following up on my post, based on the facts I discuss below, it seems to me that we cannot rule out that our upregulated ARs are not doing their job well, i.e., transcription factors, mutations,…, here is a para from Wiki about possible mutations that could lead to androgen insensitivity.
But here is my speculation 101 now:
- ARs are upregulated no longer because of lack of androgen but because their transcription is less efficient, something is not working well.
- So if you do anything that would downregulate ARs (Such as T therapy) You FEEL WORSE, because the ARs need to be working at maximum potential to get the bare minimum transcription going… The same goes if you reduce their activity directly (my example of Eucapil)…
WIKI
The androgen receptor gene contains two polymorphic trinucleotide microsatellites in exon 1.[2] The first microsatellite (nearest the 5’ end) contains 8 [17] to 60 [18][19] repetitions of the glutamine codon “CAG” and is thus known as the polyglutamine tract.[3] The second microsatellite contains 4 [20] to 31 [21] repetitions of the glycine codon “GGC” and is known as the polyglycine tract.[22] The average number of repetitions varies by ethnicity, with Caucasians exhibiting an average of 21 CAG repeats, and Blacks 18.[23] In men, disease states are associated with extremes in polyglutamine tract length; prostate cancer,[24] hepatocellular carcinoma,[25] and intellectual disability [17] are associated with too few repetitions, while spinal and bulbar muscular atrophy (SBMA) is associated with a CAG repetition length of 40 or more.[26] Some studies indicate that the length of the polyglutamine tract is inversely correlated with transcriptional activity in the AR protein, and that longer polyglutamine tracts may be associated with male infertility [27][28][29] and undermasculinized genitalia in men.[30] However, other studies have indicated that no such correlation exists.[31][32][33][34][35][36] A comprehensive meta-analysis of the subject published in 2007 supports the existence of the correlation, and concluded that these discrepancies could be resolved when sample size and study design are taken into account.[11] Some studies suggest that longer polyglycine tract lengths are also associated with genital masculinization defects in men.[37][38] Other studies find no such association.[39]
AR mutations
As of 2010, over 400 AR mutations have been reported in the AR mutation database, and the number continues to grow.[2] Inheritance is typically maternal and follows an X-linked recessive pattern;[1][40] individuals with a 46,XY karyotype will always express the mutant gene since they only have one X chromosome, whereas 46,XX carriers will be minimally affected. 30% of the time, the AR mutation is a spontaneous result, and is not inherited.[10] Such de novo mutations are the result of a germ cell mutation or germ cell mosaicism in the gonads of one of the parents, or a mutation in the fertilized egg itself.[41] In one study,[42] it was found that 3 out of 8 de novo mutations occurred in the post-zygotic stage, leading to the estimate that up to one third of de novo mutations result in somatic mosaicism.[1] It is worthwhile to note that not every mutation of the AR gene results in androgen insensitivity; one particular mutation occurs in 8 to 14 percent of genetic males,[43][44][45][46] and is thought to adversely affect only a small number of individuals when other genetic factors are present.[47]
