This is an abridged form of an article that appears here: http://blog.insidetracker.com/sex-hormone-binding-globulin-new-science-questions-old-beliefs
SHBG is a sex steroid binding protein that’s gotten a lot of bad rap in the past. But this may largely be based on faulty interpretation of in vitro research experiments that were not set up to answer an inherently physiologically complex question.
The SHBG protein, along with albumin, are the primary plasma proteins responsible for binding testosterone and estradiol, with just 2-3% of the steroids believed to be free and unbound. SHBG is glycosylated, which means that it has sugar structures attached to it, and this, as we’ll see, can mean that the protein can vary in its characteristics from person to person depending on the genetic make-up.
According to the “free hormone hypothesis” only free steroids are biologically active, whereas those complexed with SHBG are inactive. As we’ll see, this notion can no longer be taken at face value. First, the idea behind the hypothesis was that only the free or albumin-bound fractions could diffuse out of and capillaries and into cells. But, this was largely based on in vitro 1980s research in cultured cells. Here, the researchers found that testosterone could not get into these cells when SHBG was also present in the solution.
This kind of experimental set-up may be useful for looking at steroid-signalling pathways but it will tell you very little about whether SHBG will block any steroid in vivo! You see, academic researchers tend to pick cell types based on a what’s available, relatively easy to work with (some cell lines are NOT!), and not prohibitively expensive. That they chose a cell line without the capacity to interact with SHBG was unfortunate because it helped engrain the misleading notion that SHBG blocks testosterone from entering cells in general!Had these experiments been performed using cells from sex steroid responsive tissues, such as prostate or endometrium, the results would have been very different!
The lesson is that there is no way to represent all the different cell types and their myriad of differentially expressed receptors that are present in our bodies, so we should be very careful when extrapolating the results of isolated experiments to our higher-level physiology!
That intracellular SHBG exists was described over four decades ago, and it is now clear that there is a SHBG-specific cell surface receptor (termed RSHBG) that binds the molecule in its free form (but not bound to T or E2). The SHBG-receptor complex is activated (or inhibited) by certain steroids (SHBG can bind steroids with affinity equal to its solution state once bound to RSHBG) and signals a chain of events that begin with generation of cyclic adenosine monophosphaate (cAMP), with the downstream effects being tissue dependent.The fact that SHBG’s downstream intracellular effects involve cAMP is an exciting finding in and of itself because this second messenger is a key player in relaying messages from hormones on the outside to the inside of the cells.
cAMP is also involved in turning on enzymes (called protein kinases) that regulate the effects of molecules like adrenaline and glucagon. The exact mechanism of how the binding and activation of the SHBG-RSHBG complex affects cells is still unclear, but judging from the clinical metabolic trends and correlations we see (described below) these effects are definitely real.
Interestingly, RSHBG’s actions are independent of the androgen and estrogen receptors, and it seems like location is key because the same steroid can either inhibit or activate the receptor depending on the tissue type.So, as you see, SHBG is not the evil annihilator of sex steroid action, but may actually have a role in enhancing it in a tissue-specific manner.
Megalin, a member of the LDL protein family, is another cell-surface receptor known to be a key player in Vitamin A & D metabolism. These vitamin hormones also tend to be bound by plasma proteins and, when they encounter megalin, this receptor is able to sequester them into the intracellular environment.
Once within the cell, the carrier proteins are degraded and the ligands (in this case, Vitamins A & D) are released into the cytosol for further metabolism. Recent work indicates that megalin is also expressed in sex-steroid responsive tissues (including skeletal muscle!) and similarly internalizes SHBG-bound steroids!
More research is needed into the true significance of this finding, but it certainly adds to mounting evidence that SHBG may be an active little protein in all things metabolism.
Taken together, the body of research on SHBG’s multiple functions puts the biomarker’s level fluctuations into context. That Joe has a SHBG level of 50 nmol/L level and Jeff has 30 nmol/L and both have the same plasma testosterone concentration (in the optimal range) does not necessarily mean that Jeff is better off due his higher free testosterone. That’s because tissue distribution of both RSHBG, megalin, as well as the presence of SHBG glycosylation variants all factor into the ability of testosterone to enter various responsive tissues and the plasma clearance of the steroid.
Thus, 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 say that the free hormone hypothesis is a myth, at least in its absolute sense.