Prenatal betamethasone exposure results in pituitary-adrenal hyporesponsiveness in adult sheep.
Fetal exposure to synthetic glucocorticoids in sheep results in increased fetal hypothalamic-pituitary-adrenal (HPA) activity persisting to one year of age. We aimed to determine the effects of single or repeated maternal or fetal betamethasone injections on offspring HPA activity at 2 and 3 yr of age and whether changes in adrenal mediators of steroidogenesis contribute to changes in pituitary-adrenal function. Pregnant ewes or their fetuses received either repeated intramuscular saline or betamethasone injections (0.5 mg/kg) at 104, 111, 118, and 124 days of gestation (dG) or a single betamethasone injection at 104 dG followed by saline at 111, 118, and 124 dG. Offspring were catheterized at 2 and 3 yr of age and given corticotrophin-releasing hormone + arginine vasopressin challenges. Adrenal tissue was collected for quantitative RT-PCR mRNA determination at 3.5 yr of age. In 2-yr-old offspring, maternal betamethasone injections did not alter basal ACTH or cortisol levels, but repeated injections elevated ACTH responses. At 3 yr of age, basal ACTH was elevated, and both basal and stimulated cortisol levels were suppressed by repeated maternal injections. Basal and stimulated cortisol-to-ACTH ratios and basal cortisol-to-cytochrome P-450 17alpha-hydroxylase (P450c17) mRNA ratios were suppressed by repeated injections. Repeated fetal betamethasone injections attenuated basal ACTH and cortisol levels in offspring at 2 but not 3 yr of age. Plasma changes were not associated with altered adrenal P450c17, ACTH receptor, beta-hydroxysteroid dehydrogenase, or glucocorticoid receptor mRNA levels. These data suggest that maternal, but not fetal, betamethasone administration results in adrenal suppression in adulthood.
Sloboda
Deborah M
DM
Forrest Fetal Research Scientist, School of Women's and Infants' Health, The Univ. of Western Australia, King Edward Memorial Hospital, Subiaco, Western Australia, Australia. dsloboda@obsgyn.uwa.edu.au
Moss
Timothy J M
TJ
Li
Shaofu
S
Doherty
Dorota
D
Nitsos
Ilias
I
Challis
John R G
JR
Newnham
John P
JP
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D001623:Betamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D005260:Female; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D011247:Pregnancy; D011270:Pregnancy, Animal; D011297:Prenatal Exposure Delayed Effects / Q000097:blood / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012756:Sheep; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism
D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D001127:Arginine Vasopressin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D001623:Betamethasone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D013254:Steroid 17-alpha-Hydroxylase; D006854:Hydrocortisone