‘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.[1]

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.

NHRT-Associated Risks
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.[9] 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.[10] 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.[11]

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.[14] 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.[15] 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.[16]

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.[17] In observational studies, conventional HRT has been shown to prevent coronary artery disease.[18] 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.[20] 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.[21] 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[22]; 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]

Conclusions
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.

References:

1. Fournier A, Berrino F, Clavel-Chapelon F: Unequal risks for breast cancer associated with different hormone replacement therapies: Results from the E3N cohort study. Breast Cancer Res Treat 107:103-111, 2008.
2. Lau CB, Ho TC, Chan TW, et al: Use of dong quai (Angelica sinensis) to treat peri- or postmenopausal symptoms in women with breast cancer: Is it appropriate? Menopause 12:734-740, 2005.
3. Oerter Klein K, Janfaza M, Wong JA, et al: Estrogen bioactivity in fo-ti and other herbs used for their estrogen-like effects as determined by a recombinant cell bioassay. J Clin Endocrinol Metab 88:4077-4079, 2003.
4. Kuhnle GG, Dell’Aquila C, Aspinall SM, et al: Phytoestrogen content of beverages, nuts, seeds, and oils. J Agric Food Chem 56:7311-7315, 2008.
5. Fugh-Berman A: “Bust enhancing” herbal products. Obstet Gynecol 101:1345-1349, 2003.
6. Rossouw JE, Anderson GL, Prentice RL, et al, for the Women’s Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288:321-333, 2002.
7. Hendrix SL, Wassertheil-Smoller S, Johnson KC, et al: Effects of conjugated equine estrogen on stroke in the Women’s Health Initiative. Circulation 113:2425-2434, 2006.
8. Curb JD, Prentice RL, Bray PF, et al: Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med 166:772-780, 2006.
9. Cirillo DJ, Wallace RB, Rodabough RJ, et al: Effect of estrogen therapy on gallbladder disease. JAMA 293:330-339, 2005.
10. Wood CE, Clarkson TB, Chen H, et al: Comparative effects of oral conjugated equine estrogens and micronized 17beta-estradiol on breast proliferation: A retrospective analysis. Menopause 15:890-898, 2008.
11. Dinger JC, Heinemann LA, Möhner S, et al: Breast cancer risk associated with different HRT formulations: A register-based case-control study. BMC Womens Health 6:13, 2006.
12. Cobin RH, Futterweit W, Ginzburg SB, et al, for the AACE Menopause Guidelines Revision Task Force: American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of menopause. Endocr Pract 12:315-337, 2006.
13. Hedrick RE, Ackerman RT, Koltun WD, et al: Transdermal estradiol gel 0.1% for the treatment of vasomotor symptoms in postmenopausal women. Menopause 16:132-140, 2009.
14. D’Anna R, Cannata ML, Marini H, et al: Effects of the phytoestrogen genistein on hot flushes, endometrium, and vaginal epithelium in postmenopausal women: A 2-year randomized, double-blind, placebo-controlled study. Menopause Nov 20, 2008 (epub ahead of print).
15. Borrelli F, Ernst E: Black cohosh (Cimicifuga racemosa) for menopausal symptoms: A systematic review of its efficacy. Am J Obstet Gynecol 199:455-466, 2008.
16. Chandeying V, Sangthawan M: Efficacy comparison of Pueraria mirifica (PM) against conjugated equine estrogen (CEE) with/without medroxyprogesterone acetate (MPA) in the treatment of climacteric symptoms in perimenopausal women: Phase III study. J Med Assoc Thai 90:1720-1726, 2007.
17. Atmaca A, Kleerekoper M, Bayraktar M, et al: Soy isoflavones in the management of postmenopausal osteoporosis. Menopause 15(4 pt 1):748-757, 2008.
18. Bush TL: Evidence for primary and secondary prevention of coronary artery disease in women taking oestrogen replacement therapy. Eur Heart J 17(suppl D):9-14, 1996.
19. Hulley S, Grady D, Bush T, et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 280:605-613, 1998.
20. Scheiber MD, Liu JH, Subbiah MT, et al: Dietary inclusion of whole soy foods results in significant reductions in clinical risk factors for osteoporosis and cardiovascular disease in normal postmenopausal women. Menopause 8:384-392, 2001.
21. Warri A, Saarinen NM, Makela S, et al: The role of early life genistein exposures in modifying breast cancer risk. Br J Cancer 98:1485-1493, 2008.
22. 1: Helferich WG, Andrade JE, Hoagland MS: Phytoestrogens and breast cancer: A complex story. Inflammopharmacology 16:219-226, 2008.
23. Lin YJ, Hou YC, Lin CH, et al: Puerariae radix isoflavones and their metabolites inhibit growth and induce apoptosis in breast cancer cells. Biochem Biophys Res Commun 378:683-688, 2009.
24. Li Z, Li J, Mo B, et al: Genistein induces cell apoptosis in MDA-MB-231 breast cancer cells via the mitogen-activated protein kinase pathway. Toxicol In Vitro 22:1749-1753, 2008.
25. Limer JL, Parkes AT, Speirs V: Differential response to phytoestrogens in endocrine sensitive and resistant breast cancer cells in vitro. Int J Cancer 119:515-521, 2006.
26. Ju YH, Doerge DR, Woodling KA, et al: Dietary genistein negates the inhibitory effect of letrozole on the growth of aromatase-expressing estrogen-dependent human breast cancer cells (MCF-7Ca) in vivo. Carcinogenesis 29:2162-2168, 2008.