- Reaction score
- 42
Here's a copy of my old post on alt.baldspot about the study which compared the RBAs (relative binding affinity) of spironolactone and various other drugs:
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
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."
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
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."
