Alternative splicing of the human glucocorticoid receptor (hGR) pre-mRNA generates two highly homologous isoforms, termed hGRa and hGR. hGRa is a ligand-activated transcription factor which, in the hormone-bound state, modulates the expression of glucocorticoid-responsive genes by binding to specific glucocorticoid response element (GRE) DNA sequences. In contrast, hGRfi does not bind glucocorticoids and is transcriptionally inactive. We demonstrate here that hGR8 is able to inhibit the effects of hormone-activated hGRa on a glucocorticoid-responsive reporter gene in a concentration-dependent manner.['H]-Dexamethasone binding studies indicate that hGR*3 does not alter the affinity of hGRa for its hormonal ligand. The presence of hGR.8 in nuclear extracts and its ability to bind to a radiolabeled GRE oligonucleotide suggest that its inhibitory effect may be due to competition for GRE target sites.Reverse transcription-PCR analysis shows expression of hGRfi mRNA in multiple human tissues. These results indicate that hGRI3 may be a physiologically and pathophysiologically relevant endogenous inhibitor of glucocorticoid action, which may participate in defining the sensitivity of target tissues to glucocorticoids. They also underline the importance of distinguishing between the two receptor isoforms in all future studies of hGR function and the need to revisit old data. (J. Clin. Invest. 1995Invest. . 95:2435Invest. -2441

Mammals control the volume and osmolality of their body fluids from stimuli that arise from both the intracellular and extracellular fluid compartments. These stimuli are sensed by two kinds of receptors: osmoreceptor-Na+ receptors and volume or pressure receptors. This information is conveyed to specific areas of the central nervous system responsible for an integrated response, which depends on the integrity of the anteroventral region of the third ventricle, e.g., organum vasculosum of the lamina terminalis, median preoptic nucleus, and subfornical organ. The hypothalamo-neurohypophysial system plays a fundamental role in the maintenance of body fluid homeostasis by secreting vasopressin and oxytocin in response to osmotic and nonosmotic stimuli. Since the discovery of the atrial natriuretic peptide (ANP), a large number of publications have demonstrated that this peptide provides a potent defense mechanism against volume overload in mammals, including humans. ANP is mostly localized in the heart, but ANP and its receptor are also found in hypothalamic and brain stem areas involved in body fluid volume and blood pressure regulation. Blood volume expansion acts not only directly on the heart, by stretch of atrial myocytes to increase the release of ANP, but also on the brain ANPergic neurons through afferent inputs from baroreceptors. Angiotensin II also plays an important role in the regulation of body fluids, being a potent inducer of thirst and, in general, antagonizes the actions of ANP. This review emphasizes the role played by brain ANP and its interaction with neurohypophysial hormones in the control of body fluid homeostasis.

Mutations in the neurokinin B pathway are relatively common as causes of hypogonadism. Although the neurokinin B pathway appears essential during early sexual development, its importance in sustaining the integrity of the hypothalamic-pituitary-gonadal axis appears attenuated over time.