Judith S. Mondschein

The ovarian insulin-like growth factors, a local amplification mechanism for steroidogenesis and hormone action

The importance of the ovarian insulin-like growth factors (IGFs) has been suggested by data from numerous laboratories and several approaches in the last several years. In the aggregate, these data indicate that this system could function as an important local amplification mechanism for steroidogenesis and gonadotropin action. Studies supporting this hypothesis have described several interacting components of this autocrine/paracrine system. First, the several types of ovarian cells possess an IGF-response system, which includes receptors for IGFs and an effective intracellular transduction system. The IGFs can promote growth and/or differentiation of ovarian cells, and their predominant actions depend on the nature of the cells and the presence of additional modulating factors. The biochemical events leading to enhanced steroidogenesis are now understood in considerable detail and include induction of several steps in the cAMP-dependent steroidogenic cascade. The second component of the ovarian IGF system comprises hormone-responsive local production of IGFs. Both IGF-I and IGF-II may be secreted; gonadotropins, gonadal steroids and locally produced growth factors can regulate the IGF system at this level. Finally, ovarian cells secrete a heterogeneous and complex family of IGF-binding proteins (IGFBPs). These proteins can impact on multiple ovarian functions in a manner which is generally opposite to that of the IGFs themselves. As is the case for the IGFs, the secretion of these proteins by ovarian cells is regulated by gonadotropins and locally produced ovarian factors. Collectively, these several components provide an integrated, synergistically cooperative local network to promote gonadotropin-dependent growth and differentiation in the ovary.

INTERACTIONS BETWEEN HORMONES AND GROWTH FACTORS IN THE REGULATION OF GRANULOSA CELL DIFFERENTIATION IN VITRO

Evidence from studies in vitro supports the concept that growth factors modulate endocrine-dependent differentiative processes in follicle development. Based upon results from granulosa cell culture systems, it is suggested that the study of growth factors and their regulatory mechanisms (endocrine, paracrine, autocrine control) could perhaps be generalized to other areas concerned with the regulation of steroid secretion such as placental physiology, the regulation of fetal gonads and puberty, secondary steroid metabolism and steroid-secreting tumors.

Characteristics of estrogen-2/4-hydroxylase of porcine ovarian follicles: Influence of steroidal and non-steroidal agents on the activity of the enzyme In vitro

The conversion of [3H]estradiol to 2-hydroxyestradiol (2-OH-E2) by homogenates of porcine ovarian follicles was assayed in vitro in the presence and absence of 10 and 100 microM concentrations of the following potential substrates or inhibitors of estrogen-2/4-hydroxylase (E-2/4-H): (1) estrogens; estrone (E1), estriol (E3) and 17 alpha-estradiol (17 alpha-E2), (2) catecholestrogens; 2-hydroxyestradiol (2-OH-E2), 4-hydroxyestradiol (4-OH-E2) and 2-hydroxyestrone (2-OH-E1); (3) 2-methoxyestradiol (2-MeO-E2); (4) halogenated estrogens; 2-bromoestradiol, (2-Bromo-E2) 4-bromoestradiol and 2,4-dibromoestradiol; (5) androgens; testosterone (T), dihydrotestosterone (DHT) and androstenedione; (6) progesterone; (7) epinephrine; (8) inhibitors of steroid aromatase; aminoglutethimide and 4-hydroxyandrostenedione and (9) SKF 525A, an inhibitor of cytochrome P-450. Progesterone and 2-Bromo-E2 were the two most effective inhibitors (2-OH-E2 formation = 4 and 5% of control at 100 microM and 29.6 and 17.4% at 10 microM of progesterone and 2-Bromo-E2, respectively). 2-MeO-E2 at 100 microM was nearly as effective as progesterone in inhibiting E-2/4-H activity but only caused about 50% inhibition at 10 microM. The three catecholestrogens reduced 2-OH-E2 formation to about the same degree (21-23% of control at 100 microM). The 2,4-dibromo-E2 was equipotent with the catecholestrogens while 4-bromo-E2 was about half as effective. The phenolic estrogens, potential substrates for the enzyme, reduced 2-OH-E2 formation to different degrees, with E3 being the most effective. Among the androgens, DHT was almost as effective an inhibitor as the catecholestrogens, T was about half as effective while androstenedione had no effect. Epinephrine and the two inhibitors of aromatase did not inhibit E-2/4-H activity. SKF 525A inhibited E-2/4-H activity but with a potency only about 1/10th that reported for liver.

Regulation of Granulosa Cell Responsiveness to Gonadotropins: Actions of Epidermal and Platelet-Derived Growth Factors

The concept of pituitary gonadotropins as regulators of follicular and luteal development and function is central to our understanding of ovarian physiology. Patterns of gonadotropin secretion are superimposed upon patterns of target cell gonadotropin receptor levels (Richards and Midgley, 1976). The result of this well-coordinated series of events is a normal estrus or menstrual cycle. Steroid hormones provide a second level of regulation of these processes. As early as 1940 it was observed that estrogen enhanced ovarian responsiveness to gonadotropins (Pencharz, 1940). More recent studies have suggested roles for estrogens , androgens, and progestins in various aspects of ovarian physiology and pathophysiology (McNatty et al., 1979; Louvet et al., 1975; Schomberg, 1979; Schreiber and Hsueh, 1979; and references therein). The observation that growth factors can modulate follicle-stimulating hormone (FSH)-dependent luteinizing hormone (LH) receptor induction in vitro (Mondschein and Schomberg, 1981a) introduced the possibility of a third level of regulation: the growth factors, known primarily for their mitogenic effects on cultured cells, may represent a broad class of compounds which interact with more classic gonadotropic and steroidal mechanisms to determine the course of follicular and luteal development and function.

Insulin-Like Growth Factors and Their Binding Proteins: Ovarian Modulators of FSH Action

The focus of this chapter is the role of the ovarian insulin-like growth factor (IGF) system as an amplification mechanism for FSH action in the ovarian follicle. Recent data from our own laboratory will be emphasized, although numerous investigators have made important contributions to this area. Collectively, these efforts have established the ovarian IGF system as one of the most persuasive and best documented of the putative ovarian paracrine/ autocrine systems. For the purpose of discussion, it is convenient to divide the IGF system into its intracellular transduction mechanism and its extracellular components (Fig. 15.1), each of which is affected by FSH. The current emphasis in our laboratory is on the extracellular components of the IGF system—locally secreted IGFs and their binding proteins—and this emphasis will be reflected in this paper. However, a brief summary of the actions of IGFs on ovarian cells is appropriate.