If you really care about Testosterone and Endocrinology – read this. If you don’t, move on and keep believing the fairy tales.

I have consumed a lot of content that revolves around hormones and the experts in question generally sound so confident. “Low testosterone does this or that.” “If you don’t have enough Growth Hormone your toes and eyelashes will fall off.” Their overall confidence in the “facts” boggles my mind as I believe I spend as much or more time immersed in this research than anyone, but, hey, maybe they know something I don’t.

Yet, here are some things I do know.

Testosterone’s main effects are due to binding to the androgen receptor and its subsequent signal translocation and binding to the androgen response element within the nucleus (DHT also binds to the androgen receptor and with higher affinity, but not is not the major player in muscle cells). This signal cascade results in transcriptional changes at the DNA level which results in changes in the proteins that the cell machinery constructs.

In science…

“Both testosterone and DHT (either locally produced or from the circulation) exert their activities by binding to a cognate receptor, the androgen receptor (AR), a 110-kDa member of the nuclear receptor superfamily of ligand-activated transcription factors…In its basal, unliganded state, the AR resides primarily in the cytoplasmic compartment where it exists in a complex with heat shock proteins (Hsps) and immunophilin chaperones such as Hsp70, 90, 56, and p23. Upon ligand binding, alterations occur in the composition of this Hsp complex, and the AR undergoes a conformational change, allowing nuclear translocation of the AR and AR homodimer formation. Inside the nucleus, the activated AR binds to specific recognition sequences known as androgen response elements (AREs) in the promoter and enhancer regions of target genes.”

Heemers et al. 2007

Now, about 1/3 of circulating testosterone is bound to albumin, 2/3 to sex hormone binding globulin (SHBG), and roughly 1-3% is floating around free. Many in the field believe that the only hormone concentrations we have access to are the free and albumin bound testosterone.

This theory is called the “free hormone hypothesis” and albumin + free testosterone together are termed bioavailable testosterone. This ideology is from the 80s and even with gobs of research questioning it, the hypothesis is still touted as fact in the anti-aging and healthospheres.

If you talk to most hormone docs, who have been doing the right thing and researching for a long time, they don’t put a lot of stock in the free testosterone assay, besides it being expensive it seems to have a wide error rate surrounding a smaller number, not the best combo when looking for an accurate and sensitive objective test (the regular estradiol assay also has the precision of a farsighted seven year old).

Now here is the rub, it has been found that testosterone has indirect effects outside of the androgen receptor model. Further, a receptor called megalin has been isolated and this protein allows for the endocytosis of the SHBG-testosterone complex. Megalin has been isolated on human muscle cells. Furthermore, there is a receptor for SHBG which exerts its effects outside of being bound to sex steroids. Whoops!

So anyone that tells you confidently that total testosterone or free testosterone is the only piece of the puzzle is either lying to you or is ignorant. How much all this will matter is debatable. Clinically, we can’t measure the endocytosis the SHBG-Testosterone complex. I don’t know that we ever will, but we will likely learn a lot more about SHBG binding and we even may be able to measure the amount of megalin mRNA that is transcripted and the subsequent amount of megalin that is translated in the not too distant future. We are also putting out a ton of research that is trying to understand the other piece of this puzzle – Androgen Receptor Sensitivity.

You tend to hear about this as an afterthought towards the end of an interview or lecture, but I have yet to hear it thoroughly explained.

One sentence that floats around in Func Med circles that drives me absolutely bat shit crazy is this ideology that is generally stated as a fear-mongering fact – if you take testosterone your androgen receptors will “down-regulate.”

Find one scientific peer-reviewed study that has made this finding. You won’t be able to, but you will be able to find multiple cell and animal studies that show the opposite, that the androgen receptor actually upregulates with androgen administration. This makes more sense to me as the androgen receptor is a high-affinity low-capacity receptor and humans would have wanted to be able to respond to increased testosterone at different points in the life cycle.

There is also a lot of research on polyglutamine repeats or CAG repeats within the androgen receptor gene. The idea is that the less polyglutamine repeats you have the more sensitive your androgen receptor is and this has been associated with increased androgen receptor associated transcription activity.

In science…

“The androgen receptor gene contains a highly polymorphic (CAG)n repeat in exon 1 encoding a glutamine tract in the N-terminal transactivation domain of the protein, which becomes active only after AR binds to its ligand. The polyglutamine tract length is inversely correlated to the transcriptional competence of the receptor, with longer tracts being associated with lower levels of AR-mediated transcription.”
-Ackerman et al. 2012

The body of literature on this topic is far from cut and dry and there is a fantastic summary chart within the most recent paper by a Ryan et al. in 2017 that highlights the variability of these findings as they relate to characteristics related to testosterone and the testosterone values themselves.

And before you go trying to figure out your androgen receptor gene code know that no significant relationship was found between shorter CAG repeats and differences in lean mass or fitness in healthy young men. However, one recent study did find a significant difference in anaerobic performance in adolescent males with shorter CAG repeats. Also, some studies have found a relationship between CAG repeat length and serum hormone concentrations, yet some have not.

Nevertheless, there are more than a few interesting findings to date.

1) There seems to be ethnic related differences in CAG repeats with Afro-Carribean subjects having the shortest repeat lengths followed by Caucasians, Hispanics, and then those of Thai descent having the highest repeat lengths. Remember these are averages and this is a cross-sectional finding. It is just exploratory until longitudinal studies, RCTs, and meta-analyses are conducted.

2) A recently published longitudinal study by Ponce-Gonzalez et al. found that adolescents males with shorter CAG repeats had less whole body and trunk fat than those with longer CAG repeats and that this difference in body composition held into adulthood.

3) The 2D:4D ratio thing that everyone talks about has NOT been found to be related to CAG repeats or higher free or total testosterone levels (in adulthood).

4) In multiple studies by Tirabussi et al., those individuals with shorter CAG repeats have been found to respond better metabolically and sexually to TRT.

5) CAG repeat length was not related to penile length, at least in Han Chinese men. Yes, this was a real study.

One final topic – resistance exercise and the androgen receptor.

I hear this thought process brought up whenever I bring up the research that shows that the increase in anabolic hormones post-training is very likely not having much of an effect, if any on increases in strength or muscle hypertrophy.

I will keep this short as the research on resistance exercise and androgen receptor transcription/translation and AR-DNA binding is mixed. Some have found a spike in androgen receptor transcription right after training, some have not. Some have found an increase at 24 hours post training, some have not. Some have found that androgen receptor gene transcription is upregulated 48 hours post-training, some have not. Given the equivocal findings thus far, it is too early to speculate on if or how important any post-training rise in androgen receptor content would be to increases in muscle strength or hypertrophy long-term. However, given that the exercise hormone hypothesis has been chomped to bits of late, learning how or if an upregulation in the androgen receptor plays into this hypothesis is just another step down the road of our understanding, and one I look forward to reading more about.

References if you want to dig deeper.

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