Steroid levels and the spatiotemporal expression of steroidogenic enzymes and androgen receptor in developing ovaries of immature rats (original) (raw)
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Immunoexpression of 3β-hydroxysteroid dehydrogenase (3β-HSD), cytochrome P450c17 (P450c17), androgen receptor (AR), and steroid contents were studied in the ovaries of immature female Wistar rats killed between postnatal days 1 and 30. During days 1-7, ovarian somatic structures lacked AR, 3β-HSD and P450c17, except for the surface epithelium, which featured the presence of these three proteins, suggestive of its androgen responsiveness and steroidogenic function. On day 10, AR appeared in many somatic structures, including the granulosa layers, which coincided with the P450c17 immunoexpression in some theca/interstitial cells, and an increase in ovarian androgen concentration. On the following days a further rise in ovarian androgen and progesterone contents paralleled an increase in 3β-HSD and P450c17 immunoexpression in the theca layer cells and primary interstitial cells. However, the development of the follicles constituting the first follicular wave was aberrant, since they la...
Biology of Reproduction, 1993
In the adult ovary, cohorts of growing follicles are continuously generated, from which dominant follicles are selected during each estrous cycle. To compensate for the rapid proliferation of follicular cells in the growing pool of follicles, follicles are eliminated by atresia, thereby maintaining ovarian tissue mass. Estrogens and androgens have been implicated as intraovarian regulators of follicular growth and atresia, suggesting that the fate of an individual follicle to develop to the preovulatory stage or to undergo atresia is associated with distinct profiles of steroid production. We therefore have localized 3-hydroxysteroid dehydrogenase (3-HSD), an enzyme required for the biosynthesis of all major steroid hormones, in ovaries of immature and adult rats during follicular development, atresia, and corpus luteum formation. The pattern of immunostaining for 3-HSD remained constant in the interstitial cell compartment and was not affected by the age of the rats nor the stage of the estrous cycle. As thecal cells differentiated from the surrounding stroma and restructured around the secondary follicle, they expressed intense staining for 3-HSD. This staining persisted in preantral, antral, and preovulatory follicles. Granulosa cells in primary, secondary, and antral follicles did not contain detectable levels of 3-HSD and did not stain positively until the follicle reached the preovulatory stage of development. A novel finding presented in this paper is that 3-HSD persisted in the thecal cells of follicles throughout the entire process of atresia, suggesting that during atresia the potential for the synthesis of androgens is retained. These observations, together with the previous reports that anti-androgens rescue follicles from atresia induced by hCG, indicate that thecal cell-derived androgens may be involved in the regulation of follicular dynamics.
Steroids, 2002
In the present paper, we report that injection of testosterone propionate (500 g) during the critical window of rat development (postnatal day 5) induces temporary appearance of aged interstitial cells in developing ovaries (days 7 and 10). Aged interstitial cells showed large size (Ն 12 m), enhanced androgen receptor (AR) and low estrogen (ER) and luteinizing hormone receptor (LHR) expression. Although normal mature interstitial cells (large size and strong ER and LHR expression) appeared later (day 14), and ovaries of androgenized rats were similar to normal ovaries between days 14 and 35, ovaries of adult androgenized females showed only aged and no mature interstitial cells. Androgenization on day 10 caused the development of aged interstitial cells on day 14, but adult ovaries were normal. Long lasting postnatal estrogenization (estradiol dipropionate for four postnatal weeks) caused in developing and adult ovaries a lack of interstitial cell development beyond the immature state. Immature interstitial cells were characterized by a small size (Յ 7 m) and a lack of AR, ER and LHR expression. Because the critical window for steroid-induced sterility coincides with the termination of immune adaptation, we also investigated distribution of mesenchymal cells (Thy-1 mast cells and pericytes, ED1 monocyte-derived cells, CD8 T cells, and cells expressing OX-62 of dendritic cells) in developing and adult ovaries. Developing ovaries of normal, androgenized and estrogenized females were populated by similar mesenchymal cells, regardless of differences in the state of differentiation of interstitial cells. However, mesenchymal cells in adult ovaries showed distinct behavior. In normal adult ovaries, differentiation of mature interstitial cells was accompanied by differentiation of mesenchymal cells. Aged interstitial cells in ovaries of androgenized rats showed precipitous degeneration of resident mesenchymal cells. Immature interstitial cells in ovaries of estrogenized rats showed a lack of differentiation of resident mesenchymal cells. These observations indicate that an alteration of interstitial cell differentiation during immune adaptation toward the aged phenotype results in precipitous degeneration of resident mesenchymal cells and premature aging of ovaries in adult rats, and alteration toward immature phenotype results in a lack of differentiation of mesenchymal cells and permanent immaturity of ovaries in adult females.
Faseb Journal, 2007
Investigators have long postulated that granulosa cell-derived estrogens modulate thecal cell steroidogenesis via a short negative-feedback loop within the follicle. To test this hypothesis, we assessed the steroidogenic capacity of individual wild-type (WT) and estrogen receptor-␣ (ER␣)-null follicles when cultured in vitro under comparable conditions. Late-stage ER␣-null follicles exhibited markedly increased expression of the thecal cell enzyme CYP17A1 and secreted much greater amounts of its end product, androstenedione. This phenotype was reproduced in WT follicles when exposed to an aromatase inhibitor or ER-antagonist, and prevented when the former treatment was supplemented with an ER␣-specific agonist. ER␣-null follicles also exhibited increased testosterone synthesis due to ectopic expression of hydroxysteroid (17) dehydrogenase type 3 (HSD17B3), a testis-specific androgenic enzyme. These data indicate that ER␣ functions within thecal cells to negatively modulate the capacity for androgen synthesis by repressing Cyp17a1 expression, and the biological activity of androgens produced by inhibiting Hsd17b3 expression. Hence, these findings provide novel evidence of an intraovarian ER␣ function that may be critical to the latter stages of folliculogenesis and overall ovarian function.- , F., Couse, J. F., Rodriguez, K. F., Emmen, J. M. A., Poirier. D., Korach, K. S. Estrogen receptor-␣ mediates an intraovarian negative feedback loop on thecal cell steroidogenesis via modulation of CYP17A1 (cytochrome P450, steroid 17␣-hydroxylase/17,20 lyase) expression FASEB J. 21, 586 -595 (2007) Key Words: hydroxysteroid (17) dehydrogenase ⅐ hyperandrogenemia ⅐ folliculogenesis ⅐ aromatase 1 These authors contributed equally to this work.
Biology of Reproduction, 1993
In the adult ovary, cohorts of growing follicles are continuously generated, from which dominant follicles are selected during each estrous cycle. To compensate for the rapid proliferation of follicular cells in the growing pool of follicles, follicles are eliminated by atresia, thereby maintaining ovarian tissue mass. Estrogens and androgens have been implicated as intraovarian regulators of follicular growth and atresia, suggesting that the fate of an individual follicle to develop to the preovulatory stage or to undergo atresia is associated with distinct profiles of steroid production. We therefore have localized 3-hydroxysteroid dehydrogenase (3-HSD), an enzyme required for the biosynthesis of all major steroid hormones, in ovaries of immature and adult rats during follicular development, atresia, and corpus luteum formation. The pattern of immunostaining for 3-HSD remained constant in the interstitial cell compartment and was not affected by the age of the rats nor the stage of the estrous cycle. As thecal cells differentiated from the surrounding stroma and restructured around the secondary follicle, they expressed intense staining for 3-HSD. This staining persisted in preantral, antral, and preovulatory follicles. Granulosa cells in primary, secondary, and antral follicles did not contain detectable levels of 3-HSD and did not stain positively until the follicle reached the preovulatory stage of development. A novel finding presented in this paper is that 3-HSD persisted in the thecal cells of follicles throughout the entire process of atresia, suggesting that during atresia the potential for the synthesis of androgens is retained. These observations, together with the previous reports that anti-androgens rescue follicles from atresia induced by hCG, indicate that thecal cell-derived androgens may be involved in the regulation of follicular dynamics.
A shift in steroidogenesis occurring in ovarian follicles prior to oocyte maturation
Molecular and Cellular Endocrinology, 2004
Gonadotropins (GTHs; FSH and LH) require two major steroidal mediators, estradiol-17 (E 2 ) and 17␣,20-dihydroxy-4-pregnen-3-one (17␣,20-DP) to act as critical hormones to execute oocyte growth and maturation, respectively. A two-cell type model has been proposed, where the theca cells provide the precursor steroids, and the granulosa cells produce the two steroidal mediators under the direct influence of FSH and LH. A distinct shift in steroidogenesis, i.e. from E 2 to 17␣,20-DP as well as the steroidogenic enzyme genes from ovarian cytochrome P450 aromatase (oP450arom) to 20-hydroxysteroid dehydrogenase (20-HSD), occurs in the granulosa layers of ovarian follicles prior to oocyte maturation. The triggering of the steroidogenic shift by GTHs in granulosa cells occurs through the subjugation of Ad4BP/SF-1 expression in respect of oP450arom, followed by an over-expression of 20-HSD probably through the CREB. maturation with other vertebrates, including mammals. The main focus of this article will be the steroidogenic shift with a brief outline on oocyte growth and maturation.
Molecular and Cellular Endocrinology, 2009
Ovulation-associated inflammation with accompanied cytokines and reproductive hormones impact upon the human ovarian surface epithelium (hOSE) and probably have a role in the aetiology of ovarian cancer. Progesterone and progestin-related events, i.e. pregnancy and oral contraception, protect from the disease. We have investigated the pre-receptor metabolism of progesterone in primary hOSE cells and an immortalised hOSE cell line, OSE-C2, focusing on transcriptional regulation of 3-hydroxysteroid dehydrogenase (3-HSD) by inflammatory, anti-inflammatory and apoptotic factors. In hOSE cells, we show that anti-inflammatory effects of IL-1␣ and IL-4 on 3-HSD2 mRNA involve a p38 MAPK signalling pathway, whereas pro-inflammatory response of IL-1␣ to 3-HSD1 mRNA involves a NF-B inflammatory pathway. In OSE-C2 cells, retinoic acid and transforming growth factor-1 massively induce 3-HSD1 mRNA levels. In conclusion, we elaborate several mechanisms for intracrine formation of progesterone in hOSE that could contribute in the development of novel strategies to prevent, diagnose and/or treat ovarian cancer.
Molecular and Cellular Endocrinology, 1993
In situ hybridization and immunohistochemical localization of cytochrome P450 cholesterol side-chain cleavage (P45Oscc), 3&hydroxysteroid dehydrogenase (3/3HSD), cytochrome P450 17a-hydroxylase (P45Oc17) and cytochrome P450 aromatase (P45Oarom) was performed in 50 mo~hologically normal human premenopausal ovaries, and correlated these findings with their endometrial phase. In general, mRNA expression of these enzymes examined by in situ hybridization were in good agreement with immunolocalization examined by immunohistochemistry. Expression of P45Oscc, 3PHSD and P45Oc17 was observed in large-sized preantral follicles, consisting of more than five layers of granulosa cells, preovulatory follicles, corpora lutea, and some degenerating corpora lutea and atretic follicles in all endometrial phases. Several folhcies and/or corpora lutea positive for these enzymes were observed in the same ovary. Expression of P45Oarom was generally observed in only one follicle fantral or preovulatory follicle) or corpus luteum per case in mid proliferative to premenstrual phase, and was not observed in menstrual to early proliferative phase. These findings indicated that (1) expression of steroidogenic enzymes was associated with the continual human ovarian process including follicular development and atresia, and (2) especially, P450arom expression may occur only in a selected antral follicle and may have an important role in dominant follicular development.