Are Some Types of Hormone Therapy Safer Than Others?

Abstract

D espite great strides in hormone therapy (HT) research, clinical trial data on the benefit-to-risk profile of different formulations, doses, and routes administration of HT remain lacking. Most of the large-scale clinical trials 1-3 have tested oral conjugated equine estrogens with or without medroxyprogesterone acetate, and data on nonoral routes and different types and doses of estrogens and progestogens have been limited. The evidence is mounting that route of delivery and possibly type and dose of HT are important factors, particularly for venous thromboembolism (VTE). Results of clinical trials 4,5 and observational studies 6 have been concordant in demonstrating an increased risk of VTE with oral exogenous HT. Recent studies suggest that VTE risk may be lower with transdermal than oral estrogen 7 and with estrogen alone than with combined therapy. 4 However, in the absence of rigorous evidence from large-scale clinical trials on differential effects by hormone formulation or route of delivery, should these findings influence clinical practice? Article p 840The Estrogen and Thromboembolism Risk (ESTHER) study, 7 published in the current issue of Circulation, adds important, relevant data to bolster the case that HT type and route of delivery do indeed make a difference. This welldesigned, French, multicenter case-control study of VTE enrolled 271 consecutive cases of VTE in women (age, 45 to 70 years) and matched them to hospital and community controls. Current HT use was present in 46% of the VTE cases compared with 37% of controls. Oral HT users had 4-fold-increased odds of VTE; however, there was no increased risk among transdermal hormone users (odds ratio, 0.9). Previous randomized trials have suggested that the risk of VTE may be higher with combined oral estrogen and progestogen therapy than with estrogen alone. 4,5 In ESTHER, type of progestogen also appeared to influence risk of VTE. Neither micronized progesterone nor pregnane derivatives (including medroxyprogesterone acetate) were associated with VTE, whereas norpregnane derivatives were associated with a 4-fold increase in odds of VTE.The present study has several important strengths, including a large number of carefully adjudicated cases, a population with a large percent of transdermal estrogen users, and a wide variety of progestogen types. Similar data on the relationship of clinical end points to route of estrogen and type of progestogen would not be readily obtainable in the United States, where transdermal preparations and alternate types of progestogens constitute a relatively small proportion of total HT use. Because of small numbers, cases and controls using nortestosterone derivatives were excluded from the main analyses, although a significantly increased risk also was observed in this group.As for any observational or case-control study, selection and confounding biases must be considered. Reasons for choosing a particular progestogen in this population are unknown, so it is possible that clinical factors could have contributed t...

Time Since Menopause Influences the Acute and Chronic Effect of Estrogens on Endothelial Function

“…32 Furthermore, several studies have shown different effects of different progestins on endothelial function and thrombotic risk. [32][33][34][35] The WHI study has shown that in nonhysterectomized women receiving CEE-MPA in continuous combined scheme increased cardiovascular events in elderly PMW, whereas this was not the case in women receiving CEE alone. 10,11 Limitations of the present study are the lack of placebo control and of the adjunctive use of progestins.…”

Differential Effects of 17β-Estradiol on Function and Expression of Estrogen Receptor α, Estrogen Receptor β, and GPR30 in Arteries and Veins of Patients With Atherosclerosis

“…The results reported herein might add to the understanding of how natural estrogens or conjugated equine estrogens (which, among other substances, contain 17␤-estradiol 3,4 ) contribute to vascular protection and to vascular risk in humans. 46,47 …”

Loss of estrogen receptor β decreases mitochondrial energetic potential and increases thrombogenicity of platelets in aged female mice

“…Increased shedding platelet microvesicles may result from decreases in activity of enzymes of the mitochondrial electron transport chain. In women, polymorphisms in βER are associated with thrombotic events including myocardial infarction, venous ulceration, and deep vein thrombosis (Alessio et al 2007; Ashworth et al 2008; Rexrode and Manson 2007). Results of present study provide one possible mechanism of how loss of βER may increase thrombotic events in aged women by increasing activation of platelets and shedding of thrombogenic microvesicles in the circulation.…”