Topical Flutamide v. Topical Spiroactalone

[Bryan]

Re: topical flutamide can't work.

Are hampster androgen receptors the same as human androgen receptors?

You've got me on that one. I don't know how similar (or dissimilar) human and hamster androgen receptors are.

What type of receptor did Dr Proctor use when measureing the competitive ability of various anti-androges?

Dr. Proctor didn't do it himself, he cited a study which did that. I quoted extensively from it in a past post on alt.baldspot, including a list of the RBA's (relative binding affinity) of most of the substances that were tested. If you'd like, I can go find it again and post it here. BTW, it used human cells for those measurements.

Bryan

 

[CCS]

I wish i knew the oral spironolactone dose in this study and could compare it to the dose of topical spironolactone used in the creme vs liquid vehicle study, so i could get an idea of whether skin concentration was the factor in the oral study.

 

[Bryan]

I just re-read that study on hurituism. oral spironolactone affects acne but not hair loss. why?

Where'd you get the idea that oral spironolactone doesn't help hairloss? Haven't you seen that small study where they gave 200 mg spironolactone/day to people with male pattern baldness, and modest improvements were apparently seen? I can find that one for you, too, if you want...

Bryan

 

[Bryan]

Here's my post on alt.baldspot from a few years ago. Although hydroxyflutamide doesn't appear on the list below, I found a value of 4.5% for it in another study.

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The oldtimers here will recall that for years Dr. P has occasionally referred to a certain unspecified medical study that found that spironolactone has a VERY high affinity for the androgen receptor; indeed, that it binds to the androgen receptor with fully 2/3 of the affinity that DHT itself has!

I recently stumbled across the study while looking for something else. This would be: "The Use of Human Skin Fibroblasts to Obtain Potency Estimates of Drug Binding to Androgen Receptors", Eil and Edelson, J Clin Endocrinol Metab 59:51, 1984.

They found that spironolactone had BY FAR the strongest binding affinity for the human androgen receptor of all the antiandrogens they tested, and this included cyproterone acetate and flutamide (NOT hydroxyflutamide). I'm going to reproduce the entire list of substances that they tested, and the Relative Binding Affinity that they measured for each one, expressed as a percentage of DHT itself. A couple of brief notes, first: at the top of the list are R1881, DHT, and testosterone, all with relative binding affinities set at 100%. R1881 is a powerful synthetic androgen that's frequently used in studies like this because it's not metabolized into anything else. It "stays put", in other words! And you'll probably wonder why testosterone is also listed at 100% along with DHT. This is the actual result they measured, and apparently is because after they added the testosterone to the cell culture, most of it was metabolized into DHT by 5alpha-reductase.

Here's the complete list of substances they tested, and their RBAs. They are listed in descending order of activity. Afterwards I'll have a couple of interesting quotes from the study:

R1881 (methyltrienolone, a powerful synthetic androgen)
100.0

DHT
100.0

Testosterone
100.0

Spironolactone (our good friend spironolactone!)
67.0

Danazol (an androgen agonist)
41.4

R2956 (a synthetic antiandrogen from Roussel-UCLAF)
14.8

Megesterol acetate
13.6

Cyproterone acetate
12.5

Medroxyprogesterone acetate
11.6

Progesterone
6.6

Estradiol
4.9

Androstenedione
2.0

Canrenone (this is a metabolite of spironolactone)
0.84

4-Hydroxyandrostenedione
0.79

17-Hydroxyprogesterone (note: this is NOT 11alpha-hydroxyprogesterone)
0.42

Flutamide
0.079

MSD L-642,317 (this is in the finasteride family of compounds)
0.038

Testolactone
0.0029

Cimetidine
0.00084

MSD L-642,022 (another in the finasteride family)
<0.0005

Diphenylhydantoin
<0.0005

Diazoxide (this is a drug similar to minoxidil)
<0.0005

That's the complete list. Now here are some comments from the "Discussion" section: "The advantages of using dispersed cultured fibroblasts for the comparison are 2-fold: 1) the receptors are from human cells, and 2) the cells are intact, and therefore, the assay system simulates *in vitro* many of the characteristics of the *in vivo* interactions of the compounds with androgen target tissues, such as nuclear localization. The disadvantages include the fact that these *in vitro* receptor studies do not define whether an inhibitor of binding is an agonist or antagonist *in vivo*. Also, metabolism of the compounds to more or less potent congeners, which may occur after clinical use of these drugs, may not be reproduced in the dispersed cell fibroblast assay system. This may account for the unexpected high potency of spironolactone, which is cleared rapidly *in vivo*, and the unexpected low potency of flutamide, which may require hydroxylation for full antiandrogenic activity..."

"...The results of this study indicate that spironolactone is an extremely effective competitor for the androgen receptor, even more potent than previously reported by others. This probably accounts for its therapeutic efficacy in hirsute women and for the high frequency of impotence and gynecomastia in men given the drug. If it can be administered in a form that minimizes its metabolism to canrenone, a much weaker androgen receptor binder, then its antiandrogenicity *in vivo* may be even further enhanced. This could be of potentially great benefit to patients with hirsutism, acne, prostatic hypertrophy and/or carcinoma, and other disorders thought to be due to excess androgen action."

Bryan

 

[CCS]

thanks for this info, bryan.

i suspect that most testosterone is turned into DHT in the scalp when i read that high dutasteride concentrations boost testosterone in the scalp 100%. i think this is not a big deal since testosterone is so much weaker than dht and the rest of our scalp does just fine even with all the dht present.

so 200mg/day oral spironolactone helped men with male pattern baldness. This is good, but I was talking about the women who took oral spironolactone and got no help for their face. Maybe their receptors are different from ours, but i was wondering about the dose they took, and also wondered what the total amount of spironolactone was applied to the face in that 1% cream verse 1% water/alcohol vehicle study you posted. i'm just trying to figure out what dose works.

One other questioin. spironolactone was at 67% and hydroxyflutamide only 4.5%, and flutamide way smaller than that. So why did the women who took oral spironolactone not see any hair benifits, and only 50% acne and sebum benifits, when the women on flutamide saw an 80% reduction in hair? It would appear from this that either flutamide or one of its metabolites is stronger than spironolactone.

 

[CCS]

i'm not optimistic about my getting flutamide and it being easy to make into hydroxyflutamide before application, but these seemingly contradictory results are bothering me.

 

[Bryan]

so 200mg/day oral spironolactone helped men with male pattern baldness. This is good, but I was talking about the women who took oral spironolactone and got no help for their face.

Which study are you referring to? The one that Old Baldy cited that compared spironolactone and flutamide? The women taking spironolactone DID get help for their hirsutism, just not as much as the ones taking flutamide.

One other questioin. spironolactone was at 67% and hydroxyflutamide only 4.5%, and flutamide way smaller than that. So why did the women who took oral spironolactone not see any hair benifits, and only 50% acne and sebum benifits, when the women on flutamide saw an 80% reduction in hair?

The women taking oral spironolactone DID see hair benefits, just not as much as the ones taking flutamide.

It would appear from this that either flutamide or one of its metabolites is stronger than spironolactone.

Well, flutamide is metabolized into a much STRONGER antiandrogen (hydroxyflutamide), whereas spironolactone is metabolized into a much WEAKER antiandrogen (canrenone). And then there's the issue of how rapidly the original drugs and their metabolites are excreted from the body. Now you know why I only smile at attempts to calculate on paper what the effectiveness of these drugs ought to be for various conditions like hirsutism or male pattern baldness. There are SOOOO many unknown variables in all of this, it's impossible to predict what's going to happen. That's why this is such an empirical science! :wink:

Bryan

 

[Felk]

That reminds me of one of Dr P's patented responses to the comparison between spironolactone and finasteride

"on paper, spironolactone should be more powerful, but in my experience it is probably about the same"

However i for one think thats a very optimistic slant on spironolactone, which is understandable. But compared to the other doctors, Proctor dabbles in the "spin" area far less...

 

[CCS]

Ok, that makes sense. So if you take spironolactone orally, it quickly turns into something that is very weak, but it is strongest at the site when it is in a normal form, but has to be applied more often.

flutamide is weak, but hydroxyflutamide is a lot stronger and longer lasting than the metabolite spironolactone turns into, which explains why it outperforms spironolactone by just has systemic effects. So applying even hydroxyflutamide locally would not be as strong as spironolactone, and would have more systemic effects. Flutamide is just percieved as stronger because the systemic effects are stronger and longer lived.

The fact that many people don't get side effects from flutamide is explained by the same reasons that many people don't get side effects from avodart, though flutamide interferes with every androgen everywhere, inhibiting testosterone more strongly than it inhibits DHT.

The reason 750mg of flutamide is prescribed and 5mg of finasteride is prescribed is flutamide is very week, and people with cancer don't care as much about side effects.

So my question is how much cheaper is spironolactone than RU, and how much more trustworthy are the sources of spironolactone compared to the sources of RU as far as not selling blancks, and do customs officials care about RU?

 

[Felk]

So my question is how much cheaper is spironolactone than RU, and how much more trustworthy are the sources of spironolactone compared to the sources of RU as far as not selling blancks, and do customs officials care about RU?

Well spironolactone, if you make your own, can be absolutely dirt cheap. $10 or less, I'd say. RU, if you use 2ml a day, is $100 a month. So $50 if you use 1ml.

spironolactone has many sources, and i'd say most reliable (you could get brandname aldactone, for example, if it bothered you). You can get generic spironolactone from QHI and other reputable online pharmacies.

RU, on the other hand, can only be obtained by a company in China named Faith Eagle. Some posters in the past at hairsite claim it's effectiveness differs greatly, depending on how fresh it is. Most posters didn't believe this, however. Some say Faith Eagle doesnt know how to make it properly.

Go to hairsite.com, and see my post there in the topical forum regarding RU. The admin offered to re-open the RU forum for me, so i could read the posters' experiences. However the expense of the drug, and the fact that a forum was opened for RU years ago with very very high hopes, and has fallen into disuse, convinced me not to take him up on the offer. However im interested still, and you appear to be, so I'll respond and see if he opens it...

 

[Felk]

However ill also add Stax used RU, and claim it filled in his temples with fine hairs after only a month. He is someone who normally posts lots here, and he hasnt been around much, and his last post said something along the lines of "my hair is doing great. Im outta here" so RU is still a possibility. Still check out hairsite, though, as the users there have had far more of the experience.

 

[CCS]

Ok, felk, where do you buy it from? I'd rather buy it from a site that the manufacterer directs people to.

Bryan, how strong is RU compared to the other anti-androgens we discussed. Do you know how easily it is absorbed compared to spironolactone?

Felk, and anyone with propecia side effects, please look at my most recent post in the topical finasteride thread. i think I've figured out how to make the topical work. i just need someone to find out what the blood flow rate is to the scalp, in volume per unit time. if you can't find that, tell me how many times per hour all the blood circulates, or what the volume of the heart chamber is, and any other flow rates to other parts of the body. If you can get me any of this info, I might be able to estimate the scalp flow rate. Once I have that, i can tell you want topical dose you need to get local benifits without systemic DHT reduction.

the only other thing is I need a vehicle that has at least 0.2% active ingredient penetration for finasteride in 3 hours. it must give a relatively steady dose over the 3 hours. think that is feasible? If so, I'll tell you what dose you need and all you people with side effects can start using finasteride without them.

 

[Bryan]

Bryan, how strong is RU compared to the other anti-androgens we discussed. Do you know how easily it is absorbed compared to spironolactone?

Well, the only good way we have of comparing the relative strengths of antiandrogens is by comparing them in hamster flank-organ tests. Here are the results for spironolactone, cyproterone acetate, flutamide, and RU58841:

1) The most suppression of flank-organs I've ever seen by the topical application of spironolactone was 39.3%, for a dose of 0.3 mg/day. A larger dose of 3 mg/day actually produced LESS suppression (29.5%), suggesting that 0.3 mg/day is close to an optimum dose for that drug, at least in hamsters. There was no suppression of the other flank-organ in either case, indicating that the effect was apparently a local one only.

2) The same study as the previous one (for spironolactone) also tested topical cyproterone acetate. At a dose of 0.3 mg/day, it achieved a suppression of 39.7% on the treated side, and a suppression of 30.3% on the untreated side, suggesting that maybe it worked partly by a direct local effect, but mostly by systemic absorption.

3) As I mentioned earlier, the Chen et al study found an even greater 52% reduction in the flank-organ size from the same dose of 0.3 mg of flutamide, but BOTH flank-organs were affected to the same degree, suggesting a completely systemic route of absorption.

4) A study of topical RU58841 by Matias et al found a maximum reduction of about 60% in hamster sebaceous glands, with no apparent systemic effects!! So I think it's crystal clear that of all these antiandrogens that have been tested topically, RU58841 is the clear winner. Now you know why I'm so interested in RU!

Last but not least, let's also consider the effect of castration, since that was considered by Hamilton in an early 1960 study to fully arrest the further progression of balding. Castration was also tested in the previously mentioned study which tested spironolactone and cyproterone acetate. Here are the results:

5) Castration caused a 75% reduction in hamster flank-organs (both sides, obviously).

So the conclusion by both Matias (from study #4 above) and another RU study I've read is that topical RU58841 causes "near-castration" levels of antiandrogenic effect. That's saying a hell of a lot! :wink:

Bryan

 

[CCS]

I'm sure i can afford RU. if it grows vellus hairs on smooth bald temples, I can use my hair graft saving to buy the RU and liberal amounts of Prox-N and minoxdil. my brother's diffuse hair loss would really benifit.

so lower doses of spironolactone can be better. mice have more pores that people, but their androgen receptors might be different, and 0.3g is a lot on a small mouse. i think i'll order the spironolactone 2% now, one container, and use it until the RU arrives.

Bryan, since nude mice have no immune system, and the immune system plays a role in hair loss, doesn't that mean that scalp grafted on to these mice will probably have great regrowth almost any drug? Do they use placebos, or have they tried minoxdil on nude mice grafts?

 

[Felk]

I'm sure i can afford RU. if it grows vellus hairs on smooth bald temples, I can use my hair graft saving to buy the RU and liberal amounts of Prox-N and minoxdil. my brother's diffuse hair loss would really benifit.

We don't know that it grows vellus on smooth bald temples do we?

so lower doses of spironolactone can be better. mice have more pores that people, but their androgen receptors might be different, and 0.3g is a lot on a small mouse. i think i'll order the spironolactone 2% now, one container, and use it until the RU arrives.

However take into account the vehicle. One study showed that spironolactone in an alcoholic vehicle did nothing for hirsutism, whereas the same strength in the cream vehicle did. lee's 5% spironolactone is in a cream vehicle.

Not too sound critical, but you sometimes jump to conclusions a little quickly college, stating things as fact based on assumptions. Take a bit more time to think things through and make decisions.

The real decision with RU vs spironolactone/fluridil is between a weaker antiandrogen made by professionals, or a very powerful antiandrogen with no product quality regulation. We don't really know what the RU supplied by Faith Eagle is like. I for one am going to resaerch it a bit more at hairsite, before forking out $400 to try it out.

 

[techprof]

as far I remember stax has used/has been using RU, spironolactone and many other topicals. He is very good in doing research and getting responses from other users (he posts in all hair loss sites). I have a 21 year old cousin who won't use finasteride or dutasteride. I was hoping stax would give a review of topicals he has used and the ones he found worthwhile.

For some unexplained reasons he won't respond to my posts. I hope I haven't offended him in any of his posts. Though it will be purely anecdotal, I will take stax's word as he has been around for a while and has tried many topicals. (RU, spironolactone, xandrox 5, 15, fluridil, proxiphen, spintrapC etc).

 

[Bryan]

so lower doses of spironolactone can be better.

Maybe. Keep in mind that I said it SUGGESTS that there might be an optimum dose. OTOH, maybe it was just a statistical fluke, since there obviously weren't large numbers of hamsters in each dosing group.

mice have more pores that people, but their androgen receptors might be different, and 0.3g is a lot on a small mouse.

Did you mean to say 0.3 mg, rather than 0.3 g?

Bryan, since nude mice have no immune system, and the immune system plays a role in hair loss, doesn't that mean that scalp grafted on to these mice will probably have great regrowth almost any drug?

Maybe. Keep in mind that the study you're obviously referring to was the only one to report such a phenomenon. I'd like to see it duplicated by others.

Do they use placebos, or have they tried minoxdil on nude mice grafts?

Not to my knowledge.

Bryan

 

[CCS]

OK, I'll slow down. I just told a bunch a bunch of bald men I know there may be a drug that can grow back their hair. They got excited. But I'll research in on hair site. I also PM'd the purchasing direction to several people on this site. I guess I should PM them again that they should research before buying it.

 

[Bryan]

OK, I'll slow down. I just told a bunch a bunch of bald men I know there may be a drug that can grow back their hair.

My god...were you referring to RU58841?? I would never EVER characterize it that way to anyone, since it's just an antiandrogen. True, all indications are that it's a very good one, but nevertheless it's still just an antiandrogen. It should be recommended as something to help slow or stop further balding. If it actually regrows any hair on anybody, that should be considered a bonus.

Bryan

 

[CCS]

some people here on this forum and others hyped it up a bit. its hyped up everywhere, it seems. at least I did not tell anyone on this forum it grows hair. I just told them where to buy it.