Stressors elicit a complex but variable suite of endocrine events. Comparative studies of the stress response have focused primarily on the adrenocortical response to stress, in particular the measurement of plasma levels of glucocorticoids. However, a number of other factors contribute to and modify cellular and organismal responses to glucocorticoids. Notably, plasma corticosteroid binding globulins (CBGs) can regulate the general availability of steroid to tissues, and/or direct the delivery of hormones to specific sites. In this paper, we discuss possible functions of CBG and mechanisms of CBG action, review CBG characteristics among vertebrates, and discuss our recent studies indicating that CBG may indeed modulate responses to stressors. For example, in house sparrows, we found that basal and stress-induced concentrations of total corticosteroid (cortisol or corticosterone) (CORT) vary seasonally, but CBG concentrations change proportionally, so that free CORT concentrations appear static year-round. In contrast, in white-crowned sparrows and tree lizards, CBG concentrations change under conditions when total CORT levels do not, resulting in significant changes in circulating free CORT. These differences in free CORT are masked if CBG is not accounted for. We have also found that the binding properties of CBG vary considerably between species and need to be determined empirically. Such studies led to the observation that CBG in several species may also serve as a functional androgen binding protein; this is especially important for birds, because previous studies had concluded that birds lack androgen binding globulins. We propose that consideration of CBG is paramount to understanding the role of glucocorticoids in mediating behavioral and physiological responses to stress.

/pdf/plasma-binding-proteins-as-mediators-of-corticosteroid-5d5b8sj7wv.pdf

Plasma binding proteins as mediators of corticosteroid action in vertebrates

Role of endocytosis in cellular uptake of sex steroids.

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.

/pdf/plasma-steroid-binding-proteins-primary-gatekeepers-of-4smmynit2j.pdf

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

The recent discovery of mammalian stanniocalcin (STC) prompted an investigation of its gene structure and expression pattern to study its function and regulation. We show that both the human and mouse genes are composed of four exons spanning about 13 kb, with 85% nucleotide sequence identity in coding regions. Remarkably high sequence conservation between species also exists in the approximately 3-kb 3′-untranslated region. Comparative analysis of the 5′-untranslated region and flanking DNA from the rat and human STC genes showed long stretches of CAG trinucleotide repeats and an additional (CA)25 dinucleotide repeat unique to the rat promoter. An analysis of STC expression in the mouse showed that ovary contained the highest level of messenger RNA, with lower, but detectable, levels in most tissues. In situ hybridization revealed strong, specific hybridization over the thecal-interstitial cells of the ovarian stroma, whereas immunohistochemical analysis indicated that STC was present not only in the str...

Comparative analysis of mammalian stanniocalcin genes.

The sex hormone-binding globulin gene (shbg) is expressed in the liver and testis as well as in several other tissues that play important roles in reproduction. Expression of shbg in the human liver results in the production of plasma sex hormone-binding globulin (SHBG), which regulates the bioavailability of sex steroids in the blood. Although shbg is not expressed in rodent livers postnatally, it gives rise to the androgen-binding protein in their testes upon sexual maturation. Human shbg is also expressed in the testis, but its products and their function are less well characterized. To study the expression of human shbg in different tissues and the consequences of overexpressing this gene in vivo, we have produced several lines of mice containing approximately 11-kilobase (kb; shbg11) or 4.3-kb (shbg4) human shbg genomic fragments that comprise all eight exons encoding SHBG as well as approximately 6 kb or approximately 0.9 kb of 5'-flanking DNA, respectively. Northern blots indicated that human shbg transcripts were most abundant in liver, kidney, and testis of the shbg11 mice. The 4.3-kb shbg transgenes were expressed at similar levels in liver and kidney, but the abundance of human shbg transcripts in their testes was much lower than that in shbg11 mice. Primer extension analysis indicated that transcription starts 60 bp from the translation initiation codon for SHBG in liver and kidney of shbg11 mice, and that the shbg transcripts in their testis are derived from a separate promoter flanking an alternative exon that replaces the exon containing the translation initiation codon for SHBG or androgen-binding protein. At the cellular level, the human shbg transgenes are expressed in clusters of hepatocytes located mainly within the periportal region of hepatic lobules and in the epithelial cells lining the proximal convoluted tubules of the kidney. This results in high levels of human SHBG in serum (1.45-1.72 nmol/ml) and urine (6-16 pmol/ml) of mature male shbg mice. The abundance and distribution of human shbg transcripts in the Sertoli cells of shbg11 mice vary throughout the spermatogenic cycle, with levels increasing in the Sertoli cell cytoplasm until stage VII of spermatogenesis and declining after stage IX. At stages X-XII of spermatogenesis, these transcripts concentrate at the adluminal compartment of the Sertoli cells, and this suggests that they have a role in the elongation phase of spermiogenesis. The presence of human SHBG in the blood of shbg transgenic mice may result in serum levels of testosterone that are 10-100 times higher than those in wild-type littermates. Despite this, their reproductive performance is normal, and there is no obvious phenotypic abnormalities even in animals homozygous for the transgenes.

/pdf/human-sex-hormone-binding-globulin-gene-expression-in-2yy5tf5hox.pdf

Human Sex Hormone-Binding Globulin Gene Expression in Transgenic Mice

Glucocorticoids influence fetal development, and their actions are regulated by plasma corticosteroid-binding globulin (CBG). Immunohistochemistry and in situ hybridization were, therefore, used to localize CBG and its mRNA in sections of embryonic and fetal mice and their associated placental tissues from day 5 of gestation until term (day 19). In the fetus, CBG mRNA was first detectable in the hepatocytes on day 11 of gestation. The amount of CBG mRNA in these cells increased transiently to a maximum on days 15-16 of gestation and was negligible by day 19. In hepatocytes, CBG immunoreactivity correlated with the distribution and relative abundance of CBG mRNA. The fetal exocrine pancreas also contained CBG mRNA, but this was only present on days 15-16 of gestation, while immunoreactive CBG persisted in these cells until term. Immunoreactive CBG was detected in the tubular cells of the developing fetal kidney as early as day 13, but CBG mRNA was never found in the fetal kidney, suggesting that the protein is probably sequestered from fetal blood directly or via the glomerular filtrate. The placenta contained immunoreactive CBG throughout gestation, even before its detection in fetal tissues, and it was most abundant in the spongiotrophoblasts and the extracellular matrix surrounding fetal and maternal capillaries. However, CBG mRNA was not detected in the placenta at any gestational age. Therefore, CBG present in the placenta is most likely of maternal origin and may influence the activities of steroid hormones that control placental development and/or function. The presence of smaller immunoreactive polypeptides in placental extracts, compared to CBG in corresponding maternal serum samples, suggests that this process may involve an interaction between maternal CBG and placental proteinases. The results presented here suggest that temporal and spatial changes in the localization of CBG and its mRNA in the fetus may influence the effects of steroid hormones on developing tissues.

Spatial and temporal distribution of corticosteroid-binding globulin and its messenger ribonucleic acid in embryonic and fetal mice.

Serum distribution of two contraceptive progestins: 3-ketodesogestrel and gestodene.

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Spatial and temporal distribution of corticosteroid-binding globulin and its messenger ribonucleic acid in embryonic and fetal mice.

Serum distribution of two contraceptive progestins: 3-ketodesogestrel and gestodene.