Animal Reproduccion

Animal Reproduction Science 82–83 (2004) 109–126

Follicular development: the role of the follicular
microenvironment in selection of
the dominant follicle
J.E. Fortune∗ , G.M. Rivera1 , M.Y. Yang
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University,
T6-012B VRT, Ithaca, NY 14853, USA

Abstract
The importance of endocrine signals in the regulation offollicular development has long been
recognized. However, the follicular microenvironment also plays a critical role in determining
follicular fate. This review summarizes our studies on the role of the intrafollicular IGF system in
selection of the dominant follicle (DF) in cattle. During the bovine estrous cycle, the largest antral
follicles develop in two or three successive waves offollicular recruitment and selection of a DF.
High concentrations of estradiol in the follicular fluid are the hallmark of dominant and preovulatory
follicles and are associated with lower concentrations of low molecular weight (MW) insulin-like
growth factor binding proteins (IGFBP-2, -4, and -5), which can prevent binding of IGF to its
receptor. Our studies have shown that dominant and preovulatoryfollicles also have much higher
levels of an IGFBP-4/-5 protease activity, which is the bovine equivalent of the human IGFBP-4
protease, pregnancy-associated plasma protein-A (PAPP-A). Studies of follicles isolated just after
the emergence of the DF showed that PAPP-A is present in the follicular fluid of the DF as soon
as it can be detected as morphologically dominant. To examine whether higherlevels of PAPP-A
in one follicle of the cohort (the future DF) precedes morphological dominance, the four largest
follicles were isolated from pairs of bovine ovaries obtained before one follicle of the cohort was
significantly larger the others, around the time that one follicle was first detected as morphologically
dominant and after dominance was well established. Analysis of the temporalsequence of changes
in estradiol, low MW IGFBPs, free IGF, and PAPP-A in the follicular fluid suggested that an increase
in PAPP-A is the earliest biochemical difference yet detected in the future DF and that follicular
selection is the result of a progressive series of changes beginning with the acquisition of PAPP-A,
which leads to a decrease in IGFBP-4 and -5 and an increase in free IGF, whichsynergizes with
FSH to increase estradiol production. Co-dominant follicles, induced by injection of small doses
of recombinant bovine (rb) FSH, both had levels of PAPP-A similar to the single DF of control
∗ Corresponding author. Tel.: +1-607-253-3466; fax: +1-607-253-3476.
E-mail address: JF11@cornell.edu (J.E. Fortune).
1 Present address: Department of Genetics and Developmental Biology,University of Connecticut Health Center,
Farmington, CT 06030-3301, USA.

0378-4320/$ – see front matter © 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.anireprosci.2004.04.031

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J.E. Fortune et al. / Animal Reproduction Science 82–83 (2004) 109–126

heifers, supporting the hypothesized role of FSH in the induction of PAPP-A in the DF. Taken
together, these results suggest acritical role for FSH-induced PAPP-A, and thus for free IGF, in the
selection of the DF. In contrast, other experiments provided evidence for a deleterious effect of IGF
on the initiation of bovine follicular growth and the survival of primordial and primary follicles in
vitro. These results underscore the importance of the follicular microenvironment in determining
follicular fate andindicate that its effects can be stage-specific.
© 2004 Elsevier B.V. All rights reserved.
Keywords: Ovary; Ovarian follicle; Follicle selection (or dominance); Insulin-like growth factor (IGF); IGF
binding proteins; IGF binding protein protease; Cattle

1. Introduction
The “classical” concept of the regulation of ovarian function was that endocrine factors,
primarily the gonadotropic hormones,...