Abstract

The broad goal of this competing renewal is to further elucidate the relative roles of the nonsteroidal factors, inhibin B and follistatin (FS), gonadal sex steroids, and GnRH in the control of FSH secretion in the human male. SA #1, to define the role of non-steroidal factors (inhibin B and FS) relative to sex steroids in the feedback control of FSH secretion in the human male, will be pursued in studies of normal and GnRH deficient men (ON pulsatile GnRH). Subjects will be studied: in the baseline state, b)following suppression of SS by ketoconazole, and c) during physiologic replacement of testosterone (T), estradiol (E2), T+E2, T+ an aromatase inhibitor (AI). Inhibin B and FS will be monitored along with FSH, LH, FAS (free alpha subunit), T and E2. Agonadal men will provide the references ranges for FSH levels and GnRH frequency, with and without steroids. The hypotheses are: 1) gonadal non-=SS factors account for a significant proportion of the negative feedback of FSH; 2) inhibin B is predominant among these, and 3) follistatin in the peripheral circulation is of pituitary origin.
Specific Aim 2 is to establish the relative contributions of T & E2 to FSH feedback, and will be pursued by comparing FSH in response to T vs T+AI. The hypothesis is that E2 is the predominant SS negative feedback regulator of FSH.
Specific Aim 3, to examine the interactions between GnRH, SS & Non-steroidal feedback in the control of FSH, will be pursued by comparing the FSH response to SS ablation in GnRH deficient men maintained at an intact GnRH dose and frequency (q2hr) vs. in those switched to a castrate regimen. The hypothesis is that GnRH input has a significant on FSH when SS and/or inhibin B levels are low. Detailed parallel studies undertaken in normal, GnRH deficient, and agonadal males will thus provide new insights into the physiology of FSH regulation in the human which will be the cornerstone for subsequent studies of the pathophysiology of men with reproductive disorders.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD015788-13A1
Application #
2025046
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1981-07-01
Project End
2000-11-30
Budget Start
1996-12-01
Budget End
1997-11-30
Support Year
13
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199

  Publications

Cox, Kimberly H; Oliveira, Luciana M B; Plummer, Lacey et al. (2018) Modeling mutant/wild-type interactions to ascertain pathogenicity of PROKR2 missense variants in patients with isolated GnRH deficiency. Hum Mol Genet 27:338-350
Choi, Jin-Ho; Balasubramanian, Ravikumar; Lee, Phil H et al. (2015) Expanding the Spectrum of Founder Mutations Causing Isolated Gonadotropin-Releasing Hormone Deficiency. J Clin Endocrinol Metab 100:E1378-85
Xiao, Ling; Zhang, Chengkang; Li, Xiaohan et al. (2014) Signaling role of prokineticin 2 on the estrous cycle of female mice. PLoS One 9:e90860
Balasubramanian, Ravikumar; Cohen, Daniel A; Klerman, Elizabeth B et al. (2014) Absence of central circadian pacemaker abnormalities in humans with loss of function mutation in prokineticin 2. J Clin Endocrinol Metab 99:E561-6
Sidhoum, Valerie F; Chan, Yee-Ming; Lippincott, Margaret F et al. (2014) Reversal and relapse of hypogonadotropic hypogonadism: resilience and fragility of the reproductive neuroendocrine system. J Clin Endocrinol Metab 99:861-70
Costa-Barbosa, Flavia Amanda; Balasubramanian, Ravikumar; Keefe, Kimberly W et al. (2013) Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes. J Clin Endocrinol Metab 98:E943-53
Abel, Brent S; Shaw, Natalie D; Brown, Jenifer M et al. (2013) Responsiveness to a physiological regimen of GnRH therapy and relation to genotype in women with isolated hypogonadotropic hypogonadism. J Clin Endocrinol Metab 98:E206-16
Miraoui, Hichem; Dwyer, Andrew A; Sykiotis, Gerasimos P et al. (2013) Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet 92:725-43
Dwyer, Andrew A; Sykiotis, Gerasimos P; Hayes, Frances J et al. (2013) Trial of recombinant follicle-stimulating hormone pretreatment for GnRH-induced fertility in patients with congenital hypogonadotropic hypogonadism. J Clin Endocrinol Metab 98:E1790-5
Chew, Sheena; Balasubramanian, Ravikumar; Chan, Wai-Man et al. (2013) A novel syndrome caused by the E410K amino acid substitution in the neuronal ?-tubulin isotype 3. Brain 136:522-35

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