Safety and Security of Menopausal Therapies
AbstractThe climacteric syndrome is a complex condition characterized by a set of symptoms and degenerative changes that ensue due to the decline in production of sex steroids by the ovaries. Hence, there is a need for safe methods for the short- and long-term management of postmenopausal women. Hormone-replacement therapy (HRT) is widely used for the relief of menopausal symptoms and for the prevention of diseases linked to longterm hormonal deprivation. The use of HRT has increased rapidly in the past decade, but is currently a subject of debate because of the possible negative effects on the breast and on the cardiovascular system. Other molecules have been studied as alternatives to standard HRT to also relieve symptoms in women with contraindications to hormones or who refuse sex steroids for personal reasons. The aim of this article is to discuss the results of the principal studies performed in the past few years on the safety of HRT and of other climacteric therapies.
The climacteric is the consequence of the withdrawal of estradiol and progesterone due to the cessation of the cyclical ovarian function. This hormonal change affects a large series of bodily targets, causing atrophy of tissues and metabolic modifications along with psychological and sexual changes, which are experienced variably by women. The first signs include the typical vasomotor symptoms, nocturnal sweats, and psychological instability. Soon after these first manifestations, atrophic changes and metabolic and body composition changes develop. Changes in the lipid profile and in body-fat distribution and quantity are associated with estrogen deprivation and lead to a change in the metabolism of climacteric women toward ‘male’ status. The skeletal system is heavily affected in most individuals, with an accelerated bone loss that can lead to osteopenia or to overt osteoporosis. The function of the cardiovascular system is also affected by the changes in circulating sex steroids, with enhanced atherosclerotic degeneration. Circumstantial evidence indicates that the central nervous system may be affected in the long term, with an increased risk of neurodegenerative diseases such as dementia.
Hormone Replacement Therapy
Associations of estrogens with or without a progestin represent the most effective therapies for climacteric symptoms, but recent findings have opened an as yet unresolved debate on the safety of these therapies, particularly in regard to breast cancer and to cardiovascular disease (CVD).
Several long-term observational studies suggest that HRT prevents CVD in postmenopausal women. The conclusion of all of these trials is that HRT reduces the risk of coronary heart disease by about 40%. However, a large, randomized, placebo-controlled trial failed to confirm this benefit.1 The potential cardioprotective actions of estrogen may depend on the levels of pre-existing CVD at the time of therapy initiation.2 For example, the Estrogen Replacement and Atherosclerosis clinical trial reported that women with pre-existing atherosclerosis receive no benefit on the progression of carotid atherosclerosis by estrogen replacement.3 Thus, while estrogen may protect against the development of atherosclerosis, it does not appear to be protective against existing atherosclerosis. Studies in women with low CVD risk concur with this. Indeed, in the Women’s Health Initiative (WHI) study, those women who started HRT early after the menopause, probably having less-developed CVD, showed better cardiovascular outcomes with a trend toward protection.4 However, the vast majority of women included in the WHI trial had a severely diseased vasculature due to age and to the significant prevalence of cardiovascular risk factors (obesity, high cholesterol, and hypertension), and this might explain the failure of this trial in demonstrating overall cardiovascular benefits with HRT.
Osteoporosis is characterized by reduced bone mass that leads to reduced bone quality and resistance and, consequently, to an increased risk of fractures. Osteoporosis is a very common condition in postmenopausal women, causing significant morbidity and reduced quality of life. Circulating estradiol has a protective effect on the bones, reducing skeletal remodeling through many mechanisms: reduction in activation of bone metabolic units; enhanced survival of osteoclasts; improved efficiency of gastrointestinal calcium absorption; and renal calcium conservation.5 By increasing bone-mineral density (BMD), HRT is the best (and more physiological) protective therapy against osteoporosis and fractures in postmenopausal women.
In the double-blind Postmenopausal Estrogen/Progestin Intervention trial and in the Women’s Health, Osteoporosis, Progestin, Estrogen trial, women treated with estrogen or estrogen/progesterone therapy had a significant increase in BMD versus the placebo group, in which a loss of bone mass was observed.1,6–8 Prospective randomized studies confirm these results. In the WHI study there was a clear reduction in the risk of fractures among women receiving continuous combined conjugated equine estrogen plus medroxyprogesterone acetate or the estrogen therapy alone.1,9,10
Due to the widespread presence of estrogen receptors throughout the brain, estrogen effects are also widespread and affect brain structure and function and provide neuroprotection against oxidative stress via antioxidant effects.11 Moreover, estradiol in vitro promotes the breakdown of the â-amyloid precursor protein, preventing the accumulation of â-amyloid. There exists, then, a biological plausibility for the clinical hypothesis that estrogen helps to maintain cognition in women and prevents or delays the development of neurodegenerative disorders.
Observational studies in which the treatment is started in the early postmenopausal period show a decreased risk of Alzheimer’s disease with treatment.12 In contrast to these results, the WHI Memory Study (WHIMS) showed nearly a doubling of risk of all-cause dementia.13 One explanation for this discrepancy is that late initiation of hormone therapy (after 65 years), as in the WHIMS, may not be effective in preventing neurodegeneration and may instead precipitate vascular dementia, whereas early use confers benefit.2,14 While the prevention of Alzheimer’s disease with HRT is still to be established, it seems that the initiation of HRT in patients aged 65 or more may increase the risk of impaired cognitive function.
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