While the most common symptoms associated with progressive ovarian failure and estrogen deprivation during the menopause transition are vasomotor (e.g., hot flushes), perimenopausal women are also at increased risk for clinical depression. While most women will not suffer from clinically significant depressive symptoms during the menopausal transition, longitudinal studies in community samples have consistently documented an increased risk for clinically significant depressive symptoms or major depressive episodes during the menopause transition, with odds ratios generally ranging from 1.3 to 4.0 (e.g., Cohen et al, 2006; Freeman et al, 2009). That the fluctuations in hormones during the menopause transition contribute to the development of depression in vulnerable women is supported by the work of Freeman (2006) who showed that greater variability in estra-diol levels, and not the estradiol levels per se, was associated with both higher depressive symptoms and diagnosed major depressive disorder. Thus, vulnerability to the mood destabilizing effects of reproductive hormones may represent a pathophysiological mechanism contributing to the increased risk of new onset and recurrent depression during the perimenopause. Among the predictors of vulnerability to peri-menopausal depression include longer duration of the menopause transition time, vasomotor symptoms, stressful life events proximate to the menopausal transition, and histories of depression (Bromberger et al, 2009; Cohen et al, 2006; Freeman et al, 2004, 2009; and see Deecher and Dorries, 2007 for review), though it must be emphasized that perimenopausal women are twice as likely to develop new onset depression relative to premenopausal women (Cohen et al, 2006; Freeman et al, 2006).
Depression is not only a major primary source of morbidity and mortality (Chen and Dilsaver, 1996), but as well it has been associated with an increased risk for cardiovascular disease morbidity and mortality in studies of both animals and humans (e.g., Shively et al, 2008). Transition into the postmenopausal years is also associated with a rapid increase in risk of cardiovascular disease for women, with rates in postmenopausal women surpassing those of men (e.g., Moller-Leimkubler, 2007). While age is the major determinant of increased cardiovascular risk, the importance of estrogen in cardiovascular risk is supported by observations among women undergoing early menopause or oophorectomy without estradiol replacement (e.g., Colditz et al, 1987), since these women show a substantial increase in cardiovascular disease risk, as do younger women with premature ovarian failure (Kalantaridou et al, 2006; Yildirir et al, 2006). Consequently, with 1.5 million U.S. women reaching menopause each year, a substantial number of women will be at increased risk for the comorbid expression of depression and cardiovascular disease, making the perimenopause an ideal window for studying the pathophysi-ology of cardiovascular risk and depression in women.
Not only is estrogen withdrawal associated with increased risk for depression and cardiovascular disease, but it is also associated with other negative health effects, the most notable of which may be osteoporosis. Osteoporosis is a disease characterized by the loss of bone mass and strength that leads to fragility fractures. That estrogen deficiency is critical to the pathogenesis of osteoporosis came initially from the evidence that postmenopausal women are at highest risk for the disease (see Raisz, 2005 for review). Bone remodeling is a dynamic process in which old bone is removed from the skeleton and new bone is added. It consists of two phases - resorption and formation - that involve activity of cells called osteoclasts and osteoblasts. Usually the removal and formation of bone are in balance and maintain skeletal strength and integrity. In postmenopausal women there is both an increase in bone resorption and a diminishment of the increased bone formation that normally occurs in response to mechanical loading, suggesting that estrogen is both anti-catabolic and anabolic (Lee et al, 2003; Raisz, 2005).
Osteoporosis is particularly common in white postmenopausal women and causes 1.5 million fractures per year in the United States (Cummings and Melton, 2002). Hip fracture is the most severe consequence of osteoporosis, and its incidence in women rises exponentially from approximately 100 to 1000 per 100,000 women per year from age 60 to 80 years (Cummings and Melton, 2002). Hip fractures are associated with significant impairment in quality of life, the most important of which may be loss of the ability to walk. Approximately half of individuals who are ambulatory prior to hip fracture are unable to walk independently following fracture (Miller, 1978); and among women who live independently before hip fracture, half remain in long-term care or need help with activities of daily living a year after the fracture (Cummings et al 1985). Thus, osteoporosis has a high morbidity rate for mid- and later-life women, is associated with increased mortality rates (primarily following hip fracture) (Cummings and Melton, 2002), and represents a significant public health problem.
3.2 Estrogen Replacement for Depression, Cardiovascular Disease, and Osteoporosis in Peri- and Postmenopausal Women
In recent controlled trials, a significant antide-pressant effect of estrogen in moderately severe depression in perimenopausal (e.g., Cohen et al, 2003; Soares et al, 2001) but not postmenopausal (Morrison et al, 2004) women has been shown. In contrast to the beneficial effects seen with estrogen alone, a recent trial of estrogen plus a continuous progestin failed to observe antide-pressant efficacy compared with an SSRI in women with peri- and postmenopausal depression (Soares et al, 2006). Nonetheless, a meta-analysis from 26 controlled studies in peri- and postmenopausal women (Zweifel and O'Brien, 1997) reported that estrogen replacement with or without a progestin was associated with a substantial and significant reduction in depression symptoms. Thus, in peri- and postmenopausal women with moderate depression, estrogen therapy appears effective in reducing depression symptoms, with the antidepressant actions of estrogen especially apparent in studies using transdermal 17^-estradiol (see Frey et al, 2008 for review).
While the majority of cohort retrospective and prospective observational studies in peri-and postmenopausal women taking ERT or combined hormone replacement therapy (HRT) (estrogen plus a progestin) demonstrated a significant reduction in cardiovascular disease as well as all-cause mortality in hormone users (e.g., Bush, 1996; Stampfer et al, 1991), this substantial literature supporting the cardiopro-tective effects of ERT has been called in to question, if not repudiated, by several large secondary and primary prevention trials of ERT/HRT. The largest and most documented of the controlled trials for the prevention of cardiovascular disease is the Women's Health Initiative (WHI) that enrolled over 27,000 post-menopausal women, 50-79 years old (mean age - 63 years), and randomized each to either oral ERT (in those without a uterus), HRT (conjugated equine estrogen + medroxyprogesterone acetate [MPA]), or placebo. The HRT arm was terminated after 5 years due to an increased incidence of breast cancer; the results also suggested an increase in non-fatal MI and stroke (Rossouw et al, 2002).
Critical reviews subsequent to the initial WHI reports have argued that the discordant findings reflected problems in the design of the WHI, the most important of which may have been the age and condition of the study subjects (e.g., see Harman et al, 2005). Animal and human studies support the "timing hypothesis," - i.e., the effect of estrogen on cardiovascular disease risk depends on when therapy is started relative to the onset of ovarian failure: beneficial if started in the perimenopausal years (during the fatty streak to uncomplicated plaque stage of atherosclerosis) and neutral or adverse if started later (during the stage of plaque necrosis and inflammation) (Karas and Clarkson, 2003). A placebo-controlled 6-month trial of HRT from our laboratory supports the timing hypothesis since we observed significant reductions in resting and stress-induced blood pressure and vascular resistance with HRT in women who had been postmenopausal for less than 5 years, and no beneficial effects in women postmenopausal for more than 5 years (Brownley et al, 2004). Most women in the observational studies initiated HRT at or near the menopausal transition, while those enrolled into the WHI were, on average, 12 years postmenopausal, and thus, likely to be in the more advanced stages of atherosclerotic progression (Harman et al, 2005). Taken together, the animal and human data suggest that initiating HRT early in the perimenopause is a critical determinant of estradiol's beneficial effects regarding cardiovascular disease risk.
Given the age and conditions of its subjects, the International Menopause Society (IMS) concluded that "the WHI should not be considered a primary prevention trial of HRT to prevent cardiovascular disease ... at present, the only valid studies of HRT for cardioprotection of women in the menopausal transition are the epidemi-ological and observational studies that generally agree with laboratory and animal studies, indicating cardioprotection by estrogen initiated in women during the menopausal transition" (Wright, 2004). The IMS report also indicates the need to study other routes of hormone administration since the WHI used only one formulation (oral conjugated equine estrogen and MPA) and differential effects of oral versus transdermal estradiol on measures of cardiovascular risk are well established. Moreover, the progestin used in the WHI, MPA, is particularly antagonistic (among progestins) to the beneficial cardiovascular effects of estradiol (Adams et al, 1997).
Although ERT and HRT have long been known to increase bone mineral density (North
American Menopause Society, 2006), it is of interest here that the WHI was also the first large-scale controlled trial to demonstrate a significant reduction in hip fracture of about 35% associated with ERT and HRT use (Anderson et al, 2004; Cauley et al, 2003). While the controversy currently surrounding the use of ERT or HRT in postmenopausal women has limited its use in the prevention of osteoporosis, that estrogen can prevent bone loss in postmenopausal women at doses lower than those required to stimulate classic target tissues such as breast and uterus (Prestwood et al, 2003), suggests a more favorable cost/benefit ratio for estrogen in the treatment of osteoporosis. Controlled trials will be needed in order to confirm this. It should also be noted that there are a number of other available FDA approved pharmacotherapy options that have also proven to be efficacious in the treatment of osteoporosis, these include bispho-sphonates, calcitonin, and parathyroid hormone medications (see Alexander, 2009 for review). Additionally, adequate calcium and vitamin D, appropriate physical activity, smoking cessation, and reduced alcohol intake may increase bone mass but also slow bone loss and reduce fracture risk throughout life (North American Menopause Society, 2006; Raisz, 2005).
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