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Endocrinology Vol. 138, No. 11 4572-4576
Copyright © 1997 by The Endocrine Society

ARTICLES

Paradoxical Action of Activin A on Folliculogenesis in Immature and Adult Mice

Hidemi Yokota, Kiyohiko Yamada, Xiaowei Liu, Junro Kobayashi, Yumiko Abe, Hideki Mizunuma and Yoshito Ibuki

Department of Obstetrics and Gynecology, Gunma University School of Medicine, Maebashi, Gunma 371, Japan

Address all correspondence and requests for reprints to: Hideki Mizunuma, Department of Obstetrics and Gynecology, Gunma University School of Medicine, 3–39-22, Showa-machi, Maebashi, Gunma 371, Japan. E-mail: mizunuma{at}news.sb.gunma-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Activin A is a gonadal protein originally isolated from follicular fluid and is recognized as a local regulator of granulosa cell differentiation. Whether activin A promotes folliculogenesis, however, still remains unclarified. The present study was designed to elucidate the effect of activin A on follicular growth in in vitro follicle culture systems. Preantral follicles, 100–120 µm in diameter, were mechanically isolated from BDF1 hybrid immature mice (11 days old) and adult mice (8 weeks old), then cultured for 4 days in a serum-free medium supplemented with activin A (100 ng/ml), FSH (100 mIU/ml), and a combination of both. Follicular diameter was measured daily, and the amount of estradiol and inhibin released at day 4 was determined by RIA. Preantral follicles collected from immature mice showed a significant increase in diameter when cultured with activin A or both activin A and FSH. FSH alone showed no significant effect on the diameter of follicles from immature mice. In contrast, the diameter of preantral follicles from adult mice significantly increased in response to FSH. Activin A did not stimulate growth of follicles from adult mice, and more interestingly, blocked the effect of FSH. The inhibitory action of activin A was in part restored by co-culture with follistatin (100 ng/ml). These results indicate that activin A is folliculogenetic in the prepubertal mouse, but not in adults.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ACTIVIN A, a gonadal protein, is a homodimer composed of two ß-subunits of inhibin, which is a heterodimer glycoprotein consisting of an {alpha}-subunit and one of two ß-subunits (ß A and ß B) (1). Both activin A and inhibin have been isolated and purified from mammalian follicular fluid (2, 3). Activin A is composed of two ß A-subunits and was later shown to have the same structure as the erythroid differentiation factor (EDF) (2, 4). There is increasing evidence that activin A locally modulates granulosa cell function. Activin A enhances FSH-induced aromatase activity (5, 6, 7), LH binding sites (8), and progesterone production (5, 6, 7, 8) in cultured granulosa cells obtained from estrogen-treated immature rats. In addition, activin A stimulates FSH-induced inhibin production (6, 8, 9) and follistatin messenger RNA (10) in rat granulosa cells in vitro. One of the mechanisms of activin A action is to stimulate FSH receptor formation (11, 12), and indeed increased FSH messenger RNA levels by activin A treatment have been reported (6, 7). These in vitro observations are consistent with activin A as a local regulator that promotes differentiation of granulosa cells, but whether activin A is involved in folliculogenesis remains unclarified.

Folliculogenesis is a process of follicular growth characterized by morphological changes accompanied by functional development. Most in vitro studies using the granulosa cell-culture system have shown the functional aspect but have failed to prove the morphological one (2, 13). More recently, Li et al. (14) demonstrated that activin A stimulates morphological and structural changes in granulosa cell-oocyte complexes obtained from immature rats. The granulosa cell-oocyte complexes, however, are not complete follicles as they do not have a theca layer and it is shown that there are distinctive differences between cumulus cells and peripheral membrana granulosa cells (15). To overcome these inherent problems in granulosa cell culture or the granulosa cell-oocyte complexes culture system, an in vitro enclosed follicle culture system has been developed (16). The present study aimed to clarify the effect of activin A on follicular growth in the early stages in immature and adult mice by using an in vitro follicular culture system.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Chemicals
Recombinant human FSH (rhFSH) was obtained from Organon (Oss, The Netherlands). Recombinant human activin A (rh activin A) was prepared as described previously (17). Recombinant human follistatin was obtained from the National Hormone and Pituitary Program, NIDDK. All other chemicals were of analytical grade or the highest quality commercially available.

Animals
Female BDF1 hybrid mice were purchased from Japan Charles River Inc. (Tokyo, Japan) and housed in a temperature and light-controlled room with a 14-h light, 10-h dark photoperiod in accordance with the principles of the Animal Science Center of the Gunma University School of Medicine. Food and water were given ad libitum. Eight-week-old and 11-day-old female mice were killed for the experiments.

Follicle culture
Preantral follicle cultures were prepared according to Nayudu et al. (16) with modifications. Ovaries were aseptically removed from 8-week-old or 11-day-old mice and placed in 30-mm-diameter Falcon plastic Petri dishes filled with DMEM (GIBCO BRL, Tokyo, Japan). After removing the surrounding tissue, the ovaries were microdissected under a stereo microscope using 27-gauge needles attached to 1-ml syringes. Preantral follicles 100–120 µm in diameter were isolated, visually collected, and transferred into a serum-free DMEM supplemented with 6.25 µg/ml of insulin, 6.25 µg/ml of transferrin, 6.25 ng/ml of selenious acid, 5.35 µg/ml of linoleic acid, 0.15% BSA, 15 mM HEPES, 45 µg/ml of penicillin G, 350 µg/ml of streptomycin, and 1.75 µg/ml of amphotericin B. Special care was taken to retain a layer of the basal lamina, thecal cells, and some stromal cells around the isolated follicles. The criteria used for acceptable quality were a central spherical oocyte, a high density of granulosa cells, and a distinct basal lamina with theca layer. Histological examination of the isolated follicles revealed that a layer of thecal cells was partially preserved. The follicles were transferred as rapidly as possible to 15-mm polystyrene dishes (FALCON, Lincoln Park, NJ) containing 1.0 ml of the culture medium. Ten follicles per dish were incubated in a humidified chamber with 5% CO2 in air at 37 C for 4 days. Hormones were added on day 0 in the indicated concentrations and combinations.

Measurements
Two-dimensional maximum and minimum lengths of each follicle were measured daily with an inverted microscope. The mean diameter of the follicle was calculated by averaging these two measurements.

Inhibin concentrations were measured by double antibody RIA using rabbit antiserum against bovine follicular fluid inhibin as described previously (18). Estradiol concentrations were determined by direct RIA using antiestradiol antiserum kindly supplied by Dr. W. F. Crowley, Jr. (19) and a radioactive tracer of oestradiol-6-(O-carboxymethyl)oximino-(2-[125I)iodohistamine) (Amersham, Buckinghamshire, UK). The intraassay coefficients of variation of the inhibin and estradiol RIA were 2.8% and 2.6%, respectively.

Statistics
Results are expressed as mean ± SE. Differences between means of follicular diameters were analyzed by the chi-square method followed by Scheffé’s F test. Differences between means of hormone levels were analyzed by a nonparametric method by using the Kruskall-Wallis test. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Figure 1Go shows the photographic appearance of a preantral follicle from an immature mouse after 4 days of culture in the presence of activin A (100 ng/ml) and rhFSH (100 mIU/ml). On day 0 of culture, the follicle had a central spherical oocyte surrounded by several layers of granulosa cells. On day 4, they had increased in size with a growing oocyte surrounded by an increased number of granulosa cell layers, indicating that activin A and rhFSH treatment had stimulated follicular growth in this culture system.



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  		Figure 1. Morphological changes in a preantral follicle of an immature mouse cultured for 4 days in the presence of 100 ng/ml of activin A and FSH. Top, Follicle at day 0 of culture. Bottom, Follicle at day 4.

 
Figure 2Go shows changes in the diameter of follicles cultured with activin A (100 ng/ml), rhFSH (100 mIU/ml), and a combination of both. Control follicles were cultured with the medium alone. The upper graph presents the changes in follicular diameter from immature mice (11 days old), whereas the lower one presents the changes in follicles from adult mice (8 weeks old). As shown in both graphs, preantral follicles cultured in medium alone showed no increase in size during the 4-day period. Preantral follicles from immature mice showed a progressive increase in size in response to activin A treatment, and the difference from the control was significant from day 1 (P < 0.05–0.0001). FSH alone did not increase the size of follicles from immature mice but had a synergistic effect with activin A. The size of preantral follicles from immature mice cultured in the presence of both activin A and FSH was nearly twice that of the control on day 4. On the other hand, as shown in the lower graph in Fig. 2Go, preantral follicles from adult mice showed no increase in diameter in response to activin A but showed a significant increase due to the addition of FSH (P < 0.0001). The stimulatory effect of FSH, however, was completely blocked by cotreatment with activin A, but this was partially antagonized by adding follistatin, an activin A binding protein, at a dose of 100 ng/ml (Fig. 3Go).



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  		Figure 2. Changes in the diameter of preantral follicles from immature mice (top) and adult mice (bottom). Preantral follicles were cultured for 4 days with medium alone (control), rhFSH (100 mIU/ml), activin A (100 ng/ml), and rhFSH + activin A. Follicular growth was checked daily, and degenerated follicles were removed. ( ) = Number of follicles.

 


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  		Figure 3. Effect of follistatin on the growth of preantral follicles from adult mice. Preantral follicles were cultured for 4 days with medium alone (control), rhFSH (100 mIU/ml), rhFSH (100 mIU/ml) + activin A (100 ng/ml), and rhFSH (100 mIU/ml) + activin A (100 ng/ml) + follistatin (100 ng/ml).

 
As shown in Table 1Go, activin A treatment significantly increased estradiol and inhibin secretion by follicles obtained from immature mice but not from adult mice. After FSH treatment, however, there was no significant increase in estradiol or inhibin secretion by follicles from immature mice, but a significant increase in estradiol and inhibin secretion by follicles from adult mice was found. The stimulatory effect of FSH on estradiol and inhibin secretion by follicles from adult mice was completely blocked by the coadministration of activin A. The inhibitory action of activin A was partially antagonized by treatment with follistatin.


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  		Table 1. Estradiol and Inhibin secretion by 10 follicles/dish after 4 days culture

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The follicle population used in this study is the primary follicle consisting of an oocyte surrounded by several layers of follicle cells and the theca layer. These components are necessary for follicular development and are interactive (20), and folliculogenesis cannot be reproduced in a physiological manner in the absence of one or more component. Such an in vitro enclosed follicle culture system is a better method for elucidating and understanding folliculogenesis (16, 21, 22). Folliculogenesis is a series of physiological events defined by morphological and functional changes of the follicle. Of these events, antrum formation is considered the milestone of folliculogenesis, and a number of attempts have been made to produce antrum formation from preantral follicles, with limited success (16, 21, 22).

The growth of follicles after antrum formation is undoubtedly regulated by the pituitary gonadotropin FSH (23), but the answer to the basic question of whether FSH is involved in early folliculogenesis, up to the antrum formation stage, is as yet unclarified. Peters et al. (24) have demonstrated that the initiation of follicle growth is not dependent on FSH because elevated FSH levels by unilateral ovariectomy of 2-day-old mice do not change the number of normal developing follicles. The fact that estrogen treatment increases the number of preantral and small antral follicles in the hypophysectomized mouse further supports that follicular growth up to antrum formation is controlled by factors other than FSH (25). After a comprehensive review of the literature, Greenwald et al. (23) described follicular growth and cast doubt on the hypothesis that FSH is unnecessary for early follicle growth. Using an in vitro follicle culture system, Roy et al. (21) have shown that FSH induces antrum formation in preantral follicles collected from adult hamsters. Nayudu et al. (16) have succeeded in inducing antrum formation with FSH in a dose-related manner in an in vitro follicle culture system using preantral follicles from 25-day-old mice, but their culture medium contained 5% mouse serum and an insulin-like growth factor.

As shown in Fig. 2Go and Table 1Go, activin A produced a significant increase in follicular size, indicating that activin A is a local regulator that stimulates folliculogenesis in the preantral follicles from immature mice. However, FSH alone did not have such an effect on preantral follicles from immature mice, but instead had a synergistic effect with activin A. These results were consistent with those of Li et al. (14), who demonstrated that activin A, and not FSH, stimulates morphological changes in the granulosa cell-oocyte complexes obtained from 14-day-old mice. The increase in estradiol and inhibin secretion indicates that activin A promoted the functional development of cultured follicles as well. It has been shown that activin A induces FSH receptors in in vivo (26) and in in vitro granulosa cell culture system of estrogen-pretreated immature rats (11). Therefore, it is suggested that the synergistic effect of activin A and FSH may be mediated by the effect of activin A to increase a number of FSH receptors in the preantral follicle as well as to stimulate the differentiation of the follicle cells. On the other hand, FSH can induce its own receptors in granulosa cells (13, 26, 27), but whether this action of FSH is a direct effect or because of other factors such as activin A, still remains unclarified.

Compatible with previous reports using follicles from adult hamsters (21), FSH stimulated follicular growth in adult mice. However, there was a marked contrast between the growth of follicles from adult mice and immature mice. Unlike preantral follicles from immature mice, those from adult mice did not show an increase in size in response to activin A, nor in the secretion of estradiol and inhibin. Moreover, preantral follicles from adult mice showed a significant increase as a result of FSH supplementation. Of particular interest is the effect of FSH, which was completely blocked by cotreatment with activin A. Because the inhibitory effect of activin A was in part restored by follistatin administration, the effect is unlikely to be caused by the loss of viability of the collected follicles. The possibility that activin A may have atretogenic actions on follicular development has been suggested by Woodruff et al. (27) by an in vitro study using 25-day-old rats. Their experimental design consisted of unilateral intrabursal injection of activin A into one ovary, with the other ovary serving as the uninjected control. Administration of activin A resulted in minimal follicular development with an increase in the number of atretic follicles in all size classes and completely blocked the action of systemic PMSG administration.

We cannot explain the difference in response between immature and adult follicles mechanistically at this time, but we suspect that the stage-specific sequences of follicular environment may be involved in the behavior of preantral follicles. More follicles start to grow per day in the immature mouse (28) and rat (29) than in older animals, probably due to high levels of FSH in the prepubertal rodent. Most follicles in the ovary of the immature mouse (11 days old) are at the preantral stage, whereas large follicles have already differentiated by 21 days of age (29). FSH receptors are expressed in the preantral follicles of adult rats (30), and the follicles from adult animals are repeatedly exposed to cyclic changes in gonadotropins, estrogen, and progesterone. The effect of underlying differences in follicular environment on follicular development remains to be clarified.

In conclusion, the present study has demonstrated that activin A stimulates folliculogenesis of enclosed preantral follicles from immature mice, but that FSH only has a synergistic effect with activin A. In addition, FSH showed folliculogenetic activity in the preantral follicles of adult mice, and activin A blocked the action of FSH. The mechanisms of these phenomena remain unclarified, but our study has shown that activin A has a paradoxical action on follicular development.


   Acknowledgments
 
We are grateful to Dr. Y. Eto (Ajinomoto Company, Japan) for his kind gift of rh-activin A. We also thank Miss Y. Hayashi for her assistance.

Received May 19, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  3. Murata M, Eto Y, Shibai H, Sakai M, Muramatsu M 1988 Erythroid differentiation factor is encoded by the same mRNA as that of the inhibin beta A chain. Proc Natl Acad Sci USA 85:2434–2438[Abstract/Free Full Text]
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  11. Hasegawa Y, Miyamoto K, Abe Y, Nakamura T, Sugino H, Eto Y, Shibai H, Igarashi M 1988 Induction of follicle stimulating hormone receptor by erythroid differentiation factor on rat granulosa cell. Biochem Biophys Res Commun 156:668–674[CrossRef][Medline]
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J. Zhao, M. A.M. Taverne, G. C. van der Weijden, M. M. Bevers, and R. van den Hurk
Effect of Activin A on In Vitro Development of Rat Preantral Follicles and Localization of Activin A and Activin Receptor II
Biol Reprod, September 1, 2001; 65(3): 967 - 977.
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N. Kikuchi, K. Andoh, Y. Abe, K. Yamada, H. Mizunuma, and Y. Ibuki
Inhibitory Action of Leptin on Early Follicular Growth Differs in Immature and Adult Female Mice
Biol Reprod, July 1, 2001; 65(1): 66 - 71.
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X. Liu, K. Andoh, Y. Abe, J. Kobayashi, K. Yamada, H. Mizunuma, and Y. Ibuki
A Comparative Study on Transforming Growth Factor-{beta} and Activin A for Preantral Follicles from Adult, Immature, and Diethylstilbestrol-Primed Immature Mice
Endocrinology, June 1, 1999; 140(6): 2480 - 2485.
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H. Mizunuma, X. Liu, K. Andoh, Y. Abe, J. Kobayashi, K. Yamada, H. Yokota, Y. Ibuki, and Y. Hasegawa
Activin from Secondary Follicles Causes Small Preantral Follicles to Remain Dormant at the Resting Stage
Endocrinology, January 1, 1999; 140(1): 37 - 42.
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X. Liu, K. Andoh, H. Yokota, J. Kobayashi, Y. Abe, K. Yamada, H. Mizunuma, and Y. Ibuki
Effects of Growth Hormone, Activin, and Follistatin on the Development of Preantral Follicle from Immature Female Mice
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