Involvement of growth hormone (GH) and insulin-like growth factor (IGF) system in ovarian folliculogenesis

Abstract

During the last decade, involvement of growth hormone (GH), insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in ovarian folliculogenesis has been extensively studied. This review provides an update on the GH, IGF system and their role in ovarian follicular development. In vitro studies and knockout experiments demonstrated an important role of GH in preantral follicle growth and differentiation through their binding with GH receptors, which are located both in the oocyte and follicular somatic tissues. Furthermore, GH stimulates the development of small antral follicles to gonadotrophin-dependent stages, as well as maturation of oocytes. With regard to the IGF system, IGF-I has no effects on primordial follicle development, but both IGF-I and IGF-II stimulate growth of secondary follicles. Depending on the species studies and method used, these proteins have been detected in oocytes and/or somatic cells. In antral follicles, these IGFs stimulate granulosa cell proliferation and steroidogenesis in most mammals. The bioavailability of IGFs is regulated by a family of intrafollicular expressed IGF binding proteins (IGFBPs). Facilitation of IGF can be increased through the activity of specific IGFBP proteases, which degrade the IGF/IGFBP complex, resulting in the production of IGFBP fragments and release of attached IGF.

Introduction

Fully mature oocytes are the survivors of the long selection process of folliculogenesis; they are able to undergo fertilization and embryonic development, leading eventually to offspring [1]. However, the great majority of the thousands of oocytes enclosed in small antral follicles do not reach ovulation, but undergo atresia before reaching maturation. To increase ovulation rates for embryo production, techniques such as superovulation are currently used in farm animals. To this end, follicular development is stimulated by administration of gonadotrophins, followed by an induced LH surge to promote oocyte maturation. These oocytes are then fertilized in vivo and the blastocysts used for embryo transfer. Another current technique is in vitro maturation (IVM) of oocytes collected from small antral follicles by ovum pickup. After IVM, oocytes are fertilized in vitro and zygotes are cultured to the blastocyst stage.

Preantral follicles, which in our definition include primordial, primary and secondary follicles, form a far larger oocyte reservoir, as compared to the small population of antral follicles. It is therefore attractive to exploit the reservoir of preantral follicles to obtain a large number of fertilizable oocytes for embryo production. In addition to commercial purposes in farm animals, the use of cryopreserved preantral follicles may be of great importance for saving endangered animal species. However, most knowledge regarding the developmental conditions of follicles and their oocytes is hitherto restricted to the antral follicle stage, whereas events occurring during early folliculogenesis still need to be more extensively explored. Since development of primordial to early antral follicles is not dependent on gonadotrophins [2], during the last decade, the role of locally produced growth factors in ovarian folliculogenesis has been extensively studied in mammals, especially rodents. There is a growing body of evidence that growth hormone (GH) [3], [4] and members of the insulin-like growth factor (IGF) family system [5], [6] play a key role both in the development of preantral to preovulatory follicles and in the process of follicular atresia. Growth hormone exerts direct and/or indirect effects on virtually every organ in the body, with IGF-I mediating indirect actions of GH. In the ovary, there is considerable evidence that GH, as well as systemic and locally produced IGF-I, can modulate folliculogenesis.

This review focuses on the role of GH and IGF family members in the regulation of ovarian folliculogenesis in mammals, especially cattle, sheep, goats, horses, humans, and mice. Consequently, fundamental information on these proteins, their receptors, their expression in the ovary, and ovarian follicular development, will be discussed.