One thing I did not talk about in my Testosterone talk at Paleo f(x) is Sex Hormone Binding Globulin (SHBG). This is not because I wanted to side skirt the issue, it is because I only had 40 minutes and people were already getting cock punched with new information, but the hole is always deeper so here we go.

To summarize that talk on testosterone in a nutshell. Here is a picture.

Sex and Stress final

…and here is an acronym

 

COMMON

Stress (inhibits Testosterone production at the level of the brain and testes)

Estrogen (inhibits testosterone production at the level of the brain)

Nutrition (Leydig cells die from oxidative stress – cut that out and eat more plants – vitamin A, B6, D, Magnesium, and Zinc all seem to be in play to maintain adequate male hormone production)

Sleep (you don’t sleep you lose – 15% to 30% of testosterone production even in acute sleep loss)

Estrogen (Yea – No. Throw away plastics, toxic personal care products, and pesticide riddled food. Filter your air and your water. Do everything you can and then don’t be weird about it)

…and here is an article I wrote previously on the fundamentals.

 

What I covered in the talk and what we covered above is mainly Production. We also have to think about three other aspects of hormonal physiology Transport (SHBG and albumin), Sensitivity (how sensitive are your receptors), and Disposal (are you clearing estrogen or is it getting clogged in phase 1 or phase 2 liver detoxification, or reabsorbed in the GI tract because you ripped that up with poptarts, ice cream, and Jagger bombs).

 

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About two thirds of circulating testosterone is bound to SHBG (around 44-65%) and then about one third is bound to albumin (33-54%). Testosterone bound to SHBG is generally regarded as inaccessible – cock caged testosterone. Albumin is termed bioavailable and then we have anywhere from 1 to 2% free. If you have albumin, SHBG, and total testosterone you can calculate you free testosterone and bioavailable testosterone with this calculator.

Nearly everyone one of my male clients to date has fairly consistent albumin levels. And we tend to get pretty worried if albumin levels drops off the table as this is an acute phase reactant and indicative of chronic inflammatory disorders or… pregnancy. Albumin is one of our main regulators of colloid osmotic pressure between blood and tissues, so if albumin gets jacked up you can get edema or ascites. No Bueno and not something I work with.

 

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Both albumin and SHBG are primarily made in the liver. We previously had this weird conundrum in the research of a negative relationship between BMI and insulin and SHBG. AKA the higher your BMI got and the more insulin, the lower your SHBG, but recently given new data from studies utilizing magnetic resonance imaging, the main player here seems to be hepatic fat accumulation (SAD with some Coors light) not visceral or subcutaneous fat, which makes more intuitive sense. Low SHBG is a risk factor for CVD, inside the conventional medicine model. There may also be some genetic components for lower and higher SHBG and rsids are being studied. As with anything thyroid also comes into play and hyperthyroid has been found to upregulate SHBG, whereas hypothyroid tends to lower it, likely from global upregulation or downregulation of liver function. Interestingly proinflammatory cytokines (TNFα, NFκB, IL1β) have also been found to be related to lower SHBG. Thus, when we are living inside the conventional model low SHBG seems to be a canary for chronic disease states.

Positing a hypothesis here is that we know that most of the factors above downregulate testosterone production so it makes intuitive sense that the body would in turn downregulate SHBG in an attempt to hang on to hormonal health. Interestingly, in the general population we do see a 2% per year rise in SHBG while free testosterone and testosterone tend to decrease by 1 to 2% per year, which muddies up the water. Also, another key dynamic comes into play because estrogen tends to upregulate SHBG production via decreases in PPARγ expression.

If you are confused by all this so was I, but we always have to go back to the original question – what does all this mean for the non-diseased training healthy male?

I had to ruminate on this for a bit and do some more digging. In the limited amount of research available it does seem that exercise upregulates SHBG long term (for more on exercise and testosterone see here) and that both testosterone and SHBG go up transiently with training. Also, iron overload has been found to lead to increased SHBG. Thinking globally this finding is very interesting to me as it may be getting at GI function and estrogen reabsorption and retention. Furthermore, if we go full nerdery, SHBG has three metal binding sites for divalent cations, one for calcium and two for zinc. Zinc lowers the binding affinity and magnesium has been found to decrease the affinity of SHBG to testosterone. Boron has also been found to lower SHBG and increase testosterone in an acute supplementation trail in healthy males. So nutrient status comes into play and most exercising males I see have low zinc and magnesium status.

Thus, the big three take home points in regards to SHBG are not mind blowing and we wouldn’t really expect them to be.

  1. Run labs to see if anything bigger is going on that may implicate SHBG. i.e. chronic inflammation, liver dysfunction, and/or hemochromatosis.
  2. Clear Estrogens and work on GI function.
  3. Take a Multivitamin and perhaps some extra Zinc and Boron, and definitely more Magnesium.

 

References:

Araujo, A. B., Dixon, J. M., Suarez, E. A., Murad, M. H., Guey, L. T., & Wittert, G. A. (2011). Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab, 96(10), 3007-3019. doi: 10.1210/jc.2011-1137

Avvakumov, G. V., Muller, Y. A., & Hammond, G. L. (2000). Steroid-binding specificity of human sex hormone-binding globulin is influenced by occupancy of a zinc-binding site. J Biol Chem, 275(34), 25920-25925. doi: 10.1074/jbc.M004484200

Excoffon, L., Guillaume, Y. C., Woronoff-Lemsi, M. C., & Andre, C. (2009). Magnesium effect on testosterone-SHBG association studied by a novel molecular chromatography approach. J Pharm Biomed Anal, 49(2), 175-180. doi: 10.1016/j.jpba.2008.10.041

Hammond, G. L., Avvakumov, G. V., & Muller, Y. A. (2003). Structure/function analyses of human sex hormone-binding globulin: effects of zinc on steroid-binding specificity. J Steroid Biochem Mol Biol, 85(2-5), 195-200.

Hawkins, V. N., Foster-Schubert, K., Chubak, J., Sorensen, B., Ulrich, C. M., Stancyzk, F. Z., . . . McTiernan, A. (2008). Effect of exercise on serum sex hormones in men: a 12-month randomized clinical trial. Med Sci Sports Exerc, 40(2), 223-233. doi: 10.1249/mss.0b013e31815bbba9

Khaw, K. T., Dowsett, M., Folkerd, E., Bingham, S., Wareham, N., Luben, R., . . . Day, N. (2007). Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation, 116(23), 2694-2701. doi: 10.1161/CIRCULATIONAHA.107.719005

Liu, P. Y., Beilin, J., Meier, C., Nguyen, T. V., Center, J. R., Leedman, P. J., . . . Handelsman, D. J. (2007). Age-related changes in serum testosterone and sex hormone binding globulin in Australian men: longitudinal analyses of two geographically separate regional cohorts. J Clin Endocrinol Metab, 92(9), 3599-3603. doi: 10.1210/jc.2007-0862

Morales, A., & Tenover, J. L. (2002). Androgen deficiency in the aging male: when, who, and how to investigate and treat. Urol Clin North Am, 29(4), 975-982, x.

Naghii, M. R., Mofid, M., Asgari, A. R., Hedayati, M., & Daneshpour, M. S. (2011). Comparative effects of daily and weekly boron supplementation on plasma steroid hormones and proinflammatory cytokines. J Trace Elem Med Biol, 25(1), 54-58. doi: 10.1016/j.jtemb.2010.10.001

Simo, R., Saez-Lopez, C., Barbosa-Desongles, A., Hernandez, C., & Selva, D. M. (2015). Novel insights in SHBG regulation and clinical implications. Trends Endocrinol Metab, 26(7), 376-383. doi: 10.1016/j.tem.2015.05.001

Zmuda, J. M., Thompson, P. D., & Winters, S. J. (1996). Exercise increases serum testosterone and sex hormone-binding globulin levels in older men. Metabolism, 45(8), 935-939.