The overall goal of this project is to test the hypothesis that gonadotropin-releasing hormone (GnRH) pulse frequency plays a regulatory role(s) in human sexual maturation and in particular, in the maintenance of normal menstrual cyclicity. We propose that the ability to secrete GnRH at a """"""""fast"""""""" (approximately circhoral or faster) frequency is acquired during puberty and that the ability to maintain a """"""""fast"""""""" frequency is necessary for normal functioning of the adult reproductive system. This hypothesis will be approached in several ways. Specifically, we plan 1) to perform a detailed assessment of the neuroendocrine regulation of GnRH secretion during human puberty; 2) to assess whether altered (decreased) frequency of GnRH secretion plays a role in the pathogenesis of idiopathic oligospermia; and 3) to assess the role of altered GnRH pulse frequency in the maintenance of normal menstrual cycles and in the anovulation associated with hypothalamic amenorrhea and hyperprolactinemia. The principal approaches to these objectives will include: a) indirect assessment of GnRH secretion via detailed assessment of the secretory patterns of immunoreactive and bioactive LH and the Alpha-subunit; b) assessment of the acute effects of sex steroid infusion on the sleep-entrained increase in gonadotropin secretion in pubertal children; c) opiate receptor blockade via naloxone or naltrexone to investigate the role(s) of endogenous opiates in gonadotropin regulation throughout human puberty and in amenorrheic women and oligospermic men; d) longitudinal assessment of sex steroid feedback during human puberty; e) assessment of the effects of clonidine, a putative Alpha 2 agonist, on gonadotropin secretion in women with hypothalamic amenorrhea; f) examining the role of prolactin in the regulation of GnRH pulse frequency in hyperprolactinemic women and in normal women (via metoclopramide administration); g) pulsatile i.v. administration of synthetic GnRH at several frequencies but at dosages which mimic pituitary portal concentrations; and h) determining the specific feedback roles of estradiol and progesterone throughput the menstrual cycle. Normal adult men and women and adults and children with suspected or proven hypothalamic/pituitary dysfunction will participate in detailed protocols performed in the Clinical Research Center. Well-established radioimmunoassays and in vitro bioassays will be used for serial hormone determinations. These studies should provide a more thorough understanding of the physiology of human reproduction and should lead to more rational therapies for children with precocious or delayed maturation and for adults with hypogonadotropic hypogonadism and infertility.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD016000-05
Application #
3313367
Study Section
Reproductive Biology Study Section (REB)
Project Start
1982-03-01
Project End
1991-02-28
Budget Start
1986-03-01
Budget End
1987-02-28
Support Year
5
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Foster, Carol M; Olton, Pamela R; Padmanabhan, Vasantha (2005) Diurnal changes in FSH-regulatory peptides and their relationship to gonadotrophins in pubertal girls. Hum Reprod 20:543-8
Elsholz, Daniel D; Padmanabhan, Vasantha; Rosenfield, Robert L et al. (2004) GnRH agonist stimulation of the pituitary-gonadal axis in children: age and sex differences in circulating inhibin-B and activin-A. Hum Reprod 19:2748-58
Foster, Carol M; Olton, Pamela R; Racine, Michael S et al. (2004) Sex differences in FSH-regulatory peptides in pubertal age boys and girls and effects of sex steroid treatment. Hum Reprod 19:1668-76
Padmanabhan, V; Christman, G M; Randolph, J F et al. (2001) Dynamics of bioactive follicle-stimulating hormone secretion in women with polycystic ovary syndrome: effects of estradiol and progesterone. Fertil Steril 75:881-8
Foster, C M; Phillips, D J; Wyman, T et al. (2000) Changes in serum inhibin, activin and follistatin concentrations during puberty in girls. Hum Reprod 15:1052-7
Cemeroglu, A P; Kletter, G B; Guo, W et al. (1998) In pubertal girls, naloxone fails to reverse the suppression of luteinizing hormone secretion by estradiol. J Clin Endocrinol Metab 83:3501-6
Pastor, C L; Griffin-Korf, M L; Aloi, J A et al. (1998) Polycystic ovary syndrome: evidence for reduced sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab 83:582-90
Cemeroglu, A P; Barkan, A L; Kletter, G B et al. (1997) Changes in serum immunoreactive and bioactive growth hormone concentrations in boys with advancing puberty and in response to a 20-hour estradiol infusion. J Clin Endocrinol Metab 82:2166-71
Kletter, G B; Padmanabhan, V; Beitins, I Z et al. (1997) Acute effects of estradiol infusion and naloxone on luteinizing hormone secretion in pubertal boys. J Clin Endocrinol Metab 82:4010-4
Cemeroglu, A P; Foster, C M; Warner, R et al. (1996) Comparison of the neuroendocrine control of pubertal maturation in girls and boys with spontaneous puberty and in hypogonadal girls. J Clin Endocrinol Metab 81:4352-7

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