Endocrinology Vol. 141, No. 10 3792-3798
Copyright © 2000 by The Endocrine Society
The Differential Fate of Mesonephric Tubular-Derived Efferent Ductules in Estrogen Receptor-
Knockout Versus Wild-Type Female Mice1
Cheryl S. Rosenfeld,
Paul S. Cooke,
Thomas H. Welsh, Jr.,
Gretchen Simmer,
Martha G. Hufford,
Jan-Åke Gustafsson,
Rex A. Hess and
Dennis B. Lubahn
Departments of Animal Sciences, University of Missouri (C.S.R.,
D.B.L.), Columbia, Missouri 65211; Veterinary Biosciences, University
of Illinois (P.S.C., R.A.H.), Urbana, Illinois 61802; Animal Science,
Texas A & M University (T.H.W.), College Station, Texas 77843;
Biochemistry and Child Health, University of Missouri (G.S., M.G.H.,
D.B.L.), Columbia, Missouri 65211; and Medical Nutrition and
Biosciences, Karolinska Institute, NOVUM (J.-Å.G.), S-141 86 Huddinge,
Sweden
Address all correspondence and requests for reprints to: Dennis B. Lubahn, Ph.D., University of Missouri, 163 ASRC, 920 East Campus Drive, Columbia, Missouri 65211. E-mail: lubahnd{at}missouri.edu
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Abstract
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We investigated mesonephric tubular-derived efferent ductules in female
wild-type (WT) and estrogen receptor-
knockout (ERKO) mice from
late fetal to adult life. On gestational day 17, efferent ductules in
both fetal WT and ERKO females were well developed and
morphologically similar, although one third the size of the male
counterpart. Unexpectedly, efferent ductules with a ciliated epithelium
were still present on postnatal day 10 in WT and ERKO females. By
day 23, however, marked phenotypic differences occurred in efferent
ductules of WT and ERßKO vs. ERKO female
mice. In the latter, efferent ductules became hypertrophied and
dilated, whereas only small tubules remained in WT and ERßKO
adult mice. The serum testosterone concentrations were similar in 21-
to 25-day-old ERKO, heterozygous, and WT female mice, suggesting
that increased testosterone was not inducing enlargement of efferent
ductules in ERKO females. In conclusion, remnants of efferent
ductules persisted in normal adult female mice, although these
structures were greatly reduced in size compared with efferent ductules
in ERKO female mice. The underlying mechanism inducing hypertrophy
and dilation of efferent ductules in ERKO females is not clear, but
secretory and/or reabsorptive function of female efferent ductules may
involve ER.
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Introduction
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THE DEVELOPING fetus is initially
ambisexual and develops either a male or a female reproductive tract in
response to gonadal hormones. In the male, the mesonephric (Wolffian)
duct develops into the seminal vesicles, ductus deferens, and
epididymis, whereas the mesonephric tubules form the efferent ductules
(1). In the female, the paramesonephric (Mullerian) duct
develops into the oviduct, uterus, cervix, and cranial portion of the
vagina (1). As both Mullerian and Wolffian tracts are
initially present in the developing fetus, one or the other must
regress depending upon the sex. The gonads, which differentiate early
in embryogenesis (1), play a critical role in reproductive
tract development and regression. Jost showed that implantation of a
testosterone crystal into female embryos led to full development of the
male reproductive tract, but exogenous testosterone did not induce
regression of the female reproductive tract (2).
Therefore, some other substance originating from the testes must
mediate Mullerian duct regression in males.
The anti-Mullerian hormone or Mullerian inhibiting substance was later
identified as a glycoprotein hormone that is produced by Sertoli cells
and belongs to the transforming growth factor-ß superfamily
(3). The female fetus does not produce Mullerian
inhibiting substance, and so the Mul- lerian duct fails to regress.
The absence of androgen stimulation has been thought to result in
regression of the mesonephric duct and tubules in females. However, in
the female fetus the underlying mechanism inducing involution of the
tissues derived from the mesonephros remains poorly understood. Based
on Jost’s experiments, there appeared to be no role for the ovary or
specifically for estrogen in reproductive tract development or
regression (2), although estrogen regulates sexual
differentiation in fish (4), turtles (5),
reptiles (6), and birds (7, 8).
The mesonephric duct has been reported to regress completely by 18 and
75–84 days postcoitus in female mice (9) and humans
(10), respectively. In some adult women, however,
vestigial structures derived from the mesonephric tubules have been
reported next to the ovary (11). Prenatal exposure to
diethylstilbestrol (DES) leads to the development of para-ovarian
cysts of mesonephric origin in both adult women and mice (12, 13). In utero exposure to estradiol in female rats
causes persistence of the mesonephric duct (14).
Additionally, probable mesonephric neoplasms have been identified in
women (15, 16).
The estrogen receptor- knockout (ERKO) female mouse offers a
unique and definitive model system for determining any potential role
of ER in regulating the function of mesonephric tubules in the
female. In the present report, we describe these structures in
wild-type (WT) and ERKO females. Our results indicate that
mesonephric tubules persist as vestigial efferent ductules in normal
female mice. Surprisingly, efferent ductules of ERKO female mice
were markedly enlarged and dilated, suggesting that the lack of ER
results in marked hypertrophy of these structures.
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Materials and Methods
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Animals
ERKO (17), ERßKO (18), and WT
female mice of pure C57BL/6J and a mixed C57BL/6J/129 background were
maintained and used in accordance with the NIH Guide for the Care and
Use of Laboratory Animals. The University of Missouri and University of
Illinois animal care and use committees approved all experiments
reported here. The mice were housed at either the University of
Missouri Animal Sciences Research Center laboratory animal facility
(ERKO and WT) or the University of Illinois laboratory animal
facility at the College of Veterinary Medicine (ERßKO and WT),
maintained on ad libitum mouse chow soy-based formulation
5001 (Ralston-Purina, St. Louis, MO) and water, and kept on a 12-h dark
and 12-h light cycle. The genotypes of the mice were determined by PCR
analysis, as described previously (17).
Examination of mesonephric tubular-derived female efferent ductules
in WT, ERKO, ER heterozygous, and ERßKO mice
Mesonephric tubular-derived efferent ductules were examined in
fetal WT (n = 5) and ERKO (n = 4) female mice between 17
and 19 days postcoitus, postnatal WT (n = 10) and ERKO (n
= 10) female mice between 10 and 25 days of age, and in adult (8–12
weeks) WT (n = 50), maternally (n = 6) and paternally (n
= 6) derived ER heterozygous, and ERKO (n = 50) female mice.
Efferent ductules were also examined in adult (16–24 weeks) ERßKO
(n = 4) and WT (n = 4) female mice. An Olympus Corp. stereomicroscope (Hitschfel Instruments, Inc., St. Louis,
MO) was used in the dissection and examination of the tissues.
Light microscopic and transmission electron microscopic examination
of efferent ductules in WT and ERKO female mice
Ovaries with associated efferent ductules were fixed in either
Bouin’s or 4% glutaraldehyde fixative with 0.1 M
cacodylate buffer. The tissues were then embedded in paraffin or epoxy
resin. Sections (3–4 µm) were cut from paraffin-embedded tissues and
stained with hematoxylin and eosin. Tissues were prepared for
transmission electron microscopy, as described previously
(19). Light microscopic sections were observed under a
Provis microscope (Olympus Corp., New Hyde Park, NY) and
digitalized using a Spot 2 digital camera (Diagnostic Instruments,
Inc., Sterling Heights, MI), and images were printed on a Pictography
3000 printer (Fuji Photo Film Co. Ltd., Tokyo, Japan).
Measurement of efferent ductular luminal area for ERKO and WT
female mice
The luminal areas of five efferent ductules from five different
ERKO and WT female mice were measured by using the NIH Image
analysis program (HYPERLINK http://rsb.info.nih.gov/nih-image).
Testosterone RIA
Intracardiac blood was collected from mice at the same time each
day (
1300 h). Serum testosterone concentrations were measured in 21-
to 25-day-old WT (n = 20), ER heterozygous (n = 22), and
ERKO (n = 25) female mice, as described previously
(20). The intra- and interassay coefficients of variation
were 5.5% and 8.7%, respectively.
Statistical analysis
Results of the efferent ductular luminal area and serum
testosterone concentrations are presented as the mean ±
SEM. Serum testosterone concentrations in 21- to 25-day-old
ERKO, ER heterozygous, and WT female mice were compared by using
Student’s t test, and P < 0.05 was
considered significant.
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Results
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Examination of mesonephric tubular-derived female efferent ductules
in WT, ERKO, ER heterozygous, and ERßKO mice
The overall size of efferent ductules increased between 17
and 19 days gestation, but WT and ERKO female fetuses had equivalent
sized efferent ductules at all fetal time points examined. The female
efferent ductules were located medially and on the opposite side of the
ovarian hilus, and this structure was grossly distinct from the
oviduct. The entire female efferent ductular structure was embedded in
the mesenchymal mass that is the precursor of the mesovarian fat. In
both genotypes, the efferent ductules were continuous distally with the
regressing mesonephric duct, but the apical portion of this tissue did
not connect with the ovary. In contrast, male efferent ductules
predictably connected with the testes. The female efferent ductules
appeared similar to their male counterparts in that they consisted of
an anastomosing network of epithelial-lined tubules, which were
contained within an enveloping stroma and located immediately adjacent
to the gonad. These tubules coalesced into a larger bulbous tubule of
greater diameter at the distal termination of the structure, where the
connection with the mesonephric duct would normally occur in the male.
Whereas female efferent ductules were morphologically similar to those
in males, on gestational day 17 they were only approximately one third
the size of the male structures.
Surprisingly, both 10- and 20-day-old ERKO and WT female mice
had persistent efferent ductules that had equivalent branching and
length in each genotype, respectively (Fig. 1
, A and D). By 23 days of age, a
phenotypic difference in efferent ductular size occurred in WT
vs. ERKO female mice. At this age, the efferent ductules
remained small in WT female mice (Fig. 1E). In contrast, efferent
ductules in ERKO female mice became enlarged (Fig. 1B). In all adult
ERKO female mice examined the tubules were markedly enlarged and
dilated (Fig. 1C), whereas efferent ductules in all adult WT female
mice examined remained small (Fig. 1F). However, when efferent ductules
from adult ERKO and WT female mice were incised longitudinally to
expose the luminal surface and examined under a dissecting microscope,
normal ciliary movement was present in both genotypes. Adult
heterozygous female mice that inherited the null ER allele from the
mother and others that inherited the null allele from the father were
examined. Neither maternally nor paternally derived heterozygous female
mice had enlargement of efferent ductules.
Female efferent ductules were also examined in adult ERßKO and WT
sibling mice. Female efferent ductules were not enlarged in ERßKO or
WT (Fig. 2) mice.
To test whether the retention of female efferent ductules was unique to
pure C57BL/6J and mixed C57BL/6J/129 mice, two additional mice strains,
CD-1 and CBA, were examined. In both, female efferent ductules were
present in postnatal day 23 and adult female mice (data not shown) and
were similar in size and morphology to WT female efferent ductules in
C57BL/6J and C57BL/6J/129 mice.
Histological and ultrastructural examinations of efferent ductules
in WT and ERKO female mice
In adult ERKO female mice, well developed and enlarged efferent
ductules with occasional epididymal-like initial segment tubules
were identified (Fig. 3, A and B). A
ciliated simple cuboidal to columnar and in some instances
pseudostratified columnar epithelium lined the tubules (Figs. 3B and 4A). Tubules that were dilated were generally lined by a simple
cuboidal epithelium. Many lysosomal vacuoles, residual bodies, and
mitochondria were present in the cells (Fig. 4A). The small tubules in adult WT female
mice were composed of a uniform simple columnar epithelium, which
possessed few cilia, microvilli, and lysosomal vacuoles (Figs. 3D and 4B).
Luminal area of female efferent ductules
ERKO females had an approximately 5-fold increase in efferent
ductular luminal area compared with WT female mice (Table 1).
Serum testosterone concentration
To determine whether the enlargement of the efferent
ductules in ERKO female mice was androgen induced, the serum
testosterone concentration was measured in 21- to 25-day-old female
mice. The testosterone concentration in 21- to 25-day-old ERKO
female mice was similar to that in age-matched WT and ER
heterozygous female mice (Table 2).
Treatment of juvenile (21- to 27-day-old) WT female mice with
dihydrotestosterone
Juvenile WT female mice treated daily for 1 week with
supraphysiological dosages (0.2 mg) of dihydrotestosterone did not have
efferent ductular enlargement, similar to ERKO female mice (data not
shown).
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Discussion
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The fetal mesonephric (Wolffian) duct gives rise to the
epididymis, ductus deferens, and seminal vesicle in males, whereas the
mesonephric tubules develop into the efferent ductules. In females, the
Wolffian duct undergoes almost complete regression, which is presumably
due to the absence of androgenic stimulation. However, an extensive
literature spanning this past century indicates that periovarian
remnants of the fetal mesonephric tubules persist in women
(11) and other species (21). In mice,
structures similar to those that we are describing here in terms of
anatomical location, morphology, and histology have been potentially
misclassified as a portion of the extraovarian rete ovarii (21, 22).
Our results clearly indicate that these periovarian structures in WT
and ERKO female mice are the female homologs of the male efferent
ductules, also called the ductuli efferentes ovarii
(21, 22, 23) or epoophoron (22). The conclusion
that the periovarian structures found in WT and ERKO female mice are
the female homologs of the male efferent ductules rather than a portion
of the extraovarian rete ovarii, as classified by others (21, 22), was based on a number of lines of evidence. The simple to
pseudostratified columnar epithelium observed in the efferent ductules
of both WT and ERKO female mice is markedly different from the
squamous to flattened cuboidal epithelium observed in the rete ovarii.
Both epithelial cells lining the putative female efferent ductules and
male efferent ductules possess many vacuoles. However, the number of
vacuoles within the female efferent ductular epithelium was reduced
compared with vacuolar numbers described previously in male efferent
ductular epithelium (24). In contrast, a paucity of
vacuoles is present in rete ovarii (22). Critically, the
structures described in the present work possessed motile cilia, a
unique characteristic of male efferent ductules, and a structural
modification that is never found in the rete system of the mouse
(22).
Enlarged periovarian cysts in mice have been previously reported after
in utero exposure of mice to the synthetic estrogen DES
(12, 13). These cysts were postulated to be of mesonephric
tubular origin based on their location in the mesovarium, epithelial
morphology, and epithelial vacuo-lization and the presence of
cilia. All of the characteristics of these structures are identical to
those we found in the female efferent ductules. The researchers
observed that these cysts were rarely found when the mice were not
exposed in utero to DES and consequently concluded that
estrogen exposure led to the abnormal retention, as well as hypertrophy
and hyperplasia, of these structures. However, our results indicate
that efferent ductules are found in 100% of female mice examined,
albeit they are smaller than those in ERKO female mice. It is likely
that the small size, as well as the fact that they are predominantly
concealed in fat of the mesovarium, resulted in the difficulty of
finding these structures in fixed tissues of normal mice.
In males, testosterone stimulates the mesonephric duct to grow and
differentiate into the upper male reproductive tract (1),
presumably acting through androgen receptor present in these structures
(25, 26, 27). The absence of androgenic stimulation in females
results in regression of the mesonephric duct, but our present results
show that the mesonephric tubular derivatives are maintained into
adulthood in the female. Although these structures are reduced in size
compared with their male counterparts, the tubules maintain a
histological structure similar to that of the male efferent ductules.
These results indicate that hormonal regulation of the mesonephric duct
and that of tubules during fetal development is different. The
mesonephric duct is dependent upon androgen for survival as an
anatomically distinct structure. In contrast, mesonephric tubular
persistence is hormone independent (28, 29). However, the
differentiation of these structures is dependent upon hormones within
the luminal fluids originating from the testis (30). In
the efferent ductules of ERKO female mice, the hormones presumably
are from elsewhere.
Fetal and early postnatal development of the female efferent ductules
was apparently identical in WT and ERKO female mice. The enlargement
of these structures found on postnatal day 23 and at subsequent ages
relative to that in the WT controls indicates that some event occurring
during the juvenile period was affecting the size of the female
efferent ductules in ERKO mice. One obvious possibility is that
ERKO female mice have transient or permanent increases in androgen
starting in the juvenile period, which could affect the function of
these structures, as androgen does in males. However, our results
indicate that serum concentrations of testosterone were not different
in WT and ERKO female mice at 21–25 days of age. These results
suggest that the increased size and dilation of female efferent
ductules in ERKO mice may not be androgen induced. Increased
circulating androgen levels have been reported in adult ERKO female
mice (31), and thus, a contributory role for androgen
stimulation of efferent ductular dilation in ERKO females cannot be
completely excluded.
The efferent ductular dilation in ERKO female mice is consistent
with increased fluid pressure in these tubules. As is apparent in the
histological sections, efferent ductules from ERKO females have a
significant increase in luminal area compared with efferent ductules
from WT female mice. Efferent ductules of ERKO male mice do not
properly reabsorb rete testis fluid and have increased fluid secretion
(32, 33). Subsequently, it is thought that increased
efferent ductular fluid production and lack of reabsorption, beginning
at puberty, result in swelling, pressure atrophy of the seminiferous
epithelium, and ultimate infertility (32, 33). Unlike male
efferent ductules, female efferent ductules are a closed set of
tubules. However, efferent ductular epithelium possesses both secretory
and absorptive capabilities (24, 32). It is possible that
increasing vascular testosterone and/or estrogen concentrations during
juvenile life could cause increase fluid secretion by the female
efferent ductular epithelium. In WT animals, this secreted fluid may be
reabsorbed normally, so dilation does not occur. The potential impaired
absorptive capacity of efferent ductules in ERKO females compared
with WT female mice could result in dilation of these structures in a
manner analogous to that described for ERKO males (32, 33). However, the simple columnar to pseudostratified columnar
epithelium of some efferent ductules (compare differences in three
tubules in Fig. 3B
) in ERKO female mice was more comparable to the
epithelium lining efferent ductules of normal WT males. Yet, other
efferent ductules seen in adult ERKO female mice were similar to
efferent ductules in ERKO male mice, which are lined by a dysplastic
cuboidal epithelium (32, 33). Possibly, differences within
the epithelial lining of efferent ductules in ERKO females represent
different stages of dilation and subsequent enlargement of the
tubules.
ER and ERß have been identified in developing and adult male
efferent ductules (27, 34, 35, 36, 37, 38). During embryonic
development, cranial mesonephric-derived tissues, in particular
efferent ductules, have higher expression of ERs than the caudal
mesonephric-derived tissues (34). Therefore, estrogen
might preferentially regulate efferent ductular function in males and
females. Another possibility is that male and female efferent ductules
may be stimulated by estrogen binding to ERß or other novel ER
(39, 40) or by an alteration in the ER/ERß expression
ratio. Examination of efferent ductules from adult ERßKO
(18) females revealed that these structures were the same
size as their WT counterparts. These data suggest that the absence of
ERß does not alter the function of female efferent ductules. However,
the possibility still exists that it is a balance between ER and
ERß that determines the function and subsequent final size of the
female efferent ductules. To determine the effects of ablation of both
of the known ER on female efferent ductular function, the resulting
efferent ductular phenotype of ERß double KO mice
(41) will need to be examined.
In conclusion, the enlargement of female efferent ductules in ERKO
females may be directly related to the absence of ER, or these mice
might have secondary perturbations of other hormonal signaling
pathways. Nevertheless, the absence of ER results in marked
enlargement of efferent ductules in female mice, although the
underlying mechanism remains to be established.
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Acknowledgments
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We thank Kay Carnes, Jessica S. Wagner, and Colette Abbey for
their help and technical assistance, and Dr. Gordon D. Niswender
(Colorado State University) for the antiserum (GDN-250) to
testosterone. We are grateful to Dr. R. Michael Roberts for his
critical review of the manuscript.
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Footnotes
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1 This work was supported by NIH Grants AG-15500 (to P.S.C. and
D.B.L.), ES-08272 (to D.B.L.), and HD-35126 (to R.A.H.), USDA Grant NRI
94–37203-0922 (to T.H.W.), and a USDA National Needs Fellowship (to
C.S.R.). 
Received February 15, 2000.
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Abstract
Introduction
