Upon their release from the steroidogenic cells of the adrenals, gonads and placenta, biologically active steroids are sequestered and transported in the blood bound by several proteins, including albumin, sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG). Together they also regulate the non-protein bound or free fractions of steroid hormones in the blood and therefore control their ability to exit the blood circulation and enter target tissues and specific cell types. As such, these plasma proteins can be viewed as the primary gatekeepers of steroid action.
Albumin binds steroids with limited specificity and low affinity but its enormous capacity allows it to effectively buffer major fluctuations in the plasma levels of steroids. By contrast, SHBG and CBG play more dynamic roles in controlling the freedom of steroids to act in health and disease. They bind biologically active steroids with very high affinity and specificity, with SHBG binding androgens and estrogens and CBG binding glucocorticoids and progesterone. They are both glycoproteins but structurally unrelated and function in very different ways that extend well beyond a simple transport or buffering function in the blood. The liver is the major site of production for plasma SHBG and CBG, but their genes are also expressed in several other tissues, in which these proteins appear to function differently in extravascular compartments than in the blood. Programmed fluctuations in the tissue specific expression of SHBG and CBG occur throughout development, and abnormal plasma levels have been linked to disease risk or occur in response to pathologies. Understanding how the unique structures of SHBG and CBG determine their specialized functions, how changes in their plasma levels are controlled, and how they function outside the blood circulation provides insight into how they control the freedom of steroids to act in health and disease.