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Author Topic: How DIM Works, Yikes It Increases Aromatase, and Why I-3-C *Might* Be Better  (Read 4623 times)

Kierkegaard

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Okay, you guys know I've been a fan of DIM, and have been using it, for years, but could never quite explain how it works, only pointing out what the following site explains:

  • There are two main pathways in the liver for our estrogen to be normally metabolized and excreted. One pathway leads to very good metabolites called 2-hydroxy estrogens. The other pathway leads to bad metabolites called 4 or 16-hydroxy estrogens. DIM stimulates the favorable 2-hydroxy pathway for estrogen metabolism and this is how DIM works to improve our health.

Okay, so we have 2-, 4-, and 16- hydroxyestrogens, all of which are metabolites of estradiol.  Turns out these three metabolites are also broken down further (e.g., 2-hydroxyestrogen is made up of 2-hydroxyestrone, which becomes 2-methoxyestrone). 

Now consider this comprehensive graph which catalogues most (but not all) of the estrogen metabolites, and remember to scroll right because I couldn't find a way to make the graphic smaller:



So you have estrone and estradiol (17b-estradiol) which go back and forth, and from both (probably more from estradiol) you have three arrows: the left that breaks down to 2-hydroxyestrone, the middle 4-hydroxyestrone, and the right 16a-hydroxyestrone.  Remember what the excerpt from the link I posted above said: 2-hydroxyestrogens (which includes the -estrone and -estradiol) are good, and 4- and 16(a)-hydroxyestrones are bad.

Next step.  Not included in this graphic is that each arrow stands for an enzyme (which is responsible for the metabolism of one chemical to another), and more specifically a gene that codes for an enzyme: the first arrow stands for a gene/enzyme CYP1A1, the second arrow CYP1B1, and the third arrow I dunno what but it ain't relevant to our discussion.  It's very important to grasp this basic idea, because the rest of this post uses these arrows/enzymes as premises from which other conclusions follow.  When I mention CYP1A1 being upregulated or increased, this means the first arrow "leaks away" estradiol toward what it points to, 2-hydroxyestrone (which in turn means the rest of the chain below this metabolite is increased).  Same thing with CYP1B1.  Also important here: because CYP1A1 leads to increasing the pathway that shunts estradiol to 2-hydroxyestrone, and 2-hydroxyestrone is a good, non-carcinogenic estrogen, we want CYP1A1 to be increased; and because CYP1B1 leads to the increase of a bad, carcinogenic estrogen, 4-hydroxyestrone, we want CYP1B1 to be decreased.  Also note that any time either of these enzymes, CYP1A1 or 1B1, are increased, this by definition means that 16a-hydroxyestrone is decreased, because the upregulations of CYP1A1/1B1 shunt estrogen away from 16a-hydroxyestrone, which is also considered to be carcinogenic, so we want this to happen.  Got it? 

Okay, so how does DIM help? 

This abstract notes how DIM increases all three relevant CYPs:

  • Diindolylmethane (DIM) is an acid-catalyzed condensation product of indole-3-carbinol, a constituent of cruciferous vegetables, and is formed in the stomach. DIM alters estrogen metabolism and inhibits carcinogen-induced mammary tumor growth in rodents. DIM is a weak agonist for the aryl hydrocarbon (Ah) receptor and blocks the effects of estrogens via inhibitory Ah receptor-estrogen receptor cross-talk. DIM and various structural analogs were examined in H295R cells for effects on 3 cytochrome P450 (CYP) enzymes involved in estrogen synthesis and/or metabolism: CYP1A1, CYP1B1, and CYP19 (aromatase). Aromatase activity was measured by conversion of 1 beta-(3)H-androstenedione to estrone and (3)H(2)O. H295R cells were exposed to the test chemicals dissolved in dimethyl sulfoxide for 24 h prior to analyses. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) (0--30 nM) and DIM (0--10 microM) induced ethoxyresorufin-O-deethylase (EROD) activity, as a measure of CYP1A1 and possibly 1B1 activity, with EC(50) values of about 0.3 nM and 3 microM, respectively. DIM, but not TCDD, induced aromatase activity with an apparently maximal 2-fold increase at 10 microM; higher concentrations of DIM and many of its analogs were cytotoxic. TCDD (30 nM) significantly increased CYP1A1 and 1B1 mRNA levels, but had no effect on mRNA for CYP19. DIM (3 microM) significantly increased mRNA levels for all three CYPS: DIM analogs with substitutions on the 5 and 5' position (3 microM) induced aromatase and EROD activity, together with mRNA levels of CYP1A1, 1B1, and 19; analogs that were substituted on the central carbon of the methane group showed little or no inductive activity toward the CYPS: In conclusion, DIM and several of its analogs appear to induce CYPs via multiple yet distinct pathways in H295R human adrenocortical carcinoma cells.

Whoa, whoa, whoa, wait.  DIM increases the activity of the aromatase enzyme CYP19 up to 2-fold?  What.  The.  Heck.  This means that DIM is, in a very real sense, an anti-aromatase inhibitor.  But why the heck do guys tend to feel positive benefits from it?  That would have to do, presumably, with the next point: DIM also increases the activity of CYP1A1 and CYP1B1.  But wait!  CYP1B1 (look at the graph above) leads to the conversion of estrone/estradiol to 4-hydroxyestrone, which is a bad, cancer-producing estrogen pathway.

So it's not looking great for DIM so far: not only does it (so strangely) seem to increase aromatase (CYP19), but it also increases the proliferation of 4-hydroxyestrogens!  But guys feel better on it.  Therefore, the effect of DIM on CYP1A1 must explain why guys feel better and counterbalances the negative effects of DIM on aromatase and 4-hydroxyestrogens.  Well then! 

Dr Crisler (under his old pseudonym, SWALE, on a pretty old Meso-Rx forum post) writes the following:

  • I have seen two such studies which showed that DIM stimulated not only the CYP1A1 enzyme, thus increasing 2-OHE, but also the CYP1B1, which is why 4-OHE concentrations rise as well. TMG, or its child, DMG, provides methyl groups, thus helping wash the 4-OHE downstream. IF (and it's a big IF) this is true, in vivo, DIM should not be taken without a methyl donor, and would be especially dangerous in someone with a COMT enzyme deficiency.

So Dr Crisler recommends taking a methyl donor (TMG/betaine is just one option, the others being methylB12, methylfolate, etc.) in order to drain the increase 4-hydroxyestrogens as a result of DIM increasing the CYP1B1 enzyme pathway.  Therefore, any guy who takes DIM, assuming Dr Crisler's reasoning is correct (and he's cautious enough to admit that it might not be), should take a methyl donor.  But hey, it's good news for the vast majority of people to take methyl donors, so it wouldn't hurt.  Moral of the story: take a methyl donor with DIM just to be safe, and if you don't see any positive benefits from taking DIM, maybe adding a methyl donor could help in this regard.   

But let's go back to something I've said many times in other places: it seems like a lot of guys who take DIM and get a positive response from it can't really pick up on any noticeable changes in estradiol measured by a lab as a result of taking it.  Follow me here: if DIM results in increases in CYP1A1 and CYP1B1, this means that estradiol is "leaked away" to these other pathways which are upregulated, leading to increases in 2- and 4-hydroxyestrogens.  But if DIM also increases aromatase activity, perhaps this effect is canceled out (such that increases in aromatase and therefore estradiol are negated by decreases in estradiol from the increase in its conversion to 2- and 4-hydroxyestrones), and this is why we usually don't see decreases in estradiol for guys who take DIM.  This also theoretically means that some guys could see decreases in estradiol given their unique biochemistry, and also the reverse by seeing increases in estradiol if the increase in the aromatase enzyme overpowers the increase in the CYP1A1 and CYP1B1 enzymes mentioned above. 

So it seems like DIM could be a bit of a wild card, and this could explain its success or lack thereof for different guys: for some guys it increases estradiol (too much aromatase increase and not enough upregulation of CYP1A1 and CYP1B1 to cancel out this effect), others does nothing noticeable to estradiol (aromatase and CYP1A1/1B1 cancel each other out), and others see reductions in estradiol (any increases in aromatase activity are offset by upregulation of CYP1A1/1B1, which "leak away" more estradiol than the increase in aromatase produces). 

Okay, case closed, right?  Not quite.  We have another supplement to consider, indole-3-carbinol, from which DIM is a metabolite.  The study titled "Multifunctional aspects of the action of indole-3-carbinol as an antitumor agent." points out the following juicy bit:

  • We have focussed our attention on indole-3-carbinol, a compound found in cruciferous vegetables, and its further metabolites in the body, diindolylmethane (DIM) and indolylcarbazole (ICZ), because of its relative safety and multifaceted activities. It has been shown that it induces CyP4501A1, increasing 2-hydroxylation of estrogens, leading to the protective 2-OHE1, and also decreases CyP1B1 sharply, inhibiting 4-hydroxylation of estradiol, thereby decreasing the formation of the carcinogenic 4-OHE1.

Whoa!  So somehow Indole-3-carbinol, unlike DIM, sharply decreases CYP1B1, resulting in lower levels of the carcinogenic 4-hydroxyestrogens.  Unfortunately, no mention of aromatase (CYP19) was made in the abstract of the article.  What this all means is that I-3-C could be advantageous over DIM because it only increases CYP1A1 and decreases CYP1B1, whereas DIM increases both of these enzymes.  But, as said above, if you take DIM with a methyl donor, you're going to take care of the increase in 4-hydroxyestrogens from the increase in CYP1B1 DIM offers.  Therefore, DIM + methyl donor = I-3-C, and because we don't know of the effects of I-3-C on aromatase, we can't make any conclusions. 

So is DIM or Indole-3-carbinol better?  That depends on how you take them.  If you take DIM by itself, it will increase both 2- and 4-hydroxyestrone pathways, the first being a "good" estrogen pathway and the second being a "bad", carcinogenic pathway.  But, per Dr Crisler's statement, if you take a methyl donor (e.g., betaine, methylB12, etc.) you "drain away" any increases in the 4-hydroxyestrone pathway (presumably through increasing the COMT enzyme which converts hydroxyestrogens to methoxyestrogens).  DIM also increases aromatase, but we don't know if I-3-C does as well, but seeing how DIM is a metabolite of I-3-C, it's safe to assume that I-3-C probably does increase the aromatase (CYP19) enzyme as well.  I-3-C, on the other hand, appears to increase the CYP1A1 pathway (leading to an increase in the "good" estrogens) while sharply reducing the CYP1B1 pathway (leading to an increase in the "bad" carcinogenic estrogens).  So basically it seems like taking I-3-C could be less work than taking DIM, which you would have to take with a methyl donor to negate the damage done by increasing the 4-hydroxyestrone pathway.  But heck, since we should all be taking methyl donors, there's really no damage done by just taking DIM.

Whoa, science.  And while we're talking science, I should note that these differences in DIM and I-3-C could be methodological problems yielding false results; maybe DIM really does (like I-3-C) decrease CYP1B1, but I haven't found the research for this yet. 
« Last Edit: December 11, 2016, 03:15:53 am by Kierkegaard »
"The same thing that makes you live can kill you in the end." -- Neil Young

March 2014: Dx low T (158ng/dl)
September 2015: Dx hypothyroidism, other adrenal hypofunction/low cortisol
Treatment: 30-35 mg cypionate subq E3D, 50 mcg levothyroxine QD; adaptogens
Supplements: fish oil, vitamin D3, magnesium, copper (low in serum), DIM, coq10, B vitamins (including hydroxyb12), probiotic, astaxanthin, iodine
Depression and anxiety guide: http://www.peaktestosterone.com/Help_Anxiety_Depression.aspx

Retardo

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Whoa, science.  And while we're talking science, I should note that these differences in DIM and I-3-C could be methodological problems yielding false results; maybe DIM really does (like I-3-C) decrease CYP1B1, but I haven't found the research for this yet.

So K, should we keep using DIM?
I take some daily,, now I'm not too sure?
thoughts?

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Kierkegaard

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Whoa, science.  And while we're talking science, I should note that these differences in DIM and I-3-C could be methodological problems yielding false results; maybe DIM really does (like I-3-C) decrease CYP1B1, but I haven't found the research for this yet.

So K, should we keep using DIM?
I take some daily,, now I'm not too sure?
thoughts?

I think if it makes you feel better, this indicates that something right is going on in your body to justify continuing it.  But to be safe, I'd add a methyl donor, taking Dr Crisler's advice, just in case the evidence that seems to support DIM increasing the 4-hydroxyestrone is true.  As for aromatase, if you did have an increase in E2 then by definition you wouldn't feel better (unless you were low in E2 to begin with). 

As I've said a few times here, the vast majority of guys who have taken DIM on these and other forums have reported no change in E2.  These guys still exist for sure.  But I think this tells you that DIM works in a complicated way (by increasing aromatase a bit but having this effect cancelled out through increasing 2- and 4-hydroxyestrone pathways therefore draining E2).

So I'd say keep with what's working for you and consider adding a methyl group to drain the 4-OH estrogens.  Heck, you can even get this number pulled via a lab. 
"The same thing that makes you live can kill you in the end." -- Neil Young

March 2014: Dx low T (158ng/dl)
September 2015: Dx hypothyroidism, other adrenal hypofunction/low cortisol
Treatment: 30-35 mg cypionate subq E3D, 50 mcg levothyroxine QD; adaptogens
Supplements: fish oil, vitamin D3, magnesium, copper (low in serum), DIM, coq10, B vitamins (including hydroxyb12), probiotic, astaxanthin, iodine
Depression and anxiety guide: http://www.peaktestosterone.com/Help_Anxiety_Depression.aspx

Retardo

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Whoa, science.  And while we're talking science, I should note that these differences in DIM and I-3-C could be methodological problems yielding false results; maybe DIM really does (like I-3-C) decrease CYP1B1, but I haven't found the research for this yet.

So K, should we keep using DIM?
I take some daily,, now I'm not too sure?
thoughts?

I think if it makes you feel better, this indicates that something right is going on in your body to justify continuing it.  But to be safe, I'd add a methyl donor, taking Dr Crisler's advice, just in case the evidence that seems to support DIM increasing the 4-hydroxyestrone is true.  As for aromatase, if you did have an increase in E2 then by definition you wouldn't feel better (unless you were low in E2 to begin with). 
the problem I am having is
science vs placebo effect
I dont know what's really going on?
so DIM is good to take if you are low in E2?


http://www.npr.org/sections/health-shots/2014/04/14/299179468/mind-over-milkshake-how-your-thoughts-fool-your-stomach

video about how the placebo effect can change effects of ghrelin

As I've said a few times here, the vast majority of guys who have taken DIM on these and other forums have reported no change in E2.  These guys still exist for sure.  But I think this tells you that DIM works in a complicated way (by increasing aromatase a bit but having this effect cancelled out through increasing 2- and 4-hydroxyestrone pathways therefore draining E2).

So I'd say keep with what's working for you and consider adding a methyl group to drain the 4-OH estrogens.  Heck, you can even get this number pulled via a lab.

Osprey

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That post... is ... just ...awesome! I'll probably have to read it 3-4 time to understand it all. Thanks K.

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Kierkegaard

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Bump

r, will get to you shortly.
"The same thing that makes you live can kill you in the end." -- Neil Young

March 2014: Dx low T (158ng/dl)
September 2015: Dx hypothyroidism, other adrenal hypofunction/low cortisol
Treatment: 30-35 mg cypionate subq E3D, 50 mcg levothyroxine QD; adaptogens
Supplements: fish oil, vitamin D3, magnesium, copper (low in serum), DIM, coq10, B vitamins (including hydroxyb12), probiotic, astaxanthin, iodine
Depression and anxiety guide: http://www.peaktestosterone.com/Help_Anxiety_Depression.aspx

PeakT

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Okay, you guys know I've been a fan of DIM, and have been using it, for years, but could never quite explain how it works, only pointing out what the following site explains:

  • There are two main pathways in the liver for our estrogen to be normally metabolized and excreted. One pathway leads to very good metabolites called 2-hydroxy estrogens. The other pathway leads to bad metabolites called 4 or 16-hydroxy estrogens. DIM stimulates the favorable 2-hydroxy pathway for estrogen metabolism and this is how DIM works to improve our health.

Okay, so we have 2-, 4-, and 16- hydroxyestrogens, all of which are metabolites of estradiol.  Turns out these three metabolites are also broken down further (e.g., 2-hydroxyestrogen is made up of 2-hydroxyestrone, which becomes 2-methoxyestrone). 

Now consider this comprehensive graph which catalogues most (but not all) of the estrogen metabolites, and remember to scroll right because I couldn't find a way to make the graphic smaller:



So you have estrone and estradiol (17b-estradiol) which go back and forth, and from both (probably more from estradiol) you have three arrows: the left that breaks down to 2-hydroxyestrone, the middle 4-hydroxyestrone, and the right 16a-hydroxyestrone.  Remember what the excerpt from the link I posted above said: 2-hydroxyestrogens (which includes the -estrone and -estradiol) are good, and 4- and 16(a)-hydroxyestrones are bad.

Next step.  Not included in this graphic is that each arrow stands for an enzyme (which is responsible for the metabolism of one chemical to another), and more specifically a gene that codes for an enzyme: the first arrow stands for a gene/enzyme CYP1A1, the second arrow CYP1B1, and the third arrow I dunno what but it ain't relevant to our discussion.  It's very important to grasp this basic idea, because the rest of this post uses these arrows/enzymes as premises from which other conclusions follow.  When I mention CYP1A1 being upregulated or increased, this means the first arrow "leaks away" estradiol toward what it points to, 2-hydroxyestrone (which in turn means the rest of the chain below this metabolite is increased).  Same thing with CYP1B1.  Also important here: because CYP1A1 leads to increasing the pathway that shunts estradiol to 2-hydroxyestrone, and 2-hydroxyestrone is a good, non-carcinogenic estrogen, we want CYP1A1 to be increased; and because CYP1B1 leads to the increase of a bad, carcinogenic estrogen, 4-hydroxyestrone, we want CYP1B1 to be decreased.  Also note that any time either of these enzymes, CYP1A1 or 1B1, are increased, this by definition means that 16a-hydroxyestrone is decreased, because the upregulations of CYP1A1/1B1 shunt estrogen away from 16a-hydroxyestrone, which is also considered to be carcinogenic, so we want this to happen.  Got it? 

Okay, so how does DIM help? 

This abstract notes how DIM increases all three relevant CYPs:

  • Diindolylmethane (DIM) is an acid-catalyzed condensation product of indole-3-carbinol, a constituent of cruciferous vegetables, and is formed in the stomach. DIM alters estrogen metabolism and inhibits carcinogen-induced mammary tumor growth in rodents. DIM is a weak agonist for the aryl hydrocarbon (Ah) receptor and blocks the effects of estrogens via inhibitory Ah receptor-estrogen receptor cross-talk. DIM and various structural analogs were examined in H295R cells for effects on 3 cytochrome P450 (CYP) enzymes involved in estrogen synthesis and/or metabolism: CYP1A1, CYP1B1, and CYP19 (aromatase). Aromatase activity was measured by conversion of 1 beta-(3)H-androstenedione to estrone and (3)H(2)O. H295R cells were exposed to the test chemicals dissolved in dimethyl sulfoxide for 24 h prior to analyses. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) (0--30 nM) and DIM (0--10 microM) induced ethoxyresorufin-O-deethylase (EROD) activity, as a measure of CYP1A1 and possibly 1B1 activity, with EC(50) values of about 0.3 nM and 3 microM, respectively. DIM, but not TCDD, induced aromatase activity with an apparently maximal 2-fold increase at 10 microM; higher concentrations of DIM and many of its analogs were cytotoxic. TCDD (30 nM) significantly increased CYP1A1 and 1B1 mRNA levels, but had no effect on mRNA for CYP19. DIM (3 microM) significantly increased mRNA levels for all three CYPS: DIM analogs with substitutions on the 5 and 5' position (3 microM) induced aromatase and EROD activity, together with mRNA levels of CYP1A1, 1B1, and 19; analogs that were substituted on the central carbon of the methane group showed little or no inductive activity toward the CYPS: In conclusion, DIM and several of its analogs appear to induce CYPs via multiple yet distinct pathways in H295R human adrenocortical carcinoma cells.

Whoa, whoa, whoa, wait.  DIM increases the activity of the aromatase enzyme CYP19 up to 2-fold?  What.  The.  Heck.  This means that DIM is, in a very real sense, an anti-aromatase inhibitor.  But why the heck do guys tend to feel positive benefits from it?  That would have to do, presumably, with the next point: DIM also increases the activity of CYP1A1 and CYP1B1.  But wait!  CYP1B1 (look at the graph above) leads to the conversion of estrone/estradiol to 4-hydroxyestrone, which is a bad, cancer-producing estrogen pathway.

So it's not looking great for DIM so far: not only does it (so strangely) seem to increase aromatase (CYP19), but it also increases the proliferation of 4-hydroxyestrogens!  But guys feel better on it.  Therefore, the effect of DIM on CYP1A1 must explain why guys feel better and counterbalances the negative effects of DIM on aromatase and 4-hydroxyestrogens.  Well then! 

Dr Crisler (under his old pseudonym, SWALE, on a pretty old Meso-Rx forum post) writes the following:

  • I have seen two such studies which showed that DIM stimulated not only the CYP1A1 enzyme, thus increasing 2-OHE, but also the CYP1B1, which is why 4-OHE concentrations rise as well. TMG, or its child, DMG, provides methyl groups, thus helping wash the 4-OHE downstream. IF (and it's a big IF) this is true, in vivo, DIM should not be taken without a methyl donor, and would be especially dangerous in someone with a COMT enzyme deficiency.

So Dr Crisler recommends taking a methyl donor (TMG/betaine is just one option, the others being methylB12, methylfolate, etc.) in order to drain the increase 4-hydroxyestrogens as a result of DIM increasing the CYP1B1 enzyme pathway.  Therefore, any guy who takes DIM, assuming Dr Crisler's reasoning is correct (and he's cautious enough to admit that it might not be), should take a methyl donor.  But hey, it's good news for the vast majority of people to take methyl donors, so it wouldn't hurt.  Moral of the story: take a methyl donor with DIM just to be safe, and if you don't see any positive benefits from taking DIM, maybe adding a methyl donor could help in this regard.   

But let's go back to something I've said many times in other places: it seems like a lot of guys who take DIM and get a positive response from it can't really pick up on any noticeable changes in estradiol measured by a lab as a result of taking it.  Follow me here: if DIM results in increases in CYP1A1 and CYP1B1, this means that estradiol is "leaked away" to these other pathways which are upregulated, leading to increases in 2- and 4-hydroxyestrogens.  But if DIM also increases aromatase activity, perhaps this effect is canceled out (such that increases in aromatase and therefore estradiol are negated by decreases in estradiol from the increase in its conversion to 2- and 4-hydroxyestrones), and this is why we usually don't see decreases in estradiol for guys who take DIM.  This also theoretically means that some guys could see decreases in estradiol given their unique biochemistry, and also the reverse by seeing increases in estradiol if the increase in the aromatase enzyme overpowers the increase in the CYP1A1 and CYP1B1 enzymes mentioned above. 

So it seems like DIM could be a bit of a wild card, and this could explain its success or lack thereof for different guys: for some guys it increases estradiol (too much aromatase increase and not enough upregulation of CYP1A1 and CYP1B1 to cancel out this effect), others does nothing noticeable to estradiol (aromatase and CYP1A1/1B1 cancel each other out), and others see reductions in estradiol (any increases in aromatase activity are offset by upregulation of CYP1A1/1B1, which "leak away" more estradiol than the increase in aromatase produces). 

Okay, case closed, right?  Not quite.  We have another supplement to consider, indole-3-carbinol, from which DIM is a metabolite.  The study titled "Multifunctional aspects of the action of indole-3-carbinol as an antitumor agent." points out the following juicy bit:

  • We have focussed our attention on indole-3-carbinol, a compound found in cruciferous vegetables, and its further metabolites in the body, diindolylmethane (DIM) and indolylcarbazole (ICZ), because of its relative safety and multifaceted activities. It has been shown that it induces CyP4501A1, increasing 2-hydroxylation of estrogens, leading to the protective 2-OHE1, and also decreases CyP1B1 sharply, inhibiting 4-hydroxylation of estradiol, thereby decreasing the formation of the carcinogenic 4-OHE1.

Whoa!  So somehow Indole-3-carbinol, unlike DIM, sharply decreases CYP1B1, resulting in lower levels of the carcinogenic 4-hydroxyestrogens.  Unfortunately, no mention of aromatase (CYP19) was made in the abstract of the article.  What this all means is that I-3-C could be advantageous over DIM because it only increases CYP1A1 and decreases CYP1B1, whereas DIM increases both of these enzymes.  But, as said above, if you take DIM with a methyl donor, you're going to take care of the increase in 4-hydroxyestrogens from the increase in CYP1B1 DIM offers.  Therefore, DIM + methyl donor = I-3-C, and because we don't know of the effects of I-3-C on aromatase, we can't make any conclusions. 

So is DIM or Indole-3-carbinol better?  That depends on how you take them.  If you take DIM by itself, it will increase both 2- and 4-hydroxyestrone pathways, the first being a "good" estrogen pathway and the second being a "bad", carcinogenic pathway.  But, per Dr Crisler's statement, if you take a methyl donor (e.g., betaine, methylB12, etc.) you "drain away" any increases in the 4-hydroxyestrone pathway (presumably through increasing the COMT enzyme which converts hydroxyestrogens to methoxyestrogens).  DIM also increases aromatase, but we don't know if I-3-C does as well, but seeing how DIM is a metabolite of I-3-C, it's safe to assume that I-3-C probably does increase the aromatase (CYP19) enzyme as well.  I-3-C, on the other hand, appears to increase the CYP1A1 pathway (leading to an increase in the "good" estrogens) while sharply reducing the CYP1B1 pathway (leading to an increase in the "bad" carcinogenic estrogens).  So basically it seems like taking I-3-C could be less work than taking DIM, which you would have to take with a methyl donor to negate the damage done by increasing the 4-hydroxyestrone pathway.  But heck, since we should all be taking methyl donors, there's really no damage done by just taking DIM.

Whoa, science.  And while we're talking science, I should note that these differences in DIM and I-3-C could be methodological problems yielding false results; maybe DIM really does (like I-3-C) decrease CYP1B1, but I haven't found the research for this yet.

Fantastic post and information as always.

I gotta be honest with you:  the power of these phytochemicals kind of scare me now that I see you lay this out like this.  I think another good question is this:  if these affect the above enzymes so strongly, what guarantee do we have that they don't affect other enzyme systems in your body? 
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Kierkegaard

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Fantastic post and information as always.

I gotta be honest with you:  the power of these phytochemicals kind of scare me now that I see you lay this out like this.  I think another good question is this:  if these affect the above enzymes so strongly, what guarantee do we have that they don't affect other enzyme systems in your body?

Right?  Well, maybe I'm a little too pragmatic in this way, but if you're dealing with a chronic set of symptoms and take a supplement that makes you feel significantly better, that indicates to me that you're more than likely knocking out the bad stuff that could cause you problems later on.  But still, it might be a good idea for long-term DIM users to get their 4-OHE levels tested to make sure they're not being overloaded with this carcinogenic estrogen, and if so either switch to I3C or add a methyl donor. 

Heck, there's no free lunch.  Every rose has thorns, whether we're talking about aromatase inhibitors causing potential clotting problems, DIM causing potential increases in 4-OHE, or Caldium d glucarate increasing calcium, etc. 
"The same thing that makes you live can kill you in the end." -- Neil Young

March 2014: Dx low T (158ng/dl)
September 2015: Dx hypothyroidism, other adrenal hypofunction/low cortisol
Treatment: 30-35 mg cypionate subq E3D, 50 mcg levothyroxine QD; adaptogens
Supplements: fish oil, vitamin D3, magnesium, copper (low in serum), DIM, coq10, B vitamins (including hydroxyb12), probiotic, astaxanthin, iodine
Depression and anxiety guide: http://www.peaktestosterone.com/Help_Anxiety_Depression.aspx

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Kierkegaard

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Whoa, science.  And while we're talking science, I should note that these differences in DIM and I-3-C could be methodological problems yielding false results; maybe DIM really does (like I-3-C) decrease CYP1B1, but I haven't found the research for this yet.

So K, should we keep using DIM?
I take some daily,, now I'm not too sure?
thoughts?

I think if it makes you feel better, this indicates that something right is going on in your body to justify continuing it.  But to be safe, I'd add a methyl donor, taking Dr Crisler's advice, just in case the evidence that seems to support DIM increasing the 4-hydroxyestrone is true.  As for aromatase, if you did have an increase in E2 then by definition you wouldn't feel better (unless you were low in E2 to begin with). 
the problem I am having is
science vs placebo effect
I dont know what's really going on?
so DIM is good to take if you are low in E2?


http://www.npr.org/sections/health-shots/2014/04/14/299179468/mind-over-milkshake-how-your-thoughts-fool-your-stomach

video about how the placebo effect can change effects of ghrelin

DIM isn't to be taken to increase E2.  I've yet to meet a person whose E2 increased from DIM, but Dr Crisler has said in another post that DIM can increase or decrease E2, and the reasons I've said above could be the reasons why.  E2 basically changes your estrogen metabolism, and for most guys this results in feeling better, which presumably means that there is either little if any increase in aromatase activity, or any increase in aromatase activity is offset by the changes in estrogen metabolism such as increasing levels of 2- and possibly 4-hydroxyestrogens. 

I say take stuff and if it does nothing for you, don't take it any more.  Go by what your body tells you. 
"The same thing that makes you live can kill you in the end." -- Neil Young

March 2014: Dx low T (158ng/dl)
September 2015: Dx hypothyroidism, other adrenal hypofunction/low cortisol
Treatment: 30-35 mg cypionate subq E3D, 50 mcg levothyroxine QD; adaptogens
Supplements: fish oil, vitamin D3, magnesium, copper (low in serum), DIM, coq10, B vitamins (including hydroxyb12), probiotic, astaxanthin, iodine
Depression and anxiety guide: http://www.peaktestosterone.com/Help_Anxiety_Depression.aspx

Joe Sixpack

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Right?  Well, maybe I'm a little too pragmatic in this way, but if you're dealing with a chronic set of symptoms and take a supplement that makes you feel significantly better, that indicates to me that you're more than likely knocking out the bad stuff that could cause you problems later on. 

This is my barometer as well.  If I feel better in the 2-3 month range while taking it, then it must be doing something good.  Of course there are limits to this philosophy.  If I develop a tolerance to the benefits and have to increase dose, then that tells me I am just borrowing the benefits.  Lets take heroin as a silly example.  the tolerance and the hangover would tell me that I need to discontinue, because I am just borrowing the good feelings at the expense of feeling worse in the long term. 

Lithium Orotate is a better example.  Felt great on it, but developed diarhhea after a few weeks on it and had to quit.   
Age: 55, Ht: 5'08", Wt: 150 lbs
Protocol: 35mg T Cyp 3x/week, 300 IU hCG 3x/week, 50mg DHEA + 50mg Pregnenalone daily.
1/2017 test results: TT: 1152 ng/dL (348-1197), FT: 23.7 pg/mL (7.2-24), E2: 22.0 pg/mL sensitive (8.0-35.0)

Kierkegaard

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From this study:

  • As one example, DIM induces the expression of CYP1A1 and CYP1B1 members of the P450 superfamily. This study indicated that a further enhancement of expression of these genes occurred in the presence of E2. CYP1A1, a phase I enzyme, can be the first step in the detoxification of number of carcinogens. Conversely, it is known to convert many procarcinogens to carcinogens. Importantly, CYP1A1 increases 2-hydroxylation of estrone leading to 2-hydroxyestrone (not estrogenic), and which is rapidly O-methylated into compounds that are anti-proliferative, pro-apototic, and anti-angiogenic. However, induction of CYP-1B1 shifts metabolism toward 4-hydroxyestrone, which can be carcinogenic. An imbalance of estrogen metabolism is indicated in breast (31), cervical (32), and endometrial (unpublished results) cancers, which are all estrogen-enhanced cancers where I3C and DIM appear to be preventative. Systemic lupus erythematosis and rheumatoid arthritis, diseases predominantly affecting women, also have abnormal estrogen metabolism (33). An animal study indicated that a diet rich in I3C ameliorated the lupus disease and changed estrogen metabolism (34).

So I3C and DIM are preventative regarding breast, cervical, and endometrial cancers, despite DIM increasing the 4-hydroxyestrone pathway, which the authors state "can be carcinogenic.  Also fascinating stuff on lupus and rheumatoid arthritis as having abnormal estrogen metabolism and have been treated in an animal study through an I3C-rich diet (which could mean DIM, an important metabolite of I3C, would as well).
« Last Edit: December 11, 2016, 07:25:20 pm by Kierkegaard »
"The same thing that makes you live can kill you in the end." -- Neil Young

March 2014: Dx low T (158ng/dl)
September 2015: Dx hypothyroidism, other adrenal hypofunction/low cortisol
Treatment: 30-35 mg cypionate subq E3D, 50 mcg levothyroxine QD; adaptogens
Supplements: fish oil, vitamin D3, magnesium, copper (low in serum), DIM, coq10, B vitamins (including hydroxyb12), probiotic, astaxanthin, iodine
Depression and anxiety guide: http://www.peaktestosterone.com/Help_Anxiety_Depression.aspx

Retardo

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DIM isn't to be taken to increase E2.  I've yet to meet a person whose E2 increased from DIM, but Dr Crisler has said in another post that DIM can increase or decrease E2, and the reasons I've said above could be the reasons why.  E2 basically changes your estrogen metabolism, and for most guys this results in feeling better, which presumably means that there is either little if any increase in aromatase activity, or any increase in aromatase activity is offset by the changes in estrogen metabolism such as increasing levels of 2- and possibly 4-hydroxyestrogens. 

I say take stuff and if it does nothing for you, don't take it any more.  Go by what your body tells you.

I appreciate the effort you've put into this thread, I take DIM a few pills/day and I sometimes forget to take it
I never  feel anything when i take it
what do you think i should feel?
better erections? better orgasms? better what exactly?


Kierkegaard

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DIM isn't to be taken to increase E2.  I've yet to meet a person whose E2 increased from DIM, but Dr Crisler has said in another post that DIM can increase or decrease E2, and the reasons I've said above could be the reasons why.  E2 basically changes your estrogen metabolism, and for most guys this results in feeling better, which presumably means that there is either little if any increase in aromatase activity, or any increase in aromatase activity is offset by the changes in estrogen metabolism such as increasing levels of 2- and possibly 4-hydroxyestrogens. 

I say take stuff and if it does nothing for you, don't take it any more.  Go by what your body tells you.

I appreciate the effort you've put into this thread, I take DIM a few pills/day and I sometimes forget to take it
I never  feel anything when i take it
what do you think i should feel?
better erections? better orgasms? better what exactly?

Whatever is the opposite of high E2 symptoms, which can include better erections, better orgasms, better libido, penile sensitivity, but also less fatigue, less brain fog, etc.  If you're not noticing anything, then maybe DIM isn't for you.  There's a chance -- I'd say a small one -- that DIM's bigger brother, indole-3-carbinol, might be worth a try.  DIM not working likely means any problems you have with estrogen aren't related to estrogen metabolism (i.e., your proportion of 2- to 4- and 16-hydroxyestrogens is good). 

I think many people try to use DIM as an aromatase inhibitor, i.e., with the hope of reducing an absolute E2 number (which, as complicatedly can be seen in the thread above, can happen theoretically with some guys depending on their particular biologies).  Is your E2 at least over 30 pg/ml?  If so, you might find benefit first from trying to lower your absolute E2 number, which can be done by taking calcium d glucarate, injecting more frequently and/or less overall, or (at the extreme) taking an aromatase inhibitor. 
"The same thing that makes you live can kill you in the end." -- Neil Young

March 2014: Dx low T (158ng/dl)
September 2015: Dx hypothyroidism, other adrenal hypofunction/low cortisol
Treatment: 30-35 mg cypionate subq E3D, 50 mcg levothyroxine QD; adaptogens
Supplements: fish oil, vitamin D3, magnesium, copper (low in serum), DIM, coq10, B vitamins (including hydroxyb12), probiotic, astaxanthin, iodine
Depression and anxiety guide: http://www.peaktestosterone.com/Help_Anxiety_Depression.aspx

PeakT

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Fantastic post and information as always.

I gotta be honest with you:  the power of these phytochemicals kind of scare me now that I see you lay this out like this.  I think another good question is this:  if these affect the above enzymes so strongly, what guarantee do we have that they don't affect other enzyme systems in your body?

Right?  Well, maybe I'm a little too pragmatic in this way, but if you're dealing with a chronic set of symptoms and take a supplement that makes you feel significantly better, that indicates to me that you're more than likely knocking out the bad stuff that could cause you problems later on.  But still, it might be a good idea for long-term DIM users to get their 4-OHE levels tested to make sure they're not being overloaded with this carcinogenic estrogen, and if so either switch to I3C or add a methyl donor. 

Heck, there's no free lunch.  Every rose has thorns, whether we're talking about aromatase inhibitors causing potential clotting problems, DIM causing potential increases in 4-OHE, or Caldium d glucarate increasing calcium, etc.

Yes, that I agree that's a good sign about feeling good - that means at least the brain is probably okay.  Wasn't trying to be a boat anchor.   ;D
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Torrential

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Another thank-you, K.  I'm going to reintroduce sublingual B12 to my regimen.  Basically put a bottle in the car, can suck on a tab while commuting.  My E2 has crept up and DIM hasn't helped; maybe it's hurt. 
« Last Edit: December 12, 2016, 12:32:04 pm by Torrential »
Age 53, 5'11", 210#
Dec '15:  T-total 901, T-free 159.1, E2 17, SHBG 28
Mar '16:  T-total 801, T-free 208.8, E2 18, SHBG 14
Jun '16:  T-total 678, T-free 31.9 (above range); E2 9; working to increase SHBG
Sep '16:  T-total 1075, T-free 31.4, e2 50 (wow)
Jan-Mar '16:  T-cyp 120mg per week @34mg EOD; 300IU HCG EOD, 0.25 Anastrozole E3D
Apr '16: T-cyp 105mg per week @30mg EOD; 300IU HCG EOD; 0.25mg Anastrozole E3D
Jun '16:  Low E2: dropping Anastrozole, reducing HCG to 250IU EOD.  T-Cyp 16ml/32mg EOD
Supps:  SloNiacin, aspirin, Vit. C., aged garlic,
Meds:  Jan '16 10mg Lisinopril ED. Jun '16 upped to 20mg

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