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.

Sensitivity to stress-induced reproductive dysfunction is associated with a selective but not a generalized increase in activity of the adrenal axis.

Stress-induced reproductive dysfunction is a relatively common cause of infertility in women. In response to everyday life stress, some individuals readily develop reproductive dysfunction (i.e., they are stress sensitive), whereas others are more stress resilient. Female cynomolgus monkeys, when exposed to mild combined psychosocial and metabolic stress (change in social environment + 20% reduced calorie diet), 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). In this study, we examined whether increased sensitivity to stress-induced reproductive dysfunction is associated with elevated adrenal axis activity by measuring 1) the diurnal release of ACTH and cortisol, 2) ACTH and cortisol in response to an acute psychological stress, 3) the percent suppression of cortisol in response to dexamethasone negative feedback, 4) the diurnal release of ACTH and cortisol following exposure to mild psychosocial and metabolic stress, 5) the concentration of cortisol in hair, and 6) adrenal weight. SS monkeys (n = 5) did not differ from MSR (n = 5) or HSR (n = 7) monkeys in any measurement of baseline HPA axis activity or the integrated measurements of chronic HPA axis activity. However, MSR + SS monkeys (n = 10) did secrete more cortisol than HSR monkeys during the daytime hours (1000-1800) following exposure to a novel social environment and reduced diet. We conclude that increased activity of the HPA axis is unlikely to be the primary mechanism causing increased sensitivity to stress-induced reproductive dysfunction.