PHYSIOLOGY AND PATHOPHYSIOLOGY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

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In this project we seek to advance the understanding of the physiology and pathophysiology of the hypothalamic- pituitary- adrenal (HPA) and -gonadal (HPG) axes. The role of stress-related hormones in normal and disease states is being examined, and clinical applications for these hormones are sought. Several developmental/psychiatric disorders, including melancholic depression and anorexia nervosa have been associated with increased corticotropin-releasing hormone (CRH) secretion. We recently demonstrated that the postpartum blues/depression syndrome is characterized by transient profound hypoactivity of the stress system, which explains not only the mood disorder but also the propensity of these patients to develop autoimmune diseases. We also found the hCRH gene 5' regulatory region responds positively to estrogens, providing a potential explanation for the sexual dimorphism of psychiatric diseases characterized by aberrations in CRH secretion. We are currently performing preclinical studies with a newly discovered nonpeptide, oral CRH antagonist, antalarmin. Glucocorticoid resistance is an autosomal recessive or dominant disease associated with abnormalities of the glucocorticoid receptor. We have elucidated the molecular pathophysiology of this syndrome by defining mutations and/or deletions of the glucocorticoid receptor gene leading to abnormal or decreased receptors in the tissues of patients. The mineralocorticoid receptor and the subunits of the amiloride-sensitive sodium channel were studied in sporadic cases of pseudohypoaldosteronism or mineralocorticoid resistance and the defect was localized in the beta and gamma subunits of this channel. The interactions of the classic glucocorticoid receptor (GRalpha) and its nonligand binding natural homolog glucocorticoid receptor beta (Grbeta) with each other and with the heat-shock proteins and glucocorticoid-responsive elements (GREs) of the DNA are studied, as well as the importance of GRbeta in human physiology and pathophysiology. We have found an abnormal expression of the beta vs. the alpha isoform of the glucocorticoid receptor in patients with glucocorticoid resistant asthma. We have determined that Vpr, a 15KD protein product of HIV-1, is a coregulator of the glucocorticoid, androgen and estrogen receptors, the presence of which explain some of the clinical features and pathogenesis of AIDS. We have elucidated the molecular pathophysiology of hereditary ACTH resistance, an autosomal recessive disorder characterized by isolated glucocorticoid deficiency, by defining abnormalities of the ACTH receptor gene. We have elucidated the molecular pathophysiology of testicular and ovarian resistance to luteinizing hormone (LH) by defining abnormalities of the LH receptor gene. We have localized two genes for Carney Complex, a multiple neoplasia/lentiginosis syndrome, on chromosome 2p16 and 17q. We have defined the molecular defect in the excessive aromatase syndrome, a novel promoter aberrantly and ectopically expressed in affected individuals.