Testosterone in blood

Testosterone circulates in serum largely bound to transport proteins. Like other steroids and thyroid hormones, both albumin and specific binding globulins are involved in testosterone binding. Testosterone binds to albumin with low affinity but, due to its high concentration, albumin displays a very high binding capacity. The specific transport protein for testosterone, some other androgens and estradiol is SHBG. A systematic analysis of serum transport of steroid hormones and their interaction with binding proteins revealed an association constant of SHBG of 1.6 x

109 M-1 for testosterone and of 5.5 x 109 M-1 for DHT at 37°C(Dunn etal. 1981). By comparison the association constant of albumin for testosterone is five orders of magnitude lower (6 x 104 M-1) (Anderson 1974). The relative amounts ofprotein binding of circulating testosterone in men and women is shown in Table 21.1.

About 1.5-2% of serum testosterone is free and is believed to represent bioactive testosterone. According to the free hormone hypothesis, it is only the free hormone fraction that is accessible to all body compartments and can enter the cells, exerting its action where androgen receptors are available. The free diffusion of unbound testosterone in all cells and organs is demonstrated by the same free testosterone concentration in all body fluids, e.g. in blood and in saliva. Free and protein-bound testosterone and DHT are in equilibrium, so that when free hormone is subtracted from circulation because of entry into tissue, new testosterone dissociates from albumin and SHBG, a new equilibrium is promptly reached and the free hormone concentration in serum remains constant. Conversely, pathophysiological conditions causing changes inbindingprotein concentration (e.g. pregnancy, hypo-or hyperthyroidism, growth hormone excess, treatment with antiepileptic drugs) or displacement of testosterone from SHBG by drugs (e.g. danazol) results in changes in total testosterone concentration in order to maintain constant free testosterone levels (Pugeat etal. 1981).

As indicated below in this chapter, measurement of SHBG is valuable for assessment of androgenization and of free testosterone. In earlier times SHBG was measured indirectly, by estimating its binding capacity. The classic method used tritiated DHT as ligand because of its higher affinity to SHBG and lack of binding to cortisol binding globulin (CBG). Saturating amounts of labeled DHT were added to the samples and SHBG was then precipitated by ammonium sulfate. The amount of labeled DHT precipitated provided a direct measurement of SHBG binding capacity. This method did not allow absolute changes in SHBG protein concentrations to be measured, which can now be assessed by modern immunoradiometric assays. Modern assays have demonstrated that, in general, SHBG binding capacity (expressed in terms of DHT binding) corresponds acceptably to the molar SHBG concentration.

The free hormone hypothesis has been repeatedly challenged in the scientific literature, mainly due to the difficulty of reconciling the existing experimental evidence with appropriate mathematical models of hormone transport (Ekins 1990; Mendel 1992). For instance, the low affinity of testosterone for albumin binding and some experimental data led to the idea that albumin-bound testosterone is readily available for delivery to the tissues (i.e. bioavailable) while only SHBG-bound testosterone is not biologically active (Manni et al. 1985). This view has now been corroborated by serum androgen bioassays (see below). In contrast, SHBG itself has been proposed to interact with cell surface receptors, thereby contributing to the biological activity of androgens (Rosner etal. 1999). This novel, putative function of SHBG is of particular interest in the light of the essential lack of any physiological explanation why primates, unlike all other species, possess such a protein. SHBG seems to "buffer" serum testosterone levels, which, beside the physiological circadian rhythm, show only minor circhoral variations despite highly pulsatile LH secretion (Simoni etal. 1988 and 1992). On the contrary, serum testosterone levels oscillate widely in rodents, which do not have SHBG. In addition SHBG reduces the rate of hepatic testosterone degradation. There are no known cases of congenital absence of SHBG in humans but an analbuminemic strain of rats, a species which does not have circulating SHBG, is normally fertile and shows normal free testosterone levels, arguing for a dispensable role of serum testosterone binding proteins (Mendel et al. 1989). Similarly, the congenital absence of thyroxin binding globulin (TBG) in humans is compatible with normal thyroid function (Dussault et al. 1977).

Since SHBG concentrations influence total and free testosterone levels, it is important to know which factors influence SHBG production. Of the hormones, estrogens stimulate and androgens inhibit SHBG secretion. Administration of 20 |xg daily of ethinyl estradiol to men for 5 weeks resulted in a 150% increase in SHBG and, as a consequence of the reduced free testosterone levels, in a 50% increase in total serum testosterone (Anderson 1974). The estrogen effect is evident in women, who have SHBG serum levels double of those in men, and during pregnancy, when SHBG rises to levels 5-10 times higher than in non-pregnant women. In addition, SHBG levels are stimulated by thyroid hormones, resulting in high levels in thyro-toxycosis and low levels in hypothyroidism, and are reduced by growth hormone and cortisol, resulting in low levels in acromegaly and in Cushing syndrome. Finally, SHBG levels are higher in children than in adults and increase in men after the age of 50, contributing to the possible decline of free testosterone levels observed in aging men.

The most important bioactive metabolite of testosterone is DHT. The reduction of testosterone to DHT occurs in those tissues expressing 5a-reductase (see Chap. 1 and Chap. 18) and DHT is well measurable in circulation. In eugonadal, adult men serum DHT concentrations are about 10-12 times lower than testosterone and DHT is mainly bound to SHBG. Given the role of DHT in prostate growth, the measurement of serum DHT is of relevance during testosterone treatment, especially when testosterone is administered via the trans-cutaneous route, (e.g. testosterone gel or patches) since the skin is the primary organ for 5a-reduction.

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