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Topics - 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. 

Wanted to post this message and my response from a member who PM'd me:

Mr. K,

It seems to me that you know a fair amount about cortisol judging by your posts.  I hope you don't mind me picking your brain.  I've been having some challenges with my overt all wellbeing or at least perceived wellbeing. I'm wondering if it could have something to do with cortisol.  I've struggled with low bp and orthostatic hypotension off and on foot several years now. Sometimes it's worse than others but it isn't as bad now as it used to be but send to be getting worse again.  Now I mostly have trouble of I get up too fast and when I try exercises like squats or burpies. I get really light headed and dizzy and have been sweating profusely and get really out of breath.  It can be embarrassing at the gym. I've been doing these exercises for about 8 months twice a week and it seems to be getting harder rather than easier  There was a time that I couldn't stand in one place for very long or I would pass out (I have a standing desk).  I was a little under weight then and my doc thought that was the problem.  (But I've always had more trouble with it than most people). Anyway do you know if trt can interfere with cortisol?  My sister has adrenal insufficiency and low hgh and her thyroid is nonexistent. Some of this is related to her disability. However I wonder how much of this comes from our father.  He was a Ranger in Vietnam and was exposed to lots of agent orange. He passed away lady year from esophageal cancer and had other conditions related to the exposure. I know I'm rambling and I probably didn't tell you everything I wanted to.  Also I've written this on my phone so I apologize if it is a mess. I just wanted to start a dialogue because I keep putting it off.

My response:

You're describing what sounds more like a low aldosterone problem than a low cortisol one, particularly given the orthostatic hypotension and profuse sweating.  Low aldosterone often goes with low cortisol, though.  But regarding your question about TRT, the answer is unambiguously yes that cortisol can and often is lowered, both because testosterone (not so much hCG or not at all clomid) drops LH and FSH to zero, and these hormones with ACTH are responsible for synthesizing pregnenolone from cholesterol; so the less LH and FSH (and ACTH), the less pregnenolone.  There are also much more complicated ways exogenous T can lower cortisol (and to some degree aldosterone) involving adrenal enzyme downregulations, but I think the big mechanism is the zeroed out LH and FSH.

Now, pregnenolone is the starting point that leads to all sorts of things, such as progesterone, DHEA, but also cortisol and aldosterone.  Lots of folks don't know that aldosterone is only slightly regulated by ACTH, i.e., ACTH doesn't do nearly as much for aldosterone as it does for cortisol (which is equally down the chain as aldosterone and shares the same adrenal enzyme for conversion from its previous hormone).  Aldosterone is actually mostly regulated by a totally different system, the renin-angiotensin-aldosterone system (see this: http://antranik.org/the-renin-angiotensin-aldosterone-reflex/).  Now, having pregnenolone lowered can definitely put a person "over the edge" regarding low aldosterone.

So what I'd recommend is getting a bloodtest involving ACTH, cortisol, DHEA(S), renin, and aldosterone, and also a basic CMP to check for sodium levels, and if low aldosterone is present should then sodium should also be low (even if they're still in range -- anything below 142 is considered low by most insightful docs), seeing how aldosterone regulates the sodium-potassium balance and with it (via osmosis) water retention.  Until then, you can try drinking a glass of water with a teaspoon of unrefined (if possible) sea salt and seeing how you feel afterwards. 

Do you urinate a good deal more frequently than before being on TRT?  That's also another sign of low aldosterone.  Aldosterone, with vasopressin, is the body's main water-retaining hormone. 

Back in the day (a few years back) I'd have a pretty solid connection between my injection and how my body would retain water on an E3D subq schedule.  Day of the injection I'd usually have the lowest water weight (judging by a scale) and look the most muscular (more water in muscles, less in extracellular ocean?); a day after and peaking at 30-36 hours I'd notice increased water retention and likely smaller muscles (more water in the extracellular ocean?) but sometimes larger muscles; then the day after this (day before my injection) I'd look the most cut with good muscle size, and also tended to feel the best on this day (less brain fog in particular).  The main determinant of water retention -- which I think most people agree on -- is estradiol level: as estradiol levels go too high, water retention develops, and as it drops you lose water retention.

But the reverse might be true as well.  Things have gone backwards lately, and I have no idea where I'm at with estradiol, but I notice that the morning of my injection day (before injecting) I'm usually 2-4 pounds heavier (water weight) than my lightest days relative to my injection schedule, and the day I inject is usually my "constant urination" day, where I'm going to the bathroom 8-10 times a day as I lose water weight.  Now my lowest water weight day is usually on the same day as my highest weight would be in the paragraph time frame above: the day after my injection. 

Weirdest of all, I notice a strange surge of E2 symptoms, including water weight, the day before my injection (tonight was especially miserable with bad mood, emotionality, brain fog, light sensitivity, etc.).  Putting it all together it goes something like this now: most water weight on injection day before injection followed by significant loss of water weight (and usually if not always an increase in symptoms) over the next 24 hours or so, then after 30-36 hours of my injection I start feeling worse (unlike years ago when I'd start feeling better), and continue to feel worse, sometimes with a surge of high E2 symptoms, the day before my injection. 

It's weird.  I get blood drawn Tuesday, and I'm hoping this iodine has cleared out my estradiol by shunting it toward estriol (not taking any DIM now).  I previously speculated that the ever-increasing gap between estrogen and testosterone can be as important if not more important than an absolute estradiol number, and this might be what's going on after I hit my peak at 30-36 hours.  But overall if I'm at a low estrogen state (too much iodine), this could point to water retention (and other bad symptoms) that happen when E2 is both too low and too high, and/or the gap between T and E2 too high. 

Anyone else get weird water retention changes pretty consistently relative to T injections? 

Anyone get this?  It's especially apparent if I try working out even a little bit, the next day feeling worse brain fog and more fatigue, and also easy delayed onset muscle soreness.  All of this has gotten worse since taking 50 mcg of levothyroxine for the second time after being off of it for a few years (despite not having these symptoms when I was on it the first time), so there's likely some nutrient or biochemical process that's being strained by the increased metabolic rate.  Mitochondria seem to be a reasonable guess, but trying carnitine, d-ribose, and PQQ haven't been successful, but coq10 might be helping.

It's a pretty tough tradeoff with thyroid meds: if I don't take them my brainfog and fatigue are worse, but if I do take them I basically can't do anything besides light exercise. 

When you get an injection of testosterone, testosterone and estrogen rise in tandem, but what many people find (and many docs, including Mariano, have noted) is that for whatever reason estrogen stays suspended longer than testosterone as things start to fall. 

I contend that it's this ever-increasing "gap" between testosterone and estrogen that can cause symptoms just like absolutely low or high levels of estrogen can.  I've noticed this in myself: wake up in the morning of my injection when I'm having slight high E2 levels but after I inject (a lower amount with the intention of gradually bringing my T and therefore E2 levels down) testosterone, by that night I'm feeling better than that morning even though my E2 was too high in the morning, because the "gap" between T and E2 becomes proportionately smaller as both rise -- and then worse the following day around the peak (high absolute E2 levels overpowering any low "gap" as both rise), then better as the peak declines, and then finally (the second day after my injection and day before my next injection) I start feeling high E2 symptoms again as the "gap" continues to widen, provided that my absolute E2 number isn't too high.

This "gap" problem becomes a problem when my E2 is too high as an absolute number; the lower the absolute E2 number, the less E2 there is to float as testosterone drops following the peak at (for me) 30-36 hours.  Interestingly, with our nascent knowledge of genetics in relation to hormones, we can pinpoint certain SNPs (such as COMT) that involve slower breakdown of estrogen, meaning people with these SNPs will have, theoretically at least, more problems with the "gap" given that their estrogen is being suspended even longer than the "normal" HRT patient.

Resolving the "gap" problem therefore means injecting at a lower T amount (leading to lower E2), taking an aromatase inhibitor or something over the counter that acts like one (calcium d glucarate, zinc, DIM) to lower E2, and/or injecting more frequently (which decreases the size of the gap).

Just a thought. 


So I know that high dose iodine (anything over, say, a few hundred micrograms a day) is considered controversial.  I decided to take this plunge given the research ardently (and I think successfully, but not comprehensively) defended by Brownstein and Abraham, even though there are still studies out there that contradict their claims, which I think don't invalidate their claims, but instead indicate contradictory research (i.e., methodological problems too specific for any layman to parse through, and yes, as a person moderately trained in research, there's contradictory research in all types of fields). 

At the very heart of this is their defense of the idea that the Japanese consume 13.8 mg (milligrams) of iodine per day, and there was disagreement on this point by a few critics (e.g., Gaby), saying that Brownstein and Abraham confuse dry weight with wet weight to calculate the 1963 iodine intake based on seaweed.  Their response: "We estimated the average daily intake of iodine by mainland Japanese in 1963 at 13.8 mg, based on information supplied by the Japanese Ministry of Health, which used only dry weight in their calculations, confirmed by a phone interview of one of us (GEA) on June 21, 2005, with officials of this Organization (See Table II). This amount of iodine was confirmed in mainland Japanese based on urine iodide levels in this population, as previously discussed."  Brownstein says that the typical dose for his patients is between 12 and 50 mg, with the higher dosage often needed because of competitive inhibition of iodine by other halogens (iodine being one, others being bromine, flourine, and astatine), which knock iodine off of receptors in the body, and iodine hangs out basically where glandular tissue is present, most importantly with breast and thyroid tissue for ladies and prostate and thyroid tissue for males. 

(As an aside, I have a friend who at the age of 24 had a breast cyst removed and she also suffers from depression and anxiety, which makes me wonder if her problems are really related to low thyroid function caused by insufficient iodine.)

It's with this bit of information that I decided to take the risk, and also because I haven't heard of irreversible damage from high dose iodine consumption, except from one dude one a forum who took between 100-200 mg per day, largely based on the fanaticism from the curezone.org forum on iodine, where any possible negative effect is automatically branded as an indication of "detox".  I also took the leap because Dr Mariano, who I respect and trust a lot (even though he suffers from psychiatrist's disease and prescribed me a benzo that caused problems) and recommended 12.5 mg per day via Iodoral tablets. 

Before I started with my very cautious one drop (2.5 mg iodine, actually 1 mg iodine and 1.5 mg iodide) of 2% Lugol's, I had symptoms of depression, intense fatigue, moderately bad brain fog, low libido, light sensitivity, and poor erections, among other things.  A lot of this seemed to coincide with me starting a benzodiazepine, which seemed to go with increasing estradiol levels (from my usual low 20s to high 20s), and possibly a negative influence of benzos on T3, the active thyroid hormone.

So I started a system of increasing my dose by one drop every three days, and when I was at around 2.5 tabs of Iodoral (31.5 mg), I noticed in a manner of days that all the above symptoms got about 80% better, and especially how I had my first feeling of real solid elation in months.

Then things got tricky and I suspected that my iodine level was building up in my system, and I eventually realized that DIM (which I had been taking for over two years) and iodine work in similar ways by changing estrogen metabolism by reducing 16a-hydroxyestrone, with iodine (according to Dr Jonathan Wright) increasing estriol at the expense of estradiol, which he said was obviously reduced in women, so in contrast to DIM (which doesn't seem to lower estradiol much if at all while changing pathways from "bad" to "good" estradiol metabolites) iodine seems like it could actually lower estradiol while also reducing at least one "bad" estradiol metabolite (16a-hydroxyestradiol).  (This doesn't make iodine (or DIM) an aromatase inhibitor, as the reduction in estradiol isn't because the aromatase enzyme is being downregulated and therefore less estradiol is being converted, but rather the three main estrogens are being redistributed.)  Basically I was taking what amounted to a super-dose of DIM by combining high-dose iodine with my usual 75 mg pure DIM.

The tricky part came when I started experiencing what appeared to be low estradiol symptoms.  Gradually reducing my DIM dose has made me feel better, getting to that sweet spot again, and as of a few days ago I'm off DIM completely.  However, I'm having tweaking issues: my symptoms mentioned above are still overall much better, but I'm having a few of them slightly come back compared to the peak moment reached when I was on 31.5 mg of iodine. 

What I have to figure out now is whether my estradiol level has actually dropped, and if so how I need to change my TRT by increasing the dose, and if not figure out whether I need to lower my estradiol by either lowering my dose or taking calcium d glucarate.  I am noticing that my thyroid is generally larger as I approach my peak which has usually been 30-36 hours after my injection, but now I'm starting to wonder if my peaks are hitting closer to 24 hours, judging by a few days ago when I felt better and better the day of my injection and worse the second half of the following day -- which might indicate I'm too low on estradiol and need to increase my dose.  As of this week and maybe a bit last week I've noticed myself gaining more water weight and stomach distension/bloating as I approached my next injection and losing it as I approach my peak (whatever that is).

It's also possible that all the positive changes above are due to iodine hitting the thyroid (and, per Dr Mark Starr's note that many of his clients with mild adrenal issues get better with iodine, my slight adrenal issues), or a combination of thyroid and changes in estrogen metabolism.  It's hard to tell because my symptoms of thyroid going too low are basically identical to when I've had fluctuations in estrogen, especially with mood.  I have noticed that my morning temps sometimes increase from their usual stubborn 96.6 to 96.8-.9, and one time at 97.0, for example.

BUT I've also noticed moments of feeling cold with no changes in actual body temperature, which could indicate negative affect on thyroid or changes in vasodilation, e.g., norepinephrine (which is vasoconstrictive in some areas but vasodilative with the skin, causing warmth to be expelled), generally higher in hypothyroid states, is being lowered because of iodine, and I've also noticed slightly smaller pupils in the last few weeks, indicating a slight lowering of norepinephrine (which is central in determining pupil dilation, even when dopamine and serotonin are involved).  Also, if the iodine was causing negative thyroid effects, I should notice predictable increases in thyroid size a few hours or so after taking iodine, but instead I notice increases in the size of my thyroid (which I've noticed for at least a year, the most noticeably when I was on hCG, btw) relative to my injection over a three day period. 

I'm also taking 200 mcg of selenium per Dr Brownstein's and Dr Dach's protocol (Dach saying the reason people have negative reactions with iodine is solely because of insufficient selenium levels), but haven't gotten around to trying B2, B3, and vitamin C, as I could have had a negative reaction to one or more of these vitamins, so I'm taking things one slow step at a time. 

So this stuff is tricky, and I still have work to do, and because of this N=1 iodine project I still haven't gotten around to trying lithium orotate given my nonexistent lithium levels in hair and serum, which could be a big deal for me given my low intracellular (via Spectracell testing) levels of B12 and compound heterozygous MTHFR status causing a probable 70% reduction in MTHFR enzyme function.  Oh, fwiw, I'm requesting whole blood histamine testing to be done, as histamine and methylation are inversely related (histamine being broken down by methylation), so that's another rabbit trail.

Do I think everyone should go out there and try iodine?  No, unless you're looking at a milligram or two at most and know your selenium levels are good, you're working with a doctor trained in this stuff, or you need to take a chance after doing a bit of research given your condition.

So there's unambiguously something here with iodine that's having at least a moderately positive effect and there's plenty of room for changing protocol by just changing the iodine and/or testosterone dose (currently at 25 mg iodine).  How it's exactly working (especially by helping thyroid and/or helping estrogen metabolism) is still what I'm trying to figure out. 

Partly from therapy withdrawal, and partly because I'm still struggling to pin the diagnostic and treatment tail on the physiological donkey (things have been vastly better with 25 mg of iodine, likely because of estrogen metabolism reasons but possibly because of thyroid ones too), I have to open up discussion for how we're all doing with our respective illnesses.

For me the killer isn't the waiting but the loss of time.  I keep myself busy with studying (I have a weird standard that trumps even actual employment/calling to some degree in that if I can read a few hours of at least moderately challenging material a day I feel accomplished), so I feel like time is well-used here.  I spend many hours a week in a coffee house, partly because my wife works nights (therapist), and also because I get to see so many people I know (the place is like the caffeinated version of Cheers), where I read and have good conversations with people.  It's when I return home and after the wife goes to sleep that I sometimes think about that time deal -- namely how much longer this is all going to take.

And I won't be shy in saying this: I know I have the ability to make the world a better place through my work, so it sort of kills me to know my colleagues are out there and I'm "in here", stuck in my own body that does stuff that's gradually becoming less and less mysterious but still without resolution.  Will it be six months, a year, more?  I can deal with a year, but it's the not knowing how long it'll be that really gets me.  Then I think of the countless people on the Internet who have mysterious ailments that aren't resolved, then remember that many of them do eventually get resolved, and that I am in possession of better materials and more medically minded than them in putting things together, so my chances are much better.  But still.   

What about you guys?  Any struggles, comforts, hopes, despair, etc., about your illness?  Because I know a whole lot of you can't be pigeonholed into just having testosterone-related issues, and if you do you still have the trouble of dialing things in correctly. 

Testosterone, Hormones and General Men's Health / Histamine <--> Estrogen
« on: October 30, 2016, 07:14:31 am »
I always have higher estradiol during allergy season, but what I'm starting to notice is that my high estradiol symptoms -- caused by rising T levels from injections -- such as red ears and facial flushing might actually be high histamine symptoms.  They're identical to when I get hit with seasonal allergies with immediate stimuli (such as when I'm an idiot and outside with a fire and sneeze a hundred times). 

As for estrogen's effects on histamine/mast cells, "Consistently with our finding, more mast cells and higher histamine concentrations were observed in the estrous stage than in the progestrous stage and diestrous stage in the mammary glands of nonsensitized female Wister rats [33]. Ovariectomy decreased the mast cell number and histamine concentration, which were reconstituted by exogenous estradiol."  According to another study, "Alongside the authors have also shown that E2 rapidly stimulated MC degranulation which could be blocked by tamoxifen, a tissue specific ER antagonist, clearly indicating that estradiol-induced MC degranulation throughout one of its receptors."

As for histamine's effect on estrogen, the second study cited above (which is full of good info) notes increases in asthma (mediated by increased histamine/mast cell degranulation):

    In an animal model of allergic disease, the role of female sex hormone was tested. Female mice have reportedly an increased susceptibility to allergic airway disease in compared with male mice (reviewed in Carey et al., 2007). Levels of IgE are much higher in allergic female mice compared to their syngeneic male (Corteling and Trifilieff, 2004). Female rats that underwent ovariectomization developed less airway inflammation compared with sham controls animals (Ligeiro de Oliveira et al., 2004). However, estrogen replacement in the ovariectomized animals re-established airway inflammation levels of intact females (Ligeiro de Oliveira et al., 2004). Treatment of intact female rats with the selective estrogen receptor antagonist tamoxifen also reduced the development of allergic airway disease (Ligeiro de Oliveira et al., 2004). Thus, the direct effect of these hormones on disease development is hereby demonstrated.

It's also worth pointed out that quercetin, a supplement you get in natural form from apples and onions 'n stuff, is a natural aromatase inhibitor (this study is a mess of supercompacted data), albeit a weaker one.  Quercetin limits mast cell release of histamine and so is a "natural antihistamine" (without the drowsiness), but Peak has noted possible thyroid effects.  When I take quercetin during allergy season, I lose 8-10 pounds of water weight (and I weigh 190 pounds otherwise, 6 feet flat with moderate muscle), the increase in water weight likely a pro-inflammatory consequence from allergies and therefore histamine. 

Whatever the case, for a long time I thought high estrogen was associated with flushing and red ears, but that's actually clasically a low estrogen (or estrogen on the decline) symptom.  Same thing with night sweats: low estrogen symptom, but really for me (with increasing estradiol) a high histamine symptom given the increase in vasodilation which stimulates sweating.  Feeling hot in general is a symptom of vasodilation, and also something I've correlated with estrogen being high but really is more likely a result of histamine (secondary to estrogen) getting up there.

Estradiol also decreases DAO (diamine oxidase) activity, an enzyme responsible for degrading histamine.  Also, during women's luteal phase (when progesterone is dominant) DAO enzyme activity is increased.  So progesterone can also help with degrading histamine -- another reason why you need to check adrenal hormones and supplement with pregnenolone (and DHEA) if necessary.  If you're estrogen dominant, chances are you're "histamine dominant" too. 

To chase another rabbit trail, high histamine can indicate undermethylation, meaning I'm fit for a response to methyl-supplements given my compound heterozygous MTHFR status -- even though they don't appear to be doing much, hopefully because of my nonexistent lithium levels, which corresponds with my low cobalt levels and moderately high aluminum levels.

Anyways, if you're feeling hot, flushed, other vasodilation symptoms (sweating, etc.) and you're on TRT, the symptoms might not be estrogen as much as they're histamine-related.  You should have whole blood histamine levels checked, MTHFR status, and DAO (which degrades histamine) status checked (the latter through genetic testing).  Actually, the insomnia that some guys experience on TRT might also be histamine-related (again secondary to estrogen increases, especially if they're higher than they should be), as histamine is an excitatory neurotransmitter (which is why antihistamines make you sleepy). 

As a bonus, histamine seems to induce erections, which this study found, with histamine increasing the percentage of participants who get erections in a dose-dependent manner.  So maybe low histamine (and overmethylation) can be a place to look into for guys with ED that isn't ameliorated by TRT. 

It should e noted that all the mentions of histamine being a reason for symptoms I've mentioned (e.g., flushing, red ears) could more precisely be the result of increased norepinephrine, which can also invoke a vasodilation response, and norepinephrine is involved in inflammatory responses, allergies (hence histamine) being one of these. 

Anyone else?

I recently followed up with hair mineral testing, which showed 1st percentile lithium levels, with serum testing, which showed undetectable levels.  I also have no apparent reaction to B12 and folate, and low intracellular levels of the former.  This is an excellent article.  Abstract:

    In high doses, lithium acts as a drug, accompanied by potentially serious and debilitating side effects. In low doses, lithium acts as a nutrient required for B12 and folate transport and uptake, neuromodulation, and the function of many biochemical processes in both humans and animals. Studies since the 1970s have shown the ability of lithium to stimulate the proliferation of stem cells. Recent studies have described its ability to up-regulate neurotrophins such as brain-derived neurotrophic factor (BDNF) and nerve-growth factor (NGF), which are important in neuronal function, plasticity, and repair. With its newly described antioxidant and anti-inflammatory activity along with powerful neuroprotective effects, low-dose lithium therapy has largely unrealized potential to prevent or treat a wide-range of neurological disorders such as traumatic brain injury (TBI), Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), chronic pain, mercury toxicity, depression/anxiety, alcoholism, and drug addiction.


Peak used to joke and call me Dr Estradiol because I used to harp on it all the time, and used to think it was the biggest ill for people who have testosterone issues.  I've since come to change that a bit, in that I think a lot of guys with testosterone issues, primarily if their low T isn't age-related (and most guys on this forum fit this description), have other issues going on as well, such as adrenal, thyroid, insulin resistance, etc. issues, especially knowing how stress hormones (low cortisol and hypothyroidism, at least, involve elevated norepinephrine levels, putting a person in a state of sympathetic dominance) can drastically lower testosterone levels.  Dr Sapolsky says that in surgery, the very moment an incision is made sex hormones drop to near zero from the physiological stress of the cut. 

Estrogen is still a problem to watch out for, but what I'm even coming to find here is that it's not "just about your estradiol number."  As many members know, there can be a pretty big range of windows for guys hitting the sweet spot with testosterone and estradiol, with some guys needing to stick to the 20-25 pg/ml range, and others able to be between 20 and maybe 40 or more.  The real question here is why some guys get so much wiggle room while others have narrow windows (endocrinologists call people with these narrow windows "brittle").

One of the reasons for this could be genetic:

    Endogenous and exogenous estrogens undergo oxidative metabolism by hepatic microsomal cytochrome P-450. Aromatic hydroxylation at either the C2 or C4 position is a major route of Estrone metabolism in humans and other mammals, although there are less 4-hydroxylation than 2-hydroxylation events.

    Several cytochrome P450 isoforms including Cytochrome P450, family 2, subfamily C, polypeptide 9 ( CYP2C9 ), Cytochrome P450, family 3, subfamily A, polypeptides 4 ( CYP3A4 ) and 5 ( CYP3A5 ), Cytochrome P450, family 1, subfamily A, polypeptide 2 ( CYP1A2 ), and Cytochrome P450, family 2, subfamily C, polypeptide 19 ( CYP2C19 ) [1] catalyze the hydroxylation of Estrone to 2-Hydroxyestrone or/and 4-Hydroxyestrone. Further, Catechol-O-methyltransferase ( COMT ) catalyzes the methylation of 2-Hydroxyestrone and 4-Hydroxyestrone to corresponding 2-Methoxyestrone and 4-Metoxyestrone [2].

    CYP3A4 [3], [4], CYP3A5 [3], [4], and CYP2C19 [5] also catalyze 16alpha-hydroxylation of Estrone forming 16alpha-Hydroxyestrone. 16-Hydroxysteroid epimerase converts 16alpha-Hydroxyestrone to 16beta-Hydroxyestrone [6].

    16alpha-Hydroxyestrone is also formed via Estriol oxidation by Hydroxysteroid (17-beta) dehydrogenases 1, 2, 3, 7 and 8 ( HSD17B1, HSD17B2, HSD17B3, HSD17B7 and HSD17B8).

    Sulfotransferase family 1E, estrogen-preferring, member 1 ( SULT1E1 ) [7] catalyzes sulfation of Estrone to Estrone 3-sulfate. Reverse reaction, the hydrolysis of Estrone 3-sulfate, is catalyzed by Steroid sulfatase (microsomal), isozyme S ( STS ) [8].

The letters in parentheses are polymorphisms, and the following graph helps put the metabolites of estrogen into place:

Notice how much is going on other than "just" the three estrogens we're told about, estrone, estradiol, and estriol.  The polymorphisms mentioned above change how estrogen is metabolized.  Each of these changes in metabolism (e.g., increasing 2-methoxyestrone) could potentially have changes in symptoms, and this is one of the main reasons why I think guys have different windows for how high (or low) their estrogen can get

Also importantly, you can have increased rates of cancer for different polymorphisms that determine how estrogen is metabolized.  For example, Dan Purser, a doctor who writes on methylation issues, says that "several studies have shown that COMT variants especially the val108met variant of COMT, are associated with a 3-4 times increased risk for breast cancer," and goes on to say how increasing folate levels offsets this risk (but he also wisely completes the puzzle of methylation by saying you should check whole blood histamine to determine if you're an undermethylator or overmethylator, which in turn determines whether you're able to tolerate methyl folate).  Since we're beginning to realize that it's not really DHT that's predictive of prostate cancer in guys but rather estradiol (and I'd say certain forms of estradiol metabolites, i.e., the cancerous estrogens), this increase in breast cancer from COMT should also be noted by guys as well.  Having a polymorphism (heterozygous less bad than homozygous) for COMT (and there are multiple forms) means you break down estrogens slower.

FWIW, COMT (catechol-o-methyltransferase) also causes problems with catecholamine (norepinephrine, epinephrine, dopamine) breakdown as well, where the more of these polymorphisms you have and/or the more they're homozygous means slower catecholamine breakdown.  So the dude with one or more COMT polymorphisms could have problems on multiple fronts, namely dealing with stress as well as dealing with estrogen, and we know that estrogen is involved with higher levels of stress hormones.  Also FWIW, I checked my genes and I have none of the CYP polymorphisms mentioned above, but have two homozygous COMT polymorphisms, and I felt dramatically better by getting on DIM.

Oh yeah, DIM.  Check out this chart:

DIM shunts estrogen metabolism away from 4-hydroxyestradiol and 16b-hydroxyestradiol as well as 4-hydroxyestrone and 16a-hydroxyestrone, all four of which are "bad" estrogens, both in terms of increasing cancer risk (supposedly), but also I think, again, in increasing symptoms of "high E2" for guys who are prone to metabolize estradiol down these pathways (e.g., COMT or CYP polymorphism folks).  Here again it's not just estradiol that's the bad guy, because DIM doesn't really work on decreasing estradiol too much, but rather how it's metabolized to other estrogens, "good" or "bad".  I felt better on DIM because estrogen was shunted away from the "bad" pathway and toward the good one even though my E2 level didn't budge any if at all. 

Then there's iodine, with Dr Jonathan Wright, who singlehandedly created bioidentical estrogen replacement therapy (so he knows his estrogen), saying the following:
    Years ago, when applying Dr. John Myers very effective iodine therapy for fibrocystic breast disease some of the women had 24-hour urine tests for estrone, estradiol, and estriol. To my surprise, in themajority of these women the quantity of estriol greatly increased, and the total quantity of estrone and estradiol (combined) decreased following the iodine treatment. Since estradiol and estrone can metabolize to estriol only through 16a-hydroxyestrone (estradiol (estrone (16a-hydroxyestrone (estriol) theoretically it appears that iodine somehow greatly stimulated this pathway. Also theoretically, this may mean that iodine helps to “drain away” 16a-hydroxyestrone (“bad estrogen”) by helping to turn it into estriol. “Lugol's solution”, a combination of iodine and potassium iodide, was used in the “Myers treatment” noted above. As large amounts of iodine or iodide can possibly affect the thyroid adversely, it's best to work with a physician if using this material or other relatively high-dose iodine and/or iodide preparations. (Wright cites the following author who claimed iodine helps with cancer: Gerson, Max. A cancer therapy: results of 50 cases. 3rd edition. Totality Books, Del Mar, California, 1977. Pages 205-206, 409)

Getting complicated, right?  Basically DIM and iodine overlap through estrogen pathways through reducing 16a-hydroxyestrone, with iodine increasing estriol levels as an alternative (see the first chart above).  Wright mentions elsewhere using doses of 1-3 mg per day, saying to watch out for longterm use given potential influences on the thyroid (possibly a misinterpretation of the Wolff-Chaikoff effect, which only causes a temporary shutdown of thyroid hormone with high doses of iodine).  It's definitely controversial regarding high-dose iodine testing, and that's another beast.  The point here is that iodine also helps with estrogen metabolism. 

Anyways, the big point here is that it's not just about estradiol levels but about other usually completely unknown estrogen metabolites, which can determine symptoms, potentially cancer, and arguably how wide a person's estradiol window is while on TRT.  Iodine and DIM aren't aromatase inhibitors, seeing how they don't act on aromatase, which converts testosterone to estradiol.  These interventions are totally different options, and might be worth looking into for guys who have all other health markers (thyroid, etc.) under control as well as estradiol but still have problems, and also a reason for genetic testing.  It might be the "bad" estrogens (genetically or not) screwing things up. 

I'm thinking of dropping $60 and getting some liposomal glutathione because of the stuff I've been seeing on chronic fatigue (my big issue, recently slight-moderately better with 200 mg coq10, iodine, and sea salt, can't tell which is the big factor).  Dan Purser, a doctor who writes (decently) on methylation said he doesn't think NAC does anything unless you have needs for cycsteine.

Anyone have any experiences with glutathione?

Found this interesting gem at the Life Extension site (currently down for maintenance so don't have a link, will add later):
    In a 2008 study, standard CoQ10 supplements failed to improve either CoQ10 levels or cardiac performance in individuals suffering from CHF, while ubiquinol succeeded on both fronts.30

    The study involved individuals with advanced CHF. Their hearts pumped less than half as well as normal, with low CoQ10 levels despite taking an average of 450 mg/day of standard CoQ10. When the same people took ubiquinol (580 mg/day on average), their CoQ10 blood levels vaulted into the therapeutic range—and their hearts’ pumping action improved by 77%.
So they were taking pretty hefty amounts of (non-ubiquinol) coq10 with no significant changes in serum levels, and had to take almost 600 mg of ubiquinol to get their values into range and see differences in heart health.  As a contrast, most supplements recommend taking 100-200 mg of ubiquinol -- but presumably the folks they're addressing have good coq10 levels but want a bit of a boost. 

I've tried taking 100 mg of ubiquinol without any noticeable change in symptoms, and I have a significant coq10 deficiency, well below the range.  Although touted as a supplement for heart health, coq10 also helps with energy and potentially brain fog. 

Of course, ubiquinol is pretty expensive -- about $30 for LEF's brand which provides 60 100 mg tabs.  But I guess I'll have to try upping it to 200 and eventually 300 mg to see if I notice any changes. 

Anyone have coq10 serum level pretested, then tried ubiquinol or coq10 and have a posttest to see for differences? 

Anyone have this symptom?  I've noticed it consistently starting around a year ago, and it's often cited as fitting with low aldosterone (which I've had on multiple checks), seeing how aldosterone is responsible for the balance of sodium and potassium in intracellular and extracellular fluid.  I have it on random days, and drinking coffee (caffeinated or not) is a good trigger for it, and coffee has been shown in at least a case study to be associated with hypokalemia (low potassium), and caffeine is known to significantly alter electrolytes, notably decreases in urinary output for potassium and increases for sodium and chloride (i.e., the body retains more potassium and excretes more sodium and chloride). 

The electrolyte imbalance bit is one theory.  Another is that light sensitivity, insofar as it goes with "flickering pupils" (hippus) or insufficient pupil constriction with light exposure, reflects increased sympathetic activity (i.e., increased norepinephrine).  This might be why I more often have light sensitivity when my estradiol is too high, and estradiol could be either pro-inflammatory (which leads to sympathetic activation) or increases norepinephrine (and ACTH and cortisol).  Dr Mariano has this to say about the pupillary response:

"When one tests pupillary reflex to light, one is testing for several things including:
1. Intactness of the nervous system innervation to the eye (what most physicians do.)
2. Balance between sympathetic vs. parasympathetic nervous system tone.
3. Adequacy of energy supply to the sphincter and dilator muscles.

Points 2 and 3 are affected when one has adrenal fatigue.
During adrenal fatigue, one way to generate energy is through increasing sympathetic nervous system tone. This makes it more likely for the pupil to dilate even when exposed to light since the sympathetic nervous system tone may transiently override the control over pupillarly contraction. The impairment in energy production in the body may also transiently weaken the pupillary contraction in response to light, resulting in dilation."

Dr Mariano told me during a consultation that flickering pupils is high norepinephrine.  The question in my case is whether the high NE is a result of insufficient cortisol (i.e., adrenal fatigue), but this doesn't seem to be the case given my lack of success with 25-30 mg of hydrocortisone over a few months, or a chronic inflammatory or other stress-related condition.

Either way, it's a pain in the ass.  I've tried "resalting" after drinking coffeee by drinking water mixed with unrefined sea salt (to increase the loss of sodium and chloride from coffee consumption) but with no noticeable change in light sensitivity (might be there, and I might not be "resalting" enough).  FWIW, I've also noticed that when I drink coffee and have light sensitivity issues that my urine is a lot less fizzy and seems slightly thicker.

Anyways, is this a problem for anyone else, and do you notice any other associations (hormones, symptoms, etc.) when light sensitivity happens?

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