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THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS: ITS ENDOCRINE DISORDERS AND ITS INTERACTIONS WITH THE IMMUNE SYSTEM
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George P. Chrousos, MD, Head, Section on
Pediatric Endocrinology Alejandro
Ayala, MD, Staff Physician Tomoshige
Kino, MD, PhD, Staff Scientist Pamela
Stratton, MD, Commissioned Officer Evangelia
Charmandari, MD, Postdoctoral Fellow Massimo
De Martino, MD, Postdoctoral Fellow Takamasha
Ichijo, MD, PhD, Postdoctoral Fellow Sujata
Kelkar, PhD, Postdoctoral Fellow Emmanouil
Souvatzoglou, MD, Postdoctoral Fellow Emmanouil
Zoumakis, PhD, Postdoctoral Fellow Ninet
Sinaii, MS, Predoctoral Student Keith
Zachman, MS, Biolaboratory Technician Salvatore
Alesci, MD, Guest Researchera Ze’ev
Hochberg, MD, Guest Researcherb Deborah
Merke, MD, Guest Researcherc Karen
Winer, MD, Guest Researcherd |
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We investigate
the molecular basis of the following genetic disorders: pituitary and adrenal
tumors, adrenal insufficiency, ACTH resistance, congenital adrenal
hyperplasia, glucocorticoid resistance/hypersensitivity, and
mineralocorticoid resistance (hypothalamic-pituitary-adrenal [HPA] axis);
hypothalamic hypogonadism (hypothalamic-pituitary-gonadal [HPG] axis); 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, 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 and
glucocorticoid receptor genes and of genes of functionally related molecules,
we have elucidated the molecular mechanisms of such hereditary diseases as
congenital isolated glucocorticoid deficiency and glucocorticoid resistance
syndromes and of acquired states such as glucocorticoid resistance associated
with the respiratory distress syndrome or glucocorticoid hypersensitivity
associated with the AIDS-related lipodystrophy and insulin resistance
syndrome. We also conduct research to increase our understanding of the
physiologic and pathophysiologic interactions between the endocrine and
immune systems. A
natural determinant of glucocorticoid sensitivity in human tissues and its
role in human pathophysiology Kino, De Martino,
Charmandari, Souvatzoglou, Alesci, Chrousos; in collaboration with Vottero 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
co-activators and hence the transcription of glucocorticoid
receptor–responsive genes. De Martino M, Bhattacharyya N, Alesci S, Fabbri A,
Chrousos GP, Kino T. The glucocorticoid receptor (GR)
and the orphan nuclear receptor chicken ovalbumin upstream
promoter-transcription factor II (COUP-TFII) interact with and mutually
affect each other’s transcriptional activities: implications for
intermediary metabolism. Mol Endocrinol 2004;18:820-833. 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 glucocorticoid 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: multifactorial states of clinical
importance. J Allergy Clin Immunol 2002;109:609-613. Viral
determinants of glucocorticoid hypersensitivity in patients with AIDS coupled
with AIDS-related lipodystrophy and insulin resistance syndrome Kino, De Martino,
Charmandari, Souvatzoglou, Alesci, Chrousos; in collaboration with Vottero Recently,
we described a human example of a glucocorticoid hypersensitivity state: Vpr,
one of the accessory proteins of HIV-1, acts as a co-regulator 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
immunosuppression, T helper 2 shift, myopathy and muscle atrophy, and
visceral obesity–related insulin resistance with its metabolic
manifestations and cardiovascular consequences. Vpr co-activates the
glucocorticoid receptor by binding to it and to the co-integrator molecule
p300/CBP and by stabilizing the transcription initiation complex. Recently,
we identified Tat, a second HIV-1 accessory protein, that also acts as a
co-activator of the glucocorticoid receptor. This protein binds to nuclear
receptor p160 co-activators and cooperates with Vpr in potentiating the
activity of glucocorticoids on transcription of responsive genes. It appears
that the HIV-1 LTR promoter also uses p300/CBP and p160 co-activators for its
own activation. The ability of HIV-1 proteins such as Vpr to influence the
activity of nuclear receptor co-activators 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. Human 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 enhance 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 coactivator 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. Familial
and sporadic glucocorticoid resistance syndromes and inflammation-induced
glucocorticoid resistance Kino, De Martino,
Charmandari, Souvatzoglou, Alesci, Chrousos; in collaboration with Latronico,
Meduri, Vottero 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 cause 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, which 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, which
prevents proper interaction of the wild-type receptor with the p160 nuclear
receptor co-activators. Recently, we studied a newborn female infant with
severe sexual ambiguity, an unusual presentation of the glucocorticoid
resistance syndrome. In this patient, the GRalpha gene bore a homozygous
mutation that decreased the receptor’s 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-terminus that disturbs AF-2–mediated interaction
with p160 nuclear receptor co-activators. We
have further studied the mechanisms by which severe inflammation causes
resistance of immune and immune-associated cells to glucocorticoids, a
particularly important issue in pediatrics and medicine. We have determined
that the key mechanisms through which inflammation causes resistance is an
inflammatory cytokine-induced signaling cascade in which the TNFalpha and Fas
systems (1) activate NF-kappaB by phosphorylation and nuclear translocation
and (2) block the p160 glucocorticoid receptor p160 co-activators from
interacting properly with the glucocorticoid receptor through activation of
an intermediate cytoplasmic protein called FLASH. Charmandari E, Kino T, Souvatzoglou E, Vottero A, Bhattacharayya
N, Chrousos GP. Natural glucocorticoid receptor mutants causing
glucocorticoid resistance: molecular genotype, genetic transmission and
clinical phenotype. J Clin Endocrinol Metab 2004;89:1939-1949. Franchimont D, Kino T, Galon J, Meduri GU, Chrousos GP.
Glucocorticoids and inflammation revisited: 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. Mendonca BB, Leite MV, deCastro M, Kino T, Elias LL, Bachega TAS,
Billerbeck AE, Arnhold IAJP, Chrousos GP, Latronico AC. Female
pseudohermaphroditism caused by a novel homozygous missense 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 Merke, Charmandari,
Chrousos The
goal of our research is to understand the mechanisms involved in diseases
caused by adrenal hyperandrogenism. We use insights into the mechanism to
generate hypotheses for new approaches to treatment. Deborah Merke is
principal investigator for a clinical trial that is testing a new medical
treatment for children with classic congenital adrenal hyperplasia (CAH).
Preliminary results based on two years of combined therapy of an
anti-androgen and an aromatase inhibitor showed that children receiving the
new treatment regimen exhibited normalization of growth velocity and bone
maturation. Thus, the regimen represents a promising treatment approach 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, leading
to new insights regarding lymphocyte-adrenal-cell interaction and
adrenocortical tumor formation. Recent clinical studies led to findings of
adrenomedullary dysplasia and hypofunction in patients with CAH, results that
have important clinical implications. 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, a finding with negative repercussions for these patients
(Charmandari et al., J Clin Endocrinol Metab 2002;87:2139). Studies of
healthy children are also under way, and preliminary results reveal sex and
age differences in catecholamine secretion. 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. Charmandari E, Eisenhofer G, Mehlinger S, Carlson A, Wesley R, Keil
M, Chrousos GP, New MI, Merke DP. Adrenomedullary function may predict
phenotype and genotype in classic 21-hydroxylase deficiency. J Clin
Endocrinol Metab 2002;87:3031-3037. Charmandari E, Merke D, Negro PJ, Keil M, Martinez PE, Haim A,
Gold PW, Chrousos GP. Endocrinologic and psychologic evaluation of
21-hydroxylase deficiency carriers and matched normal subjects: evidence for
physical and/or psychologic vulnerability to stress. J Clin Endocrinol
Metab 2004;89:2228-2236. 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, Drinkard B, Mehlinger SL, Eisenhofer G, Chrousos GP,
Merke DP. Stress dose of hydrocortisone is not beneficial in patients with
classic congenital adrenal hyperplasia undergoing short-term high-intensity
exercise. J Clin Endocrinol Metab 2004;89:3679-3684. Weise M, Mehlinger S, Rawson E, Charmandari E, Eisenhofer G,
Yanovski J, Chrousos GP, Merke D. Patients with classic congenital adrenal
hyperplasia have decreased epinephrine reserve and defective glucose
elevation in response to high intensity exercise. J Clin Endocrinol Metab
2004;89:591-597. Role
of corticotropin releasing hormone in behavior and
behavioral/developmental/sleep disorders Charmandari, Chrousos;
in collaboration with Cizza, Deuster, Dorn, Gold, Susman We have
used corticotropin releasing hormone (CRH) to probe central mechanisms in
patients with atypical seasonal depression, the chronic fatigue/fibromyalgia
syndromes, and the postpartum blues/depression syndromes. The patients’
responses to CRH are indicative of mild, sustained hypocortisolism of central
nervous system etiology, suggesting that a spectrum of diseases exists that
are 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. 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 the
activational effects of 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 (Vgontzas et al., Endocrinol
Metab Clin North Am 2002;31:15). 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. This 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. Ayala AR, Pushkas J, Higley JD, Ronsaville D, Gold PW, Chrousos
GP, Pacak K, Calis KA, Gerald M, Lindell S, Rice KC, Cizza C. Behavioral,
adrenal and sympathetic responses to long term administration of an oral
corticotropin-releasing hormone receptor antagonist in a primate stress
paradigm. J Clin Endocrinol Metab 2004;89:5729-5737. Gold PW, Chrousos GP. Organization of the stress system and its
dysregulation in melancholic and atypical depression: high vs. low CRH/NE
states. Mol Psychiatry 2002;7:254-275. Vgontzas A, Zoumakis E, Bixler EO, Lin H-M, Follett H, Kales A,
Chrousos GP. Adverse effects of modest sleep restriction on sleepiness,
performance, and inflammatory cytokines. J Clin Endocrinol Metab
2004;89:2119-2126. Ward AM, Syddall HE, Wood PJ, Chrousos GP, Phillips DI. Fetal
programming of the hypothalamic-pituitary-adrenal (HPA) axis: low birth
weight and central HPA regulation. J Clin Endocrinol Metab
2004;89:1227-1233. Yuhas Y, Weizman A, Chrousos GP, Ovadia H, Ashkenazi S.
Involvement of the neuropeptide corticotropin-releasing hormone in an animal
model of shigella-related seizures. J Neuroimmunol 2004;153:36-39. Cytokines
and the inflammatory response in endocrine hyper- and hyposecretion states Chrousos; in
collaboration with Elenkov, Gold, Sternberg, Vgontzas Several
cytokines, including interleukin 1, tumor necrosis factor-alpha (TNF-alpha),
and interleukin-6 (IL-6), as well as several lipid mediators of inflammation,
including platelet-activating factor and several eicosanoids, cause profound
stimulation of the HPA axis, primarily by activating the CRH neuron and,
through it, by suppressing and restraining the inflammatory/immune response.
We recently studied IL-6 in humans and found that this cytokine is extremely
potent in activating the HPA axis and that, at high doses, causes systemic
vasopressin secretion. At all doses, it is not noxious, unlike TNF-alpha or
interleukin-1, which cause hypotension and vascular leakage. We demonstrated
that IL-6 is a potent stimulator of ACTH release in normal subjects and that
catecholamines and glucocorticoids regulate IL-6 secretion. IL-6 levels are
normal in patients with Cushing’s syndrome but increase markedly after
the surgical cure of hypercortisolism. The rebound elevation in circulating
IL-6 levels immediately after surgical cure of hypercortisolism may be the
cause of the systemic symptoms typical of the glucocorticoid withdrawal
syndrome in these patients. Thus, IL-6 participates in an immune-endocrine
feedback loop involving CRH, ACTH, and cortisol. We found that the stress
hormones glucocorticoids and catecholamines inhibit the secretion of
interleukin-12 and stimulate the secretion of IL-10 by monocytes/macrophages,
leading to a shift from T helper 1– to T helper 2–directed
immunity. We discovered that, in the transition from pregnancy to the
postpartum period, the hormonal changes that take place cause a T helper
2– to T helper 1–shift, 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. Bader T, Zoumakis E, Friedberg M, Chrousos GP, Hochberg Z. Human
adipose tissue under in vitro inhibition of 11beta-hydroxysteroid
dehydrogenase type 1: differentiation and metabolism changes. Horm Metab
Res 2002;34:752-757. Vgontzas AN, Zoumakis M, Papanicolaou DA, Bixler E, Prolo P, Lin
HM, Vela-Bueno A, Kales MD, Chrousos GP. Chronic insomnia is associated with
a shift of IL-6 and TNFalpha secretion from nighttime to daytime. Metabolism
2002;29:1252-1261. Leptin
and cytokines in obesity, polycystic ovary syndrome, and sleep disorders Ayala, Zoumakis,
Bornstein, Chrousos; in collaboration with 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 both 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. This holds true for 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, 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. Kalantaridou SN, Naka KK, Papanikolaou E, Kazakos N, Kravariti
M, Calis KA, Paraskevaidis EA, Sideris DA, Tsatsoulis A, Chrousos GP,
Michalis LK. Impaired endothelial function in young women with premature
ovarian failure: normalization with hormone therapy. J Clin Endocrinol
Metab 2004;89:3907-3913. 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, Zoumakis E, Lin H-M, Bixler EO, Trakada G, Chrousos
GP. Marked decrease of sleepiness in patients with sleep apnea by etanercept,
a TNFalpha antagonist. J Clin Endocrinol Metab 2004;89:4409-4413. Vgontzas AN, Zoumakis M, Bixler EO, Lin HM, Prolo P, Vela-Bueno
A, Kales A, Chrousos GP. Impaired nighttime sleep in healthy old versus young
adults is associated with elevated plasma interleukin-6 and cortisol levels:
physiologic and therapeutic implications. J Clin Endocrinol Metab
2003;88:2087-2095. Immune
and reproductive CRH and the role of CRH antagonists Zoumakis, Chrousos; in
collaboration with Dorn, Gold, Gravanis, Sano We
demonstrated that CRH is produced locally at sites of inflammation and has
profound pro-inflammatory effects at an autocrine/paracrine level. CRH is a
potent degranulator of mast cells, a phenomenon that can be inhibited by
antalarmin, the nonpeptide CRH antagonist specific for type 1 receptors. The
antagonist has marked systemic anti-inflammatory actions and has ameliorated
the disease in adjuvant-induced arthritis, a model of rheumatoid arthritis,
suggesting that CRH antagonists may be useful in the treatment of
inflammatory disorders in man. CRH was also found in the ovary and
endometrium, where it may participate in the inflammatory phenomena of
ovulation, luteolysis, blastocyst implantation, and menstruation. Antalarmin
blocked implantation in rats and labor in sheep, suggesting that CRH
antagonists may have clinical applications in reproductive medicine. Webster EL, Barrientos RM, Contoreggi C, Isaac MG, Ligier S,
Habib K, Chrousos GP, McCarthy EF, Rice KC, Gold PW, Sternberg EM.
Corticotropin-releasing hormone (CRH) antagonist attenuates adjuvant-induced
arthritis: evidence supporting major role for CRH in peripheral inflammation.
J Rheumatol 2002;29:1252-1261. aVisiting
Associate, NIMH, Bethesda, MD bTechnion-Israel
Institute of Technology, cStaff
Physician, Warren Grant Magnusson Clinical Center, Bethesda, MD dEndocrinology,
Nutrition and Growth Branch, NICHD, Bethesda, MD 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, Lorah Dorn, RN, University of Pittsburgh, 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, Edward H. Oldfield, MD, Surgical Neurology
Branch, NINDS, Martin Reincke, MD, Universität München,
Germany Hajime Sano, MD, Kyoto University, Japan Roger Smith, MD, University of Newcastle
Medical School, Australia Esther M. Sternberg, MD, PsychoNeuroImmunology
Program, NIMH, Elisabeth Susman, PhD, Pennsylvania State
University, University Park, PA Constantine Tsigos, MD, Athens University,
Greece Alexander Vgontzas, MD, Pennsylvania State
University, Alessandra Vottero, MD, Jack A. Yanovski,
MD, PhD, Developmental Endocrinology Branch, NICHD, For
further information, contact chrousog@mail.nih.gov |
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