| Successful reproduction is vital to species survival. In the female, a dynamic hormonal communication between the brain, pituitary and ovary leads to a cycle of endocrine and neuroendocrine events essential to ovulation and thus fertility. This reproductive cycle is exquisitely sensitive to disruption by a variety of environmental stressors, including immune/inflammatory stress. The objective of this thesis has been to understand mechanisms and mediators by which such immune/inflammatory stress disrupts reproductive neuroendocrine function and ovarian cyclicity. Investigations were carried out in the sheep, using the bacterial toxin endotoxin as a model of immune/inflammatory stress. The findings demonstrate that endotoxin profoundly disrupts progression of the follicular phase of the cycle, interrupting the preovulatory estrogen rise and blocking or delaying the requisite ovulation signal, the luteinizing hormone (LH) surge. The pathophysiologic bases of these disruptive effects are several-fold, including suppression of pulsatile release of the stimulatory neuropeptide of the reproductive axis, gonadotropin-releasing hormone (GnRH), into the hypophyseal portal blood and interference with the ability of the LH surge generating mechanism to respond to the stimulatory actions of estradiol. Further, endotoxin also appears to evoke inhibition at both the pituitary and ovarian levels, suppressing responsiveness to hormonal stimulation. Coincident with reproductive disruption, endotoxin potently stimulates the neuroendocrine stress axis, an action that occurs centrally via stimulation of secretion of the neuropeptides corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) into the hypophyseal portal blood. This stimulation coincides with GnRH and LH suppression. Preliminary studies investigating the potential role CRH and AVP may play in reproductive suppression induced by endotoxin provide promising data suggesting the existence of a causal link between stimulation of the stress neuropeptides and suppression of GnRH, although definitive conclusions will require further study. In summary, the findings of this dissertation have elucidated several mechanisms by which endotoxin disrupts reproductive neuroendocrine function and ovarian cyclicity. Characterizing the (neuro)endocrine impact of endotoxin at the level of the brain, pituitary and ovary and the pathophysiologic mechanisms for these effects, has furthered our understanding of the reproductive consequences of immune stress and provides a basis for future studies in this area. |
