The answer? Androgen receptors insensitivity?

General Discussion
#1

hi guys,

in these day i’ve reflected a lot trying to set up all the pieces of the puzzle; we have collected a lot of exhaustive member stories and we have done a lot of tests. all together we are a very important sample. i would like to share with you my observation about the solutions:

-Hormones: hormones can’t be the answer. some of us have good hormones. other users have low level of testo or high e2… but nobody has recovered boosting t or with a TRT. we are searching for something that affects hormones but hormones are not the key
-Prostate: a lot of us suffer of prostatitis or have symptom of prostatitis … but clearly prostate isn’t the key. as for the hormones, we are searching for something that affects the prostate

in my opinion is by now evident that something does not work good in our androgen receptors, especially in genital area. take a look at the member stories and realize how many of us suffer of mutations in the skin or in the dimension of the penis…there is only one thing that is responsible of the good health of the penile tissues: dht. and it is also the major androgen sexual hormones.

-we all have took a drug that block the dht conversion
-our dht level is returned good after the interruption
BUT
we still have all the sides of a reduced level of dht (the same sides that we were experiencing on the drugs)

So for me the answer is clear and very bad (because it’s something difficult to treat): androgen receptors insensitivity, especially about dht (don’t ask me why this insensitivity is originated but i’m sure that this is the key). this can explain all our symptoms… moreover i’am a living proof of this, because my situation isn’t stable, is going deteriorating in time (i started with a loss of libido 5 years ago and now i am in a state of full impotence) so about my situation we can observe what is changing and derive important informations: since 5 years ago my hormones are low but stable, my prostate is ok, and my sexual problems go worst every months more:

same hormones --> penile tissues, sensitivity, libido and ED deteriorating
on TRT with very good hormones --> acne, more energy, all the body feel the power of the testosterone but… zero sexual improvements, as if the genitals aren’t able to feel the hormones.

i think we should start collecting info/possible tests/possible treatments about this mutation in our receptors…

#2

This is still a theory, since nobody has had 5ARII or Androgen Receptor enzyme activity or mutation testing yet, so we don’t know for sure.

This theory has been proposed a few times already on this forum:

propeciahelp.com/forum/viewt … highlight=
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propeciahelp.com/forum/viewtopic.php?t=1415
propeciahelp.com/forum/viewtopic.php?t=1079

Since the genitals are rife in androgen receptor and 5AR-II enzymes, and Finasteride inhibits both hepatic and TISSUE 5AR2 activity, as noted here: propeciahelp.com/forum/viewtopic.php?t=1591

… perhaps it is a case of those enzymes no longer being able to function correctly post-Fin in those tissues, and properly convert T->DHT to exert the effects of DHT on the androgen receptor in those tissues correctly anymore.

You want to check 5AR2 activity/mutation and AR binding/mutation in your penile tissues? You need a genital skin fibroblast culture done, and genetic testing.

More details on testing: propeciahelp.com/forum/viewtopic.php?t=1541

#3

yes i know that this is an “old” theory … i wrote a new topic in order to describe the new elements surfaced and discuss how this elements play in favour of the receptors theory :wink:

by the way, thanks for the links and the exhaustive answer!

#4

Regarding the dick skin thing, I read that women’s genitals become darker while/after pregnancy, so it might be purely hormonal. I think this problem is multi-dimensional, hormones and the prostate are playing a key role. The articles on prostate removal have similar info. One article stated that when the nerves in the prostate are affected and people don’t get erections after the surgery, this leads to changes in the tissues and blood vessels in the penis, which might be reversible with time. But to be hit with gyno and these problems a few weeks after quitting is really a mystery. A pituitary or testicular tumor would have explained it, but nothing was wrong physically.

I think the best you can do is to fix your hormones and take viagra…and wait:( If it’s AIS, can anything be done? no?

#5

Supraphysiological doses of Testosterone or DHT may be able to partly overcome the AR defect/mutation, but the effects of maintaining such dosages for long periods of time is not really known, I believe.

propeciahelp.com/forum/viewtopic.php?t=1417

#6

Regarding androgen insensitivity and AR binding in genital tissues etc:

Reduced affinity of the androgen receptor for 5 alpha-dihydrotestosterone but not methyltrienolone in a form of partial androgen resistance. Studies on cultured genital skin fibroblasts.

FULL TEXT: pubmedcentral.nih.gov/articl … tid=425458

We have studied a child with posterior labial fusion, clitoral phallus, female urethra, and a short, blind vagina born to a mother with decreased axillary and pubic hair. Her karyotype is 46,XY. At 2 yr of age, the child’s basal level of plasma testosterone was less than 0.35 nM and after human chorionic gonadotropin stimulation, it rose to 2.6. Testis and epididymis histology were normal.

Her cultured genital (labial) skin fibroblasts have normal testosterone 5 alpha-reductase activity, and metabolize 5 alpha-dihydrotestosterone (DHT) normally, but they do not augment (up-regulate) their basal androgen-receptor binding activity during prolonged incubation with DHT.

With DHT, the androgen receptor in her genital skin fibroblasts has a normal binding capacity (maximum binding capacity = 25 fmol/mg protein), but an increased rate constant of dissociation (k = 11.6 X 10(-3) min-1; normal, 6 +/- 1.2 (+/- SD)), and a decreased apparent equilibrium binding affinity (Kd = 0.6 nM; normal, 0.22 +/- 0.09) that is evident in the results of 2-h assays but not of those lasting 0.5 h.

With the synthetic androgen, methyltrienolone, all three binding properties of the receptor are normal, and her receptor activity up-regulates normally.

We interpret these results to mean that the subject has a ligand-selective defect in the time-dependent transformation of initial, low-affinity androgen-receptor complexes to serial states of higher affinity, presumably as the result of a structural mutation at the X-linked locus that encodes the androgen receptor protein.

Human minimal androgen insensitivity with normal dihydrotestosterone-binding capacity in cultured genital skin fibroblasts: evidence for an androgen-selective qualitative abnormality of the receptor.

FULL TEXT: pubmedcentral.nih.gov/articl … id=1684524

We have studied a kindred in which two parts of siblings, maternal first cousins, have a form of “minimal” androgen insensitivity that permits morphogenesis of unambiguous male external genitalia, but interferes with normal virilization at puberty. All four had gynecomastia that required reductive surgery.

Apart from this common phenotype, they varied considerably in the temporal and regional aspects of their subvirilization and appreciably in their androgenic responsiveness to pharmacological doses of testosterone.

The cultured genital skin fibroblasts from one set of siblings have an androgen-receptor activity with the following properties: (1) a normal maximum-binding capacity (Bmax) with 5 alpha-dihydrotestosterone (DHT), or the synthetic androgen, methyltrienolone (MT; R1881) as ligand; (2) [b]a higher than normal apparent equilibrium dissociation constant /b for DHT (0.77 nM) but not for MT; and (3) an elevated dissociation rate (k) of DHT-receptor (0.013 min-1, 37 degrees C), but not MT-receptor, complexes within intact cells.

In addition, prolonged incubation with MT, but not DHT, augments the specific androgen-binding activity of the mutant cells as much as that of the controls. Normal cells yield lower values of apparent Kd for DHT (0.1-0.3 nM) after 2- than after 0.5-hr incubation (0.3-1.8 nM), and 1-hr values are intermediate.

This occurs despite concurrent catabolic consumption of DHT from the medium and is considered to reflect transformation of initial, low-affinity DHT-receptor complexes to subsequent, higher-affinity states by a process that depends on time and initial ligand concentration. The mutant complexes described here can readily attain the highest state of affinity with MT, but have an impeded, variably expressed ability to do so with DHT.

These findings suggest that a structural mutation at the X-linked locus that encodes the androgen-receptor protein is responsible for its androgen-selective dysfunction.

Synthetic, nonhepatotoxic androgens, with corrective effects in vitro comparable to those of MT, may be therapeutically useful for these subjects.

#7

What I find interesting, from the second study posted there, is this:

…"the simplest interpretation of the androgen receptor dysfunction in the present family is that it permits the formation of DHT-receptor complexes that do not readily transform from their initial lowaffinity state to their derivative high-affinity states. In contrast, with MT as ligand, the process of transformation proceeds normally. Such an interpretation is consistent with a previous postulate [31] that androgen-receptor complexes must attain their highest-affinity state in order to function as an effective signal for up-regulation.

Transformation from low-affinity to serial higher-affinity states is a property of many [33-35], if not all, steroid-receptor complexes, and it is considered an essential step in steroid hormone action. It should not be surprising that the process of transformation should be vulnerable to mutational disruption of various types. The present family exemplifies this vulnerability."

#8

so whats the practical application?? i have a boatload of MT here have used it in the past(before PSSD), but not sure it’s better than my current regimen of:

  • TRT/forskolin/AI

  • HDACi/DNMTi

also i wanted to try nandrolone next

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