ReviewPharmacology of conjugated equine estrogens: Efficacy, safety and mechanism of action
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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