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Center for Reproductive Biology, Department of Genetics and Cell Biology, Washington State University, Pullman, Washington 99163-4231
Address all correspondence and requests for reprints to: Michael K. Skinner, Center for Reproductive Biology, Department of Genetics and Cell Biology, Washington State University, Pullman, Washington 99164-4231. E-mail: skinner{at}mail.wsu.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Kit ligand (KL) and its receptor c-kit are essential for oocyte migration during embryonic development (1, 2, 3) and follicular development in the adult ovary (4, 5, 6). Although previous analysis of the actions of KL on follicle development (6) are likely in part to be due to actions on primordial follicle development, no direct analysis of primordial follicles has been reported. To our knowledge, previous studies have not rigorously examined the role of KL in primordial follicle development and the initial stages of folliculogenesis. KL and c-kit are the products of the Steel (Sl) and White Spotting (W) loci in mice, respectively (7, 8, 9, 10, 11, 12, 13). A number of mutations at Sl or W have been described that cause sterility due to defects in oocyte migration or follicular development. Ovaries in mice carrying steel panda (Slpan), steel t (Slt), and steel contrast (Slcon) mutations contain follicles that arrest at early stages of follicular development (14, 15, 16). The pool of primordial follicles is established in these mutant mice, but initiation and progression of primordial follicle development is inhibited. These observations suggest that KL may be essential for initiation and/or progression of primordial follicle development in the ovary.
When a follicle starts to develop, its oocyte begins to synthesize RNA (17, 18), and squamous pregranulosa cells enlarge to become a single layer of cuboidal granulosa cells. Theca cells are recruited from surrounding stromal stem cells and organize into distinct theca cell layers around the follicle. Organization of theca cells around the follicle provides structural integrity and helps to establish mesenchymal-epithelial cell interactions between theca cells and granulosa cells (19). Follicular development continues as granulosa cells and theca cells proliferate and differentiate. It has been suggested that theca cells differentiate from stromal stem cells in response to a putative "theca cell organizer" produced by granulosa cells (20). Such a factor may also be important for granulosa cell-oocyte interactions involved in the initiation and progression of primordial follicle development.
Granulosa cells in developing follicles produce KL (4, 21), which can act on theca cells, stromal cells, and oocytes. Differentiated theca cells, undifferentiated stromal cells, and developing oocytes express the receptor c-kit (4, 21, 22, 23). KL has a variety of effects on isolated oocytes including the promotion of growth and maintenance of meiotic arrest (5, 24, 25, 26, 27). In addition KL can directly stimulate proliferation and differentiated functions (i.e. androstenedione production) of theca cells (28). KL also stimulates the growth of ovarian stromal-interstitial cells (29). The expression patterns of KL and c-kit in the ovary, as well as the actions of KL on oocytes and theca cells, suggest that KL may be important for many stages of follicular development in the ovary.
The present study examines the ability of KL to induce primordial follicle development and initiate the early events of folliculogenesis. The current study does not address the embryonic or postnatal formation of the primordial follicles, but instead the initiation of follicle development (i.e. folliculogenesis). Experiments are designed to examine the actions of KL in whole-ovary organ cultures. KL is proposed to mediate epithelial-mesenchymal cell interactions between granulosa and theca cells, as well as directly stimulate oocyte functions. The hypothesis that KL may recruit theca cells from undifferentiated stromal stem cells is also discussed.
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Materials and Methods |
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Histology
To investigate development of ovarian follicles fresh or
cultured ovaries were embedded in paraffin, sectioned (7-µm
sections), and stained with hematoxylin and eosin. The number of
follicles at each developmental stage were counted in two serial
sections from the largest cross-section through the center of the
ovary. Follicles were classified (Fig. 1
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as primordial (stage 0), early primary (stage 1), primary (stage 2),
transitional (stage 3), or preantral (stage 4) as previously described
(32). This classification is weighted toward earlier stages of
follicular development. Primordial follicles are not developing and
consist of an oocyte partially or completely encapsulated by flattened
squamous pregranulosa cells. Early primary follicles have
initiated development and contain some cuboidal (enlarged) granulosa
cells. Primary follicles are identified by a single layer of cubiodal
granulosa cells around the oocyte. Transitional follicles have 1–2
layers and preantral follicles have more than 2 layers of cuboidal
granulosa cells. No antral follicles were observed in fresh or cultured
4-day-old rat ovaries. Multiple pole to pole sections of the ovaries
were obtained for analysis. Sections were analyzed at 400x
magnification under light microscopy and photographed with a
Kodak DCS 420 digital camera (Eastman Kodak Co., Rochester, NY).
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Statistical analysis
All data were analyzed by a JMP 3.1 statistical analysis program
(SAS Institute, Inc., Cary, NC). Effects of control
culture conditions, KL, gonadotropins (FSH + hCG) and the ACK-2
antibody on follicle development were analyzed by a one-way ANOVA.
Observed significance probabilities of 0.05 (Prob > F) or less
were considered evidence that an ANOVA model fits the data. Follicles
were counted and characterized (developmental stage 0–stage 4) on two
serial sections from each treatment in a total of four different
experiments (n = 8). In some cases, follicles were counted in half
of a section and multiplied by a factor of 2. Follicles were assessed
blindly in all experiments. In addition, results were confirmed
independently by two individuals. At least 14,000 total follicles were
counted and classified and data were expressed as % follicles per
section ± SEM. Within each developmental stage,
significant differences between each treatment were determined using
the Tukey-Kramer HSD (honestly significant difference) test, which
protects the significance tests of all combinations of pairs (33, 34).
The Tukey-Kramer test is recommended for multiple comparisons of all
pairs (35).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Sections of fresh 4-day-old rat
ovaries contained 68% primordial follicles (stage 0), 12% early
primary follicles (stage 1), 11% primary follicles (stages 2) and 9%
transitional and preantral follicles (stages 3–4). No antral follicles
were observed in freshly collected 4-day-old rat ovaries. Primordial
follicles were generally observed in the cortex (outer region) of the
ovaries and larger preantral follicles were observed in the medulla
(central region) of the ovaries (Fig. 2).
The pattern of undeveloped primordial follicles observed in the
4-day-old rat ovarian cortex is similar to prepubertal, mouse, bovine,
and human ovaries (unpublished observation). The characterization of
follicle development in 4-day-old rat ovaries demonstrated that at this
developmental period a large number of undeveloped primordial follicles
(i.e. 68% per section) are available for analysis. These
4-day-old rat ovaries were used in the in vitro system to
study the factors involved in the initiation of primordial follicle
development.
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). The total number of follicles per section
did not vary significantly under any culture condition examined (Fig. 3). Under control conditions, a small but
significant reduction in the percentage of primordial follicles (stage
0) per section was coupled to an increase in the percentage of early
primary follicles (stage 1) (Fig. 4). The
morphology of these follicles are shown in Fig. 4. No change was
observed in the percentage of primary (stage 2), transitional (stage
3), or preantral (stage 4) follicles in control cultures compared with
fresh ovaries (Fig. 5). These results
demonstrate that primordial follicles in rat ovaries can spontaneously
initiate development to early primary follicles (stage 1) in
vitro. This whole ovary organ culture system was used to examine
the ability of KL to induce primordial follicle development.
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and 5). Interestingly, over 50% of the follicles per section
in KL-treated ovaries had initiated development (i.e. stage
1–stage 4 follicles) (Fig. 6a).
Treatment with gonadotropins did not induce primordial follicle
development but did inhibit the spontaneous development that occurred
in control cultures (Figs. 4 and 5). In addition, a slight increase in
the percentage of preantral follicles (stage 4) was observed in
gonadotropin-treated ovaries, suggesting that these later stage
follicles are gonadotropin dependent. More dramatic effects of KL were
observed after 14 days of culture (Fig. 6b). Over 83% of the follicles
per section initiated development after 14 days of KL treatment. The
ability of KL to promote development of early primary (stage 1) and
primary follicles (stage 2) suggests that KL is sufficient to initiate
primordial follicle development in the ovary.
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). The percentage of primordial (stage
0) and early primary follicles (stage 1) were identical in freshly
collected ovaries and ovaries cultured in the presence of ACK-2. The
titer of ACK-2 antibody used was approximately 1/100. This inhibition
of follicle development by ACK-2 suggests that endogenous KL is
necessary for the spontaneous development of primordial follicles in
these cultures.
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). In gonadotropin-treated ovaries, ACK-2 did not affect the
percentage of primordial (stage 0), early primary (stage 1), primary
(stage 2), or transitional follicles (stage 3) per section. However,
the ACK-2 c-kit antibody did inhibit the small increase in preantral
follicles (stage 4) that occurred in response to FSH and hCG (Fig. 7c).
The ability of ACK-2 to inhibit preantral follicle development in
response to gonadotropins suggests that KL is also necessary for
preantral follicular development.
Development of early stage follicles (i.e. stage 1–4)
involves differentiation and organization of theca cells around
follicles and enlargement of squamous granulosa cells. During follicle
development, theca cells differentiate and begin to produce increasing
amounts of androstenedione. To study potential recruitment and
differentiation of theca cells, androstenedione production was examined
in the ovary organ cultures. Ovaries were cultured in the presence of
normal rat IgG or ACK-2 c-kit antibody and treated with no factor
(control), recombinant KL, or gonadotropins for 5 days. Media from the
days 2–5 collection was assayed for androstenedione accumulation by
RIA. Under control conditions, approximately 1 ng adrostenedione/ovary
was detected in the media (Fig. 8). ACK-2
did not alter basal levels of androstenedione production in control
cultures. Interestingly, KL had no effect on the production of
androstenedione in the presence or absence of ACK-2 (Fig. 8).
Gonadotropins (i.e. FSH and hCG) dramatically stimulated
production of androstenedione by ovary organ cultures (Fig. 8). This
stimulation of androstenedione production by FSH and hCG was likely due
to stimulatory actions on large preantral follicles (stage 4) because
only large follicles (i.e. stage 4 or later) normally
express gonadotropin receptors and produce steroids (39, 40).
Interestingly, the inhibitory actions of ACK-2 increased
androstenedione production by gonadotropin-stimulated ovaries (Fig. 8).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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When 4-day-old ovaries were placed in culture for 5 or 14 days, some primordial follicles proceeded to develop. This spontaneous initiation of primordial follicle development suggests that primordial follicles were actively developing in vivo and continued to develop in vitro. Alternatively, there may be inhibitory signals for primordial follicle development in vivo that were no longer present in vitro. Wandji et al. also reported spontaneous initiation of primordial follicle development in cultured ovarian cortex fragments from embryonic cows (41) and baboons (42). In the current study, spontaneous initiation of primordial follicle development was blocked by ACK-2, a c-kit monoclonal antibody that inhibits the actions of KL on the receptor c-kit. Although this is a rat monoclonal antibody to mouse c-kit, ACK-2 has been shown to cross-react in other species such as rat (27). Observations suggest that KL may be necessary for initiation of primordial follicle development.
The number of primordial follicles that initiated development was significantly increased by KL. This induction of primordial follicle development by KL treatment was partially inhibited by ACK-2. Total inhibition of primordial follicle development in response to KL may be limited in part by access of ACK-2 to the organ culture. Other factors that may contribute to the partial inhibition were that the optimal titer of antibody was not used to suppress the actions of exogenously added KL.
Initiation of primordial follicle development primarily occurs after the onset of puberty but can be observed prepubertally and during infancy when ovulation has not yet started (43, 44). Primordial follicles continue to initiate development until menopause (i.e. in the human) when the pool of primordial follicles is diminished. Interestingly, primordial follicle development continues in the adult even during pregnancy when follicles do not ovulate (45, 46, 47, 48). These observations suggest that the factors that control initiation of primordial follicle development are important at various stages of reproductive development. This study is the first to suggest that KL may be sufficient to initiate primordial follicle development. The expression and actions of KL in the ovary during these various stages of reproductive development remain to be elucidated.
Gonadotropins (i.e. FSH and LH) have been shown not to influence the initiation of primordial follicle development (49, 50, 51). However, gonadotropins are critical for preantral follicles (stage 4) to continue development (40). Preantral follicles (stage 4) express gonadotropin receptors and are completely dependent on normal levels of FSH and LH to develop. In the current study, treatment with gonadotropins resulted in a small increase in the percentage of preantral (stage 4) follicles per section. This increase in preantral follicle development was blocked by the c-kit antibody ACK-2. Observations suggest that KL in part mediates the actions of gonadotropins in preantral follicles. Laitinen et al. showed that gonadotropins can regulate KL expresssion in human granulosa cells collected from large size follicles for in vitro fertilization (52). The current results suggest that KL may also mediate gonadotropin actions in preantral follicles.
KL (also termed stem cell factor, mast cell factor or steel factor) has a wide range of activities on germ cells, melanocytes, mast cells, and primitive hematopoietic cells of the myeloid, erythroid, and lymphoid cell lineages (53, 54). Many of these multipotent stem cells alter their developmental program and differentiate in response to KL. Theca cells are recruited to differentiate from ovarian stromal stem cells during initiation of primordial follicle development. The authors have developed the hypothesis that KL may have a role in the recruitment of stromal stem cells to differentiate into theca cells. In organ culture KL had no effect on ovarian androstenedione production that is a marker of follicular phase theca cell differentiation. Differentiation of theca cells in early primary (stage 1) and primary follicles (stage 2) may not involve production of androstenedione. Elucidation of the ability of KL to recruit stromal stem cells to differentiate into theca cells will require identification of early theca cell markers of differentiation.
Gonadotropins dramatically stimulated androstenedione production by ovary organ cultures. The increased androstenedione production was likely derived from differentiated theca cells in preantral follicles (stage 4). Gonadotropins directly stimulate theca cell steroid production in developing follicles (55). Interestingly, the ACK-2 c-kit antibody enhanced the ability of gonadotropins to stimulate androstenedione production by cultured ovaries. Previous experiments have shown that theca cells from later stage follicles (i.e. preantral and antral stages) can proliferate in response to KL in vitro (28). Therefore, KL may indirectly decrease theca cell differentiated functions by promoting entry of the cells into the cell cycle. An important role of KL in preantral follicles (i.e. stage 4) may be to stimulate theca cell proliferation to establish several theca cell layers. Inhibition of KL actions with ACK-2 may indirectly increase theca cell androstenedione production in gonadotropin-stimulated follicles. As a result, observable structural development of preantral follicles may be distinct from actual androstenedione production. Stimulation of a androstenedione production by ACK-2 was likely due to effects on existing preantral follicles. A similar effect of ACK-2 has been reported on Leydig cell testosterone production (38). Serum testosterone levels were elevated 24 h after injection with ACK-2.
Recently, a role for c-kit has also been suggested for the development of preantral follicles from primary follicles (6). Some of the effects observed are likely through the primordial follicles, but this was not directly examined. Administration of ACK-2 to mice appeared to block development of follicles. It was not clear if these effects were direct on follicles or indirect due to the use of whole mice as a model system. The current study suggests a role for KL in inducing the primordial follicles to develop to the primary follicle stage. Therefore, this previous study (6) compliments the current observations and suggests KL has a role throughout follicle development.
The current study suggests that KL can initiate follicle growth in vitro. Mutations in Steel such as Steel Panda (SIpan), Steel + (SI+), and Steel Contrast (SIcon) cause ovarian follicles to arrest at early stages of development after initiation has occurred. It is possible that there are additional factors in vivo that play a role in follicle development that are absent from the in vitro experiments. In addition, Steel mutant mice may have developed other unidentified compensatory mechanisms that affect follicle development. Experiments designed to examine the potential effects of KL on follicle development in vivo are planned.
For more than 70 yr, whole ovaries have been maintained in organ culture to study follicular development (56, 57, 58, 59, 60). Early studies also examined the development of primoridal follicles in freshly isolated ovarian tissue (61, 62, 63). Despite this extensive investigation, the factors that control initiation of primordial follicle development remain to the elucidated. In the current study, 4-day-old rat ovaries were maintained in a simple floating-filter organ culture system to study the factors that control primordial follicle development. KL dramatically induced development of primordial follicles in these ovaries. The c-kit antibody ACK-2 blocked initiation of primordial follicle development. Because both oocytes and theca/stromal cells express the c-kit receptor, KL may promote early follicular development by acting on both germ cells (i.e. oocytes) and somatic cells (i.e. theca and stromal cells). These experiments suggest that KL may be both necessary and sufficient to induce primordial follicle development in ovary organ cultures. The speculation is made that KL may be a "theca cell organizer" (20) that is involved in initiation of primordial follicle development. An understanding of the factors that control primordial follicle development will be useful in understanding in part the mechanisms that underlie many phenomena such as female sterility, premature ovarian failure, polycystic ovary disease, precocious or delayed puberty, early or delayed onset of menopause, and ovarian cancer.
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Acknowledgments |
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Footnotes |
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Received September 2, 1998.
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References |
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C. J. Guigon and S. Magre Contribution of Germ Cells to the Differentiation and Maturation of the Ovary: Insights from Models of Germ Cell Depletion Biol Reprod, March 1, 2006; 74(3): 450 - 458. [Abstract] [Full Text] [PDF]
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K.J. Hutt, E.A. McLaughlin, and M.K. Holland Kit ligand and c-Kit have diverse roles during mammalian oogenesis and folliculogenesis Mol. Hum. Reprod., February 1, 2006; 12(2): 61 - 69. [Abstract] [Full Text] [PDF]
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A. Paredes, C. Garcia-Rudaz, B. Kerr, V. Tapia, G. A. Dissen, M. E. Costa, A. Cornea, and S. R. Ojeda Loss of Synaptonemal Complex Protein-1, a Synaptonemal Complex Protein, Contributes to the Initiation of Follicular Assembly in the Developing Rat Ovary Endocrinology, December 1, 2005; 146(12): 5267 - 5277. [Abstract] [Full Text] [PDF]
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P. Kezele, E. E. Nilsson, and M. K. Skinner Keratinocyte Growth Factor Acts as a Mesenchymal Factor That Promotes Ovarian Primordial to Primary Follicle Transition Biol Reprod, November 1, 2005; 73(5): 967 - 973. [Abstract] [Full Text] [PDF]
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 M. K. Skinner Regulation of primordial follicle assembly and development Hum. Reprod. Update, September 1, 2005; 11(5): 461 - 471. [Abstract] [Full Text] [PDF]
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M. Horikawa, N. J. Kirkman, K. E. Mayo, S. M. Mulders, J. Zhou, C. A. Bondy, S.-Y. T. Hsu, G. J. King, and E. Y. Adashi The Mouse Germ-Cell-Specific Leucine-Rich Repeat Protein NALP14: A Member of the NACHT Nucleoside Triphosphatase Family Biol Reprod, April 1, 2005; 72(4): 879 - 889. [Abstract] [Full Text] [PDF]
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 A. P. N. Themmen Anti-Mullerian Hormone: Its Role in Follicular Growth Initiation and Survival and as an Ovarian Reserve Marker J Natl Cancer Inst Monographs, March 1, 2005; 2005(34): 18 - 21. [Abstract] [Full Text] [PDF]
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 K. Shirota, K. Tateishi, T. Koji, Y. Hishikawa, T. Hachisuga, M. Kuroki, and T. Kawarabayashi Early Human Preantral Follicles Have Relaxin and Relaxin Receptor (LGR7), and Relaxin Promotes Their Development J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 516 - 521. [Abstract] [Full Text] [PDF]
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M. Tanaka, M. Kihara, J. D. Hennebold, J. J. Eppig, M. M. Viveiros, B. R. Emery, D. T. Carrell, N. J. Kirkman, B. Meczekalski, J. Zhou, et al. H1FOO Is Coupled to the Initiation of Oocytic Growth Biol Reprod, January 1, 2005; 72(1): 135 - 142. [Abstract] [Full Text] [PDF]
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G. A. R. Maciel, E. C. Baracat, J. A. Benda, S. M. Markham, K. Hensinger, R. J. Chang, and G. F. Erickson Stockpiling of Transitional and Classic Primary Follicles in Ovaries of Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5321 - 5327. [Abstract] [Full Text] [PDF]
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 X. Wu, L. Chen, C. A. Brown, C. Yan, and M. M. Matzuk Interrelationship of Growth Differentiation Factor 9 and Inhibin in Early Folliculogenesis and Ovarian Tumorigenesis in Mice Mol. Endocrinol., June 1, 2004; 18(6): 1509 - 1519. [Abstract] [Full Text] [PDF]
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S. Jonard and D. Dewailly The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest Hum. Reprod. Update, March 1, 2004; 10(2): 107 - 117. [Abstract] [Full Text] [PDF]
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D. Schmidt, C. E. Ovitt, K. Anlag, S. Fehsenfeld, L. Gredsted, A.-C. Treier, and M. Treier The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance Development, February 15, 2004; 131(4): 933 - 942. [Abstract] [Full Text] [PDF]
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C. Weenen, J. S.E. Laven, A. R.M. von Bergh, M. Cranfield, N. P. Groome, J. A. Visser, P. Kramer, B. C.J.M. Fauser, and A. P.N. Themmen Anti-Mullerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment Mol. Hum. Reprod., February 1, 2004; 10(2): 77 - 83. [Abstract] [Full Text] [PDF]
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 J. S. Kang, C. J. Lee, J. M. Lee, J. Y. Rha, K. W. Song, and M. H. Park Follicular Expression of c-Kit/SCF and Inhibin-{alpha} in Mouse Ovary During Development J. Histochem. Cytochem., November 1, 2003; 51(11): 1447 - 1458. [Abstract] [Full Text] [PDF]
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E. E. Nilsson and M. K. Skinner Bone Morphogenetic Protein-4 Acts as an Ovarian Follicle Survival Factor and Promotes Primordial Follicle Development Biol Reprod, October 1, 2003; 69(4): 1265 - 1272. [Abstract] [Full Text] [PDF]
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P. Kezele and M. K. Skinner Regulation of Ovarian Primordial Follicle Assembly and Development by Estrogen and Progesterone: Endocrine Model of Follicle Assembly Endocrinology, August 1, 2003; 144(8): 3329 - 3337. [Abstract] [Full Text] [PDF]
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K. A. Logan, K. P. McNatty, and J. L. Juengel Expression of Wilms' Tumor Gene and Protein Localization During Ovarian Formation and Follicular Development in Sheep Biol Reprod, February 1, 2003; 68(2): 635 - 643. [Abstract] [Full Text] [PDF]
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E. E. Nilsson and M. K. Skinner Growth and Differentiation Factor-9 Stimulates Progression of Early Primary but Not Primordial Rat Ovarian Follicle Development Biol Reprod, September 1, 2002; 67(3): 1018 - 1024. [Abstract] [Full Text] [PDF]
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A. L. L. Durlinger, M. J. G. Gruijters, P. Kramer, B. Karels, H. A. Ingraham, M. W. Nachtigal, J. Th. J. Uilenbroek, J. A. Grootegoed, and A. P. N. Themmen Anti-Mullerian Hormone Inhibits Initiation of Primordial Follicle Growth in the Mouse Ovary Endocrinology, March 1, 2002; 143(3): 1076 - 1084. [Abstract] [Full Text] [PDF]
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D. C. Eckery, S. B. Lawrence, J. L. Juengel, P. Greenwood, K. P. McNatty, and A. E. Fidler Gene Expression of the Tyrosine Kinase Receptor c-kit During Ovarian Development in the Brushtail Possum (Trichosurus vulpecula) Biol Reprod, February 1, 2002; 66(2): 346 - 353. [Abstract] [Full Text] [PDF]
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L. J. Morrison and J. L. Marcinkiewicz Tumor Necrosis Factor {alpha} Enhances Oocyte/Follicle Apoptosis in the Neonatal Rat Ovary Biol Reprod, February 1, 2002; 66(2): 450 - 457. [Abstract] [Full Text] [PDF]
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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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E.d. Vries, I. den Tonkelaar, P.A.H. van Noord, Y.T. van der Schouw, E.R. te Velde, and P.H.M. Peeters Oral contraceptive use in relation to age at menopause in the DOM cohort Hum. Reprod., August 1, 2001; 16(8): 1657 - 1662. [Abstract] [Full Text] [PDF]
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G. A. Dissen, C. Romero, A. N. Hirshfield, and S. R. Ojeda Nerve Growth Factor Is Required for Early Follicular Development in the Mammalian Ovary Endocrinology, May 1, 2001; 142(5): 2078 - 2086. [Abstract] [Full Text]
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C. T.F. Huang, S. R. Weitsman, B. N. Dykes, and D. A. Magoffin Stem Cell Factor and Insulin-Like Growth Factor-I Stimulate Luteinizing Hormone-Independent Differentiation of Rat Ovarian Theca Cells Biol Reprod, February 1, 2001; 64(2): 451 - 456. [Abstract] [Full Text]
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E. Nilsson and M. K. Skinner Cellular Interactions That Control Primordial Follicle Development and Folliculogenesis Reproductive Sciences, January 1, 2001; 8(1_suppl): S17 - S20. [Abstract] [PDF]
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J. R. McNeilly, P. T. K. Saunders, M. Taggart, M. Cranfield, H. J. Cooke, and A. S. McNeilly Loss of Oocytes in Dazl Knockout Mice Results in Maintained Ovarian Steroidogenic Function but Altered Gonadotropin Secretion in Adult Animals Endocrinology, November 1, 2000; 141(11): 4284 - 4294. [Abstract] [Full Text] [PDF]
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U. A. Vitt, E. A. McGee, M. Hayashi, and A. J. W. Hsueh In Vivo Treatment with GDF-9 Stimulates Primordial and Primary Follicle Progression and Theca Cell Marker CYP17 in Ovaries of Immature Rats Endocrinology, October 1, 2000; 141(10): 3814 - 3820. [Abstract] [Full Text] [PDF]
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N. H. Machell, O. W. Blaschuk, and R. Farookhi Developmental Expression and Distribution of N- and E-Cadherin in the Rat Ovary Biol Reprod, September 1, 2000; 63(3): 797 - 804. [Abstract] [Full Text]
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H. Louhio, O. Hovatta, J. Sjoberg, and T. Tuuri The effects of insulin, and insulin-like growth factors I and II on human ovarian follicles in long-term culture Mol. Hum. Reprod., August 1, 2000; 6(8): 694 - 698. [Abstract] [Full Text] [PDF]
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