Rambling theory of why 5-AR therapy benefit limited

[Cornholio]

Although Ive done a lot of reading about finasteride and dutasteride tonight is the first night that I've put two pieces of information together... Two facts...

1) The concentration of DHT in adult male serum is only about 10% of the value for testosterone.

2) DHT binds androgen receptors approximately 10x as strongly as testosterone.

As it seems that DHT and testosterone bind the same androgen receptors (there aren't specific DHT or testosterone receptors) then in the "normal" man about 1/2 of androgen stimulation comes from testosterone and 1/2 from DHT. ?True? (because while there is only 10% as much DHT as testosterone it is 10x as strong equaling the stimulation of testosterone).

SO, if .5mg dutasteride reduces serum DHT by 90%, then overall androgen stimulation is initially reduced to about 55% of normal in the body (if testosterone is unchanged). The body responds to .5 mg of dutasteride by increasing serum testosterone 27%, so overall serum androgen activity would be guestimated to be about 68% normal.

Finasteride reduces serum DHT by around 70% reducing androgen activity to around 65% of normal. The body responds by increasing testosterone by around 4% leaving overall serum androgen activity at around 67% of normal.

Higher doses of dutasteride 2.5 mg reduces serum DHT by 96%, reducing overall androgen activity to 52% normal. The body compensates by increasing serum testosterone by 27%, leaving overall serum androgen activity at about 65% of normal.

This guestimating suggests that all 5-ar inhibitors (finasteride, dutasteride) reduce serum androgen activity by approximately the same amount 65-68% (because of the compensatory "reflex" increase in testosterone). It is not suprising then that side-effects for finasteride and dutasteride are therefore very similar in studies. It is also (unfortunately) not suprising that dutasteride is not wildly better than finasteride... For despite its greater decrease in DHT compensatory mechanisms increase testosterone to balance out and limit reduction of serum androgen to about 65-69% normal regardless of the drug or dose used : ( .

This points out there is a definite limit to the efficacy of 5-ar therapy. To address androgens further testosterone has to be addressed. This can only be done by inducing systemic side effects (castration, oral spironolactone, flutamide...) or using topical anti-androgens (spironolactone, fluradil, 5-fu...).

I'll quit now... Didnt know this would carry on so long but it does explain some things for me anyway. PS. Some of the numbers (changes in DHT and testosterone) are pulled from the following study....
http://www.regrowth.com/hairloss-remedy ... esults.cfm

 

[everysixseconds]

nice!

BUT, you neglect to account for the fact that it has been proven the androgen-sensitive, pre-male pattern baldness hair follicles are not susceptible to testosterone. its only when DHT comes on to the scene that baldness sets in. However, it has also been proven that testosterone does contribute to male pattern baldness after it has set in. So, we can conclude that male pattern baldness follicles ARE sensitive to testosterone, but not by the the figure that you have guestimated. ie in the context of a hair follicle, testosterone is is MORE than 10x less potent. consequently, your figures of 65-68% may need revising.

However, i loved your theory. you attempt at quantifying this problem is fascinating.

 

[Bryan]

BUT, you neglect to account for the fact that it has been proven the androgen-sensitive, pre-male pattern baldness hair follicles are not susceptible to testosterone.

Really? How, when, and where was that "proven"?

Bryan

 

[Cornholio]

Im glad somebody read this... Thankyou guys . I felt like a researcher for a minute : ) I was just playing with the numbers and suprised myself by finding that the actual increase in testosterone (from studies) actually fit the theoretical formula and "balanced out" the decrease in DHT with increase in testosterone to match the amount of androgen deprivation lost by DHT reduction at the 68% normal point regardless of which drug you take. That would be the pituitary system working...

The real caveat regarding hair loss is that the androgen activity at the hair follicle may not exactly reflect the serum androgen activity which was documented in the above post ( by cornholio et al : ) because there is potentially more DHT in the scalp and follicle than there is in the serum due to local conversion of testosterone to DHT in the hair follicle and sebaceous glands... So, while serum androgen activity balances out, the further DHT reduction in the scalp available with dutasteride (more than finasteride) may in fact continue to lower local scalp or follicle androgen activity toward that of the serum because androgen activity ?is? higher at the follicle than the serum due to local 5AR activity.

This "local" androgen activity (testosterone and DHT levels at the level of the follicle itself) has not been directly or acccurately measured. The closest numbers available include measures of scalp DHT activity from the Phase II avodart study, but it groups together DHT produced in the sebaceous glands and that produced in the follicle. It is not proven how much hair loss is affected by serum vs local (interstitial) DHT levels, so it is unclear which numbers are most relavent.

IF scalp levels of DHT are more closely related to alopecia than serum levels are, and IF scalp levels of DHT are best reported in the avodart phase II study http://www.regrowth.com/hairloss-remedy ... esults.cfm
Then the following percentages are more relevant to hair loss...

"Scalp DHT was decreased 38% for Finasteride, 54% for .5mg Dutasteride, and 82% for 2.5mg dutasteride." " Rittmaster concluded that these results show that most of the DHT in the scalp comes from type 1 5-alpha reductase." Again, whether all of the DHT measured is affecting hair loss is not known (does the dht in the sebaceous gland affect the very nearby follicle? maybe but not proven).

"Scalp Testosterone rose 24% for Finasteride, 104% for 0.5mg Dutasteride, and 154% for 2.5mg Dutasteride." Why it rises at a rate different than the serum is not clear to me... ?is it locally produced? ?is it accumulated or stored in the scalp? ?are the numbers accurate?

Without the actual measured concentrations and units of scalp DHT and Testosterone, which werent available in the online abstract, you cant do the same calculation of "androgen activity" in the scalp to see how the drugs affect the balance... I am interested enough to actually think about going to a library and finding the study to see if actual units were reported on a table in the full study (is that geeky? : ) I'll let you know if i do do the same calculation on androgen activity with scalp numbers. With the robust increase in scalp testosterone when DHT is reduced in the scalp I would be curious to see if in fact androgen activity again seems to "balance" in the scalp with 5-ar supression. If so then the point would be the same... there there is a ceiling effect of androgen blockade available with 5AR therapy, and that addressing androgens locally (topically) is the best way to get further androgen blockade (rather than mega-doses of dutasteride which might have deminishing returns).

Man, that was long too... I need a hobby : )
________________________________________________________
"The imagination is more important that the fact"

 

[Bryan]

The real caveat regarding hair loss is that the androgen activity at the hair follicle may not exactly reflect the serum androgen activity which was documented in the above post ( by cornholio et al : ) because there is potentially more DHT in the scalp and follicle than there is in the serum due to local conversion of testosterone to DHT in the hair follicle and sebaceous glands... So, while serum androgen activity balances out, the further DHT reduction in the scalp available with dutasteride (more than finasteride) may in fact continue to lower local scalp or follicle androgen activity toward that of the serum because androgen activity ?is? higher at the follicle than the serum due to local 5AR activity.

Exactly. I basically agree with you on that, but the problem is that you don't go nearly FAR ENOUGH with that idea! The level of DHT in the blood is almost certainly MUCH lower than it is in target organs, because it's eliminated fairly rapidly once it hits the bloodstream. Furthermore, it's not the BLOOD levels of androgens we should be worried about, it's the FOLLICULAR levels that concern us! And without really knowing the numbers for follicular levels of T and DHT, it's virtually impossible to do an accurate analysis like you attempted above for the bloodstream.

This "local" androgen activity (testosterone and DHT levels at the level of the follicle itself) has not been directly or acccurately measured. The closest numbers available include measures of scalp DHT activity from the Phase II avodart study, but it groups together DHT produced in the sebaceous glands and that produced in the follicle. It is not proven how much hair loss is affected by serum vs local (interstitial) DHT levels, so it is unclear which numbers are most relavent.

I've said it a hundred times: I have no confidence at all in Rittmaster's numbers, because they've been contradicted by another study. We don't know who's right and who's wrong, so it's pointless even speculating about it.

Without the actual measured concentrations and units of scalp DHT and Testosterone, which werent available in the online abstract, you cant do the same calculation of "androgen activity" in the scalp to see how the drugs affect the balance... I am interested enough to actually think about going to a library and finding the study to see if actual units were reported on a table in the full study (is that geeky? : )

HUH?? There IS no study. Those results of Glaxo's and Rittmaster's testing were simply reported at a sort of medical "news conference". To the very best of my knowledge, there's never been anything published about that testing in a medical journal article.

Bryan

 

[Cornholio]

HUH?? There IS no study. Those results of Glaxo's and Rittmaster's testing were simply reported at a sort of medical "news conference". To the very best of my knowledge, there's never been anything published about that testing in a medical journal article.

Bryan

Oh. I just assumed that the percentage changes of scalp DHT and Testosterone reported in the link http://www.regrowth.com/hairloss-remedy ... esults.cfm had actual available numbers behind them.... (Rittmaster's results from the link). Those were the results I would look for. But since you've said that others have reported much different results for "scalp DHT" with dutasteride and finasteride there may not be much point in looking into it, as all available results are debatable.

 

[S Foote.]

BUT, you neglect to account for the fact that it has been proven the androgen-sensitive, pre-male pattern baldness hair follicles are not susceptible to testosterone.

Really? How, when, and where was that "proven"?

Bryan

Why can't you just be honest in these debates Bryan?

You know very well that this was proven in the macaque study we have debated many times!

http://endo.endojournals.org/cgi/content/full/138/1/356

S Foote.

 

[Cornholio]

From the link... "The inhibitory effects were shown only when bald frontal dermal papilla cells from postpubertal macaques and outer root sheath cells were cocultured in the same wells of multiplates (Table 1). The total number of outer root sheath cells cocultured with either type of dermal papilla cells increased by more than the sum of the number of dermal papilla cells and outer root sheath cells cultured alone. Testosterone (10-10 M) significantly decreased the total number of bald frontal dermal papilla cells and outer root sheath cells in coculture. RU 58841 antagonized this testosterone-elicited inhibition. By contrast, the total cell numbers in cocultures of prebald frontal or occipital dermal papilla cells and outer root sheath cells were not affected by testosterone. Testosterone (10-10 M) had no effect on proliferation of outer root sheath cells cultured alone. "

"This in vitro study also reconfirms that the frontal hair follicle of stumptailed macaques is an androgen-dependent organ, showing direct effects of testosterone on epithelial cells cocultured with bald frontal dermal papilla cells. Other androgen-regulated factors may be isolated in further studies. To the best of our knowledge, this is the first paper demonstrating the inhibitory effect of testosterone on the proliferation of outer root sheath cells cocultured with dermal papilla cells derived from the bald frontal scalp. "

The way I read it, when follicle cell types are co-cultured testosterone DOES have an inhibotory effect in older/mature follicles from an animal succeptable to balding... Showing that while isolated dermal papilla cultures are not androgen sensitive and that prebald (young) cultures are not sensitive, bald (older) cocultured (varied cell types) do show inhibition with testosterone. That would seem to be the invivo model most relavent to us older balding monkeys with multiple cell types in our follicles. But please, fight it out :wink:

 

[S Foote.]

From the link... "The inhibitory effects were shown only when bald frontal dermal papilla cells from postpubertal macaques and outer root sheath cells were cocultured in the same wells of multiplates (Table 1). The total number of outer root sheath cells cocultured with either type of dermal papilla cells increased by more than the sum of the number of dermal papilla cells and outer root sheath cells cultured alone. Testosterone (10-10 M) significantly decreased the total number of bald frontal dermal papilla cells and outer root sheath cells in coculture. RU 58841 antagonized this testosterone-elicited inhibition. By contrast, the total cell numbers in cocultures of prebald frontal or occipital dermal papilla cells and outer root sheath cells were not affected by testosterone. Testosterone (10-10 M) had no effect on proliferation of outer root sheath cells cultured alone. "

The way I read it, when follicle cell types are co-cultured testosterone DOES have an inhibotory effect in balding follicles... Showing that while isolated dermal papilla cultures are not androgen sensitive and prebald (young) cultures are not sensitive, bald (older) cocultured (varied cell types) do show inhibition with testosterone. That would seem to be the invivo model most relavent to us older balding monkeys with multiple cell types in our follicles. But please, fight it out :wink:

There is only really one point `proven' in that study that should concern people.

That is that when cell samples from follicles known to be `future' male pattern baldness, are treated with androgens, nothing happens!

This `DIRECT' exposure to androgens that is `suppose' to change these normal follicles into male pattern baldness follicles, just dosen't happen.

The current theory says these follicles are `different' in that androgens `CAUSE' these to become growth restricted (male pattern baldness).

But androgens `DONT' do what the currect theory `NEEDS', so the supporters of the current theory have to make up `magic' un-precedented mechanisms to try to explain the `actual' experimental results!

This tactic would be laughed at in mainstream science!

S Foote.

 

[Cornholio]

It does make sense if you accept that age (time) is also a factor in development of male pattern baldness... Hair loss is dependant not just androgen level but the age of the organism. That seems to be supported by this study, as there is a different response from young (balding resistant) and older (balding succeptable) follicles. A cell age factor would explain how a person survives the androgen surge of puberty with an intact hairline (the follicles are not aged and succeptible to androgen induced atrophy yet) yet develops male pattern baldness 5 or 10 or 30 years later. How can time be a factor? That is another question but cells are sensitive to time and for many cells there is a limit to the number of divisions they are allowed... I think teleomeres have been shown to have something to do with how cells can "keep track of" and deteriorate with time. This study might demonstrate that if the "young" cell lines are kept in culture and exposed to androgens in another 10 or 20 years....

 

[Bryan]

BUT, you neglect to account for the fact that it has been proven the androgen-sensitive, pre-male pattern baldness hair follicles are not susceptible to testosterone.

Really? How, when, and where was that "proven"?

Bryan

Why can't you just be honest in these debates Bryan?

You know very well that this was proven in the macaque study we have debated many times!

http://endo.endojournals.org/cgi/content/full/138/1/356

Actually, it never even occurred to me that THAT was possibly what "everysixseconds" was referring to. I assumed that he was referring to the perennial question of whether it's only DHT which causes hairloss, or whether testosterone can also do the job.

I hope he clarifies what he meant himself, rather than just let YOU speak for him.

Bryan

 

[Bryan]

It does make sense if you accept that age (time) is also a factor in development of male pattern baldness... Hair loss is dependant not just androgen level but the age of the organism. That seems to be supported by this study, as there is a different response from young (balding resistant) and older (balding succeptable) follicles. A cell age factor would explain how a person survives the androgen surge of puberty with an intact hairline (the follicles are not aged and succeptible to androgen induced atrophy yet) yet develops male pattern baldness 5 or 10 or 30 years later. How can time be a factor? That is another question but cells are sensitive to time and for many cells there is a limit to the number of divisions they are allowed... I think teleomeres have been shown to have something to do with how cells can "keep track of" and deteriorate with time.

Well, it obviously doesn't have anything to do with aging per se, because even very elderly body hair follicles continue to be stimulated by androgens (at least, as far as I know). So the fundamental paradox remains: why do most hair follicles around the body respond POSITIVELY to androgens, while those on the scalp apparently start out neutral, but then over time (after puberty has been reached) start to react NEGATIVELY? Nobody knows the exact reason(s) for that yet, although scientists are working on it.

In the meantime, it's better to avoid those cranks on the Internet with eccentric theories about male pattern baldness! :wink:

Bryan

 

[everysixseconds]

It does make sense if you accept that age (time) is also a factor in development of male pattern baldness... Hair loss is dependant not just androgen level but the age of the organism. That seems to be supported by this study, as there is a different response from young (balding resistant) and older (balding succeptable) follicles. A cell age factor would explain how a person survives the androgen surge of puberty with an intact hairline (the follicles are not aged and succeptible to androgen induced atrophy yet) yet develops male pattern baldness 5 or 10 or 30 years later. How can time be a factor? That is another question but cells are sensitive to time and for many cells there is a limit to the number of divisions they are allowed... I think teleomeres have been shown to have something to do with how cells can "keep track of" and deteriorate with time.

Well, it obviously doesn't have anything to do with aging per se, because even very elderly body hair follicles continue to be stimulated by androgens (at least, as far as I know). So the fundamental paradox remains: why do most hair follicles around the body respond POSITIVELY to androgens, while those on the scalp apparently start out neutral, but then over time (after puberty has been reached) start to react NEGATIVELY? Nobody knows the exact reason(s) for that yet, although scientists are working on it.

In the meantime, it's better to avoid those cranks on the Internet with eccentric theories about male pattern baldness! :wink:

Bryan

no, no! these eccentric ideas are good! keep em comin. im always glad to hear people sharing ideas on male pattern baldness, watever they maybe, and throwing em up for discussion and debate. its good stuff. im sure deep inside, you are too bryan!

 

[Footy]

It does make sense if you accept that age (time) is also a factor in development of male pattern baldness... Hair loss is dependant not just androgen level but the age of the organism. That seems to be supported by this study, as there is a different response from young (balding resistant) and older (balding succeptable) follicles. A cell age factor would explain how a person survives the androgen surge of puberty with an intact hairline (the follicles are not aged and succeptible to androgen induced atrophy yet) yet develops male pattern baldness 5 or 10 or 30 years later. How can time be a factor? That is another question but cells are sensitive to time and for many cells there is a limit to the number of divisions they are allowed... I think teleomeres have been shown to have something to do with how cells can "keep track of" and deteriorate with time.

Well, it obviously doesn't have anything to do with aging per se, because even very elderly body hair follicles continue to be stimulated by androgens (at least, as far as I know). So the fundamental paradox remains: why do most hair follicles around the body respond POSITIVELY to androgens, while those on the scalp apparently start out neutral, but then over time (after puberty has been reached) start to react NEGATIVELY? Nobody knows the exact reason(s) for that yet, although scientists are working on it.

In the meantime, it's better to avoid those cranks on the Internet with eccentric theories about male pattern baldness! :wink:

Bryan

If that is a sarcastic reference to my theory Bryan, people reading this should be aware that professional scientists don't think my theory is `eccentric' as you well know!

So why don't you tell everyone here just what qualifies `YOU' to judge scientific theory's in the first place??

What is your training and education in science Bryan?

If you don't answer this, as you usually don't, then please just have the good grace to keep quite about things you just don't understand will you!

S Foote.

 

[Cornholio]

Bryan.... If, however, you are referring to my eccentric theory, please be impressed that it took only an hour to come up with and I recieved no funding whatsoever. I can come up with more theories, if properly compensated.

Teaser Theories... Pending funding

1) Computer Monitor Rays contribute to frontal balding...
2) It is the ethanol in hair loss topicals, not the minoxidil or spironolactone, that causes regrowth for some. Oral ethanol works too, explaining why street people have nice hair.
3) Powerful Women's Libbers, Scientologists (Tom Cruise, John Travolta), Big Pharm, and Big media have joined forces glorify an effeminate version of male beauty (with pubescent hairlines), emasculating and depowering men. Antiandrogens like propecia are part of Phase I. Phase II involves mandatory castration for all men (and mandatory pec, chin, penile and calf implants).
4) George lucas has the cure for male pattern baldness (note his hairline) on Skywalker Ranch... Wookies were stage-hands who tested the early "not ready for lucas consumption" batches. Yoda (a Propecia boy) also had disappointing results.
5) Pressure kills follicles... explaining why men and women who sleep on their backs experience crown balding, while men and women who sleep on their stomachs with their heads turned left experience only right temple balding. Men and women who walk and sleep upright experience no balding. Because of lack of gravity in space all intergalactic travelers will develope baldness due to increased cephalic capilary pressure... This is why all aliens are bald when they arive here.
6) Country Music predisposes Westerners to male pattern baldness... However Country Music sung on Karaoke with a bad accent is protective from male pattern baldness (explaining geographic differences).


Please send funds by paypal or cashiers check...

 

[Bryan]

Bryan.... If, however, you are referring to my eccentric theory, please be impressed that it took only an hour to come up with...

NO NO NO NO NO NO NO NO NO NO NO NO NO NO!!!!!!!

I wasn't referring to YOUR theory, Cornholio, I was referring to a certain cuckoo theory around here that should have long since been dispensed with, after it had its allotted 15 minutes of fame! :wink:

Bryan

 

[Cornholio]

Oh, OK... Well, Im tired of being a hair scientist anyway (unless any of the above ideas pan out). My last idea would be a pay-for-view cage match with S.Foote vs Bryan, bare nuckles. Think about it : )

 

[Armando Jose]

Hi guys;

Bryan write:
So the fundamental paradox remains: why do most hair follicles around the body respond POSITIVELY to androgens, while those on the scalp apparently start out neutral, but then over time (after puberty has been reached) start to react NEGATIVELY? Nobody knows the exact reason(s) for that yet, although scientists are working on it.



Cornholio write:
The real caveat regarding hair loss is that the androgen activity at the hair follicle may not exactly reflect the serum androgen activity which was documented in the above post ( by cornholio et al : ) because there is potentially more DHT in the scalp and follicle than there is in the serum due to local conversion of testosterone to DHT in the hair follicle and sebaceous glands... (snip)


… This "local" androgen activity (testosterone and DHT levels at the level of the follicle itself) has not been directly or acccurately measured. The closest numbers available include measures of scalp DHT activity from the Phase II avodart study, but it groups together DHT produced in the sebaceous glands and that produced in the follicle. It is not proven how much hair loss is affected by serum vs local (interstitial) DHT levels, so it is unclear which numbers are most relavent.



I also failled looking for a unequivocal experiment in order to determinate the amount of androgens in scalp in prepubertal. Then, how is possible bet a “fortuneâ€￾ in the current theory?? Acording to my own theory androgens must exist in scalp hairs before puberty. If I am wrong please, anyone could enligthen me?.


And finally I don’t share with Bryan in “ it's better to avoid those cranks on the Internet with eccentric theories about male pattern baldness!â€￾

All time is good to develop a new concept to understand biology. Stephen’s or Cornholio theory is neccesary.

Best regards
Armando

 

[Boru]

Is DHT converted from testosterone mainly in the testes or the adrenal glands, or both, or variable? DHT can only reach the follicles through the bloodstream, in conjuction with oxygen of course. I assume that this is a protein derived hormone, as it binds to receptors on the outside of the cell membrane, unlike steroid and tyrosine hormones, which pass inside the cell.
Much more detail is needed on the origins and activity of DHT, how does it work, how do we stop it working so effectively? My routine is certainly working a treat, but I can't fully explain it, YET!
Boru

 

[Bryan]

Is DHT converted from testosterone mainly in the testes or the adrenal glands, or both, or variable? DHT can only reach the follicles through the bloodstream, in conjuction with oxygen of course.

You must be a newbie, Boru! :wink: DHT is produced in several locations around the body, including the testes, prostate, liver, kidney, brain (probably), sebaceous glands, and HAIR FOLLICLES. That's the main cause of balding: the follicular conversion of testosterone to DHT. To say that DHT can ONLY reach follicles through the bloodstream shows that you've got a lot to learn about hairloss theory. BTW, I'm not trying to be mean when I say that, I'm just flabbergasted that you'd say what you did, after all the technical discussions we've had on these hairloss sites...

I assume that this is a protein derived hormone, as it binds to receptors on the outside of the cell membrane, unlike steroid and tyrosine hormones, which pass inside the cell.

Wrong again. Androgen receptors are mobile receptors in the cytoplasm of the cell.

Much more detail is needed on the origins and activity of DHT, how does it work, how do we stop it working so effectively? My routine is certainly working a treat, but I can't fully explain it, YET!

Keep reading these sites. Or should I say, START reading these sites?? :wink:

Bryan