Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action

Abstract

Biologically active steroids are transported in the blood by albumin, sex hormone-binding globulin (SHBG), and corticosteroid-binding globulin (CBG). These plasma proteins also regulate the non-protein-bound or 'free' fractions of circulating steroid hormones that are considered to be biologically active; as such, they can be viewed as the 'primary gatekeepers of steroid action'. Albumin binds steroids with limited specificity and low affinity, but its high concentration in blood buffers major fluctuations in steroid concentrations and their free fractions. By contrast, SHBG and CBG play much more dynamic roles in controlling steroid access to target tissues and cells. They bind steroids with high (~nM) affinity and specificity, with SHBG binding androgens and estrogens and CBG binding glucocorticoids and progesterone. Both are glycoproteins that are structurally unrelated, and they function in different ways that extend beyond their transportation or buffering functions in the blood. Plasma SHBG and CBG production by the liver varies during development and different physiological or pathophysiological conditions, and abnormalities in the plasma levels of SHBG and CBG or their abilities to bind steroids are associated with a variety of 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.

Keywords: albumin; corticosteroid-binding globulin; estradiol; glucocorticoids; progesterone; serine protease inhibitor; sex hormone-binding globulin; testosterone.

Figure 1

(A) Influence of CBG on the plasma distribution of cortisol. (B) Estimated proportional occupancy of plasma CBG by its major ligands, cortisol and progesterone, in blood samples taken from women before and during pregnancy, and the invervillous compartment of the placenta at term. (A) The plasma distribution of cortisol in individuals with normal CBG (WT); a CBG D367N variant with a four-fold reduction in affinity for cortisol (Emptoz-Bonneton et al. 2000), or after heat denaturation to inactivate CBG in a normal human sample (Siiteri et al. 1982), were determined by centrifugal ultrafiltration dialysis (Hammond et al. 1980). Note that the cortisol distribution in plasma with inactive CBG is expected to resemble that in patients homozygous for naturally occurring CBG variants with undetectable steroid-binding activity, for example, CBG G237V (Perogamvros et al. 2010) or CBG W371S (Hill et al. 2012). (B) Proportional occupancy of CBG in serum from women during the luteal phase of the menstrual cycle vs the third trimester of pregnancy as estimated computationally from data of serum CBG, cortisol and progesterone levels (Dunn et al. 1981).