| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ARTICLES |
-Subunit
Department of Biochemistry, Molecular Biology, and Cell Biology, and Center for Reproductive Science, Northwestern University, Evanston, Illinois 60208
Address all correspondence and requests for reprints to: Kelly E. Mayo, Ph.D., Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, Illinois 60208. E-mail: k-mayo{at}northwestern.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-subunit gene from a metallothionein-I promoter (MT-) and
examine the effects of the MT- transgene on gonadotropin levels and
fertility. To characterize the effects of increased inhibin -subunit
on gonadal morphology and function, in this report we investigate
gonadal histology, steroid hormone levels, and the basis of ovarian
cyst formation in MT- transgenic mice. MT- transgenic female mice
develop large fluid-filled ovarian cysts of follicular origin as early
as 3 months of age. By 12 months of age, more than 92% of female
MT- transgenic mice develop ovarian cysts compared with less than
25% of wild-type littermates. Ovarian cysts form unilaterally or
bilaterally, and cystic ovaries often have a greatly expanded bursal
sac. Additionally, the ovaries of MT- transgenic mice contain
polyovular follicles and have fewer mature antral follicles and corpora
lutea. MT- female mice exhibit abnormal steroid hormone production,
with increased serum T levels and reductions in serum E with
corresponding reductions in uterine mass. In the MT- transgenic
males, testis size was decreased by 20–40% compared with control
males, and there is a corresponding reduction in seminiferous tubule
volume. After a chronic treatment with a GnRH antagonist, MT- female
mice continued to develop ovarian cysts and bursal sac expansions,
although the cysts were markedly reduced in size. These results
indicate that the expression of the rat inhibin -subunit in mice
results in significant ovarian pathology, reduced testicular size, and
altered ovarian steroidogenesis. The antagonist studies are consistent
with a direct ovarian effect of the -subunit transgene product
mediated by changes in the inhibin-to-activin ratio in these
mice. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
- and ßA-subunit mRNA
expression (10). Additionally, activins and inhibins
affect ovarian follicular growth, development, atresia, and
steroidogenesis as well as testicular spermatogonial production
(8, 11, 12). Injection of inhibin into the rat ovarian
bursa causes an increase in the size and number of follicles and
increased thymidine incorporation into DNA (7). Activin
acts in an opposite manner to decrease granulosa cell proliferation and
increase atresia of antral follicles (7). Inhibin
stimulates LH-induced androgen production in rat theca cells and Leydig
cells, an effect that is blocked by activin (11). In the
testis, inhibin decreases spermatogonial proliferation when injected
locally. Conversely, activin stimulates spermatogonial proliferation
(8). These data suggest that inhibin and activin can
function as autocrine/paracrine factors within the gonad and are often
functional antagonists.
The potential role of inhibin in the pathogenesis of ovarian disease is
unclear. Increased inhibin activity has been associated with
polycystic ovarian disease in some studies (13, 14, 15) and
with juvenile granulosa cell tumors (16, 17). Inhibin A
has also been suggested to be a useful marker for mucinous epithelial
cell tumors in women (16) and a prognostic factor for the
survival of postmenopausal women with epithelial ovarian carcinoma
(18). Granulosa-theca cell tumors in mares are also known
to express high levels of inhibin (19). Mice that are
deficient for the inhibin -subunit gene develop gonadal stromal
tumors, adrenal cortical tumors, a cachexia-like wasting syndrome, and
are infertile (20, 21). These observations indicate that
increased inhibin levels or conversely lack of inhibin is often
associated with ovarian pathogenesis. This suggests that inhibin may
exert direct autocrine/paracrine effects within the ovary.
Although abnormal inhibin levels have been associated with ovarian
pathology, it has been difficult to establish a cause-and-effect
relationship between inhibin and ovarian disorders. To establish the
importance of inhibin and the related hormone activin in gonadal
function and in reproductive disorders, transgenic mice have been
generated that overexpress the inhibin -subunit gene. These animals
provide a useful in vivo system for examining the actions of
inhibin and activin within the intact animal. Metallothionein-I
promoter (MT-) transgenic mice exhibit abnormal gonadotropin
levels and female subfertility, as described in the accompanying paper.
This report focuses on the effect of inhibin -subunit overexpression
on gonadal steroidogenesis and morphology and describes the resulting
ovarian pathologies.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
transgenic mice is described in detail
in the accompanying paper. A 1.4-kb rat inhibin cDNA was
cloned into the vector pEV142 (provided by Dr. Richard Palmiter,
University of Washington, Seattle), which includes a mouse MT- and a
human GH RNA processing and polyadenylation site (22, 23).
Transgenic animals were produced at the Northwestern University-Markey
Developmental Biology Center Core Facility under the direction of Dr.
Phillip Iannoccone. Genomic DNA was isolated from tail biopsies of the
11 F0 mice born. Three founder male mice were
identified using the 1.4-kb rat inhibin cDNA as a hybridization
probe. The males were used to establish three separate transgenic
lines, lines A–C. All subsequent generations were raised in a room
with a controlled photoperiod (14 h of light, 10 h of dark) and
temperature (22–25 C). All lines stably transmit the transgene at the
expected 50% Mendelian frequency.
Ovarian cyst analysis and gonadal histology
Ovaries of MT- transgenic and wild-type mice were examined
for the gross appearance of ovarian cysts. Animals were distributed
into three groups according to age: 3–7 months, 8–12 months, and
older than 12 months. Cysts were categorized based on size as small
(<5 mm diameter) and large (>5 mm diameter). Testes were removed and
weighed before fixation. The excised ovaries and testes were
immediately fixed in fresh 4% paraformaldehyde in PBS, pH 7.4. After
overnight fixation, tissues were dehydrated in ethanol and embedded in
paraffin. Sections of ovaries and testes (4–6 µm) were prepared
using a Reichert-Jung microtome (Cambridge Instruments, Inc., Buffalo,
NY). Ovaries with large cysts were sectioned at 10–20 µm to maintain
tissue integrity. The sections were deparaffinized with xylene,
dehydrated in absolute ethanol, and rehydrated in water. Sections were
stained with eosin and counterstained with hematoxylin. Ovaries
examined in the polyovular follicle study were prepared as described
above and then completely sectioned at 6 µm. All sections were
examined at x100 and x400 and/or x1000 magnification. Polyovular
follicles spanned several serial sections; however, only distinctly
different polyovular follicles were counted.
Hormone measurements
All female mice were cycled before collection of serum for
hormone analysis. Estrous cycle stages were determined by daily
examination of vaginal cytology. Those animals demonstrating a minimum
of two consecutive 4- to 5-d cycles were killed on the morning of
metestrus or diestrus. Ovarian cyst fluid was collected with a
26.5-gauge needle and syringe and stored at -80 C until the inhibin
-chain RIA was performed. Serum and cyst fluid hormone measurements
were determined by RIA at the Northwestern University P30 Center RIA
Core Facility under the direction of Drs. John Levine and Neena
Schwartz. National Institute of Diabetes and Digestive and Kidney
Diseases antiserum and standards (rLH-RP-3 standard/rLH-S-11 antibody
and rFSH-RP-2 standard/rFSH-S-11 antibody) were used for LH and FSH
measurements. FSH and LH results are expressed as nanograms per
milliliter. FSH assay sensitivity was 0.05 ng/sample or 1.0 ng/ml, and
LH assay sensitivity was 0.01 ng/sample or 0.2 ng/ml. A T double
antibody RIA kit (ICN, Costa Mesa, CA) and E double
antibody RIA kit (Diagnostic Products Corp., Los Angeles,
CA) containing antibodies and standards were used for T and E RIAs.
Both T assay and E assay sensitivity was at 2.0 pg/ml. Animals used in
the steroid studies ranged from 6 to 12 months of age. Reagents (Tyr 27
rat inhibin 1–27 standard/sheep anti-Tyr 27 rat inhibin 1–27
antibody 795) provided by Dr. Wylie Vale (Salk Institute, San Diego,
CA) were used for the inhibin -chain assay as described (24, 25). Results are expressed as picomoles per milliliter. The
interassay coefficients of variation were 12.0%, 12.0%, and 9.3% for
T, E, and inhibin, respectively.
GnRH antagonist treatment
Six-week-old MT- transgenic and wild-type littermate female
mice were used in this study. The GnRH antagonist Cetrorelix (Asta
Medica, Frankfurt, Germany) was administered by injection at a
dosage of 10 mg/kg body weight every 84 h for 4.5 months to 5
MT- C-line females, 5 MT- A-line females, and 10 wild-type
females. A vehicle (water) injection of the same volume was
administered to 4 MT- C-line females, 5 MT- A-line females, and
10 wild-type females as a control. Animals were killed 2–3 days after
the last injection. Serum samples were collected, gross ovarian
morphology was examined, and ovaries were fixed in 4% paraformaldehyde
and embedded in paraffin as described above for subsequent histological
analysis.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-subunit transgene
expression on ovarian morphology, both gross and microscopic
histological analyses of ovaries from MT- transgenic mice were
performed. The most striking ovarian phenotype for the MT-
transgenic females was the development of large fluid-filled ovarian
cysts (Fig. 1
). The cysts can be large
enough to distend the abdomen of MT- female mice (Fig. 1A). The
bursal sac of cystic ovaries is often expanded and filled with clear
fluid (Fig. 1B). Serial sectioning of MT- ovaries revealed that
multiple cysts are usually present within a single ovary, with an
observed range of one to three cysts per ovary (Fig. 1C).
|
ovaries revealed additional smaller
ovarian cysts not apparent by gross examination (Fig. 2, A–C). Also, transgenic ovaries are
slightly smaller than control ovaries, and in general they exhibit
fewer tertiary follicles, antral follicles, and corpora lutea. The
periphery of the MT- ovarian cysts are lined with several thin
discontinuous layers of cuboidal cells that appear to be remnants of
the granulosa cell layer cells (Fig. 2, D–E, open arrows). In
situ hybridization analysis as described in the accompanying paper
revealed no expression of the inhibin -subunit or LH receptor mRNA
in these cells (not shown), so they do not appear to be healthy
granulosa cells. The MT- cystic follicles have an additional outer
layer of flat, striated cells that exhibit the fibroblast-like
morphology of a theca layer (Fig. 2, D–E, solid arrows). Cyst
aspirates collected from both MT- and wild-type ovaries were
measured for inhibin levels by RIA. The total inhibin levels
present in MT- transgenic cyst fluid were 6-fold greater (4.31
± 1.07 pmol/ml) than fluid collected from wild-type mice with ovarian
cysts (0.71 ± 0.31 pmol/ml) (P < 0.05). Serum
total inhibin levels were increased in MT- transgenic animals
by approximately 2-fold, as described in the accompanying paper
(25A ).
|
). The
incidence of ovarian cysts varies between mouse strains and with age
(26). Therefore, to establish the basal rate of cyst
formation in the background strain of MT- transgenic mice, CD-1, we
examined ovaries from nontransgenic littermates at a range of ages. The
average rate of cyst formation for all ages of nontransgenic
littermates was 22%. The frequency of cyst formation in MT-
transgenic females increases with age. Fifty to 79% of MT- females
from 3–7 months of age develop ovarian cysts, 58–91% of MT-
females from 8–12 months of age develop ovarian cysts, and more than
90% of MT- females older than 1 yr develop ovarian cysts (Table 1).
Cysts from wild-type ovaries are typically very small (<5 mm), and
these mice generally have only one cyst per ovary. Cysts from
transgenic females are much larger (>5 mm) (Table 2), and these animals typically display
two or more cysts per ovary. The incidence of large ovarian cysts is
statistically greater in transgenic females compared with wild-type
littermates.
|
|
). The
majority of the follicles with two ova are late preantral or early
antral follicles (Fig. 3, B and C), but a few large late antral
follicles were also observed (Fig. 3A). A group of transgenic and
control ovaries were completely sectioned at 4–6 µm. Subsequently,
each section was examined for the presence of polyovular follicles
(27). On average, MT- transgenic ovaries contained
three polyovular follicles per ovary (line A, 2.8 ± 0.4, n =
6; line C, 3.0 ± 0.0, n = 5). Of the 10 wild-type ovaries
examined, only one polyovular follicle was observed (0.1 ± 0.1,
n = 10).
|
transgenic females, MT- transgenic males
are fertile, despite reduced sperm production. We have observed that in
MT- male transgenic mice, testis size is decreased (line A,
125.5 ± 16.7 mg per pair of testes, n = 4; line C,
168.3 ± 8.1 mg per pair of testes, n = 7) compared with
nontransgenic male littermates (208.8 ± 12.7 mg per pair of
testes, n = 10, P < 0.01) (Fig. 4, A and B). This reduction in testis
size is associated with reduced seminiferous tubule volume (Fig. 4, C
and D). Seminiferous tubule diameters were significantly reduced in
transgenic male mice (line A, 82.8 ± 1 5.3 µm; line C,
112.3 ± 2.4 µm; wild-type, 157.0 ± 5.3 µm;
P < 0.0001). Histological studies revealed fewer
mature sperm within most seminiferous tubules of MT- males,
consistent with reduced sperm counts shown in the accompanying
paper.
|
female mice. T levels were increased in MT- transgenic
female mice from both lines compared with wild-type female mice (Fig. 5A). Conversely, E levels were slightly
lower in MT- line C transgenic female mice (Fig. 5B), and uterine
weights were also reduced (wild-type, 152.9 ± 36.0 mg, n =
6; line A, 98.0 ± 10.0 mg, n = 5; line C, 105.0 ± 4.4
mg, n = 5).
|
mice is in part
responsible for reduced fertility, as discussed in the accompanying
paper. To determine if the gonadotropin environment also contributed to
the observed ovarian pathogenesis, FSH and LH levels were suppressed by
chronically blocking GnRH action with the GnRH antagonist Cetrorelix
(Asta Medica). If the perturbations in the gonadotropins induced the
observed ovarian cysts, then suppressing these hormones should prevent
the formation of ovarian cysts.
Six-week-old female mice were treated biweekly (every 84 h) with
the GnRH antagonist Cetrorelix until the animals reached 6 months of
age. Normally, most MT- female mice exhibit ovarian cysts by 6
months of age, as previously discussed (Table 1
). Serum hormone levels
of FSH and LH were measured and found to be significantly repressed,
indicating that the antagonist treatment was effective (Fig. 6). For vehicle-treated mice, LH levels
were variable and were not observed to be significantly greater in
MT- females compared with wild type. The disparity between these
(vehicle-treated) LH levels and the increased LH measurements reported
in the accompanying paper is likely attributable to the fact that the
animals used in the antagonist study were not matched for estrous cycle
stage. FSH levels were greatly suppressed in vehicle-treated transgenic
mice vs. vehicle-treated wild-type mice, consistent with our
previous findings. Examination of ovarian morphology from
antagonist-treated control mice showed a reduction in ovarian size and
the absence of corpora lutea, again indicating that the GnRH antagonist
was effective (Fig. 7, A and B). In
Cetrorelix-treated transgenic mice, ovarian cysts persisted (Fig. 7, C
and D). However, the morphology of the ovarian cysts in the
antagonist-treated animals was quite different from that seen in
vehicle-treated transgenic females (Fig. 7, C and D). Ovaries from
antagonist-treated mice often exhibited extended and fluid-filled
bursal sacs, but the internal ovarian cysts were generally smaller that
those observed in vehicle-treated transgenic mice. The overall
percentage of MT- transgenic female mice that developed ovarian
cysts was reduced by 15–20% compared with vehicle-treated MT-
transgenic female mice (Fig. 8). Thus,
although the cyst phenotype is somewhat attenuated by chronic
gonadotropin inhibition, ovarian cysts persist, consistent with a
potential direct effect of the inhibin -subunit transgene on the
ovary.
|
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-transgene has a negative impact on gamete production
and fertility in MT- transgenic mice. In the present study, we focus
on changes in ovarian steroidogenesis and on several intriguing ovarian
pathologies, including expansion of the bursal sac, development of
polyovular follicles, and formation of cystic follicles, all of which
suggest a disruption of normal folliculogenesis. Although these
pathologies might be explained by the altered gonadotropin ratios in
MT- transgenic mice, our findings using chronic GnRH antagonism to
suppress FSH and LH are consistent with a direct effect of the inhibin
-subunit transgene on ovarian steroidogenesis; additionally, they
are in agreement with observed paracrine effects of inhibin on thecal
cell androgen production in cell culture systems (28).
MT- female transgenic mice have several ovarian phenotypes similar
to transgenic mice overexpressing the LH ß-subunit and ER-deficient
mice, which also exhibit ovarian cysts (29, 30, 31, 32, 33). In
addition to the commonality of cystic ovaries, all of the discussed
genetic mouse models display aberrant hormone levels, specifically
increased LH and T. The LHß transgenic mice have increased LH,
increased androgens, and, in the specific CF-1 genetic background, the
females develop ovarian tumors. Both LH and T are increased as early as
2 wk of age, resulting in the later development of
gonadotropin-dependent hyperandrogenemia, precocious puberty, and
hemorrhagic ovarian cysts (29, 30). E receptor-deficient
mice (ERKO) also exhibit hemorrhagic ovarian cysts and a 10-fold
increase in serum E2 and T (31, 32, 33). The cyst formation in
ERKO mice may be attributable to increased LH resulting from the block
in the E negative feedback loop. Although MT- female mice exhibit
ovarian cysts and increased T and LH, the pathology of MT- cysts
differs considerably from those observed in the LHß or ERKO mice. The
cysts from MT- female mice are not hemorrhagic, except in a few rare
cases, and are often associated with a distended bursal sac filled with
fluid, unlike the hemorrhagic cysts observed in these other models.
The hormone profile of MT- female mice resembles that of human
polycystic ovarian syndrome (PCOS), which is characterized by increased
androgen levels, increased LH levels, and anovulation (34, 35). In some studies, increased serum levels of inhibin A and
inhibin B and increased follicular fluid inhibin levels have been
associated with PCOS (13, 14, 15). Conversely, other studies
have reported no link between high inhibin levels and PCOS (36, 37). The mechanisms underlying PCOS are not known, but evidence
indicates that alterations in the endocrine, paracrine, and autocrine
control of folliculogenesis are involved. PCOS is likely to be one
example of a group of larger disorders that result in functional
ovarian hyperandrogenism, for which the primary abnormality is
gonadotropin-dependent hyperandrogenemia (38). Recent cell
culture studies with thecal cells isolated from PCOS ovaries suggest
that there is an increase in the steroidogenic activity of these cells,
including changes in the androgen biosynthetic pathway
(39). Despite some of the similarities in hormonal
profile, the ovarian cysts from MT- females are very different
morphologically from the cysts observed in women with PCOS. The
transgenic mouse cysts are massive and are usually limited to one to
three cysts per ovary; they would appear to represent developed
follicles that fail to appropriately ovulate. The cysts from PCOS
ovaries are much smaller, subcapsular, and more numerous, representing
a state of arrested early follicular maturation (38).
Thus, the altered gonadotropin and steroid levels result in very
distinct ovarian pathologies in this mouse model and in the human
disease.
A related ovarian pathology, ovarian hyperstimulation syndrome, is
characterized by massive ovarian enlargement and ovarian cysts after
exogenous administration of human CG (hCG) (40). The
ovarian cysts from women with ovarian hyperstimulation syndrome in many
respects resemble MT- transgenic ovarian cysts. Although the
pathophysiology of the syndrome is still unclear, it is reported that
treatment with hCG or LH causes increased permeability of ovarian
capillary vessels, resulting in follicular cysts (40).
Currently, several proteins such as vascular endothelial factor and
factors of the renin-angiotensin system are believed to be responsible
for stimulating increased vascular permeability after ovulation
induction. In severe cases, vascular leakage can lead to fluid
accumulation, ascites, and greatly enlarged ovaries with follicular and
luteal cysts (41). The twice-daily treatment of rats with
subovulatory doses of hCG results in the development of large ovarian
cysts, suggesting that long-term exposure to LH is a factor in ovarian
cyst formation (42). Cyst formation in MT- transgenic
mice may be associated with increased ovarian vessel permeability,
although this has not been directly investigated. Consistent with a
perturbation in vascular permeability is the pronounced distention of
the bursal sac and the accumulation of fluid that is observed in most
MT- transgenic ovaries.
FSH and LH are important modulators of ovarian steroidogenesis and
folliculogenesis, and the abnormal gonadotropin environment in MT-
transgenic females appears to contribute to the reduced fertility of
these mice, as described in the accompanying paper. It is also likely
that the reduction in serum FSH levels in the MT- transgenic mice
contributes to the ovarian and testicular growth phenotypes.
Morphological examination of MT- ovaries revealed a decrease in
ovarian size and fewer corpora lutea and antral follicles compared with
wild-type littermates. The MT- ovarian morphology is similar in some
respects to that of the activin receptor type II-deficient mouse and
the follistatin overexpression transgenic mouse. Activin opposes
inhibin function by stimulating the secretion of FSH from the anterior
pituitary. Activin receptor type II-deficient mice are defective for
activin signaling and exhibit suppressed FSH levels, small ovaries, and
fewer corpora lutea (43). Follistatin is an
activin-binding protein that is able to act in vivo as an
activin antagonist (44). Some lines of follistatin
overexpression transgenic mice are infertile, with small ovaries
containing follicles blocked at various stages of follicular
development, and these mice also have reduced FSH levels
(45). MT- transgenic male mice exhibit a reduction in
testis size, tubule volume, and sperm numbers. MT- transgenic males,
unlike MT- females, are fertile. MT- transgenic males exhibit a
strikingly similar phenotype to both FSH-deficient male mice and FSH
receptor-deficient males (46, 47). The common phenotype is
the reduction in testis volume and sperm numbers. Despite abnormal FSH
levels and sperm production, MT- transgenic males are fully fertile,
thus supporting the hypothesis that FSH is not essential for male
fertility in the rodent (46, 47).
Altered gonadotropin levels might also be expected to be causative in
the ovarian pathologies and cyst formation observed in these mice.
Administration of excess LH or hCG to pregnant or hypothyroid rats is
known to cause the formation of ovarian follicular cysts (42, 48). However, in our studies, chronic suppression of both LH and
FSH release in MT- female mice using the GnRH antagonist Cetrorelix
failed to block cyst formation. Ovarian cysts from the
antagonist-treated MT- females are smaller in size, but they
occur at about the same frequency as in control animals. In
addition, fluid accumulation in the ovarian bursal sac continue to
occur in antagonist-treated animals. This suggests a
gonadotropin-independent action of the inhibin -subunit transgene
product, most likely at the level of the ovary. An attractive
possibility is that excess ovarian inhibin results in increased ovarian
androgen production. Inhibin is reported to stimulate LH-induced
androgen production by rat thecal or Leydig cells in cultures
(11, 28), and T levels are increased in transgenic mice.
Consistent with this idea, T or dehydroepiandrosterone treatment of
rats also results in the formation of ovarian cysts, indicating that
steroids alone can induce ovarian pathologies similar to those observed
in the MT- transgenic mice (49, 50). Alterations in
ovarian steroidogenesis, therefore, may be the mechanism by which the
inhibin transgene induces these complex ovarian pathologies. As
discussed in the accompanying paper, this action may represent a
combination of increased inhibin levels and suppressed activin levels,
resulting in an altered inhibin-to-activin ratio. These studies support
an important role for inhibin and activin in the maintenance of normal
ovarian follicular development and ovulation.
|
Acknowledgments |
|---|
-subunit RIA reagents and Asta Medica for
donating the GnRH antagonist Cetrorelix. We also thank Dr. Teresa
Woodruff for her comments on the manuscript. |
Footnotes |
|---|
1 Present address: Division of Life Science, The Catholic University
of Korea, Puchon, South Korea 421-743. 
Abbreviations: ERKO, E receptor-deficient mice; hCG, human CG;
MT-, metallothionein-I promoter inhibin -subunit; PCOS,
polycystic ovarian syndrome.
Received May 22, 2001.
Accepted for publication July 11, 2001.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-
and ßA-subunit messenger ribonucleic acids and
proteins. Biol Reprod 43:1050–1057[Abstract]
-Inhibin is a tumour-suppressor gene with gonadal specificity
in mice. Nature 360:313–319[CrossRef][Medline]
-subunit gene. Endocrinology 142:4994–5004 gene in female mice: characterization of ovarian responses
and phenotype in the adult. Endocrinology 140:2733–2744This article has been cited by other articles:
 |
|
 |
|
  H. Kim, T. Nakajima, S. Hayashi, P. Chambon, H. Watanabe, T. Iguchi, and T. Sato Effects of Diethylstilbestrol on Programmed Oocyte Death and Induction of Polyovular Follicles in Neonatal Mouse Ovaries Biol Reprod, November 1, 2009; 81(5): 1002 - 1009. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Gold, N. Jetly, M. K. O'Bryan, S. Meachem, D. Srinivasan, S. Behuria, L. G. Sanchez-Partida, T. Woodruff, S. Hedwards, H. Wang, et al. Activin C Antagonizes Activin A in Vitro and Overexpression Leads to Pathologies in Vivo Am. J. Pathol., January 1, 2009; 174(1): 184 - 195. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.L.H. Ireland, D. Scheetz, F. Jimenez-Krassel, A.P.N. Themmen, F. Ward, P. Lonergan, G.W. Smith, G.I. Perez, A.C.O. Evans, and J.J. Ireland Antral Follicle Count Reliably Predicts Number of Morphologically Healthy Oocytes and Follicles in Ovaries of Young Adult Cattle Biol Reprod, December 1, 2008; 79(6): 1219 - 1225. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Williams and P. Stanley Mouse fertility is enhanced by oocyte-specific loss of core 1-derived O-glycans FASEB J, July 1, 2008; 22(7): 2273 - 2284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Kipp, S. M. Kilen, T. K. Woodruff, and K. E. Mayo Activin Regulates Estrogen Receptor Gene Expression in the Mouse Ovary J. Biol. Chem., December 14, 2007; 282(50): 36755 - 36765. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Pangas, C. J. Jorgez, M. Tran, J. Agno, X. Li, C. W. Brown, T. R. Kumar, and M. M. Matzuk Intraovarian Activins Are Required for Female Fertility Mol. Endocrinol., October 1, 2007; 21(10): 2458 - 2471. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Mayo, L. Jameson, and T. K. Woodruff Eggs in the Nest Endocrinology, August 1, 2007; 148(8): 3577 - 3579. [Full Text] [PDF]
|
|
|
|
|
|
T. R. Kumar Multiple Ovulations, Ovarian Epithelial Inclusion Cysts, and It'SMAD Two! Endocrinology, August 1, 2007; 148(8): 3591 - 3594. [Full Text] [PDF]
|
|
|
|
|
|
J. E. Burdette, R. M. Oliver, V. Ulyanov, S. M. Kilen, K. E. Mayo, and T. K. Woodruff Ovarian Epithelial Inclusion Cysts in Chronically Superovulated CD1 and Smad2 Dominant-Negative Mice Endocrinology, August 1, 2007; 148(8): 3595 - 3604. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Chen, W. N. Jefferson, R. R. Newbold, E. Padilla-Banks, and M. E. Pepling Estradiol, Progesterone, and Genistein Inhibit Oocyte Nest Breakdown and Primordial Follicle Assembly in the Neonatal Mouse Ovary in Vitro and in Vivo Endocrinology, August 1, 2007; 148(8): 3580 - 3590. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Kipp, S. M. Kilen, S. Bristol-Gould, T. K. Woodruff, and K. E. Mayo Neonatal Exposure to Estrogens Suppresses Activin Expression and Signaling in the Mouse Ovary Endocrinology, May 1, 2007; 148(5): 1968 - 1976. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Balciuniene, V. J. Bardwell, and D. Zarkower Mice Mutant in the DM Domain Gene Dmrt4 Are Viable and Fertile but Have Polyovular Follicles Mol. Cell. Biol., December 1, 2006; 26(23): 8984 - 8991. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.R. Barnett, C. Schilling, C.R. Greenfeld, D. Tomic, and J.A. Flaws Ovarian follicle development and transgenic mouse models Hum. Reprod. Update, September 1, 2006; 12(5): 537 - 555. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Jefferson, R. Newbold, E. Padilla-Banks, and M. Pepling Neonatal Genistein Treatment Alters Ovarian Differentiation in the Mouse: Inhibition of Oocyte Nest Breakdown and Increased Oocyte Survival Biol Reprod, January 1, 2006; 74(1): 161 - 168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Bristol-Gould, C. G. Hutten, C. Sturgis, S. M. Kilen, K. E. Mayo, and T. K. Woodruff The Development of a Mouse Model of Ovarian Endosalpingiosis Endocrinology, December 1, 2005; 146(12): 5228 - 5236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Park, E. T. Maizels, Z. J. Feiger, H. Alam, C. A. Peters, T. K. Woodruff, T. G. Unterman, E. J. Lee, J. L. Jameson, and M. Hunzicker-Dunn Induction of Cyclin D2 in Rat Granulosa Cells Requires FSH-dependent Relief from FOXO1 Repression Coupled with Positive Signals from Smad J. Biol. Chem., March 11, 2005; 280(10): 9135 - 9148. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. B. Billiar, J. B. St. Clair, N. C. Zachos, M. G. Burch, E. D. Albrecht, and G. J. Pepe Localization and Developmental Expression of the Activin Signal Transduction Proteins Smads 2, 3, and 4 in the Baboon Fetal Ovary Biol Reprod, March 1, 2004; 70(3): 586 - 592. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Bristol and T. K. Woodruff Follicle-Restricted Compartmentalization of Transforming Growth Factor {beta} Superfamily Ligands in the Feline Ovary Biol Reprod, March 1, 2004; 70(3): 846 - 859. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yang, A. Balla, N. Danilovich, and M. R. Sairam Developmental and Molecular Aberrations Associated with Deterioration of Oogenesis During Complete or Partial Follicle-Stimulating Hormone Receptor Deficiency in Mice Biol Reprod, October 1, 2003; 69(4): 1294 - 1302. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. B. Billiar, N. C. Zachos, M. G. Burch, E. D. Albrecht, and G. J. Pepe Up-Regulation of {alpha}-Inhibin Expression in the Fetal Ovary of Estrogen-Suppressed Baboons Is Associated with Impaired Fetal Ovarian Folliculogenesis Biol Reprod, June 1, 2003; 68(6): 1989 - 1996. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Jimenez-Krassel, M. E. Winn, D. Burns, J. L. H. Ireland, and J. J. Ireland Evidence for a Negative Intrafollicular Role for Inhibin in Regulation of Estradiol Production by Granulosa Cells Endocrinology, May 1, 2003; 144(5): 1876 - 1886. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Welt, Y. Sidis, H. Keutmann, and A. Schneyer Activins, Inhibins, and Follistatins: From Endocrinology to Signaling. A Paradigm for the New Millennium Experimental Biology and Medicine, October 1, 2002; 227(9): 724 - 752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
2 goodness of fit based on 1 degree of freedom and