Endocrine Abstracts

Steroid bioavailability is delineated by the “free hormone hypothesis” and its underlying tenet that only steroids not bound by plasma proteins enter cells. Steroid hormones, as well as their unconjugated precursors and metabolites, circulate bound by several unrelated plasma proteins, including albumin, orosomucoid, sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG), while the more water soluble sulphated steroid conjugates are bound largely by albumin. The amounts and physicochemical properties of these proteins collectively determine the plasma distribution of their respective steroid ligands and how much of them exists in the nonprotein-bound or ‘free’ fraction that is accessible to cells. The tissue localization and extravascular disposition of plasma steroid-binding proteins varies considerably and is not well understood in the context of determining steroid bioavailability. With the exception of aldosterone, biologically active steroid hormones and some of their immediate precursors and metabolites are bound primarily by one of the high affinity binding proteins, SHBG or CBG, and this limits their metabolic clearance and bioavailability. Many steroid hormone precursors or metabolites are bound primarily by albumin and their non-protein bound concentrations in the blood approach or even exceed those of the active hormones, and this underpins the importance of their local metabolic ‘intracrine’ conversion into active sex steroids. Genetic differences that alter the production and function of SHBG and CBG have been identified and have confirmed these proteins are the main determinants the plasma concentrations of their respective steroid ligands, and some have been linked to specific clinical conditions. Pharmaceutical interventions to increase plasma SHBG levels have been used to treat symptom of androgen excess in women, and non-steroidal ligands that competitively occupy the steroid-binding sites of SHBG and CBG may provide a means of enhancing the biological activities of their natural steroid hormone ligands.