A Acanthosis nigricans, with Cushing's

disease, 281 Acne, with Cushing's disease, 281 ACTH deficiency, isolated, 9-10 ACTH precursors, pathological conditions,

85-\08 biological significance of, 10 I-I 02 Cushing's syndrome, pituitary dependent,

96 ectopic ACTH syndrome, ACTH

precursors in, 93-95 measurement, ACTH related peptides,

87-88 mechanisms for secretion, 101 Nelson's syndrome, ACTH precursors in,

97-99 normal tissues, ACTH precursors in,

89-92 cerebrospinal fluid, POMC, derived

peptides in, 91 hypothalamus, POMC, derived

peptides in, 90-91 pituitary, POMC peptides, release into

circulation, 89-90 pregnancy, POMC peptides in, 92 skin, POMC, derived peptides in, 92

pituitary tumors, large, invasive, ACTH precursors in, 96-97

POMC, processing to ACTH related peptides, 85-86

regulation of secretion, 100 ACTH receptor, mutations, 171-190

adrenal tumors, ACTH receptor in, 185 clinical features, 181-182 differential diagnosis, 181-182 in disease, 180·185 expression, cloned MC2R, 179-180 ligand binding, 171-173 MC2R promotor, 178-179 melanocortin receptors, human

chromosomal location, ligand selectivity of, 176

molecular pathogenesis, 182-183

Index

normal ACTH receptors, FGD with, 184 receptor purification, cloning, 175-177 regulation of MC2R, 178 signal transduction, 173-175 targets of ACTH-stimulated protein

kinase A regulation, 174 tissue distribution, 177-178 triple A syndrome, 184-185

ACTH secretion bronchial carcinoid tumors, V3 gene

expression, POMC gene, 40-41 ectopic, non-pituitary tumors responsible

for, POMC gene, 36-42 entities for, 41--42 POMC gene transcription, 37--42 POMC processing, 36-37

Addison's disease, 181 Adrenal cytokine level,

hypothalamo-pituitary-adrenal axis modulation, liS

Adrenal hormone receptors, aberrant, Cushing's syndrome due to, 207-228

angiotensin-responsive Cushing's syndrome, 215

catecholamine-dependent Cushing's syndrome, 212

clinical screening, 218 ectopic adrenal hormone receptors, 208 food-dependent Cushing's syndrome,

209-210 functional aberrant adrenal receptors,

clinical demonstration, 209-216 GIP-dependent Cushing's syndrome,

209-210 investigation strategy, 216-218 LH-dependent adrenal androgen-secreting

tumors, 214 LH/hcG-dependent Cushing's syndrome,

212-214 molecular mechanisms, 219-221 pharmacological therapies, 221-222 serotonin-responsive Cushing's

syndrome, 214

330

vasopressin-responsive Cushing's syndrome, 210-211

Adrenal hyperplasia, 181 Adrenal hypoplasia, 181 Adrenal imaging

in diagnosis of Cushing's syndrome, 247, 293-294

Adrenalectomy, bilateral, in treatment of Cushing's syndrome, 300

Adrenoleukodystrophy, 181 Alcoholism, with pseudo-Cushing's

syndrome,287-288 Alkalosis, with Cushing's disease, 281 Allgrove's syndrome, 181, 184-185 Alzheimer's disease, 74 Amenorrhea, with Cushing's disease, 281 Aminoglutethimide, 300 Angiotensin-responsive Cushing's

syndrome, 215 Anxiety, with pseudo-Cushing's syndrome,

288 Appetite, melanocortin pathway and,

153-170 agouti-related protein, 158 anorexia, role in, 162-164 arcuate nucleus, 159-160

efferent signals, integration of, 160· 162 cachexia, role in, 162-164 human obesity and MC4-R, 157 leptin, energy homeostasis and, 154-155 melanocortin-3 receptor, 158-159 murine obesity syndromes,

melanocortin-4 receptors, 155-157 Arthritis, 125, 320

5 Letter = B Baseline hormone determinations, in

diagnosis of Cushing's syndrome, 289 bHLH factor NeuroDI,

corticotroph-specific, 7-8 ACTH-secreting pituitary tumors, 8

Bilateral adrenalectomy, in treatment of Cushing's syndrome, 300

Bilateral inferior petrosal sinus sampling, 239,244,294

Biochemical confirmation, Cushing's syndrome, 232-236

circadian rhythm assessment, 233-234 low-dose dexamethasone suppression test,

235-236 urinary free cortisol, 234-235

Index

Blood-brain barrier, cytokines, hypothalamo-pituitary-adrenal axis modulation, 116--118

Bronchial carcinoid tumors ACTH-secreting, V3 gene expression,

POMC gene, 40-41 POMC gene expression, corticotroph

phenotype, 40-41 Bruising, with Cushing's disease, 281

5 Letter = C Catecholamine-dependent Cushing's

syndrome, 212 Catheterization studies, in diagnosis of

Cushing's syndrome, 294-296 Cerebrospinal fluid, POMC, derived

peptides in, 91 Chemical transformations,

proopiomelanocortin gene expression, processing, 35

Circadian rhythm assessment, Cushing's syndrome, 233--234

Complications, from Cushing's syndrome, follow-up after, post-op evaluation for, 301302

Corticotrope axis, leptin and, 193-195 "Corticotroph" adenomas, silent, pars

intermedia, pituitary, role in histogenesis of, 259-276

historical overview, 259-260 subtype 1,265-269 subtype 2, 269-271

Corticotroph axis, multifactorial regulation, 47-64

11 beta dehydrogenase 1, 61 corticotrophin releasing hormone, 4851

receptor lIcorticotrophin releasing hormone receptor 2,55-57

receptors, 51-55 leukemia inhibiting factor, 58-59 proinflammatory cytokines, 59-60

interleukin-6, 59-{i0 steroidogenic factor I, 60-{i I tumor necrosis factor alpha, 59

vasopressin, 57 Corticotroph differentiation, 6--9

Pitx factors as general pituitary regulators, 6--7

Corticotroph ontogenesis, l-{i Corticotroph phenotype, bronchial carcinoid

tumors, POMC gene expression, 40-41 Corticotrophin releasing hormone

Index

altered expression, animal models with, 72-73

binding protein, 73-74 corticotroph axis regulation, 48-51

receptor 1,52-54 receptor 2,54-55

Cushing's syndrome, 240--242 in diagnosis of Cushing's syndrome,

292-293 historical review, 65 ligands, 74-75

non-peptidic, 76-77 peptidic,75

receptor, ligands, 65-84 receptor I, 52-54, 71

tissue distribution of, 71 receptor 2,54-55,71

tissue distribution of, 71 receptors, 68-70 related peptides

affinities, activities of, 72 amino acid sequences, 66 isolation, characterization of, 65-66

tissue distribution, 70--72 urocortin, corticotrophin releasing

hormone physiological, pathophysiological roles,

66-67 tissue distribution, 67-68

Corticotrophin releasing hormone test. See Corticotrophin releasing hormone

Corticotrophin releasing hormone-BP, corticotroph axis regulation, 57

Corticotroph-specific bHLH factor NeuroDI,7-8

ACTH-secreting pituitary tumors, 8 Corticotroph-specific transcription, POMC

gene, 10--14 NeuroDI heterodimers, cell specificity

and, 13-14 Pitx I, protein interactions, 12--13 POMC promoter, 10--12 Tpit, as Ptix I obligate partner, 14

Cushing's disease, 97, 99, 321 algorithm, diagnostic, 296-298 baseline hormone determinations, 289 catheterization studies, 294-296 chronic disease, 286 clinical presentation, 280284 corticotrophin releasing hormone,

292-293 diagnosis, 284--285, 290, 291 differential diagnosis, 287-298

331

mild Cushing's syndrome, vs. pseudo-Cushing states, 287-289

endocrine dynamic testing ofHPA axis, 289-291

endogenous, classification of, 279 etiology of, 278-280 follow-up after treatment, 301-302

complications, post-op evaluation for, 301-302

patient cure, determination of, 30 I postoperative glucocorticoid

replacement, 301 hypercortisolemic states, with unusual

laboratory behavior, 285-287 hypercortisolism, classification of, 288 hypothalamic-pituitary-adrenal axis,

physiology of, 278 imaging evaluation, 293

adrenals, 293-294 pituitary, 293

Liddle dexamethasone suppression test, 290,292

metyrapone stimulation test, 290, 292 periodic Cushing's syndrome, 285 POMC gene expression, 35-36 in pregnancy, 286 primary cortisol resistance, 286 symptoms/signs, frequency of

in adults, 280 in pediatric patients, 281

therapeutic strategies, 277-306 treatment, 299-300

bilateral adrenalectomy, 300 drug therapy, 287, 300. See also under

specific drug gamma knife, 299 linear accelerator-mediated

radiosurgery, 299 pituitary X-irradiation, mitotane,

combined, 299 transphenoidal adenomectomy, 299

Cushing's syndrome, 93, 96, 99, 198, 232, 242,308

angiotensin-responsive Cushing's syndrome, 215

biochemical confirmation of, 232--236 circadian rhythm assessment, 233-234 low-dose dexamethasone suppression

test, 235---236 urinary free cortisol, 234-235

catecholamine-dependent Cushing's syndrome, 212

clinical features, 232

332

clinical screening, 218 corticotrophin releasing hormone test,

240--242 diagnosis, 229-258 differential diagnosis of, 236-237 due to aberrant adrenal hormone

receptors, 207-228 investigation strategy, 216-218 molecular mechanisms, 219-221

dynamic tests, 239-240 high dose dexamethasone suppression

test, 239-240 ectopic ACTH syndrome, etiology, 231 ectopic adrenal hormone receptors, 208 etiology, 230--231 food-dependent Cushing's syndrome,

209-2\0 functional aberrant adrenal receptors,

clinical demonstration, 209-216 GIP-dependent Cushing's syndrome,

209-2\0 imaging, 245-248

adrenal, 247 ectopic tumors, 248 pituitary, 245-247

inferior petrosal sinus sampling, 244-245, 294

LH-dependent adrenal androgen-secreting tumors, 214

LHlhcG-dependent Cushing's syndrome, 212-214

metyrapone test, 240, 290, 292 non-dynamic tests, 237-238 other peptides, testing with, 242-244 pathophysiology, 230--231 pharmacological therapies, 221-222 pituitary dependent, ACTH precursors, 96 pseudo-Cushing's syndrome, differential

diagnosis, 232, 236, 242 serotonin-responsive Cushing's

syndrome, 214 source, identifying, 237-245 vasopressin-responsive Cushing's

syndrome, 210--21 I Cytokines

HP A axis modulation, pituitary level, macrophage migration inhibitory factor, 113-114

hypothalamo-pituitary-adrenal axis modulation, 111-1l9

adrenal gland level, 115 blood-brain barrier, 116-118 hypothalamic level, 115-116

Index

physiologic, pathophysiologic significance, 118-120

pituitary level, leukemia inhibitory factor, 114-115

D Depression, in pseudo-Cushing's syndrome,

287-288 Desmopressin, 243 Dexamethasone suppression, 235-236, 244,

315,318 Diabetes, 153-170, 281 Diagnostic algorithm, Cushing's disease,

296-298 Differential diagnosis, Cushing's syndrome,

236-237,287-298 pseudo-Cushing's syndrome, 232, 236,

242 Dual embryonic origin of pituitary, 2 Dynamic tests, Cushing's syndrome,

239-240

E

high dose dexamethasone suppression test, 239-240

Ectopic ACTH secretion, non-pituitary tumors responsible for, POMC gene, 36-42

entities for, 41--42 POMC gene transcription, 37--42 POMC processing, 36-37

Ectopic ACTH syndrome ACTH precursors in, 93-95 etiology, 231

Ectopic adrenal hormone receptors, 208 Ectopic tumors, imaging, Cushing's

syndrome, 248 II beta dehydrogenase I, corticotroph axis

regulation, 61 Embryonic origin of pituitary, 2 Endocrine dynamic testing ofHPA axis, in

diagnosis of Cushing's syndrome, 289-291

Estrogen, 214

F Fatigue, with Cushing's disease, 281 Femoral capital epiphysis, slipped, with

Cushing's disease, 281 FGD with normal ACTH receptors, 184

Index

Follow-up after treatment for Cushing's syndrome, 301-302

complications, post-op evaluation for, 301-302

patient cure, determination of, 30 I postoperative glucocorticoid replacement,

301 Food intake, melanocortin pathway, 153-170

agouti-related protein, 158 anorexia, role in, 162-164 arcuate nucleus, 159-160 arcuate nucleus efferent signals,

integration of, 160-162 cachexia, role in, 162-164 human obesity and MC4-R, 157 leptin, energy homeostasis and, 154-155 melanocortin-3 receptor, 158-159 murine obesity syndromes,

melanocortin-4 receptors, 155-157 Food-dependent Cushing'S syndrome, 198,

200,209-210

G Gamma knife, in treatment of Cushing's

syndrome, 299 GIP-dependent Cushing's syndrome,

209-210 Glucocorticoid resistance syndromes,

307-327 clinical presentation, 313,314 glucocorticoid receptor, 308--311 hereditary glucocorticoid resistance,

311-319 molecular characterization, 313 receptor alterations, 313 tissue specific glucocorticoid sensitivity,

320-322 GPl30-mediated POMC gene expression in

vitro, negative regulation of, pituitary corticotroph SOCS-3, 141-145

cAMP-dependent SOCS-3 gene expression in corticotrophs, 144--145

STAT-dependent POMC gene expression, negative regulator of, 142-143

STAT-dependent POMC gene expression in corticotrophs, 141-142

STAT -dependent SOCS-3 gene expression in corticotrophs, 143-144

Grave's disease, 125 Growth retardation, with Cushing's disease,

281

333

H Hashimoto's thyroiditis, 125 Hereditary glucocorticoid resistance,

311-319 Hexarelin, 243 High dose dexamethasone suppression test,

Cushing's syndrome, 239-240 Hirsutism, with Cushing's disease, 281 Hormonal regulation, POMC expression,

14-20 activation by corticotrophin releasing

hormone, 15-17 corticotrophin releasing hormone

signaling, LIF in, 17-18 glucocorticoid repression, 18-20

direct repression, at nGRE, 18 GR repression in vivo. mechanism of,

19-20 transrepression by GR, 18-19

Hypercalcemia, with Cushing's disease, 281 Hypercortisoiemic states, with unusual

laboratory behavior, 285-287 Hypercortisolism, classification of, 288 Hyperpigmentation, with Cushing's disease,

281 Hyp~rtension, with Cushing's disease, 281 Hypokalemia, with Cushing's disease, 281 Hypothalamic level, cytokines,

hypothalamo-pituitary-adrenal axis modulation, 115-116

Hypothalamo-pituitary-adrenal axis immune system interaction, 109-136

adrenal gland level, 115 blood-brain barrier, 116-118 cytokines, 111-119

pituitary level, macrophage migration inhibitory factor, 113-114

hypothalamic level, 115-116 physiologic, pathophysiologic

significance, 118-120 pituitary level, 112-115 sexual dimorphism, of

neuroendocrine-immune interactions, 125-126

immunodeficiency state effect on HP A axis, hypothalamic,

pituitary stimuli response, 121 effect on hypothalamo-pituitary-adrenal

axis, 120-125 ACTH stimulation, adrenal response

to, 122

334

immune reconstitution, nude athymic mice, 122-123

T-Iymphocytes, ACTH release, immune cells, 123-125

leptin, 191-206 adrenal effects, 196--198 animal studies, 193-195 central effects, 198-200

hypothalamus, 198-200 pituitary gland, 200

corticotrope axis, 193-195 leptin and, 193-195

human studies, 195 physiology ofleptin, 191-193

physiology of, 278 pituitary level, leukemia inhibitory factor,

114-115 Hypothalamus

leptin, central effects, 198-200 POMC, derived peptides in, 90-91

Imaging, Cushing's syndrome, 245-248, 293 adrenal, 247 ectopic tumors, 248 pituitary, 245-247

Immune system interaction, hypothalamo-pituitary-adrenal axis, 109-136

cytokines, 111-119 adrenal gland level, 115 blood-brain barrier, 116--118 hypothalamic level, 115-116 physiologic, pathophysiologic

significance, 118-120 pituitary level, 112-115

leukemia inhibitory factor, 114-115 macrophage migration inhibitory

factor, 113-114 immunodeficiency state

effect on HP A axis, hypothalamic, pituitary stimuli response, 121

effect on hypothalamo-pituitary-adrenal axis, 120-125

ACTH stimulation, adrenal response to, 122

immune reconstitution, nude athymic mice, 122--123

T -lymphocytes, ACTH release, immune cells, 123-125

Index

sexual dimorphism, of neuroendocrine-immune interactions, 125-126

Immunodeficiency state effect on HP A axis, hypothalamic,

pituitary stimuli response, 121 effect on hypothalamo-pituitary-adrenal

axis, 120-125 Inferior petrosal sinus sampling, Cushing's

syndrome,244-245,294 Interleukin-6, corticotroph axis regulation,

59-60

J JaK -STAT signaling, pituitary corticotroph

K

SOCS-3,138-141 gp 130 cytokine family, 139 Jak-STAT signaling cascade, 138-139 SOCS protein structure and function,

139--140 STAT-dependent SOCS gene expression,

140-141

Ketoconazole, 300

L Leptin

adrenal effects, 196--198 hypothalamo-pituitary-adrenal axis,

191--206 adrenal effects, 196--198 animal studies, 193-195 central effects, 198--200

hypothalamus, 198-200 pituitary gland, 200

corticotrope axis, leptin and, 193-195 human studies, 195 physiology ofleptin, 191-193

Leukemia inhibiting factor corticotroph axis regulation, 58-59 pituitary level, cytokines,

hypothalamo-pituitary-adrenal axis modulation, 114-115

Leuprolide acetate, 213 LH-dependent adrenal androgen-secreting

tumors, 214 LH/hcG-dependent Cushing's syndrome,

212-214

Index

Liddle dexamethasone suppression test, in diagnosis of Cushing's syndrome, 290, 292

Ligands, 74-75 corticotrophin releasing hormone

receptors, 65-84 altered expression, animal models with,

72-73 binding protein, 73-74 CRH-receptor I, tissue distribution of, 71 CRH -receptor 2, tissue distribution of, 71 historical review, 65 non-peptidic ligands, 76-77 peptidic ligands, 75 receptors, 68-70 related peptides

affinities, activities of, 72 amino acid sequences, 66 isolation, characterization of, 65--66

tissue distribution, 70-72 urocortin, corticotrophin releasing

hormone physiological, pathophysiological

roles, 66-67 tissue distribution, 67-68

Linear accelerator-mediated radiosurgery, Cushing's syndrome, 299

M Melanocortin pathway, food intake, 153-170

agouti-related protein, 158 anorexia, role in, 162-164 arcuate nucleus, 159-160

efferent signals, integration of, 160--162 cachexia, role in, 162-164 human obesity and MC4-R, 157 leptin, energy homeostasis and, 154 -155 melanocortin-3 receptor, 158-159 murine obesity syndromes,

melanocortin-4 receptors, 155-157 Menstrual irregularities, with Cushing's

disease, 281 Mental changes, with Cushing's disease, 281 Metyrapone, in diagnosis of Cushing's

syndrome, 240, 290, 292, 300 Mild Cushing's syndrome, vs.

pseudo-Cushing states, 287-289 Mitotane, 300

pituitary X-irradiation, combined, with Cushing's syndrome, 299

Muscle weakness, with Cushing's disease, 281

N Nelson's syndrome, 98

ACTH precursors in, 97-99 NeuroDI heterodimers, POMC gene, cell

specificity and, 13-14 Non-dynamic tests, Cushing's syndrome,

237-238 Non-Hodgkin's lymphoma, 110 Non-peptidic ligands, corticotrophin

releasing hormone receptors, 76-77 Non-pituitary tissues, POMe gene

expression in, 33-34

335

Non-pituitary tumors responsible for ectopic ACTH secretion, POMC gene, 36-42

entities for, 41-42 POMC gene transcription, 37-42 POMe processing, 36-37

Normal tissue, ACTH precursors in, 89-92 cerebrospinal fluid, POMe derived

peptides in, 91 hypothalamus, POMe derived peptides

in, 90-91 pituitary, POMe peptides, release into

circulation, 89-90 pregnancy, POMC peptides in, 92 skin, POMC derived peptides in, 92

o Obesity

melanocortin pathway, 153-170 agouti-related protein, 158 anorexia, role in, 162-164 arcuate nucleus, 159-160 arcuate nucleus efferent signals,

integration of, 160-162 cachexia, role in, 162-164 human obesity and MC4-R, 157 leptin, energy homeostasis and,

154-155 melanocortin-3 receptor, 158-159 murine obesity syndromes,

melanocortin-4 receptors, 155--157 Ontogenesis

corticotroph, 1-6 pituitary, 1-6

dual embryonic origin of pituitary, 2 pituitary fate commitment, 5-6 pituitary primordium, induction of, 2--3

336

p Panic attack, with pseudo-Cushing's

syndrome, 288 Pars intermedia, human pituitary, in

histogenesis of silent "corticotroph" adenomas,259-276

historical overview, 259-260 silent "corticotroph" adenoma subtype I,

265-269 silent "corticotroph" adenoma subtype 2,

269-271 Pediatric patients, symptoms/signs of

Cushing's syndrome, frequency of, 281 Peptides, corticotrophin releasing hormone

receptors, ligands amino acid sequences, 66 isolation, characterization ot: 65-66

Peptidic ligands, corticotrophin releasing hormone receptors, 75

Periodic Cushing's syndrome, 285 Pharmaceuticals, in treatment of Cushing's

syndrome, 221-222, 287, 300. See also under specific drug

Pituitary pars intermedia, role in histogenesis of

silent "corticotroph" adenomas, 259-276

historical overview, 259-260 silent "corticotroph" adenoma subtype

1,265-269 silent "corticotroph" adenoma subtype

2,269-271 POMC gene expression in, 33 POMC peptides, release into circulation,

89-90 Pituitary corticotroph SOCS-3, 137-170

GP130-mediated POMC gene expression in vitro, negative regulation of, 141-145

cAMP-dependent SOCS-3 gene expression in corticotrophs, 144-145

STAT -dependent POMC gene expression, negative regulator of, 142-143

STAT-dependent POMC gene expression in corticotrophs, 141-142

STAT-dependent SOCS-3 gene expression in corticotrophs, 143-144

JaK-STAT signaling, role in, 138-141 gp130 cytokine family, 139 Jak-ST AT signaling cascade, 138-139

Index

SOCS protein structure and function, 139-140

ST AT -dependent SOCS gene expression, 140--141

pituitary LIF, SOCS-3 gene expression in vivo, 145

HP A axis stress response, hypothalamic, pituitary LIF, 145

hypothalamic, pituitary SOCS-3, early response gene in vivo, 145

signaling between corticotrophin releasing hormone, GP 130 cytokines in corticotroph cell, 146-148

Pituitary corticotroph system, 1-28 ACTH deficiency, isolated, 9-10 corticotroph differentiation, 6--9

Pitx factors as general pituitary regulators, 6-7

corticotroph-specific bHLH factor NeuroD1,7-8

ACTH-secreting pituitary tumors, 8 hormonal regulation, POMC expression,

14-20 activation by corticotrophin releasing

hormone, 15-17 corticotrophin releasing hormone

signaling, LIF in, 17-18 glucocorticoid repression, 18-20

direct repression, at nGRE, 18 GR repression in vivo, mechanism

of,19-20 transrepression by GR, 18-19

pituitary ontogenesis, 1-6 corticotroph ontogenesis, 1-6 dual embryonic origin of pituitary, 2 pituitary fate commitment, 5-6 pituitary primordium, induction of, 2-3 pouch formation, definitive, 4-5 proliferation, 5-6

POMC gene corticotroph-specific transcription, 10--14

NeuroD I heterodimers, cell specificity and,1314

Pitx I, protein interactions, 12-13 POMC promoter, 10--12 Tpit, as Ptixl obligate partner, 14

Tpit, pituitary POMC lineages, factor for, 8-9

Pituitary imaging, in diagnosis of Cushing's syndrome,245-247293

Pituitary LIF, SOCS-3 gene expression in vivo. pituitary corticotroph SOCS-3, 145

Index

HP A axis stress response, hypothalamic, pituitary LIF, 145

hypothalamic, pituitary SOCS-3, early response gene in vivo, 145

Pituitary tumors, large, invasive, ACTH precursors in, 96-97

Pituitary X-irradiation, mitotane, combined, with Cushing's syndrome, 299

Pitx factors, as general pituitary regulators, 67

Pitxl, POMC gene, protein interactions, 12-13 Postoperative glucocorticoid replacement, in

follow-up after treatment for Cushing's syndrome, 30 I

Pregnancy Cushing's syndrome in, 286 POMC peptides in, 92

Primary cortisol resistance, 286 Primordium, pituitary, induction of, 2-3 Progestogen, 214 Proinflammatory cytokines, corticotroph

axis regulation, 59-60 interleukin-6, 59-60 steroidogenic factor I, 60-61 tumor necrosis factor alpha. 59

Proopiomelanocortin gene, 3, 10-12,42-43 corticotroph-specific transcription, 10··14

NeuroD I heterodimers, cell specificity and, 13-14

Pitx I, protein interactions, 12-13 POMC gene, 10 POMC promoter, 10-12 Tpit, as Ptix I obligate partner, 14

discovery of, 30-31 expression in pathological situations,

35-43 bronchial carcinoid tumors,

corticotroph phenotype, 40-41 Cushing's disease, 35-36 pituitary tumors, 35-36. See also

Cushing's disease SCCL line (DMS 79),

POMC-producing, 3840 V3 gene expression studies,

ACTH-secreting bronchial carcinoid tumors, 40-41

hormonal regulation, 14-20 activation by corticotrophin releasing

hormone, 15-17 corticotrophin releasing hormone

signaling, LIF in, 17-18 glucocorticoid repression, 18-20

direct repression, at nGRE, 18

337

GR repression in vivo, mechanism of, 19-20

transrepression by GR, 18-19 human POMC gene, 31-32 NeuroD I heterodimers, cell specificity

and, 13-14 non-pituitary tumors responsible for

ectopic ACTH secretion, POMC gene, entities for, 41-42

PCI, POMC gene defects, 42-43 Pitx I , protein interactions, 12-13 processing, 34-35

chemical transformations, 35 proteolytic processing, 34-35

processing to ACTH related peptides, 85-86 Tpit

POMC gene defects, 43 as Ptix I obligate partner, 14

Protein kinase A regulation, ACTH-stimulated, targets of, 174

Proteolytic processing, POMC gene, 34-35 Pseudo-Cushing states, mild Cushing's

syndrome, differential diagnosis, 287-289

Pseudo-Cushing's syndrome, 287 Cushing's syndrome, differential

diagnosis, 232, 236, 242 Ptix I, Tpit as obligate partner, 14

R Receptor homodimers, "zink fingers," DNA,

310 Receptor purification, ACTH receptor,

175-177 Rheumatoid arthritis, 125,320

S SCCL line (DMS 79), POMC gene

expression, 38-40 Serotonin-responsive Cushing's syndrome,

214 Sexual development, secondary

delayed, with Cushing's disease, 281 early, with Cushing's disease, 281

Sexual dimorphism, of neuroendocrine-immune interactions, 125-126

SF I. See Steroidogenic factor I Silent "corticotroph" adenomas, pars

intermedia, pituitary, role in histogenesis of, 259-276

338

historical overview, 259-260 silent "corticotroph" adenoma subtype I,

265-269 silent "corticotroph" adenoma subtype 2,

269-271 Skin, POMC, derived peptides in, 92 Sleep disturbances, with Cushing's disease, 281 SOCS-3, pituitary corticotroph, 137-170

GPl30-mediated POMC gene expression in vitro, negative regulation of, 141-145

cAMP-dependent SOCS-3 gene expression in corticotrophs, 144--145

STAT-dependent POMC gene expression, negative regulator of, 142-143

STAT -dependent POMC gene expression in corticotrophs, 141-142

STAT-dependent SOCS-3 gene expression in corticotrophs, 143-144

JaK-STAT signaling, role in, 138-141 gpl30 cytokine family, 139 Jak-ST AT signaling cascade, 138-139 SOCS protein structure and function,

139-140 STAT -dependent SOCS gene

expression, 140-141 pituitary L1F, SOCS-3 gene expression in

vivo, 145 HP A axis stress response,

hypothalamic, pituitary L1F, 145 hypothalamic, pituitary SOCS-3, early

response gene in vivo, 145 signaling between corticotrophin

releasing hormone, GPI30 cytokines in corticotroph cell, 146-148

Steroidogenic acute regulatory protein, 196 Steroidogenic factor I, corticotroph axis

regulation, 60-61 Systemic lupus erythematosus, 125

T Tissue specific glucocorticoid sensitivity,

320-322 T-Iymphocytes, ACTH release, immune

cells, 123-125 TNF alpha. See Tumor necrosis factor alpha Tpit

pituitary POMC lineages, factor for, 8-9

Index

POMC gene defects, 43 as Ptix I obligate partner, 14

Transphenoidal adenomectomy, in treatment of Cushing's syndrome, 299

Trilostane, 300 Triple A syndrome, 181, 184--185 Tumor necrosis factor alpha, corticotroph

axis regulation, 59

U Urinary free cortisol, Cushing's syndrome,

234-235 Urocortin, corticotrophin releasing hormone

receptor, ligands

V

physiological, pathophysiological roles, 66-67

tissue distribution, 67-{)8

V3 gene expression, ACTH-secreting bronchial carcinoid tumors, POMC gene, 40-41

Vasopressin corticotroph axis regulation, 57 Cushing's syndrome responsive to,

210-211 Violaceous skin striae, with Cushing's

disease, 281

W Weakness, with Cushing's disease, 281 Weight gain

Z

melanocortin pathway and, 153-170 agouti-related protein, 158 anorexia, role in, 162-164 arcuate nucleus, 159-160 arcuate nucleus efferent signals,

integration of, 160-162 cachexia, role in, 162-164 human obesity and MC4-R, 157 leptin, energy homeostasis and, 154--155 melanocortin-3 receptor, 158-159 murine obesity syndromes,

melanocortin-4 receptors, 155-157

"Zink fingers," receptor homodimers, DNA, 310