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This protocol was developed for practitioners using Fullscript in Canada and the templates cannot be applied to accounts operating outside of Canada

Protocol development in integrative medicine is not typically a simple process. Individuals require individualized care, and what works for one patient may not work for another.

To establish these protocols, we first developed a Rating Scale that could be used to discern the rigor of evidence supporting a specific nutrient’s therapeutic effect.

The following protocols were developed using only A through C-quality evidence.

Qualifying studies
Minimum requirements
Systematic review or meta-analysis of human trials
RDBPC human trials
2+ studies and/or 1 study with 50 + subjects
RDBPC human trials
1 study

Xenoestrogens are synthetic or natural foreign substances that mimic endogenous estrogens by imperfectly binding to the body’s estrogen receptors. (33) They are able to alter gene expression and cellular function through the initiation of various signaling cascades. (45) Chronic exposure to xenoestrogens obtained through the environment, the diet, and other sources such as product packaging, can impact human health. (33)

Xenoestrogens are widely referred to as endocrine-disrupting chemicals (EDCs). EDCs can interrupt natural production, action, and elimination of natural hormones. (33)  Xenoestrogens are associated with a wide variety of health concerns, including obesity, diabetes, asthma, cancer, altered hormonal and immune functions, and disrupted neurodevelopment. Exposure to xenoestrogens can have important implications during pregnancy and lactation, as EDCs may transfer from mother to fetus or to breastfeeding children. (33)(45)

The following list provides some of the contributing sources of xenoestrogens: 

  • Δ9-Tetrahydrocannabinol (THC)
  • By-products from food preservatives (e.g., butylated hydroxyanisole) and industrial surfactants (e.g., alkylphenols)
  • By-products from plastics (e.g., bisphenol A (BPA) in water and food packaging, thermal coating on paper receipts, inner linings in food cans, dental repair materials, etc.)
  • Consumption of fish, animals, and/or their by-products exposed to water contaminated by urban sewage or wastewater treatment plants
  • Dietary phytoestrogens (e.g., genistein, daidzein, resveratrol, S-equol) 
  • Mycoestrogens (e.g., mycotoxins produced from some fungal strains found in the food chain)
  • Pesticides (e.g., dieldrin, endosulfan), herbicides (e.g., chlordecone, methoxychlor), dioxins (e.g., 2,3,7,8-tetrachloro-p-dioxin – TCDD)
  • Pharmaceuticals (e.g., ethinyl estradiol, equine, mestranol, tamoxifen, trenbolone)
  • Personal care products (e.g., containing butylparaben, ethylparaben, methylparaben)
  • UV filters in sunscreens and cosmetic products (e.g., benzophenone-2, 4-methylbenzylidene camphor) (22)(24)(33)(45)

It is important to note that compared to other xenoestrogens, phytoestrogens do not bioaccumulate as they are reliably metabolized and excreted from the body. They may provide various health benefits including the promotion of antioxidant activity, cardiovascular health, and pro-apoptotic effects. However, they can also alter estrogen synthesis and metabolism through tissue-specific agonistic or antagonistic action. (22)

Please note that the following ingredients may either support estrogen production or increase its metabolism to counteract the disruptive effects of xenoestrogens caused by EDC’s interference with estrogen receptors. Practitioners may need to pre-emptively determine the direction of estrogenic imbalance prior to initiating a specific ingredient protocol.

200-400 mg, once per day, for 1-3 months (5)(6)(35)(49)

  • Increased 2OHE1/16α-OHE1 or 2OHE1/E3 ratios (indicator of estradiol metabolism) in pre- and postmenopausal healthy non-obese and healthy obese women, women at higher risk for estrogen-dependent breast cancer, cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), or systemic lupus erythematosus, and patients with recurrent respiratory papillomatosis (5)(6)(25)(27)(29)(35)(37)(43)(49)
  • Conjunctionally induced CYP1A2 and glutathione S-transferase activities, which may contribute to estradiol metabolism (35)
  • Increased 2OHE1/16α-OHE1 ratio in patients with wild-type CYP1A1 but not CYP1A1 Msp1 polymorphism, which may increase susceptibility to estrogen-related breast cancer (43)
  • Increased 2OHE1/16α-OHE1 ratios positively correlate with clinical responses in remission of papillomatous growth and reduced requirements for future surgeries (36)(37)
  • Increased regression of CIN and reduced itch, pain, lesion size, and severity of VIN (5)(29)
Indole-3-carbinol in the Fullscript catalog

Diindolylmethane (DIM)

100-200 mg, once or twice per day, for 3-6 weeks and up to one year (9)(12)(19)(44)

  • Increased the 2OHE1/16α-OHE1 ratio, indicating increased estrogen metabolism in pre- and postmenopausal women with early-stage breast cancer, in patients with prostate cancer, or in patients with thyroid proliferative disease  (9)(12)(34)(44)
  • Increased sex hormone-binding globulin and cortisol in women (9)(44)
  • Reduced the active metabolites of the xenoestrogen pharmaceutical tamoxifen during adjunct use, possibly reducing effectiveness (44)
  • DIM detected in prostate tissue with reduced nucleic androgen receptor expression and prostate-specific antigen (PSA) (15)
  • Increased BRCA1 to normalize protein expression in women with an increased breast cancer risk (19)
  • Reduced pelvic pain and improved bleeding pattern in women with endometriosis when used as an adjunct to the progestin medication dienogest, and reduced estradiol in endometriotic tissues (28)
  • Increased estrogen hydroxylation and DIM detection in thyroid tissue may have implications in modulation of thyroid proliferative disease and its risk of development (34)
Diindolylmethane in the Fullscript catalog

Black Cohosh (Cimicifuga/Actaea racemosa)

20 mg, twice per day, as Remifemin ®, or 40 mg, once per day, as CR BNO 1055 extract, for 3-6 months in postmenopausal women (2)(3)(14)(16)(21)(30)(31)(32)(38)(39)(47)(50)(51

  • Safely and effectively treated menopausal vasomotor symptoms (e.g., hot flushes) by 26% for up to six months by the first month of treatment (2)(3)(11)(14)(16)(21)(30)(31)(32)(38)(39)(41)(47)(51)
  • Increased sleep efficiency and physical domains in QoL scores, and decreased wake after sleep onset duration (16)
  • Improved anxiety and depression scores (30)
  • CR BNO 1055 possessed weak estrogen-like activity, reduced bone degradation, and increased bone formation (50)(51) 
  • Reduced the number and severity of hot flashes caused by tamoxifen (xenoestrogen pharmaceutical) and Kupperman Menopausal Index (KMI) scores in menopausal syndrome induced by LHRH-a treatment (14)(47)
  • Provided similar efficacy to 0.6 mg conjugated estrogens, low dose transdermal estradiol, and 2.5 mg tibolone, with a greater safety profile than tibolone (2)(3)(30)(51)
  • Provided greater efficacy than 20 mg fluoxetine  (31)
Black Cohosh in the Fullscript catalog


The Fullscript Integrative Medical Advisory team has developed or collected these protocols from practitioners and supplier partners to help health care practitioners make decisions when building treatment plans. By adding this protocol to your Fullscript template library, you understand and accept that the recommendations in the protocol are for initial guidance and may not be appropriate for every patient.

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  1. Acacio, B. D., Stanczyk, F. Z., Mullin, P., Saadat, P., Jafarian, N., & Sokol, R. Z. (2004). Pharmacokinetics of dehydroepiandrosterone and its metabolites after long-term daily oral administration to healthy young men. Fertility and Sterility, 81(3), 595–604. (C)
  2. Bai, W., Henneicke-von Zepelin, H.-H., Wang, S., Zheng, S., Liu, J., Zhang, Z., Geng, L., Hu, L., Jiao, C., & Liske, E. (2007). Efficacy and tolerability of a medicinal product containing an isopropanolic black cohosh extract in Chinese women with menopausal symptoms: A randomized, double blind, parallel-controlled study versus tibolone. Maturitas, 58(1), 31–41. (C)
  3. Bai W.-P., Wang S.-Y., Liu J.-L., Geng L., Hu L.-N., Zhang Z.-L., Chen S.-L., & Zheng S.-R. (2009). [Efficacy and safety of remifemin compared to tibolone for controlling of perimenopausal symptoms]. Zhonghua fu chan ke za zhi, 44(8), 597–600. (C)
  4. Barnhart, K. T., Freeman, E., Grisso, J. A., Rader, D. J., Sammel, M., Kapoor, S., & Nestler, J. E. (1999). The effect of dehydroepiandrosterone supplementation to symptomatic perimenopausal women on serum endocrine profiles, lipid parameters, and health-related quality of life. The Journal of Clinical Endocrinology and Metabolism, 84(11), 3896–3902. (B)
  5. Bell, M. C., Crowley-Nowick, P., Bradlow, H. L., Sepkovic, D. W., Schmidt-Grimminger, D., Howell, P., Mayeaux, E. J., Tucker, A., Turbat-Herrera, E. A., & Mathis, J. M. (2000). Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecologic Oncology, 78(2), 123–129. (C)
  6. Bradlow, H. L., Michnovicz, J. J., Halper, M., Miller, D. G., Wong, G. Y., & Osborne, M. P. (1994). Long-term responses of women to indole-3-carbinol or a high fiber diet. Cancer Epidemiology, Biomarkers & Prevention, 3(7), 591–595. (C)
  7. Caufriez, A., Leproult, R., L’Hermite-Balériaux, M., Kerkhofs, M., & Copinschi, G. (2013). Effects of a 3-week dehydroepiandrosterone administration on sleep, sex steroids and multiple 24-h hormonal profiles in postmenopausal women: A pilot study. Clinical Endocrinology, 79(5), 716–724. (C)
  8. Corona, G., Rastrelli, G., Giagulli, V. A., Sila, A., Sforza, A., Forti, G., Mannucci, E., & Maggi, M. (2013). Dehydroepiandrosterone supplementation in elderly men: A meta-analysis study of placebo-controlled trials. The Journal of Clinical Endocrinology and Metabolism, 98(9), 3615–3626. (A)
  9. Dalessandri, K. M., Firestone, G. L., Fitch, M. D., Bradlow, H. L., & Bjeldanes, L. F. (2004). Pilot study: Effect of 3,3’-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutrition and Cancer, 50(2), 161–167. (C)
  10. Dayal, M., Sammel, M. D., Zhao, J., Hummel, A. C., Vandenbourne, K., & Barnhart, K. T. (2005). Supplementation with DHEA: Effect on muscle size, strength, quality of life, and lipids. Journal of Women’s Health , 14(5), 391–400. (B)
  11. Fugate, S. E., & Church, C. O. (2004). Nonestrogen treatment modalities for vasomotor symptoms associated with menopause. The Annals of Pharmacotherapy, 38(9), 1482–1499. (A)
  12. Gee, J. R., Saltzstein, D. R., Messing, E., Kim, K., Kolesar, J., Huang, W., Havighurst, T. C., Harris, L., Wollmer, B. W., Jarrard, D., House, M., Parnes, H., & Bailey, H. H. (2016). Phase Ib placebo-controlled, tissue biomarker trial of diindolylmethane (BR-DIMNG) in patients with prostate cancer who are undergoing prostatectomy. European Journal of Cancer Prevention, 25(4), 312–320. (C)
  13. Genazzani, A. R., Stomati, M., Valentino, V., Pluchino, N., Pot, E., Casarosa, E., Merlini, S., Giannini, A., & Luisi, M. (2011). Effect of 1-year, low-dose DHEA therapy on climacteric symptoms and female sexuality. Climacteric: The Journal of the International Menopause Society, 14(6), 661–668. (C)
  14. Hernández Muñoz, G., & Pluchino, S. (2003). Cimicifuga racemosa for the treatment of hot flushes in women surviving breast cancer. Maturitas, 44(1), S59–S65. (C)
  15. Hwang, C., Sethi, S., Heilbrun, L. K., Gupta, N. S., Chitale, D. A., Sakr, W. A., Menon, M., Peabody, J. O., Smith, D. W., Sarkar, F. H., & Heath, E. I. (2016). Anti-androgenic activity of absorption-enhanced 3, 3’-diindolylmethane in prostatectomy patients. American Journal of Translational Research, 8(1), 166–176. (D)
  16. Jiang, K., Jin, Y., Huang, L., Feng, S., Hou, X., Du, B., Zheng, J., & Li, L. (2015). Black cohosh improves objective sleep in postmenopausal women with sleep disturbance. Climacteric: The Journal of the International Menopause Society, 18(4), 559–567. (B)
  17. Kahn, A. J., & Halloran, B. (2002). Dehydroepiandrosterone supplementation and bone turnover in middle-aged to elderly men. The Journal of Clinical Endocrinology and Metabolism, 87(4), 1544–1549. (C)
  18. Kenny, A. M., Boxer, R. S., Kleppinger, A., Brindisi, J., Feinn, R., & Burleson, J. A. (2010). Dehydroepiandrosterone combined with exercise improves muscle strength and physical function in frail older women. Journal of the American Geriatrics Society, 58(9), 1707–1714. (B)
  19. Kotsopoulos, J., Zhang, S., Akbari, M., Salmena, L., Llacuachaqui, M., Zeligs, M., Sun, P., & Narod, S. A. (2014). BRCA1 mRNA levels following a 4-6-week intervention with oral 3,3’-diindolylmethane. British Journal of Cancer, 111(7), 1269–1274. (C)
  20. Lin, H., Li, L., Wang, Q., Wang, Y., Wang, J., & Long, X. (2019). A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA supplementation of bone mineral density in healthy adults. Gynecological Endocrinology, 35(11), 924–931. (A)
  21. Liske, E., Hänggi, W., Henneicke-von Zepelin, H.-H., Boblitz, N., Wüstenberg, P., & Rahlfs, V. W. (2002). Physiological investigation of a unique extract of black cohosh (Cimicifugae racemosae rhizoma): A 6-month clinical study demonstrates no systemic estrogenic effect. Journal of Women’s Health & Gender-Based Medicine, 11(2), 163–174. (B)
  22. Lóránd, T., Vigh, E., & Garai, J. (2010). Hormonal action of plant derived and anthropogenic non-steroidal estrogenic compounds: phytoestrogens and xenoestrogens. Current Medicinal Chemistry, 17(30), 3542–3574. (F)
  23. Martina, V., Benso, A., Gigliardi, V. R., Masha, A., Origlia, C., Granata, R., & Ghigo, E. (2006). Short-term dehydroepiandrosterone treatment increases platelet cGMP production in elderly male subjects. Clinical Endocrinology, 64(3), 260–264. (C)
  24. Mattison, D. R., Karyakina, N., Goodman, M., & LaKind, J. S. (2014). Pharmaco- and toxicokinetics of selected exogenous and endogenous estrogens: A review of the data and identification of knowledge gaps. Critical Reviews in Toxicology, 44(8), 696–724. (F)
  25. McAlindon, T. E., Gulin, J., Chen, T., Klug, T., Lahita, R., & Nuite, M. (2001). Indole-3-carbinol in women with SLE: Effect on estrogen metabolism and disease activity. Lupus, 10(11), 779–783. (D)
  26. Merritt, P., Stangl, B., Hirshman, E., & Verbalis, J. (2012). Administration of dehydroepiandrosterone (DHEA) increases serum levels of androgens and estrogens but does not enhance short-term memory in post-menopausal women. Brain Research, 1483, 54–62. (C)
  27. Michnovicz, J. J. (1998). Increased estrogen 2-hydroxylation in obese women using oral indole-3-carbinol. International Journal of Obesity and Related Metabolic Disorders, 22(3), 227–229. (D)
  28. Morales-Prieto, D. M., Herrmann, J., Osterwald, H., Kochhar, P. S., Schleussner, E., Markert, U. R., & Oettel, M. (2018). Comparison of dienogest effects upon 3,3’-diindolylmethane supplementation in models of endometriosis and clinical cases. Reproductive Biology, 18(3), 252–258. (C)
  29. Naik, R., Nixon, S., Lopes, A., Godfrey, K., Hatem, M. H., & Monaghan, J. M. (2006). A randomized phase II trial of indole-3-carbinol in the treatment of vulvar intraepithelial neoplasia. International Journal of Gynecological Cancer, 16(2), 786–790. (D)
  30. Nappi, R. E., Malavasi, B., Brundu, B., & Facchinetti, F. (2005). Efficacy of Cimicifuga racemosa on climacteric complaints: A randomized study versus low-dose transdermal estradiol. Gynecological Endocrinology, 20(1), 30–35. (C)
  31. Oktem, M., Eroglu, D., Karahan, H. B., Taskintuna, N., Kuscu, E., & Zeyneloglu, H. B. (2007). Black cohosh and fluoxetine in the treatment of postmenopausal symptoms: A prospective, randomized trial. Advances in Therapy, 24(2), 448–461. (C)
  32. Osmers, R., Friede, M., Liske, E., Schnitker, J., Freudenstein, J., & Henneicke-von Zepelin, H.-H. (2005). Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms. Obstetrics and Gynecology, 105(5 Pt 1), 1074–1083. (B)
  33. Paterni, I., Granchi, C., & Minutolo, F. (2017). Risks and benefits related to alimentary exposure to xenoestrogens. Critical Reviews in Food Science and Nutrition, 57(16), 3384–3404. (F)
  34. Rajoria, S., Suriano, R., Parmar, P. S., Wilson, Y. L., Megwalu, U., Moscatello, A., Bradlow, H. L., Sepkovic, D. W., Geliebter, J., Schantz, S. P., & Tiwari, R. K. (2011). 3,3’-diindolylmethane modulates estrogen metabolism in patients with thyroid proliferative disease: A pilot study. Thyroid: Official Journal of the American Thyroid Association, 21(3), 299–304. (D)
  35. Reed, G. A., Peterson, K. S., Smith, H. J., Gray, J. C., Sullivan, D. K., Mayo, M. S., Crowell, J. A., & Hurwitz, A. (2005). A phase I study of indole-3-carbinol in women: Tolerability and effects. Cancer Epidemiology, Biomarkers & Prevention, 14(8), 1953–1960. (C)
  36. Rosen, C. A., & Bryson, P. C. (2004). Indole-3-carbinol for recurrent respiratory papillomatosis: Long-term results. Journal of Voice: Official Journal of the Voice Foundation, 18(2), 248–253. (D)
  37. Rosen, C. A., Woodson, G. E., Thompson, J. W., Hengesteg, A. P., & Bradlow, H. L. (1998). Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngology–Head and Neck Surgery, 118(6), 810–815. (D)
  38. Ross, S. M. (2012). Menopause: a standardized isopropanolic black cohosh extract (remifemin) is found to be safe and effective for menopausal symptoms. Holistic Nursing Practice, 26(1), 58–61. (B)
  39. Sarri, G., Pedder, H., Dias, S., Guo, Y., & Lumsden, M. A. (2017). Vasomotor symptoms resulting from natural menopause: A systematic review and network meta-analysis of treatment effects from the National Institute for Health and Care Excellence guideline on menopause. BJOG: An International Journal of Obstetrics and Gynaecology, 124(10), 1514–1523. (A)
  40. Scheffers, C. S., Armstrong, S., Cantineau, A. E. P., Farquhar, C., & Jordan, V. (2015). Dehydroepiandrosterone for women in the peri- or postmenopausal phase. Cochrane Database of Systematic Reviews, 1, CD011066. (A)
  41. Shams, T., Setia, M. S., Hemmings, R., McCusker, J., Sewitch, M., & Ciampi, A. (2010). Efficacy of black cohosh-containing preparations on menopausal symptoms: A meta-analysis. Alternative Therapies in Health and Medicine, 16(1), 36–44. (A)
  42. Stangl, B., Hirshman, E., & Verbalis, J. (2011). Administration of dehydroepiandrosterone (DHEA) enhances visual-spatial performance in postmenopausal women. Behavioral Neuroscience, 125(5), 742–752. (C)
  43. Taioli, E., Bradlow, H. L., Garbers, S. V., Sepkovic, D. W., Osborne, M. P., Trachman, J., Ganguly, S., & Garte, S. J. (1999). Role of estradiol metabolism and CYP1A1 polymorphisms in breast cancer risk. Cancer Detection and Prevention, 23(3), 232–237. (D)
  44. Thomson, C. A., Chow, H. H. S., Wertheim, B. C., Roe, D. J., Stopeck, A., Maskarinec, G., Altbach, M., Chalasani, P., Huang, C., Strom, M. B., Galons, J.-P., & Thompson, P. A. (2017). A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen. Breast Cancer Research and Treatment, 165(1), 97–107. (B)
  45. Viñas, R., Jeng, Y.-J., & Watson, C. S. (2012). Non-genomic effects of xenoestrogen mixtures. International Journal of Environmental Research and Public Health, 9(8), 2694–2714. (F)
  46. von Mühlen, D., Laughlin, G. A., Kritz-Silverstein, D., Bergstrom, J., & Bettencourt, R. (2008). Effect of dehydroepiandrosterone supplementation on bone mineral density, bone markers, and body composition in older adults: the DAWN trial. Osteoporosis International, 19(5), 699–707. (B)
  47. Wang, C., Huang, Q., Liang, C.-L., Zhang, Y.-W., Deng, D.-H., Yu, Y., Chen, D.-B., Yang, H.-J., & Yu, X.-F. (2019). Effect of cimicifuga racemosa on menopausal syndrome caused by LHRH-a in breast cancer. Journal of Ethnopharmacology, 238, 111840. (C)
  48. Weiss, E. P., Shah, K., Fontana, L., Lambert, C. P., Holloszy, J. O., & Villareal, D. T. (2009). Dehydroepiandrosterone replacement therapy in older adults: 1- and 2-y effects on bone. The American Journal of Clinical Nutrition, 89(5), 1459–1467. (C)
  49. Wong, G. Y., Bradlow, L., Sepkovic, D., Mehl, S., Mailman, J., & Osborne, M. P. (1997). Dose-ranging study of indole-3-carbinol for breast cancer prevention. Journal of Cellular Biochemistry. Supplement, 28-29, 111–116. (B)
  50. Wuttke, W., Gorkow, C., & Seidlová-Wuttke, D. (2006). Effects of black cohosh (Cimicifuga racemosa) on bone turnover, vaginal mucosa, and various blood parameters in postmenopausal women: A double-blind, placebo-controlled, and conjugated estrogens-controlled study. Menopause , 13(2), 185–196. (B)
  51. Wuttke, W., Seidlová-Wuttke, D., & Gorkow, C. (2003). The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: Effects on menopause symptoms and bone markers. Maturitas, 44 Suppl 1, S67–S77. (B)

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