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

Geoffrey L Hammond

doi:10.1530/joe-16-0070

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.

Highlights

Upon their release from steroidogenic cells, biologically active steroids are transported in the blood largely by albumin, sex hormone-binding globulin (SHBG), and corticosteroid-binding globulin (CBG)
Plasma CBG and SHBG are structurally unrelated and function in very different ways that extend well beyond simple transportation or buffering functions in the blood. Their crystal structures have demonstrated how they interact with their preferred steroid ligands, as well as providing insight into other functionally important properties, including the consequences of the reactive center loop’ (RCL) cleavage of CBG by specific proteases in the context of infectious and inflammatory diseases, and the impact of dimerization and the binding of divalent cations (Ca2+ and Zn2+) on the steroid-binding properties of SHBG
Knowledge of the structures together with the identification of naturally occurring variants of CBG and SHBG provide additional insight into their production and functions. They illustrate the limitations of current methods for measuring their plasma concentrations, which are used in algorithms to calculate free steroid levels, and highlight the need for more direct methods to measure plasma free steroid concentrations

Summary

Introduction

Upon their release from steroidogenic cells, biologically active steroids are transported in the blood largely by albumin, sex hormone-binding globulin (SHBG), and corticosteroid-binding globulin (CBG). The liver is responsible for plasma SHBG and CBG production, but their genes are expressed in several other tissues where their protein products function differently than in the blood (Hammond 2002, 2011).

Results

Conclusion