Intra-uterine growth restriction (IUGR) is a significant in utero complication that can have profound effects on brain development including reduced myelination and deficits that can continue into adulthood. Progesterone increases oligodendrocyte proliferation and myelin expression, an action that may depend on the expression of progesterone receptor (PR) isoforms A (PRA) and B (PRB). The objective of this study was to determine the effect of IUGR on PR isoform expression in the brain of male and female fetuses and whether effects were associated with a reduction in myelination. We used a guinea pig model that involves selective reduction in maternal perfusion to the placenta at midgestation (35 days, term 70 days). This resulted in a significant reduction in body weight with marked sparing of brain weight. PRA, PRB and myelin basic protein (MBP) expression were measured in the brains of male and female growth-restricted and control fetuses at late gestation. MBP, as a measure of myelination, was found to decrease in association with IUGR in the CA1 hippocampal region with no change observed in the cortical white matter. There was a marked increase in PRA, PRB and total PR expression in the IUGR fetal brain. Control female fetuses demonstrated significantly higher PRA:PRB ratios than males; however, this sex difference was abolished with IUGR. These data suggest the central nervous system effects of clinical use of progesterone augmentation therapy in late pregnancy should be carefully evaluated. The overall upregulation of PR isoforms in association with IUGR suggests increased progesterone action and a possible neuroprotective mechanism.

Keywords:
Intra-uterine growth restriction, Progesterone receptor, Compromised pregnancy, Fetal development, Perinatal brain injury, Neurosteroids
1.
Bryan SM, Hindmarsh PC: Normal and abnormal fetal growth. Horm Res 2006;65:19–27.
2.
Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A: Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction. Am J Obstet Gynecol 2000;182:198–206.
3.
Zubrick SR, Kurinczuk JJ, McDermott BM, McKelvey RS, Silburn SR, Davies LC: Fetal growth and subsequent mental health problems in children aged 4 to 13 years. Dev Med Child Neurol 2000;42:14–20.
4.
Strauss RS: Adult functional outcome of those born small for gestational age: twenty-six-year follow-up of the 1970 British Birth Cohort. JAMA 2000;283:625–632.
5.
Low JA, Handley-Derry MH, Burke SO, Peters RD, Pater EA, Killen HL, Derrick EJ: Association of intrauterine fetal growth retardation and learning deficits at age 9 to 11 years. Am J Obstet Gynecol 1992;167:1499–1505.
6.
Bridges RS: A quantitative analysis of the roles of dosage, sequence, and duration of estradiol and progesterone exposure in the regulation of maternal behavior in the rat. Endocrinology 1984;114:930–940.
7.
O’Connor CA, Cemak I, Johnson F, Vink R: Effects of progesterone on neurologic and morphologic outcome following diffuse traumatic brain injury in rats. Exp Neurol 2007;205:145–153.
8.
Sayeed I, Wali B, Stein DG: Progesterone inhibits ischemic brain injury in a rat model of permanent middle cerebral artery occlusion. Restor Neurol Neurosci 2007;25:151–159.
9.
Schumacher M, Sitruk-Ware R, De Nicola AF: Progesterone and progestins: neuroprotection and myelin repair. Curr Opin Pharmacol 2008;8:740–746.
10.
Gonzalez Deniselle MC, Garay L, Gonzalez S, Saravia F, Labombarda F, Guennoun R, Schumacher M, De Nicola AF: Progesterone modulates brain-derived neurotrophic factor and choline acetyltransferase in degenerating Wobbler motoneurons. Exp Neurol 2007;203:406–414.
11.
Frye CA and Walf AA: Progesterone enhances learning and memory of aged wild-type and progestin receptor knockout mice. Neurosci Lett 2010;472:38–42.
12.
Djebaili M, Guo Q, Pettus EH, Hoffman SW, Stein DG: The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis and functional deficits after traumatic brain injury in rats. J Neurotrauma 2005;22:106–118.
13.
Yawno T, Yan EB, Walker DW, Hirst JJ: Inhibition of neurosteroid synthesis increases asphyxia-induced brain injury in the late gestation fetal sheep. Neuroscience 2007;146:1726–1733.
14.
McKendry AA, Palliser HK, Yates DM, Walker DW, Hirst JJ: The effect of betamethasone treatment on neuroactive steroid synthesis in a foetal guinea pig model of growth restriction. J Neuroendocrinol 2010;22:166–174.
15.
Kelleher MA, Palliser HK, Walker DW, Hirst JJ: Sex-dependent effect of a low neurosteroid environment and intrauterine growth restriction on fetal guinea pig brain development. J Endocrinol 2011;208:1–9.
16.
Schumacher M, Guennoun R, Stein DG, De Nicola AF: Progesterone: Therapeutic opportunities for neuroprotection and myelin repair. Pharmacol Ther 2007;116:77–106.
17.
Brinton RD, Thompson RF, Foy MR, Baudry M, Wang J, Finch CE, Morgan TE, Pike CJ, Mack WJ, Stanczyk FZ, Nilsen J: Progesterone receptors: form and function in brain. Front Neuroendocrinol 2008;29:313–339.
18.
Schumacher M, Guennoun R, Robert F, Carelli C, Gago N, Ghoumari A, Gonzalez Deniselle MC, Gonzalez SL, Ibanez C, Labombarda F, Coirini H, Baulieu EE, De Nicola AF: Local synthesis and dual actions of progesterone in the nervous system: neuroprotection and myelination. Growth Horm IGF Res 2004;14:S18–S33.
19.
Ghoumari AM, Baulieu EE, Schumacher M: Progesterone increases oligodendroglial cell proliferation in rat cerebellar slice cultures. Neuroscience 2005;135:47–58.
20.
Swamydas M, Bessert D, Skoff R: Sexual dimorphism of oligodendrocytes is mediated by differential regulation of signaling pathways. J Neurosci Res 2009;87:3306–3319.
21.
Ghoumari AM, Ibanez C, El-Etr M, Leclerc P, Eychenne B, O’Malley BW, Baulieu EE, Schumacher M: Progesterone and its metabolites increase myelin basic protein expression in organotypic slice cultures of rat cerebellum. J Neurochem 2003;86:848–859.
22.
Nitsos I, Rees S: The effects of intrauterine growth retardation on the development of neuroglia in fetal guinea pigs. An immunohistochemical and ultrastructural study. Int J Dev Neurosci 1990;8:233–244.
23.
Olivier P, Baud O, Evrard P, Gressens P, Verney C: Prenatal ischemia and white matter damage in rats. J Neuropathol Exp Neurol 2005;64:998–1006.
24.
Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer H, Chambon P: Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J 1990;9:1603–1614.
25.
Vegeto E, Shahbaz MM, Wen DX, Goldman ME, O’Malley BW, McDonnell DP: Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function. Mol Endocrinol 1993;7:1244–1255.
26.
Camacho-Arroyo I, Guerra-Araiza C, Cerbon MA: Progesterone receptor isoforms are differentially regulated by sex steroids in the rat forebrain. Neuroreport 1998;9:3993–3996.
27.
Guerra-Araiza C, Coyoy-Salgado A, Camacho-Arroyo I: Sex differences in the regulation of progesterone receptor isoforms expression in the rat brain. Brain Res Bull 2002;59:105–109.
28.
Camacho-Arroyo I, González-Arenas A, González-Agüero G, Guerra-Araiza C, González-Morán G: Changes in the content of progesterone receptor isoforms and estrogen receptor-α in the chick brain during embryonic development. Comp Biochem Physiol A Mol Integr Physiol 2003;136:447–452.
29.
Guerra-Araiza C, Villamar-Cruz O, González-Arenas A, Chavira R, Camacho-Arroyo I: Changes in progesterone receptor isoforms content in the rat brain during the oestrous cycle and after oestradiol and progesterone treatments. J Neuroendocrinol 2003;15:984–990.
30.
Quadros PS, Pfau JL, Wagner CK: Distribution of progesterone receptor immunoreactivity in the fetal and neonatal rat forebrain. J Comp Neurol 2007;504:42–56.
31.
Dobbing J, Sands J: Growth and development of the brain and spinal cord of the guinea pig. Brain Res 1970;17:115–123.
32.
Illingworth DV, Challis JRG, Ackland N, Burton AM, Heap RB, Perry JS: Parturition in the guinea pig; plasma levels of steroid hormones, steroid-binding proteins, and oxytocin, and the effect of corticosteroids, prostaglandins and adrenocorticotrophin. J Endocrinol 1974;63:557–570.
33.
Lafeber HN, Rolph TP, Jones CT: Studies on the growth of the fetal guinea pig. The effects of ligation of the uterine artery on organ growth and development. J Dev Physiol 1984;6:441–459.
34.
Turner AJ, Trudinger BJ: A modification of the uterine artery restriction technique in the guinea pig fetus produces asymmetrical ultrasound growth. Placenta 2009;30:236–240.
35.
Jones CT, Parer JT: The effect of alterations in placental blood flow on the growth of and nutrient supply to the fetal guinea-pig. J Physiol 1983;343:525–537.
36.
Jensen A, Klonne HJ, Detmer A, Carter AM: Catecholamine and serotonin concentrations in fetal guinea-pig brain: relation to regional cerebral blood flow and oxygen deliver in the growth-restricted fetus. Reprod Fertil Dev 1996;8:355–364.
37.
Inder TE, Volpe JJ: Mechanisms of perinatal brain injury. Semin Neonat 2000;5:3–16.
38.
Skoff RP, Bessert DA, Barks JDE, Song D, Cerghet M, Silverstein FS: Hypoxic-ischemic injury results in acute disruption of myelin gene expression and death of oligodendroglial precursors in neonatal mice. Int J Dev Neurosci 2001;19:197–208.
39.
Volpe JJ: Neurobiology of periventricular leukomalacia in the premature infant. Pediatr Res 2001;50:553–562.
40.
Back SA, Han BH, Luo NL, Chricton CA, Xanthoudakis S, Tam J, Arvin KL, Holtzman DM: Selective vulnerability of late oligodendrocyte progenitors to hypoxia-ischemia. J Neurosci 2002;22:455–463.
41.
Tung L, Mohamed MK, Hoeffler JP, Takimoto GS, Horwitz KB: Antagonist-occupied human progesterone B-receptors activate transcription without binding to progesterone response elements and are dominantly inhibited by A-receptors. Mol Endocrinol 1993;7:1256–1265.
42.
Mani SK, Reyna AM, Chen JZ, Mulac-Jericevic B, Conneely OM: Differential response of progesterone receptor isoforms in hormone-dependent and -independent facilitation of female sexual receptivity. Mol Endocrinol 2006;20:1322–1332.
43.
Richer JK, Jacobsen BM, Manning NG, Abel MG, Wolf DM, Horwitz KB: Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. J Biol Chem 2002;277:5209–5218.
44.
Mallard EC, Rehn A, Rees S, Tolcos M, Copolov D: Ventriculomegaly and reduced hippocampal volume following intrauterine growth-restriction: implication for the aetiology of schizophrenia. Schizophr Res 1999;40:11–21.
45.
Mallard C, Loeliger M, Copolov D, Rees S: Reduced number of neurons in the hippocampus and the cerebellum in the postnatal guinea-pig following intrauterine growth-restriction. Neuroscience 2000;100:327–333.
46.
Dieni S and Rees S: Dendritic morphology is altered in hippocampal neurons following prenatal compromise. J Neurobiol 2003;55:41–52.
47.
Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, Salomone JP, Dent LL, Harris OA, Ander DS, Lowery DW, Patel MM, Denson DD, Gordon AB, Wald MM, Gupta S, Hoffman SW, Stein DG: ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med 2007;49:391–402.e392.
48.
Xiao G, Wei J, Yan W, Wang W, Lu Z: Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care 2008;12:R61.
49.
Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, Spong CY, Hauth JC, Miodovnik M, Varner MW, Leveno KJ, Caritis SN, Iams JD, Wapner RJ, Conway D, O’Sullivan MJ, Carpenter M, Mercer B, Ramin SM, Thorp JM, Peaceman AM, Gabbe S, National Institute of Child Health and Human Development Maternal-Fetal Medicine Units N: Prevention of recurrent preterm delivery by 17 α-hydroxyprogesterone caproate. N Engl J Med 2003;348:2379–2385.
50.
Ness A, Dias T, Damus K, Burd I, Berghella V: Impact of the recent randomized trials on the use of progesterone to prevent preterm birth: a 2005 follow-up survey. Am J Obstet Gynecol 2006;195:1174–1179.
51.
Dodd JM, Flenady VJ, Cincotta R, Crowther CA: Progesterone for the prevention of preterm birth: a systematic review. Obstet Gynecol 2008;112:127–134.
52.
Trotter A, Bokelmann B, Sorgo W, Bechinger-Kornhuber D, Heinemann H, Schmucker G, Oesterle M, Kohntop B, Brisch K-H, Pohlandt F: Follow-up examination at the age of 15 months of extremely preterm infants after postnatal estradiol and progesterone replacement. J Clin Endocrinol Metab 2001;86:601–603.
© 2012 S. Karger AG, Basel
2012
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.