The objectives of this proposal are to determine the heterogeneous forms in which the gonadotropins, luteininzing hormone (LH) and follicle stimuating hormone (FSH) are secreted, circulated and are excreted. Methods used for characterization include chromatography, radioimmunoassay measurements of free gonadotropin subunits and fragments, comparison of in vitro biologic (B) and immunologic (I) concentration of gonadotropins, and rates or serum disappearance and renal clerance. In vitro bioassays have been developed for serum hLH, and validation of an assay for serum hFSH (using testosterone aromatization to estradiol in rat Sertoli cell cultures) is in progress. We propose to study mechanisms by which endogenously secreted and exogenously administered LHRH alters the B/T ratio and how gonadal steroids modulate these changes in the human and the rat. Perifused rat pituitary cells will be used to characterize newly secreted LH and FSH, and rat hepatocyte cultures to determine gonadotropin binding, metabolism and degradation. Besides advancing current knowledge regarding biologically active and inactive forms of gonadotropins, these studies are of potential benefit to patients. We have identified patients with normal or high levels of immunoreactive gonadotropins but immeasurable bioactive levels. In one group (alpha-secreting pituitary tumors) the discrepancy was traceable to immuno-crossreactivity of the biologically inert alpha subunit; in another, the LH molecule was abnormal (i.e., retained immunologic but lacked biological activity). Such patients are candidates for replacement therapy. Others exhibited biologic effects (precocious puberty) yet lacked measureable immuno- or bioactive gonadotropins. In such cases receptor avidity or target cell stimulation by other means is postulated. Conceivably, patients will be identified with normal bioactivity but abnormalities at the receptor level. Detailed characterization of the abnormal hormones will contribute to understanding of the clinical and physical determinants essential for biologic activity. Long-term benefits can be envisioned when regions responsible for biologic function are identified, synthesized and used as therapeutic agents, whereas analogs can be employed as contraceptive agents.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD018515-04
Application #
3315606
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1983-04-01
Project End
1991-04-30
Budget Start
1988-05-01
Budget End
1989-04-30
Support Year
4
Fiscal Year
1988
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
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
Ulloa-Aguirre, A; Midgley Jr, A R; Beitins, I Z et al. (1995) Follicle-stimulating isohormones: characterization and physiological relevance. Endocr Rev 16:765-87
Kasa-Vubu, J Z; Padmanabhan, V; Kletter, G B et al. (1993) Serum bioactive luteinizing and follicle-stimulating hormone concentrations in girls increase during puberty. Pediatr Res 34:829-33
Kletter, G B; Padmanabhan, V; Brown, M B et al. (1993) Serum bioactive gonadotropins during male puberty: a longitudinal study. J Clin Endocrinol Metab 76:432-8
Krey, L C; Padmanabhan, V; Beitins, I Z (1993) Progesterone modulation of gonadotropin secretion by dispersed rat pituitary cells in culture. IV. Follicle-stimulating hormone synthesis and release. Mol Cell Endocrinol 91:13-20
Padmanabhan, V; Sairam, M R; Hassing, J M et al. (1991) Follicle-stimulating hormone signal transduction: role of carbohydrate in aromatase induction in immature rat Sertoli cells. Mol Cell Endocrinol 79:119-28
Beitins, I Z; McArthur, J W; Turnbull, B A et al. (1991) Exercise induces two types of human luteal dysfunction: confirmation by urinary free progesterone. J Clin Endocrinol Metab 72:1350-8
Beitins, I Z; Padmanabhan, V; Kasa-Vubu, J et al. (1990) Serum bioactive follicle-stimulating hormone concentrations from prepuberty to adulthood: a cross-sectional study. J Clin Endocrinol Metab 71:1022-7
Page, L A; Beauregard, L J; Bode, H H et al. (1990) Hypothalamic-pituitary-ovarian function in menstruating women with Turner syndrome (45,X). Pediatr Res 28:514-7
Hassing, J M; Padmanabhan, V; Kelch, R P et al. (1990) Differential regulation of serum immunoreactive luteinizing hormone and bioactive follicle-stimulating hormone by testosterone in early pubertal boys. J Clin Endocrinol Metab 70:1082-9

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