Review
Pharmacology of conjugated equine estrogens: Efficacy, safety and mechanism of action

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Highlights

  • Ring B unsaturated estrogens are formed by an alternate steroidogenesis.

  • Ring B unsaturated estrogens express biological activity mainly via ER β.

  • Some protective effects of CEE may involve inhibition of LDL and HDL oxidation.

  • CEE components modulate apoptosis and inhibit this form of cell death in neurons.

  • Eqn, Δ8-E1 and Δ3-17β-E2 may help prevent cardiovascular and Alzheimer's disease.

Abstract

Oral conjugated equine estrogens (CEE) are the most used estrogen formulation for postmenopausal hormone therapy either alone or in combination with a progestin. CEE is most commonly used for the management of early menopausal symptoms such as hot flashes, vaginitis, insomnia, and mood disturbances. Additionally, if used at the start of the menopausal phase (age 50–59 years), CEE prevents osteoporosis and may in some women reduce the risk of cardiovascular disease (CVD) and Alzheimer's disease (AD). There appears to be a common mechanism through which estrogens can protect against CVD and AD.

CEE is a natural formulation of an extract prepared from pregnant mares’ urine. The product monogram lists the presence of only 10 estrogens consisting of the classical estrogens, estrone and 17β-estradiol, and a group of unique ring B unsaturated estrogens such as equilin and equilenin. The ring B unsaturated estrogens are formed by an alternate steroidogenic pathway in which cholesterol is not an obligatory intermediate. Both the route of administration and structure of these estrogens play a role in the overall pharmacology of CEE. In contrast to 17β-estradiol, ring B unsaturated estrogens express their biological effects mainly mediated by the estrogen receptor β and not the estrogen receptor α.

All estrogen components of CEE are antioxidants, and some ring B unsaturated estrogens have several fold greater antioxidant activity than estrone and 17β-estradiol. The cardioprotective and neuroprotective effects of CEE appear to be, to some extent, due to its ability to prevent the formation of oxidized LDL and HDL, and by inhibiting or modulating some of the key proteases involved in programmed cell death (apoptosis) induced by the excess neurotransmitter glutamate and other neurotoxins.

Selective combinations of ring B unsaturated estrogens have the potential of being developed as novel therapeutic agents for the prevention of cardiovascular disease and Alzheimer's disease in both aging women and men.

This article is part of a Special Issue entitled ‘Menopause’.

Introduction

The average age at which menopause occurs is approximately 50 years, and with an average life expectancy of over 85 years, a woman will live for more than a third of her life in the postmenopausal state. During this phase, the ovary essentially stops secreting 17β-estradiol and progesterone, although small amounts of estrogen are still being produced by the peripheral aromatization of mainly adrenal androgens [1], [2]. The reduced levels of circulating estrogen in postmenopause compared to premenopause results in a deficiency affecting the genitourinary tract, central nervous system, bone, skin and cardiovascular system. Afflictions frequently associated with the onset of menopause are vasomotor symptoms (hot flashes), vaginal dryness, sleep disorders, and mood changes. While it is difficult to separate the effects of aging from those due to lack of estrogen, it is well established that estrogen replacement therapy (ERT), more recently termed estrogen therapy (ET), can relieve many of the menopausal symptoms. Substantial clinical and epidemiological evidence from observational and some randomized control trials show that ET can relieve vasomotor symptoms and lower the risk of osteoporosis. ET could also possibly reduce the risk of cardiovascular disease (CVD) and Alzheimer's disease (AD) in women who initiated hormone therapy (HT) in the very early phase or preferably at the start of menopause. The objective of this review is to discuss the pharmacology of CEE and its individual components with special emphasis on their mechanism of action in the etiology of CVD and AD in healthy postmenopausal women. The use of CEE in animal models is outside the scope of this brief review. Detailed epidemiological aspects of these benefits and risks as well as a number of other effects associated with ET and HT are discussed by several others in this special issue.

Section snippets

Estrogen preparations used for ET

Numerous estrogen preparations are available on the market for ET; however, in this brief review, we will discuss the pharmacology of conjugated equine estrogens (CEE) only, with emphasis on the unique ring B unsaturated estrogenic components. For more than 70 years, CEE has been and still is the most prescribed drug for estrogen replacement, with over 3000 publications dealing with its safety profile and efficacy. The drug CEE is a complex ‘natural’ extract of pregnant mares’ urine containing

Absorption

In the majority of postmenopausal women, the oral route of administration appears to be the most preferred. It has been established that a small fraction of estrogen sulfates present in CEE are absorbed from the gastrointestinal tract without prior hydrolysis soon after ingestion [10]. However, the bulk of these sulfate conjugates are absorbed after the removal of the sulfate ester by hydrolysis [10]. Unconjugated ring B unsaturated estrogens such as Eq are absorbed more rapidly than their

Mechanism of action of various equine estrogens

The main pharmacological effects of equine estrogens are mediated by genomic interactions involving two estrogen receptor (ER) subtypes: ERα and ERβ. These receptors are expressed in a number of tissues and the basic mechanism has been extensively reviewed [34], [35], [36], [37], [38]. In this review, only the newer aspect dealing with the interactions of the various components of CEE with human ERα and ERβ are highlighted.

Earlier studies with crude ER preparations from human endometrium and

Effects of CEE on heart disease risk

For more than 3 decades, we have known that the prevalence of CVD and coronary heart disease (CHD) increases significantly after menopause [58]. A number of observational studies suggest that the use of either estrogen alone (ET) or in combination with progestin (HRT) in healthy 50–59-year-old postmenopausal women is associated with a reduced risk of CVD [59], [60], [61], [62], [63]. In an intervention randomized, double-blind, placebo-controlled study where unopposed 17β-E2 was administered

Potential mechanism by which CEEs exert their cardioprotective and neuroprotective effects

It is well established that circulating lipid levels play an important role in the etiology of CHD [5], [58], [79], [80], [81], [82], [83]. Moreover, oral estrogens such as CEE undergo extensive first pass metabolism that results in a significant lowering of LDL-cholesterol (LDLc) levels and an increase in HDL-cholesterol (HDLc) levels in postmenopausal women. Several studies indicate that oxidatively modified LDL (oLDL) can be formed in vivo by free radical-based mechanisms, and is perhaps

Conclusions and future directions

With major advances in healthcare, menopausal women now live one-third of their lives in the postmenopausal years. This important period of their life is associated with normal physiological changes that result in a sex hormone-deficient state. Many women during the early phase of menopause experience a number of symptoms such as hot flashes, dyspareunia, insomnia, mood disturbances, and atrophic vaginitis. All of these impact the quality of life of symptomatic women. The long-term consequences

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