The Effect of Steroid Hormones

Patients having hepatic cirrhosis (Laennec s and biliary cirrhosis, primary and metastatic liver carcinoma, and hepatitis) were found to have partially desialylated thyroxine-binding globulin (TBG) (Marshall et al,y 1974). Previously, it was found that the amount of thyroxine bound was not appreciably altered by removal of sialic acid residues (Blumberg and Warren, 1961). Asialo-TBG binds to liver cell plasma membranes and it is rapidly cleared by the liver in rats, rabbits, and humans. Marshall et al. (1974) studied the inhibitory effect of normal and cirrhotic serums on the binding of asialo-TBG to the liver cell plasma membrane and found that glycoproteins present in serum from cirrhotic patients had a marked elevation of inhibitory activity which 

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Receptors for lipophilic hormones mediate the effects of steroid hormones and related signaling substances. They regulate the transcription of specific genes (see p. 378). The products of several oncogenes (e.g., erbA) belong to this superfamily of ligand-controlled transcription factors. 

Of recent concern has been the ability of some xenobiotics to mimic the effects of steroidal hormones. Before the toxic mechanism can be understood, it is necessary to understand the role of steroidal hormones as regulators of cellular processes. 

R15. Rose, D. P., and McGinty, F., The effect of steroid hormones on tryptophan metabolism. Advan. Steroid Biochem. Pharmacol. 1, 97-136 (1970). 

General metabolic significance. Vitamin D stimulates intestinal absorption of calcium and phosphate, renal reabsorption of these ions, deposition and mobilization of minerals in the hard tissue, controlling normal calcium and phosphate blood level by means of these processes. Molecular mechanism of the vitamin D effects most frequently conform to the effect of steroid hormones (induction of protein biosynthesis). 

Vernon-Roberts B (1969) The effects of steroid hormones on macrophage activity. Int Rev Cytol 25 131-159... 

In explanation of the effect of steroid hormones upon bone formation, Albright suggests that this effect is determined by their influence upon protein anabolism. Those which promote this, androgens and estrogens,... 

Among these factors, social organizations, including inter- and intrasexual relationships, provide a matrix within which other behaviors occur. The behavioral effects of steroid hormones, especially in humans, have for the most part not been considered in these contexts. 

Lipophilic hormones, which include steroid hormones, iodothyronines, and retinoic acid, are relatively small molecules (300-800 Da) that are poorly soluble in aqueous media. With the exception of the iodothyronines, they are not stored by hormone-forming cells, but are released immediately after being synthesized. During transport in the blood, they are bound to specific carriers. Via intracellular receptors, they mainly act on transcription (see p. 358). Other effects of steroid hormones—e.g., on the immune system—are not based on transcriptional control. Their details have not yet been explained. 

Lipophilic signaling substances include the steroid hormones, calcitriol, the iodothy-ronines (T3 and T4), and retinoic acid. These hormones mainly act in the nucleus of the target cells, where they regulate gene transcription in collaboration with their receptors and with the support of additional proteins (known as coactivators and mediators see p.244). There are several effects of steroid hormones that are not mediated by transcription control. These alternative pathways for steroid effects have not yet been fully explained. 

The transcription factors AP-1 and NFkB are at the end of a signal cascade activated by growth factors (see chapters 9,10,11), The ability of steroid hormone receptors in certain situations to nullify the effect other transcription factors demonstrates that two different signaling pathways can converge at the level of transcription. 

Several systems have been established which can regulate gene expression. For instance, there are systems which rely on the addition of steroid hormones or heavy metal ions. However, certain physiologic or toxic effects may result and high basal-transcriptional activity may limit their usefulness (Furth et al., 1994). Another approach has been developed which is based on the tetracycline-resistance operon tet from E. coli transposon Tn70. 

Some cellular responses occur too rapidly following steroid hormone exposure to involve the multi-step process of nuclear receptor activation. For example, 17/6-estradiol can rapidly stimulate adenylate cyclase and cause a near-instantaneous increase in intracellular cAMP in cultured prostate cells. These effects are mediated by the interaction of steroid hormones with cell surface proteins. 

Berger, C.E., Horrocks, B.R., and Datta, H.K. 1999. Direct non-genomic effect of steroid hormones on superoxide generation in the bone resorbing osteoclasts. Mol. Cell. Endocrinol. 149, 53-59. 

These receptors are chiefly responsible for the physiological effects of steroid hormones such as cortisol as well as thyroid hormone and vitamin A. They are proteins that share a common basic structure consisting of a ligand binding domain and a DNA binding domain (comprised of zinc finger motifs). They operate as ligand-responsive transcription factors (see Chap. 17 for further discussion). 

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