Molecular mechanisms of end-organ resistance

Hormone resistance is caused by mutations in hormone receptors or by functional desensitization of hormone signaling pathways. Mutations that cause hormone resistance have been described for most classes of hormones, including peptides like growth-hormone releasing hormone (GHRH); large proteins such as insulin and the glycoprotein hormones; steroid hormones; and even ions such as calcium. In the case of proteins, many of these receptors include seven transmembrane, G-protein-coupled receptors such as those for thyroid- stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), adrenocorticotrophic hormone (ACTH), GHRH and vasopressin. However, other classes of membrane receptors can also be affected. For example, the insulin receptor is a tyrosine kinase receptor, the growth hormone (GH) and leptin receptors belong to the cytokine family of receptors, and the Mullerian inhibiting substance (MIS, also known as anti-Mullerian hormone [AMH]) receptor is related to the transforming growth factor beta (TGFbeta) serine kinase group of receptors. G-protein mutations cause Albright's hereditary osteodystrophy, and, as might be expected, there is resistance to many different hormones that act through G-protein -coupled receptors. A variety of resistance syndromes involve members of the nuclear receptor superfamily, including resistance to androgens, vitamin D, thyroid hormone, glucocorticoids and estrogen. Mutations in orphan nuclear receptors such as steroidogenic factor-1 (SF-1) or DAX-1 result in defective glandular development, thereby indirectly causing hormone resistance. Another form of resistance, sometimes referred to as "post-receptor" resistance, is typified by acquired forms of insulin or leptin resistance, and the pathophysiology remains elusive. Studies of naturally occurring mutations have provided important insights into the structure and function of receptors. By definition, the mutations that cause disease identify important functional domains in the proteins. Although therapy is straightforward in some disorders, it is challenging or incompletely studied in others. (C) 2004 Elsevier Ltd. All rights reserved.