Infertility, overpopulation and reproductive disorders are major problems facing Society. This proposal focuses on integration of the three great communication systems in the body - the endocrine, the central nervous and the immune systems - and how this impacts the ovulatory cycle of females. The importance of the endocrine and nervous systems in orchestrating the events of the cycle, and in coordinating reproductive processes with the external environment, has long been recognized. Only recently, however, has the role of the immune system come to the forefront. The immune system elaborates a cascade of neural and humoral signals when challenged by inflammatory stimuli and invasion of the body by foreign organisms. Through mechanisms not fully understood, these immune signals powerfully inhibit reproduction. The broad objective of this research is to determine how an immune challenge impacts the neuroendocrine axis to inhibit the ovarian cycle. The general approach is to integrate current knowledge of the physiologic basis for the estrous cycle of sheep with observed changes in neuroendocrine activity following a standardized immune challenge (endotoxin). In this manner, processes critical to reproductive suppression will be pinpointed.
Specific Aim 1 elucidates the influence of an immune challenge on the estrous cycle. This will be achieved by assessing the effects endotoxin on progression of the hormonal events of the follicular and luteal phases of the cycle, and by assessing the influence of ovarian steroids on neuroendocrine responses to an immune challenge.
Specific Aim 2 addresses mechanisms whereby an immune challenge inhibits pulsatile secretion of GnRH and LH. This includes investigations directed at both the hypothalamic level (secretion of GnRH into pituitary portal blood) and the pituitary level (responsiveness to GnRH).
Specific Aim 3 focuses on the impact of an immune challenge on surge secretion of GnRH and LH. This includes how an immune challenge impacts activation of estradiol receptive neurons in the hypothalamus, the transduction of the surge inducing signal to the GnRH neuronal network, and the actual surge processes of GnRH and LH release. The research incorporates a variety of approaches including monitoring secretion of hormones from the hypothalamus, the pituitary and the ovary, and immunocytochemical analysis of hypothalamic systems known to be crucial to reproduction. The health-related relevance of this work is that it will provide an in depth integrated analysis of how immune challenges, infectious and inflammatory disease, physical injury and trauma, and a variety of noxious stimuli lead to reproductive failure.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD030773-07
Application #
2889094
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
De Paolo, Louis V
Project Start
1993-09-01
Project End
2003-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Physiology
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Wagenmaker, Elizabeth R; Breen, Kellie M; Oakley, Amy E et al. (2010) The estrous cycle of the ewe is resistant to disruption by repeated, acute psychosocial stress. Biol Reprod 82:1206-15
Oakley, Amy E; Breen, Kellie M; Tilbrook, Alan J et al. (2009) Role of estradiol in cortisol-induced reduction of luteinizing hormone pulse frequency. Endocrinology 150:2775-82
Pierce, B N; Stackpole, C A; Breen, K M et al. (2009) Estradiol enables cortisol to act directly upon the pituitary to suppress pituitary responsiveness to GnRH in sheep. Neuroendocrinology 89:86-97
Pierce, B N; Clarke, I J; Turner, A I et al. (2009) Cortisol disrupts the ability of estradiol-17beta to induce the LH surge in ovariectomized ewes. Domest Anim Endocrinol 36:202-8
Wagenmaker, Elizabeth R; Breen, Kellie M; Oakley, Amy E et al. (2009) Cortisol interferes with the estradiol-induced surge of luteinizing hormone in the ewe. Biol Reprod 80:458-63
Oakley, Amy E; Breen, Kellie M; Clarke, Iain J et al. (2009) Cortisol reduces gonadotropin-releasing hormone pulse frequency in follicular phase ewes: influence of ovarian steroids. Endocrinology 150:341-9
Wagenmaker, Elizabeth R; Breen, Kellie M; Oakley, Amy E et al. (2009) Psychosocial stress inhibits amplitude of gonadotropin-releasing hormone pulses independent of cortisol action on the type II glucocorticoid receptor. Endocrinology 150:762-9
Breen, Kellie M; Davis, Tracy L; Doro, Lisa C et al. (2008) Insight into the neuroendocrine site and cellular mechanism by which cortisol suppresses pituitary responsiveness to gonadotropin-releasing hormone. Endocrinology 149:767-73
Breen, Kellie M; Oakley, Amy E; Pytiak, Andrew V et al. (2007) Does cortisol acting via the type II glucocorticoid receptor mediate suppression of pulsatile luteinizing hormone secretion in response to psychosocial stress? Endocrinology 148:1882-90
Stackpole, Catherine A; Clarke, Iain J; Breen, Kellie M et al. (2006) Sex difference in the suppressive effect of cortisol on pulsatile secretion of luteinizing hormone in sheep. Endocrinology 147:5921-31

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