Neurosteroids such as allopregnanolone are potent agonists at the GABAA receptor and suppress the fetal CNS activity. These steroids are synthesized in the fetal brain either from cholesterol or from circulating precursors derived from the placenta. The concentrations of allopregnanolone are remarkably high in the fetal brain and rise further in response to acute hypoxic stress, induced by constriction of the umbilical cord. This response may result from the increased 5α-reductase and cytochrome P-450SCC expression in the brain. These observations suggest that the rise in neurosteroid concentrations in response to acute hypoxia may represent an endogenous protective mechanism that reduces excitotoxicity following hypoxic stress in the developing brain. In contrast to acute stress, chronic hypoxemia induces neurosteroidogenic enzyme expression without an increase in neurosteroid concentrations and, therefore, may pose a greater risk to the fetus. At birth, the allopregnanolone concentrations in the brain fall markedly, probably due to the loss of placental precursors; however, stressors, including hypoxia and endotoxin-induced inflammation, raise allopregnanolone concentrations in the newborn brain. This may protect the newborn brain from hypoxia-induced damage. However, the rise in allopregnanolone concentrations was also associated with increased sleep. This rise in sedative steroid levels may depress arousal and contribute to the risk of sudden infant death syndrome. Our recent findings indicate that acute hypoxic stress in pregnancy initiates a neurosteroid response that may protect the fetal brain from hypoxia-induced cell death, whereas the decline in allopregnanolone levels after birth may result in greater vulnerability to brain injury in neonates.

Keywords:
Pregnane steroids, Allopregnanolone, Progesterone, Placental steroidogenesis, Fetus, Neuroprotection, Placenta
1.
Corpechot C, Young J, Calvel M, Wehrey C, Veltz JN, Touyer G, Mouren M, Prasad VV, Banner C, Sjovall J, et al: Neurosteroids: 3-alpha-hydroxy-5 alpha-pregnan-20-one and its precursors in the brain, plasma, and steroidogenic glands of male and female rats. Endocrinology 1993;133:1003–1009.
2.
Mellon SH, Griffin LD, Compagnone NA: Biosynthesis and action of neurosteroids. Brain Res Brain Res Rev 2001;37:3–12.
3.
Dolling M, Seamark RF: Progestagen metabolites in fetal sheep plasma: the effect of fetal nephrectomy. J Dev Physiol 1979;1:399–413.
4.
Bernardi F, Pluchino N, Begliuomini S, Lenzi E, Palumbo M, Luisi M, Genazzani AR: Disadaptive disorders in women: allopregnanolone, a sensitive steroid. Gynecol Endocrinol 2004;19:344–353.
5.
Nguyen PN, Billiards SS, Walker DW, Hirst JJ: Changes in 5-alpha-pregnane steroids and neurosteroidogenic enzyme expression in the perinatal sheep. Pediatr Res 2003;53:956–964.
6.
Billiards SS, Walker DW, Canny BJ, Hirst JJ: Endotoxin increases sleep and brain allopregnanolone concentrations in newborn lambs. Pediatr Res 2002;52:892–899.
7.
Baulieu EE: Neurosteroids: a new function in the brain. Biol Cell 1991;71:3–10.
8.
Lapchak PA: The neuroactive steroid 3-alpha-ol-5-beta-pregnan-20-one hemisuccinate, a selective NMDA receptor antagonist, improves behavioral performance following spinal cord ischemia. Brain Res 2004;997:152–158.
9.
Nicol MB, Hirst JJ, Walker DW: Effects of pregnanolone on behavioural parameters and the responses to GABAA receptor antagonists in the late gestation fetal sheep. Neuropharmacology 1999;38:49–63.
10.
Harrison NL, Majewska MD, Harrington JW, Barker JL: Structure-activity relationships for steroid interaction with the gamma-aminobutyric acid A receptor complex. J Pharmacol Exp Ther 1987;241:346–353.
11.
Covey DF, Evers AS, Mennerick S, Zorumski CF, Purdy RH: Recent developments in structure-activity relationships for steroid modulators of GABAA receptors. Brain Res Brain Res Rev 2001;37:91–97.
12.
Harrison NL, Majewska MD, Harrington JW, Barker JL: Structure-activity relationships for steroid interaction with the gamma-aminobutyric acidA receptor complex. J Pharmacol Exp Ther 1987;241:346–353.
13.
Seamark RF, Nancarrow CD, Gardiner J: Progesterone metabolism in ovine blood: the formation of 3α-hydroxy-pregn-4-en-20-one and other substances. Steroids 1970;15:589–604.
14.
Crossley KJ, Walker DW, Beart PM, Hirst JJ: Characterisation of GABAA receptors in fetal, neonatal and adult ovine brain: region- and age-related changes and the effects of allopregnanolone. Neuropharmacology 2000;39:1514–1522.
15.
Crossley KJ, Nitsos I, Walker DW, Lawrence AJ, Beart PM, Hirst JJ: Steroid-sensitive GABAA receptors in the fetal sheep brain. Neuropharmacology 2003;45:461–472.
16.
Frye CA, Duncan JE, Basham M, Erskine MS: Behavioral effects of 3-alpha-androstanediol. II. Hypothalamic and preoptic area actions via a GABAergic mechanism. Behav Brain Res 1996;79:119–130.
17.
Stromberg J, Backstrom T, Lundgren P: Rapid non-genomic effect of glucocorticoid metabolites and neurosteroids on the gamma-aminobutyric acid-A receptor. Eur J Neurosci 2005;21:2083–2088.
18.
Baulieu EE: Neurosteroids: a novel function of the brain. Psychoneuroendocrinology 1998;23:963–987.
19.
McKay SA: Mechanisms Involved in the Control of Steroidogenesis during the Oestrous Cycle and Pregnancy in Sheep; PhD thesis Monash University, Melbourne, 1987.
20.
Saunders NR, Knott GW, Dziegielewska KM: Barriers in the immature brain. Cell Mol Neurobiol 2000;20:29–40.
21.
Robel P, Bourreau E, Corpechot C, Dang DC, Halberg F, Clarke C, Haug M, Schlegel ML, Synguelakis M, Vourch C, et al: Neurosteroids: 3-beta-hydroxy-delta-5 derivatives in rat and monkey brain. J Steroid Biochem 1987;27:649–655.
22.
Yan E, Castillo-Melendez M, Nicholls T, Hirst J, Walker D: Cerebrovascular responses in the fetal sheep brain to low-dose endotoxin. Pediatr Res 2004;55:855–863.
23.
Herzog AG, Frye CA: Seizure exacerbation associated with inhibition of progesterone metabolism (see comment). Ann Neurol 2003;53:390–391.
24.
Soderpalm AH, Lindsey S, Purdy RH, Hauger R, Wit de H: Administration of progesterone produces mild sedative-like effects in men and women. Psychoneuroendocrinology 2004;29:339–354.
25.
Gilbert Evans SE, Ross LE, Sellers EM, Purdy RH, Romach MK: 3-Alpha-reduced neuroactive steroids and their precursors during pregnancy and the postpartum period. Gynecol Endocrinol 2005;21:268–279.
26.
Dawes GS, Fox HE, Leduc BM, Liggins GC, Richards RT: Respiratory movements and rapid eye movement sleep in the foetal lamb. J Physiol 1972;220:119–143.
27.
Crossley KJ, Nicol MB, Hirst JJ, Walker DW, Thorburn GD: Suppression of arousal by progesterone in fetal sheep. Reprod Fertil Dev 1997;9:767–773.
28.
Nicol MB, Hirst JJ, Walker DW, Thorburn GD: Effect of alteration of maternal plasma progesterone concentrations on fetal behavioural state during late gestation. J Endocrinol 1997;152:379–386.
29.
Nicol MB, Hirst JJ, Walker DW: Effect of finasteride on behavioural arousal and somatosensory evoked potentials in fetal sheep. Neurosci Lett 2001;306:13–16.
30.
Brinton RD: The neurosteroid 3α-hydroxy-5α-pregnan-20-one induces cytoarchitectural regression in cultured fetal hippocampal neurons. J Neurosci 1994;14:2763–2774.
31.
De Nicola AF, Labombarda F, Gonzalez SL, Gonzalez Deniselle MC, Guennoun R, Schumacher M: Steroid effects on glial cells: detrimental or protective for spinal cord function? Ann N Y Acad Sci 2003;1007:317–328.
32.
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(Suppl A):S18–S33.
33.
Mirmiran M: The function of fetal/neonatal rapid eye movement sleep. Behav Brain Res 1995;69:13–22.
34.
Mellon SH, Deschepper CF: Neurosteroid biosynthesis: genes for adrenal steroidogenic enzymes are expressed in the brain. Brain Res 1993;629:283–292.
35.
Zwain IH, Yen SS: Neurosteroidogenesis in astrocytes, oligodendrocytes, and neurons of cerebral cortex of rat brain. Endocrinology 1999;140:3843–3852.
36.
Guennoun R, Fiddes RJ, Gouezou M, Lombes M, Baulieu EE: A key enzyme in the biosynthesis of neurosteroids, 3-beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD), is expressed in rat brain. Brain Res Mol Brain Res 1995;30:287–300.
37.
Martini L, Celotti F, Melcangi RC: Testosterone and progesterone metabolism in the central nervous system: cellular localization and mechanism of control of the enzymes involved. Cell Mol Neurobiol 1996;16:271–282.
38.
Wallace JM, Aitken RP, Cheyne MA, Humblot P: Pregnancy-specific protein B and progesterone concentrations in relation to nutritional regimen, placental mass and pregnancy outcome in growing adolescent ewes carrying singleton fetuses. J Reprod Fertil 1997;109:53–58.
39.
Belelli D, Lambert JJ: Neurosteroids: endogenous regulators of the GABAA receptor. Nature Rev Neurosci 2005;6:565–575.
40.
Rogawski MA, Reddy DS: Neurosteroids and infantile spasms: the deoxycorticosterone hypothesis. Int Rev Neurobiol 2002;49:199–219.
41.
Kishimoto W, Hiroi T, Shiraishi M, Osada M, Imaoka S, Kominami S, Igarashi T, Funae Y: Cytochrome P450 2D catalyze steroid 21-hydroxylation in the brain. Endocrinology 2004;145:699–705.
42.
Barbaccia ML, Roscetti G, Bolacchi F, Concas A, Mostallino MC, Purdy RH, Biggio G: Stress-induced increase in brain neuroactive steroids: antagonism by abecarnil. Pharmacol Biochem Behav 1996;54:205–210.
43.
Nguyen PN, Yan EB, Castillo-Melendez M, Walker DW, Hirst JJ: Increased allopregnanolone levels in the fetal sheep brain following umbilical cord occlusion. J Physiol 2004;560:593–602.
44.
Hirst JJ, Petratos S, Mendis S, Walker DW: Neuroactive steroid synthesis in the ovine fetal and newborn brain (abstract). FASEB Exp Biol 2000:C-493.
45.
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.
46.
Viscardi RM, Sun CC: Placental lesion multiplicity: risk factor for IUGR and neonatal cranial ultrasound abnormalities. Early Hum Dev 2001;62:1–10.
47.
Mallard EC, Rees S, Stringer M, Cock ML, Harding R: Effects of chronic placental insufficiency on brain development in fetal sheep. Pediatr Res 1998;43:262–270.
48.
Cock ML, McCrabb GJ, Wlodek ME, Harding R: Effects of prolonged hypoxemia on fetal renal function and amniotic fluid volume in sheep. Am J Obstet Gynecol 1997;176:320–326.
49.
Nguyen PN, Billiards SS, Walker DW, Hirst JJ: Changes in 5alpha-pregnane steroids and neurosteroidogenic enzyme expression in fetal sheep with umbilicoplacental embolization. Pediatr Res 2003;54:840–847.
50.
Gunn AJ, Quaedackers JS, Guan J, Heineman E, Bennet L: The premature fetus: not as defenseless as we thought, but still paradoxically vulnerable? Dev Neurosci 2001;23:175–179.
51.
Dean J, George S, Wassink G, Gunn A, Bennet L: Suppression of post-hypoxic-ischemic EEG transients with dizocilpine is associated with partial striatal protection in the preterm fetal sheep. Neuropharmacology 2005;50:491–503.
52.
Bailey CD, Brien JF, Reynolds JN: Neurosteroid modulation of the GABAA receptor in the developing guinea pig cerebral cortex. Brain Res Dev Brain Res 1999;113:21–28.
53.
Reddy DS, Rogawski MA: Enhanced anticonvulsant activity of ganaxolone after neurosteroid withdrawal in a rat model of catamenial epilepsy. J Pharmacol Exp Ther 2000;294:909–915.
54.
Barbaccia ML, Roscetti G, Trabucchi M, Cuccheddu T, Concas A, Biggio G: Neurosteroids in the brain of handling-habituated and naive rats: effect of CO2 inhalation. Eur J Pharmacol 1994;261:317–320.
55.
Billiards S, Nguyen PN, Canny BJ, Walker DW, Hirst JJ: Hypoxia and endotoxin interact to regulate sleep and allopregnanolone concentrations in the newborn lambs. Biol Neonate 2006;90:258–267.
56.
Pratt L, Magness RR, Phernetton T, Hendricks SK, Abbott DH, Bird IM: Repeated use of betamethasone in rabbits: effects of treatment variation on adrenal suppression, pulmonary maturation, and pregnancy outcome (see comment). Am J Obstet Gynecol 1999;180:995–1005.
57.
O’Shea TM, Doyle LW: Perinatal glucocorticoid therapy and neurodevelopmental outcome: an epidemiologic perspective. Semin Neonatol 2001;6:293–307.
58.
di Michele F, Lekieffre D, Pasini A, Bernardi G, Benavides J, Romeo E: Increased neurosteroid synthesis after brain and spinal cord injury in rats. Neurosci Lett 2000;284:65–68.
59.
Frank C, Sagratella S: Neuroprotective effects of allopregnenolone on hippocampal irreversible neurotoxicity in vitro. Prog Neuropsychopharmacol Biol Psychiatry 2000;24:1117–1126.
60.
Bucolo C, Drago F: Effects of neurosteroids on ischemia-reperfusion injury in the rat retina: role of sigma1 recognition sites. Eur J Pharmacol 2004;498:111–114.
61.
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.
62.
Gonzalez-Vital MD, Cervera-Gaviria M, Ruelas R, Escobar A, Cervantes M: Progesterone: protective effects on the cat hippocampal neuronal damage due to acute global cerebral ischemia. Arch Med Res 1998;29:117–124.
63.
Bender AS, Norenberg MD: Effect of benzodiazepines and neurosteroids on ammonia-induced swelling in cultured astrocytes. J Neurosci Res 1998;54:673–680.
64.
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.
65.
Ibanez C, Shields SA, El-Etr M, Baulieu EE, Schumacher M, Franklin RJ: Systemic progesterone administration results in a partial reversal of the age-associated decline in CNS remyelination following toxin-induced demyelination in male rats. Neuropathol Appl Neurobiol 2004;30:80–89.
66.
Martin LJ, Brambrink A, Koehler RC, Traystman RJ: Primary sensory and forebrain motor systems in the newborn brain are preferentially damaged by hypoxia-ischemia. J Comp Neurol 1997;377:262–285.
67.
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.
68.
Yawno T, Walker D, Yan E, Hirst J: Inhibition of neurosteroid synthesis increases asphyxia-induced brain injury in the late gestation fetal sheep. Soc Gynecol Invest 2006;53:abstract 31.
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2007
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