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1.  Results from a dose response study using 3, 3′-diindolylmethane in the K14-HPV16 transgenic mouse model: Cervical histology 
The Human Papilloma Virus is the major cause of cervical cancer. Viral infection initiates cervical intraepithelial neoplasia which progresses through several stages to cervical cancer. The objective of this study is to identify the minimum effective dose of diindolylmethane that prevents the progression from cervical dysplasia to carcinoma in situ. We document cervical histology in K14-HPV16 mice receiving different doses of diindolylmethane. Urinary diindolylmethane concentrations are reported. Diindolylmethane could enhance the efficacy of human papilloma virus vaccines, creating a new therapeutic use for these vaccines in women already infected with the virus. Five doses (0 to 2500ppm) of diindolylmethane were incorporated into each mouse diet. The reproductive tract was serially sectioned and urine was obtained for analysis of urinary diindolylmethane. The results indicate that 62% of mice receiving 1,000ppm diindolylmethane, remained dysplasia free after 20 weeks compared to 16% of mice receiving no diindolylmethane and 18% receiving 500ppm. 1000ppm of 3,3′-diindolylmethane in the diet completely suppressed the development of cervical cancer. Urinary diindolylmethane levels increased significantly as diindolylmethane in food increased. These findings imply usefulness for diindolylmethane in the search to prevent cervical cancer when used in combination with prophylactic or therapeutic vaccines.
PMCID: PMC3107883  PMID: 21383027
cervical cancer; cervical intraepithelial neoplasia; 3,3′-diindolylmethane
3.  Diindolylmethane Inhibits Cervical Dysplasia, Alters Estrogen Metabolism and Enhances Immune Response in The K14-HPV16 Transgenic Mouse Model 
This study was designed to establish whether 3,3′-Diindolylmethane (DIM) can inhibit cervical lesions, alter estrogen metabolism in favor of C-2 hydroxylation and enhance immune function in the K14-HPV16 transgenic mouse model. Mice were bred, genotyped, implanted with E2 pellets (0.25mg/90 day release) under anesthesia and divided into groups. Wild type and transgenic mice were given either AIN76A diet alone or with 2000ppm DIM for 12weeks. Blood and reproductive tracts were obtained. Blood was analyzed for estrogen metabolites and IFN-gamma. The cervical transformation zone was sectioned and stained for histology. Estradiol C-2 hydroxylation and serum IFN-gamma levels were significantly increased over controls in wild type and transgenic mice receiving DIM. In wild type mice without DIM, hyperplasia of the squamous epithelium was observed. Wild type mice fed DIM displayed a normal thin epithelium. In transgenic mice without DIM, epithelial cell projections into the stroma (papillae) were present. An additional degree of nuclear anaplasia in the stratum espinosum was observed. Dysplastic cells were present. Transgenic mice fed DIM displayed some mild hyperplasia of the squamous epithelium. DIM increases estrogen C-2 hydroxylation in this model. Serum INF-γ was increased indicating increased immune response in the DIM fed animals. Histopathology showed a marked decrease in cervical dsyplasia in both wild type and transgenic mice indicating that DIM delays or inhibits the progression from cervical dysplasia to cervical cancer. Using the K14-HPV16 transgenic mouse model, we have shown that DIM inhibits the development of E6/E7 oncogene induced cervical lesions.
PMCID: PMC2783856  PMID: 19861518
4.  Polychlorinated biphenyl exposure, diabetes and endogenous hormones: a cross-sectional study in men previously employed at a capacitor manufacturing plant 
Environmental Health  2012;11:57.
Studies have shown associations of diabetes and endogenous hormones with exposure to a wide variety of organochlorines. We have previously reported positive associations of polychlorinated biphenyls (PCBs) and inverse associations of selected steroid hormones with diabetes in postmenopausal women previously employed in a capacitor manufacturing plant.
This paper examines associations of PCBs with diabetes and endogenous hormones in 63 men previously employed at the same plant who in 1996 underwent surveys of their exposure and medical history and collection of bloods and urine for measurements of PCBs, lipids, liver function, hematologic markers and endogenous hormones.
PCB exposure was positively associated with diabetes and age and inversely associated with thyroid stimulating hormone and triiodothyronine-uptake. History of diabetes was significantly related to total PCBs and all PCB functional groupings, but not to quarters worked and job score, after control for potential confounders. None of the exposures were related to insulin resistance (HOMA-IR) in non-diabetic men.
Associations of PCBs with specific endogenous hormones differ in some respects from previous findings in postmenopausal women employed at the capacitor plant. Results from this study, however, do confirm previous reports relating PCB exposure to diabetes and suggest that these associations are not mediated by measured endogenous hormones.
PMCID: PMC3476446  PMID: 22931295
PCB; Hormones; Diabetes; Employees; Capacitor; Plant
5.  3,3′-Diindolylmethane Modulates Estrogen Metabolism in Patients with Thyroid Proliferative Disease: A Pilot Study 
Thyroid  2011;21(3):299-304.
The incidence of thyroid cancer is four to five times higher in women than in men, suggesting a role for estrogen (E2) in the pathogenesis of thyroid proliferative disease (TPD) that comprises cancer and goiter. The objective of this study was to investigate the antiestrogenic activity of 3,3′-diindolylmethane (DIM), a bioactive compound derived from cruciferous vegetables, in patients with TPD.
In this limited phase I clinical trial study, patients found to have TPD were administered 300 mg of DIM per day for 14 days. Patients subsequently underwent a total or partial thyroidectomy, and tissue, urine, and serum samples were collected. Pre- and post-DIM serum and urine samples were analyzed for DIM levels as well as estrogen metabolites. DIM levels were also determined in thyroid tissue samples.
DIM was detectable in thyroid tissue, serum, and urine of patients after 14 days of supplementation. Urine analyses revealed that DIM modulated estrogen metabolism in patients with TPD. There was an increase in the ratio of 2-hydroxyestrones (C-2) to 16α-hydroxyestrone (C-16), consistent with antiestrogenic activity that results in more of C-2 product compared with C-16.
Our data suggest that DIM enhances estrogen metabolism in TPD patients and can potentially serve as an antiestrogenic dietary supplement to help reduce the risk of developing TPD. The fact that DIM is detected in thyroid tissue implicates that it can manifest its antiestrogenic activity in situ to modulate TPD.
PMCID: PMC3048776  PMID: 21254914
6.  Effects of A Breast-Health Herbal Formula Supplement on Estrogen Metabolism in Pre- and Post-Menopausal Women not Taking Hormonal Contraceptives or Supplements: A Randomized Controlled Trial 
Both indole-3-carbinol and dietary lignans have beneficial effects on estrogen metabolism and breast cancer risk. There is no published literature on the effects of a combination product. This study was designed to investigate the impact of a combination product on estrogen metabolism. The major trial objective was to determine whether a breast health supplement containing indole-3-carbinol and hydroxymatairesinol lignan would alter estrogen metabolism to favour C-2 hydroxylation and reduce C-16 hydroxylation. Higher concentrations of C-2 metabolites and lower concentrations of C-16 metabolites may reduce breast cancer risk and risk for other hormonally-related cancers.
Forty-seven pre-menopausal and forty-nine post-menopausal women were recruited for this study, and were divided by random allocation into treatment and placebo group. The treatment supplement contained HMR lignan, indole-3-carbinol, calcium glucarate, milk thistle, Schisandra chinesis and stinging nettle, and each woman consumed either treatment or placebo for 28 days. At day 0 and day 28, blood samples were analysed for serum enterolactone concentrations, and first morning random urine samples were assessed for estrogen metabolites. Repeated measures ANOVA statistical testing was performed.
In pre-menopausal women, treatment supplementation resulted in a significant increase (P < 0.05) in urinary 2-OHE concentrations and in the 2:16α-OHE ratio. In post-menopausal women, treatment supplementation resulted in a significant increase in urinary 2-OHE concentrations. In pre- and post-menopausal women combined, treatment supplementation produced a significant increase in urinary 2-OHE concentration and a trend (P = 0.074) toward an increased 2:16α-OHE ratio. There were no significant increases in serum enterolactone concentrations in the treatment or placebo groups.
Supplementation with a mixture of indole-3-carbinol and HMR lignan in women significantly increased estrogen C-2 hydroxylation. This may constitute a mechanism for the reduction of breast cancer risk as well as risk for other estrogen-related cancers. Further studies with higher numbers of subjects are indicated.
Trial registration registration #NCT01089049.
PMCID: PMC3018890  PMID: 21234288
herbal supplement; breast health; estrogen metabolites

Results 1-6 (6)