Tommaso Simoncini1, Silvia Pisaneschi1, Stefania Spina1, Guja Bernacchi1, Silvia Di Bello1, Elena Cecchi1, Paolo Mannella1 and Andrea R. Genazzani1
(1)
Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, Pisa, 56126, Italy
Andrea R. Genazzani
Email: argenazzani@tiscali.it
25.1 The Menopause
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, metabolic modifications along with psychological and sexual changes that are variably experienced by women. The first signs include the typical vasomotor symptoms, nocturnal sweats, and the 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 towards a “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 for neurodegenerative diseases, such as dementia.
25.2 Hormone Replacement Therapy
Associations of estrogens with or without a progestin represent the most effective therapies for climacteric symptoms, but recent findings have opened a debate that has not yet settled, on the safety of these therapies, particularly in regard to breast cancer and to cardiovascular disease (CVD).
25.2.1 Cardiovascular System
Several long-term observational studies suggest that hormone replacement therapy (HRT) prevents CVD in postmenopausal women. The conclusion of all these trials is that HRT reduces the risk of coronary heart disease (CHD) of about 40 %. This has been largely confirmed by the main prospective clinical trial available so far, the Women’s Health Initiative [1] showing that women receiving estrogens soon after the menopause are protected in the long term from CVD.
The potential cardioprotective actions of estrogen indeed depend on the levels of preexisting CVD at the time of therapy initiation [2]. For example, the ERA clinical trial reported that women with preexisting 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 WHI, those women who started HRT early after the menopause, probably having less developed CVD, showed better cardiovascular outcomes [1]. However, the vast majority of the women included in the WHI trial had a severely diseased vasculature due to the age and to the large prevalence of cardiovascular risk factors (obesity, high cholesterol, and hypertension) and this explains the failure of this trial in showing overall cardiovascular benefits with HRT in women over 60 years of age.
25.2.2 Bones
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, and improved efficiency of gastrointestinal calcium absorption and renal calcium conservation [4].
By increasing bone mineral density, HRT is the best (and more physiological) protective therapy against osteoporosis and fractures in postmenopausal women.
In the double-blind Postmenopausal Estrogen/Progestin Intervention (PEPI) trial and in the Women’s Health, Osteoporosis, Progestin, Estrogen (HOPE) trial, women treated with estrogen or estrogen/progesterone therapy had a significant increase in the BMD vs. the placebo group, in which a loss of bone mass was observed [5]. Prospective randomized studies confirm these results. In the Women’s Health Initiative study (WHI), there was a clear reduction in the risk of fractures among women receiving continuous combined CEE plus MPA or the estrogen alone therapy [1].
25.2.3 Cognitive Function
Because of the presence of ERs throughout the brain, estrogen effects are also widespread and affect brain structure and function and provide neuroprotection against oxidative stress via an antioxidant effects [6]. Moreover, estradiol, in vitro, promotes the breakdown of the β-amyloid precursor protein preventing the accumulation of β-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 for Alzheimer’s disease with treatment [7]. In contrast with these results, the Women’s Health Initiative Memory Study (WHIMS) showed a nearly doubling of the risk for all-cause dementia [8]. One explanation for this discrepancy is that late initiation of hormone therapy (after 65 years), as in the WHIMS study may not be effective in preventing neurodegeneration and may instead precipitate vascular dementia, whereas an early use confers benefit [2, 9].
While the prevention of Alzheimer’s disease with HRT is still to be established it seems that the initiation of hormone therapy in patients aged 65 or more may increase the risk of impaired cognitive function.
25.2.4 Breast Cancer
Breast cancer is the most common cancer in women in the Western countries. Estrogens have clear proliferative activity on breast cancer cells in vivo and in vitro [10], so it may be biologically sound that prolonged exposure to estrogens increases the risk of breast cancer. However, it is not clear if exposure to estrogens has any effect on cancer development per se. Most of the currently available evidence suggests that cancer transformation may not be related to estrogens exposure, but that once this primal event takes place, then estrogens may promote tumor growth and eventually spread. On the other side, progestins have traditionally been seen as protective against breast cancer development despite the absence of a strong biologic rationale for an antiestrogenic effect of progestins on the breast.
Correlation between HRT use and breast cancer risk has been studied in many epidemiological studies. A large meta-analysis published on the Lancet in 1997 indicated that the risk of breast cancer is increased in women using HRT and increases with increasing duration of use [11]. This excess risk is reduced after HRT cessation and disappears within 5 years [11]. Recently, the WHI study reported a 26 % increase in the relative risk of breast cancer for combined estrogen–progestogen when compared with a placebo [1]. However, the parallel arm of the WHI study investigating the effect of the administration of estrogens alone showed no increase of breast cancer, with a trend toward a reduction of the risk [1]. This study, along with the long-term analysis of the Nurse’s Health Study, in general indicates that the impact on the incidence of breast cancer of HRT is limited and associated only with very long administrations [12]. In addition, recent trials call for new research to better understand the role of progestins, showing that based on the compound, the risk of breast cancer changes [13].
25.2.5 Endometrial Cancer
The vast majority of all endometrial malignancies occur mostly in perimenopausal and early postmenopausal women. The pathogenesis is in part linked to a prolonged and excessive exposure to endogenous or exogenous estrogens, not balanced by the cyclical production of progesterone. The risk of endometrial cancer is not clearly related with the dose but with the duration of unopposed estrogen exposure, as long-term administration correlates with fivefold higher risk [14]. HRT with estrogen alone increases endometrial cancer risk, whatever the type and the dose of estrogen and the route of administration [14]. Progesterone has a well-known antiestrogenic effect on the endometrium. The addition of a progestogen to the estrogen replacement therapy (ERT) is then mandatory to avoid the risk of endometrial cancer, contrasting the stimulation of the endometrium by estrogens. To this extent, in the presence of a progestin, endometrial cancer risk is decreased either with cyclic or continuous HRT. Cyclic regimens including more than 10 days of progestogen exposure per month appear to provide maximum protection [15].
25.2.6 Colorectal Cancer
Colorectal carcinoma is a leading cause of illness and death in the Western countries, being the second most common cancer in women after breast cancer [16]. There is strong evidence to show that the incidence of colorectal carcinoma can be significantly reduced by HRT. A meta-analysis of 18 epidemiological studies of HRT and colorectal cancer showed a 20 % reduction of colon and rectal cancer risk in women who had ever taken HRT compared with those had never taken HRT [16]. In addition, the WHI trial showed a significant reduction in colon cancer risk in HRT users. The possible biological explanation of this reduction of risk include effect of sex steroids on bile acid metabolism and direct effects on the colonic epithelium [17].
25.3 Other Therapies
Other molecules have been studied as alternatives to standard replacement therapy with sex steroid hormones.
25.3.1 Tibolone
Tibolone is a synthetic steroid that is rapidly converted to two metabolites with estrogenic activity and to a third metabolite characterized by a mixed progestogenic/androgenic activity [18]. Tibolone controls hot flushes, sweating, mood symptoms and is effective in improving libido, due to its androgenic component [19].
25.3.1.1 Cardiovascular System
Cardiovascular clinical outcomes from randomized controlled trials are not available yet. Surrogate endpoint studies for arterial disease and venous thromboembolic disease are inconclusive with regard to benefit or risk [20].
25.3.1.2 Bones
Randomized, controlled studies show that tibolone increases bone mineral density and reduces fracture risk. These beneficial effects are seen over long-term treatments [21] (over 10 years) and both in early and late postmenopausal women as well as in women with established osteoporosis.
25.3.1.3 Breast Cancer
The Million Women Study reported an increased risk of breast cancer in women treated with tibolone, although this was significantly less than that seen with combined therapies with estrogens and progestins [22]. However, this study has many biases, including the likely selective prescription of tibolone to women at higher risk of breast cancer, due to the assumption that this compound could be less active on the breast respect to standard HRT. The combined analysis of randomized clinical studies on tibolone indicates no increase in risk of breast cancer development compared with placebo. Tibolone treatment is associated with a reduction of proliferation and a stimulation of apoptosis in normal breast cells that is possibly attributable to the impact of this compound on the activity of estrogen-metabolizing breast enzymes [23]. However, the LIBERATE has shown increased risk of relapse in breast cancer survivors receiving tibolone to treat menopausal symptoms [24].
25.3.1.4 Endometrial Cancer
The metabolization of tibolone is tissue selective, and the conversion to the progestogenic metabolite is particularly active in the endometrium. Investigation of endometrial histology in women treated with tibolone shows no hyperplasia and a high level of atrophic endometrium, indicating no proliferative effect of this molecule [25].
25.3.2 Phytoestrogens
Phytoestrogens are biologically active compounds found in certain plants in high concentrations. They have a chemical structure similar to that of estradiol and the ability to bind to ERs exerting variable estrogenic and antiestrogenic effects [26]. Many clinical studies have been conducted to assess the effects of phytoestrogens on postmenopausal syndrome but while some studies report a modest benefit compared to placebo, others do not [27].
25.3.2.1 Cardiovascular System
In vitro, genistein, a phytoestrogenic molecule, stimulates the synthesis of nitric oxide from endothelial cells [28]. Clinical trials demonstrate that consuming 25–50 g/day of soy protein is effective in reducing LDL cholesterol by approximately 4–8 % [29] and the Framingham Offspring Study reports that a high intake of phytoestrogens in postmenopausal women is associated with a favorable metabolic cardiovascular risk profile [30]. The beneficial effects of phytoestrogens on CVDs need, anyway, to be confirmed.
25.3.2.2 Bones
Some observational epidemiologic studies reported that soy proteins and phytoestrogens are beneficial for bone mass in postmenopausal women [31]. Only few randomized trials have been conducted on this issue, but recent trials seem to confirm that phytoestrogens are effective against postmenopausal bone loss [32]. However, the optimal dosage and the component responsible for the favorable effects are still unclear.
25.3.2.3 Cognitive Function
The effects of phytoestrogens on the central nervous system in humans are poorly understood.
Scattered reports suggest a beneficial effect of phytoestrogens on memory, but the evidence on this issue is insufficient.
25.3.2.4 Breast Cancer
To date, several studies have been performed to assess the direct relation between the individual dietary intake of soy products and the risk of breast cancer, but none of them reported statistically significant breast cancer reductions. Recent data indicates that surrogate markers of breast cancer risk, such as mammographic breast density, are not altered by phytoestrogens [33], supporting the view that this class of compounds may act differently from standard hormonal therapies on the breast.
25.3.2.5 Endometrial Cancer
The reports on the effect of phytoestrogens on endometrial cancer are limited. In the Hawaii’s multiethnic population, soy intake has been related to reduced endometrial cancer risk [34]. Similar data have been found in non-Asian women in San Francisco [35].
25.3.3 Raloxifene
Raloxifene is a nonsteroidal Selective Estrogen Receptor Modulator (SERM). This compound induces estrogenic or antiestrogenic actions depending on the tissue. Raloxifene is not effective on vasomotor symptoms that can even be worsened during raloxifene administration, therefore making it an unsuitable agent for the treatment of symptomatic menopausal women.
25.3.3.1 Cardiovascular System
While previous trials suggested potential reduction of cardiovascular events in postmenopausal women receiving raloxifene [36], the publication of the Raloxifene use for the Hearth (RUTH) trial has instead shown no reduction of cardiovascular events [37]. However, this compound is active in vascular cells, where in general it behaves like an estrogen, possibly inducing protective effects [38, 39].
25.3.3.2 Bones
Raloxifene acts as a powerful estrogen on the bone, where it prevents bone loss and provides an effective treatment for osteoporosis [40].
25.3.3.3 Breast Cancer
The large Study of Tamoxifen and Raloxifene (STAR) trial indicates that raloxifene administration to postmenopausal results in a clinically relevant reduction of breast cancer risk that is comparable to that achieved with tamoxifen [41].
Newer SERMs with partially different characteristics are currently under development by the pharmaceutical industry and many of these compounds are in advanced clinical development.
25.4 Conclusions
In conclusion, while all the available therapies for early postmenopausal symptoms or for the prevention of the consequences of the long-term estrogen deprivation have specific risk/benefit ratios, clinical selection is the key to maximize the advantage for each patient. Overall, the safety profile of hormonal preparations is extremely reassuring, and the big claims of carcinogenetic actions of these drugs are not justified.
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