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in the Rat Ovary
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709-2137
Address all correspondence and requests for reprints to: Madhabananda Sar, Ph.D., Chemical Industry Institute of Toxicology, 6 Davis Drive, P.O. Box 12137, Research Triangle Park, North Carolina 27709-2137. E-mail: sar{at}ciit.org
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, was performed in neonatal, early postnatal,
immature, and adult rats to determine whether ER and ERß are
differentially expressed in the ovary. ERß and ER were visualized
using a polyclonal anti-ERß antibody and a monoclonal ER (ID5)
antibody, respectively. Postfixed frozen sections and antigen-retrieved
paraffin sections of the ovary revealed nuclear ERß immunoreactivity
(IR) in granulosa cells, which was prevented when peptide-adsorbed
antibody was used instead. In immature and adult rat ovaries, ERß was
expressed exclusively in nuclei of granulosa cells of primary,
secondary, and mature follicles. Atretic follicle granulosa cells
showed only weak or no staining. No specific nuclear ERß IR was
detected in thecal cells, luteal cells, interstitial cells, germinal
epithelium, or oocytes. In neonatal rat ovary, no ERß expression was
found. In ovaries of 5- and 10-day-old rats, weak ERß IR was observed
in granulosa cells of primary and secondary follicles, but no staining
was detected in the primordial follicles. ER protein exhibited a
differential distribution in the ovary with no detectable expression in
the granulosa cells but evidence of ER IR in germinal epithelium,
interstitial cells, and thecal cells. In the oviduct and uterus, IR for
ER, but not ERß, was found in luminal epithelium, stromal cells,
muscle cells, and gland cells. Our present study demonstrates that
ERß and ER proteins are expressed in distinctly different cell
types in the ovary. The exclusive presence of ERß in granulosa cells
implies that this specific new subtype of ERß mediates some effects
of estrogen action in the regulation of growth and maturation of
ovarian follicles. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recently, a novel ER complementary DNA (cDNA), designated and now known
as the ERß subtype, was cloned from the rat prostate (19) and mouse
ovary (20). This cDNA is distinct from the classical ER cDNA (21),
which is now recognized as the ER subtype. The ERß protein has
highly conserved DNA- and ligand-binding domains compared with the
ER subtype (19, 22). The ERß protein shares with the ER protein
about 95% homology in the DNA-binding domain and 55% homology in the
C-terminal ligand-binding domain. Ligand binding assays have also shown
that the ERß protein binds estrogen with an affinity and specificity
similar to those of the ER protein (22). RT-PCR analysis and
in situ hybridization revealed the highest levels of ERß
messenger RNA (mRNA) expression in the rat ovary and prostate (19, 22).
Recent investigations also indicate the existence of several isoforms
of rat ERß mRNA (23, 24), one of which is known as ERß2 and is
expressed in the ovary, prostate, and other tissues (24). Rat ovary
expresses both ERß and ER mRNA, but the ERß mRNA is localized
predominately in the granulosa cells of small, growing, and
preovulatory follicles (25). However, limited information exists about
the specific cellular localization of ERß and ER protein in rat
ovary. The present study describes the differential distribution of
ERß and ER in rat ovary, as visualized by differential
immunocytochemical reactivity using a polyclonal antibody to synthetic
ERß peptide and a monoclonal antibody, ID5, which recognizes ER,
respectively. The results demonstrated that ERß and ER proteins
were differentially expressed in rat ovary. ERß was detected in
granulosa cells, whereas ER was localized in thecal cells,
interstitial gland cells, and germinal epithelium.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Tissue preparation
One-, 5-, and 10-day-old female rat pups were killed by
decapitation, whereas immature and adult female rats were killed by
CO2 asphyxiation. The reproductive tract tissues, including
ovary, oviduct, and uterus, were immediately removed and either frozen
(see below) or fixed in buffered formalin for 6–24 h. Tissue sections
were prepared from three to five rats in each age group.
For frozen sections, tissues were placed on Tissue-Tek OCT (Sakura Finetek, USA, Inc., Torrance, CA) mounts, frozen in isopentane precooled in liquid nitrogen (-180 C), and stored in a deep freezer (-80 C) until cryosectioning. Frozen sections of 8-µm thickness were cut and processed for immunocytochemistry. Fixed tissues were embedded in paraffin, and 5-µm sections were cut and processed for immunocytochemistry.
Histology
The classification of developmental stages of follicles were
followed as previously described for the mouse and hamster ovaries (26, 27) and later adopted for the rat ovary (28).
Immunocytochemistry
The frozen sections were air-dried and then fixed for 5 min at
room temperature in a mixture of 4% paraformaldehyde, 10% sucrose,
and 0.1 M sodium phosphate buffer, pH 7.2. The paraffin
sections were first deparaffinized and then treated with 3%
H2O2 in PBS (pH 7.6) for 5 min. These steps
were followed by heating the sections in a microwave oven (three times,
4 min each time) for antigen retrieval using a citrate buffer, pH
5.5–5.7 (1:10 dilution; HIER buffer, Ventana Medical Systems, Inc.,
Santa Barbara, CA). Postfixed frozen sections were treated with 3%
H2O2 in PBS for 3 min to reduce endogenous
peroxidase activity and then incubated with 0.2% Triton X-100 for 5
min. Postfixed frozen sections and antigen-retrieved paraffin sections
were processed for immunostaining by the avidin-biotin peroxidase
method as previously described (8). The sections were incubated
overnight at 4 C with ERß antibody (see below for details),
preadsorbed ERß antibody, and monoclonal antibody, ID5 (Dako Corp., Carpinteria, CA; see below for details). ERß antibody
was used at a concentration of 4 µg/ml in frozen sections and 10
µg/ml in paraffin sections. Monoclonal antibody was used at a
concentration of 0.1–0.2 µg/ml. The optimal working dilution of
antibody was determined by incubating sections with varying
concentrations of antibody, ranging from 0.1–10 µg/ml. Sections were
washed in 1 mM PBS (pH 7.6) followed by incubation with the
secondary antibody goat antirabbit IgG or horse antimouse IgG and
Elite avidin-biotin peroxidase at a concentration of either
1:100 or 1:200 for 30–60 min each at room temperature. After a 5-min
wash, the sections were treated with liquid diaminobenzidine (Biogenex,
San Ramon, CA) followed by a 10-min wash in PBS and then counterstained
with hematoxylin. The immuostained slides were evaluated with an
Olympus Corp. Vanox-S photomicroscope (Melville, NY). For
comparison of immunostains, sections of ovaries from rats of different
age groups were processed for immunostaining in parallel with the
standard procedure described. The intensity of immunostaining was
semiquantitatively designated as weak, medium, strong, or no
staining.
Antibody
ERß. A rabbit polyclonal antibody (PAI-310) raised against
a synthetic peptide corresponding to the C-terminal amino acid residues
467–485 of rat ERß was purchased from Affinity BioReagents, Inc. (Golden, CO). Characterization of this antibody by Western
blot and gel supershift was limited to rat ERß being overexpressed in
COS-7 cells. Preadsorbed ERß antibody was prepared by incubating
4–10 µg/ml ERß antibody with 16–40 µg synthetic peptide for
24 h at 4 C.
ER. Monoclonal antibody (clone 1D5; Dako Corp.) binds to ER and localizes ER in target tissues by both
immunofluorescence and immunoperoxidase (29). In the present study, we
compared immunostaining of the rat uterus using the monoclonal
(Dako Corp.) antibody with that produced by a polyclonal
antibody ER (MC20, Santa Cruz Biotechnology, Inc., Santa
Cruz, CA). MC-20 is an affinity-purified rabbit polyclonal antibody
raised against a peptide corresponding to amino acids 580–599 mapping
at the carboxyl-terminus of the ER of mouse origin.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, A, B, and C;
2A; and 3). The pattern of ERß
distribution appeared similar with the two types of tissue preparation,
but the intensity of ERß IR was stronger in frozen tissue sections
(Fig. 1) than in paraffin-embedded tissue sections (Fig. 3). The specificity of the ERß
antibodies in the immunohistochemical reaction was ascertained by
incubating adjacent tissue sections with the antibody preadsorbed with
the synthetic peptide used as immunogen. Preadsorbed ERß antibody did
not reveal nuclear granulosa cell immunostaining in frozen sections
(Fig. 1D) or in paraffin sections (Fig. 2B). Similarly, normal rabbit
serum did not show nuclear immunoreaction (data not shown).
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, A and B, and Fig. 3, A and B). The intensity of
ERß immunoreactivity was stronger in secondary and mature follicles
than in primary follicles. Within the follicles, some granulosa cells
did not show nuclear staining with ERß antibody. Thecal cells,
interstitial gland cells, oocytes, and germinal epithelium revealed a
lack of nuclear ERß immunoreactivity. However, interstitial gland
cells showed cytoplasmic staining, which was not completely blocked but
was reduced when preadsorbed ERß antibody was used. In the uterus
(data not shown) and oviduct (Fig. 1A), ERß IR was not detected in
luminal, stromal, gland, or muscle cells.
In both immature (21- to 23-day-old) and adult (60-day-old) female
rats, nuclear ERß expression was observed in granulosa cell nuclei of
the growing follicles at all stages from primary to secondary and
mature follicles (Fig. 3), including preantral and antral follicles.
The intensity of ERß immunostaining in granulosa cells of atretic
follicles varied considerably. Some completely lacked IR, whereas in
others, granulosa cells of the basal cell layers showed IR, and
granulosa cells toward the center of the atretic follicle revealed no
staining (data not shown). The atretic follicles were identified, as
they consisted of granulosa cells with pyknotic nuclei and were clearly
seen in adjacent ovarian sections stained with hematoxylin and
eosin. Thecal cells and oocytes showed no nuclear staining;
corpora lutea cells and interstitial gland cells had some cytoplasmic
staining that was not completely blocked, as judged from sections
incubated with preadsorbed ERß.
ERß expression in the developing reproductive organs
On postpartum day 1, histological examination of the ovary showed
oocytes, differentiating stromal cells, and pregranulosa cells.
Immunocytochemistry performed on sections of 1-day-old rat ovaries
revealed no immunostaining with ERß antibody in either oocytes or
differentiating stromal cells and pregranulosa cells (Fig. 4A). From postpartum days 1–10, the
ovary progressively increased in size; in ovaries from 5- and
10-day-old rats, primordial follicles, intermediate follicles, and
growing follicles (primary and secondary) were recognizable (Fig. 4, B
and C). At this age a small number of granulosa cells in the growing
follicles showed nuclear ERß staining (Fig. 4B), although the
intensity of the IR appeared to be weaker than that in cells from
immature and adult rat ovaries. No ERß staining was detected in
primordial follicles, but very weak staining was seen in
differentiating granulosa cells of the intermediate follicles (Fig. 4C). Oocytes, stromal cells, and germinal epithelium had no ERß IR.
Similarly, neither the uterus nor the oviduct of day 1 and day 10 rats
revealed ERß expression (data not shown).
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ER immunocytochemistry in female rat reproductive organs
Immunocytochemistry with the ID5 monoclonal antibody revealed
nuclear ER expression in the uterus and oviduct of immature and
adult rats (Fig. 5, A and F). The
staining was specific, as adjacent sections of ovary and uterus did not
show a positive immunoreaction when normal mouse IgG was used instead.
A strong nuclear ER IR was observed in luminal epithelial cells and
gland cells as well as in stroma and muscle cells (Fig. 5F). The
staining was also detected in the nuclei of these tissue sections,
where the polyclonal MC-20 antirabbit ER antibody was used in place of
the ID-5 monoclonal antibody (data not shown).
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nuclear
staining was observed in thecal cells, interstitial gland cells, and
germinal epithelium (Fig. 5, A–C). In contrast, no nuclear ER IR
was observed in granulosa cells of primary, secondary, and mature
follicles. Similarly, granulosa cells of the same maturational stage
follicles in adult rat ovary did not show nuclear ER staining (Fig. 5, D and E). Corpora lutea cells also lacked nuclear staining with
ER antibody (Fig. 5D). In contrast, thecal cells, interstitial gland
cells (Fig. 5, C–E), and germinal epithelial cells (Fig. 5, A and B)
showed nuclear ER staining. In both immature and adult rats, ER
staining was not detected in oocytes (O).
In neonatal rats, uterine stroma and muscle cells showed intense
nuclear ER staining, whereas luminal epithelial cells lacked IR
(data not shown). In the oviduct, stromal cells, muscle cells, and
luminal epithelial cells displayed strong nuclear staining. In the
ovary, the germinal epithelium as well as differentiating stromal cells
revealed specific nuclear ER staining, whereas no reaction product
was observed in pregranulosa cells and oocytes (Fig. 6A). In ovaries of 5- and 10-day-old
rats, nuclear ER staining was not detected in granulosa cells of
primordial and growing follicles (Fig. 6, B–D). In contrast, ER
staining was seen in the nuclei of some stromal cells and germinal
epithelial cells (Fig. 6, B and C), but weak staining was detected in a
few thecal cells (Fig. 6D).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In our immunocytochemical study, the distribution of ERß protein
differed from that of ER in the rat ovary. ERß was expressed in
nuclei of granulosa cells but not in thecal cells or in interstitial
gland cells and germinal epithelium. In contrast, ER was localized
in thecal cells, interstitial gland cells, and germinal epithelium, but
not in granulosa cells. Immunoreactive ERß was not detectable in
either the uterus or the oviduct, although RT-PCR analysis has shown
moderate expression of ERß mRNA in the uterus. The lack of ERß IR
in the uterus may be attributable to low antigenicity of the primary
antibody, which could not detect low levels of the ERß protein. A
recent report also indicates the presence of low levels of ERß mRNA
in the uterus and oviduct of mice (34). With the application of novel
and more sensitive antibodies against ERß protein, whether thecal
cells, corpora lutea, and interstitial gland cells as well as uterine
tissue express ERß remains to be determined.
ER and ERß have similar binding affinities for estradiol (22), and
nuclear localization of [3H]estradiol has been
demonstrated in granulosa cells, thecal cells, and interstitial gland
cells (14). The coexistence of ligand-binding sites and ER in the ovary
indicate that estrogen’s effects on follicular cells and thecal cells
are probably mediated through ERß and ER, respectively. The ERß
protein appears to be involved in follicular growth and maturation, as
disruption of the ER gene does not prevent the growth and maturation
of small follicles (35), which express the ERß, but not the ER,
protein. This interpretation is supported by recent findings that ERß
is down-regulated by gonadotropins in granulosa cells, suggesting the
possibility of the physiological role of estrogen action in the ovary
mediated by ERß (25).
In the present study, we did not detect ER receptor in oocytes using
the ID5 monoclonal antibody. This observation does not exclude the
possibility of a presence of receptors in oocytes or an effect of
estradiol on oocyte maturation. Recent data indicate that murine and
human oocyte and cumulus-oocyte complexes express ER transcripts,
suggesting that a paracrine effect of estrogen is exerted on oocyte
maturation (36, 37). Furthermore, transcription-independent or
nongenomic effects of steroids, which presumably occur through plasma
membrane receptors, have been reported (38, 39, 40). ER message has also
been detected in purified human granulosa cells, but the findings were
not consistent (41). Similarly, ER protein was not localized to
granulosa cells, but has been detected in the granulosa cells of the
antral follicles in primates and humans (42, 43, 44, 45) and was found only in
the P450 aromatase-containing granulosa cells of the antral follicle in
humans (45). Specific binding of estradiol has been demonstrated in
granulosa cells (43), and estradiol directly augumented stimulation of
granulosa cell aromatase activity by FSH (46). A direct role of
estradiol has been suggested in ovarian function in primates and humans
(41). As estrogen binds to the ERß protein with an affinity and
specificity similar to those of ER protein (22), a role of ERß in
ovarian tissue cannot be ruled out. On the basis of our findings of
ERß expression in rat ovary, a specific expression of ERß protein
can be expected in primate and human ovary.
The present data demonstrate the expression of ERß IR in ovarian
granulosa cells of growing follicles on postnatal day 5, whereas no
ERß IR was detected in the ovary on postnatal day 1, which only
contains undifferentiated stromal cells and oocytes. In the postnatal
day 5 ovary, weak immunoreactivity was observed in some granulosa
cells. As follicles grew in size and granulosa cells proliferated to
form a multiple layered epithelium, the numbers of ERß-positive
granulosa cells and their IR increased. An increase in staining
intensity could be seen in growing follicles, which is clearly evident
in the ovaries of 10- and 20-day-old rats. In contrast, expression of
ER protein was observed in stromal cells on postnatal days 1, 5, and
10; in thecal and interstitial cells of the 20-day-old ovaries; as well
as in adult ovary. The developmental expression of ERß indicates that
the ERß protein may be involved in follicular growth during postnatal
development.
The expression of transcription factors GATA-4 and GATA-6 mRNA has been
investigated in the mouse ovary during development and after hormonal
stimulation (47). Abundant expression of GATA-4 mRNA has been detected
in granulosa cells of primary and antral follicles, with lesser amounts
in thecal cells, interstitial cells, and germinal epithelium. Estrogen
stimulation in immature mice has also been shown to increase the
expression of GATA-4 and GATA-6 mRNA in granulosa cells (47). The
results of this study indicated that GATA-4 and GATA-6 may play a role
in the regulation of ovarian development, especially in the maturation
and maintenance of follicles (47). As granulosa cells of primary and
growing follicles express ERß mRNA (19, 22) and ERß protein, and
the distribution of GATA-4 transcripts and ERß protein overlaps in
the granulosa cells of primary and growing follicles, ERß protein
probably interacts with the transcription factor GATA-4 in the
regulation of granulosa cell function. Recent studies have indicated
that members of the GATA-binding protein family form heterodimers with
other GATA-binding proteins (48) and also form complexes with
other classes of transcription factors (49, 50), including steroid
hormone receptors (51). For example, estrogens exert effects on
erythropoiesis by modulating GATA-1 activity through protein-protein
interaction with the ER (48). Recent observations also indicate that
ERß can form a heterodimer complex and that a ERß-ER heterodimer
is functionally active in subpopulations of target cells (52, 53).
Thus, there is a possibility that ERß may interact with GATA-4
through protein-protein interaction to induce some of the cellular
functions in granulosa cells, as ERß and GATA-4 are coexpressed in
granulosa cells.
The present results indicate that ERß was exclusively present in
granulosa cells of primary and growing follicles, where it probably
mediates some of the effects of estrogen action in the regulation of
growth and development of the follicles. The differential expression of
ER and ERß in specific cell populations of the rat ovary in
conjunction with previously reported results of ERKO mice (35) suggests
that both ER subtypes, ER and ERß, are essential for normal
ovarian function. However, the biological function of the ERß subtype
is presently still unknown, and future studies of knockout mice with
the disrupted ERß gene function may provide information needed to
understand the physiological action of ERß.
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Acknowledgments |
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Received May 29, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and ß. Endocrinology 138:863–870 (ER) and estrogen receptor ß (ERß) messenger
ribonucleic acid in the wild-type and ERß knockout mouse.
Endocrinology 138:4613–4621. Mol Endocrinol 11:1486–1496 and ß form heterodimers on DNA. J Biol
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J. F. Couse, M. M. Yates, R. Sanford, A. Nyska, J. H. Nilson, and K. S. Korach Formation of Cystic Ovarian Follicles Associated with Elevated Luteinizing Hormone Requires Estrogen Receptor-{beta} Endocrinology, October 1, 2004; 145(10): 4693 - 4702. [Abstract] [Full Text] [PDF]
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K. P. Lehmann, S. Phillips, M. Sar, P. M. D. Foster, and K. W. Gaido Dose-Dependent Alterations in Gene Expression and Testosterone Synthesis in the Fetal Testes of Male Rats Exposed to Di (n-butyl) phthalate Toxicol. Sci., September 1, 2004; 81(1): 60 - 68. [Abstract] [Full Text] [PDF]
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A. R. Beker-van Woudenberg, H. T.A. van Tol, B. A.J. Roelen, B. Colenbrander, and M. M. Bevers Estradiol and Its Membrane-Impermeable Conjugate (Estradiol-Bovine Serum Albumin) During In Vitro Maturation of Bovine Oocytes: Effects on Nuclear and Cytoplasmic Maturation, Cytoskeleton, and Embryo Quality Biol Reprod, May 1, 2004; 70(5): 1465 - 1474. [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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J. F. Couse, M. M. Yates, V. R. Walker, and K. S. Korach Characterization of the Hypothalamic-Pituitary-Gonadal Axis in Estrogen Receptor (ER) Null Mice Reveals Hypergonadism and Endocrine Sex Reversal in Females Lacking ER{alpha} But Not ER{beta} Mol. Endocrinol., June 1, 2003; 17(6): 1039 - 1053. [Abstract] [Full Text] [PDF]
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N. J. Barlow, S. L. Phillips, D. G. Wallace, M. Sar, K. W. Gaido, and P. M. D. Foster Quantitative Changes in Gene Expression in Fetal Rat Testes following Exposure to Di(n-butyl) Phthalate Toxicol. Sci., June 1, 2003; 73(2): 431 - 441. [Abstract] [Full Text] [PDF]
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 A. J. Jakimiuk, S. R. Weitsman, H.-W. Yen, M. Bogusiewicz, and D. A. Magoffin Estrogen Receptor {alpha} and {beta} Expression in Theca and Granulosa Cells from Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5532 - 5538. [Abstract] [Full Text] [PDF]
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S. Jesmin, C. N. Mowa, N. Matsuda, A.-E. Salah-Eldin, H. Togashi, I. Sakuma, Y. Hattori, and A. Kitabatake Evidence for a Potential Role of Estrogen in the Penis: Detection of Estrogen Receptor-{alpha} and -{beta} Messenger Ribonucleic Acid and Protein Endocrinology, December 1, 2002; 143(12): 4764 - 4774. [Abstract] [Full Text] [PDF]
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K.-i. Matsuda, I. Ochiai, M. Nishi, and M. Kawata Colocalization and Ligand-Dependent Discrete Distribution of the Estrogen Receptor (ER){alpha} and ER{beta} Mol. Endocrinol., October 1, 2002; 16(10): 2215 - 2230. [Abstract] [Full Text] [PDF]
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W. N. Jefferson, J. F. Couse, E. Padilla-Banks, K. S. Korach, and R. R. Newbold Neonatal Exposure to Genistein Induces Estrogen Receptor (ER){alpha} Expression and Multioocyte Follicles in the Maturing Mouse Ovary: Evidence for ER{beta}-Mediated and Nonestrogenic Actions Biol Reprod, October 1, 2002; 67(4): 1285 - 1296. [Abstract] [Full Text] [PDF]
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D. Lopez, M. D. Sanchez, W. Shea-Eaton, and M. P. McLean Estrogen Activates the High-Density Lipoprotein Receptor Gene via Binding to Estrogen Response Elements and Interaction with Sterol Regulatory Element Binding Protein-1A Endocrinology, June 1, 2002; 143(6): 2155 - 2168. [Abstract] [Full Text] [PDF]
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P. Yang, A. Kriatchko, and S. K. Roy Expression of ER-{alpha} and ER-{beta} in the Hamster Ovary: Differential Regulation by Gonadotropins and Ovarian Steroid Hormones Endocrinology, June 1, 2002; 143(6): 2385 - 2398. [Abstract] [Full Text] [PDF]
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C. M. Klinge, S. C. Jernigan, and K. E. Risinger The Agonist Activity of Tamoxifen Is Inhibited by the Short Heterodimer Partner Orphan Nuclear Receptor in Human Endometrial Cancer Cells Endocrinology, March 1, 2002; 143(3): 853 - 867. [Abstract] [Full Text] [PDF]
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 K. A. Brenneman, D. F. Meleason, M. Sar, M. W. Marshall, R. A. James, E. A. Gross, J. T. Martin, and D. C. Dorman Olfactory Mucosal Necrosis in Male CD Rats Following Acute Inhalation Exposure to Hydrogen Sulfide: Reversibility and the Possible Role of Regional Metabolism Toxicol Pathol, February 1, 2002; 30(2): 200 - 208. [Abstract] [PDF]
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Y. Ikeda, A. Nagai, M.-a. Ikeda, and S. Hayashi Increased Expression of Mullerian-Inhibiting Substance Correlates with Inhibition of Follicular Growth in the Developing Ovary of Rats Treated with E2 Benzoate Endocrinology, January 1, 2002; 143(1): 304 - 312. [Abstract] [Full Text] [PDF]
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G. Cheng, Z. Weihua, S. Makinen, S. Makela, S. Saji, M. Warner, J.-A. Gustafsson, and O. Hovatta A Role for the Androgen Receptor in Follicular Atresia of Estrogen Receptor Beta Knockout Mouse Ovary Biol Reprod, January 1, 2002; 66(1): 77 - 84. [Abstract] [Full Text]
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K. M. Waters, S. Safe, and K. W. Gaido Differential Gene Expression in Response to Methoxychlor and Estradiol through ER{alpha}, ER{beta}, and AR in Reproductive Tissues of Female Mice Toxicol. Sci., September 1, 2001; 63(1): 47 - 56. [Abstract] [Full Text] [PDF]
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H. T. Jansen, C. West, M. N. Lehman, and V. Padmanabhan Ovarian Estrogen Receptor-{beta} (ER{beta}) Regulation: I. Changes in ER{beta} Messenger RNA Expression Prior to Ovulation in the Ewe Biol Reprod, September 1, 2001; 65(3): 866 - 872. [Abstract] [Full Text] [PDF]
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S. Saji, H. Sakaguchi, S. Andersson, M. Warner, and J.-A. Gustafsson Quantitative Analysis of Estrogen Receptor Proteins in Rat Mammary Gland Endocrinology, July 1, 2001; 142(7): 3177 - 3186. [Abstract] [Full Text] [PDF]
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 S. Signoretti and M. Loda Estrogen Receptor {beta} in Prostate Cancer : Brake Pedal or Accelerator? Am. J. Pathol., July 1, 2001; 159(1): 13 - 16. [Full Text] [PDF]
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H. Cardenas, K.A. Burke, R.M. Bigsby, W.F. Pope, and K.P. Nephew Estrogen Receptor {beta} in the Sheep Ovary During the Estrous Cycle and Early Pregnancy Biol Reprod, July 1, 2001; 65(1): 128 - 134. [Abstract] [Full Text] [PDF]
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C. Guo, L. Savage, K. D. Sarge, and O.-K. Park-Sarge Gonadotropins Decrease Estrogen Receptor-{beta} Messenger Ribonucleic Acid Stability in Rat Granulosa Cells Endocrinology, June 1, 2001; 142(6): 2230 - 2237. [Abstract] [Full Text] [PDF]
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K.-C. Choi, S. K. Kang, C.-J. Tai, N. Auersperg, and P. C. K. Leung Estradiol Up-Regulates Antiapoptotic Bcl-2 Messenger Ribonucleic Acid and Protein in Tumorigenic Ovarian Surface Epithelium Cells Endocrinology, June 1, 2001; 142(6): 2351 - 2360. [Abstract] [Full Text] [PDF]
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S. K. Kang, K.-C. Choi, C.-J. Tai, N. Auersperg, and P. C. K. Leung Estradiol Regulates Gonadotropin-Releasing Hormone (GnRH) and its Receptor Gene Expression and Antagonizes the Growth Inhibitory Effects of GnRH in Human Ovarian Surface Epithelial and Ovarian Cancer Cells Endocrinology, February 1, 2001; 142(2): 580 - 588. [Abstract] [Full Text] [PDF]
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T. Kurita, K.-j. Lee, P. T.K. Saunders, P. S. Cooke, J. A. Taylor, D. B. Lubahn, C. Zhao, S. Mäkelä, J.-A. Gustafsson, R. Dahiya, et al. Regulation of Progesterone Receptors and Decidualization in Uterine Stroma of the Estrogen Receptor-{{alpha}} Knockout Mouse Biol Reprod, January 1, 2001; 64(1): 272 - 283. [Abstract] [Full Text]
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G. Pelletier and M. El-Alfy Immunocytochemical Localization of Estrogen Receptors {{alpha}} and {beta} in the Human Reproductive Organs J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4835 - 4840. [Abstract] [Full Text]
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B. Bao, N. Kumar, R. M. Karp, H. Allen Garverick, and K. Sundaram Estrogen Receptor-{beta} Expression in Relation to the Expression of Luteinizing Hormone Receptor and Cytochrome P450 Enzymes in Rat Ovarian Follicles Biol Reprod, December 1, 2000; 63(6): 1747 - 1755. [Abstract] [Full Text]
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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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H. Wang, H. Eriksson, and L. Sahlin Estrogen Receptors {alpha} and {beta} in the Female Reproductive Tract of the Rat During the Estrous Cycle Biol Reprod, November 1, 2000; 63(5): 1331 - 1340. [Abstract] [Full Text]
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C.-H. Chiang, K. W. Cheng, S. Igarashi, P. S. Nathwani, and P. C. K. Leung Hormonal Regulation of Estrogen Receptor {alpha} and {beta} Gene Expression in Human Granulosa-Luteal Cells in Vitro J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3828 - 3839. [Abstract] [Full Text]
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P. T.K. Saunders, M. R. Millar, K. Williams, S. Macpherson, D. Harkiss, R. A. Anderson, B. Orr, N. P. Groome, G. Scobie, and H. M. Fraser Differential Expression of Estrogen Receptor-{alpha} and -{beta} and Androgen Receptor in the Ovaries of Marmosets and Humans Biol Reprod, October 1, 2000; 63(4): 1098 - 1105. [Abstract] [Full Text]
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T. A. Ishunina, F. P. M. Kruijver, R. Balesar, and D. F. Swaab Differential Expression of Estrogen Receptor {alpha} and {beta} Immunoreactivity in the Human Supraoptic Nucleus in Relation to Sex and Aging J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3283 - 3291. [Abstract] [Full Text]
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C. Patrone, G. Pollio, E. Vegeto, E. Enmark, I. de Curtis, J.-A. Gustafsson, and A. Maggi Estradiol Induces Differential Neuronal Phenotypes by Activating Estrogen Receptor {alpha} or {beta} Endocrinology, May 1, 2000; 141(5): 1839 - 1845. [Abstract] [Full Text] [PDF]
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S. Chu, P. Mamers, H. G. Burger, and P. J. Fuller Estrogen Receptor Isoform Gene Expression in Ovarian Stromal and Epithelial Tumors J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 1200 - 1205. [Abstract] [Full Text]
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C. S. Rosenfeld, A. A. Murray, G. Simmer, M. G. Hufford, M. F. Smith, N. Spears, and D. B. Lubahn Gonadotropin Induction of Ovulation and Corpus Luteum Formation in Young Estrogen Receptor-{alpha} Knockout Mice Biol Reprod, March 1, 2000; 62(3): 599 - 605. [Abstract] [Full Text]
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W. N. Jefferson, J. F. Couse, E. P. Banks, K. S. Korach, and R. R. Newbold Expression of Estrogen Receptor {beta} Is Developmentally Regulated in Reproductive Tissues of Male and Female Mice Biol Reprod, February 1, 2000; 62(2): 310 - 317. [Abstract] [Full Text]
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 S Dupont, A Krust, A Gansmuller, A Dierich, P Chambon, and M Mark Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes Development, January 10, 2000; 127(19): 4277 - 4291. [Abstract] [PDF]
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 J. F. Couse, S. C. Hewitt, D. O. Bunch, M. Sar, V. R. Walker, B. J. Davis, and K. S. Korach Postnatal Sex Reversal of the Ovaries in Mice Lacking Estrogen Receptors and Science, December 17, 1999; 286(5448): 2328 - 2331. [Abstract] [Full Text]
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J. F. Couse, D. O. Bunch, J. Lindzey, D. W. Schomberg, and K. S. Korach Prevention of the Polycystic Ovarian Phenotype and Characterization of Ovulatory Capacity in the Estrogen Receptor-{alpha} Knockout Mouse Endocrinology, December 1, 1999; 140(12): 5855 - 5865. [Abstract] [Full Text]
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M. L. O’Brien, K. Park, Y. In, and O.-K. Park-Sarge Characterization of Estrogen Receptor-{beta} (ER{beta}) Messenger Ribonucleic Acid and Protein Expression in Rat Granulosa Cells Endocrinology, October 1, 1999; 140(10): 4530 - 4541. [Abstract] [Full Text]
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 J. F. Couse and K. S. Korach Estrogen Receptor Null Mice: What Have We Learned and Where Will They Lead Us? Endocr. Rev., June 1, 1999; 20(3): 358 - 417. [Abstract] [Full Text]
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S. L. Fitzpatrick, J. M. Funkhouser, D. M. Sindoni, P. E. Stevis, D. C. Deecher, A. R. Bapat, I. Merchenthaler, and D. E. Frail Expression of Estrogen Receptor-{beta} Protein in Rodent Ovary Endocrinology, June 1, 1999; 140(6): 2581 - 2591. [Abstract] [Full Text]
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 E. J. Routledge, R. White, M. G. Parker, and J. P. Sumpter Differential Effects of Xenoestrogens on Coactivator Recruitment by Estrogen Receptor (ER) alpha and ERbeta J. Biol. Chem., November 10, 2000; 275(46): 35986 - 35993. [Abstract] [Full Text] [PDF]
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