Other Climacteric Symptoms
Genitourinary atrophy, bladder dysfunction resulting in stress incontinence and infections, dyspareunia, and decreased libido frequently develop at the time of menopause. These symptoms, a result of estrogen deficiency, may become increasingly troublesome with time. Nonhormonal lubricants are often used to improve dyspareunia but provide no relief of bladder problems.
Vaginal estrogen in the form of an ointment or a slow-release ring can be very helpful when used judiciously and at doses low enough to avoid significant systemic absorption but high enough to correct genitourinary symptoms. It is generally possible to monitor systemic levels of estrogen and gonadotropin and to adjust the dose of topical estrogen with good results.
Other hormonal preparations to relieve genitourinary atrophy may be obtained without prescription; however, as with topical estrogen, concerns regarding systemic absorption apply.
Caution should be exercised with all hormonal preparations, regardless of whether they require medical prescription.
Emotional symptoms such as irritability, nervousness, depression, insomnia, and inability to concentrate are also described by many menopausal women, but whether there is a causal association between these symptoms and estrogen deficiency is still being debated. A number of herbal remedies, such as hypericum (St. John’s wort), are advocated by the health-food industry and are widely used, but information about their efficacy remains anecdotal.
Selective Estrogen Receptor Modulators
A number of compounds have been developed that have antiestrogenic effects on some tissues but act as estrogens in others. These compounds are known as selective estrogen receptor modulators (SERMs).
Tamoxifen, the oldest SERM, is a very effective antineoplastic agent that is in widespread use and is used for prolonged periods in postmenopausal women with breast cancer. Early concerns that this antiestrogen might have deleterious effects on the cardiovascular and skeletal systems have, fortunately, proved unwarranted.
Tamoxifen administration is associated with a fall of total and LDL cholesterol levels; the effects of tamoxifen on HDL cholesterol levels are less consistent. These beneficial effects persist during at least 2 years of continuous tamoxifen therapy and may be accompanied by improvements in clinical cardiovascular morbidity.
The possibility of benefit is supported by reports that among patients randomly assigned to tamoxifen or no treatment, fewer tamoxifen-treated patients were admitted to the hospital for cardiac disease or suffered a fatal heart attack (Love et al., 1991; Rutqvist et al., 1993).
Equally promising is evidence that tamoxifen may exert an estrogenic effect on the skeleton and thus prevent postmenopausal bone loss (Fornander et al., 1990). In the National Surgical Adjuvant Breast and Bowel Project P-1 trial, in which women at risk for breast cancer were randomly assigned to either tamoxifen or placebo and prospectively followed for 5 years, tamoxifen was found to reduce the rate of fractures by 29% in women aged 50 years or older (Fisher et al., 2005). However, a long-term reduction in the rate of vertebral and hip fractures has yet to be clearly demonstrated. On the other hand, tamoxifen may exacerbate climacteric vasomotor symptoms and depression and may cause additional side effects, especially endometrial proliferation.
At this time, the most effective uses of tamoxifen are adjuvant therapy for breast cancer and chemoprevention of breast cancer rather than management of menopause. The recent increased use of aromatase inhibitors, such as anastrozole, in place of tamoxifen has been predicated upon accumulating data showing greater effectiveness of aromatase inhibitors in all stages of breast cancer. Although anastrozole has no significant detrimental effect on serum lipids or cardiovascular health, it is associated with increased bone turnover and may predispose patients to more pronounced bone loss than that caused by tamoxifen; systematic skeletal surveillance is very important in this setting.
Raloxifene, another SERM, is approved for the prevention of osteoporosis (Delmas et al., 1997). Like tamoxifen, raloxifene decreases total and LDL cholesterol. The Multiple Outcomes of Raloxifene Evaluation trial prospectively followed osteoporotic postmenopausal women randomly assigned to raloxifene or placebo for 3 years (Ettinger et al., 1999; Barrett-Connor et al., 2002). Results of the study were notable for a reduced risk of new vertebral fractures (reduced up to 50%) among raloxifene users.
A decrease in CHD events in women with increased cardiovascular risk was also observed in the raloxifene group. The use of raloxifene was associated with a 72% reduction in the risk of invasive breast cancer, largely due to an 84% reduction in the risk of estrogen receptor-positive breast cancers (there was no effect on estrogen receptor-negative breast cancers). The Continued Outcomes Relevant to Evista trial studied the same population of women for an additional 4 years and found a continued reduction in the risk of invasive breast cancer with extended use of raloxifene (Martino et al., 2004). Initial results from the Study of Tamoxifen and Raloxifene, a large, randomized trial comparing raloxifene to tamoxifen for breast cancer prevention in postmenopausal women, have recently been announced (National Cancer Institute, 2006). The study found that women treated with raloxifene had 29% fewer deep venous thromboses and Pulmonary embolisms than women treated with tamoxifen, but there was no difference in the number of strokes or deaths from strokes in the two groups.
There was a higher incidence of uterine cancer in the tamoxifen group than in the raloxifene group, but further review of the data is necessary to determine the significance of this finding. Raloxifene was shown to be as effective as tamoxifen in lowering the incidence of invasive breast cancer. The incidences of lobular carcinoma in situ and ductal carcinoma in situ were reduced by half in the tamoxifen group, but there was no apparent reduction in the incidence of these noninvasive cancers in the raloxifene group.
Additional SERMs, including tibolone and droloxifene, are under investigation or available outside the United States for management of menopausal symptoms.
Gilbert G. Fareau and Rena Vassilopoulou-Sellin
Estrogen replacement therapy in breast cancer patients: a time for change? Proc Am Soc Clin Oncol 1996;15:121.