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DIM and Men: Prostate Cancer and Beyond

Clinical insights on nutritional bioactive from cruciferous vegetables

by Whitney Crouch, RDN, CLT 

Cruciferous vegetables belong to the Brassica genus of plants and include foods such as broccoli, arugula, Brussels sprouts, mustard and collard greens, cabbage, and watercress. Known for their cancer-fighting biological properties and support of the body’s natural detoxification system, these veggies contain sulfur-containing chemicals called glucosinolates, which are responsible for the vegetable’s pungent aroma and bitter flavor.1

During the digestion of cruciferous vegetables, glucosinolates are broken down to form biologically active compounds such as indoles, nitriles, thiocyanates, and isothiocyanates.2 One of these compounds, indole-3-carbinol (I3C), is then converted into 3,3’-diindolylmethane (DIM) in the stomach; both compounds are known for their health supportive characteristics.3

Studies investigating these unique nutritional bioactives, I3C and DIM, have found that I3C is unstable in the acidic stomach acid environment and is rapidly converted to DIM.4 To simplify the discussion, some of the observed effects of I3C will be assumed for DIM, except for any dose-specific references.4-6

I3C and DIM are best known for their use in cancer prevention applications and female hormone balance, with DIM regarded as a go-to support for reducing excess estrogens in the body.7-8 While it’s predominantly regarded as a women’s health ingredient, DIM is not a compound just for women.

DIM for Men

Prostate cancer

Prostate cancer is the most common non-skin cancer in American men, with a lifetime risk for diagnosis of approximately 15.9%.9 It is estimated that 164,690 new cases were diagnosed, and 29,430 patients died from prostate cancer in 2018.9

Nutrition represents a modifiable cancer risk factor that practitioners can and should leverage in their patients. Epidemiological evidence demonstrates that consumption of cruciferous foods has been associated with decreased prostate cancer incidence10 and risk.11 So, how much broccoli, you ask? Consuming ≥ 3 servings of cruciferous vegetables (as compared to < 1 serving/week) was associated with a 41% risk reduction in prostate cancer.11

Crucifer bioactives I3C and DIM have been studied for their anti-cancer pathophysiological properties. Mechanistically, it is thought that the anti-prostate cancer effects of I3C and DIM are driven by DIM’s inhibitory effects on androgen-mediated pathways, meaning multiple testosterone-producing pathways are reduced through different mechanisms of DIM’s bioactivity.8 Furthermore, DIM imparts anti-cancer effects via its ability to reduce cell proliferation, provoke cell cycle arrest, induce cell death (apoptosis) and autophagy in human prostate cancer cells.12-13

A preclinical study in a mouse model found that a combination of DIM (10 mg/kg) and chloroquine (60 mg/kg), taken 3x/week, significantly decreased prostate cancer (PC-3) tumor growth in vivo after 3 and 4 weeks of treatment.10 The mouse prostate cancer model used was a unique one, as the researchers performed a xenograft (i.e., tissue graft from a donor of a different species from the recipient) of human prostate cancer cells A more active type of DIM, 4,4′-Br2DIM, given at the same dose (10 mg/kg, 3x/week) was found to significantly inhibit tumor growth after 4 weeks of treatment, making DIM a novel addition to prostate health plans and prostate cancer treatments.10 Translation: DIM paired with chloroquine for 3 to 4 weeks can slow prostate tumor progression.

Next, a clinical study used a nutritional grade, absorption-enhanced DIM (BR-DIM) given in 225 mg doses 2x/day for a minimum of 14 days in 41 Caucasian (55%) and African American (40%) patients with localized prostate cancer.13 Baseline plasma DIM blood levels were assessed in patients, who were given BR-DIM for 14-72 days before undergoing a radical prostatectomy; blood DIM levels were re-tested immediately prior to surgery and during a follow-up to surgery within 24 months post-operation. Prostate tissue DIM was also measured at the time of surgery.

Biologically significant levels of DIM concentrations were found in prostate tissue by day 14 of BR-DIM supplementation, with no incremental increases achieved with BR-DIM treatment of longer duration.13 Further, a reduction in PSA levels was observed in the majority (71%) of study participants.13 Lastly, BR-DIM had a significant, anti-androgenic impact on the nuclear translocation of the androgen receptor (i.e., exclusion from the nucleus) in 96% of patients; this receptor plays a key role in prostate tumor pathogenesis via testosterone binding.13 Translation: BR-DIM treatment produced clinically relevant DIM levels in the prostate and reduced the effectiveness of androgen receptors to bind testosterone, which has potential chemopreventive implications for prostate cancer.

Finally, a double-blind, randomized, placebo-controlled clinical trial examined the efficacy of a pharmaceutical DIM-containing drug (900 mg/day DIM) in 21 patients with high-grade prostatic intraepithelial neoplasia (PIN), a major risk factor for development of prostate cancer.14 An interim analysis of data after 12 months of treatment demonstrated a significant reduction in the morphological index (based on histological examination of prostate biopsy specimens) in the treatment group as compared to placebo.14 Additional treatment group effects include an improvement in maximal urinary flow rate and a complete regression of PIN in 45% of patients. Translation: intermediate results from a DIM drug trial demonstrate significant clinical promise for patients with high-grade PIN.

Other male-centric hormonal applications

In addition to its aforementioned role in hormone-related prostate cancer, DIM may support other areas of men’s health.

Obesity

A preclinical study in mice compared the effects of a high-fat diet (HFD) vs. control diet within the context of DIM supplementation.15 In the mice fed the HFD, 50 mg DIM per kg body weight suppressed HFD-induced obesity; the group receiving the HFD alone gained weight and fat tissue, while the group receiving the HFD plus DIM did not gain weight nor adipose tissue, likening them to the control diet group.15 Furthermore, cellular analyses revealed that DIM significantly inhibited adipogenesis of pre-adipocyte cells.15 In other words, DIM has anti-obesity properties.

Estrogen-related effects

More often discussed in women’s health conversations, one well-known characteristic of DIM is its ability to reduce excess estrogen in the body and convert the more carcinogenic type of estrogens (16-hydroxy and 16-methoxy estrogens) into the “good estrogens” (2-hydroxy and 2-methoxy estrogens).16 But, men make estrogens too through the conversion of testosterone into estradiol via the aromatase enzyme. By DIM reducing excess estrogens in men (possibly caused by genetics, diet, or xenoestrogen exposure), there may also be a reduction in estrogen-excess symptoms like fatigue, erectile dysfunction, obesity, and estrogen-related cancers.15-16

Clinical Takeaways

  • DIM is not just an indole phytochemical that supports women’s health, but men’s health as well
  • DIM may be used as a preventative measure in men with certain risk factors for prostate cancer (e.g., PIN), and as an adjunct therapy during conventional treatment for certain types of prostate cancers
  • DIM may support healthy testosterone-to-estrogen balance in males, which in turn can improve myriad symptoms and clinical manifestations of estrogen excess

If you suspect estrogen excess or would like to learn more about DIM’s appropriateness for a specific prostate condition, consult with a qualified healthcare provider for hormone testing and personalized clinical recommendations.

Citations

  1. NIH. Cruciferous vegetables and cancer prevention. https://www.cancer.gov/about-cancer/causes-prevention/risk/diet/cruciferous-vegetables-fact-sheet. Accessed December 18, 2018.
  2. Hayes JD et al. The cancer chemopreventive actions of phytochemicals derived from glucosinolates. Eur J Nutr.2008;47 Suppl 2:73-88.
  3. Li Y et al. Recent progress on nutraceutical research in prostate cancer. Cancer Metastasis Rev. 2014;33(2-3):629-640.
  4. Anderton MJ et al. Pharmacokinetics and tissue disposition of indole-3-carbinol and its acid condensation products after oral administration to mice. Clin Cancer Res. 2004;10:5233–5241.
  5. Weng JR et al. Indole-3-carbinol as a chemopreventive and anti-cancer agent. Cancer Lett. 2008;262:153–163.
  6. Grose KR et al. Oligomerization of indole-3-carbinol in aqueous acid. Chem Res Toxicol. 1992;5:188–193.
  7. Murillo G et al. Cruciferous vegetables and cancer prevention. Nutr Cancer. 2001;41(1-2):17-28.
  8. Wang TT et al. Broccoli-derived phytochemicals indole-3-carbinol and 3,3′-diindolylmethane exerts concentration-dependent pleiotropic effects on prostate cancer cells: comparison with other cancer preventive phytochemicals. Mol Carcinog. 2012;51(3):244-256.
  9. Siegel RL et al. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.
  10. Kristal AR et al. Brassica vegetables and prostate cancer risk: a review of the epidemiological evidence. Nutr Cancer. 2002;42(1):1-9.
  11. Cohen JH et al. Fruit and vegetable intakes and prostate cancer risk. J Natl Cancer Inst. 2000;92(1):61-68.
  12. Draz H et al. Autophagy inhibition improves the chemotherapeutic efficacy of cruciferous vegetable-derived diindolylmethane in a murine prostate cancer xenograft model. Invest New Drugs. 2018;36(4):718-725.
  13. Hwang C et al. Anti-androgenic activity of absorption-enhanced 3, 3′-diindolylmethane in prostatectomy patients. Am J Transl Res. 2016;8(1):166-176.
  14. Paltsev M et al. First results of the double-blind randomized placebo-controlled multicenter clinical trial of DIM-based therapy designed as personalized approach to reverse prostatic intraepithelial neoplasia (PIN). EPMA J. 2016;7:5.
  15. Yang H et al. 3,3′-Diindolylmethane suppresses high-fat diet-induced obesity through inhibiting adipogenesis of pre-adipocytes by targeting USP2 activity. Mol Nutr Food Res. 2017;61(10).
  16. Wendlová J. Scientific medicine in integrative treatment of erectile dysfunction. J Integr Nephrol Androl. 2015;2:5-18
  17. Wu F et al. Levels of estradiol and testosterone are altered in Chinese men with sexual dysfunction. Andrology. 2016;4(5):932-938.

 

Whitney Crouch, RDN, CLT

Whitney Crouch is a Registered Dietitian who received her undergraduate degree in Clinical Nutrition from the University of California, Davis. She has over 10 years of experience across multiple areas of dietetics, specializing in integrative and functional nutrition and food sensitivities. When she’s not writing about nutrition or educating others, she’s spending time with her husband and young son. She’s often found running around the bay near her home with the family’s dog or in the kitchen cooking up new ideas to help her picky eater expand his palate.

 

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