A pilot clinical study of resveratrol in postmenopausal women with high body mass index: effects on systemic sex steroid hormones

Journal of Translational Medicine

Terri L Cornelison¹  Wade M Chew²  Catherine A Cordova²  Valerie D Butler²  Chiu-Hsieh Hsu²  Brandy M Heckman-Stoddard¹  Linda L Garland²  H-H Sherry Chow² 

[1] Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland;University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, 85724, AZ, USA

关键词: Post-menopausal women;    High adiposity;    Sex steroid hormones;    Resveratrol;   

Others  :  1148473
DOI  :  10.1186/s12967-014-0223-0

 received in 2014-04-17, accepted in 2014-08-01,  发布年份 2014

【 摘 要 】

Background

Breast cancer risk is partially determined by several hormone-related factors. Preclinical and clinical studies suggested that resveratrol may modulate these hormonal factors.

Methods

We conducted a pilot study in postmenopausal women with high body mass index (BMI ≥ 25 kg/m²) to determine the clinical effect of resveratrol on systemic sex steroid hormones. Forty subjects initiated the resveratrol intervention (1 gm daily for 12 weeks) with six withdrawn early due to adverse events (AEs). Thirty-four subjects completed the intervention.

Results

Resveratrol intervention did not result in significant changes in serum concentrations of estradiol, estrone, and testosterone but led to an average of 10% increase in the concentrations of sex steroid hormone binding globulin (SHBG). Resveratrol intervention resulted in an average of 73% increase in urinary 2-hydroxyestrone (2-OHE₁) levels leading to a favorable change in urinary 2-OHE₁/16α-OHE₁ ratio. One participant had asymptomatic Grade 4 elevation of liver enzymes at the end of study intervention. Two subjects had Grade 3 skin rashes. The remaining adverse events were Grade 1 or 2 events. The most common adverse events were diarrhea and increased total cholesterol, reported in 30% and 27.5% of the subjects, respectively.

Conclusion

We conclude that among overweight and obese postmenopausal women, daily 1 gm dose of resveratrol has favorable effects on estrogen metabolism and SHBG. Further placebo-controlled studies are needed to confirm our findings on these hormone-related breast cancer risk factors and the attribution of the adverse effects observed in the study population.

Trial registration

ClinicalTrials.gov: NCT01370889 webcite.

【 授权许可】

   
2014 Chow et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Lukanova A, Lundin E, Zeleniuch-Jacquotte A, Muti P, Mure A, Rinaldi S, Dossus L, Micheli A, Arslan A, Lenner P, Shore RE, Krogh V, Koenig KL, Riboli E, Berrino F, Hallmans G, Stattin P, Toniolo P, Kaaks R: Body mass index, circulating levels of sex-steroid hormones, IGF-I and IGF-binding protein-3: a cross-sectional study in healthy women. Eur J Endocrinol 2004, 150:161-171.
• [2]Boyapati SM, Shu XO, Gao YT, Dai Q, Yu H, Cheng JR, Jin F, Zheng W: Correlation of blood sex steroid hormones with body size, body fat distribution, and other known risk factors for breast cancer in post-menopausal Chinese women. Cancer Causes Control 2004, 15:305-311.
• [3]Kaye SA, Folsom AR, Soler JT, Prineas RJ, Potter JD: Associations of body mass and fat distribution with sex hormone concentrations in postmenopausal women. Int J Epidemiol 1991, 20:151-156.
• [4]Mahabir S, Baer DJ, Johnson LL, Hartman TJ, Dorgan JF, Campbell WS, Clevidence BA, Taylor PR: Usefulness of body mass index as a sufficient adiposity measurement for sex hormone concentration associations in postmenopausal women. Cancer Epidemiol Biomarkers Prev 2006, 15:2502-2507.
• [5]Key TJ, Appleby PN, Reeves GK, Roddam A, Dorgan JF, Longcope C, Stanczyk FZ, Stephenson HE Jr, Falk RT, Miller R, Schatzkin A, Allen DS, Fentiman IS, Key TJ, Wang DY, Dowsett M, Thomas HV, Hankinson SE, Toniolo P, Akhmedkhanov A, Koenig K, Shore RE, Zeleniuch-Jacquotte A, Berrino F, Muti P, Micheli A, Krogh V, Sieri S, Pala V, Venturelli E, et al.: Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 2003, 95:1218-1226.
• [6]Key T, Appleby P, Barnes I, Reeves G: Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 2002, 94:606-616.
• [7]Zhu BT, Han GZ, Shim JY, Wen Y, Jiang XR: Quantitative structure-activity relationship of various endogenous estrogen metabolites for human estrogen receptor alpha and beta subtypes: insights into the structural determinants favoring a differential subtype binding. Endocrinology 2006, 147:4132-4150.
• [8]Yue W, Santen RJ, Wang JP, Li Y, Verderame MF, Bocchinfuso WP, Korach KS, Devanesan P, Todorovic R, Rogan EG, Cavalieri EL: Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis. J Steroid Biochem Mol Biol 2003, 86:477-486.
• [9]Ursin G, London S, Stanczyk FZ, Gentzschein E, Paganini-Hill A, Ross RK, Pike MC: Urinary 2-hydroxyestrone/16alpha-hydroxyestrone ratio and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 1999, 91:1067-1072.
• [10]Fuhrman BJ, Schairer C, Gail MH, Boyd-Morin J, Xu X, Sue LY, Buys SS, Isaacs C, Keefer LK, Veenstra TD, Berg CD, Hoover RN, Ziegler RG: Estrogen metabolism and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 2012, 104:326-339.
• [11]Serrero G, Lu R: Effect of resveratrol on the expression of autocrine growth modulators in human breast cancer cells. Antioxid Redox Signal 2001, 3:969-979.
• [12]Alkhalaf M: Resveratrol-induced growth inhibition in MDA-MB-231 breast cancer cells is associated with mitogen-activated protein kinase signaling and protein translation. Eur J Cancer Prev 2007, 16:334-341.
• [13]Bhat KP, Lantvit D, Christov K, Mehta RG, Moon RC, Pezzuto JM: Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models. Cancer Res 2001, 61:7456-7463.
• [14]Bowers JL, Tyulmenkov VV, Jernigan SC, Klinge CM: Resveratrol acts as a mixed agonist/antagonist for estrogen receptors alpha and beta. Endocrinology 2000, 141:3657-3667.
• [15]Wang Y, Lee KW, Chan FL, Chen S, Leung LK: The red wine polyphenol resveratrol displays bilevel inhibition on aromatase in breast cancer cells. Toxicol Sci 2006, 92:71-77.
• [16]Eng ET, Williams D, Mandava U, Kirma N, Tekmal RR, Chen S: Anti-aromatase chemicals in red wine. Ann N Y Acad Sci 2002, 963:239-246.
• [17]Ciolino HP, Daschner PJ, Yeh GC: Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor. Cancer Res 1998, 58:5707-5712.
• [18]Yueh MF, Kawahara M, Raucy J: Cell-based high-throughput bioassays to assess induction and inhibition of CYP1A enzymes. Toxicol In Vitro 2005, 19:275-287.
• [19]Revel A, Raanani H, Younglai E, Xu J, Rogers I, Han R, Savouret JF, Casper RF: Resveratrol, a natural aryl hydrocarbon receptor antagonist, protects lung from DNA damage and apoptosis caused by benzo[a]pyrene. J Appl Toxicol 2003, 23:255-261.
• [20]Piver B, Berthou F, Dreano Y, Lucas D: Inhibition of CYP3A, CYP1A and CYP2E1 activities by resveratrol and other non volatile red wine components. Toxicol Lett 2001, 125:83-91.
• [21]Chang TK, Yeung RK: Effect of trans-resveratrol on 7-benzyloxy-4-trifluoromethylcoumarin O-dealkylation catalyzed by human recombinant CYP3A4 and CYP3A5. Can J Physiol Pharmacol 2001, 79:220-226.
• [22]Chow HH, Garland LL, Hsu CH, Vining DR, Chew WM, Miller JA, Perloff M, Crowell JA, Alberts DS: Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. Cancer Prev Res (Phila) 2010, 3:1168-1175.
• [23]Tai SS, Welch MJ: Development and evaluation of a reference measurement procedure for the determination of estradiol-17beta in human serum using isotope-dilution liquid chromatography-tandem mass spectrometry. Anal Chem 2005, 77:6359-6363.
• [24]Moal V, Mathieu E, Reynier P, Malthiery Y, Gallois Y: Low serum testosterone assayed by liquid chromatography-tandem mass spectrometry. Comparison with five immunoassay techniques. Clin Chim Acta 2007, 386:12-19.
• [25]Boocock D, Patel KR, Faust GES, Normolle DP, Marczylo TH, Crowell JA, Brenner DE, Booth TD, Gescher A, Steward WP: Quantitation of trans-resveratrol and detection of its metabolites in human plasma and urine by high performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 2006, 848:182-187.
• [26]Hunter DJ, Willett WC: Diet, body size, and breast cancer. Epidemiol Rev 1993, 15:110-132.
• [27]Stephenson GD, Rose DP: Breast cancer and obesity: an update. Nutr Cancer 2003, 45:1-16.
• [28]Pugeat M, Nader N, Hogeveen K, Raverot G, Dechaud H, Grenot C: Sex hormone-binding globulin gene expression in the liver: drugs and the metabolic syndrome. Mol Cell Endocrinol 2010, 316:53-59.
• [29]Sodergard R, Backstrom T, Shanbhag V, Carstensen H: Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature. J Steroid Biochem 1982, 16:801-810.
• [30]Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF: Pilot study: effect of 3,3′-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer 2004, 50:161-167.
• [31]Reed GA, Peterson KS, Smith HJ, Gray JC, Sullivan DK, Mayo MS, Crowell JA, Hurwitz A: A phase I study of indole-3-carbinol in women: tolerability and effects. Cancer Epidemiol Biomarkers Prev 2005, 14:1953-1960.
• [32]Wong GY, Bradlow L, Sepkovic D, Mehl S, Mailman J, Osborne MP: Dose-ranging study of indole-3-carbinol for breast cancer prevention. J Cell Biochem Suppl 1997, 28–29:111-116.
• [33]Brown VA, Patel KR, Viskaduraki M, Crowell JA, Perloff M, Booth TD, Vasilinin G, Sen A, Schinas AM, Piccirilli G, Brown K, Steward WP, Gescher AJ, Brenner DE: Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis. Cancer Res 2010, 70:9003-9011.
• [34]Crandall JP, Oram V, Trandafirescu G, Reid M, Kishore P, Hawkins M, Cohen HW, Barzilai N: Pilot study of resveratrol in older adults with impaired glucose tolerance. J Gerontol A Biol Sci Med Sci 2012, 67:1307-1312.
• [35]Movahed A, Nabipour I, Lieben Louis X, Thandapilly SJ, Yu L, Kalantarhormozi M, Rekabpour SJ, Netticadan T: Antihyperglycemic effects of short term resveratrol supplementation in type 2 diabetic patients. Evid Based Complement Alternat Med 2013, 2013:851267.