What is the real story on SHBG?
As the name implies sex hormone-binding globulin (SHBG) is a globulin (a protein made up of about 400 amino acids) that binds to sex hormones which include testosterone, estrogen and more.
It is the main component that is the difference between Total Testosterone and Free Testosterone. Free testosterone is what is not bound to SHBG as well as another protein, albumin. The binding is stronger with SHBG and weaker with albumin. That means that testosterone is not likely to separate from SHBG once bound but can more easily do so with albumin.
Sometimes these are even subdivided further. Bioavailable testosterone is total testosterone minus that bound to SHBG but NOT to albumin. Whereas free testosterone is total testosterone found minus that bound to SHBG AND to albumin.
Technically there will be total and free estradiol, total and free dihydrotestosterone (DHT), etc. but these are not often measured.
SHBG has a stronger affinity for certain hormones. Science says that it’ll bind in this order:
DHT > Testosterone > Androstenediol > Estradiol > Estrone [1]
It also binds to other sex hormones, such as DHEA, progesterone, but where those fit in the above isn’t quite clear. Interestingly, androstenedione does not bind to SHBG.
Women tend to have about twice as much SHBG than men. During pregnancy, levels can increase by five to ten times the amount.[2]
SHBG is produced primarily in the liver and enters the bloodstream from there. But it can also be produced in the brain, testes, kidneys, prostate, uterus, and placenta.[3]
To make it more confusing the testis-produced SHBG is sometimes called androgen-binding protein. The only known difference in it is the attachment of oligosaccharides.
Reference Ranges
Men: 10–57 nmol/L
Women: 18–144 nmol/L
As with all reference ranges, different labs and different doctors will say different amounts should be used. These are typical ranges, but some will be somewhat different.
The Old (Incomplete) Story of SHBG
Testosterone can only exert its action if it is freely available. That means it is able to enter into cells and attached to receptors.
If testosterone is bound to SHBG it will not be able to do anything. SHBG effectively renders it inert.
…But this is a flawed picture, or incomplete at best.
As often happens in science. We find something and identify what it does. So we think that is all that it does. But more science happens, and we eventually realize that there are 100 different things happening. Biology is complex!
This original idea about SHBG was born out of the limited cell culture studies. And what happens in a petri dish is not necessarily what happens inside the body…especially when only certain cell types are looked at.
The New Science and Latest Studies on SHBG
SHBG does NOT just bind to hormones and render them inert. It transports them around the body. It keeps them from degrading and passing out of the body.
Perhaps most important, there are SHBG binding sites on certain cells. This means that SHBG, bound with testosterone or whatever else, can still connect and be active on certain cell receptors. It is not just testosterone or the other sex hormones by themselves that are “active”.
A literature review on the topic said this:
“Starting with the idea that SHBG is an active participant in steroid action demands a re-evaluation of data demonstrating a primary change in blood SHBG levels in association with various pathologies. Here we discuss the postulate that SHBG may act at its own receptor at the plasma membrane level to influence other receptors.”[4]
Its sort of similar to vitamin D. Vitamin D is not really a vitamin so much as a hormone-precursor. Originally, it was thought to be important in bone health. It is…but that is just one of the hundreds, even thousands, of functions. Vitamin D has receptors on pretty much every cell in the body.
It’s looking like SHBG plays such a role. Maybe not quite as big, but certainly far more than was previously thought.
InsideTracker put it this way, “SHBG is a multifunctional player that can orchestrate steroid action to a degree far greater than that attributed to it just through its binding ability, so I think it’s safe to say that the free hormone hypothesis is a myth, at least in its absolute sense.”
And you can read more of the specific details with megalin, cAMP and more on their blog here.
This picture shows the difference in how free hormones may interact with cells compared to SHBG basically docking onto a cell then releasing the hormones. [5]
SHBG and Genetics
Every test I personally do I have high SHBG.
And my brother Zane has also tested his SHBG a couple of times and he found the same thing.
Looking into genetic research we do see a bit of information on this topic. A mutation on Chromosome 17 can cause changes with a longer half-life for SHBG, thus greater circulating levels.[6]
Although I am far removed from being a genetic determinist, that doesn’t mean that genetics don’t matter at all. They do. And SHBG seems to be one place where we can see some differences.
My guess is that we may have such mutations that increase SHBG based on this limited information. But I’m interested in hearing from more people. Do you always have high or low SHBG no matter what you do? Post in the comments below and share your story.
SHBG and EDC’s
Inside of Upgrade Your Testosterone, I was still under the spell of the old theory about SHBG. The next time that is updated the newer information will be in it. Unfortunately, this is how science progresses…which is why these days I tend to look at the bigger picture principles which help me to not fall into such traps.
But I did mention a theory, that shows I was looking at the bigger picture a bit, I had in there:
“I have a theory that aging people in Western societies are seeing such higher amounts of
SHBG because of the excess of estrogenic chemicals. It’s possible that the human body is
producing more SHBG to try to bind to these and transport them around. It’s just that this
has a higher affinity for the androgens. Just a theory though, as I haven’t seen evidence to
back this idea up specifically.”
When researching this article I came across a study saying, “Evidence suggests that SHBG is capable of binding a wide range of xenobiotics.”[7]
This is exciting. It means that SHBG has the capacity to bind to at least some of the many endocrine-disrupting chemicals. This was shown in oral contraceptives but likely occurs with others.
As I’ve covered the subject many times before, including a recent comprehensive article on Endocrine Disrupting Chemicals, I do as much as I can to avoid these. But because they’re in the very air we breathe, we can’t avoid them entirely.
So is my high SHBG in part because my body deals well with the limited EDC’s I come into contact with? I certainly can’t say for sure, but it is a hypothesis worth exploring further.
That’s going to wrap up this first part on SHBG. In part two, we’ll be looking at various interventions in diet, training, body fat and more and how these can raise or lower SHBG. And, of course, herbs that affect this area too.
References:
1. Somboonporn W, Davis SR (June 2004). “Testosterone effects on the breast: implications for testosterone therapy for women”. Endocrine Reviews. 25 (3): 374–88. doi:10.1210/er.2003-0016. PMID 15180949. https://www.ncbi.nlm.nih.gov/pubmed/15180949
2. Winters SJ, Huhtaniemi IT (25 April 2017). Male Hypogonadism: Basic, Clinical and Therapeutic Principles. Humana Press. p. 307. ISBN 978-3-319-53298-1
3. Hammond GL, Bocchinfuso WP (1996). “Sex hormone-binding globulin: gene organization and structure/function analyses”. Hormone Research. 45 (3–5): 197–201. doi:10.1159/000184787. PMID 8964583. https://www.ncbi.nlm.nih.gov/pubmed/8964583
4. Caldwell, Jack & Jirikowski, Gustav. (2008). Sex Hormone Binding Globulin and Aging. Hormone and Metabolic Research 41(3):173-82 November 2008 https://www.researchgate.net/publication/23424055_Sex_Hormone_Binding_Globulin_and_Aging
5. John S. Adams. “Bound” to Work: The Free Hormone Hypothesis Revisited. Cell Volume 122, Issue 5, 9 September 2005, Pages 647-649. https://www.sciencedirect.com/science/article/pii/S0092867405008615|
6. Piotrowski P, Gasik R, Lianeri M, Cieślak D, Wudarski M, Hrycaj P, Łacki JK, Jagodziński PP (January 2010). “Asp327Asn polymorphism of sex hormone-binding globulin gene is associated with systemic lupus erythematosus incidence”. Molecular Biology Reports. 37 (1): 235–9. doi:10.1007/s11033-009-9639-7. PMID 19649728. https://www.ncbi.nlm.nih.gov/pubmed/19649728
7. Hammond GL. Diverse roles for sex hormone-binding globulin in reproduction. Biol Reprod. 2011;85(3):431–441. doi:10.1095/biolreprod.111.092593. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480437/
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Lost Empire Herbs
Great Article my SHBG has been very high for years as the last test I did was at 70. I have done my own research on how to lower shbg to free up my low T. I have tried various supplements including Boron and Nettle Root however it has not really budged. I have decided to take some time away from the Gym as perhaps lowering my CK and muscle tissue break down from regular exercise might help ?
I am really looking forward to reading part two in your series and finding a way to bring my SHBG down. Keep up the good work.
Let me know if the break from the gym moves the number at all.
I have had to endure lower Testosterone most of my life and so ive been tested a bunch of times and have been to the endocrinoligist a few times. The lack of information we get from endo doctors is angering to be quite frank. My peak morning total Testosterone usually 400+ ng/dl. Over the years I have had SHBG, estradiol, LH etc all tested as well. Regarding SHBG my latest tests have come in on the lower side 25 or below with the end being close to 60. I was wondering is there a way to raise SHBG a bit? Also I think it would be interesting if you did a deep dive blog post on Prolactin as well. These two take a negative beating but there both not all bad and having low levels of either is not necessarily a good thing. Even though thats what high T seekers and bodybuilding types have believed for years!
Part two on SHBG goes into what can be done as far as raising or lowering it.
And as for prolactin, my brother did an article on that one a while back: https://lostempireherbs.com/prolactin/
Hi Logan ,
Very interesting article , thank you . I was regularly obtaining private blood tests , partly to learn how my body works and also the effect of herbs and supplements on my blood markers . The last time i had my SHBG checked was in June 2018 and it came in at : SEX HORMONE BINDING GLOB 54 nmol/L ( 16.00 – 55.00 was the recommended levels according to the company i use ) . I love your theory around SHBG helping us in our fight against EDC’s . I’ve never really believed fully that a raised SHBG level was a fully negative factor and always thought there was a lot more to it than the information that it renders our testosterone inert . As you say , science and the biology are always making giant leaps forward and information is constantly changing . I look forward to the second part .
It seems that the level itself doesn’t show cause. Based on this it seems like SHBG could be high for good reasons and SHBG can be high for bad reasons. Glad you like the article.