In the HEAL Study, neither overall EBS use nor the number of EBS types used was associated with HRQOL, fatigue, or hormone-related symptoms. Use of specific EBS types (soy supplements, ginseng, flaxseed oil, red clover, alfalfa, and DHEA) was associated with several outcomes of interest and we focus the discussion on these forms of EBS.
It is postulated that associations between soy supplements and breast cancer risk or progression may be in part related to the presence of isoflavones, which bind to estrogen receptors and activate estrogen response genes, although the hormone-like effect is much weaker than that of endogenous estradiol or estrone [43
]. The estrogen-antagonist/-agonist effects of isoflavones may depend on a woman's endogenous estrogen levels or on the isoflavones concentration in the EBS compound. These compounds may function as estrogen agonists in women with low estrogen levels [44
]. Results from clinical trials which have evaluated the impact of soy products on hot flashes are mixed; three showed no effect in breast cancer survivors [45
] and one showed protective effects in postmenopausal women experiencing ≥ 5 hot flushes per day [48
]. One randomized controlled trial observed that the incidence and severity of hot flashes were reduced two weeks after treatment with oral soy isoflavone extract, with no immediate reductions observed in the placebo group; the group differences achieved statistical significance at 6 weeks (P
= 0.03), but decreased by 12 weeks (P
= 0.08) [48
]. Soy supplement use in the HEAL Study participants was associated with a better PCS score, but not with other outcomes examined. Our results suggest, on the whole, that soy supplements are unlikely to be detrimental to breast cancer survivors' HRQOL, fatigue, or hormone-related symptoms.
Ginsenosides (Rh1, Rb1, and Rg1) from ginseng have estrogen-like characteristics [49
] and hence ginseng might ease menopausal symptoms. Ginseng did not influence hot flashes in a randomized, double blind, placebo-controlled study of ginseng in women reporting high frequency of hot flashes [51
]. An observational study conducted in 2-5 years Chinese breast cancer survivors reported that ginseng use after cancer diagnosis, particularly current use, was positively associated with higher HRQOL scores in the psychological and social well-being domains, but was not associated with scores in the physical domain [52
]. The findings from China may not translate to US populations because the major type of ginseng used could be different. An epidemiologic study conducted in US breast cancer survivors who were, on average, 6.5 years post diagnosis reported that ginseng users had lower SF-36 MCS scores [16
]. We observed that ginseng use was associated with a lower PCS score, a higher fatigue score, and several hormone-related symptoms. Although these associations with different symptoms are consistent with previous studies outlining the adverse effects of ginseng [53
], we cannot exclude the possibility that the symptoms experienced by women who took ginseng motivated their ginseng use.
Flaxseed oil is derived from the seeds of the flax plant that contain phytoestrogens and alpha-linolenic acid [56
]. Colonic microflora convert phytoestrogens to enterolactone and enterodiol, both of which have estrogenic and antiestrogenic properties [58
]. Alpha-linolenic acid had growth-inhibitory and proapoptotic effects on estrogen-positive breast cancer cells [59
] and decreased the incidence, number, and growth of tumors in rats [60
]. In human studies, flaxseed stabilized mood, improved depression symptoms [62
], and reduced blood pressure during mental stress induced by frustrating cognitive tasks [63
]. Our results are consistent with these findings as flaxseed oil was associated with higher MCS scores.
Red clover is another source of isoflavones, and had some efficacy in reducing hot flashes, but did not influence quality of life, in a 12-week randomized clinical trial [64
]. In the HEAL Study, red clover use was associated with neither HRQOL nor hot flashes. However, red clover users were less likely to report three symptoms (weight gain, night sweats, and difficulty concentrating) than non-EBS users. Although these results support an association of red clover with fewer menopausal symptoms, it is important to note that we had only 38 users.
Alfalfa also contains phytoestrogens and has weak estrogenic effects [65
]. In animal studies, alfalfa was associated with antioxidant activity [67
] and protected against atherosclerotic lesions [68
]. A small Italian study of women experiencing hot flashes and night sweats found that use of alfalfa and sage extracts for three months completely alleviated symptoms in 20 of 30 women studied [69
]. In the HEAL Study, alfalfa users had a substantial but non-statistically-significant lower risk for hot flashes and were less likely to report interrupted sleep than non-EBS users. These results based on 31 alfalfa users provide some evidence that alfalfa may reduce menopausal symptoms.
DHEA is an endogenous steroid produced and secreted by the adrenal gland. Its sulfated form is converted into androgens and estrogens by specific steroidogenic enzymes. Blood DHEA levels begin to decrease around age 30, and by menopause are decreased 60%, on average [70
]. It is reasonable to speculate that DHEA supplements may alleviate the symptoms caused by estrogen deficiency. A study that administered 50 mg of DHEA to 22 women found hot flash scores decreased 50% from baseline to week 5 of treatment [71
]. In the HEAL Study, DHEA users had lower odds of hot flashes than non-EBS users. Our findings, based on 24 users, support that DHEA use may reduce hot flashes.
This study has several important limitations. First, the analysis relied on self-reported EBS use. Although our HRQOL and symptom data were collected, on average, 10 months after the information on EBS use that was collected, it is possible that the lower HRQOL or the symptoms experienced by women who took EBS were what motivated EBS use. This might bias our results towards the null value, underestimate the associations of EBS use with better health-related outcomes, or yield a false association of EBS use with poorer HRQOL or severe fatigue or other symptoms. Second, we were unable to rule out the possibility that some women might have changed their number or type of EBS they used, or non-EBS-users may have become users during an average of 10 month interval between our two surveys. If these events occurred, they would have biased our results toward the null, limiting our ability to detect associations with EBS use. Third, we did not collect some important information regarding EBS use such as when EBS use was initiated, duration or frequency of use, dosage level of supplements taken, or reasons for use. Furthermore, as this study is exploratory, we did not adjust for multiple comparisons. Clearly limitations restrict interpretation of observed associations. The results do provide preliminary information for future epidemiologic studies or clinical trials and add to the sparse literature on the association of EBS use with health-related outcomes.
We believe that this is the first epidemiologic analysis examining the potential association of overall EBS use, number of EBS types, and eleven commonly used types of EBS with multiple health-related outcomes. EBS use among breast cancer survivors is common, and data showing the efficacy of these agents (or lack thereof) on symptoms and HRQOL would be useful to survivors and their healthcare providers.