Shufelt C, Bairey Merz CN, Yang YC, Kirschner J, Polk D, Stanczyk F, Paul-Labrador M, Braunstein GD. Red versus white wine as a nutritional aromatase inhibitor in premenopausal women. J Women’s Health, 2011;DOI: 10.1089/jwh.2011.3001
Background: An increased risk of breast cancer is associated with alcohol consumption; however, it is controversial whether red wine increases this risk. Aromatase inhibitors (AIs) prevent the conversion of androgens to estrogen and occur naturally in grapes, grape juice, and red, but not white wine. We tested whether red wine is a nutritional AI in premenopausal women.
Methods: In a cross-over design, 36 women (mean age [SD], 36  years) were assigned to 8 ounces (237 mL) of red wine daily then white wine for 1 month each, or the reverse. Blood was collected twice during the menstrual cycle for measurement of estradiol (E2), estrone (E1), androstenedione (A), total and free testosterone (T), sex hormone binding globulin (SHBG), luteinizing hormone (LH), and follicle stimulating hormone (FSH).
Results: Red wine demonstrated higher free T vs. white wine (mean difference 0.64 pg/mL [0.2 SE], p = 0.009) and lower SHBG (mean difference – 5.0 nmol/L [1.9 SE], p = 0.007). E2 levels were lower in red vs. white wine but not statistically significant. LH was significantly higher in red vs. white wine (mean difference 2.3 mIU/mL [1.3 SE], p = 0.027); however, FSH was not.
Conclusion: Red wine is associated with significantly higher free T and lower SHBG levels, as well as a significant higher LH level vs. white wine in healthy premenopausal women. These data suggest that red wine is a nutritional AI and may explain the observation that red wine does not appear to increase breast cancer risk.
Forum reviewers thought that this was a well-done clinical trial producing evidence of differences between red wine and white wine in terms of their effects on indices of aromatase inhibition. The authors refer to a number of other papers suggesting that the higher polyphenol content of red wine could relate to the risk of breast cancer.
One reviewer stated that “alcohol is a co-factor in breast cancer only if there is a folate deficiency. Adequate folate levels may prevent any increase in risk of breast cancer from alcohol intake. Given that alcohol increases circulating estrogens, an aromatase inhibitor could therefore be protective against breast cancer.” Another reviewer commented that “the health impact of non-alcoholic substances in red or white wine or in beer is difficult to measure in epidemiologic studies, so intervention studies such as this are needed.”
Another reviewer agreed: “The authors themselves admit that their research is only a beginning. But it is a good, useful, and timely one.” Another added: “I like this kind of paper. It may be chipping away at the confusion surrounding and fog covering the possible causal relationship of alcohol to breast cancer (though, even if this mechanism is found to be operative, we have a long way to go).”
However, other Forum reviewer pointed out problems with the study: “The power of the study is poor, there is no placebo group, and the days of the cycle when women were tested is not indicated. Moreover, these values will fluctuate from woman to woman from cycle to cycle, and no baseline data were collected on this patient population for comparison. The conclusion is not supported by the data.”
Other Forum reviewers had concerns with certain statements of the authors suggesting a lack of effect of red wine on breast cancer risk. The authors did not point out that many studies have shown that risk increases for all drinkers, regardless of type of beverage consumed. The authors failed to refer to papers with evidence of increased risk of breast cancer among consumers in red wine-drinking populations.1-5 Further, a recent paper from a large study in the United States by Newcomb et al6 stated: “Wine consumption was not associated with risk of breast cancer (OR, 1.01; 95% CI, 0.99-1.02) and no differential was observed between red and white wine.”
One Forum reviewer pointed out that the authors did not describe “what may be the major issues concerning alcohol and breast cancer: the effects of folate deficiency7 and binge-drinking8 (and not whether to choose white or red wine). The minor changes of proxy endpoints of estrogens found in this study cannot override the results of large population studies.”
Another Forum reviewer thought that “the link of wine to aromatase inhibition in this study is rather vague, especially considering that there is not positive evidence for a decrease in estradiol.” He did not believe that we can derive important conclusions about red wine and breast cancer from these analyses.
References for Forum critique:
1. La Vecchia C, et al. Alcohol and breast cancer: Update from an Italian case-control study. Eur J Cancer Clin Oncol 1989;25:1711-1717.
2. Levi F, et al. Alcohol and breast cancer in the Swiss canton of Vaud. Eur J Cancer 1996;32A:2108-2113.
3. Viel J-F, et al. Alcoholic calories, red wine consumption and breast cancer among premenopausal women. Eur J Epidemiol 1997;13:639-643.
4. Ferraroni M, et al. Alcohol consumption and risk of breast cancer: a multicentre Italian case-control study. Eur J Cancer 1998;34:1403-1409.
5. Li Y, et al. Wine, liquor, beer and the risk of breast cancer in a large population. Eur J Cancer 2009;45:843-850.
6. Newcomb PA, et al. No difference between red wine or white wine consumption and breast cancer risk. Cancer Epidemiol Biomarkers Prev 2009;18:1007-1010.
7. Tjønneland A, et al. Folate intake, alcohol and risk of breast cancer among postmenopausal women in Denmark. Eur J Clin Nutr 2006;60:280-286.
8. Mørch LS, et al. Alcohol drinking, consumption patterns and breast cancer among Danish nurses: a cohort study. European Journal of Public Health 2007;17:624-629
Aromatase inhibitors (AIs) prevent the conversion of androgens to estrogens, and could play a role in the development of breast cancer. This study of 36 pre-menopausal women consisted of a cross-over intervention trial to determine if there were differences between red wine and white wine in their effects on AIs. Subjects sequentially consumed eight ounces of red wine, followed by white wine (or vice versa), each beverage for a one-month period. The investigators concluded that red wine, but not white wine, was associated with significant effects on some indices of estrogen metabolism; free testosterone and luteinizing hormone were increased, but no significant differences were noted in estrogen levels.
Forum reviewers considered the results interesting and that they contribute to our understanding of the relation of wine to hormonal levels. On the other hand, they were concerned about methodological problems, including a lack of baseline data and variations in the timing during the menstrual period of blood sampling (which could affect estrogen levels). Also, no significant effect of the interventions was seen on blood levels of estradiol.
Further, the Forum thought that it should be pointed out that data are inconsistent on the relation of red wine consumption to the risk of breast cancer; many studies do not show beverage-specific effects on risk. More research will be needed to determine if the polyphenols in red wine can play a role in lowering the risk of breast cancer.
Comments on this paper were provided by the following members of the International Scientific Forum on Alcohol Research:
Lynn Gretkowski, MD, Obstetrics/Gynecology, Mountainview, CA, Stanford University, Stanford, CA, USA
Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark
Creina Stockley, clinical pharmacology, Health and Regulatory Information Manager, Australian Wine Research Institute, Glen Osmond, South Australia, Australia
Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA
Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway
Ulrich Keil, MD, PhD, Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa
Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy
Gordon Troup, MSc, DSc, School of Physics, Monash University, Victoria, Australia
R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA