Date

May 2009

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Behavioral Neuroscience

Institution

Oregon Health & Science University

Abstract

In women, one of the most common forms of infertility is known as ‘stress-induced amenorrhea’, thought to be caused by a combined effect of mild psychosocial stress + metabolic stress acting to suppress gonadotropin-releasing hormone (GnRH) drive to the reproductive (HPG) axis and inhibit normal reproductive function. Women with this disorder report a greater degree of psychosocial stress in their lives as compared to healthy women, although they do not experience more stressful life events. They also tend to diet and exercise in an attempt to control stress. It thus appears that stress-induced amenorrhea occurs in women who have an increased sensitivity to everyday life stresses. Cortisol has been reported to be elevated in this patient population, and activation of the hypothalamic-pituitary-adrenal (HPA) axis has been suggested as a potential neural mechanism underlying the etiology of stress-induced amenorrhea. Our laboratory has developed a non-human primate model of sensitivity to stress-induced reproductive dysfunction based on clinical descriptions of the stressors experienced by this clinical population. Female monkeys, when exposed to mild combined psychosocial + metabolic stress (i.e. move to a novel room + a 20% reduction in available calories), can be categorized as highly stress-resilient (“HSR”; maintain normal menstrual cycles in response to stress), medium stress-resilient (“MSR”; slowly become anovulatory in response to stress), or stress-sensitive (“SS”; rapidly become anovulatory in response to stress). Our laboratory has shown that SS monkeys have increased expression of corticotropin-releasing hormone (CRH) in the caudal regions of the paraventricular nucleus (PVN). CRH provides the central neural drive to the HPA axis. To test the hypothesis that elevated activity of the HPA axis is a primary neural mechanism underlying the sensitivity to stress-induced reproductive dysfunction, I conducted physiological, pharmacological and immunocytochemical studies in two different groups of female cynomolgus monkeys (Macaca fascicularis). For all studies in Chapters 2 and 3, monkeys were fitted with indwelling catheters that allowed undisturbed collection of blood samples and infusion of drugs for physiological characterization and pharmacological manipulation of HPA axis activity. SS monkeys did not differ from HSR or MSR monkeys in adrenocorticotropic hormone (ACTH) or cortisol secretion over a normal day, in ACTH or cortisol response to an acute psychological stressor, in cortisol response to dexamethasone negative feedback, in concentration of cortisol found in hair, or in adrenal weight. However, when exposed to the specific condition of mild psychosocial + metabolic stress, monkeys that became anovulatory in response to this mild combined stress (MSR+SS monkeys) had an increase in daytime cortisol release. These findings suggested that greater activation of the HPA axis in response to everyday life stresses may be playing a role in sensitizing animals to stress-induced reproductive dysfunction. I next performed a pharmacological study to test whether a blockade of stress-induced activation of the HPA axis could prevent stress-induced suppression of the reproductive axis. Monkeys were exposed to mild combined stress and the immediate effects of stress exposure on pulsatile LH secretion were studied. Monkeys that became anovulatory in response to stress (MSR+SS monkeys) showed a significant suppression of pulsatile LH secretion when stressed, whereas HSR monkeys did not. Treatment with the specific CRH-R1 antagonist, antalarmin, prevented the stress-induced suppression of LH pulse frequency in monkeys that became anovulatory in response to stress (MSR+SS), without blocking the stress-induced increase in cortisol. These findings indicated that activation of the HPA axis was not causing acute suppression of reproductive function in stress-sensitive individuals, but that CRH acting through another system besides the HPA axis appears to be involved in stress-induced suppression of the reproductive axis in MSR+SS animals. In Chapter 4, immunocytochemical staining of CRH-positive neural fibers was examined in brain tissue previously collected from a second group of animals in the early follicular phase of a control, non-stressed menstrual cycle. Our laboratory had previously shown that SS monkeys have lower release of serotonin in the brain and suppressed expression of serotonin-related genes in the dorsal raphe nucleus, the central site of serotonin production in the brain. Therefore, I chose to examine CRH neuronal input to the raphe nucleus, as CRH signaling is inhibitory to the serotonin neurons in this region. The area of CRH immunopositive fiber staining was greater in both the dorsal and median raphe nucleus of SS animals compared to HSR animals, indicating that the increased CRH expression in SS monkeys may be interacting with serotonin to affect reproductive function. The results of this dissertation suggest a new direction for research directed towards improving our understanding of the etiology of stress-induced reproductive dysfunction would be to examine the possible interactions between CRH and serotonin neurotransmitter systems.

Identifier

doi:10.6083/M42805KW

School

School of Medicine

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