![]() ![]() Patient recruitment and DIM administration Delineating the effect of DIM on estrogen metabolism can potentially allow for the development of DIM as a novel effective antiestrogenic compound for TPD and may have implications for new modalities in the management of thyroid disease. A portion of the patient's urine and serum samples were collected and analyzed for the DIM's effect on estrogen metabolism by quantitating the levels of 2-OHE and 16-OHE1. At the end of 14-day DIM supplementation, the concentration of DIM was determined in thyroid tissues and urine and serum samples of obtained from same patients. This study recruited seven patients and examined the effect of oral administration of 300 mg DIM/day for 14 days. Based on these findings, we initiated a pilot clinical study to examine the effects of oral DIM supplementation in women with TPD. Our preclinical thyroid cell culture models strongly implicated the role of estradiol ( 12) and indicate that DIM is an indirect modulator of estradiol-mediated mitotic activity. I3C readily dimerizes into 3,3′-diindolylmethane (DIM), which is an acid catalyzed stable compound and a presumed active chemopreventive agent. The major drawback with clinical use of I3C as an anticancer drug is its molecular instability. We were one of the first groups to recognize anticancer properties of I3C against hormonally dependent breast and prostate cancer ( 16, 20, 21). One such dietary indole, Indole-3-carbinol (I3C), is the bioactive phytochemical and a presumed modulator of reduced cancer risk in areas with high cruciferous vegetable consumption ( 16– 19). ![]() It is the goal of our chemoprevention program to examine the preclinical and clinical efficacies of that compound.ĭietary indoles present in cruciferous vegetables, such as broccoli and cauliflower, have been shown to possess chemopreventive and chemotherapeutic properties against a wide variety of cancers ( 16– 19). In recent years, natural compounds found in diet, such as indoles, have been shown to possess antiestrogenic activity ( 16). ![]() The fact that thyroid cancer cells are estrogen responsive and that TPD patients metabolize estrogen, leading to pro-mitogenic conditions, opens up a new area for the use of established therapies or discovery of novel therapies targeted at increasing the 2-OHE:16-OHE1 ratio as a desired outcome resulting from treatment of anticancer agents. demonstrated that estrogen metabolism in patients with TPD is distinct from matched controls, with a similar low urinary 2-OHE:16-OHE1 ratio observed among TPD patients as other hormone related cancers ( 15). Some studies from literature, including a recent study from our laboratory, provide evidence that thyroid cells express functional estrogen receptor and are estrogen responsive ( 12– 14). 2-hydroxyestrone and 16-alphahydroxyestrone are the major metabolites in estrogen metabolism.Īccording to American Thyroid Association, women are four to five times more prone to developing thyroid disorders than men, with pregnancy and early menopause increasing the risk ( 11), suggesting the significance of hormonal factors such as estrogen in the etiology and pathogenesis of TPD. 1) and is used as a predictive biomarker for these cancers ( 10) but has not been evaluated in response to chemopreventive agents in thyroid proliferative diseases (TPDs).Įstradiol metabolism schema. The relative concentration of 2-OHE:16-OHE1 can increase or decrease the risk of developing hormone responsive cancers (breast and cervical) ( 1, 2, 5– 9) ( Fig. Several studies using cell culture models have demonstrated the proliferative effects of 16-OHE1 and the antiproliferative effects of 2-OHE ( 1– 4). Some other estrogen metabolites, 4-OHE1 and 4-OHE2, are also estrogen agonists but their relative concentrations are too low to be of physiological significance. Two estrogen metabolites, in particular, 16-OHE1 and 2-OHE, have contrasting cellular activities with 16-OHE1 being an estrogen agonist, whereas 2-OHE is an estrogen antagonist. Premenopausal women naturally produce hundreds of micrograms of estrogen daily, which is enzymatically converted to specific estrogen metabolites such as 2-hydroxyestrogens (2-OHE's), 2-methoxyestrogens, 16α-hydroxyestrone (16-OHE1), and 4-hydroxyestrogens (4-OHE's) ( 1). The mitotic activity of estradiol in estrogen responsive tissue such as breast has resulted in development of several antiestrogenic compounds as preventive or therapeutic agents. E strogens are a group of three biochemically distinct hormones, estradiol (E 2), estrone (E 1), and estriol (E 3), with 17β-estradiol being the active form. ![]()
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