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Division of Reproductive Biology (U.A.V., M.H., A.J.W.H.), Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, California 94305-5317; and Division of Reproductive Endocrinology (E.A.M.), Department of Obstetrics and Gynecology, Chandler Medical Center, University of Kentucky, Lexington, Kentucky 40536-0084
Address all correspondence and requests for reprints to: Aaron J. W. Hsueh, Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, California 94305-5317. E-mail: aaron.hsueh{at}stanford.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One of the distinctive features of primary and preantral follicle development is the formation of a thecal cell layer. Theca cells are derived from the mesenchymal tissue surrounding the follicles. Some of these mesenchymal cells seem to be associated with follicles as early as the primordial stage (9). Primary follicles show a thin layer of theca cells which increase in number during follicle progression. Following stimulation by LH, theca cells secrete androgens to serve as substrates for the estrogen-producing granulosa cells (10, 11).
It is well accepted, that pituitary-derived gonadotropins stimulate follicle growth and maturation to reach the preovulatory stage (12). However, follicular growth cannot be completely accounted for by changes in circulating gonadotropins. Small follicles enter the growing pool even in hypophysectomized mice (13), whereas follicles can grow up to the small antral stage in hypogonadotrophic mice (14). In addition to endocrine hormones, folliculogenesis is controlled by intraovarian autoregulatory factors that could initiate and stimulate the growth of follicles independent of gonadotropins (2, 15).
Apart from paracrine factors of granulosa and theca cell origin, growth differentiation factor-9 (GDF-9) secreted by the oocyte has recently been shown to play a role in follicular development. GDF-9-deficient mice, similar to steel panda mutants of the kit ligand gene (16), display an arrest of follicle growth at the primary follicle stage (17). The ovaries of GDF-9 null animals lack several theca cell markers including CYP17 and c-kit (18). Although our recent studies showed that treatment with recombinant GDF-9 induces preantral follicle growth in vitro (19), the effect of in vivo treatment with GDF-9 has not been investigated. In the present study, we demonstrate that treatment with recombinant GDF-9 in vivo, enhances ovarian weight and primordial as well as primary follicle progression up to the small preantral stage in immature rats. In addition, ovarian CYP17, a marker for the theca interna cells (20), is also increased in these animals.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animal model
Neonatal Sprague Dawley female rats were obtained from Simonsen
Laboratories (Gilroy, CA). Groups of ten rats each were housed together
with a lactating mother for the duration of the experiments. Animals
were housed under controlled humidity, temperature and light regimen
and fed ad libitum on a standard rat chow. After hormonal
treatments, animals were anesthetized and killed using
CO2. Animal care was consistent with
institutional and NIH guidelines.
To assess the role of GDF-9 on follicular development, female rats at 5 days of age were injected ip twice daily with 10 µg recombinant rat GDF-9 in 200 µl conditioned media or with FSH (10 IU). Both the GDF-9 and the FSH dose corresponded to approximately 100-fold of the concentrations needed for optimal in vitro bioactivity (21). Animals at 5 days of age were used because their ovaries contain mainly primary and primordial follicles, the progression of which were found to be altered in GDF-9 null mice (17).
Control animals were injected with PBS (200 µl). Rats were injected for either 7 or 10 days. The body weight of the animals was recorded daily as an index of animal growth. All animals were killed 12 h after the last injection. The ovaries were collected in L-15 Leibovitz medium (Life Technologies, Inc., Gaithersburg, MD) and cleaned from surrounding tissues. Each ovary was weighed individually using a scale sensitive for µg ranges (Mettler balance, Mettler Instrument Corp. Hightstown, NJ). One of the ovaries of each animal was fixed in Karnowsky solution (2.5% glutaraldehyde and 3% paraformaldehyde in 0.1 M phosphate buffer). The remaining ovary was frozen and stored at -80 C.
Histological evaluation
Ovaries fixed for at least 24 h were dehydrated, embedded
in paraffin, and serially sectioned at 6 µm intervals. The sections
were mounted on glass slides and stained with Mayers hematoxylin and
eosin. Follicles were counted using the dissector and fractionator
principles (22, 23). One-fifth of the sections of each
ovary was chosen for analysis. Follicle stages were determined in a
manner similar to the classification used by Flaws et al.
(24). Only follicles with a visible nucleolus in the
oocyte were considered, thus avoiding the counting of atretic
follicles. Primordial and primary follicles were counted at a
magnification of 400x, whereas preantral follicles were counted at a
magnification of 200x.
Immunoblot analysis
Frozen rat ovaries collected after in vivo treatment
with either GDF-9, FSH or saline were thawed in lysis buffer (50
mM Tris-HCl, 150 mM NaCl,
1% SDS, 5 mM EGTA, 0.5 mM
MgCl2, 0.5 mM MnCl2, and 0.2
mM phenylmethyl-sulfonylfluoride) at 150 µl per
ovary and homogenized. The samples were fractionated using SDS-PAGE in
10% polyacrylamide gels and transferred to polyvinylidene difluoride
membranes (Hybond-P, Amersham Pharmacia Biotech,
Piscataway, NJ). The membranes were then incubated with a rabbit
polyclonal antibody to porcine CYP-17 (1:8000 dilution, obtained from
Dr. Anita Payne, Stanford University School of Medicine, Stanford, CA),
followed by incubation with horseradish peroxidase-conjugated sheep
antirabbit IgG and immunofluorescent imaging with the ECL System
(Amersham Pharmacia Biotech).
Immunohistochemistry
Immunohistochemistry was performed on paraffin sections from
each treatment group as previously described (25) using
the Vectastain ABC elite kit from Vector Laboratories, Inc. (Burlingame, CA). Briefly, tissue sections
were deparaffinized in xylene and rehydrated in graduated ethanol
washes. Endogenous peroxidase activity was blocked with hydrogen
peroxide in absolute methanol. Nonspecific binding was blocked with
20% goat serum. Sections were incubated with the rabbit polyclonal
antibody to CYP-17 at 1:1000 dilution for 2 h at room temperature.
After washing, the sections were incubated for 30 min with second
antibody conjugated to horseradish peroxidase, and diamino/benzoate
staining was performed. The sections were washed, counterstained
lightly with hematoxylin, and dehydrated before mounting with Permount
(Fisher Scientific, Fair Lawn, NJ). Negative control
sections were treated identically except that nonimmune serum was
substituted for the first antibody. Photomicroscopy was performed at
200x magnification using a Nikon optiphot system.
Statistical analysis
Differences in ovarian weight and in the number of follicles
between treatment groups were evaluated by ANOVA. Significant
differences were assigned at P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, ovarian weight was
increased by 32 and 29% above controls in rats treated with GDF-9
after 7 and 10 days of treatment, respectively. Likewise, treatment
with FSH induced 45 and 74% increases in ovarian weight above controls
after 7 and 10 days of treatment, respectively.
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, left panel).
Follicles were scored as primary if they consisted of an intact
enlarged oocyte and a single layer of cuboidal granulosa cells (Prim.,
Fig. 2A, left panel). Intermediate follicles with a single
granulosa layer that consisted of both flattened and cuboidal cells
were considered to be in transition from primordial to primary
follicles (Int., Fig. 2A, left panel) and also scored as
primary in the present study. As described before (26),
preantral follicles in rats cannot be classified accurately according
to the number of granulosa cell layers as used by Pedersen and Peters
(27) for mice. Therefore, we divided preantral follicles
into two categories. Follicles with more than one but less than four
layers of granulosa cells were scored as small preantral follicles
(SPA, Fig. 2A, middle panel), whereas follicles with four or
more granulosa cell layers were scored as large preantral follicles
(LPA, Fig. 2A, right panel).
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). Furthermore, treatment with GDF-9 increased the number of
primary follicles by 23% above control levels. In addition, the number
of small preantral follicles was increased by 75% above control
levels. However, no effect of GDF-9 on the number of large preantral
follicles was observed (P > 0.05). In contrast to
GDF-9, treatment with FSH had no effect on the number of primordial and
primary follicles but increased the number of small and large preantral
follicles by 60 and 92%, respectively.
After 10 days of treatment (Fig. 2C), the number of primordial
follicles was reduced by 29% in animals treated with GDF-9.
Furthermore, GDF-9 treatment significantly enhanced the number of both
primary (30%) and small preantral follicles (60%), whereas the number
of large preantral follicles was not significantly affected
(P > 0.05). Again, treatment with FSH predominantly
affected the number of large preantral follicles as reflected by an
increase of 177%, whereas the number of small preantral follicles was
increased only by 36%.
The differential effects between GDF-9 and FSH treatments on follicle
progression can also be seen in representative ovarian sections of the
three groups analyzed (Fig. 3). While the
ovaries in control animals contained multiple primordial and primary
follicles in the ovarian lobe region (Fig. 3A), the GDF-9-treated group
showed few primordial follicles but many primary and small preantral
follicles (Fig. 3B). In contrast, ovaries from the FSH-treated group
contained mainly large preantral follicles. These morphological
observations are consistent with the hypothesis that GDF-9 mainly
promotes the development of primordial and primary follicles, whereas
FSH preferentially enhances preantral follicle progression.
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, treatment with GDF-9 increased the
amount of CYP17 per ovary approximately 3-fold above controls. In
contrast, treatment with FSH did not affect CYP17 levels in the
ovary.
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). Theca cells of preantral
follicles in ovaries from GDF-9-treated, as well as FSH-treated,
animals showed distinctive CYP17 staining (Fig. 5, B and C). In
contrast, theca cells in ovarian sections from control (Fig. 5A) did
not show a marked staining.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our results indicate that primordial follicles are responsive to GDF-9 and that the oocyte factor, when produced in a given follicle, could influence the initiation of primordial follicle growth. Because the expression of GDF-9 messenger RNA (mRNA) and protein was confined to primary and larger follicular stages in rats (19, 28), mice (17, 29), and human (30), the present findings suggest that once GDF-9 is produced by the oocyte of a given primordial follicle, this follicle could start to grow. Of interest, in ovine and bovine ovaries, GDF-9 mRNA was found in primordial follicles as well (31). Because follicles can progress to the primary stage in GDF-9 null mice (17), it is possible that GDF-9 is not absolutely required for the transition from primordial to primary follicles. Furthermore, the enhancement of primary follicle progression could lead to an increase in the number of primordial follicles entering the growing pool (32). Therefore, one cannot exclude the possibility that the effect observed here of GDF-9 on primordial follicles is secondary to its stimulation of primary follicle progression to small preantral follicles. The observed stimulatory effect of GDF-9 on the increase in number of small preantral follicles could be due to the enhanced initiation of primordial follicle growth and/or the transition of the primary to the small preantral follicle stage. A predominant role of GDF-9 on the progression of primary follicles to the preantral stage is consistent with the arrest of follicles at the primary stage in GDF-9 null mice.
Based on antibody neutralization experiments, the initiation of primordial follicle growth also has been shown to be regulated by the granulosa cell-derived kit ligand acting on the c-kit receptors present in the oocyte (33). Furthermore, kit ligand, similar to GDF-9, was shown to induce primordial follicle growth in ovarian explants in vitro (34). Therefore, early follicle progression could be coordinated through the combined actions of oocyte-derived GDF-9 and granulosa cell-derived kit ligand. This hypothesis is underscored by kit ligand stimulation of oocyte development and the observation that kit ligand is up-regulated in GDF-9-deficient animals (18, 35).
In addition to the involvement of GDF-9 and kit ligand in early follicular development, the differentiation processes occurring during early follicle growth have been shown to be initiated by neurotransmitters contained in ovarian nerves (36, 37). Furthermore, a recent study indicated that androgens promote the initiation of primordial follicle growth in primates (38). However, GDF-9 is the only characterized factor of oocyte origin shown to influence the initiation of follicle growth.
The regulatory role of oocyte factors in the control of antral follicle development has been extensively studied (39, 40, 41). A recent study showed that oocytes influence kit ligand expression in preantral follicles (42). The present results show that the oocyte, via secretion of GDF-9, not only affects preantral and antral follicular stages (21), but also influences the initiation of follicular growth at the primordial stage, and the progression into primary and preantral follicles.
In addition to follicular growth, GDF-9 enhances the ovarian CYP17 content and CYP17 staining in theca cells. CYP17 is present in steroidogenic theca interna cells and is found in immature rat ovaries (43). Few theca cells are present during the initiation of growth of primordial follicles (9) and primary follicles contain one layer of theca cells. These cells proliferate and the number of theca cell layers increases with follicular progression, likely in response to intraovarian factors (44). In our study, the amount of CYP17 is increased after GDF-9 treatment. The increase in ovarian CYP17 content could be due to either a higher abundance of preantral follicles and therefore more follicles with more layers of theca cells and/or to a specific increase in CYP17 levels per cell. Consistent with these findings, GDF-9-deficient animals show reduced CYP17 expression (18). To date, the localization of GDF-9 receptors is not known. Therefore, the observed effect of GDF-9 on CYP17 expression could be either mediated through direct action on theca cells or indirectly through granulosa cells. Future studies on GDF-9-responsive promoter elements in the CYP17 gene are of interest.
In contrast to GDF-9, FSH treatment did not affect the number of primary follicles but induced more small and large preantral follicles. This is consistent with earlier studies showing that FSH stimulates preantral follicular growth (25) and that a decrease of circulating FSH levels retards folliculogenesis in immature rats (45). Furthermore, it is known that both ovarian FSH receptors and circulating FSH are present in immature rats (46, 47, 48). Therefore, although FSH is not absolutely required for follicular development at this stage as shown by studies using hypophysectomized and hypogonadotrophic animals (49, 50), the rate of follicle development is augmented by FSH.
In conclusion, treatment with GDF-9 was shown to induce primordial follicle growth and enhance the transition from the primordial and primary to the small preantral follicular stage. To date, GDF-9 is the only factor secreted by the oocyte shown to influence these specific stages of follicular development in vivo. Current ovarian stimulation protocols for infertility treatment mainly influence antral follicle growth using gonadotropins (51). In poor responders to gonadotropin stimulation (52) and in cases of premature ovarian failure, enhanced ovulation rates are difficult to achieve with current infertility treatment protocols. Oocyte donation is the only option for these patients desiring pregnancy (53). Because ovaries from most women with premature ovarian failure contain primordial follicles (54), treatment with GDF-9 to stimulate both primordial and primary follicle development represents an alternative approach. Although kit ligand also stimulates these follicular stages, it has been used to promote the proliferation of pluripotent progenitor cells in the hematopoietic system in patients undergoing chemotherapy (55). Due to its wide-ranging actions, the potential use of kit ligand for infertility treatment is likely to be complicated. Because the GDF-9 null mice, unlike kit ligand mutants, lack severe defects in tissues other than the ovary, the tissue-specific role of GDF-9 in follicle growth makes this oocyte hormone a potential candidate for future infertility treatments.
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Acknowledgments |
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Footnotes |
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Received February 17, 2000.
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References |
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R.A. Cushman, C.M. Wahl, and J.E. Fortune Bovine ovarian cortical pieces grafted to chick embryonic membranes: A model for studies on the activation of primordial follicles Hum. Reprod., January 1, 2002; 17(1): 48 - 54. [Abstract] [Full Text] [PDF]
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 F. Otsuka, S. Yamamoto, G. F. Erickson, and S. Shimasaki Bone Morphogenetic Protein-15 Inhibits Follicle-stimulating Hormone (FSH) Action by Suppressing FSH Receptor Expression J. Biol. Chem., March 30, 2001; 276(14): 11387 - 11392. [Abstract] [Full Text] [PDF]
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