigarh
Department of Pharmacology, Government College & Hospital, Chandigarh, India
Chandigarh, India