Hostname: page-component-89b8bd64d-ktprf Total loading time: 0 Render date: 2026-05-13T14:46:26.002Z Has data issue: false hasContentIssue false
  • English
  • Français

Effect of postnatal progesterone therapy following preterm birth on neurosteroid concentrations and cerebellar myelination in guinea pigs

Published online by Cambridge University Press:  24 April 2015

H. K. Palliser ,
M. A. Kelleher ,
M. Tolcos ,
D. W. Walker  and
J. J. Hirst
H. K. Palliser*
Affiliation:
Mothers and Babies Research Centre, Hunter Medical Research Institute, Newcastle, NSW, Australia School of Biomedical Science, University of Newcastle, NSW, Australia
M. A. Kelleher
Affiliation:
Oregon National Primate Research Centre, Oregon, USA
M. Tolcos
Affiliation:
Department of Obstetrics and Gynaecology, The Ritchie Centre, MIMR-PHI Institute of Medical Research, Monash University, Clayton, Victoria, Australia
D. W. Walker
Affiliation:
Department of Obstetrics and Gynaecology, The Ritchie Centre, MIMR-PHI Institute of Medical Research, Monash University, Clayton, Victoria, Australia
J. J. Hirst
Affiliation:
Mothers and Babies Research Centre, Hunter Medical Research Institute, Newcastle, NSW, Australia School of Biomedical Science, University of Newcastle, NSW, Australia
*
*Address for correspondence: H. Palliser, Mothers and Babies Research Centre, Hunter Medical Research Institute, University of Newcastle, Callaghan, NSW 2308, Australia. (Email Hannah.palliser@newcastle.edu.au)
Get access Rights & Permissions [Opens in a new window]

Abstract

Allopregnanolone protects the fetal brain and promotes normal development including myelination. Preterm birth results in the early separation of the infant from the placenta and consequently a decline in blood and brain allopregnanolone concentrations. Progesterone therapy may increase allopregnanolone and lead to improved oligodendrocyte maturation. The objectives of this study were to examine the efficacy of progesterone replacement in augmenting allopregnanolone concentrations during the postnatal period and to assess the effect on cerebellar myelination – a region with significant postnatal development. Preterm guinea pig neonates delivered at 62 days of gestation by caesarean section received daily s.c. injections of vehicle (2-Hydroxypropyl-β-cyclodextrin) or progesterone (16 mg/kg) for 8 days until term-equivalent age (TEA). Term delivered controls (PND1) received vehicle. Neonatal condition/wellbeing was scored, and salivary progesterone was sampled over the postnatal period. Brain and plasma allopregnanolone concentrations were measured by radioimmunoassay; cortisol and progesterone concentrations were determined by enzyme immunoassay; and myelin basic protein (MBP), proteolipid protein (PLP), oligodendroctye transcription factor 2 (OLIG2) and platelet-derived growth factor receptor-α (PDGFRα) were quantified by immunohistochemistry and western blot. Brain allopregnanolone concentrations were increased in progesterone-treated neonates. Plasma progesterone and cortisol concentrations were elevated in progesterone-treated male neonates. Progesterone treatment decreased MBP and PLP in lobule X of the cerebellum and total cerebellar OLIG2 and PDGFRα in males but not females at TEA compared with term animals. We conclude that progesterone treatment increases brain allopregnanolone concentrations, but also increases cortisol levels in males, which may disrupt developmental processes. Consideration should be given to the use of non-metabolizable neurosteroid agonists.

Keywords

allopregnanolonecortisolneonateoligodendrocytepremature

Information

Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 6 , Issue 4 , August 2015 , pp. 350 - 361
Check for updates
Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

1. Mwaniki, M, Atieno, M, Lawn, J, Newton, C. Long-term neurodevelopmental outcomes after intrauterine and neonatal insults: a systematic review. Lancet. 2012; 379, 445–452.CrossRefGoogle ScholarPubMed
2. Behrman, RE, Butler, AS. eds. Preterm Birth: Causes, Consequences and Prevention. 2007. National Academy of Sciences: Washington.Google Scholar
3. Petrini, J, Dias, T, McCormick, M, et al. Increased risk of adverse neurological development for late preterm infants. J Pediatr. 2009; 154, 169–176.CrossRefGoogle ScholarPubMed
4. Saigal, S, Doyle, LW. An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet. 2008; 371, 261–269.CrossRefGoogle ScholarPubMed
5. Huppi, P, Schuknecht, B, Boesch, C, et al. Structural and neurobehavioural delay in postnatal brain development of preterm infants. Pediatr Res. 1996; 39, 895–901.CrossRefGoogle ScholarPubMed
6. Inder, TE, Warfield, SK, Wang, H, Huppi, PS, Volpe, JJ. Abnormal cerebral structure is present at term in premature infants. Pediatrics. 2005; 115, 286–294.CrossRefGoogle ScholarPubMed
7. Altman, J. Autoradiographic and histological studies of postnatal neurogenesis. III. Dating the time of production and onset of differentiation of cerebellar microneurons in rats. J Comp Neurol. 1969; 136, 269–293.CrossRefGoogle Scholar
8. Buckner Randy, L. The cerebellum and cognitive function: 25 years of insight from anatomy and neuroimaging. Neuron. 2013; 80, 807–815.CrossRefGoogle ScholarPubMed
9. Abraham, H, Tornoczky, T, Kosztolanyi, G, Seress, L. Cell formation in the cortical layers of the developing human cerebellum. Int J Dev Neurosci. 2001; 19, 53–62.CrossRefGoogle ScholarPubMed
10. Knickmeyer, RC, Gouttard, S, Kang, C, et al. A structural MRI study of human brain development from birth to 2 years. J Neurosci. 2008; 28, 12176–12182.Google ScholarPubMed
11. Limperopoulos, C, Soul, JS, Gauvreau, K, et al. Late gestation cerebellar growth is rapid and impeded by premature birth. Pediatrics. 2005; 115, 688–695.CrossRefGoogle ScholarPubMed
12. Messerschmidt, A, Brugger, P, Bolthauser, E, et al. Disruption of cerebellar development: potential complications of extreme prematurity. Am J Neuroradiol. 2005; 26, 1659–1667.Google ScholarPubMed
13. Haldipur, P, Bharti, U, Alberti, C, et al. Preterm delivery disrupts the developmental program of the cerebellum. PLoS One. 2011; 6, e23449.CrossRefGoogle ScholarPubMed
14. Biran, V, Verney, C, Ferriero, DM. Perinatal cerebellar injury in human and animal models. Neurol Res Int. 2012; 2012, 858929.CrossRefGoogle ScholarPubMed
15. Davis, M, Plotz, E. Progesterone, the pregnancy hormone. Fertil Steril. 1957; 8, 603–618.CrossRefGoogle ScholarPubMed
16. Challis, J, Lockwood, C, Myatt, L, et al. Inflammation and pregnancy. Repro Sci. 2009; 16, 206–215.CrossRefGoogle ScholarPubMed
17. Gilbert Evans, SE, Ross, LE, Sellers, EM, Purdy, RH, Romach, MK. 3alpha-reduced neuroactive steroids and their precursors during pregnancy and the postpartum period. Gynecol Endocrinol. 2005; 21, 268–279.Google ScholarPubMed
18. Paul, SM, Purdy, RH. Neuroactive steroids. FASEB J. 1992; 6, 2311–2322.CrossRefGoogle ScholarPubMed
19. Kelleher, MA, Hirst, JJ, Palliser, HK. Changes in neuroactive steroid concentrations after preterm delivery in the guinea pig. Reprod Sci. 2013; 20, 1365–1375.CrossRefGoogle ScholarPubMed
20. Nguyen, PN, Billiards, SS, Walker, DW, Hirst, JJ. Changes in 5a-pregnane steroids and neurosteroidogenic enzyme expression in the perinatal sheep. Pediatr Res. 2003; 53, 956–964.CrossRefGoogle Scholar
21. 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.Google ScholarPubMed
22. Mellon, SH, Deschepper, CF. Neurosteroid biosynthesis: genes for adrenal steroidogenic enzymes are expressed in the brain. Brain Res. 1993; 629, 283–292.Google ScholarPubMed
23. Ukena, K, Usui, M, Kohchi, C, Tsutsui, K. Cytochrome P450 side-chain cleavage enzyme in the cerebellar Purkinje neuron and its neonatal change in rats. Endocrinology. 1998; 139, 137–147.CrossRefGoogle ScholarPubMed
24. Petratos, S, Hirst, JJ, Mendis, S, Anikijenko, P, Walker, DW. Localization of p450scc and 5alpha-reductase type-2 in the cerebellum of fetal and newborn sheep. Brain Res Dev Brain Res. 2000; 123, 81–86.CrossRefGoogle ScholarPubMed
25. Tsutsui, K. Biosynthesis and organizing action of neurosteroids in the developing Purkinje cell. Cerebellum. 2006; 5, 89–96.CrossRefGoogle ScholarPubMed
26. Ghoumari, A, Baulieu, E, Schumacher, M. Progesterone increases oligodendroglial cell proliferation in rat cerebellar slice cultures. Neuroscience. 2005; 135, 47–58.CrossRefGoogle ScholarPubMed
27. Sakamoto, H, Ukena, K, Tsutsui, K. Effects of progesterone synthesized de novo in the developing Purkinje cell on its dendritic growth and synaptogenesis. J Neurosci. 2001; 21, 6.CrossRefGoogle ScholarPubMed
28. Yawno, T, Hirst, JJ, Castillo-Melendez, M, Walker, DW. Role of neurosteroids in regulating cell death and proliferation in the late gestation fetal brain. Neuroscience. 2009; 163, 838–847.CrossRefGoogle ScholarPubMed
29. McKendry, A, Palliser, H, Yates, D, Walker, D, Hirst, J. The effect of betamethasone treatment on neuroactive steroid synthesis in a foetal guinea pig model of growth restriction. J Neuroendocrinol. 2010; 22, 166–174.CrossRefGoogle Scholar
30. Purdy, R, Moore, P, Rao, P, et al. Radioimmunassay of 3 alpha-hydroxy-5 alpha-pregnan-20-one in rat and human plasma. Steroids. 1990; 55, 290–296.CrossRefGoogle Scholar
31. Timby, E, Balgard, M, Nyberg, S, et al. Pharmacokinetic and behavioral effects of allopregnanolone in healthy women. Psychopharmacology (Berl). 2006; 186, 414–424.CrossRefGoogle ScholarPubMed
32. Jakovcevski, I, Filipovic, R, Mo, Z, Rakic, S, Zecevic, N. Oligodendrocyte development and the onset of myelination in the human fetal brain. Front Neuroanat. 2009; 3, 5. doi:10.3389/neuro.05.005.2009.Google ScholarPubMed
33. Tolcos, M, Bateman, E, O’Dowd, R, et al. Intrauterine growth restriction affects the maturation of myelin. Exp Neurol. 2011; 232, 53–65.CrossRefGoogle ScholarPubMed
34. Huang, WL, Harper, CG, Evans, SF, Newnham, JP, Dunlop, SA. Repeated prenatal corticosteroid administration delays myelination of the corpus callosum in fetal sheep. Int J Dev Neurosci. 2001; 19, 415–425.CrossRefGoogle ScholarPubMed
35. Bohn, MC, Friedrich, VL Jr. Recovery of myelination in rat optic nerve after developmental retardation by cortisol. J Neurosci. 1982; 2, 1292–1298.CrossRefGoogle ScholarPubMed
36. Clifton, VL. Review: sex and the human placenta: mediating differential strategies of fetal growth and survival. Placenta. 2010; 31(Suppl.), S33–S39.Google ScholarPubMed
37. Abdel-Latif, ME, Kecskes, Z, Bajuk, B. Actuarial day-by-day survival rates of preterm infants admitted to neonatal intensive care in New South Wales and the Australian Capital Territory. Arch Dis Child Fetal Neonatal Ed. 2011; 98, F212–F217.Google Scholar
38. Miller, WL, Auchus, RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011; 32, 81–151.CrossRefGoogle ScholarPubMed
39. Knickmeyer, R, Gouttard, S, Kang, C, et al. A structural MRI study of human brain development from brith to 2 years. J Neurosci. 2008; 28, 12176–12182.CrossRefGoogle Scholar
40. Castillo-Melendez, M, Chow, JA, Walker, DW. Lipid peroxidation, caspase-3 immunoreactivity, and pyknosis in late-gestation fetal sheep brain after umbilical cord occlusion. Pediatr Res. 2004; 55, 864–871.CrossRefGoogle ScholarPubMed
41. Andrews, T, Li, D, Halliwell, J, Cowen, T. The effect of age on dendrites in the rat superior cervical ganglion. J Anat. 1994; 184, 111–117.Google ScholarPubMed
42. Jacobs, B, Driscoll, L, Schall, M. Life-span dendritic and spine changes in areas 10 and 18 of human cortex: a quantitative Golgi study. J Comp Neurol. 1997; 386, 661–680.3.0.CO;2-N>CrossRefGoogle ScholarPubMed
43. Rees, S, Loeliger, M, Munro, K, et al. Cerebellar development in a baboon model of preterm delivery: impact of specific ventilatory regimes. J Neuropathol Exp Neurol. 2009; 68, 605–615.CrossRefGoogle Scholar
44. Agis-Balboa, RC, Pinna, G, Zhubi, A, et al. Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis. Proc Natl Acad Sci U S A. 2006; 103, 14602–14607.CrossRefGoogle ScholarPubMed
45. Bixo, M, Andersson, A, Winblad, B, Purdy, R, Backstrom, T. Progesterone, 5α-pregnane-3,20-dione and 3α-hydroxy-5α-pregnane-20-one in specific regions of the human female brain in different endocrine states. Brain Res. 1997; 764, 173–178.CrossRefGoogle ScholarPubMed
46. Alin, M, Matsumoto, H, Santhouse, A, et al. Cognitive and motor function and the size of the cerebellum in adolescents born very pre-term. Brain. 2001; 124, 60–66.CrossRefGoogle Scholar
47. Stoodley, CJ, Schmahmann, JD. Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex. 2010; 46, 831–844.Google ScholarPubMed
48. Fields, RD. White matter in learning, cognition and psychiatric disorders. Trends Neurosci. 2008; 31, 361–370.CrossRefGoogle ScholarPubMed
49. Ghoumari, A, Ibanez, C, El-Etr, M, et al. Progesterone and its metabolites increase myelin basic protein expression in organotypic slice cultures of rat cerebellum. J Neurochem. 2003; 86, 848–859.CrossRefGoogle ScholarPubMed
50. Matthews, S. Dynamic changes in glucocorticoid and mineralocorticoid receptor mRNA in the developing guinea pig brain. Dev Brain Res. 1998; 107, 123–132.Google ScholarPubMed
51. Bennett, GA, Palliser, HK, Saxby, B, Walker, DW, Hirst, JJ. Effects of prenatal stress on fetal neurodevelopment and responses to maternal neurosteroid treatment in guinea pigs. Dev Neurosci. 2013; 35, 416–426.CrossRefGoogle ScholarPubMed
52. Norwitz, ER, Caughey, AB. Progesterone supplementation and the prevention of preterm birth. Rev Obstet Gynecol. 2011; 4, 60–72.Google ScholarPubMed
53. Dodd, J, Crowther, C, McPhee, A, Flenady, V, Robinson, J. Progesterone after previous preterm birth for prevention of neonatal respiratory distress syndrome (PROGRESS): a randomised controlled trial. BMC Pregnancy Childbirth. 2009; 9, 6–12.CrossRefGoogle ScholarPubMed
54. Trotter, A, Maier, L, Grill, HJ, et al. Effects of postnatal estradiol and progesterone replacement in extremely preterm infants. J Clin Endocrinol Metab. 1999; 84, 4531–4535.CrossRefGoogle ScholarPubMed
55. Trotter, A, Steinmacher, J, Kron, M, Pohlandt, F. Neurodevelopmental follow-up at five years corrected age of extremely low birth weight infants after postnatal replacement of 17β-estradiol and progesterone. J Clin Endocrinol Metab. 2012; 97, 1041–1047.CrossRefGoogle Scholar