Back to the roots: Causes and effects of elevated DHT

[BigTexasSexy]

Sorry to not really contribute at all, but anyone have an idea as to how big of a role sebum might play in hairloss?

Edit
I found this a while back when I was researching the kind of affect accutane would have on hairloss/regrowth. This is a quote from Squeegee

Taken from immortalhair

Ok I was at my GP not too long ago, an Egyptian doctor who I have been seeing for about a decade.

For the first time we spoke about my hair loss, well well fkn well.. what a surprise when that topic was brought up.

Turns out he used to work for Merck & Sharpe as a researcher back in Egypt and he was booted out for his theory on hair loss. This is no bull****.. this guy was a fkn knowledge machine. All this time!

DHT isn't the cause of hair loss is. Sebum is. This is why:

DHT triggers the glands in your follicle to overproduce sebum. Bacteria gathers in this overflow and your immune system then attacks the bacteria, INCLUDING the hair follicle with inflammation. He said it's very similar to the process of acne.

Propecia works by stopping the DHT triggering the sebum overflow. He said Propecia could make your hair worse if like me hyperandrogenicity causes the extra oil.

He said he proved this theory by putting an early stage patient on low dose accutane. He said the patient regrew hair. He said this is why Retinoid helps, not because it tackles DHT, but because it tackles the sebaceous gland and stops the production of sebum.. hence stopping the gathering of bacteria.. hence no inflammation and no immune response.

I also asked why some medications work and why some don't. He said in theory it should work for all, but there are 2 reasons it doesnt:

1. Internal drugs can cause hyperandrogenicity like I've experienced
2. Topical drugs don't reach the follicle BECAUSE of the sebum build up blocking it. He said minoxidil works best with retin-A not because retin-A helps hair loss through DHT, but helps the minoxidil flow down the follicle wall by eliminating sebum build up.

He said he never really gave it the years of research it deserves, but his theory is ultra-low-doses of Accutane stops hair loss. He said 10mg twice a week will do the job.

He said when he kept trying to push this idea through his experiments, Merck kicked him off the research team."

Squeegee, if you see this I would love to ask you some questions about Coenzyme A

 

[Armando Jose]

But why do you think finasteride isn't administered in bioactive form when applied locally or orally ? For instance Propecia pill contains active ingredient (finasteride) and sugar and other stuff which form film coton. I don't exactly understand biochemistry behind mechanisms and how exactly finasteride inhibit 5ard. Is finasteride decomposed / converted to other enzymes or substances which then bind or adhere to 5ard molecules or ? Can someone who studied and understand biochemistry shed light how exactly is 5ard inhibited by finasteride, does that mean binding (attaching) to 5ard which results in changing of electro-chemical properties (chemical signature is changed, and T doesn't recognise 5ard any more, hence it is disabled to receive two hydrogen atoms to form DHT)

http://www.ncbi.nlm.nih.gov/pubmed/7689728 Finas is a competitive inhibitor of 5 alfa II redictase Finasteride is a synthetic 4-azasteroid that is a specific competitive inhibitor of 5 alpha-reductase, an intracellular enzyme that converts testosterone to dihydrotestosterone (DHT). It has no binding affinity for androgen receptor sites and itself possesses no androgenic, antiandrogenic, or other steroid hormone-related properties. Finas competes with Testosterone when binding to the receptor

 

[Ventures]

This article only describes what is finasteride, but not mechanism how is 5ard inhibited.

Where did you find Finas competes with Testosterone when binding to the receptor - if article clearly says finasteride has no binding affinity for androgen receptor sites and itself possesses no androgenic, antiandrogenic, or other steroid hormone-related properties.


@ BigTexasSexy Hair loss science didn't exclude importance of sebum. I personally think it has a huge role in downstream effects of DHT. But, not all males who have even extremely oily scalp and lots of sebum experience male pattern baldness. So it is rather indirect cause. But I heard it is important to reduce production of sebum and sweat in sebaceous glands for the reason DHT is locally overproduced in those environments.

 

[benjt]

But why do you think finasteride isn't administered in bioactive form when applied locally or orally ? For instance Propecia pill contains active ingredient (finasteride) and sugar and other stuff which form film coton. I don't exactly understand biochemistry behind mechanisms and how exactly finasteride inhibit 5ard. Is finasteride decomposed / converted to other enzymes or substances which then bind or adhere to 5ard molecules or ?

As I said, finasteride not being bioactive was just a hypothesis which I can neither confirm nor rule out. It is just a possibility. Potentially, it is not even known that finasteride itself is not bioactive. It was only found out for minoxidil a few years ago that minoxidil is not bioactive, but in fact only minoxidil sulfate.

Can someone who studied and understand biochemistry shed light how exactly is 5ard inhibited by finasteride, does that mean binding (attaching) to 5ard which results in changing of electro-chemical properties (chemical signature is changed, and T doesn't recognise 5ard any more, hence it is disabled to receive two hydrogen atoms to form DHT)

As far as I understand this is mostly correct; the minor difference in my understanding from yours is that T does not have issues "recognizing" 5ar, but that the 5ar is simply occupied by the inhibitor. Boils down to the same effect though.
Remember how 5ar works: 5ar "flies around" as an enzyme with is dockable by T (just like ARs). When T docks to 5ar, 5ar takes T and converts it to DHT. Finasteride seems to dock to 5ar as well, thus occupying 5ar and blocking from T docking as well. Thus, T stays T instead of becoming DHT.


Unfortunately, I dont think we have biochemists here, but one or two med students.

 

[heisenberg]

From my understanding, Finas is a competitive inhibitor - it therefore competes with Testosterone for the binding site on the enzyme. Once bound, it can just as easily become unbound and Testosterone can then bind.

BUT, the more Finas we have in our body, the less chance there is for Testosterone to bind.

That being said, Finas is NOT a non-competitive inhibitor - it does not change the active site of the enzyme, making testosterone incapable of binding.

 

[Armando Jose]

This article only describes what is finasteride, but not mechanism how is 5ard inhibited.

Where did you find Finas competes with Testosterone when binding to the receptor - if article clearly says finasteride has no binding affinity for androgen receptor sites and itself possesses no androgenic, antiandrogenic, or other steroid hormone-related properties.


@ BigTexasSexy Hair loss science didn't exclude importance of sebum. I personally think it has a huge role in downstream effects of DHT. But, not all males who have even extremely oily scalp and lots of sebum experience male pattern baldness. So it is rather indirect cause. But I heard it is important to reduce production of sebum and sweat in sebaceous glands for the reason DHT is locally overproduced in those environments.

http://www.cmj.org/ch/reader/view_abstract.aspx?volume=126&issue=4&start_page=711

The existing 5a-RIs may be classified into two types: competitive 5a-RI (represented by finasteride) and noncompetitive 5a-RI (represented by epristeride) according to their distinctive action mechanisms. Finasteride affects the first half of the reaction, where it competes with testosterone and combines with 5a-R and coenzyme NADPH to form a binary complex. They then block the conversion of testosterone to DHT. Epristeride affects the second half of the reaction. It combines with the oxidized binary complex which releases DHT to form a stable ternary complex, and prevents 5a-R from being involved in additional reaction cycles.[SUP]18[/SUP] Therefore competitive and noncompetitive 5a-RIs prevent the conversion of testosterone to DHT in entirely different ways.

Finasteride don't bind to androgen receptors all the time....

BTW In my idea sebum production (more or less) is not the problem, the problemn arise when the sebum flow (creation and elimination) stop. When sebum is oxidized

 

[drgs]

My theory is chronically enlarged prostate converts proportially large amounts of T > DHT, ie. the bigger the prostate the more DHT you end up with

What enlarges the prostate? I don't know

 

[Ventures]

So you mean people with male pattern baldness usually have large prostate - BPH ? I guess is there any study showing correlation between BPH and male pattern baldness, both is result of elevated DHT levels in target tissues

 

[odalbak]

About benjt's #2 question, I have no certainty about it but I'm pretty sure lifestyle has an impact on the skin as an independent endocrine organ and therefore on T/DHT conversion. These days I'm enquiring about pre-agricultural hunter gatherer diets.

Results of research conducted at Colorado State University in 2002 by Dr. Loren Cordain, state that while there is a genetic component to male pattern baldness, your diet also plays a part. A diet full of high glycemic carbohydrates, says Dr. Cordain induces a condition called hyperinsulinemia.

Loren Cordain: "While genetic factors seem to play a major role in the development and progression of androgenic alopecia, lifestyle also plays a minor role as demonstrated by the vast increase in male and female pattern baldness in Japan after World War II. A scientific paper our group has written in part addresses male pattern baldness and how a number of studies indicate that high glycemic load diets may set off a hormonal cascade that is characteristic of men with male pattern baldness. To date, no randomized controlled interventions of low glycemic load diets (basically Paleo Diets) have yet been conducted, so we have no human on whether or not a Paleo Diet may be effective in combating male pattern baldness. However, having said this, numerous historical photographs of hunter gatherers rarely if ever depict young or middle age men with male pattern baldness. I have read anecdotal accounts of hunter gatherers who were described in 19th century writings suggesting that premature graying also rarely occurred."

Independent research appears to support Dr. Cordain's claims linking hyperinsulinemia to male pattern baldness. The results of a study published in the general medical journal "Lancet" in 2000 establish a connection between hyperinsulinemia and early onset male pattern baldness, as well as other insulin resistance-associated disorders such as obesity, high blood pressure and dyslipidemia, or an abnormal amount of fat in the blood. (livestrong.com, 2011)

Hair loss could be yet another sign of the cascade of detrimental effects that are part of the metabolic derangement known as “Syndrome X”. Is it possible that the Paleo diet could prevent hair loss if it provides proper nutrition? There is the old school of thought that offered the theory that high levels of insulin in the blood is the root cause of hair loss. High levels of Sex Hormone Binding Globulin (SBGH) limit the negative effects of DHT, by binding to free testosterone, which blocks the conversion of testosterone to DHT. On the inverse, high levels of insulin lowers the levels of SBGH, which allows more testosterone to be converted to DHT and damage hair follicles. Put simply, lots of insulin allows lots of DHT to be made. Studies show that people who are insulin resistant, or diabetic have a significantly higher incidence of hair loss. Coincidently, people who are balding have a significantly higher risk of heart disease. Because of this theory, it’s obvious that hair loss is yet another condition that is caused by poor eating habits, since insulin resistance is typically established after years of over-consumption of sugars and processed carbohydrates. (paleodietnews.com, 2011)

Studies show that people who are insulin resistant, or diabetic have a significantly higher incidence of hair loss. Why? With insulin resistance you have astronomically high amounts of insulin in your system. High levels of insulin significantly lower if not totally cut off two other hormones, Glucagon, the insulin’s adversary (also produced in the same part of the pancreas) which removes artherosclerotic plaques, lowers triglycerides and improves overall blood flow, and SHGB (Sex Hormone Binding Globulin). Without SHGB, testosterone is free to be converted into DHT. When SHBG is not in the blood stream in optimal quantity, a lot of this free testosterone in excess may be converted in the scalp to DHT. Less SHBG means much more free testosterone therefore more DHT in the bloodstream. Hence my opinion that high levels of insulin, and even worse insulin resistance, may be the central cause of hair loss. People will come back at me with the fact that 1. many balding people are not actually insulin resistant. and 2. some insulin resistant people are not balding. My responses would be 1. Some people are obviously less tolerant of high insulin levels than others and 2. this is where the genetic factor of baldness comes in. Androgens. The people who are insulin resistant but are not balding lack the Alpha reductase and androgens to convert it to DHT locally. If you have elevated insulin levels, and DO have the capacity to convert Testosterone to DHT locally, you will bald. (healthmad.com, 2012)

 

[drgs]

So you mean people with male pattern baldness usually have large prostate - BPH ? I guess is there any study showing correlation between BPH and male pattern baldness, both is result of elevated DHT levels in target tissues

A large part of DHT is synthesized in the prostate, which again makes it grow… Kind of a bad loop here.

 

[benjt]

The vast majority of the DHT leading to our hairloss, though, is produced locally in the scalp. It has nothing to do with the prostate, at least as far as research goes in this field.

 

[Ventures]

The vast majority of the DHT leading to our hairloss, though, is produced locally in the scalp. It has nothing to do with the prostate, at least as far as research goes in this field.

So in your opinion, DHT has effects only in tissues were it is locally produced which is characteristic of autocrine hormone. For DHT formation 5ard is required to be present in target tissues. Majority of 5ard is prouduced locally in prostate, testis, hair follcles ?

Do you maybe have clue what sort of mechanisms are important for body to start producing 5ard ? I am aware of fact that DHT is response to low T levels which happens in old age. This starts to be separate topic, but I want to get more informations regarding control mechanisms of endocrine system.

• How exactly 5-alpha-reductase (5ard) enzyme is produced or synthesized in tissue?

• What feedback mechanism decides how many 5ard will be produced ?

Last quesion is very significant since level of DHT hormone is among other things regulated by T level. When there is decrease in total T level, body produces more 5ard to convert T to its more potent DHT to cover loses. But in the same way, following is what happens when using finasteride or dutasteride; body notice lack of DHT and produce more T to compensate it. But if body can increase T production when there is decrease in DHT level, why body in first place produce DHT if it can up or down regulate production of pure T regardless of DHT ?


Can someone propose some literature except Wikipedia for beginners?

 

[benjt]

Unfortunately, the matter is not that easy, and 5ar hasnt even been figured out by science 100%. I'll try to summarize, first regarding DHT (the easy part, 5ar is much less clearer to me):

You have to distinguish between serum DHT and local DHT. Serum DHT, seldomly referred to as system DHT, provides the body with a certain base level of DHT. As it is in your serum, it is transported by the same. It is produced mostly by the testes, like its precursor testosterone. T and DHT transport happens through SHBG (which is why some approaches at stopping Androgenetic Alopecia/male pattern baldness try to reduce SHBG).
Then there's tissue/local DHT. It is produced by 5ar locally - depending on where this is, there may be a lot of 5ar (e.g., in the scalp, in the prostate, or in the testes and seminal vesicles).

5ar is mostly locally expressed, though local production of DHT through 5ar can then be supplied to the serum (as is the case with prostate- and testes (incl. seminal vesicles)-produced DHT - as far as I know they produce most of the serum DHT with their local 5ar). This DHT makes most of the base level of DHT in our body.
Then there's also 5ar expressed in the human scalp. Thus, DHT is produced locally from free/serum testosterone. This DHT is however not resupplied to the serum.
Just like in the scalp, by the way, men also produce DHT in most of their skin in general - the reason why we have body hair.

The question for us Androgenetic Alopecia/male pattern baldness sufferers is: Is there effectively more 5ar in our scalp than in the scalp of non-Androgenetic Alopecia/male pattern baldness sufferers, or is our scalp tissue more sensitive to DHT in general and we produce "normal" amounts of 5ar and DHT?

How exactly 5-alpha-reductase (5ard) enzyme is produced or synthesized in tissue?

I'm not a chemist or biologist, so I'll not try to explain this as I don't think I understand it completely. If you find anything, please report it back.

What feedback mechanism decides how many 5ard will be produced ?

Good question which I also can't answer unfortunately. The next question is: Is 5ar production higher in the scalp of people suffering from Androgenetic Alopecia/male pattern baldness (case 1), or do we produce normal amounts of 5ar and thus DHT but our scalp reacts oversensitively to these normal amounts of DHT produced by normal amounts of 5ar?

Either way: Keep up the great work. We need to go about these questions systemically. And you're asking all the right questions.
Please keep me updated on your findings.


Edit: You might want to take a look at this thread where I tried to put together everything that I knew in one big model. Please use the information in that model with great caution: The model does not depict causality but only correlation, and it makes no statements about whether that correlation is big or not. Some of the edges in that model may be completely meaningless as their effect is negligible.
It is just an accumulation of all factors I could find, no matter how small their influence. Some have almost none at all (like dietary factors), others may have very big ones (like finasteride, minoxidil, etc.).
The model is also quite old. I did not include all the new findings that have been published since November 2013, mostly regarding Dkk-1.
Note that in the model there is nothing indicating what might lead to 5ar being increased in our scalp (as compared to "normal" scalp, i.e. that of non-Androgenetic Alopecia/male pattern baldness people). That however does not mean that 5ar is not abnormally elevated in our scalp. I simply didnt find anything at that time. 5ar might be very high, or it might be normal and only our reaction to DHT is abnormally high.

 

[Ventures]

@benjt Thank you for great explanation. I will post studies which I consider important. Yes, there are still many unanswered questions and science haven't yet managed to explain all facts regarding male pattern baldness. Besides in medicine and biochemistry it doesn't always need to be true that 1+1 equals 2. You know what I mean...


Do you agree with @odalbak low SHBG raises free T, and in individuals with expressed activity or 5ard there is increase in DHT. So, in order to suppress DHT it is advisable to increase SHBG ?

 

[benjt]

Besides in medicine and biochemistry it doesn't always need to be true that 1+1 equals 2. You know what I mean...

I know exactly what you mean. Though the problem is much bigger with scientists with a background in medicine than with publications with their authors having a background in biochemistry. I'd (almost) always trust a biochemist over a med when the two are in disagreement.

Do you agree with @odalbak low SHBG raises free T, and in individuals with expressed activity or 5ard there is increase in DHT. So, in order to suppress DHT it is advisable to increase SHBG ?

I tend to disagree, but let me elaborate. SHBG is the main means of transport for T. Occasionally, T will de-bind from SHBG and become free - but if there are no androgen receptors around, it will quckly rebind to SHBG. The affinity of T to androgen receptors is bigger than to SHBG, which ensures that SHBG will serve as a means of transportation for T and not bind T forever. If T would prioritize binding to SHBG (i.e. T affinity for SHBG was higher) over binding to androgen receptors, T would simply not be able to do its workings. It would be glued to SHBG forever and not activate androgen receptors.
Probably (it makes sense, but I dont have a source for that) 5ar is also priorized by T over SHBG. Makes sense because otherwise 5ar wouldnt be able to convert T to DHT, if T would just bind to SHBG which is virtually everywhere.

That being said, I can now explain why I disagree with odalbak in that matter:
Low SHBG may raise free T, but that will likely not result in increased DHT. If 5ar is around, T will bind to 5ar anyway.

Additionally - and that is the most important point here - take into account that DHT is produced locally all over the body (in high doses in the testes, prostate, and in Androgenetic Alopecia/male pattern baldness sufferers probably in the scalp; and in low doses in almost all of our skin), but T is almost exclusively produced in the testes.
As a consequence, for local DHT production, T needs to get there first (as T is not produced where DHT is produced). So in the case of the scalp, for the scalp to produce DHT (which we want to avoid!), T needs to be transported there some way, as the scalp does not have T otherwise. And how does the T get transported to the scalp? By binding to SHBG. You can imagine SHBG as the "bus" the T gets on to drive to its destinations all over the body, including the scalp.
If we lower SHBG, T will be delivered only in lower amounts to the rest of the body, and in the case of the scalp there will be less DHT as the supply of T is lower.
Thus, in theory, it should be beneficial to lower SHBG. We can make sure that DHT cannot be produced locally if we prohibit T from getting to the DHT production site.

One or two papers actually theorized that the beneficial effects of some forms of tea to slow down hair loss (I think they were on black tea) are because the tea lowers SHBG.

 

[I.D WALKER]

I'm familiar with a Harvard mice study conducted maybe 3 years that showed that black tea (camellia sinensis) and black tea extract decreased DHT levels by an impressive 72% and T levels 34%. If my memory is accurate I believe Finasteride lowers DHT in male men by 71% and T maybe by 10%? Naturally I'm very intrigued as to what impact if any BT or BTE may have on humans. Thanks for sharing.

 

[Armando Jose]

Good inputs....
BTW, what happen with scalp hair in childrens before puberty?
Clearly T is not circulating in the blood (no sebum in the body except the hairy zone), but sebaceous gland is operative, (hair shaft needs sebum to break the ORS in the infundibulum) and SG need Testosterone to make DHT, what use to syntehtize Testosterone? Cholesterol it is a possible with enzymes in this zone, that is traveling in the blood.
This is one of my keys to try to understand the process of common alopecia, ....., acording to the current theory, hairloss is only after puberty when androgens reach to the hairs in suscepted genetical persons, and it is 90% clear that androgens are present in scalp hairs years before puberty.......
What do you think? Comments are wellcome

 

[peacemaker]

Good inputs....
BTW, what happen with scalp hair in childrens before puberty?
Clearly T is not circulating in the blood (no sebum in the body except the hairy zone), but sebaceous gland is operative, (hair shaft needs sebum to break the ORS in the infundibulum) and SG need Testosterone to make DHT, what use to syntehtize Testosterone? Cholesterol it is a possible with enzymes in this zone, that is traveling in the blood.
This is one of my keys to try to understand the process of common alopecia, ....., acording to the current theory, hairloss is only after puberty when androgens reach to the hairs in suscepted genetical persons, and it is 90% clear that androgens are present in scalp hairs years before puberty.......
What do you think? Comments are wellcome

Interesting post, can you prove though that androgens exist at pre-puberty periods? Isn't there a huge gap between the amount of both systematic and local scalp DHT between those two periods?

Also, isn't there also a difference between the amount of growth factors? Even though androgens might be present during initial years, there is a plethora of growth factors as humans grow in every aspect. Both growth factors and androgens top off during puberty. Afterwards, growth subsides, whereas androgens still remain.

 

[benjt]

I'm familiar with a Harvard mice study conducted maybe 3 years that showed that black tea (camellia sinensis) and black tea extract decreased DHT levels by an impressive 72% and T levels 34%. If my memory is accurate I believe Finasteride lowers DHT in male men by 71% and T maybe by 10%? Naturally I'm very intrigued as to what impact if any BT or BTE may have on humans. Thanks for sharing.

I think it was one of those mice studies or a follow-up study saying that it might be the SHBG decrease that leads to this decrease in DHT. And I guess through my explanation from my last post it is obvious why SHBG would lead to a decrease in DHT.

The problem with black tea is that it distributes its effects all over the body instead of having a big impact in one spot. Instead of just blocking T supply to (or DHT production in) our scalps, it lowers T in equal parts all over the body. Thus, it has effects everywhere - but not very big ones. These are probably (not definitely!) not big enough for substantially slowing hairloss.
If you drink large amounts of black tea, by the way, you increase your chances of infertility and prostate cancer - this hints at the black tea messing with DHT biosynthesis all over the body.

BTW, what happen with scalp hair in childrens before puberty?
Clearly T is not circulating in the blood (no sebum in the body except the hairy zone), but sebaceous gland is operative, (hair shaft needs sebum to break the ORS in the infundibulum) and SG need Testosterone to make DHT, what use to syntehtize Testosterone?

According to Wikipedia until the age of 4 to 6 months (!!) androgen levels in children are as high as in puberty:

In the first weeks of life for male infants, testosterone levels rise. The levels remain in a pubertal range for a few months, but usually reach the barely detectable levels of childhood by 4–6 months of age.

acording to the current theory, hairloss is only after puberty when androgens reach to the hairs in suscepted genetical persons, and it is 90% clear that androgens are present in scalp hairs years before puberty.......

As stated in the Wikipedia article, T levels are very high until 4 to 6 months. Then they drop rapidly and only increase again in puberty.

 

[Armando Jose]

"According to Wikipedia until the age of 4 to 6 months (!!) androgen levels in children are as high as in puberty:"
Exactly, and regarding hair growth, it is the possible reason that we born with hair, but, then at 1/2 year the androgens level drop in all the body, except, in my opinion, in the neighbouring of pilosebaceous unit in scalp hairs.

Androgens only will exist near scalp hairs before puberty, if they could move to other zones, will make grow body hair...., do you read studies regarding childrens in contact with androgens cream?

It is very interesting know very well this issue in order to know which is the trigger and initial cause of the named androgenetic alopecia , or better said common hairloss

Peacemaker, pilosebaceous unit is very complex, you know, and the if childrens have a good hair is possible due a total operative mechanims as in afters years, exactly the same network, including androgens, growts factors, etc There is no differences, and, also very interesting, no differences between sexes.
My theory apply the equality of all scalp hairs, even in different sexes.