‘Natural’ Hormone Replacement and Breast Cancer Risk: Evidence for Safety and Efficacy
‘Natural’ Hormone Replacement and Breast Cancer Risk: Evidence for Safety and Efficacy
Many women have turned to natural forms of hormone replacement for menopause since learning that conventional hormone replacement therapy (HRT) may increase their risks of breast cancer and other health problems. Most women have assumed that “natural” or “bioidentical” HRT is safer than conventional HRT. However, recent research has shown that this is not the case and that, in fact, the risks are probably similar.
Bioidentical HRT and Phytoestrogens
The most common “natural” HRT (NHRT) products are bioidentical hormone replacement therapy and phytoestrogen supplements. Bioidentical hormone products, frequently derived from plant extracts, are usually administered as oral supplements or transdermal injections modified to be chemically similar to naturally produced hormones. They are usually compounded into custom formulations that combine three estrogens—estriol, estradiol, and estrone—in varying proportions. These preparations are marketed under a number of names including Bi-Est, Tri-Est, and others that do not sound like they might be estrogen. There are also “bioidentical” forms of progesterone known as oral micronized progesterone, or OMP. Additionally, transdermal forms of “natural progesterone” are available; most are topical creams. These preparations have not been well studied for safety and efficacy but they are promoted as safe, effective, and free of the risks of conventional forms of HRT in the popular media. Recent, early data suggest that OMP use is associated with a decreased risk in breast cancer compared to other progestins.
Naturally occurring plant hormones known as phytoestrogens are also frequently used to decrease menopausal symptoms. Common sources include soy and some herbs such as red clover (see Table 1).[2-5] Generally, phytoestrogens exert a weaker estrogenic effect than either conventional or bioidentical HRT.
The Women’s Health Initiative (WHI) data showed that women who took conventional HRT had a higher risk of breast cancer, blood clots, and stroke.[6-8] Estrogen use was also found to increase the risk of gallbladder disease. The women in the WHI study used Premarin or PremPro (conjugated equine estrogens with or without medroxyprogesterone acetate). The hope for bioidentical hormones was that they would be safer because they are purported to be more similar to the hormones naturally produced by a woman’s body. Unfortunately, there is little reason to believe that this is true. In fact, some data suggest that standard doses of conjugated equine estrogens may result in less estrogen-induced epithelial proliferation in the breast compared with estradiol. A 2006 European study found little variation in breast cancer risk among women taking various forms of HRT, including some bioidentical forms, suggesting that all estrogens increase breast cancer risk.
Clinical Benefits of NHRT
Both conventional HRT and bioidentical HRT effectively treat vasomotor symptoms of menopause.[12,13] However, data on efficacy of phytoestrogens for vasomotor symptoms are mixed, and for many herbs, nonexistent.
In 2008, D’Anna et al reported a reduction of hot flashes in women taking genistein, a soy phytoestrogen, compared to controls. However, that effect was not long-lived. Black cohosh (Cimicifuga racemosa), a popular herb used to treat vasomotor symptoms, was found to have questionable efficacy in treating menopausal symptoms in a recent meta-analysis. A small Thai study comparing a native plant phytoestrogen (Pueraria mirifica) to conjugated equine estrogens with or without progestin, showed similar results when used for the treatment of vasomotor symptoms.
Estrogen replacement has been shown to provide other clinical benefits including prevention of osteoporosis and coronary artery disease. Estrogens are needed to maintain bone density in women. Data on the effect of phytoestrogens on bone health are limited, with few randomized controlled trials available. A recent review of the evidence concludes that soy estrogens may have beneficial effects on bone mineral density in postmenopausal women. In observational studies, conventional HRT has been shown to prevent coronary artery disease. However, in randomized controlled trials no long-term benefit has been shown, and both the WHI and the Heart and Estrogen/Progestin Replacement Study (HERS) showed an increased risk of cardiovascular events with conjugated equine estrogen and medroxyprogesterone acetate use.[6,19] The data on phytoestrogens and coronary heart disease are less clear. Epidemiologic data have indicated a possible protective effect of soy on heart disease. One observational study concluded that dietary soy intake in postmenopausal women lowered total cholesterol, raised high-density lipoprotein (HDL) cholesterol and lowered the total cholesterol (TC)/HDL ratio. The available studies have examined these and other biomarkers but, to date, there are no randomized controlled trials of phytoestrogens that look at coronary events as the endpoint.
In epidemiologic studies, dietary soy consumption appears to decrease breast cancer risk. This effect has been noted particularly in Asian cultures, where soy is a traditional dietary staple. Increasing evidence suggests that this effect is strongest when soy is consumed earlier in life, particularly in adolescence and prior to menopause. We have almost no data on breast cancer risk among postmenopausal women who initiated soy use for amelioration of menopausal symptoms. In vitro and murine studies of the effects of phytoestrogens on breast cancer risk have had mixed results. Some studies suggest that these substances may increase breast cancer risk; others suggest the opposite.[23,24] Of particular interest is the effect of phytoestrogens on breast cancer survivors with estrogen receptor–positive disease who may be taking tamoxifen or an aromatase inhibitor; recent data suggest that soy isoflavones, particularly genistein, may inhibit the positive effects of these agents on breast cancer cells.[25,26]
The current level of evidence for safety and efficacy of “natural” hormone replacements is not conclusive. In terms of safety, the majority of data suggests that NHRTs demonstrate risks similar to those of conventional HRT. Efficacy trials of NHRTs have produced mixed and sometimes contradictory results.
We suggest that NHRT advice to women should be based on the same risk/benefit assessment that would be used when considering conventional HRT. High-risk patients such as the survivors of hormone-driven cancers are not appropriate candidates for estrogen supplementation from any source. New clinical trials will hopefully provide more definitive evidence and confidence, but until such time, erring on the side of patient safety is recommended. Clinicians should be prepared to respond to aggressive marketing claims when advising patients.
In addition to nonhormonal pharmaceuticals, patients seeking safe alternatives to NHR products may also wish to consider diet, lifestyle, nutritional, and nonestrogenic botanical strategies that have demonstrated positive clinical evidence for efficacy.
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