How long do we stay on arimedex for? live in Uk and they want to stop it!

[TSund]

Deb,

I have not looked at these in detail, but if you google


diindolylmethane and breast cancer you'll get some hits.


http://carcin.oxfordjournals.org/cgi...tract/26/4/771

check out the footnotes on that article with several references to what appears to be scientific studies.

and

http://diindolylmethane.redtoenail.org/ NOT a study itself but has references to studies below also.

Ruth takes it as a recommendation from a naturalpath we trustI can't help much with the science. It appears to help the liver process out the estrogen?

[Laurel]

Debbie,

Here are a few abstracts that I hope you will find informative. I am beginning a study at my med center where my onc. is testing for the efficacy of Tamoxifen. I have been taking DIM and Calcium D-glucarate ever since my dx. I stopped during chemo and resumed thereafter. DIM works in a different manner than Tamox. so I figure it's a double whammy, and protects my uterus. Still, it will be interesting to see how the Tamoxifen is fairing in conjunction with these 2 supplements. I'll let you know when I know.

http://www.diindolylmethane.org/molecular_biology.htm

http://mct.aacrjournals.org/cgi/mjgc...3B65%2F1%2F364

http://www.springerlink.com/content/u361486110t68517/

http://www.dimfaq.com/index.htmhttp://www.aacrmeetingabstracts.org/cgi/content/abstract/2005/1/577-c

[TSund]

disclaimer: this is from a practioner respected supplement company. I cannot testify to its veracity, but it explains things in more understandable language.

Plant indoles, also called glucosinolates, found in cruciferous vegetables provide health benefits to humans. Cruciferous vegetables are known for their cancer protection. Two such indoles provided by cruciferous vegetables are I3C (Indole 3 Carbinol) and DIM (Diindolylmethane). DIM is not naturally present in these plants. It gets released with the help of enzymes upon crushing of the broccoli, cauliflower, cabbage or brussel sprouts or during human digestion. [1,3] Stomach acid, or HCl, can also aid the joining of two indole 3 carbinols to make diindolylmethane. Lack of HCl will hinder one's ability to make DIM from I3C. [2]
So basically, DIM is 2 molecules of I3C combined together. I3C in a capsule is not shelf stable because it is sensitive to light, heat and moisture. I3C is irritating to the stomach and research tells us that it can have very negative side effects in doses over 300 mg daily such as dizziness and unsteady gait which may be due to nervous system toxicity. One study shows evidence that 90% of orally consumed I3C converts to other compounds. Perhaps it is these other compounds that cause these side effects. One compound I3C converts to is ICZ, or indololcarbizol. This compound causes DNA damage.4 DIM studies show no toxicity when given triple the dose in humans.
What Actions Does DIM Have on the Body that Make it Beneficial to our Health?
It has been suggested that a low level of the 2-hydroxyestrogen metabolites (2-OHE) and a high level of 16 alpha-hydroxyestrone (16 alpha-OHE1) is associated with an enhanced risk of breast cancer. DIM increases 2 hydroxyestrone and therefore improves the 2/16 hydroxyestrone ratio, making it very protective for women at high risk for this condition. [6]
Research by Bradlow says that DIM also reduces availability of 4-androstenedione for aromatization to estrone. [7] He concludes that DIM is more potent than I3C at protecting against mammary carcinoma due to decreased formation of 16 alpha-hydroxyestrone from estrone. [6]
What About Toxicity Studies?
In acute toxicity studies in mice “DIM produced no observable 24-hr acute toxicity up to 4 g/kg body weight, except for a slight decrease in haematocrit. However, I-3-C exhibited a dose-dependent toxicity above 100 mg/kg body weight, including a decrease in hepatic reduced glutathione after 2 hr and severe neurological toxicity, and the release of liver enzymes to the plasma at 24 hr.”9
Bottom Line: Supplementation of DIM should be recommended over supplementation of I3C for safety purposes.
DIM is a More Potent Antioxidant Than I3C
When tested side by side with I3C, DIM was shown to be a more potent antioxidant with greater activity than vitamin E because of its hydrogen (electron) donating ability.
Should we Just Eat Cruciferous Vegetables?
Eating 2 pounds of cruciferous vegetables like raw cabbage or broccoli can ultimately supply, via I3C conversion into DIM, about 20-30 mg of DIM. Therefore, supplementation is ideal along with eating cruciferous vegetables.
What Does DIM Do?
Research clearly shows that 4 hydroxy estrogen and 16 hydroxy estrogen are not favorable when elevated. Low risk for breast cancer is marked by a high 2/16 ratio (2 hydroxy to 16 hydroxy estrogen). It is clearly established by research that DIM raises the 2/16 ratio without elevating 4 hydroxy estrogen. DIM helps men too because it may be an aromatase inhibitor. DIM helps to block the conversion of testosterone to estrogen.

Can DIM be Taken with Medications?
DIM is safe when taken with Tamoxifen, birth control pills and other herbs such as St. John’s Wort that affect cytochrome p450 enzymes. Because of its effects on CYP enzymes, I3C should not be taken with any of these. I3C blocks ovulation, can interfere with birth control pills and may alter the effects of many herbs such as St John's Wort and could lead to Tamoxifen toxicity if taken simultaneously. Researchers in Minneapolis, MN found that DIM does not effect the metabolism of Tamoxifen. I3C on the other hand, converts Tamoxifen into N-desmethyl-Tamoxifen 3 fold, which itself gets transformed into a genotoxic metabolite. [13] Research titled Endocrine Disruption by I3C and Tamoxifen: Blockage of Ovulation may be disturbing to some. This is a quote from the Gao ovulation study: “In the current study, I3C disrupted ovulation already at doses that did not elicit systemic toxicity as indicated by a lack of reduced body weight gain, which was then observed at higher doses.” Gao asserts that “I3C appears to have TCDD-like inhibitory effects on ovulation.” [14] TCDD is a heavy duty dioxin chemical. Researchers in Denmark state “Indolo[3,2- b]carbazole (ICZ), which is formed in the acidic environment of the stomach after intake of I3C, has a similar structure to, and shares biological effects with, the well-known tumor promoter [2,3,7, 8] tetrachlorodibenzo-p-dioxin (TCDD).” This is the conclusion of their study: “Further studies are needed in order to clarify the anticarcinogenic/carcinogenic effects of I3C and ICZ before high doses of I3C may be recommended as a dietary supplement.” They feel that ICZ's tumor promoting activity is due to its activation of the Ah receptor and stimulation of certain cytochrome p450 enzymes mainly Cyp1a1, Cyp1a2 and Cyp1b1. [15]
DIM's proven safety means that DIM can be used by women wishing to get pregnant but should be discontinued during pregnancy and lactation. There are no known contraindications for DIM supplementation.

• Helps protect against breast cancer
• Improves hormone related conditions including: PMS, PCOS (Polycystic Ovary Syndrome), endometriosis, fibroid tumors, menopausal symptoms, weight problems
• Highly absorbable formulation including emulsified lecithin

Due to its crystalline structure, absorption of DIM when given orally simply as a powder in a capsule is minimal, similar to CoQ10. DIM absorption can be greatly enhanced by emulsifying it with lecithin in rice bran oil, including with it compounds that hold it in solution such as beeswax, and finally adding fat-soluble nutrients that aid absorption through the gut wall. Research tells us that a low level of the 2-hydroxyestrone and a high level of 16 alpha-hydroxyestrone is associated with an enhanced risk of breast cancer. DIM increases 2-hydroxyestrone and therefore improves the 2/16 hydroxyestrone ratio, making it very protective for women and men at high risk for this condition. Research by Bradlow has shown that DIM also reduces availability of 4-androstenedione for aromatization to estrone, a more dangerous form of estrogen. He concludes that DIM is more potent than I3C at protecting against breast cancer due to decreased formation of 16 alpha-hydroxyestrone from estrone. DIM supplementation improves the estrogen ratio in a favorable direction that protects both men and women without the negative effect of raising 4 hydroxyestrogen as seen with I3C. DIM does not block ovulation the way I3C does, and can be used safely along with Tamoxifen, unlike I3C. DIM should be considered first line therapy for hormone imbalances that can lead to negative conditions such as PMS, PCOS, endometriosis, fibroid tumors, menopausal symptoms, weight problems and the list goes on. Recent research is positive so far that DIM improves weight loss resistance due to hormonal imbalance.

“In summary, both the ER antagonist tamoxifen and the AhR agonist I3C blocked ovulation and disrupted the preovulatory surge in LH and FSH in the gonadotropin-primed immature rat model. The effect of I3C on ovulation and gonadotropin secretion prior to ovulation was similar to the action of TCDD (dioxin compound) in that reduced ovulation was not fully restored by exogenous hCG, indicating direct actions of I3C on the preovulatory ovary in addition to DISRUPTION OF THE HYPOTHALAMIC-HYPOPHYSEAL AXIS.”

Another study showed that TCDD induces ovarian tumors. No adverse interactions were seen with DIM and oral contraceptives in the study by Stresser “Report: Examination of potential for absorbable DIM to induce and inhibit cytochrome p450 isoforms.”
Who should take DIM?
DIM has been shown to be cancer preventive, reduce the risk of breast cancer, improve endometriosis, cervical dysplasia, PMS symptoms, and symptoms of perimenopause. Women on HRT benefit from DIM supplementation as well as men with estrogen related conditions like prostate hypertrophy. DIM may be an aromatase inhibitor.
Who should take therapeutic doses of I3C beyond what they get in their cruciferous vegetables? You decide. Read the abstracts below.

Intrinsic acute toxicity and hepatic enzyme inducing properties of the chemoprotectants indole-3-carbinol and 5,10-dihydroindeno[1,2-b]indole in mice.
Food Chem Toxicol. 1991 Apr;29(4):237-42.
Shertzer HG, Sainsbury M.
Department of Environmental Health, University of Cincinnati Medical Center, OH 45267-0056.
Indole-3-carbinol (I-3-C) and 5,10-dihydroindeno[1,2-b]indole (DHII) have been shown to be protective against carbon tetrachloride and other chemicals that cause hepatic toxicity. In part, this protection appears to be afforded by the ability of these compounds to act as antioxidants, with DHII having much the greater efficacy. In order to understand the mechanisms of chemoprotection, as well as the potential for therapeutic and pharmaceutical use in humans, the antioxidants I-3-C and DHII were examined for their intrinsic acute toxicity, and their hepatic enzyme inducing properties in mice. The results were compared with those of the well characterized agent phenobarbital. Following treatment by gavage for 10 days with 50 mg compound/kg body weight, I-3-C produced modest (10-50%) increases in hepatic cytochrome P-450, aminopyrine N-demethylase, UDP-glucuronosyl transferase (UDPGT) and glutathione S-transferase (GST), and a four-fold increase in NAD(P)H: (quinone acceptor) oxidoreductase (quinone reductase) activity. DHII did not alter oxidative enzyme activities, but increased GST and UDPGT by about 50%, and quinone reductase over five-fold. In the acute toxicity studies, DHII produced no observable 24-hr acute toxicity up to 4 g/kg body weight, except for a slight decrease in haematocrit. However, I-3-C exhibited a dose-dependent toxicity above 100 mg/kg body weight, including a decrease in hepatic reduced glutathione after 2 hr and severe neurological toxicity, and the release of liver enzymes to the plasma at 24 hr. We conclude, on the basis of the superior antioxidation efficacy of DHII, its enzyme-inducing properties, and intrinsic toxicity, that DHII or cogeners thereof have great potential as chemoprotective or therapeutic agents. However, I-3-C does not have such potential.

1. Johnson IT. Glucosinolates: bioavailability and importance to health. Int J Vitam Nutr Res. 2002 Jan;72(1):26-31.
2. McDanell R, McLean AE, Hanley AB, Heaney RK, Fenwick GR. Chemical and biological properties of indole glucosinolates. J Agric Food Chem. 1999 Apr;47(4):1541-8.
3. Grose, KR, and Bjeldanes, LF. Oligermization of indole-3-carbinol in aqueous acid. Chem Res Toxicol 1992: 5:188-193. (glucobrassicins): a review. Food Chem Toxicol. 1988 Jan;26(1):59-70. Review.
4. Park JY, Shigenaga MK, Ames BN. Induction of cytochrome P4501A1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin or indolo(3,2-b)carbazole is associated with oxidative DNA damage.
5. Jensen-Jarolim E, Gajdzik L, Haberl I, Kraft D, Scheiner O, Graf J.Hot spices influence permeability of human intestinal epithelial monolayers. J Nutr. 1998 Mar;128(3):577-81.
6. 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):161-7.
7. Jellinck PH, Makin HL, Sepkovic DW, Bradlow HL. Influence of indole carbinols and growth hormone on the metabolism of 4-androstenedione by rat liver microsomes. J Steroid Biochem Mol Biol. 1993 Dec;46(6):791-8.
8. Yoshida M, Katashima S, Ando J, Tanaka T, Uematsu F, Nakae D, Maekawa A. Dietary indole-3-carbinol promotes endometrial adenocarcinoma development in rats initiated with N-ethyl-N'- nitro-N-nitrosoguanidine, with induction of cytochrome P450s in the liver and consequent modulation of estrogen metabolism. Carcinogenesis. 2004 Nov;25(11):2257-64. Epub 2004 Jul 7.
9. Shertzer HG, Sainsbury M. Intrinsic acute toxicity and hepatic enzyme inducing properties of the chemoprotectants indole-3-carbinol and 5,10-dihydroindeno[1,2-b]indole in mice. Food Chem Toxicol. 1991 Apr;29(4):237-42..
10. Hien T. Le, Charlene M. Schaldach, Gary L. Firestone, and Leonard F. Bjeldanes. Plant-derived 3,3_-Diindolylmethane Is a Strong Androgen Antagonist in Human Prostate Cancer Cells. Journal of Biological Chemistry Vol. 278, No. 23, Issue of June 6, pp. 21136-21145, 2003.
11. Nachshon-Kedmi M, Yannai S, Fares FA Induction of apoptosis in human prostate cancer cell line, PC3, by 3,3'-diindolylmethane through the mitochondrial pathway. Br J Cancer. 2004 Oct 4;91(7):1358-63.
12. Wortelboer HM, van der Linden EC, de Kruif CA, Noordhoek J, Blaauboer BJ, van Bladeren PJ, Falke HE. Effects of indole-3-carbinol on biotransformation enzymes in the rat: in vivo changes in liver and small intestinal mucosa in comparison with primary hepatocyte cultures. Food Chem Toxicol. 1992 Jul;30(7):589-99.
13. Parkin DR, Malejka-Giganti D. Differences in the hepatic P450-dependent metabolism of estrogen and tamoxifen in response to treatment of rats with 3,3'-diindolylmethane and its parent compound indole-3-carbinol. Cancer Detect Prev. 2004;28(1):72-9.
14. Gao X, Petroff B, Oluola O, Georg G, Terranova P, Rozman K. Endocrine Disruption by Indole-3-carbinol and Tamoxifen: Blockage of Ovulation. Toxicol Appl Pharmacol. 2002 Sep 15;183(3):179
15. Herrmann S, Seidelin M, Bisgaard HC, Vang O. Indolo[3,2-b]carbazole inhibits gap junctional intercellular communication in rat primary hepatocytes and acts as a potential tumor promoter. Carcinogenesis. 2002 Nov;23(11):1861-8.
16. Lambert JD, Hong J, Kim DH, Mishin VM, Yang CS.Piperine enhances the bioavailability of the tea polyphenol (-)-epigallocatechin-3-gallate in mice. J Nutr. 2004 Aug;134(8):1948-52.
17. Effect of piperine on the epididymis of adult male rats. D'cruz SC, Mathur PP. Asian J Androl. 2005 Dec;7(4):363-8.
18. Effects of piperine on gastric acid secretion in albino rats. Ononiwu IM, Ibeneme CE, Ebong OO. Afr J Med Med Sci. 2002 Dec;31(4):293-5.

[Debbie L.]

Hi Laurel, Terri, and all,

Thanks for the links. I'd found some of those earlier. But it's all in cell lines (petrie dishes) or in mice. If we had a nickel for every idea that looked promising there yet turned out to be useless or even harmful, in humans ...

I'm not saying this isn't going to be something good. Nor that it isn't going to be something bad. I think that until studies are done on humans (with survival/recurrence data), we do not know.

It makes me nervous to mix hormonal treatments. Look at ATAC. Logic and cell behavior said that combining an AI and Tamoxifen would be good. 'Turned out it was no better and probably a bit worse than one or the other alone. Just because it makes good sense or works in mice does not guarantee success (or even lack of harm) in humans.

So Laurel, can you explain in more detail what the study you're participating in is looking at? Thanks in advance.

Regards,
Debbie Laxague

[Laurel]

Debbie,

This is a study conducted within my Medical Center. I do not know if it is a national study or not. I will find out more in mid-March when I see my Onc. I do know that blood work will be done testing to see if I am able to effectively utilize the drug, mostly liver studies I think. I believe Tamoxifen is working for me as I experience the most lovely hot-flashes. I say I am feeling all "furnacy" ! That's the best description I can give of a hot-flash. I feel like I am a furnace radiating serious BTU's! HA! Well, I am grateful that I suffer little from body aches and stiffness. I am a bit stiff when I get up in the morning in my lower legs, but they seem to loosen up quickly. I still have some neuropathy in my feet so perhaps that is part of it.

I understand your reticence regarding supplementation. I suppose it is a personal decision; a call we must make on our own.

[TSund]

Debbie,

You are correct on all points. So much of this is a guess. What are the chances that really extensive studies will be made? If I understand the process, DIM is classified a "nutritional supplement" and available over the counter, therefore big pharmaceuticals can't have a patent unless they change the formula significantly. Witness the HRT fiasco. Now big pharma is pushing hard to remove the compounding pharmacy's right to provide compounded estriol as an option. Sorry if this sounds like a rant, I just feel like so much of this is a crap-shoot.



TRS