Ray Peat Email Advice Depository Discussion/Comment Thread

I'm very interested in this. From someone who suffers with acne and wondering if it is a problem with my gut, do you think this product would benefit me?

 

Sounds crazy enough to work; we'll try this and get back to you in nine months!

 

I don't know but you could try it to see if it helps. There are different bacteriophages that target specific bacteria, however I read where a specific phage that was intended for a specific bacteria seemed to also treat other non specified bacteria.

 

I think he only recommends transdermal route for steroids because they get absorbed better that way.


And fat soluble vitamins because they are irritating to intestine.

 

Thanks for the information paymanz. Haidut would say bypassing first pass metabolism could also be important when considering supplementation, depending on the desired effets (on liver or in the blood).

Does anyone understand what Ray meant with his reply on topical T3? The post I'm referring to is this one:
Ray Peat Email Advice Depository

Is he talking about the concentration of t3 in the solution that is applied or is he talking about the approximate concentration of T3 achieved in the blood ?

 

To get 1ml of Tyronene or TyroMix you need 24-25 drops. Given that each drop is 8mcg, the products are lot more concentrated than what Ray mentioned here unless he meant a tenth of a milligram per ml, which would be 100mcg per ml, and in that case our Tyronene would still be more concentrated as it has 200mcg per ml.
Btw, we got the results from the lab testing and both TyroMix and Tyronene definitely contain T3 and T3/T4. We specifically created a small batch and let is stay for 2 months in solution to see if the T4/T3 chemicals somehow degrade with time. Apparently they do not, at least not in the 2 months that we waited before the testing.

 

Well he said microgram , of course it could have been a mistake but I think @schultz mentioned that the skin could turn t3 into rt3 , so maybe what Ray is saying is that for topical use the right concentration to prevent the body from doing so is as low as the one he suggested. The very low concentration may be one of the reasons (apart from systemic effect being superior) he's not a huge fan of using t3 transdermally . I don't know how dmso and ethanol would affect all of this though.

 

Can you show me the reference where schultz said T3 can be converted into rT3 topically? I am not aware of any cell in the body able to convert T3 into rT3, so this is very interesting to follow up on.

 

Applying Pure T3 (tyronene) On Scrotum
Applying Pure T3 (tyronene) On Scrotum

 

@schultz had wrote: Yah it can turn T4 and T3 into rT3 as it contains the D3 enzyme.

D2 (deiodinase) converts T4 into T3. It's a pretty neat topic! D2 is apparently present in brown fat and allows local T4 to T3 conversion for thermogenesis when it's cold. Bone remineralization may also require D2 and a local conversion of T4 to T3. I'm wondering if this would have an effect on teeth. I couldn't find much information on thyroid hormone and teeth.
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That isn't T3 turning into rT3. It's T4 metabolizing into T3 and/or rT3, which we know. The insight is that this can occur in brown fat cells and in other cells that involve bone building. Not just in the liver (I suppose.)

I am not surprised. I still think fatty liver disease can cause sluggish conversion of T4 into T3. But I'm sure the reason isn't that simple that the liver is fatty. There may be other cytokines that inhibit cells from metabolizing T4 to T3.

 

Anyways, let's wait for the defendant to chime in .

 

Does that mean me?

When I was reading about topical thyroid I read through a lot of information. I am not sure I can re-find all my sources quickly. Sometimes when you're going through pubmed you read things that are interesting but not necessarily what you're searching for. This stuff gets cataloged in your brain, but you forget where you read it! I don't understand the significance of D3 (good or bad) but it seems to be some kind of growth regulator.

Thyroid Hormone and Wound Healing
"The predominant circulating thyroid hormone is the prohormone, T4. T4 is converted to the active thyroid hormone, T3, by intracellular thyroid hormone deiodinases [13, 14]. Two of the enzymes (D1, D2) primarily activate T4 to T3. The third enzyme, D3, converts T4 to inactive reverse T3 (rT3). Investigators have showed conversion of T4 to either T3 or rT3 in cutaneous cultures, demonstrating indirectly the presence of thyroid hormone deiodinases in skin [15–17]. D3 is not expressed significantly in most peripheral tissues. However, assays of enzyme activity suggest that D3 is active in goat epidermis [18], mouse epidermis [19], and human skin in vivo [20, 21]. D2 activity has been demonstrated in cultured human fibroblasts [22]. Neither D1 nor D3 has been found to be active in the dermal fibroblasts, suggesting that D3 expression may be limited to epidermis."

The paragraph sort of leaves you wondering how much deactivation is happening.

Expression of Hypothalamic–Pituitary–Thyroid Axis Related Genes in the Human Skin
D2 catalyzes 5′ (outer ring) deiodination of T4 to T3, whereas D3 catalyzes 5 (inner ring) deiodination of T4 and T3 to inactive T3 (rT3) and 3,3′-diiodothyronine (T2) (St Germain, 1999; Bianco et al, 2002). The structure of both genes is brown. D2 is predominantly expressed in pituitary, brain, brown fat, thyroid, heart, and skeletal muscle, whereas D3 is predominantly expressed in the brain, uterus, placenta, fetal membranes, and skin (rodents) (St Germain, 1999). Actual transformation of T4 to T3, and of T3 to T2 have been demonstrated in cultured epidermal keratinocytes (Kaplan et al, 1988), although the pattern of expression of the corresponding genes has not been evaluated in human skin.

There may be some info in the paper below. I didn't read it though (I read the abstract)

Role for inner ring deiodination preventing transcutaneous passage of thyroxine. - PubMed - NCBI
Creams containing thyroid hormone are commonly employed for cosmetic purposes. To verify whether T(4) applied to the skin surface can enter the bloodstream either directly or as a metabolite, a cream containing L-T(4) [3,5,3',5'-tetraiodothyronine (T(4))] was self-applied by volunteers for 2 wk. No significant variations in urinary iodide, TSH, and serum (total and free) T(4) and T(3) concentrations were observed at any time relative to pretreatment values, whereas rT(3) concentrations increased significantly 6 and 12 h after cream application. The increased rT(3) concentration led us to investigate the presence of inner ring type III deiodinase (D3) activity in human skin. Using human surgical discard skin, we found that T(4) can be carried across human epidermis in a liposome cream. Substantial inner ring deiodination was suggested by the fact that only 10% of transferred thyroid hormone remained as T(4), and T(3) was not detected. We then measured D3 activity in a surgical skin specimen. The K(m) for T(3) was 1.74 nmol/liter, and the maximum velocity was 23.5 fmol/microg microsomal protein/h. In conclusion, our study indicates that normal human skin serves as a substantial, but incomplete, barrier to T(4) passage. D3 plays an important role in augmenting T(4) blockade by inactivating T(4) to rT(3).


This one is interesting.
The sonic hedgehog-induced type 3 deiodinase facilitates tumorigenesis of basal cell carcinoma by reducing Gli2 inactivation. - PubMed - NCBI
Here, we demonstrate that D3 action is critical in the proliferation and survival of BCC cells.

This link is like a whole paper devoted to D3.
Local impact of thyroid hormone inactivation

 

Thank you!

Yes.

 

Great links,quote from the below link you posted-

"D3 protein is present in both mouse and human skin. The skin is the largest organ in humans and serves as a metabolically active biological barrier that separates internal tissues from the external environment. The epidermis and dermis, which are the two layers constituting the adult skin, are targeted by TH. D3 is first expressed in the mouse epidermis at E13.5; it is highly expressed in the epidermal layers and in hair follicle keratinocytes at E17.5. D3 expression is very high in anagen (growing) phase of the hair follicle cycle, as well as in the surrounding outer root sheath. It progressively decreases during catagen and is virtually absent in telogen (Dentice et al. 2007). D3 activity has been detected in vitro in the culture of brown preadipocytes. In this system, differentiation of precursor cells to adipocytes parallels decreased levels of D3 expression "
Full paper-
Local impact of thyroid hormone inactivation

Danny Roddy in one of his articles on balding uses the below study I believe,he doesn't discuss the the diodinase enzymes,just uses the study in relation to thyroid a importance in hair follicle.

"hvan Beek, N., et al. Thyroid hormones directly alter human hair follicle functions: anagen prolongation and stimulation of both hair matrix keratinocyte proliferation and hair pigmentation. J Clin Endocrinol Metab. 2008 Nov;93(11):4381-8. Epub 2008 Aug 26. "Studying microdissected, organ-cultured normal human scalp HFs, we show here that T4 up-regulates the proliferation of hair matrix keratinocytes, whereas their apoptosis is down-regulated by T3 and T4. T4 also prolongs the duration of the hair growth phase (anagen) in vitro, possibly due to the down-regulation of TGF-beta2, the key anagen-inhibitory growth factor. Because we show here that human HFs transcribe deiodinase genes (D2 and D3), they may be capable of converting T4 to T3.""Thus, we present the first evidence that human HFs are direct targets of thyroid hormones and demonstrate that T3 and/or T4 modulate multiple hair biology parameters, ranging from HF cycling to pigmentation".


I'm curious if D3 is involved with grey hair,the above study is pointing that way. Peats recommendation is to correct thyroid function to stop excess serotonin,dopamine,estrogen issues etc,the study's we posted on grey hair were generally about downstream influences like serotonin,estrogen and dopamine,all of course with complex feedback mechanisms.
Nevertheless it Would be interesting to try a specific D3 inhibitor topically for baldness and grey hair. Can't find anything that specifically inhibits D3 right now.
Does androsterone increase conversion of T4 to T3 by using the Diodinase enzymes?

 

I'm not sure of specific things that inhibit D3. I wonder what the consequence would be of that (positive or negative)? I would be interested in research like that! I believe there is a D3 "knockout" mouse strain.

...

Okay I just was searching around found this interesting study

Acute downregulation of Type II and Type III iodothyronine deiodinases by photoperiod in peripubertal male and female Siberian hamsters. - PubMed - NCBI
Across many vertebrates, Type 2 iodothyronine deiodinase (DIO2) is elevated under reproductively stimulatory long days (LD) and synthesizes the conversion of thyroxine to T3; Type 3 iodothyronine deiodinase (DIO3) reduces T3 production and signaling, and is upregulated under reproductively-inhibitory short days (SD).

Among birds and mammals, thyroid hormone signaling provides a crucial step in inducing seasonal reproductive phenotypes. Infusions of exogenous triiodothyronine (T3) delivered under a winter-like short day (SD) photoperiod promote robust gonadal development in long day (LD)-breeding Japanese quail (Coturnix japonica; Yoshimura et al., 2003) and Siberian hamsters (Phodopus sungorus; Barrett et al., 2007; Freeman et al., 2007).

In my chicken coop I have a light timer so the chickens can get extra light. Apparently they lay more with the extra light. The above gives a clue for why that is. Ray has talked about this before on podcasts but this explains it a little better maybe?

Photoperiod manipulations have little effect on circulating plasma triiodothyronine (T3) or thyroxine (T4) concentrations (O’Jile & Bartness, 1992; Prendergast et al., 2002; Yoshimura et al., 2003). Rather, thyroid hormone availability and receptor-signaling are regulated locally through differential expression of iodothyronine deiodinase enzyme types II and III (DIO2 and DIO3) in the mediobasal hypothalamus (MBH; Yoshimura et al., 2003). Deiodinase enzymes have opposing effects on T3 production: DIO2 converts the prohormone T4 into biologically-active T3, whereas DIO3 both catabolizes T3 into diiodothryonine (T2) and converts T4 into biologically-inactive reverse-triiodothyronine (rT3; Lechan & Fekete, 2005; Yasuo et al., 2005). Changes in expression of either or both of these enzymes offer a potential mechanism for photoperiodic control of T3 availability in the MBH.

 

There's also another study with the knockout which shows the mice have lowered anxiety and are more exploratory,the researchers do acknowledge this but also claim the mice are hyperactive.
Typing DIO3 into pubmed and it should come up.

I'm thinking if you did rub said substance into scalp the hair follicle metabolism should speed up and possibly fall out if the fuel isn't their,thing is applying T3 topically seemingly is reversed by DIO3.
Flavones can do it,would explain Peats mentioning of them recently in his work,the flavones work both ways as we know.
Taurine possibly according to this linked study-https://raypeatforum.com/community/threads/how-taurine-may-treat-diabetes.9317/#post-120792

I have posted on the forum about these enzymes before,here is one on flavones-https://raypeatforum.com/community/threads/decreased-anxiety-and-depression-like-behaviors-and-hyperactivity-in-a-type-3-deiodinase-deficient.12487/

 

Some information on how d3 and d2 work. Cracking the Code for Thyroid Hormone Signaling

D2 expression is the target of a rapidly growing number of molecules that accelerate energy expenditure and metabolic programs in cells and animal models. These include bile acids (30), flavonols (31), and chemical chaperones (32), which in turn confer protection against diet-induced obesity. Insulin and PPARγ agonists are also bona fide inducers of D2 in skeletal muscle (33). On the other hand, signaling through the D2 pathway is dampened by ER stress (34) and the LXR-RXR pathway (35), the metabolic consequence of which is currently under investigation.


The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation. - PubMed - NCBI

The cAMP-responsive gene for type 2 iodothyronine deiodinase (D2), an intracellular enzyme that activates thyroid hormone (T3) for the nucleus, is approximately threefold upregulated by KPF; furthermore, the activity half-life for D2 is dramatically and selectively increased as well. The net effect is an approximately 10-fold stimulation of D2 activity as measured in cell sonicates, with a concurrent increase of approximately 2.6-fold in the rate of T3 production, which persists even 24 h after KPF has been removed from the system. The effects of KPF on D2 are independent of sirtuin activation and only weakly reproduced by other small polyphenolic molecules such as quercetin and fisetin. These data document a novel mechanism by which a xenobiotic-activated pathway can regulate metabolically important genes as well as thyroid hormone activation and thus may influence metabolic control in humans.

 

The flavanol that targets dio3 and eliminates Rt3 would be well worth trying,not sure the mainstream will be fond of this substance is it appears.
Even the substance you posted is helping against cancer and Dio3 is expressed in tumour cells.