Q: Why do we need SHBG? What would happen if we lowered SHBG too much? Can lowering SHBG be used as a form of Testosterone Replacement Therapy?
A: Total Testosterone (TT), BT and DHEA-S decreased with age; 0.2, 0.7 and 1.2%/year respectively. SHBG showed an increase with age of 1.1%/year. Clinically if an individual is symptomatic, a TT test is sufficient if the level is low normal oe abnormal. However, if the TT is normal one would measure SHBG and FT (or calculate FT using SHGB level) to see if the individual is T deficient using FT or BT as a reference. I know of no method naturally to manipulate SHBG levels without also affecting sex hormones.
Androgen action is the sum effect of bioactive androgens and the intrinsic responsiveness of the androgen receptor (AR) in target cells. The major circulating androgen in males is testosterone and ~98% of testosterone molecules are bound to proteins in the blood, principally to sex hormone-binding globulin (SHBG) and also to albumin and cortisol-binding globulin. It is assumed that bound hormones cannot exit blood capillaries and are therefore not bioavailable, and so SHBG concentrations are commonly measured as a supplement to total testosterone determinations. The measurement of unbound free testosterone has been proposed as a better measure of bioactive testosterone.
SHBG, corticosteroid binding globulin, and albumin are important steroid hormone binding proteins in human plasma. SHBG is best known for its role as a binding protein of sex hormones in human plasma. In normal men and women, between 40 and 65% of circulating testosterone (T) and between 20 and 40% of circulating estradiol (E2) is bound to SHBG. Binding of T to SHBG decreases its metabolic clearance rate and its conversion rate to androstenedione. Binding to SHBG also prevents bound hormone from diffusing out of the bloodstream, thereby preventing hormone binding to the intracellular androgen or estrogen receptors. The non-SHBG-bound fraction of hormone is considered to be bioactive (free hormone hypothesis).
The free hormone hypothesis states that the biological activity of a given hormone is affected by its unbound (free) rather than protein- bound concentration in the plasma. This hypothesis is likely to be valid for any given hormone will depend largely on which step in the tissue uptake process (plasma flow, dissociation from plasma binding proteins, influx, or intracellular elimination) is rate-limiting to the net tissue uptake of that hormone. The free hormone hypothesis could hold even if tissue uptake of hormone occurred by a mechanism that acted directly on one or more circulating protein- bound pools of hormone. The free hormone hypothesis is not likely to be valid for all hormones with respect to all tissues. It is likely to be valid with respect to all tissues for the thyroid hormones, for cortisol, and for the hydroxylated metabolites of vitamin D. Many of the other steroid hormones it is likely to be valid with respect to some tissues, but not with respect to others (in particular, the liver) and for some of the steroid hormones (in particular, progesterone) it may not hold at all.
The definition of androgen deficiency (AD) is still a matter of controversy. AD can be defined purely biochemically, using T levels with percentile cutoff values (e.g. 2.5 standard deviations below the range for normal young males), or using only signs and symptoms. This has attempted to be remedied by using FT as a measurement. The growing interest in measuring blood free testosterone (FT) is constrained by the unsuitability of the laborious reference methods for wider adoption in routine diagnostic laboratories. Various alternative derived testosterone measures have been proposed to estimate FT from either additional assay steps or calculations using total testosterone (TT) and sex hormone-binding globulin (SHBG) measured in the same sample. Currently, there is no standardized reference for FT.
The place of SHBG in the androgen system is controversial. On one hand, it is generally accepted that androgens, unlike estrogens, reduce SHBG concentrations. Thus, SHBG concentrations are lower in males administered AAS. Administration of testosterone results in a 2-fold lowering of SHBG in normal and hypogonadal men. On the other hand, concentrations of testosterone and SHBG in males appear to be positively correlated.
In vitro experiments show that with increasing levels of SHBG and stable levels of T and E2 the ratio of unbound E2 to unbound T increases. T and E2 bind to the same binding site on SHBG, but the binding affinity for T is higher than that for E2. On the basis of the relatively greater decrease in the bioavailability of T compared with that of E2, SHBG has been regarded as an estrogen amplifier.
Clinical findings show with increasing SHBG levels the non-SHBG-bound fraction of T decreased from 80 to 36% and that of E2 from 89 to 53%. Higher levels of SHBG were associated with higher levels of both total T and total E2. Higher SHBG levels are associated with lower levels of non-SHBG-E2 but slightly higher levels of non-SHBG-T (SHBG levels were negatively related with levels of non-SHBG-E2 whereas there was a positive association between levels of SHBG and non-SHBG-T.) There is a negative relationship between SHBG levels and the E2/T ratio of either total or non-SHBG-bound hormone. High concentration of SHBG is associated with a lower (non-SHBG-bound) estrogen/androgen ratio and vice versa.
In eugonadal men the HPTA will respond to a decreasing level of non-SHBG-T with an increase in LH and T, assuming that non-SHBG-T is driving the feedback inhibition of the HPTA. In cross-sectional studies, the plasma concentrations of T and SHBG are positively correlated. This correlation not only reflects the high binding affinity of SHBG for T, resulting in increased storage of the steroid, but may also be explained by the effect of SHBG levels on the bioavailability of T. Higher SHBG levels would then lead to lower levels of bioactive T, a decreased feedback signal on GnRH and thereby on LH secretion by the pituitary and a subsequent increase of T levels until a new set point is reached. Endogenous E2 can also have an effect on LH release by the pituitary. When bioavailable E2 levels decrease, this might lead to increased LH release by the pituitary with a resulting increase in testicular T production. The decreased feedback inhibition of non-SHBG-E2 on the release of LH by the pituitary probably explains the slightly positive relationship between levels of non-SHBG-T and SHBG.
The fact that an intact HPTA appears to prevent the non-SHBG-T concentration to fall with increasing SHBG levels makes the in vivo situation in eugonadal men totally different from the in vitro situation where changes in hormone binding to SHBG do not evoke adaptations in the HPTA. This means that SHBG cannot be regarded as an estrogen amplifier in eugonadal men.
This has important implications for androgen action since <40% of testosterone is physiologically bound to SHBG, and is therefore not biologically active. The positive correlation of SHBG with testosterone will tend to minimize and moderate the androgenic effects of changing total testosterone in men.
Low serum SHBG, low total testosterone, and clinical AD are associated with increased risk of developing Metabolic Syndrome over time, particularly in nonoverweight, middle-aged men (BMI, <25). Low SHBG and/or AD may provide early warning signs for cardiovascular risk and an opportunity for early intervention in nonobese men.
Total E2 levels will be increased only if T is subsequently aromatized, the extent of which is influenced by parameters such as age and BMI. However, in contrast to T, E2 levels are not directly regulated by HPTA activity. The regulation of peripheral E2 levels by the HPTA is indirect and therefore probably not as tight compared with T levels.
Conditions associated with high SHBG levels in men such as advanced age, liver disease, hyperthyroidism, and estrogen administration. These conditions are associated with increased estrogen/androgen ratios and gynecomastia, and they seem to confirm the concept of SHBG as an estrogen amplifier.
In the pathogenesis of gynecomastia, a high estrogen/androgen balance seems to be of importance. Men with low levels of SHBG and a resulting high estrogen/androgen ratio would have a higher risk of developing gynecomastia, although this association has not been reported in the literature. Probably the changes in the estrogen/androgen ratio brought about by SHBG in eugonadal men are too subtle to cause gynecomastia.
However, besides the altered SHBG levels, these conditions are also associated with altered gonadal function. Hypogonadism is frequently observed in liver cirrhosis patients. In hyperthyroid men, lower levels of non-SHBG-T are frequently but not always reported, which suggests that the HPTA in these men is not always able to fully compensate for the rise in SHBG concentration. Moreover, the increased estrogen/androgen ratio in hyperthyroid subjects might be caused by increased androgen aromatization. The age-associated increase in SHBG is not associated with an increase in T levels, which suggests that the HPTA of older men is not capable of responding to a fall in T levels. Therefore, it is likely that the relative hypogonadism and not the increased SHBG per se may explain the high estrogen/androgen ratio in these men.