Anti-Cancer and Other Biological Effects of a Dietary Compound 3,3′-Diindolylmethane Supplementation: A Systematic Review of Human Clinical Trials

Figures & data

Figure 1 Annual count of DIM (3,3ʹ-diindolylmethane) articles indexed in PubMed. The results include articles with the keyword “3,3ʹ-diindolylmethane”.

Note: “DIM review” represents both human (in vivo) and in vitro studies.

Table 1 Summary of Peer-Review Published Clinical Trials (Indexed in PubMed, Cochrane-Embase and Google Scholar Databases) Regarding DIM Supplementation

No.	Authors	Participants	Objectives	Form of DIM and Doses	Outcomes
1.	Castanon et al 2012^Citation130	551 women (age range 19–65 years).	A double-blind randomized controlled trial to see the effect of BR-DIM on HPV infection or cytology	150 mg BR-DIM (BioResponse DIM) or placebo daily for 6 months	– DIM supplementation was well tolerated - No effect on HPV infection or cytology
2.	Dalessandri et al 2004^Citation28	19 (postmenopausal women aged 50–70 year) with a history of early-stage breast cancer	A double-blind randomized controlled trial to determine the effect of DIM supplements on urinary estrogen metabolites	10 in the BR-DIM (108mg/day) treatment group or 9 in the placebo for 30 days	–DIM increased the estrogen metabolism where the ratio of 2-OHE1 to 16α-OHE1 increased from 1.46 to 2.14
3.	Del Priore et al 2010^Citation127	64 women (age between 18 to 61)	– DIM efficacy and toxicity in the treatment of cervical intraepithelial neoplasia grade II or III lesions.	–2 mg/kg body-weight BR-DIM per day or placebo for 3 months	– DIM was well tolerated –21 subjects (47%) in the DIM group improved with a decrease by 1–2 grades cervical intraepithelial neoplasia or a normal result.
4.	Fujioka et al 2014^Citation74	25 healthy, non-vegetarian, and non-smoking adults (10 males and 15 females; ages 22 to 63 years)	A randomized controlled trial to determine DIM level in urine	50g of raw Brussels sprouts (high in 13C content) or cabbage (low in 13C content) were ingested per day for 3 days	–Urinary DIM was successfully quantified: with higher quantity in Brussels sprouts ingestion than in cabbage
5.	Fujioka et al 2016^Citation75	45 subjects (19 males and 26 females, age 18 to 60 years)	A randomized clinical trial to determine the consistency and level of urinary DIM excretion	Glucobrassicin dose in the vegetables were in the range of 25, 50, 100, 200, 300, 400 or 500 μmol per day for two days	–Urinary DIM increased with dose-dependent and reached plateau between 200 and 300 μmol doses. – Majority of DIM was eliminated in the first 12 hours of intervention.
6.	Gee et al 2016^Citation76	45 men patients (mean age of 61.1 years) with prostate cancer and who have scheduled radical prostatectomy	A double-blind controlled trial to assess the endpoints of DIM	100 or 200 mg BR-DIM to 28 patients or 17 patients’ placebo twice daily for 21–28 days.	– DIM was well tolerated –DIM was detected in prostate tissue in the seven patients specimens – Significant increase in urinary 2-OHE1^* to 16α-OHE1^* ratio in the exposed group. –DIM induces metabolizing enzymes CYP1A1 (31 % reduction) and CYP2B6 (87% reduction) in peripheral mononuclear cells –DIM detected in plasma
7.	Kong et al 2012”^Citation115	11 prostate cancer patients (age between 47 and 64)	DIM role in the regulation of let-7 and EZH2 in prostate cancer tissue	–A dose of BR-DIM is not disclosed	– BR-DIM up-regulated the let-7 and down-regulated the EZH2 expression
8.	Kotsopoulos et al 2014^Citation99	18 healthy women but with BRCAI mutation carriers	–clinical efficacy of DIM in up-regulating BRCA1 expression in breast cancer cells.	The intervention group (n=13) ingested 300mg BR-DIM per day for 4–6 weeks	– BRCA1 mRNA expression was increased in 10 of the exposed subjects
9.	Lorincz et al 2013^Citation132	84 women with low-grade cytological abnormalities, of which 82 had HPV16 at baseline study	A double-blind, randomized a controlled clinical trial to see DIM efficacy to treat cytological abnormalities with HPV16.	150 mg DIM or placebo daily for 6 months	–No cancer detected after 6 months -Only 11 subjects were HPV16 negative, hence clinically non-significant
10.	Morales-Prieto et al 2018^Citation133	10 women with endometriosis	Randomized control trial to see BR-DIM combined effect with DNG drug in bleeding pattern and endometriosis-related pelvic pain.	2 mg DNG per day and 100 mg BR- DIM three time per day	-Bleeding pattern significantly improved in the DNG-DIM group compared to the DNG group (64.5 ± 8.0 days vs 47.0 ± 2.5, respectively).
11.	Rajoria et al 2011^Citation77	7 women Patients (between ages of 39–56 years) with Thyroid Proliferative Disease	-investigate the anti-estrogenic activity of DIM	300mg of BR-DIM per day for 14 days	-DIM was detected in serum, urine and thyroid tissue of patients. - Significant increase in the ratio of OHE1 ^* to 16α-OHEI^*
12.	Reed et al 2006^Citation72	24 healthy, nonsmoking women (age between 23 and 58 years) but had an elevated risk of breast cancer (due to family history)	To assess the pharmacokinetics of the parent compound (13C) and its major acid condensation product DIM.	Oral capsules: single doses at 400, 600, 800, 1000, and 1200 mg 13C per day; and multiple doses: 400 mg 13C twice daily for 2 months	-For the single dose: 5 women among the 20 reported short term gastrointestinal distress - 13C was not detected in the plasma samples. -DIM was detected consistently in plasma samples.
13.	Reed et al 2008^Citation131	24 healthy subjects (13 Men and 11 Women) ages 22 to 58 years	Randomized control clinical trial to determine the pharmacokinetics, and tolerability of DIM	An oral single dose of BR-DIM or matching placebo were: 50, 100, 150, 200, and 300 mg.	-DIM was detected in plasma with a dose-dependent manner with maximum concentration was reached at 200 mg
14.	Thomson et al 2017^Citation97	98 women (mean age 53; 47 DIM +tamoxifen vs 51 tamoxifen) completed the interventions	A double-blind, randomized, controlled trial to determine estrogen metabolites, androgen hormone- binding globulin, breast density, serum estrogens, and tamoxifen metabolites after the combined exposure of BR-DIM and tamoxifen	150 mg BR-DIM+ tamoxifen twice daily or tamoxifen, for 12 months.	-DIM increased 2/16α-OHE1^* ratio by (+3.2) compared to the placebo (–0.7). -Serum androgen hormone-binding globulin increased with BR-DIM (+25 ± 22) group compared to placebo (1.1 ± 19 nmol/L). -No change observed in breast density - Plasma tamoxifen metabolites decreased in the DIM group.
15.	Nikitina et al 2015^Citation98	20 healthy women (age between 25 and 65 years) with a BRCAI mutation carriers.	- effect of DIM on the ratio of urinary estrogen metabolites (2/16α-OHE)	15 subjects exposed to 300 mg/day BR-DIM or 5 subjects’ placebo for 4–6 weeks.	- no significant change in the ratio of 2 to 16α-OHE
16.	Paltsev et al 2014^Citation128	14 men patients (ages 18 to 60 years) with Prostatic intraepithelial neoplasia	Randomized control clinical trial to evaluate the safety of DIM	900 mg DIM (Infemin capsule) daily or placebo for 3 months	- mild and transient toxicity (nausea and diarrhea in 2 subjects) - No other clinical significant effects were observed
17.	Paltsev et al 2016^Citation129	21 men patients with a high-grade prostatic intraepithelial neoplasia	Double-blind randomized placebo-controlled multicenter a clinical trial to assess the efficacy of DIM as a therapy	11 patients received Infemin (bioavailable DIM) at 900 mg of a day, and 10 patients placebo group for 12 months.	- A complete reversion n of prostatic intraepithelial neoplasia was observed in the 45.5% of patients in the DIM group compared to 0% in the placebo. - Urinary flow rate increased by 53.3% compared to the baseline
18.	Heath et al 2010^Citation78	12 patients (age 62–91 years) with non-metastatic prostate cancer	To evaluate DIM effect on molecular targets, adverse effects, and its pharmacokinetics	-Oral doses with clustered exposure to either 75 mg, 150 mg,225 mg, or 300 mg BR-DIM twice daily for 4 months.	- BR-DIM rapidly absorbed 2 to 4 h - DIM plasma level was dose-proportional - 2 of 4 patients exposed to 300 mg experienced grade 3 asymptomatic hyponatremia. -Initially, 10 subjects had a decrease in their prostate-specific antigen rise but an eventual progression.
19.	Hwang et al 2016^Citation79	41 men patients (age range, 40–76 years) with prostate cancer	Determine the effects of DIM on the androgen receptor in prostate cancer patients. DIM levels and its androgen receptor activity were determined at the time of prostatectomy.	–36 patients took an oral dose of BR-DIM at 225 mg twice daily for two weeks	-DIM was well tolerated. –26 (93%) patients had detectable DIM (mean value of 14.2 ng/gm tissue) in the prostate biopsy. - mean DIM plasma level was 9.0 g/mL. - 27 (96%) of patients displayed exclusion of the androgen receptor from the cell nucleus of prostate cells. - prostate-specific antigen was declined in the 20 (71%) of patients
20.	Sepkovic et al 2001^Citation69	10 Women (age not disclosed) with cervical dysplasia	A clinical trial to quantify DIM in urine following 13C ingestion	-13C doses: placebo (7 women), 200 mg of 13C (5 women), or 400 mg of 13C (5 women) for 1 month.	-A mean value of 12.1 ± 2.5 and 15.6± 22.2 μg DIM/mg creatinine was observed for the 200 mg, and 400 mg treatment groups, respectively.
21.	Zeligs and Michael, 2012^Citation23	4 women (mean age between 20 to 62) with common warts and HPV-related cervical dysplasia	To determine DIM treatment of common warts and oral-genital epithelial dysplasias due to human papilloma-virus infections	450 mg/day DIM for 1 to 4 months	- A combination of topical and oral DIM resulted in the regression and disappearance of warts from affected patients. - 112 mg/day and above of oral DIM were associated with HPV therapeutic uses
22.	Ashrafian et al 2015^Citation60	78 women e (age between 19 to 39 years) with cervical intraepithelial neoplasia grade l-ll	-A multicenter, double-blind randomized controlled clinical trial to assess the efficacy and safety of DIM in the patients.	-Three cohort groups each consist of 26 patients were exposed to 100 mg DIM, 200 mg DIM and placebo, respectively for 90–180 days	-DIM efficacies were 100.0%, 98.83%, and 61.1% for the high dose, low dose, and placebo, respectively. - Adverse events were reported in the placebo group 22% of patients, in the 100 mg/day group 40% and in the 200 mg/ day group 42%.

Notes:

* 2-OHEI, 2-hydroxyestrone; 16 α-OHE1, 16-hydroxyestrone.

Abbreviations: HPV, human papillomavirus; DNG, dienogest; EZH2, enhancer of zeste homolog 2; BRCAI, breast cancer type 1.

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