Transport of Steroid Hormones in Blood

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diol. When the circulating levels of the active form of vitamin D (1, 25(OH)2D3) are high, hydroxylations at the 24 and 25 positions are favored and the inactive 24,25
(OH)2­vitamin D3 compound is generated.
21.6— Transport of Steroid Hormones in Blood
Steroid Hormones Are Bound to Specific Proteins or Albumin in Blood
There are four major proteins in the circulation that account for much of the steroid hormones bound in the blood. They assist in maintaining a level of these hormones in the circulation and protect the hormone from metabolism and inactivation. The binding proteins of importance are corticosteroid­binding globulin protein, sex hormone­binding protein, androgen­binding protein, and albumin.
Corticosteroid­binding globulin (CBG) or transcortin is about 52 kDa, is 3–4 mg% in human plasma, and binds about 80% of the total 17­hydroxysteroids in the blood. In the case of cortisol, which is the principal antistress corticosteroid in humans, about 75% is bound by CBG, 22% is bound in a loose manner to albumin, and 8% is in free form. The unbound cortisol is the form that can permeate cells and bind to intracellular receptors to produce biological effects. The CBG has a high affinity for cortisol with a binding constant (Ka) of 2.4 × 107 M–1. Critical structural determinants for steroid binding to CBG are the 4­3­ketone and 20­ketone structures. Aldosterone binds weakly to CBG but is also bound by albumin and other plasma proteins. Normally, 60% of aldosterone is bound to albumin and 10% is bound to CBG. In human serum, albumin is 1000­fold the concentration of CBG and binds cortisol with an affinity of 103 M–1, much lower than the affinity of CBG for cortisol. Thus cortisol will always fill CBG­binding sites first. During stress, when secretion of cortisol is very high, CBG sites will be filled but there will be sufficient albumin to accommodate excess cortisol.
Sex hormone binding globulin (SHBG) (40 kDa) binds androgens with an affinity constant of about 109 M–1, which is much tighter than albumin binding of androgens. One to three percent of testosterone is unbound in the circulation and 10% is bound to SHBG, with the remainder bound to albumin. The level of SHBG is probably important in controlling the balance between circulating androgens and estrogens along with the actual amounts of these hormones produced in given situations. About 97–99% of bound testosterone is bound reversibly to SHBG but much less estrogen is bound to this protein in the female. As mentioned above, only the unbound steroid hormone can permeate cells and bind to intracellular receptors, thus expressing its activity. The level of SHBG before puberty is about the same in males and females, but, at puberty, when the functioning of the sex hormones becomes important, there is a small decrease in the level of circulating SHBG in females and a larger decrease in males, ensuring a relatively greater amount of the unbound, biologically active sex hormones—testosterone and 17b ­estradiol. In adults, males have about one­ half as much circulating SHBG as females, so that the unbound testosterone in males is about 20 times greater than in females. In addition, the total (bound plus unbound) concentration of testosterone is about 40 times greater in males. Testosterone itself lowers SHBG levels in blood, whereas 17 b ­estradiol raises SHBG levels in blood. These effects have important ramifications in pregnancy and in other conditions.
Androgen binding protein (ABP) is produced by Sertoli cells in response to testosterone and FSH, both of which stimulate protein synthesis in these cells. Androgen­binding protein is doubtless not of great importance in the entire blood circulation but is important because it maintains a ready supply of testosterone for the production of protein constituents of spermatozoa. Its