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Endocrinology Vol. 140, No. 6 2480-2485
Copyright © 1999 by The Endocrine Society

ARTICLES

A Comparative Study on Transforming Growth Factor-ß and Activin A for Preantral Follicles from Adult, Immature, and Diethylstilbestrol-Primed Immature Mice

Xiaowei Liu, Kazumichi Andoh, Yumiko Abe, Junro Kobayashi, Kiyohiko Yamada, Hideki Mizunuma and Yoshito Ibuki

Department of Obstetrics and Gynecology, Gunma University School of Medicine, Maebashi, Gunma 371-8511, Japan

Address all correspondence and requests for reprints to: Dr. Hideki Mizunuma, Department of Obstetrics and Gynecology, Gunma University School of Medicine, 3–39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. E-mail: mizunuma{at}news.sb.gunma-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Both transformation growth factor-ß (TGFß) and activin belong to the TGFß superfamily, and each receptor is structurally related. We have shown that the action of activin A on folliculogenesis is different in immature and adult mice, so it is of interest to study whether TGFß has such an action on follicular development. The effect of TGFß on folliculogenesis was studied in isolated preantral follicles from immature, adult, and diethylstilbestrol (DES)-primed immature mice and was compared with that of activin A. TGFß caused a significant increase in follicular diameter and estradiol and immunoreactive inhibin secretion in adult mice in a dose-related manner, but did not affect the size of preantral follicles from immature mice. Activin A, on the other hand, caused a significant increase in the size of follicles from immature mice, but did not change the size of preantral follicles from adult mice. TGFß enhanced the effect of FSH, whereas activin A completely blocked the action of FSH on preantral follicles from adult mice. Such a specific action of TGFß and activin A was age dependent because preantral follicles obtained from 28-day-old mice, compared with those from 11- and 56-day-old mice, showed an intermediate reaction to TGFß and activin A. DES pretreatment of 11- and 28-day-old mice caused an enhanced response to FSH, but this response was completely inhibited by TGFß. These results indicate that both TGFß and activin A have proliferative action and cytodifferentiative action on granulosa cells, but the action of each is age dependent and opposite in direction. In conclusion, although both TGFß and activin A belong to the same family, and each receptor is structurally related, both share a specific role in early folliculogenesis before and after puberty.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
TRANSFORMATION growth factor-ß (TGFß) is a family of multifunctional growth factors synthesized by a variety of tissues. Presently there are five TGFß subtypes, three of which, TGFß1, TGFß2, and TGFß3, have been shown to be expressed by cells of the mammalian ovary. TGFß1, TGFß2, and TGFß3 share 70–80% amino acid sequence homology and are functionally indistinguishable in most bioassays (1). Evidence has been accumulated to show a potent cytodifferential action on granulosa cell function (2, 3, 4, 5, 6, 7, 8), but whether TGFß has a proliferation action remains unclear. Skinner et al. (2) demonstrated that thecal cell-derived TGFß inhibited epidermal growth factor-stimulated bovine granulosa cell DNA synthesis, and Mondscheim et al. (3) reported that TGFß inhibited both basal and epidermal growth factor-stimulated DNA synthesis in granulosa cells harvested from 1- to 3-mm porcine follicles. In contrast to porcine granulosa cells, TGFß has been shown to elicit no significant effect on rat granulosa cell DNA content (4, 5, 6). Dorrington et al. (7), however, showed a stimulatory effect of TGFß on rat granulosa cell DNA synthesis, but the effect was moderate. Thus, although the action of TGFß on rat granulosa cell proliferation is still conflicting, it is generally thought that TGFß appears to be predominantly an inhibitor of granulosa cell growth (8). These results were, however, obtained from granulosa cells of immature rats pretreated with estrogen. It has been reported that estrogen-pretreated granulosa cell culture systems are extremely valuable in studying cytodifferentiation (9, 10), but are not appropriate for testing the proliferation of granulosa cells as evidenced by the fact that FSH and estrogen, know to stimulate DNA synthesis in vivo, failed to exert the same effect in vitro (11). To overcome these problems, an in vitro follicle culture system was developed (12, 13). Using this technique, Roy (14) has shown that TGFß stimulated DNA synthesis in adult hamster preantral and early antral follicles, but it is still unknown whether TGFß stimulates folliculogenesis characterized by morphological changes accompanied by functional development.

More recently, it has been shown that the action of activin A, a homodimer of inhibin B subunit (15), on follicular growth is paradoxical in immature and adult mice (16). Because both TGFß and activin belong to the TGFß superfamily (17), and each receptor is structurally related (18, 19), it is important to reevaluate the effect of TGFß on follicular growth in immature and adult animals. The present study aimed to clarify the physiological significance of TGFß in the follicular growth of preantral follicles by comparing its effects on follicular growth in adult and immature mice and in estrogen-primed immature mice.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Chemicals
Recombinant human FSH (rhFSH) was obtained from Organon (Oss, The Netherlands). Human erythroid differentiation factor/activin A (activin A) was prepared as described previously (20). TGFß1 was obtained from Sigma Chemical Co. (St. Louis, MO). All other chemicals were of analytical grade or the highest quality commercially available.

Animals
Female BDF1 hybrid mice were purchased from Japan Charles River Laboratories, 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 (Gunma, Japan). Food and water were given ad libitum. Eleven-, 28-, and 56-day-old mice were killed for the experiment. To obtain estrogen-primed 11- and 28-day-old mice, 0.05 mg/g body weight of diethylstilbestrol (DES) was sc administered daily for 3 days to 7- and 24-day-old mice, and they were killed at 11 and 28 days of age, respectively.

Follicle culture
Preantral follicles were prepared as described previously (21). Briefly, ovaries were removed aseptically and placed in 15-mm diameter Falcon plastic petri dishes (Falcon 3037, Becton Dickinson and Co., Rutherford, NJ) filled at room temperature with DMEM (Life Technologies, Tokyo, Japan). After removing the surrounding tissue, the ovaries were microdissected using two 27-gauge needles attached to 1-ml syringes under the stereomicroscope, and preantral follicles (100–120 µm in diameter) with one or two layers of granulosa cells around the oocyte and an intact basal lamina with thecal cells were mechanically isolated. Histological examination of these isolated follicles revealed that although the number of thecal cells attached to the basement membrane varied, 86.9% of follicles had at least one thecal cell on an examined section. It was also revealed that preantral follicles with a diameter of 100–120 µm had 84.5 ± 12.8 granulosa cells on an examined section, whereas those with a diameter of 120–140 µm after in vitro culture had 157 ± 10.9 granulosa cells, suggesting that the increase in follicular diameter is accompanied by an increase in cell number. No remarkable differences were histologically evidenced in preantral follicles collected from 11-day-old mice and 8-week-old mice. To test the effects of FSH, activin A, and TGFß on preantral follicles, 10 preantral follicles were transferred into a Falcon plastic petri dish filled with 1 ml serum-free DMEM supplemented with 6.25 µg/ml insulin, 6.25 µg/ml transferrin, 6.25 ng/ml selenious acid, 5.35 µg/ml linoleic acid, 0.15% BSA, 15 mM HEPES, 45 µg/ml penicillin G, 350 g/ml streptomycin, and 1.75 µg/ml amphotericin and were cultured in a humidified chamber with 5% CO2 in the air at 37 C for 4 days. Each experiment was repeated 5–10 times. TGFß, activin A, and rhFSH were added on day 0 at the indicated concentrations. Follicles cultured with the medium alone served as the control.

Measurements and statistics
Two-dimensional maximum and minimum lengths of each follicle were measured daily with an inverted microscope (IMT-2, Olympus Corp., Tokyo, Japan). Interstitial cells and thecal cells around the basement membrane were not included in the measurement of the follicle. The mean diameter of the follicle was calculated by averaging these two measurements. Inhibin and estradiol concentrations were measured by double antibody RIA as described previously (21). Differences between means of follicular diameters were analyzed by ANOVA followed by Scheffe’s F test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Morphological changes in preantral follicles of immature and adult mice cultured for 4 days in the presence of activin A (100 ng/ml) and TGFß (100 ng/ml) are shown in Fig. 1Go. As follicles showed linear increase in size during 4-day culture, follicular size on day 4 of culture was presented. Changes in follicular diameter and estrogen and immunoreactive (IR-) inhibin secretion from preantral follicles of 56- and 11-day-old mice as a result of stimulation by TGFß and activin A at various doses are shown in Fig. 2Go. Preantral follicles harvested from 11-day-old mice showed no significant changes as a result of stimulation by TGFß, whereas those from 56-day-old mice showed a dose-dependent increase in follicular diameter and IR-inhibin and estradiol secretion as a result of stimulation by TGFß. On the contrary, preantral follicles harvested from 11-day-old mice showed significant changes in follicular diameter and IR-inhibin and estradiol secretion in a dose-dependent manner as a result of stimulation by activin A, whereas those from 56-day-old mice showed no significant changes. Even though a minimal effective dose of 10 ng/ml TGFß and activin A induced detectable changes (Fig. 2Go), follicular diameter reached a maximal response as a result of stimulation by 100 ng/ml TGFß and activin A, respectively. As the aim of this study was to highlight the different effects of TGFß and activin A, the experiments were carried out using the maximal dose. Therefore, the results are also representative of a physiological condition.



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  		Figure 1. Morphological changes in preantral follicles of immature and adult mice cultured for 4 days in the presence of activin A (100 ng/ml) and TGFß (100 ng/ml).

 


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  		Figure 2. Changes in follicular diameter of preantral follicles cultured for 4 days and in IR-inhibin secretion and estradiol secretion from preantral follicles harvested from immature and adult mice as a result of stimulation with various doses of TGFß and activin A. The mean and SEM follicular diameter of each dose were determined for 50–100 follicles. The mean and SEM of IR-inhibin and estradiol secretion were obtained from 5 assays. *, P < 0.01; **, P < 0.001 (vs. control).

 
Figure 3AGo shows age-related changes in follicular diameter of preantral follicles as a result of stimulation by rhFSH, TGFß, and activin A. There were significant differences between 11-, 28-, and 56-day-old mice in response to rhFSH, activin A, TGFß, and a combination of each. Preantral follicles harvested from 11-day-old mice showed no significant response to rhFSH or TGFß, whereas those harvested from 56-day-old mice showed significant follicular growth as a result of rhFSH and TGFß treatments. Moreover, preantral follicles from 11-day-old mice showed significant growth as a result of activin A administration, but those from adult mice showed no change. Preantral follicles from 28-day-old mice, however, showed intermediate response between 11- and 56-day-old mice. Figure 3BGo shows age-related changes in the follicular diameter of preantral follicles as a result of stimulation by a combination of rhFSH and TGFß, and rhFSH and activin A. Both TGFß and activin A enhanced the action of rhFSH on preantral follicles from 11- and 28-day-old mice. TGFß enhanced the action of rhFSH in 56-day-old mice, but activin A suppressed the action of rhFSH in these mice. The IR-inhibin and estradiol concentrations in the culture medium show changes parallel to those in follicular diameter (Table 1Go).



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  		Figure 3. Comparison of follicular response between 11-, 28-, and 56-day-old mice to stimulation of 100 ng/ml rhFSH, 100 IU/ml activin A, 100 ng/ml TGFß, and a combination of each. The mean and SEM follicular diameter of each were determined for 50–100 follicles. *, P < 0.01; **, P < 0.001; a, P < 0.0001; b, P < 0.01 (vs. follicular diameter of preantral follicles from mice of the same age and cultured for 4 days with rhFSH).

 

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  		Table 1. The levels of estradiol and ir-inhibin in the cultured medium after 4 days

 
The effects of DES treatment on follicular responses to rhFSH, TGFß, and activin A are shown in Fig. 4Go. Preantral follicles from 11-day-old mice pretreated with DES became responsive to rhFSH and showed enhanced response to a combination of activin A and rhFSH. Although neither TGFß nor activin A had a significant effect on preantral follicular diameter from 11-day-old mice regardelss of DES pretreatment, preantral follicles pretreated with DES showed an enhanced response to a combination of activin A and rhFSH. Of interest is the finding that TGFß caused significant suppression of follicular growth in preantral follicles from DES-pretreated 11- and 28-day-old mice stimulated by rhFSH. Preantral follicles from 28-day-old mice pretreated with DES showed enhanced responses to rhFSH, activin A, and TGFß. However, TGFß inhibited FSH action in preantral follicles from DES-pretreated 28-day-old mice. The IR-inhibin and estradiol concentrations in the culture medium show changes parallel to those in follicular diameter (Table 2Go).



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  		Figure 4. Effect of DES treatment on follicular responses to rhFSH, activin A, TGFß, and a combination of each. The mean and SEM of follicular diameter of each were obtained from 50 follicles. **, P < 0.001.

 

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  		Table 2. The levels of estradiol and ir-inhibin in the cultured medium after 4 days

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Previous reports using a granulosa cell culture system of DES-pretreated immature rats have shown conflicting results on the proliferative action of TGFß in follicular granulosa cells (2, 3, 4, 5, 6, 7). The present study, using a preantral follicle culture system, clearly demonstrated that TGFß can increase follicular diameter. Although the present study used a follicle culture system including the follicle basal lamina and thecal cells, our results agreed with those reported by Roy (13, 14), who used enzymatically isolated preantral follicles and showed that there was an increase in [3H]thymidine incorporation into preantral follicles as a result of stimulation by TGFß. The present study also showed for the first time that TGFß can stimulate preantral follicular growth and that the action of TGFß is age dependent. Moreover, the results presented here not only supported that TGFß can up-regulate the action of FSH in adult rodents (13, 22), but also indicated for the first time that TGFß can induce the responsiveness to FSH of preantral follicles from 11-day-old mice, although neither TGFß nor FSH has a significant effect on follicular growth of 11-day-old mice when administered separately.

Both TGFß and activin A belong to the same family, and their receptors are structurally related (17, 18, 19); however, the action of each on preantral follicles was opposite in nature. Activin A stimulated follicular growth in 11-day-old mice, whereas TGFß did not have such an effect on preantral follicles from 11-day-old mice. On the other hand, TGFß stimulated the follicular growth of 56-day-old mice, but activin A did not have such an effect on follicles from 56-day-old mice. Interestingly, preantral follicles of 28-day-old mice showed an intermediate response between those of 11- and 56-day-old mice, suggesting that the different responses are related to the process of physical maturity. In the normal course of pubertal growth of the rodent, the prepubertal gonadotropin surge occurs around 11 days of age and has ended by 28 days of age (23). This postnatal gonadotropin surge is believed to exist in almost all mammals and is important in the initiation of sexual maturity. Our preliminary results have indicated that an artificial prepubertal gonadotropin surge causes preantral follicles of 11-day-old mice to become responsive to FSH and nonresponsive to activin A, suggesting that the prolonged gonadotropin surge is responsible for this functional differentiation of preantral follicles, as can be seen in immature to adult mice. It has been proposed that follicular development up to the preantral stage is FSH independent (24, 25). The present study has confirmed that preantral follicles can initiate their own growth even in the absence of FSH, and we propose a novel hypothesis that TGFß and activin A are alternatively involved in this mechanism between immature and adult mice.

Bendell et al. (26) have shown that granulosa cells from DES-treated immature rats respond to TGFß with increases in DNA synthesis and FSH-stimulated aromatase activity, whereas Dodson et al. (4), Adashi et al. (5), and Feng et al. (6) could not find such an effect in granulosa cells from DES-treated immature rats. All of these experiments used a granulosa cell culture system and DES-treated rats, but for unknown reasons the results were not supportive. Therefore, an attempt was made here to compare the effect of TGFß on preantral follicles harvested from both normal mice and DES-treated mice of the same age. The present study using a preantral follicle culture system has shown that DES treatment enhanced the responsiveness of preantral follicles to TGFß and activin A in 28-day-old mice, but not in 11-day-old mice, and has shown that TGFß suppressed the action of FSH in 11- and 28-day-old DES-treated mice. It is difficult to account for this novel action of TGFß in DES-treated mice. It has been shown that daily injection of DES into immature rats increases granulosa cell number per ovary approximately 4-fold, but DES after 72 or 96 h significantly reduces tritiated thymidine incorporation into cells (27). Because we killed DES-treated animals at 4 days after DES injection, the observed behavior of the follicles may be related to the specific changes in atretic follicles. Moreover, it is shown that DES increases granulosa cell expression of TGFß messenger RNA approximately 6.8-fold in granulosa cells collected 4 days after DES injection (28). Thus, the precise nature of the relationship between TGFß messenger RNA expression and granulosa cell proliferation during DES exposure needs further investigation.

In conclusion, the present study has shown that although both TGFß and activin belong to the same family, the action of each is age specific and opposite in direction.


   Acknowledgments
 
We thank Dr. Yuzuru Eto (Ajinomoto Central Research Laboratories, Kawasaki, Japan) for his kind donation of recombinant human activin A. We also thank Miss Y. Hayashi and Miss T. Ishihara for their assistance.

Received November 20, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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