Why free testosterone isn’t everything

Some may think that free testosterone is the only form of androgens that can exert an anabolic/androgenic effect as only free testosterone is able to enter a cell, or bind to an androgen receptor. Total testosterone is currently classified in four major fractions: SHBG-bound testosterone (∼44%), albumin-bound testosterone (∼50%), cortisol-binding globulin–bound testosterone (∼4%), and unbound or free testosterone (∼2%) (1). Whereas only 20 to 40% of circulating estradiol is bound to SHBG.

Testosterone binds with a much higher affinity (greater strength) to SHBG than to albumin, which makes albumin-bound testosterone still somewhat useful as it can still disassociate from the transport protein and bind to a receptor.

Free testosterone – most available, albumin-bound testosterone – somewhat available, SHBG testosterone – useless…

Or so it is believed by many.

Free testosterone

Free testosterone is able to enter a cell much faster than bound testosterone, but it is also cleared out of the cell much faster and degraded and excreted by the liver. Free androgen uptake is in any way regulated by the condition of the cell. A lipophilic (fat loving) cell due to low levels of PUFA would resist entry of hydrophilic (water-loving) steroids like estrogen, cortisol and aldosterone while allowing entry of steroid like DHT, androsterone, T, pregnenolone, progesterone, and DHEA more easily. PUFA inhibits cellular uptake of testosterone and DHT, while promoting uptake of cortisol and estrogen.

 

Albumin-bound testosterone

Albumin-bound testosterone is also able to enter a cell and exert an anabolic androgenic effect. (2) Also, albumin-bound testosterone greatly exceeds free testosterone transport into the brain. Neither free testosterone of globulin bound testosterone appear to be transported into the brain to a significant extent. (3)

However, albumin-bound steroid hormones are freely cleared (not metabolized and excreted) by the liver and, in the case of cortisol or estradiol, the fraction bound to a specific globulin is also transported into the liver.

The plasma proteins (albumin and specific globulins) in human serum inhibits the liver clearance of the respective steroid hormones to a variable extent. (4)

 

Globulin bound testosterone

SHBG is a glycoprotein produced mainly in the liver, as well as locally in other tissue including the testes.

Just like albumin-bound testosterone, SHBG bound testosterone decreases the metabolic clearance rate of androgens and also prevents the testosterone conversion rate to androstenedione (a weaker androgenic metabolite). (5)

SHBG actually has its own receptor, R(SHBG), which is on cell membranes and when SHBG binds to its receptor, it forms an SHBG-R(SHBG) complex. When an appropriate steroid binds to this complex, there is a rapid rise in intracellular cyclic adenosine monophosphate (cAMP) via G protein.  (6) This in itself can stimulate muscle protein synthesis, testosterone synthesis, etc…

It has been suggested that estradiol can activate the SHBG/SHBG-R complex and cross-talk with the androgen receptors, and is then able to activate androgen receptors even in the absence of DHT. Thus human SHBG has an anti-proliferative and anti-estrogenic effect. (7)

SHBG is internalized into cells through the Megalin receptor (8). Intracellular expression of SHBG in mouse proximal tubule cells have been demonstrated to increase the uptake of DHT and also prolong the expression of androgen-responsive genes (8).

In this study, they have demonstrated that in the absence of SHBG large amounts of testosterone rapidly enter the cell where they are inactivated by conjugation to glucuronic acid and effluxed. In the presence of SHBG however, while there is reduced testosterone uptake, glucuronidation and efflux of testosterone are also reduced and the effects of testosterone on androgen-responsive genes are enhanced. (8)

As quoted from the study: “LNCaP cells internalized SHBG by a testosterone independent process. Testosterone was rapidly taken up and effluxed (transported out) as testosterone-glucuronide via testosterone glucuronidation, however, this effect was reduced by the presence of SHBG. Addition of SHBG, rather than reducing testosterone bioavailability, further increased testosterone-induced expression of prostate-specific antigen and enhanced testosterone-induced reduction of androgen receptor mRNA expression.” (8)

SHBG has consequently been regarded as an estrogen amplifier from in vitro results studies, but now: “we conclude that in eugonadal men, higher SHBG levels are associated with lower levels of non-SHBG-E2 (bio-available estrogen) but slightly higher levels of non-SHBG-T (bio-available testosterone). This means that SHBG cannot be regarded as an estrogen amplifier in eugonadal men.”

Furthermore, from the same study, a positive relationship was seen between SHBG levels and the T/E2 ratio (more testosterone less estrogen). All this concludes, more SHBG results in less free or bioavailable estradiol, and more total and bioavailable testosterone. (11)

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This might be explained by, when bioavailable E2 levels decrease, LH is released by the pituitary with a resulting increase in testicular T production. Total E2 levels will be increased only if T is subsequently aromatized. (5) More on inhibiting the aromatase here…

Lower SHBG means more free estrogen than free testosterone as SHBG prefers to rather bind to testosterone than to estrogen. (12)

To sum it up, SHBG:

  • Inhibits androgen clearance by the liver
  • Amplifies androgens function
  • Increases total, and slightly free, testosterone
  • Decreases total, and slightly free, estrogen
  • slows the rate of T uptake into the cerebrospinal fluid during non-equilibrium conditions, protecting the tissue from androgen overload. (2)

4 thoughts on “Why free testosterone isn’t everything

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