The overall objective of the proposal is to investigate interactions between two major endocrine axes, the hypothalamo-pituitary-adrenal (HPA) and the hypothalamo-pituitary-gonald (HPG) axes in a non human primate model, the rehesus monkey, which is known for its similarity to the human in regard to the control of the menstrual cycle. More specifically in the first 3 aims, we will study the mechanisms by which stressful stimuli may interfer with the normal reproductive process. Our previous studies in the ovariectomized (OVX) monkey support the classical concept that stress, by activating HPA and the release of central HPA neuropeptides, suppresses pulsatile gonadotropin secretion. Yet, these studies also clearly indicate that the response to stress is modulated by the ovarian steroids. Thus, our first 2 aims will compare effects of an immune/inflammatory-like stress challenge on gonadotropin release at different stages of the menstrual cycle and the mechanisms which differentiate the acute and the chronic response. A pilot study has demonstrated surprising responses to the stress challenge, in that under specific ovarian endocrin conditions the challenge becomes stimulatory rather than inhibitory to gonadotropin secretion. The long term effects of these responses to the stress challenge on the menstrual cycle will then be investigated.
In aim 3, we will examine the role of HPA in the genesis of the stress related hypothalamic amenorrhea syndrome and determine whether the use of specific antagonists may activate the return to cyclicity. In the final aim, we will focus on HPA-HPG interactions during the follicular phase, in the absence of stress. Pilot studies in OVX-estrogen replaced monkeys suggest that HPA, in its unstimulated state, may play a small but relevant role in support of tonic gonadotropin secretion. The relevance of this process to folliculogenesis will be studied in the intact monkey. Overall, the data will provide information about novel mechanisms by which HPA and stress influence themenstrual cycle and may suggest new therapeutical approaches to the problem of hypothalamic amenorrhea.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Biochemical Endocrinology Study Section (BCE)
Program Officer
Sato, Sheryl M
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Columbia University (N.Y.)
Obstetrics & Gynecology
Schools of Medicine
New York
United States
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Xiao, Ennian; Xia-Zhang, Linna; Vulliemoz, Nicolas et al. (2007) Astressin B, a corticotropin-releasing hormone receptor antagonist, accelerates the return to normal luteal function after an inflammatory-like stress challenge in the rhesus monkey. Endocrinology 148:841-8
Vulliemoz, Nicolas R; Xiao, Ennian; Xia-Zhang, Linna et al. (2005) Central infusion of agouti-related peptide suppresses pulsatile luteinizing hormone release in the ovariectomized rhesus monkey. Endocrinology 146:784-9
Vulliemoz, Nicolas R; Xiao, Ennian; Xia-Zhang, Linna et al. (2004) Decrease in luteinizing hormone pulse frequency during a five-hour peripheral ghrelin infusion in the ovariectomized rhesus monkey. J Clin Endocrinol Metab 89:5718-23
Xiao, Ennian; Xia-Zhang, Linna; Vulliemoz, Nicolas R et al. (2003) Leptin modulates inflammatory cytokine and neuroendocrine responses to endotoxin in the primate. Endocrinology 144:4350-3
Xiao, Ennian; Xia-Zhang, Linna; Ferin, Michel (2002) Inadequate luteal function is the initial clinical cyclic defect in a 12-day stress model that includes a psychogenic component in the Rhesus monkey. J Clin Endocrinol Metab 87:2232-7
Zimmermann, R C; Xiao, E; Husami, N et al. (2001) Short-term administration of antivascular endothelial growth factor antibody in the late follicular phase delays follicular development in the rhesus monkey. J Clin Endocrinol Metab 86:768-72
Xiao, E; Xia-Zhang, L; Ferin, M (2000) Inhibitory effects of endotoxin on LH secretion in the ovariectomized monkey are prevented by naloxone but not by an interleukin-1 receptor antagonist. Neuroimmunomodulation 7:15-Jun
Xiao, E; Xia-Zhang, L; Ferin, M (1999) Stress and the menstrual cycle: short- and long-term response to a five-day endotoxin challenge during the luteal phase in the rhesus monkey. J Clin Endocrinol Metab 84:623-6
Xiao, E; Xia-Zhang, L; Barth, A et al. (1998) Stress and the menstrual cycle: relevance of cycle quality in the short- and long-term response to a 5-day endotoxin challenge during the follicular phase in the rhesus monkey. J Clin Endocrinol Metab 83:2454-60
Xiao, E; Xia-Zhang, L; Shanen, D et al. (1997) Tonic support of luteinizing hormone secretion by adrenal progesterone in the ovariectomized monkey replaced with midfollicular phase levels of estradiol. J Clin Endocrinol Metab 82:2233-8

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