Clinical Review


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Our understanding deepens of the benefits and risks of hormone therapy in different formulations and populations



Ten years have passed since the Women’s Health Initiative (WHI) investigators published initial findings from the estrogen-progestin arm, shaking up the field of menopause management and leading to a sharp decline in the number of prescriptions being written for hormone therapy (HT). Over the course of the ensuing decade, numerous studies have filled in gaps in our understanding of the menopausal transition and the decades that follow—studies that have been detailed in OBG Management in this Update in Menopause and other articles. In this installment of the Update, I review:

  • two studies that address the lower risk of venous thromboembolism (VTE) when transdermal HT is prescribed rather than oral estrogen
  • the characteristics of a new oral medication to treat vulvar and vaginal atrophy
  • a study highlighting the distinct effects on the breast of unopposed estrogen and combination estrogen-progestin HT
  • two reports on ovarian conservation at the time of hysterectomy for benign indications
  • a study from Sweden on the health impact of early menopause
  • a closer look at the mood effects—or lack of them—of progestin therapy.

In addition, JoAnn E. Manson, MD, DrPH, NCMP, weighs in on what we have learned from the WHI and the Kronos Early Estrogen Prevention Study (KEEPS).


American College of Obstetricians and Gynecologists. Committee Opinion #556: Postmenopausal estrogen therapy: Route of administration and risk of venous thromboembolism. Obstet Gynecol. 2013;121(4):887–890.

Roach RE, Lijfering WM, Helmerhorst FM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy. J Thromb Haemost. 2013;11(1):124–131.

Sweetland S, Beral V, Balkwill A, et al; The Million Women Study Collaborators. Venous thromboembolism risk in relation to use of different types of ­postmenopausal hormone therapy in a large prospective study [published online ahead of print September 10, 2012]. J Thromb Haemost. doi:10.1111/j.1538-7836.2012.04919.x.

The estrogen-progestin arm of the WHI clarified the most statistically prominent risk associated with combination HT: a higher incidence of VTE in women ­allocated to oral conjugated equine estrogen and medroxyprogesterone acetate (MPA).1

Although no randomized trials have been large enough to compare the safety of oral versus transdermal HT with respect to VTE in a statistically meaningful manner, the issue has been investigated in observational (case-control and cohort) studies. In past Updates in Menopause, I have detailed studies from France,2,3 the United Kingdom,4 and the United States,5 each of which has suggested that, in contrast with oral HT, transdermal HT does not increase the risk of VTE.

One British study also indicated that while oral estrogen therapy slightly increased the risk of stroke (as demonstrated by the WHI), transdermal estradiol at a dose of 0.05 mg or less did not.6 In 2012, two additional observational reports—one from the United Kingdom and one from Holland—provided additional data confirming the safety of transdermal HT with respect to thrombosis.

Sweetland and colleagues drew from a large population
Using data from the massive British Million Women’s Study (MWS), investigators compared the risk of VTE between oral and transdermal HT. Of 1,058,259 postmenopausal women followed in the MWS cohort, 36% were current HT users. Of current users, 23% were using oral and 14% were using transdermal HT.

The risk of VTE—including deep venous thrombosis and pulmonary embolism—was significantly elevated with the use of oral HT, with a relative risk (RR) of 1.42, compared with nonuse of HT (95% confidence interval [CI], 1.21–1.66).

The risk of VTE was not elevated among users of transdermal therapy (RR, 0.82; 95% CI, 0.54–1.06).

Roach and colleagues studied VTE among 1,000 HT users
In a large case-control study from the Netherlands, investigators identified 1,082 cases of VTE among women older than age 50. Women who used oral estrogen-progestin HT had four times the risk of VTE, compared with nonusers. Although oral unopposed estrogen therapy was also associated with an elevated risk of VTE, this risk was lower than with combination HT and appeared to be dose-dependent.

In contrast, the risk of VTE associated with transdermal estrogen therapy was almost identical to the risk observed in nonusers.

With the addition of these two new studies, there are now six observational studies that agree that transdermal estrogen is safer than oral estrogen with respect to the risk of VTE.2–5

ACOG weighs in
In April 2013, ACOG published a Committee Opinion on the route of administration of HT and the risk of VTE, stating: “When prescribing estrogen therapy, the gynecologist should take into consideration the possible thrombosis-sparing properties of transdermal forms of estrogen therapy.”


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