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A Potential Role for Insulin-Like Growth Factor Binding Protein-4 Proteolysis in the Establishment of Ovarian Follicular Dominance in Cattle¹

^e Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853 ^f Department of Obstetrics and Gynecology, Stanford University Medical Center, Stanford, California 94305

ABSTRACT

A critical transition in ovarian follicular development is the selection of a dominant follicle, capable of ovulating, from a cohort of synchronously growing antral follicles. However, little is known about mechanisms and factors that regulate the selection and growth of dominant ovarian follicles. We have investigated whether a component of the insulin-like growth factor (IGF) system, namely IGFBP-4 protease, is associated with the establishment of follicular dominance in cattle. IGFBP proteases degrade IGFBPs, freeing IGFs to interact with their receptors. In experiment 1, follicular fluid from preovulatory follicles (n = 4) degraded about 80% of the added recombinant human (rh) IGFBP-4 within 18 h of incubation. The IGFBP-4 protease exhibited optimal activity at neutral/basic pH and its sensitivity to various protease inhibitors suggested a metalloprotease. The decline in the intensity of the band corresponding to intact rhIGFBP-4 was accompanied by the appearance of immunoreactive fragments of molecular weights 18 and 14 kDa, which were not detectable by ligand blot analysis. In experiment 2, follicular fluid samples were collected from dominant and subordinate follicles on Day 2 or 3 of the first follicular wave, after ovariectomy (experiment 2a, n = 3/day) or by ultrasound-guided follicular aspiration (experiment 2b, n = 4–5/day). Estradiol concentrations in follicular fluid from dominant vs. subordinate follicles confirmed their identities and indicated that the dominant follicle had been selected by Day 2 of the follicular wave. In both experiments 2a and 2b, IGFBP-4 proteolytic activity was 2- to 3.5-fold (P < 0.05) and 5-fold (P < 0.01) higher in follicular fluid from dominant than subordinate follicles on Days 2 and 3 of the follicular wave, respectively. The finding that IGFBP-4 proteolytic activity is higher in dominant, estrogen-active follicles than in subordinate follicles of the same cohort, as early as Day 2 of the follicular wave, strongly suggests a role for IGFBP-4 protease in the establishment of ovarian follicular dominance.

FOOTNOTES

First decision: 13 November 2000.

¹ Supported by National Institutes of Health grants HD38276 to J.E.F. and HD31579 to L.C.G., a Lalor Foundation Fellowship to Y.A.C., and a Fulbright-Universidad Nacional de Río Cuarto (Argentina) Fellowship to G.M.R.

² Correspondence: J.E. Fortune, Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853. FAX: 607 253 3476;jf11{at}cornell.edu

³ Current address: ZymoGenetics, 1201 Eastlake Avenue East, Seattle, WA 98102.

⁴ Current address: Department of Animal Science and Production, University College Dublin, Dublin 4, Ireland.

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