An understanding of the regulation of the gonadotropin surge leading to ovulation has potential applications in fertility control as well as in the management of infertility. Estradiol is the primary trigger for the ovulatory surge and progesterone modulates the estradiol-induced surge. Among the many actions of progesterone, a depletion of the occupied estrogen receptors of the pituitary appears to be an important one. Progesterone also attenuates the effect of subsequent estrogen injections during the period of it's nuclear occupancy. The proposed study will determine the specificity of progesterone for its effects on estrogen receptors in the pituitary and interference with subsequent estrogen action by using steroids such as cholesterol, testosterone, dihydrotestosterone, 5a-dihydroprogesterone, corticosterone and cortisol. Furthermore, the mechanism of action of progesterone will be examined by investigating (a) whether progesterone altered salt-soluble or salt-resistant forms of the estrogen receptor, (b) does progesterone enhance dissociation of the ER complex from DNA, (c) can the stimulation of 17B-hydroxysteroid dehydrogenase explain progesterone action, (d) does progesterone act through the stimulation of a protease or a phosphatase and (e) is progesterone effect prolonged if progesterone receptor processing is delayed.
In Specific Aim 2, the effect of steroids such as testosterone, DHT, cortisol and corticosterone on estrogen receptor dynamics will be correlated with the effect of these steroids on FSH and LH secretion. Most of these steroids are present in the female and influence gonadotropin secretion.
The third aim will determine whether progesterone has a biphasic effect on the opioid tome similar to it's biphasic effect on gonadotropin secretion. The procedures used to evaluate the opioid tone will be the effect of naloxone on FSH and LH secretion in conjunction with hypothalamic LHRH measurements and pituitary sensitivity to LHRH. The opioid tone will also be evaluated in the dose-related effect of progesterone on gonadotropin secretion. In the fourth aim, the question whether progesterone metabolites act by using the progesterone receptor will be addressed by using R5020 binding in vitro and RU486 in vivo. The fifth aim will examine the direct effect of progesterone on the pituitary using dispersed cell culture techniques and enrichment of pituitary gonadotropes. These studies will provide important new information on the regulation of gonadotropin secretion by steroids.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Reproductive Biology Study Section (REB)
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Medical College of Georgia (MCG)
Schools of Medicine
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Mahesh, Virendra B (2012) Hirsutism, virilism, polycystic ovarian disease, and the steroid-gonadotropin-feedback system: a career retrospective. Am J Physiol Endocrinol Metab 302:E4-E18
Brann, Darrell W; Unda, Richard; Mahesh, Virendra B (2002) Role of the progesterone receptor in restrained glutamic acid decarboxylase gene expression in the hypothalamus during the preovulatory luteinizing hormone surge. Neuroendocrinology 76:283-9
Mahesh, V B; Brann, D W (1998) Neuroendocrine mechanisms underlying the control of gonadotropin secretion by steroids. Steroids 63:252-6
Mahesh, V B; Brann, D W (1998) Regulation of the preovulatory gonadotropin surge by endogenous steroids. Steroids 63:616-29
Brann, D W; Mahesh, V B (1997) Excitatory amino acids: evidence for a role in the control of reproduction and anterior pituitary hormone secretion. Endocr Rev 18:678-700
Zamorano, P L; Mahesh, V B; Brann, D W (1996) Quantitative RT-PCR for neuroendocrine studies. A minireview. Neuroendocrinology 63:397-407
Mahesh, V B; Brann, D W; Hendry, L B (1996) Diverse modes of action of progesterone and its metabolites. J Steroid Biochem Mol Biol 56:209-19
O'Conner, J L; Wade, M F; Brann, D W et al. (1995) Evidence that progesterone modulates anterior pituitary neuropeptide Y levels during the progesterone-induced gonadotropin surge in the estrogen-primed intact immature female rat. J Steroid Biochem Mol Biol 52:497-504
Unda, R; Brann, D W; Mahesh, V B (1995) Progesterone suppression of glutamic acid decarboxylase (GAD67) mRNA levels in the preoptic area: correlation to the luteinizing hormone surge. Neuroendocrinology 62:562-70
Brann, D W; Mahesh, V B (1995) Glutamate: a major neuroendocrine excitatory signal mediating steroid effects on gonadotropin secretion. J Steroid Biochem Mol Biol 53:325-9

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