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 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 it.

References if you want to dig deeper.

1. Ackerman CM, Lowe LP, Lee H, et al. Ethnic variation in allele distribution of the androgen receptor (AR) (CAG)n repeat. Journal of andrology. 2012;33(2):210-215.
2. Ahtiainen JP, Hulmi JJ, Kraemer WJ, et al. Heavy resistance exercise training and skeletal muscle androgen receptor expression in younger and older men. Steroids. 2011;76(1-2):183-192.
3. Ahtiainen JP, Lehti M, Hulmi JJ, et al. Recovery after heavy resistance exercise and skeletal muscle androgen receptor and insulin-like growth factor-I isoform expression in strength trained men. J Strength Cond Res. 2011;25(3):767-777.
4. Ahtiainen JP, Nyman K, Huhtaniemi I, et al. Effects of resistance training on testosterone metabolism in younger and older men. Exp Gerontol. 2015;69:148-158.
5. Aluja A, Garcia LF, Marti-Guiu M, et al. Interactions among impulsiveness, testosterone, sex hormone binding globulin and androgen receptor gene CAG repeat length. Physiology & behavior. 2015;147:91-96.
6. Butler MG, Manzardo AM. Androgen receptor (AR) gene CAG trinucleotide repeat length associated with body composition measures in non-syndromic obese, non-obese and Prader-Willi syndrome individuals. J Assist Reprod Genet. 2015;32(6):909-915.
7. Carson JA, Lee WJ, McClung J, Hand GA. Steroid receptor concentration in aged rat hindlimb muscle: effect of anabolic steroid administration. Journal of applied physiology. 2002;93(1):242-250.
8. Choi SM, Lee BM. Comparative safety evaluation of selective androgen receptor modulators and anabolic androgenic steroids. Expert Opin Drug Saf. 2015;14(11):1773-1785.
9. Coss CC, Jones A, Hancock ML, Steiner MS, Dalton JT. Selective androgen receptor modulators for the treatment of late onset male hypogonadism. Asian J Androl. 2014;16(2):256-261.
10. Crabbe P, Bogaert V, De Bacquer D, Goemaere S, Zmierczak H, Kaufman JM. Part of the interindividual variation in serum testosterone levels in healthy men reflects differences in androgen sensitivity and feedback set point: contribution of the androgen receptor polyglutamine tract polymorphism. J Clin Endocrinol Metab. 2007;92(9):3604-3610.
11. Dalton JT, Taylor RP, Mohler ML, Steiner MS. Selective androgen receptor modulators for the prevention and treatment of muscle wasting associated with cancer. Curr Opin Support Palliat Care. 2013;7(4):345-351.
12. De Naeyer H, Bogaert V, De Spaey A, et al. Genetic variations in the androgen receptor are associated with steroid concentrations and anthropometrics but not with muscle mass in healthy young men. PLoS One. 2014;9(1):e86235.
13. Dillon EL, Durham WJ, Urban RJ, Sheffield-Moore M. Hormone treatment and muscle anabolism during aging: androgens. Clinical nutrition. 2010;29(6):697-700.
14. Eisenberg ML, Hsieh TC, Pastuszak AW, et al. The relationship between anogenital distance and the androgen receptor CAG repeat length. Asian J Androl. 2013;15(2):286-289.
15. Eisenegger C, Kumsta R, Naef M, Gromoll J, Heinrichs M. Testosterone and androgen receptor gene polymorphism are associated with confidence and competitiveness in men. Horm Behav. 2017;92:93-102.
16. Folland JP, Mc Cauley TM, Phypers C, Hanson B, Mastana SS. The relationship of testosterone and AR CAG repeat genotype with knee extensor muscle function of young and older men. Exp Gerontol. 2012;47(6):437-443.
17. Folland JP, Mc Cauley TM, Phypers C, Hanson B, Mastana SS. Relationship of 2D:4D finger ratio with muscle strength, testosterone, and androgen receptor CAG repeat genotype. Am J Phys Anthropol. 2012;148(1):81-87.
18. Goutou M, Sakka C, Stakias N, Stefanidis I, Koukoulis GN. AR CAG repeat length is not associated with serum gonadal steroids and lipid levels in healthy men. Int J Androl. 2009;32(6):616-622.
19. Guadalupe-Grau A, Rodriguez-Gonzalez FG, Dorado C, et al. Androgen receptor gene polymorphisms lean mass and performance in young men. Br J Sports Med. 2011;45(2):95-100.
20. Hammes A, Andreassen TK, Spoelgen R, et al. Role of endocytosis in cellular uptake of sex steroids. Cell. 2005;122(5):751-762.
21. Heemers HV, Tindall DJ. Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev. 2007;28(7):778-808.
22. Hofer MD, Kapur P, Cordon BH, et al. Low Testosterone Levels Result in Decreased Periurethral Vascularity via an Androgen Receptor-mediated Process: Pilot Study in Urethral Stricture Tissue. Urology. 2017;105:175-180.
23. Hooper DR, Kraemer WJ, Focht BC, et al. Endocrinological Roles for Testosterone in Resistance Exercise Responses and Adaptations. Sports medicine. 2017.
24. Kadi F. Cellular and molecular mechanisms responsible for the action of testosterone on human skeletal muscle. A basis for illegal performance enhancement. Br J Pharmacol. 2008;154(3):522-528.
25. Kraemer WJ, Ratamess NA. Hormonal responses and adaptations to resistance exercise and training. Sports medicine. 2005;35(4):339-361.
26. Lakshman KM, Bhasin S, Corcoran C, et al. Measurement of myostatin concentrations in human serum: Circulating concentrations in young and older men and effects of testosterone administration. Molecular and cellular endocrinology. 2009;302(1):26-32.
27. Lakshman KM, Bhasin S, Corcoran C, et al. Measurement of myostatin concentrations in human serum: Circulating concentrations in young and older men and effects of testosterone administration. Molecular and cellular endocrinology. 2009;302(1):26-32.
28. Ma YM, Wu KJ, Ning L, et al. Relationships among androgen receptor CAG repeat polymorphism, sex hormones and penile length in Han adult men from China: a cross-sectional study. Asian J Androl. 2014;16(3):478-481.
29. MacKrell JG, Yaden BC, Bullock H, et al. Molecular targets of androgen signaling that characterize skeletal muscle recovery and regeneration. Nucl Recept Signal. 2015;13:e005.
30. McEwan IJ. Androgen receptor modulators: a marriage of chemistry and biology. Future Med Chem. 2013;5(10):1109-1120.
31. Ng Tang Fui M, Hoermann R, Prendergast LA, Zajac JD, Grossmann M. Symptomatic response to testosterone treatment in dieting obese men with low testosterone levels in a randomized, placebo-controlled clinical trial. Int J Obes (Lond). 2017;41(3):420-426.
32. Ponce-Gonzalez JG, Rodriguez-Garcia L, Losa-Reyna J, et al. Androgen receptor gene polymorphism influence fat accumulation: A longitudinal study from adolescence to adult age. Scand J Med Sci Sports. 2016;26(11):1313-1320.
33. Poole CN, Roberts MD, Dalbo VJ, Sunderland KL, Kerksick CM. Megalin and androgen receptor gene expression in young and old human skeletal muscle before and after three sequential exercise bouts. J Strength Cond Res. 2011;25(2):309-317.
34. Ratkevicius A, Joyson A, Selmer I, et al. Serum concentrations of myostatin and myostatin-interacting proteins do not differ between young and sarcopenic elderly men. The journals of gerontology Series A, Biological sciences and medical sciences. 2011;66(6):620-626.
35. Roberts MD, Dalbo VJ, Hassell SE, Kerksick CM. The expression of androgen-regulated genes before and after a resistance exercise bout in younger and older men. J Strength Cond Res. 2009;23(4):1060-1067.
36. Rodriguez-Garcia L, Ponce-Gonzalez JG, Gonzalez-Henriquez JJ, et al. Androgen receptor CAG and GGN repeat polymorphisms influence performance in boys and girls. The Journal of sports medicine and physical fitness. 2017;57(1-2):18-25.
37. Rossetti ML, Steiner JL, Gordon BS. Androgen-mediated regulation of skeletal muscle protein balance. Molecular and cellular endocrinology. 2017;447:35-44.
38. Ryan CP, Georgiev AV, McDade TW, et al. Androgen receptor polyglutamine repeat length (AR-CAGn) modulates the effect of testosterone on androgen-associated somatic traits in Filipino young adult men. Am J Phys Anthropol. 2017;163(2):317-327.
39. Ryan CP, McDade TW, Gettler LT, et al. Androgen receptor CAG repeat polymorphism and hypothalamic-pituitary-gonadal function in Filipino young adult males. American journal of human biology : the official journal of the Human Biology Council. 2017;29(1).
40. Sheppard RL, Spangenburg EE, Chin ER, Roth SM. Androgen receptor polyglutamine repeat length affects receptor activity and C2C12 cell development. Physiol Genomics. 2011;43(20):1135-1143.
41. Sinha-Hikim I, Taylor WE, Gonzalez-Cadavid NF, Zheng W, Bhasin S. Androgen receptor in human skeletal muscle and cultured muscle satellite cells: up-regulation by androgen treatment. J Clin Endocrinol Metab. 2004;89(10):5245-5255.
42. Sinha-Hikim I, Taylor WE, Gonzalez-Cadavid NF, Zheng W, Bhasin S. Androgen receptor in human skeletal muscle and cultured muscle satellite cells: up-regulation by androgen treatment. J Clin Endocrinol Metab. 2004;89(10):5245-5255.
43. Spiering BA, Kraemer WJ, Vingren JL, et al. Elevated endogenous testosterone concentrations potentiate muscle androgen receptor responses to resistance exercise. The Journal of steroid biochemistry and molecular biology. 2009;114(3-5):195-199.
44. Spillane M, Schwarz N, Willoughby DS. Upper-body resistance exercise augments vastus lateralis androgen receptor-DNA binding and canonical Wnt/beta-catenin signaling compared to lower-body resistance exercise in resistance-trained men without an acute increase in serum testosterone. Steroids. 2015;98:63-71.
45. Tirabassi G, Corona G, Falzetti S, Delli Muti N, Maggi M, Balercia G. Influence of Androgen Receptor Gene CAG and GGC Polymorphisms on Male Sexual Function: A Cross-Sectional Study. Int J Endocrinol. 2016;2016:5083569.
46. Tirabassi G, Cutini M, Beltrami B, Delli Muti N, Lenzi A, Balercia G. Androgen receptor GGC repeat might be more involved than CAG repeat in the regulation of the metabolic profile in men. Intern Emerg Med. 2016;11(8):1067-1075.
47. Tirabassi G, Delli Muti N, Corona G, Maggi M, Balercia G. Androgen Receptor Gene CAG Repeat Polymorphism Regulates the Metabolic Effects of Testosterone Replacement Therapy in Male Postsurgical Hypogonadotropic Hypogonadism. Int J Endocrinol. 2013;2013:816740.
48. Tirabassi G, Delli Muti N, Corona G, Maggi M, Balercia G. Androgen receptor gene CAG repeat polymorphism independently influences recovery of male sexual function after testosterone replacement therapy in postsurgical hypogonadotropic hypogonadism. The journal of sexual medicine. 2014;11(5):1302-1308.
49. Vingren JL, Kraemer WJ, Hatfield DL, et al. Effect of resistance exercise on muscle steroid receptor protein content in strength-trained men and women. Steroids. 2009;74(13-14):1033-1039.
50. Vingren JL, Kraemer WJ, Ratamess NA, Anderson JM, Volek JS, Maresh CM. Testosterone physiology in resistance exercise and training: the up-stream regulatory elements. Sports medicine. 2010;40(12):1037-1053.
51. Willoughby DS, Taylor L. Effects of sequential bouts of resistance exercise on androgen receptor expression. Med Sci Sports Exerc. 2004;36(9):1499-1506.
52. Zhang X, Sui Z. Deciphering the selective androgen receptor modulators paradigm. Expert Opin Drug Discov. 2013;8(2):191-218.
53. Zhao J, Bauman WA, Huang R, Caplan AJ, Cardozo C. Oxandrolone blocks glucocorticoid signaling in an androgen receptor-dependent manner. Steroids. 2004;69(5):357-366.
54. Zitzmann M, Gromoll J, von Eckardstein A, Nieschlag E. The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men. Diabetologia. 2003;46(1):31-39.

Drop Your Email Below for All The Bro Research Updates and Latest Articles

You're In!