title: Antenatal glucocorticoid exposure enhances the inhibition of adrenal steroidogenesis by leptin in a sex-specific fashion.
abstract: Antenatal treatment with glucocorticoids (GC) poses long-lasting effects on endocrine and cardiovascular function. Given that leptin attenuates adrenal function and the reported sex differences in plasma leptin concentration, we hypothesized that antenatal GC will affect leptin levels and leptin modulation of adrenal function in a sex-specific manner. Pregnant sheep were randomly given betamethasone or vehicle at 80 days of gestational age, and offspring were allowed to deliver at term. Adrenocortical cells (ADC) were studied from male and female animals at 1.5 yr of age. Plasma leptin was increased 66% in male and 41% in female GC-treated animals (P < 0.05), but adrenal leptin mRNA was increased only in GC-treated males (P < 0.05). Whereas mRNA expression of adrenal leptin receptor isoforms showed sex (Ob-Ra and Ob-Rb) and treatment-dependent (Ob-Rb) differences, protein expression remained unchanged. GC-treated females showed greater plasma cortisol and greater ACTH-stimulated cortisol production (P < 0.05) in ADC. Leptin exerted a greater inhibitory effect on basal and stimulated cortisol by ADC from GC-treated males (P < 0.05), with no differences in females. Similarly, greater inhibitory effects on basal and ACTH-stimulated StAR and ACTH-R mRNA expression by leptin were observed in cells from GC males (P < 0.05), with no changes in females. Persistent effects of antenatal GC on leptin levels and leptin modulation of adrenal function are expressed in a sex-specific manner; males are more sensitive than females to the inhibitory influences of leptin on adrenal function, and this effect appears to be mediated by a greater inhibition of StAR and ACTH-R expression in adrenals of adult GC-treated males.
authors: Department of Obstetrics and Gynecology.
authors: Yixin
authors: Y
authors: Su
authors: Luke C
authors: LC
authors: Carey
authors: James C
authors: JC
authors: Rose
authors: Victor M
authors: VM
authors: Pulgar
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D001623:Betamethasone / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis / Q000097:blood; D020738:Leptin / Q000097:blood / Q000235:genetics / Q000494:pharmacology*; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D018043:Receptors, Corticotropin / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics; D012756:Sheep
chemical_list: D005938:Glucocorticoids; D020738:Leptin; D012333:RNA, Messenger; D018043:Receptors, Corticotropin; D054411:Receptors, Leptin; C018230:betamethasone acetate phosphate; D001623:Betamethasone; D006854:Hydrocortisone
keywords: adrenal responsiveness; adrenocorticotropic hormone receptor; betamethasone; leptin; steroidogenic acute regulatory protein
references: J Clin Endocrinol Metab. 2004 Jun;89(6):2672-7
references: 15181040
references: Obstet Gynecol. 2009 May;113(5):1082-1088
references: 19384124
references: J Biol Chem. 1996 Mar 8;271(10):5301-4
references: 8621378
references: Neurosci Lett. 2010 Jul 19;479(1):18-21
references: 20471454
references: Cochrane Database Syst Rev. 2006 Jul 19;(3):CD004454
references: 16856047
references: J Perinatol. 2006 Mar;26(3):147-53
references: 16467857
references: Trends Endocrinol Metab. 1996 Sep;7(7):227-33
references: 18406752
references: PLoS One. 2008;3(10):e3466
references: 18941624
references: Endocrinology. 1998 Oct;139(10):4264-8
references: 9751508
references: J Clin Invest. 1998 Sep 1;102(5):869-73
references: 9727054
references: N Engl J Med. 2007 Sep 20;357(12):1190-8
references: 17881751
references: Domest Anim Endocrinol. 2007 Apr;32(3):155-66
references: 16531001
references: Am J Physiol Regul Integr Comp Physiol. 2009 Feb;296(2):R309-17
references: 19036827
references: Am J Clin Nutr. 2000 Aug;72(2):484-9
references: 10919945
references: J Clin Endocrinol Metab. 1997 Feb;82(2):579-84
references: 9024258
references: Eur J Endocrinol. 2011 Aug;165(2):177-88
references: 21602319
references: Dev Psychobiol. 2011 Mar;53(2):175-83
references: 21298632
references: Reprod Biol Endocrinol. 2009 Oct 22;7:115
references: 19849856
references: J Pediatr. 2006 May;148(5):606-612
references: 16737870
references: Am J Physiol Regul Integr Comp Physiol. 2006 Nov;291(5):R1406-13
references: 16825421
references: Diabetologia. 1997 Oct;40(10):1178-84
references: 9349599
references: Neuroendocrinology. 2011;93(4):201-10
references: 21464566
references: J Endocrinol. 2000 Dec;167(3):479-86
references: 11115775
references: Am J Obstet Gynecol. 2012 Dec;207(6):446-54
references: 22840973
references: Placenta. 2013 May;34(5):407-15
references: 23465880
references: Int Rev Cytol. 2007;263:63-102
references: 17725965
references: Am J Physiol Endocrinol Metab. 2007 Jan;292(1):E61-70
references: 16882931
references: Aust N Z J Obstet Gynaecol. 2007 Feb;47(1):42-5
references: 17261099
references: Reprod Sci. 2012 Oct;19(10):1075-84
references: 22534336
references: Am J Physiol. 1995 Apr;268(4 Pt 1):E623-9
references: 7733260
references: Front Behav Neurosci. 2009 Sep 07;3:19
references: 19826624
references: Endocrinology. 1997 Sep;138(9):3859-63
references: 9275075
references: FEBS Lett. 1997 Sep 29;415(2):179-82
references: 9350991
references: Horm Metab Res. 2012 Sep;44(10):790-4
references: 22903278
references: Am J Physiol. 1997 Aug;273(2 Pt 1):E448-52
references: 9277400
references: Biochim Biophys Acta. 2000 Jun 26;1486(1):184-97
references: 10856721
references: Endocrinology. 2001 Aug;142(8):3302-8
references: 11459771
references: Am J Physiol Heart Circ Physiol. 2010 Apr;298(4):H1146-54
references: 20139324
references: J Endocrinol. 2000 May;165(2):519-26
references: 10810316
references: Endocrinology. 1997 Aug;138(8):3374-9
references: 9231790
references: Am J Obstet Gynecol. 2012 Mar;206(3):187-94
references: 21982021
references: Am J Obstet Gynecol. 2006 Sep;195(3):633-42
references: 16846587
references: Diabetes. 1997 Feb;46(2):313-6
references: 9000710
references: Int J Obes Relat Metab Disord. 2001 Sep;25(9):1365-71
references: 11571601
references: J Clin Endocrinol Metab. 2006 Sep;91(9):3592-7
references: 16822822
references: Endocrinology. 1997 Feb;138(2):847-50
references: 9003026
references: Pediatr Res. 2005 Sep;58(3):510-5
references: 16148065
references: Mol Endocrinol. 2005 Nov;19(11):2647-59
references: 15831519
references: J Clin Endocrinol Metab. 2006 Jul;91(7):2761-9
references: 16684834
references: Endocr Rev. 1996 Jun;17(3):221-44
references: 8771357
references: J Endocrinol. 2000 Sep;166(3):519-28
references: 10974646
references: Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):674-9
references: 9892692
references: Diabetes. 1997 Jun;46(6):1087-93
references: 9166685
references: Am J Obstet Gynecol. 2013 Mar;208(3):217.e1-8
references: 23220271
references: Circ Res. 2007 Sep 14;101(6):545-59
references: 17872473
references: Reproduction. 2013 Jan 08;145(1):R1-13
references: 23081892
references: Curr Opin Pharmacol. 2011 Dec;11(6):670-5
references: 21962440
references: Obstet Gynecol. 2001 Jul;98(1):144-50
references: 11430973
references: J Physiol. 2010 Mar 1;588(Pt 5):887-99
references: 20064858
references: Am J Physiol Endocrinol Metab. 2005 Oct;289(4):E695-702
references: 15886225
references: Mol Pharmacol. 2011 Apr;79(4):639-48
references: 21187369
references: Front Neuroendocrinol. 1999 Oct;20(4):317-63
references: 10569281
references: Am J Obstet Gynecol. 2012 Sep;207(3):203.e1-8
references: 22939726
references: Circulation. 2003 Aug 12;108(6):644-6
references: 12912793
references: Diabetes. 1997 Jul;46(7):1235-8
references: 9200662