RE: DIM Acts as a Potent Anti-Androgen

[stat1951]

Anyone familiar with this article?

http://www.vrp.com/art/1090.asp

In reading it one first suspects that it refers to DIM reducing DHT levels, but then at closer reading it seems that it doesn't actually seem to say that...

QUOTE:
DIM also inhibited dihydrotestosterone (DHT) stimulation of DNA synthesis in the androgen-dependent cancer cells.
END QUOTE

But am more concerned with the following statements:

QUOTE:
Researchers have now unveiled evidence that DIM also affects testosterone... The researchers determined that DIMs molecular structure is similar to Casodex, a synthetic anti-androgen drug.
END QUOTE

Info on "Casodex"...

CASODEX: Mechanism of Action - CASDODEX 50 mg, once daily, is indicated for use in combination therapy with a luteinizing hormone-releasing hormone (LHRH) analog for the treatment of Stage D2 metastatic carcinoma of the prostate. CASODEX is a nonsteroidal antiandrogen with no other known endocrine activity. It competitively inhibits the action of androgens


Larry

 

[SPE]

Wow...

I don't know whether to throw my DIM out or what???

 

[SPE]

A few More

Plant-derived 3,3'-Diindolylmethane is a strong androgen antagonist in human prostate cancer cells.

Le HT, Schaldach CM, Firestone GL, Bjeldanes LF.

Department of Nutritional Sciences and Toxicology, The University of California, Berkeley, California 94720-3104, USA. lfb@nature.berkeley.edu

3,3'-Diindolylmethane (DIM) is a major digestive product of indole-3-carbinol, a potential anticancer component of cruciferous vegetables. Our results indicate that DIM exhibits potent antiproliferative and antiandrogenic properties in androgen-dependent human prostate cancer cells. DIM suppresses cell proliferation of LNCaP cells and inhibits dihydrotestosterone (DHT) stimulation of DNA synthesis. These activities were not produced in androgen-independent PC-3 cells. Moreover, DIM inhibited endogenous PSA transcription and reduced intracellular and secreted PSA protein levels induced by DHT in LNCaP cells. Also, DIM inhibited, in a concentration-dependent manner, the DHT-induced expression of a prostate-specific antigen promoter-regulated reporter gene construct in transiently transfected LNCaP cells. Similar effects of DIM were observed in PC-3 cells only when these cells were co-transfected with a wild-type androgen receptor expression plasmid. Using fluorescence imaging with green fluorescent protein androgen receptor and Western blot analysis, we demonstrated that DIM inhibited androgen-induced androgen receptor (AR) translocation into the nucleus. Results of receptor binding assays indicated further that DIM is a strong competitive inhibitor of DHT binding to the AR. Results of structural modeling studies showed that DIM is remarkably similar in conformational geometry and surface charge distribution to an established synthetic AR antagonist, although the atomic compositions of the two substances are quite different. Taken together with our published reports of the estrogen agonist activities of DIM, the present results establish DIM as a unique bifunctional hormone disrupter. To our knowledge, DIM is the first example of a pure androgen receptor antagonist from plants.

PMID: 12665522 [PubMed - indexed for MEDLINE]

 

[SPE]

Indole-3-carbinol is a negative regulator of estrogen.

Auborn KJ, Fan S, Rosen EM, Goodwin L, Chandraskaren A, Williams DE, Chen D, Carter TH.

North Shore-Long Island Jewish Research Institute, Manhasset, NY 11030, USA. kauborn@nshs.edu

Studies increasingly indicate that dietary indole-3-carbinol (I3C) prevents the development of estrogen-enhanced cancers including breast, endometrial and cervical cancers. Epidemiological, laboratory, animal and translational studies support the efficacy of I3C. Whereas estrogen increases the growth and survival of tumors, I3C causes growth arrest and increased apoptosis and ameliorates the effects of estrogen. Our long-range goal is to best use I3C together with other nutrients to achieve maximum benefits for cancer prevention. This study examines the possibility that induction of growth arrest in response to DNA damage (GADD) in genes by diindolylmethane (DIM), which is the acid-catalyzed condensation product of I3C, promotes metabolically stressed cancer cells to undergo apoptosis. We evaluated whether genistein, which is the major isoflavonoid in soy, would alter the ability of I3C/DIM to cause apoptosis and decrease expression driven by the estrogen receptor (ER)-alpha. Expression of GADD was evaluated by real-time reverse transcription-polymerase chain reaction. Proliferation and apoptosis were measured by a mitochondrial function assay and by fluorescence-activated cell sorting analysis. The luciferase reporter assay was used to specifically evaluate expression driven by ER-alpha. The estrogen-sensitive MCF-7 breast cancer cell line was used for these studies. We show a synergistic effect of I3C and genistein for induction of GADD expression, thus increasing apoptosis, and for decrease of expression driven by ER-alpha. Because of the synergistic effect of I3C and genistein, the potential exists for prophylactic or therapeutic efficacy of lower concentrations of each phytochemical when used in combination.

 

[SPE]

Don't Know about this one...

Acid reaction products of indole-3-carbinol and their effects on cytochrome P450 and phase II enzymes in rat and monkey hepatocytes.

Wortelboer HM, de Kruif CA, van Iersel AA, Falke HE, Noordhoek J, Blaauboer BJ.

Research Institute of Toxicology (RITOX), University of Utrecht, The Netherlands.

The effects of three acid condensation products of indole-3-carbinol (I3C), i.e. 3,3'-diindolylmethane (DIM), 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b"]tri-indole (CTI) and 2,3-bis[3-indolylmethyl]indole (BII), on cytochrome P450 and phase II enzymes were studied in primary cultures of rat and cynomolgus monkey liver cells. In rat hepatocytes all three indole derivatives dose-relatedly induced the ethoxyresorufin O-dealkylation (EROD) activity (to 24-fold) and 7 alpha-hydroxylation of testosterone (to 4-fold), whereas all three decreased the 16 alpha- and 2 alpha-testosterone hydroxylation (DIM to 60%, CTI and BII to a mere 5% of the control cells). Treatment of monkey hepatocytes with DIM and BII enhanced the EROD activity to 6- and 9-fold, respectively. Furthermore, BII decreased the 6 beta-hydroxylation of testosterone (to 60% of the untreated cultures) in monkey cells. Phase II enzymes were also affected. In rat hepatocytes DIM, CTI and BII enhanced DT-diaphorase (DTD) (= NAD(P)H-quinone reductase) activity, and DIM and BII the glucuronidation of 1-naphthol. In monkey cells BII only enhanced DTD, and no changes were observed in the glucuronidation of 1-naphthol after treatment with either DIM or BII. The indole derivatives did not affect glutathione S-transferase activity and sulfation of 1-naphthol in either rat or monkey hepatocytes. These results identify two novel acid condensation products of I3C, CTI and BII, as potent compounds in affecting biotransformation in rat as well as in monkey hepatocytes.

 

[SWALE]

We clearly have much important work to do in this area, and must keep an open mind along the way. The possibility of DIM acting as an androgen antagonist is troubling, indeed.

Even IF it were to be shown to antagonize androgens at tissues other than prostate cancer positive cells, it is important to remember that these issues must be evaluated from a perspective of ascertaining the "balance" between positive and negative effects. For instance, if we can reduce the risk of cancer through DIM supplementation, while simultaneously inducing increased health and vigor via TRT, then we are much ahead in the game.

I can scarcely think of a more imprtant topic for us to explore on this Forum.

 

[SPE]

Completely agree

It is exciting indeed. I should be getting my DHT results back in a day or two after being on Indoplex/Dim and TMG for roughly two weeks. Although that time isn't very long, it might give me an idea of how the DIM is affecting DHT. This actually might turn out to be a possitive thing. Some individuals on TRT experience DHT levels above the top of the range. While we aren't really sure what impact this has on long term health, DIM might help bring this level back to the normal range.

 

[HeadDoc]

at first glance this effect on testosterone seems counterproductive. Then I began to wonder if this is not also good news. For instance we are really after the enhanced production of free or unbound testosterone with trt. If the testosterone is bound to the prostate, it is no longer free. So having dim/i3c unbind the testosterone from the prostate is actually good! Yes?No?

 

[SPE]

Yeah...

That would make sense, wouldn't it.

 

[pmgamer18]

It is exciting indeed. I should be getting my DHT results back in a day or two after being on Indoplex/Dim and TMG for roughly two weeks. Although that time isn't very long, it might give me an idea of how the DIM is affecting DHT. This actually might turn out to be a possitive thing. Some individuals on TRT experience DHT levels above the top of the range. While we aren't really sure what impact this has on long term health, DIM might help bring this level back to the normal range.

My DHT was very high 3 times the normal range. From doing the Gels now after using Indolplex/DIM my DHT is good. When it was high it was aggravating prostate now that it is down I am good.
Phil

 

[HeadDoc]

 

[gearjunky]

My DHT was very high 3 times the normal range. From doing the Gels now after using Indolplex/DIM my DHT is good. When it was high it was aggravating prostate now that it is down I am good.
Phil

So if you take Indolplex/Dim, there is no need for SawPalmeto supplementation? Plus it could also replace arimidex?

 

[HeadDoc]

I wouldn't drop the saw palmetto without additional research. Not everyone needs arimidex. This going to be determined by your body's response to testosterone.

 

[pmgamer18]

We all are not the same so you need to try it and see what happens I stopped the Saw Palmetto. By accident when I ordered my supplements 2 months ago and can't tell the difference. When my DHT was very high my Dr. said to try it I don't feel it helped me. When I started on the Indolplex/DIM and my DHT started comming down my prostate settled down and all is well now. And now that I know about Indolplex/DIM I would try this first before trying Arimidex.
Phil

 

[stat1951]

Agree completely.

Facts supported by evidence and clinical studies and not simply ancedotal stories.

Some of which I will be posting in a moment.....

We clearly have much important work to do in this area, and must keep an open mind along the way. The possibility of DIM acting as an androgen antagonist is troubling, indeed.

Even IF it were to be shown to antagonize androgens at tissues other than prostate cancer positive cells, it is important to remember that these issues must be evaluated from a perspective of ascertaining the "balance" between positive and negative effects. For instance, if we can reduce the risk of cancer through DIM supplementation, while simultaneously inducing increased health and vigor via TRT, then we are much ahead in the game.

I can scarcely think of a more imprtant topic for us to explore on this Forum.

 

[stat1951]

In my initial posting I noted the following:

QUOTE:
Researchers have now unveiled evidence that DIM also affects testosterone... The researchers determined that DIMs molecular structure is similar to Casodex, a synthetic anti-androgen drug.
END QUOTE

I then located this information:

http://www.casodex.net/9678_9795_3_3_1.aspx

QUOTE:
Non-steroidal anti-androgens e.g. bicalutamide ('Casodex'), act by competitively binding to the androgen receptors on prostate cells, preventing testosterone from binding and effectively inhibiting the stimulatory effects of androgens on the prostate. They do not reduce circulating LH, and could even increase testosterone levels, which results in a reduced impact on libido and a lower incidence of impotence.
END QUOTE

So is it possible that DIM, being molecularly similar to Casodex, operates in a similar fashion where it (in addition to reducing E2 mildly) binds "to the androgen receptors on prostate cells, preventing testosterone from binding and effectively inhibiting the stimulatory effects of androgens on the prostate. They do not reduce circulating LH, and could even increase testosterone levels"???

That's a significant question.

Unfortunately, top-notch, high-level studies are unlikely to be done using DIM as it is a natural product and simply cannot command the extremely high prices that pharmaceutical medications can!

But still interesting food for thought.

Larry

 

[1cc]

Non-steroidal anti-androgens e.g. bicalutamide ('Casodex'), act by competitively binding to the androgen receptors on prostate cells, preventing testosterone from binding and effectively inhibiting the stimulatory effects of androgens on the prostate. They do not reduce circulating LH, and could even increase testosterone levels, which results in a reduced impact on libido and a lower incidence of impotence.
END QUOTE

I'm not sure what they are saying. Is this saying that Casodex, or DIM which acts similarly, reduces DHT levels?

If DIM reduces DHT levels, then I'm certain I would be very reluctant to use it.

 

[SWALE]

If Casodex (and therefore, perhaps DIM) binds to AR's at the cancerous prostate cells, but not those in the Hypothalamus and pituitary, then we would not have to worry about it blocking testosterone in other tissues perhaps.

What else can we find on this? Come on, guys, I'm lecturing on this in Chicago in a month!

 

[stat1951]

It's specifically referring to Casodex (a pharmaceutical drug used in prostate cancer cases), but the earlier posting (initial one I believe) talked about how DIM was molecularly similar to Casodex.

And...

I believe ("believe" - IMHO) that they're not saying that Casodex reduces DHT levels, that they are asying that Casodex (and possibly DIM???) binds to the androgen receptors on prostate cells, thus preventing testosterone from binding and effectively inhibiting the stimulatory effects of androgens on the prostate....

That said.....

I have also seen other posts that insist that DIM also does inhibit DHT levels. I belieev that Phil (pmgamer18) has some strong views in that regard, but I don't know if that is simply ancedotal "evidence" on his part or if there are any studies or research that backs that up.

DIM wasn't "developed" (discovered?) as some type of TRT aid, but was primarily formulated as a primary aid as an OTC supplement for breast cancer situations. Developers then realized that it would likely have a opretty positive role in prostate cancer cases also. (Now there's a big hint that the real culprit in prostate cancer situations is estrogen and not testosterone!).

You might PM / e-mail Phil and see if he has any research links as to DIM and its impact on DHT that could be posted here.... I am not aware of any research involving DIM as pertains to E2 control and / or DHT effects as specifically relates to the TRT environment.

Larry

I'm not sure what they are saying. Is this saying that Casodex, or DIM which acts similarly, reduces DHT levels?

If DIM reduces DHT levels, then I'm certain I would be very reluctant to use it.

 

[pmgamer18]

This is all I have on DIM lowing DHT.
http://www.lef.org/whatshot/2003_05.html#i3cb
May 19, 2003
Indole-3-carbinol byproduct acts as antiandrogen to halt prostate cancer cell growth

In a study funded in part by the National Institutes of Health, to be published in the June 6 2003 issue of the Journal of Biological Chemistry, University of California, Berkeley researchers have found that a digestive product of indole-3-carbinol, which occurs naturally in broccoli and other cruciferous vegetables, halts the growth of prostate cancer cells in vitro. The compound, 3,3-diindolymethane (DIM), inhibits androgenic hormones that fuel prostate cancer growth. Although androgen is important for the normal development of the prostate, it is believed to be involved in the early stages of prostate cancer.

The researchers administered DIM to androgen dependent and androgen independent prostate cancer cells and found that androgen-dependent cells experienced a 70 percent reduction in growth compared to those that did not receive the compound. Androgen-independent prostate cancer cells were not affected by DIM. The scientists went on to discover that DIM inhibited dihydrotestosterone, the primary androgenic hormone that is believed to be the culprit in prostate cancer. Dihydrotesterone stimulates prostate specific antigen, or PSA, which is elevated in prostate cancer. When DIM was administered to the androgen-dependent prostate cancer cells, PSA levels dropped.

A study of the molecular structure of DIM showed that it is similar to the androgen-blocking drug Casodex. Lead author Hien Le, PhD, explained, DIM works by binding to the same receptor that DHT uses, so it's essentially blocking the androgen from triggering the growth of the cancer cells."

Principle researcher and professor nutritional sciences and toxicology at UC Berkeley's College of Natural Resources, Leonard Bjeldanes, summarized, "As far as we know, this is the first plant-derived chemical discovered that acts as an antiandrogen. This is of considerable interest in the development of therapeutics and preventive agents for prostate cancer."

D Dye

Phil