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Granulosa Cell Differentiation in Rats A Intraovarian mechanisms in the hormonal control of granulosa cell differentiation in rats A. J. W. Hsueh, P. B. C. Jones, E. Y. Adashi, Christina Wang, L.-Z. Zhuang and T. H. Welsh, Jr Department of Reproductive Medicine, M-025, University of California, San Diego, La Jolla, California 92093, U.S.A. Summary. The present review summarizes our studies on the hormonal control of the differentiation of granulosa cells in vitro. Studies on the hormonal regulation of granulosa cell oestrogen and progestagen biosynthesis by various regulatory agents facilitate our understanding of the control processes involved in follicular maturation and luteinization in vivo. This multiple hormonal control mechanism also provides an interesting model for future studies on the diverse mode of hormone action. Introduction Ovarian follicles have been shown to be the basic functional unit of the ovary and consist of an outer layer of theca cells which encircle inner layers of granulosa cells. The granulosa cells, in turn, surround the innermost oocyte-cumulus cell complex. In response to cyclic pituitary gonadotrophin secretion, the various follicular compartments interact in a highly integrated manner to secrete sex steroids (oestrogens and progestagens) and to produce a fertilizable ovum. Ovulation occurs in one of the two ovaries during a given cycle in many species. Although pituitary gonadotrophins (LH, FSH and prolactin) are the major regulators of follicular development (Richards & Midgley, 1976) and the blood concentrations of these hormones perfusing the two ovaries are identical, not all follicles respond to pituitary gonadotrophins during a given cycle. Only a limited number of the 'selected' follicles ovulate during the life span of the females, while most of the follicles become atretic. After ovulation, the granulosa cells undergo profound changes in their hormonal responsiveness and their capacity to produce steroids. These luteinized granulosa cells constitute the major component of the corpora lutea and are the main source of ovarian progestagens. In rats, the follicular granulosa cells transform from an FSH-dominated cell type to a cell type mainly controlled by LH and prolactin. To understand the basis for the disparate maturation of ovarian follicles and the luteinization of maturing granulosa cells, functional and morphological correlates of intraovarian changes in different hormonal environments are required. In the present review, our attempts to elucidate intraovarian control mechanisms during the differentiation of granulosa cells to luteal cells in vitro will be discussed. Since several extensive reviews on the hormonal regulation of granulosa cell functions are available (Channing, 1970; Richards & Midgley, 1976; Bjersing, 1978; Richards, 1979 ; Dorrington & Armstrong, 1979 ; Hillier, Zeleznik, Knazek & Ross, 1980), we do not intend to provide a comprehensive survey of the literature on in-vivo studies concerning the hormonal control of follicle maturation. Instead, we will summarize the results from our laboratory concerning the hormonal regulation of cultured granulosa cells in vitro. 0022-4251 /83/050325-18S02-00/0 © 1983 Journals of Reproduction & Fertility Ltd Downloaded from Bioscientifica.com at 09/30/2021 10:42:11PM via free access Granulosa cell differentiation: induction of hormonal responsiveness in vitro To study the hormonal control of the functions of granulosa cells during a given stage of development in a defined experimental condition, it is necessary to synchronize the maturation of a large group of follicles to obtain a homogeneous population of granulosa cells as well as to establish a functional culture system for in-vitro studies. An experimental model was set up to yield large numbers of relatively undifferentiated granulosa cells from preantral follicles of immature hypophysectomized rats implanted with oestrogen (diethylstilboestrol or oestradiol) capsules (Richards & Midgley, 1976; Hillier et al., 1980). Hypophysectomy eliminates possible influences of endogenous gonadotrophins on ovarian granulosa cells while treatment with oestrogens enhances the proliferation of granulosa cells. The follicular granulosa cells are completely separated from blood vessels and other cell types by the basement membrane lining the follicle; hence, it is relatively easy to isolate pure granulosa cells. Bjersing & Carstensen (1964) performed short-term incubation of granulosa cells and demonstrated the steroidogenic capacity of these cells in vitro. Several groups further modified this procedure and cultured the 'pure' granulosa cells in serum-containing medium to study progestagen biosynthesis (Channing, 1970). Rat granulosa cells cultured in serum-containing media, however, do not respond to gonadotrophins by the induction of aromatases or gonadotrophin receptors (Nimrod, Tsafriri & Lindner, 1977). This is presumably due to the presence of uncharacterized serum inhibitory factors, e.g. epidermal growth factor (Hsueh, Welsh & Jones, 1981), which interfere with FSH action. Further improvement of the culture conditions was achieved by use of serum-free culture conditions. Primary cultures of granulosa cells maintained in serum-free medium retain hormonal responsiveness in vitro (Dorrington, Moon & Armstrong, 1975; Erickson & Hsueh, 1978a) and undergo hormonal differentiation in a way similar to that in vivo. The preantral follicles obtained from immature hypophysectomized, oestrogen-treated rats contain multiple layers of granulosa cells and a fully grown oocyte which is arrested in the dictyate stage of meiotic prophase. These granulosa cells possess cell membrane receptors for FSH and intracellular receptors for oestrogen, androgen and other steroids (Richards, 1975, 1979 ; Schreiber & Ross, 1976; Schreiber & Hsueh, 1979). In response to FSH treatment in vitro, the granulosa cells luteinize to become cells resembling those obtained from mature antral follicles and the corpus luteum. The maturation and differentiation of the cultured granulosa cells to 'granulosa-luteal' cells is accompanied by sequential acquisition of hormone receptors and profound changes in the hormonal responsiveness of these cells. We have studied the in-vitro differentiation of granulosa cells to 'granulosa-luteal' cells by investigating changes in hormone receptor content using radioligand receptor assay. We also studied the hormonal regulation of the steroidogenic capacity of these cells by measuring oestrogen and progestagen biosynthesis. In the primary cultures of granulosa cells, treatment with FSH and A4-androstenedione increases the formation of oestrogen, progesterone and 20a-dihydroprogesterone (Wang, Hsueh & Erickson, 1979). These cultured cells contain all the necessary enzymes for de-novo biosynthesis of progesterone by the cholesterol—pregnenolone biosynthetic pathway (Text-fig. 1). FSH treatment presumably increases cholesterol through de-novo synthesis or enhanced utilization of serum lipoproteins. This is accompanied by increases in the activities of cholesterol side-chain cleavage enzymes (which convert cholesterol to pregnenolone) in the mitochondria and 3ß-hydroxysteroid dehydrogenase (3ß-HSD)/A5-A4-isomerase (which converts pregnenolone to progesterone) in the microsomal fraction (Jones & Hsueh, 1982a, b). Since isomerase activity appears to be in excess, production of progesterone from pregnenolone is mainly regulated by 3ß-HSD. The bioactive progesterone may be further metabolized by 20a-hydroxysteroid dehydrogenase (20a-HSD) to a much less active progestagen, 20a-dihydroprogesterone. In contrast to theca cells, granulosa cells possess negligible concentrations of 17a-hydroxylase or 17-20 desmolase to convert progestagens into androgens. Treatment of granulosa cells with FSH, Downloaded from Bioscientifica.com at 09/30/2021 10:42:11PM via free access CELL MEMBRANE CHOLESTEROL MITOCHONDRIA ESTER SMOOTH ENDOPLASMIC RETICULUM £> CHOLESTEROL ^> CHOLESTEROL ^> PREGNENOLONE ^> PREGNENOLONE^ ^ZJJJO^ li 20 - - ±= PROGESTERONE__EST_ ACETATE ._ CHOLESTEROL & other : i> BIOSYNTHESIS • - », substrates ANDROGENS ESTROGENS Text-fig. 1. The steroidogenic pathway involved in progestagen and oestrogen biosynthesis in the granulosa cell. 20a-OH-P = 20a-dihydroprogesterone. however, induces high concentrations of aromatase enzymes which convert androgens to oestrogens (Text-fig. 1). Furthermore, granulosa cells also contain 17ß-hydroxysteroid dehydrogen¬ ase which converts androstenedione to testosterone or oestrone to oestradiol. In most studies described below, androstenedione was added to the culture medium to serve as the substrate for aromatases and the production of total oestrogens was measured. In addition to its role as aromatase substrate, androgens have also been shown to augment FSH-stimulated progestagen production through an androgen receptor-mediated mechanism (Daniel & Armstrong, 1980; Hillier & deZwart, 1981). In contrast to the stimulatory actions of FSH, treatment of granulosa cells from preantral follicles with LH/hCG, prolactin or adrenergic agents does not enhance oestrogen or progestagen biosynthesis (Wang et al., 1979). In addition, radioligand receptor studies also demonstrate a low concentration of receptors for LH/hCG (Erickson, Wang & Hsueh, 1979) or prolactin (Navickis, Jones & Hsueh, 1982) in these cells. However, FSH treatment of granulosa cells for 2 days in vitro increases the concentration of LH and prolactin receptors and the induction of receptors for these peptide hormones is accompanied by an enhancement
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