Insight into the neuroendocrine site and cellular mechanism by which cortisol suppresses pituitary responsiveness to gonadotropin-releasing hormone.
Stress-like elevations in plasma glucocorticoids rapidly inhibit pulsatile LH secretion in ovariectomized sheep by reducing pituitary responsiveness to GnRH. This effect can be blocked by a nonspecific antagonist of the type II glucocorticoid receptor (GR) RU486. A series of experiments was conducted to strengthen the evidence for a mediatory role of the type II GR and to investigate the neuroendocrine site and cellular mechanism underlying this inhibitory effect of cortisol. First, we demonstrated that a specific agonist of the type II GR, dexamethasone, mimics the suppressive action of cortisol on pituitary responsiveness to GnRH pulses in ovariectomized ewes. This effect, which became evident within 30 min, documents mediation via the type II GR. We next determined that exposure of cultured ovine pituitary cells to cortisol reduced the LH response to pulse-like delivery of GnRH by 50% within 30 min, indicating a pituitary site of action. Finally, we tested the hypothesis that suppression of pituitary responsiveness to GnRH in ovariectomized ewes is due to reduced tissue concentrations of GnRH receptor. Although cortisol blunted the amplitude of GnRH-induced LH pulses within 1-2 h, the amount of GnRH receptor mRNA or protein was not affected over this time frame. Collectively, these observations provide evidence that cortisol acts via the type II GR within the pituitary gland to elicit a rapid decrease in responsiveness to GnRH, independent of changes in expression of the GnRH receptor.
Breen
Kellie M
KM
Reproductive Sciences Program, Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA. kbchurch@UCSD.edu
Davis
Tracy L
TL
Doro
Lisa C
LC
Nett
Terry M
TM
Oakley
Amy E
AE
Padmanabhan
Vasantha
V
Rispoli
Louisa A
LA
Wagenmaker
Elizabeth R
ER
Karsch
Fred J
FJ
D000818:Animals; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D006854:Hydrocortisone / Q000378:metabolism* / Q000494:pharmacology; D010052:Ovariectomy; D010902:Pituitary Gland / Q000166:cytology* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011966:Receptors, LHRH / Q000235:genetics* / Q000378:metabolism*; D012756:Sheep
D005938:Glucocorticoids; D012333:RNA, Messenger; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D003907:Dexamethasone; D006854:Hydrocortisone