1601 A Pilot and Feasibility Study on the Effects of Naturopathic Botanical and Dietary Interventions on Sex Steroid Hormone Metabolism in Premenopausal Women Heather Greenlee,1 Charlotte Atkinson,2 Frank Z. Stanczyk,3 and Johanna W. Lampe2 1Mailman School of Public Health, Columbia University, New York, New York; 2Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington; and 3Keck School of Medicine, University of Southern California, Los Angeles, California Abstract Naturopathic physicians commonly make dietary and/or insulin-like growth factor-I, insulin-like growth factor dietary supplement recommendations for breast cancer binding protein-3, and leptin). Serum samples collected prevention. This placebo-controlled, parallel-arm, pilot during the mid-luteal phase of cycles 1 and 5 were analyzed study tested the effects of two naturopathic interventions for total estradiol, free estradiol, and sex hormone-binding over five menstrual cycles on sex steroid hormones and globulin. Urine samples collected during the late follicular metabolic markers in 40 healthy premenopausal women. phase of cycles 1 and 5 were analyzed for 2-hydroxyestrone The intervention arms were as follows: combination and 16A-hydroxyestrone. During the early follicular phase, botanical supplement (Curcuma longa, Cynara scolymus, compared with placebo, the botanical supplement decreased Rosmarinus officinalis, Schisandra chinensis, Silybum mar- dehydroepiandrosterone (À13.2%; P = 0.02), dehydroepian- inum, and Taraxacum officinalis; n = 15), dietary changes drosterone-sulfate (À14.6%; P = 0.07), androstenedione (3 servings/d crucifers or dark leafy greens, 30 g/d fiber, 1-2 (À8.6%; P = 0.05), and estrone-sulfate (À12.0%; P = 0.08). liters/d water, and limiting caffeine and alcohol consump- No other trends or statistically significant changes were tion to 1 serving each/wk; n = 10), and placebo (n = 15). observed. When comparing dietary changes with placebo, Early-and late-follicular phase serum samples from cycles 1 no statistically significant differences were observed. and 5 were analyzed for estrogens (estrone, estrone-sulfate, Overall, in this pilot study, the naturopathic interventions total estradiol, and free estradiol), androgens (dehydroe- had no substantial effects on estrogen measures. Early- piandrosterone, dehydroepiandrosterone-sulfate, androste- follicular phase androgens decreased with the botanical nedione, total testosterone, and free testosterone), sex supplement. (Cancer Epidemiol Biomarkers Prev 2007; hormone-binding globulin, and metabolic markers (insulin, 16(8):1601–9) Introduction Epidemiologic studies suggest that premenopausal women menopausal women at high breast cancer risk (7). The recent with higher exposure to endogenous sex steroid hormones, Study of Tamoxifen and Raloxifene trial showed that ralox- especially estrogens and androgens, have increased risk of ifene is as effective as tamoxifen in reducingthe risk of developingpostmenopausal breast cancer (1, 2). The epidemi- invasive breast cancer (8). However, the Study of Tamoxifen ologic literature is inconsistent about the relationship between and Raloxifene trial was limited to postmenopausal women. premenopausal urinary estrogen metabolites (2-hydroxy- Pilot studies of raloxifene have been conducted in premeno- estrone, 16a-hydroxyestrone, and their ratio; refs. 3, 4) and pausal women but have shown increases in estradiol concen- metabolic markers [insulin, insulin-like growth factor (IGF)-I, trations and decreases in bone mineral density (9, 10). Surgical IGF bindingprotein-3, and leptin; refs. 5, 6] and subsequent breast cancer prevention options include mastectomy and breast cancer risk. The incidence of breast cancer is low before oophorectomy (11-13), yet these options are undesirable for menopause. However, the time before menopause may be a many women given their side effects (e.g., loss of ovarian critical period for institutingpreventive interventions to alter estrogen production and increased risk of endometrial cancer) hormonal and metabolic factors that could influence both and implications (e.g., disfigurement and inability to conceive). premenopausal and postmenopausal breast cancer risk. Some women may prefer to take a more proactive role in their Effective breast cancer prevention strategies for women to breast cancer prevention strategies by adopting lifestyle begin while premenopausal are limited. Tamoxifen, a selective modifications. Many women are usingforms of complemen- estrogen receptor modulator, is the only U.S. Food and Drug tary and alternative medicine for breast cancer prevention Administration–approved chemopreventive agent for pre- approaches and/or options that are more attune with their personal belief systems (14). Licensed naturopathic physicians (15) are a group of complementary and alternative medicine providers who often Received 11/5/06; revised 4/4/07; accepted 5/30/07. counsel women on dietary and lifestyle strategies to reduce Grant support: National Center for Complementary and Alternative Medicine F32AT00794 their breast cancer risk. Naturopathic physicians commonly (PI: Greenlee), National Cancer Institute R25CA09406 (PI: Neugut), National Cancer Institute recommend dietary changes and botanical supplements to R25CA94880 (PI: White), and the Fred Hutchinson Cancer Research Center. premenopausal women who are concerned about their breast The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. cancer risk, with the aim of decreasingendogenousexposure Section 1734 solely to indicate this fact. to sex steroid hormones and the ultimate goal of decreasing Requests for reprints: Heather Greenlee, Department of Epidemiology, Mailman School of premenopausal and postmenopausal breast cancer risk. Natu- Public Health, Columbia University, 7th Floor, 722 West 168th Street, New York, NY 10028. Phone: 212-342-4130; Fax: 212-305-9413. E-mail: [email protected] ropathic physicians hypothesize that specific foods and Copyright D 2007 American Association for Cancer Research. botanical supplements increase hepatic conjugation of sex doi:10.1158/1055-9965.EPI-06-0938 steroid hormones and aid in the urinary and fecal excretion of Cancer Epidemiol Biomarkers Prev 2007;16(8). August2007 Downloaded from cebp.aacrjournals.org on September 23, 2021. © 2007 American Association for Cancer Research. 1602 Naturopathic Interventions in Premenopausal Women sex steroid hormones (16, 17). Typical dietary recommenda- questionnaire (developed by the Nutrition Assessment Shared tions (and rationale for use) presented by naturopathic Resource of the Fred Hutchinson Cancer Research Center) and physicians include the following: increasing intake of specific a baseline questionnaire (demographics, medical history, and vegetables, including cruciferous vegetables (high in indole-3- use of complementary and alternative medicine), and their carbinol, which has been shown to shift estrogen metabolism height and weight were measured. Women were instructed on from the 16a-hydroxyestrone pathway toward the less how to complete a daily menstrual cycle and lifestyle tracking carcinogenic 2-hydroxyestrone pathway; ref. 18), beets (to booklet and were asked to call the study phone line when they decrease intestinal transit time and provide folic acid, a methyl started their next menstrual cycle (cycle 1, day 1). Women were group donor in many hepatic enzyme systems; refs. 16, 17), scheduled for an early-follicular phase (cycle 1, days 3-5) and a and dark leafy greens (also high in folic acid; refs. 16, 17); late-follicular phase (cycle 1, days 9-11) clinic visit for a fasting increasingdietary fiber (to decrease intestinal transit time and morningblood draw and spot urine collection. At the late- decrease the bioavailability of endogenous hormones and follicular phase clinic visit, women were provided with metabolites; ref. 19); increasingwater consumption (to increase urinary ovulation test kits (Clearblue) and instructed to begin overall hormone excretion rates through urine and bowel usingthe kits a few days before their anticipated ovulation movements; refs. 16, 17); and decreasingintake of caffeine and date (beginning fday 11 of their menstrual cycle). Once alcohol (both metabolized by hepatic enzymes; refs. 16, 17). ovulation was detected, women called the study phone line Recommendations for botanical supplements may include and were scheduled to attend a mid-luteal phase clinic visit botanicals that increase bile production and excretion, such 5 days after ovulation for a fastingmorningblood draw and as Curcuma longa (turmeric) root, Cynara scolymus (artichoke) spot urine collection. If the kit did not detect ovulation, the leaf, Rosmarinus officinalis (rosemary) leaf, Schisandra chinensis mid-luteal phase clinic visit was scheduled between days 19 (schisandra) berry, and Taraxacum officinalis (dandelion) root and 23 of her menstrual cycle. (to increase the rate at which endogenous hormone metabolites Randomization. At the last clinic visit (mid-luteal phase are excreted; refs. 17, 20, 21), and botanicals that increase visit) of the run-in phase, eligibility and interest in participat- hepatocyte regeneration, such as Silybum marianum (milk ingin the study was confirmed, and a total of 40 participants thistle) seed (to allow for more hepatocytes to be available to were randomized to three study arms usinga