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Estrogens - The Female Hormones

ESTROGENS:
ABOUT
Estrogen Dominance
HEALTH EFFECTS
NO HRT

I3C (becomes DIM)

I3C (=>DIM) in Crucifer Vegetables:
ABOUT
HOW-TO

DIM (derived from cruciferous vegetables in stomach/intestines) - Estrogen Blocker with Anti-Cancer Benefits

I3C (=> DIM) in crucifer vegetables - estrogen blocker with anti-cancer benefits

DIM is derived from crucifer vegetables

The compound I3C (Indole-3-carbinol) is derived from cruciferous vegetables. By the hydrolysis (breakdown) of glucobrassicin (an indole glucosinolate) found in broccoli and other members of the Brassica family, such as brussels sprouts, bok choy, kale, chard, mustard greens, cauliflower, cabbage, rutabaga and turnips.

I3C increases the conversion of ESTRADIOL to a "weaker" estrogen (2OHE). The body converts I3C to diindolylmethane (DIM), which then induces certain enzymes in the liver to block the production of the toxic estrogens and step up the production of the beneficial forms. To protect I3C levels, the best way to eat them is lightly steamed or even better, pickled; Helpful for those with "allergies", asthma, chronic fatigue, or MCS.

I3C forms active reaction products in the body, including DIM

When plant cells in cruciferous vegetables are chopped or chewed. The interaction of the myrosinase enzyme andglucobrassicin(previously separated In the intact plant) rresults in the formation of I3C

In the acidity of the stomach, I3Cs combine to form various active acid condensation products. These reactionproducts are responsible for the activity attributed to I3C, BUT NOT ALL of them have a positive effect with health problems..

DIM (dimer 3,3'-diindolylmethane) is one of I3C's beneficial reaction products. ~ 10-20% of I3C consumed is converted to DIM in the stomach.

Boiling brassica vegetables deactivates myrosinase, but a lesser amount of I3C is still formed (via glucobrassin hydrolysis by bacteria in the intestines) - the alklaline environment of the intestine is, however, less likely to form reaction products.

Most NATURAL way to obtain quantities of I3C is by eating broccoli sprouts

The natural way to obtain I3C is to consume it in the whole foods that contain it. E.g by eat broccoli. However, broccoli sprouts are even better, since they contain hundreds of times more I3C than broccoli.

Broccoli sprouts can be found at many health food stores, certain grocery stores (E.g. Publix), also some farmer's markets. If not available ready-grown, purchase organic broccoli seeds and sprout your own; they can be added to salads and sandwiches, but to consume in quantity, they can be lightly steamed and eaten as a vegetable - they taste similar to steamed spinach.

Using I3C as an ISOLATED supplement is NOT recommended due to its mixed study results (detailed on this page). The brassica vegetables contain many phytonutrients, which could be responsible for their generally favorable effect on health and with cancer. In particular the nutrient sulfuraphane:

Sulforaphane -"Eat Your Broccoli"

DIM supplementation is a useful anti-estrogen / anti-cancer "tool"

The reaction product DIM is considered a safe and effective supplement used as an estrogen-blocker and for its anti-cancer effects. Having benefits and safety properties not attributed to an I3C supplement. Estrogen can be broken down to both "good" metabolites (E.g.2-hydroxy estrogen) and "bad" i.e. carcinogenic metabolites (E.g. 4-hydroxy estrogenand 16-hydroxy estrogen) - DIM supplementation promotes more of the "good" metabolites and less of the "bad", which are affiliated with breast cancer and other health problems

DIM particularly seems to be a worthwhile supplement for:

Any Estrogen-sensitive (E.g. reproductive cancers, lung cancer) or HPV-related cancer (E.g. squamous cell lung cancer)
Losing weight resulting from estrogen-related weight gain

I3C /DIM and cancer

I3C has had mixed results as an anti-cancer mechanism

Studies Supporting I3C/DIM Anti-Cancer Action
Cancer Type	I3C or DIM	Study Findings	StudyType#	Study
Prostate	I3C	Induces apoptosis in prostate cancer cells	C	PubMed
Breast	DIM	Induces apoptosis in breast cancer cells	C	PubMed
Breast	I3C	Induces apoptosis in breast cancer cells	C	PubMed
Cervical		Estrogen protects cervical cancer cells from apoptosis	C	PubMed
Breast	I3C*	INHIBITS cancer development	A	PubMed PubMed
Uterus	I3C*	INHIBITS cancer development	A	PubMed
Stomach	I3C*	INHIBITS cancer development	A	PubMed
Colon	I3C*	INHIBITS cancer development	A	PubMed PubMed
Colon	I3C	Induced cell-cycle arrest and apoptosis in human colon cancer cells	C	PubMed
Lung	I3C*	INHIBITS cancer development	A	PubMed
Liver	I3C*	INHIBITS cancer development	A	PubMed PubMed
Breast	I3C	Interferes with the breast cancer cell cycle ^; also had an indirect role in selective apoptosis-inducing ability in premalignant and malignantbreast epithelial cells	C	PubMed
Breast	I3C	Revealed an important connection between I3C and the mammalian gene Cdc25A, necessary for cells to divide and proliferate; When a vegetable compound containing I3C was given orally to lab mice, it dramatically reduced tumor size up to 65 %	A	Cancer Prevention Research, online pubn.Jun 29, 2010

# Study Type is Cultured (C), Animal(A) or Human (H)

*Administered BEFORE or AT THE SAME TIME as a carcinogen (required to cause cancer in most animal models)

^In what may be a previously unknown signaling pathway in the cell, its unusual mechanism promotes a sharp drop in production of the gene CDK6 (cyclin-dependent kinase 6) which encodes for the CDK6 enzyme, important in the cell's growth cycle.

% Cdc25A occurs at abnormally high levels in cancers of the breast, prostate, liver, esophagus, endometrium and colon, and in non-Hodgkin lymphoma; it is also elevated in other diseases, including Alzheimer's disease. The Ohio State researchers discovered that I3C causes the destruction of Cdc25A, resulting in a sudden halt to breast cancer cell growth.
About half of breast cancer cases have abnormally high levelsof Cdc24A, which is associated with a poor prognosis."I3C can have striking effects on cancer cells", according to Dr. Zou, one of the study's research team, "and a better understanding of this mechanism may lead to the use of this dietary supplement as an effective and safe strategy for treating a variety of cancers and other human diseases associated with the overexpression of Cdc25A."

I3C / DIM are likely to benefit prostate cancer and other hormone-sensitive cancers. Which have similar contributing factors.

I3C has been used for some benign cancers and abnormal growths: Voicebox and respiratory tract tumors caused by a virus, and cervical dysplasia (abnormal growth in cervix)

Unlike Tamoxifen, I3C / DIM work independently of the hormone estrogen. I3C (or its reaction product DIM) could be used as a complimentary treatment with drugs that do interfere with estrogen.

Cancer prevention. Researchers are particularly interested in supplementation of I3C or its reaction products, such as DIM, for prevention of breast, cervical, endometrial and colectoral cancers

Studies NOT Supporting I3C/DIM Anti-Cancer Action
Cancer Type	I3C or DIM	Study Findings	StudyType#	Study
Breast	I3C	Shown INeffective in controlling experimental cancer growth in rats; First study concluded that, over time, IC3increased carcinogenic estrogen metabolites (E.g. 4-OH and 16-OH), which may be counteracting those of the less estrogenic 2-OH metabolites	A	PubMed PubMed+
Liver	I3C	I3C promoted or enhanced cancer development when administered chronically to rainbow trout AFTER administration of cancer promoting carcinogen (post-initiation).	A	PubMed+ PubMed +
Breast, liver, colon	I3C	continuous I3C diet for 25 weeks did not alter tumor incidence or multiplicity among surviving rats	A	PubMed+ PubMed+ PubMed+
Liver, Thyroid	I3C	Enhanced cancer development in rats	A	PubMed+
Colon		Enhanced cancer development in rats; second study states I3C increased proliferation and decreased apoptosis	A	PubMed PubMed+
Uterus	I3C	study concluded that excess increased activityof carcinogenic 4-OH estrogen metabolites compared to 2-OH metabolites in the liver contributed to increased uterine uterine adenocarcinomas and/or multiplicities of uterine proliferative lesions; study showed no effect on 16-OHactivity.	A	PubMed+

# Study Type is Cultured (C), Animal(A) or Human (H)

+ Administered post-initiation i.e. after carcinogen (required to cause cancer in most animal models)

I3C reaction products have been shown to reduce immune system natural killer cell activity in rats

Exon JH, South EH, "Dietary indole-3-carbinol alters immune functions in rats."J Toxicol Environ Health A. 2000 Feb 25;59(4):271-9.

I3C reaction products associated with reproductive toxicity in rats -similarly to dioxin

Wilker C, Johnson L, Safe S, "Effects of developmental exposure to indole-3-carbinol or 2,3,7,8-tetrachlorodibenzo-p-dioxin on reproductive potential of male rat offspring." Toxicol Appl Pharmacol. 1996 Nov;141(1):68-75.

Larsen-Su SA, Williams DE, "Transplacental Exposure to Indole-3-carbinol Induces Sex-Specific Expression of CYP1A1 and CYP1B1 in the Liver of Fischer 344 Neonatal Rats." Toxicol Sci. 2001 Dec;64(2):162-8.

DIM is neither Estrogen icor a growth promoter of cancer cells. DIM exerts its control over cancer growth by promoting production of beneficial 2OHE1 estrogen, whilstinducing less of the unwanted enzymes that producehighly estrogenic and carcinogenic16OHE1from I3C; (see below: IC3/DIM and Hormone Balancing /Alterations in Estrogen Activity and Metabolism)

Other I3C reaction products have mixed effects

Linear Trimer (LTR). Anti-estrogenic, but activates dioxin receptor
Cyclic Trimer (CTR). Directly activates the estrogen receptor, powerfully stimulates breast cancer cell growth, whether or not estrogen is present;
Indole-3-acetonitrile (IAN). Shown protective in animal model of stomach cancer, but it has also been found to be mutagenic and to produce DNA-damaging reaction products in the presence of nitrates (common in foods)

Yamashita K, Wakabayashi K, Kitagawa Y, Nagao M, Sugimura T. "32P-postlabeling analysis of DNA adducts in rat stomach with 1-nitrosoindole-3-acetonitrile, a direct-acting mutagenic indole compound formed by nitrosation." Carcinogenesis. 1988 Oct;9(10):1905-7.

Wakabayashi K, Nagao M, Ochiai M, et al., "A mutagen precursor in Chinese cabbage, indole-3-acetonintrile, which becomes mutagenic on nitrite treatment." Mutat Res 1985; 143(1-2):17-21.

IAN also found to activate inflammation-causing leukotrienes in cell membranes (via arachadonic fatty acid cascade)

Maybe other ingredients in cruciferous vegetables are responsible for their hypothesized lower risk for some types of cancer in epidemiological studies.

Verhoeven DT, Goldbohm RA, van Poppel G, Verhagen H, van den Brandt PA. Epidemiological studies on brassica vegetables and cancer risk. Cancer Epidemiol Biomarkers Prev. 1996;5(9):733-748. (PubMed).

-brassica are relatively good sources of other phytonutrients including vitamin C, folate, selenium, carotenoids, fiber and other glucosinolates, in addition to I3C, that may be hydrolyzed to a variety of potentially protective isothiocyanates (E.g. Sulforaphane -"Eat Your Broccoli").

The I3C reaction product ICZ (indolocarbazole) is generally undesireable

ICZ has both antiestrogenic and estrogenic activities. It down-regulatesestrogenreceptors, but is itself estrogenic, promoting enzymes which produce the carcinogenic estrogenic metabolite4-hydroxy estrogenassociated with uterine tumors
ICZ activates the dioxin receptors just like dioxin. Although dioxin has toxic properties, it is a powerful estrogen activity inhibitor, as is ICZ. ICZ is more quickly metabolized than dioxin, but has been shown to damage the thymus gland and immune system and to damage DNA.

d'Argy R, Bergman J, Dencker L, "Effects of immunosuppressive chemicals on lymphoid development in foetal thymus organ cultures." Pharmacol Toxicol. 1989 Jan;64(1):33-8.

Park JY, Shigenaga MK, Ames BN, "Induction of cytochrome P4501A1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin or indolo(3,2-b)carbazole [ICZ] is associated with oxidative DNA damage," Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2322-7.

Another I3C condensation product, ascorbigen (ASG) is converted to ICZ in the lower intestine. In the presence of vitamin C (naturally abundant in cruciferous vegetables), ASG is the most plentifully produced reaction product from I3C, occurring in the stomach.Some of this ASG is converted to ICZ in the lower intestine, making it available for unwanted enzyme production to promote carcinogenic4-hydroxy estrogen.

Preobrazhenskaya MN, Bukhman VM, Korolev AM, Efimov SA, "Ascorbigen and other indole-derived compounds from Brassica vegetables and their analogs as anticarcinogenic and immunomodulating agents." Pharmacol Ther. 1993 Nov;60(2):301-13.

DIM cannot be converted to the undesireable ICZ in vivo

I3C/DIM and hormone balancing /alterations in estrogen activity and metabolism

"Good" and "Bad" estrogens at work in the body

Estrogens must be removed from the body when they have finished their work. Generally, estrogens positively promote the tissue growth predominately underlying female maturation. Ideally, once their job is done, they are promptly metabolized and removed from the body. If this is not efficiently achieved, they can hang around and wreak havoc.

Removal of hormones is achieved in two main ways:

1. Physically removed viaurination and bowel movements

2. Metabolized ( Chemically altered ) mainly by the liver to prepare them for removal - requires certain nutrients and is achieved by two main pathways:

(i) CARCINOGENIC 16 alpha-hydroxylation pathway - more active in women with estrogen-sensitive cancers; produces the carcinogenic estrogen metabolite 16alpha-hydroxyestrone (16OHE1), which is highly estrogenic and has been found to stimulate the proliferation of several estrogen-sensitive cancer cell lines.

Telang NT, Suto A, Wong GY, Osborne MP, Bradlow HL. Induction by estrogen metabolite 16 alpha-hydroxyestrone of genotoxic damage and aberrant proliferation in mouse mammary epithelial cells. J Natl Cancer Inst. 1992;84(8):634-638. (PubMed)

Yuan F, Chen DZ, Liu K, Sepkovic DW, Bradlow HL, Auborn K. Anti-estrogenic activities of indole-3-carbinol in cervical cells: implication for prevention of cervical cancer. Anticancer Res. 1999;19(3A):1673-1680. (PubMed)

(ii) PROTECTIVE 2 hydroxylation pathway - produces the cancer-protective estrogen metabolite 2-hydroxyestrone (2OHE1).

What factor(s) determine whether estrogen is metabolized by the carcinogenic or protective pathway?

Removal of hormones is negatively impacted by low thyroid function. Explains the link between hypothyroidism and breast or prostate cancer.

Can depend on our genetic expression, diet, lifestyle and elimination habits. E.g. a deficiency in B vitamins (B6 in particular) and/or Magnesium reduces liver's estrogen clearance rate.

Several tactics can be used to reduce unwanted estrogen presence in the body. E.g. A coffee enema will stimulate bile production to cleanse liver. Attend to B6/ Magnesium deficiencies

How to Reduce Estrogen levels

Many of estrogen's risks can be related to a lack of its beneficial metabolites and too many of its carcinogenic metabolites

It is now known that a lower risk of future breast cancer is associated with high beneficial 2-hydroxy estrogen levels and low carcinogenic 16OHE1. Which is prone to behave like "super-estrogen" and its higher levels create a particularly carcinogenic form of estrogen dominance which can result in:

â€¢Mutations, abnormal growth (as in cervical dysplasia)

Sepkovic DW, Bradlow HL, Ho G, et al.Estrogen metabolite ratios and risk assessment of hormone related cancers:assay validation and prediction of cervical cancer risk.Ann NY Acad Sci. 1995; 768:312-316.

â€¢Increased risk of breast cancer.

Muti P, et al.Metabolism and risk of breast cancer:A prospective analysis of 2:16 hydroxyestrone ratio in premenopausal and postmenopausal women.Cancer Epidemiol Biomarkers Prev, 2000; in press.

Overproduction of 16OHE1 is also seen in:

â€¢Obesity

Hershcope RJ, Bradlow HL.Obesity, diet, endogenous estrogens, and the risk of hormone-sensitive cancer.Am J Clin Nutl: 1987;45(1 Supp1):283-289.

â€¢High-fat diets

Musey PI, Collins DC, Bradlow HL, Gould KG, Preedy JR.Effect of diet on oxidation of 17-Beta-ESTRADIOL in vivo.J Clin Endoc Metab. 1987;65:792-795.

â€¢Exposure to "estrogenic" environmental chemicals (xenoestrogens)

Bradlow HL, Davis DL, Lin G, Sepkovic D, Tiwari R.Effects of pesticides on the ratio of 16/2-hydroxyestrone'a biologic marker of breast cancer risk.Environ Health Perspect. 1995; 103(SuppI7): 147-150.

Endogenous estrogens exert their estrogenic effects by binding to estrogen receptors (ERs). Within the nucleus, the estrogen-ER complex can bind to DNA sequences(estrogen response elements/EREs) in estrogen-responsive genes (stimulated by the ligand-activated transcription factor Aryl hydrocarbon receptor/AhR) and thereby enhance transcription of these estrogen-responsive genes. ER-mediated effects that promote cellular proliferation in the breast and uterus can increase the risk of developing estrogen-sensitive cancers.

Effect of I3C/DIM on estrogen metabolism and receptor activity

IC3 /DIM creates more "good" estrogen and less "bad" estrogen. In controlled clinical trials, oral supplementation with:

300-400 mg/day of I3C has consistently increased urinary 2OHE1 levels or urinary 2OHE1: 16OHE1 ratios in women.

McAlindon TE, Gulin J, Chen T, Klug T, Lahita R, Nuite M. Indole-3-carbinol in women with SLE: effect on estrogen metabolism and disease activity. Lupus. 2001;10(11):779-783. (PubMed)

Bradlow HL, Michnovicz JJ, Halper M, Miller DG, Wong GY, Osborne MP. Long-term responses of women to indole-3-carbinol or a high fiber diet. Cancer Epidemiol Biomarkers Prev. 1994;3(7):591-595. (PubMed)

Michnovicz JJ. Increased estrogen 2-hydroxylation in obese women using oral indole-3-carbinol. Int J Obes Relat Metab Disord. 1998;22(3):227-229. (PubMed)

Michnovicz JJ, Adlercreutz H, Bradlow HL. Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans. J Natl Cancer Inst. 1997;89(10):718-723. (PubMed)

Wong GY, Bradlow L, Sepkovic D, Mehl S, Mailman J, Osborne MP. Dose-ranging study of indole-3-carbinol for breast cancer prevention. J Cell Biochem Suppl. 1997;28-29:111-116. (PubMed)

Reed GA, Peterson KS, Smith HJ, et al. A phase I study of indole-3-carbinol in women: tolerability and effects. Cancer Epidemiol Biomarkers Prev. 2005;14(8):1953-1960. (PubMed)

108 mg/day of DIM increased urinary 2OHE1 levels in postmenopausal women. Meaning the body was producing them.

Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF. Pilot study: effect of 3,3'-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer. 2004;50(2):161-167. (PubMed)

Oral I3C supplementation can increase production of dangerous estrogen metabolites at the same time it increases the beneficial 2-hydroxy metabolites. Animal studies demonstrate unwanted enzyme-inducing effects from oral I3C supplementation

Ritter CL, Prigge WF, Reichert MA, Malejka-Giganti D, "Oxidations of 17 beta-ESTRADIOL and estrone and their interconversions catalyzed by liver, mammary gland and mammary tumor after acute and chronic treatment of rats with indole-3-carbinol or beta-naphthoflavone." Can J Physiol Pharmacol. 2001 Jun;79(6):519-32.

I3C/DIM downgrade estrogen receptor activity. In culture, I3C has been found to INHIBIT the transcription of estrogen-responsive genes stimulated by ESTRADIOL. Also, it was found that DIM binds and activates the Ah receptor (AhR) with an anti-estrogenic and anti-tumorigenic effect; it may inhibit the transcription of estrogen-responsive genes by competing for coactivators or increasing ER degradation.

Chen I, McDougal A, Wang F, Safe S. Aryl hydrocarbon receptor-mediated antiestrogenic and antitumorigenic activity of diindolylmethane. Carcinogenesis. 1998;19(9):1631-1639. (PubMed)

Meng Q, Yuan F, Goldberg ID, Rosen EM, Auborn K, Fan S. Indole-3-carbinol is a negative regulator of estrogen receptor-alpha signaling in human tumor cells. J Nutr. 2000;130(12):2927-2931. (PubMed)

In contrast, a RAINBOW TROUT model found that DIM enhanced the transcription of estrogen-responsive genes.

Shilling AD, Carlson DB, Katchamart S, Williams DE. 3,3'-Diindolylmethane, a major condensation product of indole-3-carbinol, is a potent estrogen in the rainbow trout. Toxicol Appl Pharmacol. 2001;170(3):191-200. (PubMed)

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