Treatment with a CRH-R1 antagonist prevents stress-induced suppression of the central neural drive to the reproductive axis in female macaques.
In response to everyday life stress, some individuals readily develop reproductive dysfunction (i.e., they are stress sensitive), whereas others are more stress resilient. When exposed to mild combined psychosocial plus metabolic stress (change in social environment plus reduced diet), female cynomolgus monkeys can be categorized as stress sensitive (SS; they rapidly become anovulatory in response to stress), medium stress resilient (MSR; they slowly become anovulatory in response to prolonged stress), or highly stress resilient (HSR; they maintain normal menstrual cycles in response to stress). Previously, we reported that monkeys that develop abnormal menstrual cycles following exposure to mild combined stress (MSR + SS) have increased plasma cortisol levels the day they move to a novel room and start a reduced diet compared with HSR monkeys. In this study, we examined whether there is a similar acute effect of mild combined stress on the reproductive axis specifically in the combined group of MSR + SS animals by measuring LH pulse frequency and whether treatment with a CRH-R1 antagonist can prevent a stress-induced suppression of LH pulse frequency presumably by inhibiting activity of the HPA axis. Animals that developed abnormal menstrual cycles in response to stress (MSR + SS monkeys) suppressed LH pulse frequency in response to stress exposure. Pretreatment with 10 mg/kg iv antalarmin prevented the stress-induced suppression of LH secretion in these animals without the stress-induced increase in cortisol secretion being blocked. We conclude that CRH, acting via nonneuroendocrine mechanisms to regulate neurotransmitter systems other than the HPA axis, plays a role in causing stress-induced reproductive impairment in stress-sensitive individuals.
Herod
S M
SM
Department of Behavioral Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon, USA.
Pohl
C R
CR
Cameron
J L
JL
D000818:Animals; D000858:Anovulation / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002490:Central Nervous System / Q000187:drug effects*; D002940:Circadian Rhythm; D004032:Diet / Q000009:adverse effects; D005260:Female; D006854:Hydrocortisone / Q000097:blood; D007247:Infertility, Female / Q000517:prevention & control; D007275:Injections, Intravenous; D007986:Luteinizing Hormone / Q000097:blood; D008252:Macaca fascicularis; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use*; D011897:Random Allocation; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D012931:Social Environment; D013315:Stress, Psychological / Q000097:blood / Q000503:physiopathology*; D000099052:CRF Receptor, Type 1
D014151:Anti-Anxiety Agents; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; C103016:antalarmin; D000099052:CRF Receptor, Type 1; D007986:Luteinizing Hormone; D006854:Hydrocortisone
J Clin Endocrinol Metab. 1977 Sep;45(3):488-95
198424
Endocrinology. 1996 Dec;137(12):5747-50
8940412
Fertil Steril. 1997 Jun;67(6):1024-30
9176439
J Clin Endocrinol Metab. 1987 Apr;64(4):755-62
2880864
Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E270-6
17405827
Clin Chem. 2000 Dec;46(12):1998-2000
11106336
Fertil Steril. 2007 Jan;87(1):136-42
17094981
Clin Endocrinol (Oxf). 1999 Feb;50(2):229-35
10396367
Am J Reprod Immunol. 2004 Apr;51(4):269-74
15212679
Endocrinology. 1998 Apr;139(4):1546-55
9528933
Am J Primatol. 2007 Aug;69(8):877-89
17397037
Semin Reprod Endocrinol. 1997 Feb;15(1):37-45
9065976
Nat Immunol. 2001 Nov;2(11):1018-24
11590404
Behav Brain Res. 2005 Jun 3;161(1):39-44
15904708
Proc Natl Acad Sci U S A. 2000 May 23;97(11):6079-84
10823952
Eur J Pharmacol. 2004 Sep 19;499(1-2):135-46
15363960
Mol Neurobiol. 2008 Dec;38(3):199-230
18931961
J Clin Endocrinol Metab. 2001 Nov;86(11):5184-93
11701675
Annu Rev Physiol. 1982;44:583-93
7041807
Bioorg Med Chem. 2002 Jan;10(1):175-83
11738619
Am J Obstet Gynecol. 1990 Nov;163(5 Pt 2):1732-6
2122729
Peptides. 2001 May;22(5):733-41
11337086
J Clin Endocrinol Metab. 1988 Apr;66(4):733-9
3346352
Psychopharmacology (Berl). 2006 Dec;189(3):277-86
17016707
J Clin Endocrinol Metab. 1989 Feb;68(2):301-8
2493024
Fertil Steril. 2001 Aug;76(2):310-6
11476778
Endocrinology. 1991 Mar;128(3):1532-40
1999171
Endocrinology. 1983 Jun;112(6):2076-80
6406208
Neuroscience. 2005;132(1):151-66
15780474
J Clin Endocrinol Metab. 2004 Nov;89(11):5729-37
15531536
Fertil Steril. 2005 Jan;83(1):148-55
15652901
Neuropsychopharmacology. 2004 Jun;29(6):1112-21
14997174
J Clin Endocrinol Metab. 1990 Feb;70(2):311-7
2153693
J Clin Endocrinol Metab. 1985 Nov;61(5):851-8
3900122
Pharmacol Biochem Behav. 2002 Aug;73(1):147-58
12076734
J Neuroimmunol. 1999 Oct 29;99(2):230-41
10505980
Fertil Steril. 2001 Oct;76(4):748-52
11591409
Endocrinology. 2001 Jun;142(6):2381-9
11356685
Neuroendocrinology. 2007;86(4):277-88
17934253
Am J Physiol Endocrinol Metab. 2011 Jan;300(1):E28-36
20959528
Brain Res. 2007 Apr 20;1142:1-12
17320837
Am J Physiol. 1982 Oct;243(4):E310-8
6889816
Eur J Endocrinol. 2000 Mar;142(3):280-5
10700723
Fertil Steril. 1993 Sep;60(3):486-92
8375531
J Clin Endocrinol Metab. 1998 Jan;83(1):25-32
9435412
J Clin Endocrinol Metab. 2006 Apr;91(4):1561-5
16464944
Recent Prog Horm Res. 1985;41:473-531
3931190
Endocrinology. 1998 Jul;139(7):3357-60
9645712
Fertil Steril. 2007 Apr;87(4):876-85
17274991
Contraception. 2008 Apr;77(4):303-7
18342656
Endocrinology. 1999 Jan;140(1):79-86
9886810
Life Sci. 1999;65(4):PL53-8
10421433