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THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS: ITS ENDOCRINE DISORDERS AND ITS INTERACTIONS WITH THE IMMUNE SYSTEM
| George P. Chrousos, MD, Head, Section on Pediatric Endocrinology
Salvatore Alesci, MD, Guest Researchera |
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| We investigate the molecular basis of genetic disorders of the hypothalamic-pituitary-adrenal (HPA) axis, such as pituitary and adrenal tumors, adrenal insufficiency, ACTH resistance, congenital adrenal hyperplasia (CAH), glucocorticoid resistance/hypersensitivity, and mineralocorticoid resistance; diseases of the hypothalamic-pituitary-gonadal (HPG) axis, such as hypothalamic hypogonadism; and metabolic and immune disorders related to the functions of the HPA and HPG axes and the autonomic system, such as premature adrenarche, eating disorders that include anorexia and bulimia nervosa and adolescent obesity, childhood asthma and rheumatoid arthritis, premenstrual tension syndrome, and postpartum and climacteric depression and autoimmunity. We also study the critical influences of early life stress on the later development of behavioral disorders (dysthymia, depression, dissociative and conduct disorders, substance abuse) and metabolic disorders (metabolic syndrome X). By identifying pathogenetic defects of the adrenocorticotropic hormone (ACTH) and glucocorticoid receptor genes and of genes of functionally related molecules, we have elucidated the molecular mechanisms of the diseases congenital isolated glucocorticoid deficiency and glucocorticoid resistance syndromes and of acquired states such as glucocorticoid resistance associated with respiratory distress syndrome or glucocorticoid hypersensitivity associated with the AIDS-related lipodystrophy and insulin resistance syndrome. We also study the physiologic and pathophysiologic interactions between the endocrine and immune systems. A natural determinant of glucocorticoid sensitivity and its role in pathophysiology Chrousos, Kino, de Martino, Charmandari, Souvatzoglou, Vottero,d Alesci The glucocorticoid receptor gene, located in the long arm of chromosome 5, encodes two proteins produced by alternative splicing: the classic glucocorticoid receptor, designated GRalpha, and a nonligand-binding variant called GRbeta. We demonstrated that both isoforms are expressed in human tissues and that the nonligand-binding receptor is present at high concentrations in normal human tissues and exerts dominant negative effects on the classic receptor. Given that alteration in glucocorticoid receptor gene splicing produces different ratios of GRalpha to GRbeta, we hypothesized that the ratio of glucocorticoid receptor types regulates tissue sensitivity to glucocorticoids. A change in sensitivity might have major implications for human pathophysiology in that both glucocorticoid resistance and glucocorticoid hypersensitivity can produce disease states. The former causes hyperandrogenism and hypertension while the latter could be involved in metabolic disorders such as visceral obesity or syndrome X, affective disorders such as depression, and immune disorders characterized by suppression of the inflammatory/ immune response and vulnerability to infectious diseases and/or tumors. We showed that glucocorticoid-resistant asthma type II is associated with a major shift in the GRalpha-to-GRbeta ratio toward GRbeta predominance, explaining the profound resistance of patients' cells to glucocorticoids. We observed a similar shift in cells from glucocorticoid-resistant New World monkeys. We demonstrated that normal human neutrophils, which are naturally glucocorticoid-resistant, also overexpress GRbeta. Recently, we showed how the GRbeta isoform causes glucocorticoid insensitivity. This isoform forms heterodimers with GRalpha, which then inhibit interaction with the nuclear receptor p160 transcription coactivators and, hence, the transcription of glucocorticoid receptor-responsive genes. Galon J, Franchimont D, Hiroi N, Boettner A, Ehrhart-Bornstein M, Chrousos GP, Bornstein S. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J 2002;16:61-71. Hauk PJ, Goleva E, Strickland I, Vottero A, Chrousos GP, Kisich KO, Leung DY. Increased glucocor- ticoid receptor beta expression converts mouse hybridoma cells to a corticosteroid-insensitive phenotype. Am J Respir Cell Mol Biol 2002;27:361-367. Kino T, Chrousos GP. Tissue-specific glucocorticoid resistance-hypersensitivity syndromes: multi- factorial states of clinical importance. J Allergy Clin Immunol 2002;109:609-613. Kraft M, Hamid Q, Chrousos GP, Martin RJ, Leung DY. Decreased steroid responsiveness at night in nocturnal asthma. Is the macrophage responsible? Am J Respir Crit Care Med 2001;163:1219-1225. Maurer M, Trajanoski Z, Hiroi N, Frey G, Galom J, Willenberg HS, Gold PW, Chrousos GP, Scherbaum WA, Bornstein SR. Differential gene expression profile of glucocorticoids, testosterone and de-hydroepiandrosterone in human cells. Horm Metab Res 2001;33:691-695. Viral determinants of glucocorticoid hypersensitivity in patients with AIDS and AIDS-related lipodystrophy and insulin resistance syndrome Chrousos, Kino, de Martino, Charmandari, Souvatzoglou, Vottero,d Alesci Recently, we described a human example of a glucocorticoid hypersensitivity state: one of the accessory proteins of the HIV-1, called Vpr, acts as a coregulator of the glucocorticoid receptor, altering the sensitivity of human cells to glucocorticoids so that viral replication is favored. Such hypersensitivity explains several manifestations of AIDS, including innate and T helper 1 immunosupression, T helper 2 shift, myopathy and muscle atrophy, and visceral obesity-related insulin resistance with its metabolic manifestations and cardiovascular consequences. Vpr coactivates the glucocorticoid receptor by binding to it and to the cointegrator molecule p300/CBP and by stabilizing the transcription initiation complex. Recently, we identified a second HIV-1 accessory protein called Tat that also acts as a coactivator of the glucocorticoid receptor. This protein binds to nuclear receptor p160 coactivators and cooperates with Vpr in potentiating the activity of glucocorticoids on transcription of responsive genes. It appears that the HIV-1 LTR promoter uses p300/ CBP and p160 coactivators for its own activation as well. The ability of HIV-1 proteins such as Vpr to influence the activity of nuclear receptor coactivators extends beyond the glucocorticoid signaling system. We recently identified the PPAR-gamma and the insulin signaling systems as targets of Vpr in the host cell. Indeed, Vpr causes resistance to PPAR-gamma and insulin by directly interfering with the actions of the former on transcription and by indirectly blocking insulin actions on the activity of the fork-head transcription factor, a major modulator of insulin actions. Kino T, Gragerov A, Slobodskaya O, Tsopanomihalou-Nglotsou M, Chrousos GP, Pavlakis G. Hu man immunodeficiency virus type 1 (HIV-1) accessory protein Vpr induces transcription of the HIV-1 and glucocorticoid-responsive promoters by binding directly to p300/CBP coactivators. J Virol 2002;76:9724-9734. Kino T, Slobodskaya O, Pavlakis N, Chrousos GP. Nuclear receptor coactivator p160 proteins en hance the human immunodeficiency virus (HIV) type 1 long terminal repeat promoter by bridging promoter bound factors and the Tat/pTEB complex. J Biol Chem 2002;277:2396-2405. Kino T, Souvatzoglou E, De Martino MU, Tsopanomihalou M, Wan Y, Chrousos GP. Protein 14- 3-3 sigma interacts with and favors cytoplasmic subcellular localization of the glucocorticoid receptor, acting as a negative regulator of the glucocorticoid signaling pathway. J Biol Chem 2003;252:32-44. Kino T, Tsukamoto M, Chrousos GP. Transcription factor TFIIH components enhance the GR coacti- vator activity but not the cell cycle-arresting activity of the human immunodeficiency virus type-1 protein Vpr. Biochem Biophys Res Commun 2002;298:17-23. Mirani M, Elenkov I, Volpi S, Hiroi N, Chrousos GP, Kino T. HIV-1 protein Vpr suppresses IL-12 production from human monocytes by enhancing glucocorticoid action: potential implications of Vpr coactivator activity for the innate and cellular immunity deficits observed in HIV-1 infection. J Immunol 2002;169:6361-6368. Comparison of familial and sporadic glucocorticoid resistance syndromes with inflammation-induced glucocorticoid resistance Chrousos, Kino, de Martino, Charmandari, Souvatzoglou, Vottero,d Alesci; in collaboration with Meduri, Latronico Our group recently analyzed patients with the familial/sporadic glucocorticoid resistance syndrome, which is caused by mutations of the glucocorticoid receptor gene. Two novel glucocorticoid receptor mutations, one replacing isoleucine (I) 559 with aspartic acid (N) and another in which isoleucine (I) 747 was replaced by methionine (M), both caused glucocorticoid resistance in the heterozygote state, acting in a transdominant negative fashion by forming function-deficient dimers with wild-type GRalpha. We examined the cause of the transdominant activity of these mutant receptors and found that GRI559N has a nuclear localization sequence defect that interferes with the translocation of wild-type GRalpha from the cytoplasm into the nucleus while GRI747M has a defective Activation Function-2 (AF-2) domain that prevents proper interaction of the wild-type receptor with the p160 nuclear receptor coactivators. Recently, we studied a newborn female infant with severe sexual ambiguity, a novel presentation of the glucocorticoid resistance syndrome. In this patient, the GRalpha gene bore a homozygous mutation that decreased its affinity for glucocorticoids and its ability to activate glucocorticoid-responsive genes. We are studying an American kindred in which the proposita has a heterozygote amino acid substitution in its C-terminal, disturbing AF-2-mediated interaction with p160 nuclear receptor coactivators. We have further studied the mechanisms by which severe inflammation causes resistance of immune and immune-associated cells to glucocorticoids. We have determined that the critical mechanism is an inflammatory cytokine-induced signaling cascade in which the TNF alpha and Fas system (1) activate NF-kappaB by phosphorylation and nuclear translocation and (2) block the p160 glucocorticoid receptor p160 coactivators from interacting properly with the glucocorticoid receptor through activation of an intermediate cytoplasmic protein called FLASH. the state of the art. NIH Clinical Staff Conference. Neuroimmunomodulation 2003;10:247-260. Kino T, Chrousos GP. Tumor necrosis factor alpha receptor- and Fas-associated FLASH inhibit transcriptional activity of the glucocorticoid receptor by binding to and interfering with its interaction with p160 type nuclear receptor coactivators. J Biol Chem 2003;278:3023-3029. Meduri GU, Tolley EA, Chrousos GP, Stentz F. Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving ARDS: evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids. Am J Resp Crit Care Med 2002;165:983-991. Mendonca BB, Leite MV, deCastro M, Kino T, Elias LL, Bachega TAS, Billerbeck AE, Arnhold IAJP, Chrousos GP, Latronico AC. Female pseudohermaphrodotism caused by a novel homozygous missence mutation of the glucocorticoid receptor gene. J Clin Endocrinol Metab 2002;87:1805-1809. Vottero A, Kino T, Combe H, Lecomte P, Chrousos GP. A novel, C-terminal dominant negative mutation of the glucocorticoid receptor causes familial glucocorticoid resistance through abnormal interactions with p160 steroid receptor coactivators. J Clin Endocrinol Metab 2002;87:2658-2667. Pathophysiology and therapy of adrenal hyperfunction-congenital adrenal hyperplasia and other congenital endocrine disorders Chrousos, Merke, Charmandari The goal of our research is to understand the mechanisms involved in diseases caused by adrenal hyperandrogenism. Deborah Merke is principal investigator for a clinical trial that is testing a treatment for children with classic congenital adrenal hyperplasia (CAH). Preliminary results based on two years of therapy showed that children receiving the treatment had normalization of growth velocity and bone maturation. Thus, the regimen represents a promising treatment for children with classic 21-hydroxylase deficiency. Reproductive, metabolic, and other morbidities, including risk of tumor formation, particularly testicular tumors, are currently under investigation in the severe forms of the disease. Bilateral adrenalectomy performed on a severe case revealed massive lymphocytic infiltration and histologic signs of adrenal carcinoma. Recent clinical studies revealed adrenomedullary dysplasia and hypofunction in patients with CAH and that the protective function of the adrenal medulla may be absent in the most severe cases. Studies of hypoglycemia and exercise tolerance in patients are under way. It appears that the lack of a proper epinephrine response to exercise prevents an appropriate glucose response in CAH. Recently, children with CAH were found to be resistant to insulin. Preliminary results from studies of healthy children reveal sex and age differences in catecholamine secretion. New clinical initiatives include studies of the pathophysiology of premature adrenarche and the effects of androgens and other hormones on the brain. Psychological testing and head MRI studies are being conducted with children suffering from endocrine disorders, including CAH, Cushing's syndrome, and familial male precocious puberty. The studies will provide insight into hormonal influences on the brain during growth and development. Merke DP. Adrenomedullary function may predict phenotype and genotype in classic 21-hydroxy-lase deficiency. J Clin Endocrinol Metab 2002;87:3031-3037. Charmandari E, Weise M, Bornstein SR, Eisenhofer G, Keil MF, Chrousos G, Merke DP. Children with classic congenital adrenal hyperplasia have elevated serum leptin concentrations and insulin resistance. J Clin Endocrinol Metab 2002;87:2139-2143. Merke DP, Bornstein SR, Avila NA, Chrousos GP. Future directions in the study and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. NIH conference. Ann Intern Med 2002;136:320-334. Merke DP, Fields JD, Keil MF, Vaituzis AC, Chrousos GP, Giedd JN. Children with classic congenital adrenal hyperplasia have decreased amygdala volume: potential prenatal and postnatal hormonal effects. J Clin Endocrinol Metab 2003;88:1760-1765. Weise M, Mehlinger S, Rawson E, Charmandari E, Eisenhoffer G, Yanovski J, Chrousos GP, Merke DP. Patients with classic congenital adrenal hyperplasia have decreased epinephrine reserve and defective glucose elevation in response to high intensity exercise. J Clin Endocrinol Metab 2003; in press. Role of CRH in behavior and behavioral/developmental/sleep disorders Chrousos, Charmandari; in collaboration with Cizza, Deuster, Dorn, Gold, Susman The group has used corticotropin releasing hormone (CRH) to probe central mechanisms in patients with atypical, seasonal depression, the chronic fatigue/bromyalgia syndromes, and the postpartum blues/depression syndromes. The patients' responses to CRH are indicative of mild, sustained hypocortisolism of central nervous system etiology, suggesting the existence of a spectrum of diseases characterized by hypofunction of the central stress system. These syndromes contrast with melancholic depression, panic anxiety, and anorexia nervosa, for which we earlier demonstrated hyperactivity of the CRH system. As we have shown, the behavioral similarities between patients with Cushing's syndrome and atypical depression probably stem from a similar pathologic decrease in CRH secretion. Recently, we demonstrated that preadolescent and adolescent girls with a history of sexual abuse exhibited an HPA axis response to CRH similar to that of patients with melancholic depression or recovering anorexics. The findings suggest that major stress in children may have long-term effects on the HPA axis accompanied by effects on the psyche. Indeed, we found dysthymia or depression in all the sexually abused children studied. In a social nonhuman primate model, we demonstrated effects of parental abuse not only on the HPA axis but also on growth. Individuals who are carriers of a 21-hydroxylase deficiency, such as parents of patients with CAH, are presumably totally asymptomatic. We studied the mood and HPA axis of such subjects, testing the hypothesis that a compensatory elevation of CRH secretion would be associated with indices of increased anxiety. We found that, indeed, compensatory changes in the activity of the HPA axis are apparent in a standard CRH test and that these changes correlate positively with anxiety. As a group, the carriers had higher anxiety scores than appropriate controls. Studies in healthy normal volunteers demonstrated that, in middle age, the sleep centers in the brain are sensitized to CRH and glucocorticoids, a finding that explains the increasing vulnerability to stress- or caffeine-induced insomnia with advancing age. Studies in young and middle-aged patients with idiopathic insomnia showed that such patients have significant evening activation of their HPA axis and an overall activation of the axis that correlates positively with indices of poor-quality sleep, such as decrements in amount of deep sleep and increments in wakefulness. We also recently showed that antalarmin, a nonpeptide CRH antagonist that crosses the blood barrier, inhibits the stress-mimicking properties of CRH, including its effects on the HPA axis and behavior. The drug thus represents a new class of pharmacologic agents for the potential treatment of diseases characterized by CRH hypersecretion, such as melancholic depression, chronic anxiety disorder, anorexia nervosa, and idiopathic insomnia. atypical depression: high vs. low CRH/NE states. Mol Psychiatry 2002;7:254-275. Grammatopoulos DK, Chrousos GP. Functional characteristics of CRH receptors and potential clinical applications of CRH-receptor antagonists. Trends Endocrinol Metab 2002;13:436-444. Vgontzas AN, Bixler EO, Lin HM, Prolo P, Mastorakos G, Vela-Bueno A, Kales A, Chrousos GP. Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications. J Clin Endocrinol Metab 2001;86:3787-3794. Vgontzas AN, Chrousos GP. Sleep, the hypothalamic-pituitary-adrenal axis, and cytokines: multiple interactions and disturbances in sleep disorders. Endocrinol Metab Clin North Am 2002;31:15-immunity.
We discovered that, in the transition from pregnancy to the postpartum period, the hormonal changes that take place cause a shift from T helper 2 to T helper 1, which explains the vulnerability of postpartum women to autoimmune disorders of the T helper 1 type, such as Hashimoto thyroiditis, multiple sclerosis, and rheumatoid arthritis. vitro inhibition of 11beta-hydroxysteroid dehydrogenase type 1: differentiation and metabolism changes. Horm Metab Res 2002;34:752-757. Elenkov IJ, Wilder RL, Bakalov VK, Link AA, Dimitrov M, Fisher S, Crane M, Kanik K, Chrousos GP. Interleukin 12, tumor necrosis factor-alpha and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times. J Clin Endocrinol Metab 2001;86:4933-4938. Path G, Bornstein SR, Gurniak M, Chrousos GP, Scherbaum WA, Hauner H. Human breast adipocytes express interleukin-6 (IL-6) and its receptor system: increased IL-6 production by beta-adrenergic activation and effects of IL-6 on adipocyte function. J Clin Endocrinol Metab 2001;86:2281-2288. Vgontzas AN, Zoumakis M, Papanicolaou DA, Bixler E, Prolo P, Lin HM, Vela-Bueno A, Kales A, Chrousos GP. Chronic insomnia is associated with a shift of IL-6 and tumor necrosis factor secretion from nighttime to daytime. Metabolism 2002;51:887-892. Leptin and cytokines in obesity, polycystic ovary syndrome, and sleep disorders Chrousos, Ayala, Zoumakis; in collaboration with Bornstein, Vgontzas We recently demonstrated that, in addition to leptin, human fat secretes large amounts of TNF-alpha and Il-6 and that the secretion of adipose tissue cytokines is regulated by food intake and the sympathetic nervous system. The secretion of these cytokines, e.g., IL-6, has a circadian rhythm that is influenced by sleep while circulating levels increase in proportion to BMI and are further elevated by visceral adiposity. Sleep deprivation is associated with elevations of daytime IL-6, whose levels correlate with somnolence and fatigue, particularly among patients with insomnia who, during the day, have elevated levels not only of cortisol but also of IL-6. Interestingly, IL-6 concentrations in plasma are proportional to body fat, and viscerally obese subjects have further elevations that correlate with sleep apnea measures. Women with polycystic ovary syndrome exhibit high cytokine and leptin levels and are at markedly increased risk for sleep apnea while girls with premature adrenarche show features of visceral adiposity such as high fasting leptin and insulin levels, predictors of later development of polycystic ovary syndrome and sleep apnea. The elevation of inflammatory cytokines in obesity and its correlation with many pathologic manifestations of this condition have led us to conduct clinical studies with biological antagonists of such cytokines. Cizza G, Dorn LD, Lotsikas A, Sereika S, Rotenstein D, Chrousos GP. Circulating plasma leptin and IGF1 levels in girls with premature adrenarche: potential implications of a preliminary study. Horm Metab Res 2001;33:138-143. Vgontzas AN, Bixler EO, Chrousos GP. Metabolic disturbances in obesity versus sleep apnoea: the importance of visceral obesity and insulin resistance. J Intern Med 2003;254:32-44. Vgontzas AN, Legro RS, Bixler EO, Grayev A, Kales A, Chrousos GP. Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness role of insulin resistance. J Clin Endocrinol Metab 2001;86:517-520. Vgontzas AN, Zoumakis M, Bixler EO, Lin HM, Prolo P, Vela-Bueno A, Kales A, Chrousos GP. Impaired COLLABORATORS Stefan Bornstein, MD, University of Düsseldorf, Germany Giovanni Cizza, MD, PhD, Clinical Neuroendocrinology Branch, NIMH, Bethesda MD Patricia A. Deuster, PhD, Uniformed Services University of the Health Sciences, Bethesda MD Lorah Dorn, RN, University of Pittsburgh, Pittsburgh PA Ilia Elenkov, MD, PhD, Georgetown University, Washington DC Lucia Ghizzoni, MD, University of Parma, Italy Philip W. Gold, MD, Clinical Neuroendocrinology Branch, NIMH, Bethesda MD Achilles Gravanis, PhD, University of Crete, Heraklion, Greece Ana-Claudia Latronico, MD, University of São Paulo, Brazil Donald Y. Leung, MD, University of Colorado Health Sciences Center, Denver CO Maria A. Magiakou, MD, Athens University Medical School, Greece Andrew Margioris, MD, PhD, University of Crete, Heraklion, Greece George Mastorakos, MD, Athens University, Greece G. Umberto Meduri, MD, University of Tennessee Medical Center, Memphis TN Edward H. Oldfield, MD, Surgical Neurology Branch, NINDS, Bethesda MD Martin Reincke, MD, University of Munich, Germany Hajime Sano, MD, Kyoto University, Japan Roger Smith, MD, University of Newcastle Medical School, Australia Esther M. Sternberg, MD, PsychoNeuroImmunology Program, NIMH, Bethesda MD Elisabeth Susman, Pennsylvania State University, University Park PA Constantine Tsigos, MD, Athens University, Greece Alexander Vgontzas, MD, Pennsylvania State University, Hershey PA Jack A. Yanovski, MD, PhD, Developmental Endocrinology Branch, NICHD, Bethesda MD aVisiting Associate, NIMH, Bethesda MD bSabbatical, Technion University, Haifa, Israel cStaff Physician, Warren Grant Magnuson Clinical Center, NIH, Bethesda MD dAlessandra Vottero, MD, former Guest Researcher, now University of Parma, Italy
For further information, contact chrousog@mail.nih.gov |
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