8 April 2019:
Commentary on "Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases" by Vinogradova Y, et al
It is well known that postmenopausal estrogen or hormone therapy improve vasomotor symptoms, vulvovaginal atrophy/genitourinary syndrome of menopause, prevent osteoporotic bone loss, and even enhance sexual function. However, since the publication of the initial clinical trial results of the Women’s Health Initiative E+P trial in 2002, use of both estrogen and hormone therapy has decreased despite these benefits. This phenomenon occurred largely due to a shift in focus from the benefits of hormone therapy to the risks of these treatments. Paramount among these risks are the potential for estrogen with or without progestogen to increase deep vein thrombosis and thromboembolism (VTE). While randomized clinical trial information comparing oral vs transdermal or non-oral regimens is lacking, observational studies like this one, demonstrate a reduced risk for DVT and PE with transdermal or non-oral treatments . Risks with such non-oral approaches are comparable to non-users of estrogen therapy even in women with prior thrombotic event histories and obesity, independent risks for thrombosis and thromboembolism [2, 3 for review]. This retrospective analysis by Vinogradova and colleagues consisted of approximately 80,000 women with VTEs compared with about 390,000 non-VTE controls from the QResearch and CPRD databases. The authors found no added risk for VTE associated with estradiol patches, gels, or subcutaneous formulations (adjusted odds ratio: 0.93, 95% CI 0.87-1.01). In contrast, oral estrogen therapy was associated with a significantly increased risk for VTE (adjusted OR 1.58, 95% CI 1.52-1.64). This increased risk remained significant for both estrogen oral preparations (aOR 1.40, 95% CI 1.32-1.48), as well as estrogen+progestogen oral combinations (aOR 1.73, 95% CI 1.65-1.81). Other database reviews document similar findings  Further, Vinogradova and colleagues found the risks of VTE with oral conjugated equine estrogens(CEE) or combined formulas of CEE and a progestogen were higher than oral estradiol therapies (aOR 0.85, 95% CI 0.76-0.95; aOR 0.83, 95% CI 0.76-0.91, respectively) and nearly double the VTE risk of women non-users (aOR 2.10, 95% CI 1.92-2.31). Taken together these findings support prior studies documenting the higher procoagulant and thrombotic risks of CEE compared with oral estradiol . Estradiol combined with dydrogesterone, a formulation not available in the US, showed a slightly elevated VTE risk compared to non-users, but the lowest of the combined oral formulations (aOR 1.18, 95% CI 0.98-1.42).
In this study, more than half of the women with VTEs were ≥65 years of age, and were more likely to have additional comorbidities (cancer, heart disease) versus controls (56% vs 36%). Women with VTE also were more likely than controls to have recent medical problems (27% vs 12%), such as respiratory or urinary tract infections, hip fractures, or surgery with or without hospital admission, or hospital admission for other reasons. These events may have added immobilization to their inherent risks.
One of this study’s limitations, like most observational studies, was the authors' inability to document the patient’s actual exposure to their therapy, as group assignment was based on prescription data and not on confirmed use. Other similar investigations  suffer from this same weakness. Non-oral estradiol therapies may have additional benefits. While the focus here was on thrombosis and VTE, thought to be dependent upon “first-pass” liver effects of oral, but not non-oral treatments, sex hormone binding globulin (SHBG) likewise is increased by “first-pass” metabolism. The increases in SHBG with oral estrogen or estrogen + progestogen therapy decrease both free estradiol and free testosterone concentrations known to adversely affect libido and several associated domains of sexual function . Like the current study, women on non-oral or transdermal estradiol and those not on estrogen or hormone therapy likely have no increase in SHBG, while women on oral CEE have a significant increases in these liver proteins including SHBG resulting in reduced sexual function . The benefits of non-oral or transdermal estradiol therapy vs oral estradiol or CEE on prothrombotic changes, thrombosis or VTE events and sexual function changes await the very large randomized clinical trials that would be needed to document the differences described here. Such trials are likely never to take place.
James A. Simon
Clinical Professor, Obstetrics & Gynecology, George Washington University, IntimMedicine Specialist, Washington, DC
- 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.
- Canonico M, Plu-Bureau G, Scarabin PY. Progestogens and venous thromboembolism among postmenopausal women using hormone therapy. Maturitas. 2011 Dec;70(4):354-60.
- Olié V, Canonico M, Scarabin PY. Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women. Curr Opin Hematol. 2010 Sep;17(5):457-63.
- Simon JA, Laliberté F, Duh MS, et al. Venous thromboembolism and cardiovascular disease complications in menopausal women using transdermal versus oral estrogen therapy. Menopause. 2016;23(6): 600-610.
- Smith NL, Blondon M, Wiggins KL, et al. Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens. JAMA Intern Med. 2014;174(1):25-34.
- Nastri CO, Lara LA, Ferriani RA, Rosa-E-Silva AC, Figueiredo JB, Martins WP. Hormone therapy for sexual function in perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2013;(6):CD009672.
- Taylor HS, Tal A, Pal L, et al. Effects of Oral vs Transdermal Estrogen Therapy on Sexual Function in Early Postmenopause: Ancillary Study of the Kronos Early Estrogen Prevention Study (KEEPS). JAMA Intern Med. 2017 Oct 1;177(10):1471-1479.