Reference
Laidlaw M, Cockerline CA, Sepkovic DW. Effects of a breast-health herbal formula supplement on estrogen metabolism in pre- and post-menopausal women not taking hormonal contraceptives or supplements: a randomized controlled trial. Breast Cancer. 2010;4:85-95.
Design
Prospective, double-blind, placebo-controlled, parallel study. Subjects were recruited to 1 of 2 arms of the study. One arm consisted of premenopausal women not using hormonal contraceptives, while the other consisted of postmenopausal women not receiving hormone replacement therapy (HRT). Each arm of the study was carried out concurrently and in one phase, with no washout period.
Participants
Forty-seven premenopausal and 49 postmenopausal women were recruited for the study, and the data for 68 subjects was used in the statistical analysis.
Intervention
Subjects were divided by random allocation into treatment and placebo groups. The treatment supplement (femMED Breast Health) contained 200 mg indole-3-carbinol, 10 mg HMR lignan, 100 mg milk thistle, 75 mg calcium glucarate, 75 mg Schisandra chinensis, 50 mg stinging nettle, and 10 mcg vitamin D, and each woman consumed 2 capsules daily either treatment or placebo for 28 days.
Outcome Measures
Blood samples and first morning urine samples were collected and analyzed at day 0 and day 28. Blood samples were analysed for serum enterolactone concentrations. First morning random urine samples were collected and analyzed for creatinine and estrogen metabolites. Repeated measures ANOVA statistical testing was performed to compare the treatment group to placebo.
Key Findings
femMED Breast Health significantly increased estrogen C-2 hydroxylation. In both pre- and postmenopausal women, treatment supplementation resulted in a statistically significant increase (P<0.05) in urinary 2-hydroxyestrone concentrations (2-OHE). In the premenopausal group, treatment resulted in an increase in the estrogen metabolite ratio, 2:16α-OHE. In pre- and postmenopausal women combined, treatment supplementation produced a significant increase in urinary 2-OHE concentration. There was also a trend (P=0.074) toward an increased 2:16α-OHE ratio in the combined group. There were no significant increases in serum enterolactone concentrations in the treatment or placebo groups.
Practice Implications
It is estimated that 230,480 women will be diagnosed with and 39,520 women will die of cancer of the breast in 2011.1 Several of the known risk factors for breast cancer are associated with estrogen exposure, namely early menstruation, late menopause, late or no pregnancy, and use of oral contraceptives or hormone replacement therapy. Alcohol, which can impair the liver’s ability to metabolize estrogen, is considered a risk, and the level of risk rises as the amount of alcohol consumed rises. Alcohol ingestion can lead to a rise in levels of both natural and synthetic estrogens. Being overweight or obese is associated with increased risk of breast cancer, especially for women after menopause. Since adipose tissue is the body’s main source of estrogen after menopause, having more adipose tissue means having higher estrogen levels, which can increase breast cancer risk. It is estimated that about 80% of breast cancers are estrogen-receptor positive.2 Avoiding known risk factors for breast cancer, such as alcohol ingestion and use of oral contraceptives and HRT, and maintaining a healthy body weight and getting regular physical activity are important measures for breast cancer prevention. Dietary supplements may play a supportive role in reducing risk.
Estrogen Metabolite Ratio and Risk Reduction
Studies have found that 2 specific metabolites of estrogen metabolism affect breast cancer susceptibility. As urinary levels of 2-hydroxyestrone (2-OHE) increase and levels of 16-alpha-hydroxyestrone decrease (16α-OHE), the risk for breast cancer decreases, because 16α-OHE is an independent risk factor for breast cancer. In most human trials, results are presented as a ratio of urinary 2-OHE to urinary 16α-OHE, and the higher the ratio, the more favorable the risk reduction for breast cancer. The optimal urinary ratio of 2-OHE to 16α-OHE is 2:1, while a 1:1 ratio is associated with increased cancer risk. This ratio is commonly referred to as the estrogen metabolite ratio (EMR).3–6
In a prospective study, 10,786 Italian women were followed for 5.5 years, and the EMR was measured at baseline in all of these women. The number of diagnosed breast cancer cases that developed during the study period was compared with baseline EMRs. In premenopausal women, those with the higher ratio had, on average, an odds ratio for breast cancer of 0.58, compared to those with a lower ratio.3
In a case-control trial of postmenopausal there was a strong inverse relationship between EMR and breast cancer, and a strong positive relationship between 16-α OHE and breast cancer.4 In another prospective trial, researchers reported that postmenopausal women who developed breast cancer over the 8 years of the trial had, on average, a 15% lower EMR than matched controls. Also, women whose ratio was in the highest third had a 30% lower risk of breast cancer development than those in the lower two-thirds EMR.7
Mechanism of Action
The ingredients in the supplement utilized in this clinical study may modulate estrogen metabolism and estrogen levels in a number of ways. In order to apply this study and formulation to clinical practice, it is important to understand the mechanism of action of the ingredients and their impact on estrogen levels.
The most widely studied component, indole-3-carbinol, helps maintain healthy estrogen levels in the body by balancing estrogen metabolites. In vitro studies have found that indole-3-carbinol can alter the hepatic microsomal metabolism of estrogen. Specifically, indole-3-carbinol can up regulate phase I and phase II enzymes, which leads to increased capacity for detoxification and inhibition of carcinogens. Thus, indole-3-carbinol can shift the pathway by which estrogens are metabolized. Many of the indole-3-carbinol metabolites have antiestrogenic activity, competing with estrogen for binding sites. There is also evidence that indole-3-carbinol can inhibit cell proliferation and induce apoptosis in tumors.8–13
Milk thistle exerts phytoestrogenic properties. It contains compounds that act as estrogen agonists, blocking estrogen receptors to endogenous estrogen and preventing estrogen from delivering its message to breast tumor cells to divide and multiply. Phytoestrogens may also inhibit the local production of estrogens from circulating precursors in breast tissue. Milk thistle has also been well researched for its liver protectant effects and ability to enhance detoxification.14–17
Calcium-D-glucarate has anticarcinogenic properties and has been shown to inhibit carcinogenesis during both the promotion and the initiation phases. Its anticarcinogenic properties are attributed in part to its ability to increase glucuronidation and excretion of potentially toxic compounds. Specifically, it inhibits beta-glucuronidase activity, which allows the body to excrete hormones such as estrogen before they can become reabsorbed. This reduces endogenous estrogen in the body, which helps maintain a healthy estrogen balance.18–20
Schisandra chinensis contains dibenzo[a,c]cyclooctadiene lignans, a type of phytoestrogen. In general, consumption of phytoestrogens is associated with a lower risk of breast cancer. In addition, schisandra may also decrease endogenous sex hormone exposure by increasing the excretion of their metabolites.15,21
The use of dietary supplements that can improve estrogen balance should be considered as part of an overall approach for breast cancer prevention.
The HMR lignans are Norway spruce polyphenols, which share a number of structural similarities with mammalian estrogens. Epidemiological and experimental research shows that a lignan-rich diet may reduce the risk of human breast cancer. Serum enterolactone, a metabolite of HMR lignan with phytoestrogenic properties, is inversely correlated with breast cancer risk. In rat studies, HMR lignans have been shown to reduce both tumor volume and growth.14,16,22–27
There is mounting research regarding on the role of vitamin D for reducing breast cancer risk. Specifically, 1,25-OH D3, the biologically active form of vitamin D, has been found to act as a potent negative regulator of breast cancer cells.28–30 Vitamin D acts through the vitamin D receptor, a nuclear transcription regulating factor that signals the synthesis of proteins involved in cell cycle regulation. Many of these proteins regulate proliferation, differentiation, and survival of breast cancer cells. When vitamin D status is suboptimal, these activities are impaired.31,32 Research has also shown that vitamin D can down-regulate estrogen receptors as a mechanism of reducing breast cancer cell growth.33 Several well-researched and -designed cohort studies have reported reductions in breast cancer risk among women with higher levels of dietary or supplemental vitamin D intake.34–37
Practice Implications
The ingredients in the supplement formula studied have documented evidence of beneficial effects on estrogen balance, with varying mechanisms of action; however, this is the first human clinical study to examine the impact and possible synergistic value of a combination formula on estrogen metabolism and breast cancer risk. While further research with a higher number of subjects is warranted, the results obtained in this clinical study are promising.
The use of dietary supplements that can improve estrogen balance should be considered as part of an overall approach for breast cancer prevention, along with dietary and lifestyle modifications known to reduce risk such as exercise, maintaining a healthy body weight, not smoking, limiting alcohol intake, and avoidance of estrogen.
While there is no way to test the efficacy of many of our interventions, supplements that can modulate estrogen metabolites have a distinct advantage in this area. Clinicians can assess the impact of the intervention though urinary testing of 2-OHE and 16-OHE, which should instill confidence in both patients and practitioners.
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