This page intentionally left blank Birth, Distress and Disease This volume examines the role of steroids and peptides in the regulation of pregnancy and pregnancy outcome, and their long-term effects including possible influences on adult-onset diseases During pregnancy the placenta acts as a central regulator and coordinator of maternal and fetal physiology, and of the onset of labor, through its production and regulation of steroids and peptides Perturbations to this regulatory system can result in poor pregnancy outcome, such as preterm birth and low birth weight These in turn are linked to diseases in later life Intriguingly, many of these regulatory actions of steroids and peptides also occur in the brain The induction and suppression of peptides by steroids appear to be the key to regulatory function in both brain and placenta These various interweaving strands, linking basic sciences with obstetrics, are all reviewed in depth here producing a fascinating account of an important area of materno-fetal medicine Birth, Distress and Disease Placental–Brain Interactions Edited by Michael L Power Smithsonian National Zoological Park Washington DC, USA American College of Obstetricians and Gynecologists Washington DC, USA and Jay Schulkin American College of Obstetricians and Gynecologists Washington DC, USA Georgetown University School of Medicine Washington DC, USA National Institute of Mental Health Bethesda MD, USA cambridge university press Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo Cambridge University Press The Edinburgh Building, Cambridge cb2 2ru, UK Published in the United States of America by Cambridge University Press, New York www.cambridge.org Information on this title: www.cambridge.org/9780521831482 © Cambridge University Press 2005 This publication is in copyright Subject to statutory exception and to the provision of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press First published in print format 2005 isbn-13 isbn-10 978-0-511-12900-1 eBook (EBL) 0-511-12900-9 eBook (EBL) isbn-13 isbn-10 978-0-521-83148-2 hardback 0-521-83148-2 hardback Cambridge University Press has no responsibility for the persistence or accuracy of urls for external or third-party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate Every effort has been made in preparing this publication to provide accurate and up-to-date information that is in accord with accepted standards and practice at the time of publication Nevertheless, the authors, editors and publisher can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation The authors, editors and publisher therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use This volume is dedicated to the students and young (and not so young) scientists we confidently predict will extend and improve on the research presented here We would also like to acknowledge and thank certain individuals for the personal contributions they have made to one of us (JS): E E Krieckhaus; Ellen Oliver; and Stanley Schulkin Michael L Power, Ph.D Jay Schulkin, Ph.D November 17, 2004 Contents List of contributors Preface Introduction: brain and placenta, birth and behavior, health and disease page ix xi Michael L Power and Jay Schulkin Placental expression of neurohormones and other neuroactive molecules in human pregnancy 16 Felice Petraglia, Pasquale Florio and Wylie W Vale The regulation of human parturition 74 Roger Smith, Sam Mesiano, Richard Nicholson, Vicki Clifton, Tamas Zakar, Eng-Cheng Chan, Andrew Bisits and Warwick Giles Maternal nutrition and metabolic control of pregnancy 88 Michael L Power and Suzette D Tardif Fetal HPA activation, preterm birth and postnatal programming 114 Deborah M Sloboda, Timothy J M Moss, John P Newnham and John R G Challis Prenatal glucocorticoids and the programming of adult disease 142 Jonathan R Seckl, Amanda J Drake and Megan C Holmes Prenatal stress and stress physiology influences human fetal and infant development 183 Elysia Poggi Davis, Calvin J Hobel, Curt A Sandman, Laura Glynn, Pathik D Wadhwa Glucocorticoids and the ups and downs of neuropeptide gene expression Alan G Watts 202 viii Contents Glucocorticoid facilitation of corticotropin-releasing hormone in the placenta and the brain: functional impact on birth and behavior 235 Jay Schulkin, Louis Schmidt and Kristine Erickson Index 269 265 Glucocorticoid facilitation of CRH in the placenta and the brain Robinson, B G., Emanuel, R L et al (1988) Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta Proc Natl Acad Sci USA, 85(14), 5244–8 Roozendaal, B., Brunson, K L., Holloway, B L., McGaugh, J L and Baram, T Z (2002) Involvement of stress-released corticotropin-releasing hormone in the basolateral amygdala in regulating memory consolidation Proc Natl Acad Sci., 99, 13908–13 Rosen, J B and Schulkin, J (1998) From normal fear to pathological anxiety Psychol Rev., 105, 325–50 Rosenbaum, J F., Biederman, J et al (2000) A controlled study of behavioral inhibition in children of parents with panic disorder and depression Am J Psychiatr., 157(12), 2002–10 Sachar, E J., Hellman, L., Fukushima, d K and Gallagher, T F (1970) Cortisol production in depressive illness: a clinical and biochemical clarification Arch Gen Psychiatr., 23, 289–98 Sanchez, M M., Young, L J., Plotsky, P M and Insel, T R (2000) Distribution of corticosteroid receptors in the rhesus brain: relative absence of glucocorticoid receptors in the hippocampal formation J Neurosci., 20, 4657–68 Sandman, C A., Wadhwa, P D., Chicz-DeMet, A., Porto, M and Garite, T J (1999) Maternal corticotropin-releasing hormone and habituation in the human fetus Develop Psychobiol., 34, 163–73 Sapolsky, R M (2000) Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders Archiv of Gen Psychiatr., 57, 925–35 Schmidt, L A and Schulkin, J (1999) Extreme Fear, Shyness and Social Phobia, Oxford: Oxford University Press Schmidt, L A., Fox, N A., Rubin, K J et al (1997) Behavioral and neuroendocrine responses in shy children Develop Psychobiol., 30, 127–40 Schmidt, L A., Fox, N A., Schulkin, J and Gold, P W (1999a) Behavioral and psychophysiological correlates of self-presentation in temperamentally shy children Develop Psychobiol., 35, 119–35 Schmidt, L A., Fox, N A., Sternberg, E M et al (1999b) Adrenocortical reactivity and social competence in seven year-olds Pers Indiv Differ., 26, 977–85 Schneider, F., Weiss, U et al (1999) Subcortical correlates of differential classical conditioning of aversive emotional reactions in social phobia Biol Psychiatr., 45(7), 863–71 Schulkin, J (1999) CRH signals adversity in both the placenta and the brain: regulation by glucocorticoids and allostatic overload J Endocrinol., 161, 340–56 Schulkin, J (2003) Rethinking Homeostasis, Cambridge: MIT Press Schulkin, J., Gold, P W and McEwen, B S (1998) Induction of corticotropin-releasing hormone gene expression by glucocorticoids: implication for understanding the states of fear and anxiety and allostatic load Psychoneuroendocrinology, 23(3), 219–43 Schwartz, C E., Snidman, N et al (1999) Adolescent social anxiety as an outcome of inhibited temperament in childhood J Am Acad Child Adolesc Psychiatr., 38(8), 1008–15 Schwartz, C E., Wright, C I et al (2003a) Inhibited and uninhibited infants ‘grown up’: adult amygdala response to novelty Science, 300, 1952–3 Schwartz, C E., Wright, C I et al (2003b) Differential amygdalar response to novel versus newly familiar neutral faces: a functional MRI probe developed for studying inhibited temperament Biol Psychiatr., 53(10), 854–62 266 J Schulkin et al Seckl, J R (1997) Glucocorticoids, feto-placental 11 beta-hydroxysteroid dehydrogenase type 2, and the early life origins of adult disease Steroids, 62, 89–94 Shepard, J D., Barron, K W and Myers, D A (2000) Corticosterone delivery to the amygdala increases corticotropin-releasing hormone mRNA in the central nucleus of the amygdala and anxiety-like behavior Brain Res., 851, 288–95 Shepard, J D., Barron, K W and Myers, D A (2003) Sterotaxic localization of corticosterone to the amygdala enhances hypothalamic–pituitary adrenal responses to behavioral stress Brain Res., 963, 203–13 Shin, L M., Kosslyn, S M et al (1997) Visual imagery and perception in posttraumatic stress disorder A positron emission tomographic investigation Arch Gen Psychiatr., 54(3), 233–41 Strome, E M., Trevor-Wheler, G H., Higley, J D et al (2002) Intracerebroventricular CRH increases limbic glucose metabolism and has social context dependent behavioral effects in nonhuman primates Proc Natl Acad Sci., 99, 15749–54 Sullivan, R M and Gratton, A (2002) Prefrontal cortical regulation of HPA function in the rat and implications for psychopathology Psychoneuroendocrinology, 27, 99–114 Swanson, L W and Simmons, D M (1989) Differential steroid hormone and neural influences on peptide mRNA levels in CRH cells of the paraventricular nucleus: a hybridization histochemical study in the rat J Comp Neurol., 285, 413–35 Swanson, L W., Sawchenko, P E., Rivier, J and Vale, W W (1983) Organization of ovine corticotropin releasing hormone immunoreactive cells and fibers in the rat brain: an immunohistochemical study Neuroendocrinology, 36, 165–86 Swerdlow, N R., Briton, K T and Koob, G F (1989) Potentiation of acoustic startle by corticotropin-releasing factor (CRF) and by fear are both reversed by alpha-helical CRF (9–41) Neuropsychopharmacology, 2, 285–92 Takahashi, L K., Kalin, N H., Vanden-Burgt, J A and Sherman, J E (1989) Corticotropinreleasing hormone modulates defensive-withdrawal and exploratory behavior in rats Behav Neurosci., 3, 648–54 Takahashi, L K and Kim, H (1994) Intracranial action of corticosterone facilitates the development of behavioral inhibition in the adrenalectomized preweanling rat Neurosci Lett., 176, 272–6 Tanimura, S M and Watts, A G (1998) Corticosterone can facilitate as well as inhibit corticotropin-releasing hormone gene expression in the rat hypothalamic paraventricular nucleus Endocrinology, 139, 3830–6 Thompson, B L., Erickson, K., Schulkin, J and Rosen, J B (2004) Repeated corticosterone administration facilitates retention of contextual fear conditioning and increases CRH mRNA expression in the amygdala Behav Brain Res., 149, 209–15 Trautman, P D., Meyer-Bahlburg, H F., Postelnek, J and New, M I (1995) Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children: results of a pilot study Psychoneuroendocrinology, 20, 439–49 Valentino, R J et al (1994) Evidence for widespread afferents to Barrington’s nucleus, a brainstem region rich in CRF neurons Neuroscience, 62, 123–45 Valentino, R J., Pavcovich, L A and Hirata, H (1995) Evidence for corticotropin-releasing hormone projections from Barrington’s nucleus to the periaqueductal gray and dorsal motor nucleus of the vagus in the rat J Comp Neurol., 363, 402–22 267 Glucocorticoid facilitation of CRH in the placenta and the brain Van Ameringen, M., Mancini, C et al (1998) The relationship of behavioral inhibition and shyness to anxiety disorder J Nerv Ment Dis., 186(7), 425–31 Wadhwa, P D., Sandman, C A., Porto, M., Dunkel-Schetter, C and Garite, T J (1993) The association between prenatal stress and infant birth weight and gestational age at birth: a prospective investigation Am J Obstet Gynecol., 169, 858–65 Wadhwa, P D., Sandman, C A et al (2001) The neurobiology of stress in human pregnancy: implications for prematurity and development of the fetal central nervous system Progr Brain Res., 133, 131–42 Warren, S L., Gunnar, M R et al (2003) Maternal panic disorder: infant temperament, neurophysiology, and parenting behaviors J Am Acad Child Adolesc Psychiatr., 42(7), 814–25 Watts, A G and Sanchez-Watts, G (1995) Region-specific regulation of neuropeptide mRNAs in rat limbic forebrain neurones by aldosterone and corticosterone J Physiol., 484(Pt 3), 721–36 Welberg, L A., Seckl, J R and Holmes, M C (2000) Inhibition of 11 beta-hydroxysteroid dehydrogenase, the foeto-placental barrier to maternal glucocorticoids, permanently programs amygdala GR mRNA expression and anxiety-like behavior in the offspring Eur J Neurosci., 12, 1047–54 Welberg, L A and Seckl, J R (2001) Prenatal stress, glucocorticoids and the programming of the brain J Neuroendocrinol., 13, 113–28 Wolfe, C D., Patel, S P et al (1988) Plasma corticotrophin-releasing factor (CRF) in normal pregnancy Br J Obstet Gynaecol., 95, 997–1002 Wong, M L., Kling, M A et al (2000) Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone Proc Natl Acad Sci USA, 97(1), 325–30 Yehuda, R (2002) Current status of cortisol findings in post-traumatic stress disorder Psychiatr Clin North Am., 25(2), 341–68, vii Yehuda, R., Giller, E L et al (1991) Hypothalamic–pituitary–adrenal dysfunction in posttraumatic stress disorder Biol Psychiatr., 30(10), 1031–48 Index actions of mechanisms receptor mechanisms 151, 213 signal transduction mechanisms 210, 213 actions on the gene 212, 220 activator protein (AP-2) 164 adenylate cyclase activity 24, 41 adipoinsular axis 130, 131 adipose tissue adiponectin 156 muscle and fat 154 leptin 155 adrenal glands 92, 96, 247 adrenal hormones 30, 185, 191 adrenal steroids glucocorticoids 242 mineralocorticoids 243 adrenalectomized (ADX) 10, 93, 151, 205, 206, 207, 228, 231 adrenocorticotrophic hormone (ACTH) AVP 115, 159, 202–206, 208–209, 216–223, 226–227 CRH 8, 21, 79, 95, 116, 162, 185, 205, 206 median eminence (ME) 115, 203 adult pancreatic morphology 127 adult-onset disease fetal physiology glucocorticoids 6, hypothalamic–pituitary–adrenal (HPA) epidemiological studies 89 allergic symptoms 251 amygdala 8, 92, 93, 94, 157, 162, 163, 184–185, 203, 243, 252 animal models diversity 103 steroidogenesis 104 antenatal glucocorticoid exposure see prenatal glucocorticoid exposure antenatal glucocorticoids on CNS antioxidants 161 dexamethasone 162, 163 structural effects 160 anterior pituitary cells 21, 24 anthropoid primates 6, 90, 94, 104, 185 anxiety-related behaviors 151, 162, 259 arginine vasopressin (AVP) 23, 115, 159, 202, 231 AVP gene expression 208, 217, 218 AVP gene 220–223, 227 CRH neuroendocrine neurons 209, 214, 227 rapid negative-feedback signal 227 basal conditions ACTH secretion 217, 218, 221, 226, 227 corticosterone’s long-term actions 219 CRH gene expression 218, 225–228 CRH gene transcription 220 HPA axis 218 neuroendocrine terminals 218 RNA transcripts 218 basal plasma 43, 120, 158 bed nucleus 8, 11, 92, 215, 246, 250, 258 -endorphin (E) 20, 38, 183 3-adrenoceptors 144 betamethasone administration 122, 124 betamethasone exposure 124, 161 270 Index binding protein activin A 53 CBG 122 CRE 213 CRH 24, 80, 97, 191, 242 IGF 101, 154 receptors 52 birth and behavior 1, 235 blood–brain barrier 235, 243 body mass index (BMI) 90, 124 brain and placenta 1–15 brush-border membrane 41, 43 CBG 122, 128 calcitonin-gene-related peptide 40, 42 calcium channel blockers 46 calcium homeostasis 46 cAMP 24, 30, 49, 52, 54, 81, 117, 164, 213 cannabinoid receptors 19 carbenoxolone 120, 127, 149, 150, 151, 154 catecholaminergic inputs 214, 215 cell specificity glucocorticoids 209 CRH gene expression 208, 211, 215, 225 CRH neuroendocrine motor 207, 209, 214 cell: actions on mechanisms receptor mechanism 213 signal transduction mechanism 210, 213 cell culture 16, 24, 56 cellular proliferation 117 central nervous system 2, 3, 8, 40, 98, 145, 184, 202 see also CNS central nucleus of the amygdala (CeA) 9, 93, 162, 184, 203, 241 cerebral palsy 74, 85 cerebrospinal fluid (CSF) 12, 249 CGRP, effect of sex steroid hormones 49, 50 chorionic corticotropin 24 chorionic plate 42, 49 chromogranin A colocalization 32 enkephalins 33 vasointestinal peptide 32 enkephalins 33 classic review 216 classical lifestyle risk factors 142 closed-loop feedback negative-feedback signals 203, 204, 206 secretogogue peptides 204 upper- and lower-limit values 204 CNS programming mechanisms 161 CNS antenatal glucocorticoids 145, 160 calcitonin-gene-related peptide 42 estrogens 145 glucocorticoid programming 156–157 neuropeptide Y 40 programming mechanisms 161 programming the HPA axis 157 comfort foods saccharin 93 compromised immune system 91 concept of programming 142 corpus callosum 123 corpus luteum 104 corticosteroid binding globulin 122 see also CBG corticosteroid–receptor complexes 243 corticosterone’s long-term actions AVP gene expression 217, 218, 220, 221, 227 CRH hnRNA levels 218, 220, 227 CRH immunoneutralization 220 extero- and interosensory information 221 corticosterone 115, 121, 147, 153, 162, 206, 214, 217, 222 corticotropin-releasing gene expression 258 corticotropin-releasing hormone (CRH) acetylcholine 22, 25, 163 arginine vasopressin 22, 25, 30, 115, 159, 202 cerebrospinal fluid 12, 13, 249 fetal plasma 21, 28 glucocorticoids 8, 10, 25, 79, 80, 93, 96, 186, 202, 207, 212 neurons 8, 9, 10, 116, 203, 207, 211, 214, 216, 221, 226 paraventricular nucleus 8, 92, 115, 157, 202, 239 corticotropin-releasing hormone (CRH) cortisol treatment 129 271 Index starvation time 98 synthesis 31, 81 CRE-binding protein (CREB) 213–214 CRH or AVP gene transcription initiation 222 CRH, NPY, effect of 47 CGRP, effect 49 PTHrp, effect 50 CRH gene expression autonomic 208 behavioural actions 208 neuroendocrine 208 CRH gene transcription 213, 214, 216, 217, 218, 220, 224, 225, 226, 227 CRH immunoneutralization 220 CRH messenger ribonucleic acid see also CRH mRNA amygdala 203, 243, 248 human placenta 8, 10, 203 CRH mRNA 10, 11, 94, 206 CRH neuroendocrine motor CRH gene control 209 CRH neuronal function CRH hnRNA 211, 217 peptide biosynthesis 202, 211 CRH neurons 8, 9, 209, 211, 213, 214, 216, 221, 245 CRH programming acetylcholine transmission 163 amygdala 162 hippocampal GR mRNA 164 monoaminergic system 165 neuronal pathway and mechanism 164 CRH receptors 21, 36, 80, 81, 243, 248, 254 CRH release 21, 81, 131, 158, 228, 247 CRH synthesis endoplasmic reticulum 211 Golgi complex 211 CRH system appetitive behaviors 93 survival elicit approach 93 CRH, role of human parturition 37 myometrial contractility 37 neuroendocrine factors 35 ovine pregnancy 36 CRH-binding protein (CRH-BP) 23, 94, 190, 239 CRH-cortisol axis 96 CRH hnRNA signal transduction cascades 211 CRH regulation cell type 10, 202, 207, 227 intracellular and extracellular factors 10, 207 cultured placental cell ACTH 24, 25 CRH 22, 24, 81 GnRH 55 OT 25, 35 cultured trophoblast cells 24, 52 Cushing’s syndrome 129, 146 cyclic adenosine monophosphate 24, 79, 117, 212, 238 see also cAMP cytoarchitechtural development hippocampal neurons 125 cytotrophoblast cell ACTH 24 CRH 20, 81 gonadotropin-releasing hormone 52, 54 NPY, CGRP role 40 opioid peptides 38 decapeptidic hormone 54 decidual cells 20, 23, 26, 32, 42, 43, 50 dehydroepiandrosterone (DHEA) 116 dehydroepiandrosterone sulfate 30, 80, 92 see also DHEA-S deoxyribonuclei acid (DNA) 195 developmental programming of adult disease coronary artery disease 118 hypertension 118 lower birth weight 124 dexamethasone (DEX) 238 DHEA-S 30, 36, 37, 81, 92, 95, 96, 107, 108 DNA-binding factors 243 Doppler flow studies 80 dynamics of transcriptional activation ADX animals 225, 226 plasma corticosterone 224, 225 pre-proenkephalin 225 dynorphin 38, 56, 209 272 Index early life programming 142 ECS 33, 43, 45 efferent organization catecholaminergic 214–215 CRH neuronal-control process 214 immunocytochemical 213 mitogen activated protein (MAP) kinases 214 pulse-chase design 213 hypothalamic and amygdalar projections 215 somatic motor systems 214, 215 neural-control processes 214 corticosterone-dependent-control processes 214 elective Cesarean 27 see also ECS electroencephalography (EEG) 252 elevated cortisol 254 11-hydroxysteroid dehydrogenase mRNA type 97, 154 type 8, 90, 91, 97, 108, 114, 241 endocrine hormones 192 endocrine physiology neuroendocrine mechanisms of homeostasis 203 enkephalin 33, 38, 209, 225 epidemiology cardiovascular risk 143 epithelial amnion cells 41 epithelial cells 20, 23, 52 epithelial–mesenchymal interactions 44 estradiol formation 81 estrogen 30, 35–36, 37, 75, 76, 96, 107, 145 exterosensory and interosensory information 221 extra-hypothalamic brain regions 246 fail-safe system 4, 84 fear-related behaviors 243 feedback principles open and closed-loop feedback 205, 206, 226 positive and negative feedback 92, 115, 117, 125, 157, 184, 203, 239 feed-forward mechanisms 37, 93, 118 feed-forward processes 255 fertilized human ovum 88 fetal and infant development 8, 183, 186 fetal glucocorticoid exposure 120, 122, 127, 149, 160 fetal growth and premature growth (placental CRH) antepartum risk 189 intrauterine pregnancies 186, 189 maternal plasma 189, 237 radioimmuno assay 189 fetal growth restriction 29, 104, 152, 189 fetal heart rate (FHR) 186, 191 fetal HPA activation prostaglandin 5, 21, 75, 81, 84, 118 fetal HPA axis cyclic adenosine monophosphate 117 dehydroepiandrostendione (DHEA) 116 paraventricular nuclei 115, 157, 202, 239 fetal lung maturation 121, 122, 123 fetal ovine adipose tissue maturation 129 fetal physiology 237 fetal pituitary–adrenal axis 238 fetal plasma cortisol 118, 146 fetal programming 118, 119, 120, 127, 149 fetal undernutrition 108, 144 fetal–placental blood flow peptide signaling 46 5-hydroxytryptamine (5-HT) 19, 164 follicle-stimulating hormone see FSH follistatin-related gene (FLRG) 52 FSH gonadotropin-releasing hormone 52, 54 hCG 52, 53 inhibin-related peptide 50, 51 functional compartmentalization corticosterone 209, 211, 213 CRH gene transcription 210, 213, 214, 216 CRH neuronal function 211 interact with CRH neurons 209 membrane excitability 210, 211, 228 neuron’s specific complement 211 CRH neurons 209 stimulus-release coupling mechanisms 211 translation of CRH mRNA 211, 228 functional magnetic resonance imaging (fMRI) 252 future directions (conclusions) deoxyribonucleic acid (DNA) 195 273 Index embryonic 194–195 human fetus 194 predictors 194 psychoneuroendocrine 195 transgenerational effect 194 gene transcription factor 165 gestational age (GA) 187, 188, 190 gestational diabetes mellitus (GDM) 90, 102 glucocorticoid (natal) treatment 130, 145, 193 glucocorticoid exposure 151–152 glucocorticoid facilitation corticotropin-releasing hormone 235 glucocorticoid induction CRH 243 glucocorticoid metabolites 124 glucocorticoid programming birthweight 144 calreticulin 152 cardiac metabolic regulators 152 congenital adrenal hyperplasia 145 low-birth-weight baby syndrome 144, 146 metabolic regulators 144 mineralocorticoid receptor 146 neuropsychiatric disorders 156 neurotransmitters 156 osteoporosis 146 programming the heart 151 programming of the brain 156 tissue maturation 146 brain 156 organizational effects 145 steroids 145 humans 166 glucocorticoid receptor (GR) cyclic adenosine monophosphate (cAMP) 212 control elements 212 glucocorticoid sensitive genes 132–133 glucocorticoid-dependent hepatic enzymes 154 glucocorticoid-regulatory element (GRE) 212, 226 glucocorticoids birth weight 145 low-birth-weight baby syndrome 146 tissue maturation 146 extrahypothalamic 184 frontal cortex 184 hippocampus 125, 161, 184, 243 neuropeptides 33, 227, 228 see also NPY vasopressin response 228 maternal–placental–fetal axis 1, 202 neuronal function 202, 216 neuropeptide biosynthesis 202 secretion 97 glucose intolerance 124, 126, 127, 129, 153, 154, 167 transporter 127, 152 glucose–insulin homoeostasis see also metabolic function of glucocorticoid adiponectin 156 adipose tissue programming 154 CRH programming 162 forced-swim test 160 glucocorticoid-dependent hepatic enzymes 154 gluconeogenesis 152–153 hippocampal neurones 160–164 hyperglycaemia 152 hyperinsulinaemia 152 ketanserin 164 neonatal handling paradigm 161 pancreas programming 154 PEPCK 152–153 periportal zone 165–166 schizophrenia 160 thiazolidinedione 155 GnRH 52–56 gonadotropin-releasing hormone 52, 54, 99 see also GnRH G-protein-coupled receptor 26, 45 GR gene 164 GR gene expression hippocampal neurones 164 granulocyte and monocyte colony stimulating factor 52 growth hormone insulin-like growth factor (GH-IGF) principal fetal growth factor 101 principal embryonic growth factor 101 274 Index HDL 90, 126 health and disease functional roles peptide and steroid HELLP syndrome 42 hemodynamic stressors CRH and AVP genes 226 hepatic gluconeogenic enzymes 127 hepatic glucose output 127 hepatic-insulin resistance 127–128, 155 high density lipoprotein see also HDL glucocorticoids 90, 92, 96, 108 poor fetal nutrition 90 high-pressure liquid chromatography (HPLC) 41 hindbrain 208, 209, 215 hippocampus 243 HPA axis arginine vasopressin (AVP) 115 corticotrophin-releasing hormone (CRH) 115 cyclic adenosine monophosphate 117 dehydroepiandrostendione 116 HPA secretory dynamics 222 initiation 222 negative feedback 222 response (stress) 222 which genes 222, 226 HPA–placental axis 185, 190 hCG 32, 52, 53, 55 human chorionic gonadotropin 52 see also hCG human fetal CNS development 190 human infant development (endocrine hormones) fetal CNS 191 HPA axis 192–194 maternal and placental hormones 192 human myometrial activation 5, 81 human myometrium 21, 36, 43, 81 human parturition Heisenberg’s Uncertainty Principle 74 human umbilical vein endothelial cells (HUVEC) 47 hyperactive amygdala 250 hypercortisolemia 29, 133, 255 hyperglyc(a)emia 100, 127, 128, 152, 221, 158 hyperinsulin(a)emia 131, 152 hyperleptin(a)emia 99, 131 hyperparathyroidism 46 hypocortisolemia 255 hypothalamic corticotropin-releasing hormone 183–184 hypothalamic eminence 21 hypothalamic neurons 54 hypothalamic PVN 116, 162 hypothalamic–pituitary–adrenal (HPA) axis 6–7, 23, 29, 75, 92, 96–98, 108, 114, 115, 121 hypothalamic–pituitary–gonadal axis gonadotropin-releasing hormone (GnRH) 52, 53, 99 hypothalamus 243 hypovolemia initiation 222 IGF type-1 101, 102, 107 type-2 101, 102, 107 inhibin-related peptide heteromeric complex 51 transforming growth factor- 50 insulin receptor substrate 127 insulin secretion 127, 131 insulin-like growth factor metabolic control 89 pregnancy outcome 90 preterm birth type diabetes 126 intracellular mechanisms initiation 222 intra-hepatic levels 128 intrauterine environment 7, 80, 114, 118, 143, 184–185, 190 intrauterine growth restriction see also IUGR neonatal morbidity, mortality 89 umbilical cord plasma 45 IUGR 2, 5, 6, 7, 11, 90, 91, 101, 102, 103, 104, 107, 118 intrauterine homeostasis 92 lactogen 50, 102 LDL 90 275 Index leptin central nervous system 98 obese mouse model 98 resistance 99, 131 Level neurons catecholaminergic inputs 214, 215 somatic motor system 214, 215 Level neurons amygdalar projections 215 hypothalamic projections 215 lifestyle risk factors adult weight 106, 142 alcohol 142, 186 lack of exercise 142 smoking 142, 186 social class 142 lipid metabolism 90, 131 local cellular environment extracellular factors 10, 207 intracellular factors 10, 207 locus coeruleus (Barringtons’ nucleus) 10, 245 low-density lipoprotein 90, 126 see also LDL low-birth-weight babies 90, 143, 146, 150, 239, 241, 258 luteinizing hormone 40, 54 marmoset 92, 94, 104, 106 maternal behavior 25, 161, 186 maternal glucocorticoid 8, 90, 108, 121, 125, 127, 149, 150, 151, 152, 228 maternal interaction 121 maternal nutrition placental 11-hydroxysteroid dehydrogenase 108, 114, 146 maternal nutrition 1, 5, 88, 89, 90, 91, 99 maternal physiology 3, 11, 102, 237 maternal pituitary–adrenal axis 107, 185, 191 maternal plasma concentration 78, 84 maternal psychosocial stress 8, 91, 186, 187, 195 maternal separation 121 maternal serum CRH 5, 6, 11, 94, 98, 107, 108 maternal serum leptin 99 maternal stress 107, 114, 120, 183–189, 194 maternal undernutrition 90, 107, 149, 159 maternal–placental–fetal axis 1, 202 maternal–placental–fetal–neuroendocrine mechanisms 8, 185 maternal–placental–fetal physiology melancholic depressive 255 membrane excitability 210, 211, 228 heteronuclear (hn) 211, 218 membrane excitability adaptive response 211, 228 immediate response 211, 228 Menkes disease 91 messenger ribonucleic acid (mRNA) amygdala 203, 207, 215 human placenta 203, 211 metabolic function of glucocorticoid gluconeogenesis 152 glucose metabolism 152 hypoglycemia 152–153 uncoupling proteins 152 metabolic functions 122, 126, 127, 152 metabolic signals corticotropin-releasing hormone (CRH) 5, 89 insulin-like growth factor system 89, 144 leptin 89 maternal malnutrition 90, 108, 156 pre-eclampsia 90, 99 metabolic syndrome 146 micronutrient deficiencies 91 mineralocorticoid receptor 115, 146, 212 see also MR mitogen-activated protein kinase (MAPK) 54 MR 126, 146, 147, 150, 157, 158, 162, 163, 164 multiple levels (interaction) glucocorticoid interaction 212 myometrial relaxation 81 National Institutes of Health 122, 228 negative feedback closed-loop negative-feedback signal 203, 204, 206, 226 CRH hnRNA and mRNA levels 226–227 hypovolemic stress 227 steroid hormones 203 neonatal development 240 neonatal handling 161 neonatal morbidity 7, 89, 120, 121 276 Index neonatal mortality pre-eclampsia 28 preterm birth 74 nerve growth factor-inducible factor A (NGFI-A) 164 neural systems 214, 216 neurobiological model neuroendocrine functions 190, 203, 221 neuroendocrine compartment magnocellular motor neurons 209 posterior pituitary 209 oxytocin 209 neuroendocrine function chronic maternal psychologic distress 191 environmental stress 190 fetal CNS 184, 188, 190, 191 heart rate (HR) 186, 191 HPA–placental axis 185, 191 VA stimuli 186, 191 neuroendocrine mechanisms 8, 185, 203, 206 neurons 202, 208, 214, 218, 222, 227 system 23, 32, 195, 258 terminals 211, 218, 222 neurohormones placental expression 16 placental secretion 17, 19 neuronal degeneration hippocampal neurones 160 neuronal function 202, 211, 216 neuropeptide gene expression arginine vasopressin 22, 23, 202, 203 biosynthesis 202, 211 corticotropin-releasing hormone (CRH) 202, 206, 209 HPA axis 203 paraventricular hypothalamic nucleus (PVH) 202, 203 median eminence (ME) 203 neuropeptide Y (NPY) 40–42, 130, 213 neuropeptides central nervous system 41, 202 corticotropin-releasing hormone (CRH) 22, 23, 203, 228 neuromodulators 202 neurosteroids, monoamines 16, 18 neurotransmitter CRH 20, 21, 22, 212–213 neuropeptide Y 40 oxytocin 25 non-human primate model 101, 104, 145, 183 NPY 130, 213 NPY, CGRP, role of adenyl cyclase 44 myometrial contractility 40 nitric oxide formation 44 nutrition fetal nutrition 90 obstetric risk factors 187, 194 OMPFC 254 opioid peptide 38–39, 56 opioids, role of brainstem inputs 37 umbilical cord plasma 40 organizational effects estrogen 145 OT, role of decidual mRNA 35 myometrial responsiveness 34 proof of concept 33 OTR 26, 35 overnutrition 103, 107 oxytocin receptor 76, 82, 84 see also OTR oxytocin cultured placental cells 25, 26, 36 maternal plasma 27 neurophyseal hormone 25 oxytocinase 26 pancreatic duodenal homeobox-1 127 parabrachial region 10, 245 parathyroid hormone 44, 46 parathyroid hormone-related peptide 44–45 see also PTHrP PVH 202, 203, 208, 209, 211, 212, 213, 214, 221, 227 paraventricular nucleus 8, 10, 92, 115, 157, 202, 239 see also PVN parturition 34, 37, 75, 77, 88 parturition in mammals fetal adrenal synthesis 76 progesterone concentrations 75, 81 277 Index parturition primates endocrinology 77 parvicellular division 9, 245 parvicellular pre-autonomic neurons 208 paternal genome 77 paternal–maternal conflict 77 PE 28, 29, 42, 43, 45, 53 peptide biosynthesis 202, 211 peptide signaling CGRP, effect of 49–50 CRH, NPY, effects of 47–49 CRH, role of 35–37 myometrial contractility 33 NPY, CGRP, role of 40–44 opioids, role of 37–40 OT, role of 33–51 PTHrP, effects of 50 PTHrp, role of 44–46 peptide synthetic mechanisms 222 peptide tyrosine 40 peripheral cortisol metabolism 129 peripheral nervous system 40 peripheral neuroendocrine markers 240 peripheral programming cardiac metabolic regulators 152 cardiovascular control 150 renin–angiotensin system 151 peroxisome proliferator-activated receptor 144 see also PPAR␥ phenotype hypothesis 127 phosphatidyl inositol 127 phosphoenolpyruvate carboxykinase (PEPCK) 152 physical disorders 235 physiological states basal conditions 218 stress 20, 35, 183, 185, 218, 221 physiology of placental 11-HSD-2 birth weight 148 carbenoxolone 149 placenta ACTH 24, 36 calcium transport 44, 46 CRH 6, 8, 10, 21, 24, 27, 29, 30, 36, 37, 47, 81, 90, 185, 189, 238 hCG secretion 53 placental endocrinology hormonal production 19 placental neuroendocrine markers 240 placental villi calcitonin-gene-related peptide 42 CRH 20 inhibin-related peptide 50 neuropeptide Y 40 opioid peptides 38 POMC 24, 38, 49, 191 positron emission tomography (PET) 255 postnatal adiposity 130 postnatal development 37, 39, 156, 188, 192, 194, 249 postnatal metabolic function 126, 127 postpartum period 49, 186 post-traumatic stress disorder (PTSD) 255, 257 PPAR␥ 152, 157 pre-adipocyte differentiation 129 pre-eclampsia 5, 11, 19, 42, 49, 80, 90, 99, 146 see also PE prefrontal cortex 161, 252, 254, 255, 258 pregnancy, birth outcomes (maternal stress) population-based epidemiological studies 187 prenatal stress 186 psychosocial process 186, 187 stress physiology 187 pregnancy, infant developmental outcomes lower Brazelton 188 psychological state and gestational age 188 pregnancy outcome 5, 6, 89, 90, 107 premature birth 6, 46, 78, 189, 194 premature labor 89, 121, 190 prenatal glucocorticoid exposure adipose tissue, programming 154 antenatal administration 121 betamethasone 119, 121, 122, 123, 127 CBG 122 Cushing’s syndrome 129 experimental studies 148 HPA axis 159, 162 hyperinsulinemia 131 hyperleptinemia 131 hyperglycemia 127, 128 insulin resistance 127, 129–130 278 Index prenatal glucocorticoid exposure (contd) low-density lipid cholesterol 126 pancreatic -cells 130 peripheral programming 150 postnatal metabolic function 126 premature pulmonary development 121 prenatal undernutrition 125, 127 preterm birth cerebral palsy 74, 85 CRH 5, 80, 96, 107, 189, 194–195 human parturition 5, 37, 74, 77, 84 intrauterine growth restriction 2, 45, 89, 114 see also IUGR mammalian pregnancy protein-energy malnutrition preterm delivery CRH 11, 78, 79, 80 glucocorticoids 121, 122, 133, 145, 146, 167 IUGR 89 risk 78, 79, 84, 122, 166 tissue maturation 146 preterm labor preterm birth CRH 11, 27, 90, 96, 98, 241 oxytocin 26 peptide signaling 33 plasma concentration 78 production of growth hormones (pGH) 101–103, 107 progesterone withdrawal 76, 84 programming HPA axis function adult disease 124, 125 animal evidence 124–126 body mass index 124 glucose intolerance 124, 126 human and animal evidence 124 programming of adult disease 118–119, 142 programming the heart 151 pro-opiomelanocortin 24, 115, 185, 191, 212 see also POMC pro-pregnancy environment 75 prostaglandin fetal membrane 81 in vitro 84 parturition in mammals 75 protein kinase A (PKA) 54, 213 PTHrP 43, 45, 47, 50 PTHrP, effect of potent vasodilator 50 puberty 98, 167 pulmonary development 121 push–pull principle HPA neuroendocrinology 206 neuroendocrine mechanisms 206 suprachiasmatic nucleus (SCH) 206 PVH hypothalamic motor nucleus 208 neuroendocrine motor neurons 207, 208, 209, 214 structural compartmentalism 208 PVHmp afferents corticosterone 220, 226 PVN 9, 10, 11, 93, 115, 131, 158, 162, 243, 245, 246, 249, 250 pyschiatric disorders 156, 235, 254, 255, 258 radioimmunoassay 42 real-time protein-coupled receptor 42, 43, 45 receptor mechanisms gamma amino butyric acid (GABA) 213 renin–angiotensin system (RAS) 151 respiratory distress syndrome 7, 121 reverse transcription polymerase chain reaction 54 rodents 89, 99, 101, 104, 146 role of PTHrP 44 RT-PCR 42, 43, 45 secretogogue gene expression adrenalectomized (ADX) 206 AVP mRNA 206 CRH mRNA 206, 224 exogenous corticosterone 206 hemodynamic stressors 226 negative-feedback 226–227 pre-proenkephalin gene 225 PVHmp 206 secretogogue gene transcription 218, 222, 223, 226 serotonin transporter 19 279 Index signal transduction mechanisms 2-deoxyglucose (2-DG) 214 CRE-binding protein (CREB) 213 CREB-binding protein (CBP) 213 mitogen-activated protein (MAP) 214 protein kinase (PK) 213 social phobia 257 sociodemographic characteristics 186–187 solitary nucleus 10, 245 somatogenic 102 Southern blot hybridization 43 spatial domains 216 spinal cord 208, 209 steroid production 2, 92, 127, 149, 154 steroidogenesis 24, 99, 104 stress hormones ACTH 8, 20, 30, 81, 96, 115, 120, 183, 186, 203, 218 cortisol 2, 8, 29, 47, 92, 100, 115, 129, 146, 185 placental CRH 6, 21, 30, 47, 84, 94, 185, 189 -endorphin (E) 183, 185, 186, 191 stress types pathological stress 19 physiological stress 35, 184, 195 postnatal stress 194 prenatal stress 118, 159, 162, 183, 194 psychosocial stress 8, 91, 185, 195, 241, 258 stress homeostatic motor events 221 hypotension or hypoglycemia 221 peptide synthetic mechanisms 222 PVH neuroendocrine peptide gene expression 221 stria terminalis 8, 9, 11, 92, 215, 243, 245, 246, 248, 249, 250, 258 structural compartmentalization magnocellular motor neurons 209 neuroendocrine motor neurons 208 parvicellular pre-autonomic neurons 208, 209 structural effects of antenatal glucocorticoids on the CNS 160 subtraction hybridization 83 suprachiasmatic nucleus (SCH) 206, 218, 221 sustained hypovolemia 222, 223, 224, 226 syncytial cells 20, 23, 79 syncytiotrophoblast cell 20, 24, 52, 54, 55 synthetic glucocorticoid betamethasone 119, 121–123, 127, 147, 149, 152, 158, 161, 166, 238 dexamethasone 121–123, 125, 126, 145, 147, 149–150, 152, 158–162, 238 temperamental shyness 250, 259 time domains 212, 216 timing of birth in humans biochemical markers 78 gestational length 79 transgenic mice 127, 153, 163, 164 transport amino acid 101 calcium 45, 46 CRH 238 glucose 127, 152 intracellular 91 monoamine 19 receptor 155 tumour necrosis factor alpha (TNF␣) 26, 52, 144 type diabetes 5, 91, 114, 118, 126, 127, 131, 142, 143, 146, 156 ultrasonography 186 umbilical cord plasma 21, 33, 40, 45 umbilical venous plasma 21 uncoupling proteins (UCP) 152 undernutrition 5, 90, 107, 108, 125, 127, 144, 149, 154, 159 urocortin 20, 21, 23, 24, 25, 48 U-shaped curve 91, 107 uterine contraction 28, 33, 37, 46, 88, 191 utero-placental blood flow 47 vaginal delivery 27, 33, 39, 40, 41, 43 vibroacoustic 186, 191 visceral adiposity vulnerability to affective disorders 254 zona fasciculata 115, 116 zona glomerulosa 116 zoonosis factor 104 ... birth, and fetal growth restriction: a prospective investigation Am J Obstet Gynecol., 191, 1063–9 Introduction: brain and placenta, birth and behavior, health and disease Michael L Power1 and. .. Singapore, São Paulo Cambridge University Press The Edinburgh Building, Cambridge cb2 2ru, UK Published in the United States of America by Cambridge University Press, New York www .cambridge. org Information... Dunkel-Schetter, C and Porto, M (1997) Maternal stress, HPA activity, and fetal/infant outcome Ann NY Acad Sci USA, 814, 266–75 15 Introduction: brain and placenta, birth and behavior, health and disease