The Safety of Oral Versus Transdermal Estrogen

Denise Black, MD, FRCSC


Menopause. 2020;27(11):1328-1329. 

In This Article

Women of Average Risk

Several smaller, randomized, controlled trials (RCTs) may add to our evidence base when considering effect of route of administration of estrogen in younger postmenopausal women. All these studies enrolled young (average age, 52–55 y), symptomatic, relatively healthy women. All these studies used lower-dose (1 mg 17β-estradiol or 0.45 mg conjugated estrogens [CE]) opposed to "standard"-dose estrogens (CE 0.625 mg or equivalent), and most used micronized progesterone (MP) when endometrial protection was required. However, all these studies were underpowered to demonstrate a difference in risk because adverse events (AEs) in this age group are a rare occurrence.

The Kronos Early Estrogen Prevention Study (KEEPS; N = 727) is the only RCT in which there was a head-to-head comparison of relatively bioequivalent doses of oral and transdermal estrogens over a longer time period.[8] Cyclical MP was used as the endometrial protective agent. The incidence of AEs in this young (mean age, 52.5 y) and healthy population over 48 months was low. There was no difference seen between oral or transdermal estrogen or placebo in VTE incidence, stroke, or adverse cardiovascular outcomes.

The Early Versus Late Postmenopausal Treatment With Estradiol (ELITE) study compared oral 17β-estradiol (1 mg) and vaginal MP with placebo.[9] In the early group (<6 y from final menstrual period; n = 248; median age, 55.4 y), the VTE rate was low, and there was no difference seen between treatment and control groups over the duration of the study (median, 5 y). Stroke and cardiovascular events were rare and not different between groups.

The REPLENISH trial looked at varying doses of oral 17 β-estradiol paired with MP in a group of healthy, young, symptomatic women (N = 1,835; mean age, 54.5 y).[10] Over the 12 months of the trial, no difference was seen in VTE incidence between the treatment and control groups, and no significant difference was seen in cardiometabolic parameters. There was no difference in cardiovascular events between treatment and placebo groups.

The Selective Estrogens, Menopause, and Response to Therapy (SMART) trials, using oral CE 0.45 mg with bazedoxifene as an endometrial protective agent, demonstrated no difference in VTE, stroke, or CVD risk between treatment and control groups over the 2-year duration of the trial (N = 2,826; mean age, 55 y).[11]