Estrogen Receptor Null Mice - Endocrine Reviews

June, 1999 ESTROGEN RECEPTOR NULL MICE 373
Nonetheless, the deciduomas induced in the �ERKO females
are neither reduced in size nor appear less complex or differentiated
than those observed in the wild type (183). It is
also possible that a lack of ER� during development as well
as adulthood has resulted in a uterus with a heightened
tendency toward decidualization, caused by to the altered
expression of other gene products. The complexity of the
decidual process is illustrated by the several models that lack
the ability to exhibit uterine decidualization, such as mice
lacking leukemia-inhibitory factor (188), prostaglandin synthase-2
(189), and Hoxa-10 (190). Furthermore, a process
thought to be critical to implantation is the acquired ability
of portions of the uterine epithelium to self-destruct and
become detached from the uterine wall, possibly clearing a
route by which the underlying swelling endometrium can
breach and provide a site for implantation (186, 191). Histological
analysis of �ERKO uteri indicates a uterine epithelium
that may be less healthy and more often exhibits sloughing
compared with wild-type uteri. It is therefore possible
that the inherently impaired luminal epithelium of the
�ERKO female has resulted in a lowering of the threshold
required to induce decidualization.
B. Vagina
The fully developed adult vagina serves as both a copulatory
receptacle and a birth canal in the female and may be
divided into two distinct sections, the upper vagina and
lower vagina. The cranial end of the upper vagina is attached
to the cervix and is derived from the Müllerian ducts during
differentiation of the female tract (143). The lower vagina,
which connects the tract to the vulva and external genitalia,
is differentiated from the urogenital sinus (143). As shown in
Fig. 3, the wild-type vagina is a highly sensitive estrogen
target tissue, composed of an inner mucosal layer of stroma
and overlying epithelia, a middle layer of muscularis, and an
outer sheath of connective tissue. Detectable levels of ER� are
present in both the stromal and epithelial compartments
making up the mucosa of the duct (7). Estradiol exposure
during the ovarian cycle induces a series of effects in the
vaginal mucosa that are often used to estimate serum gonadal
hormone levels and approximate the current stage in
the estrous cycle (107). These changes in the mucosa include
cytodifferentiation of the stromal cells and a rapid proliferation
and differentiation of the epithelial cells, resulting in a
stratified and cornified epithelial layer closest to the lumen
(192). This process also involves the estrogen stimulation of
a series of keratins (193, 194). As shown in Fig. 3, despite the
chronically elevated levels of estradiol in the serum of
�ERKO females, histological analysis consistently indicates
a complete lack of vaginal estrogenization. A similar effect on
the vaginal mucosa has been produced in mice (195, 196) and
rats (197) after prolonged ovariectomy or treatments with the
antiestrogens, ZM-189,154, EM-800, and tamoxifen. Administration
of exogenous estradiol, DES, or hydroxytamoxifen
to �ERKO mice results in no discernible vaginal response
(153). In contrast, the vaginal mucosa of the �ERKO female
appears to undergo the normal cyclic changes associated
with ovarian steroidogenesis (Fig. 3) (47), strongly indicating
that this is an ER�-mediated process.
Buchanan et al. (198) have used the stromal-epithelial tissue
recombinant scheme described above for uterine tissue to dissect
the contributions of the different tissue compartments in
the estradiol response of vaginal tissue as well. As in the uterus,
these studies demonstrated that stromal ER�, but not epithelial
ER�, are required for estradiol-induced epithelial proliferation
in the mouse vagina (198). Similar to the observations in the
uterine recombinants, both vaginal stromal and epithelial ER�
were required for estradiol-induced stratification and cornification
of the epithelium, including the induction of the gene for
the secretory protein cytokeratin 10 (198). All recombinations
involving tissue from the �ERKO vagina became atrophied,
even in the presence of estradiol (198).
C. Oviduct
The mouse oviduct is a coiled tubular organ connecting the
uterus to the ovarian bursa and derived from the Müllerian
duct during fetal development of the female reproductive
tract (143). It functions as a route for passage of sperm to the
ovulated oocyte and the subsequently fertilized blastocyst to
the uterus. In the CD-1 mouse, ER� immunoreactivity is
easily detectable in both the stroma and the epithelium of the
oviduct as early as day 2 of life (144). The levels of ER�
immunoreactivity in the epithelium continue to rise and
plateau at approximately day 15 and remain high throughout
adulthood (144). Furthermore, Newbold et al. (199, 200) described
the high degree of sensitivity of the fetal and neonatal
oviduct to the detrimental effects of developmental DES
exposure. During adulthood, the levels of ER� in the oviductal
epithelium fluctuate during the ovarian cycle, reaching
peak levels during the proliferative phase (201). The
ovarian sex hormones found in high concentrations in the
oviductal fluid are thought to play a role in ovum and zygote
transport through the oviduct (201). However, studies using
ovariectomized laboratory animals have produced conflicting
results in terms of what this role may be, depending on
the animal model and hormone dosing regimen used (202).
Despite the apparent ontogeny of ER� in the developing and
adult mouse oviduct, no gross phenotypes in the oviduct of
�ERKO females have been observed. Similar to the uterus,
the epithelium of the �ERKO oviduct usually appears
healthy yet unstimulated, despite the chronically high levels
of serum estradiol. Due to the inability of the �ERKO to
ovulate, possible defects in the transport functions of the
oviduct are not easily studied. Assays for ER� mRNA in the
mouse oviduct detect little if any ER� transcripts. Accordingly,
in �ERKO females there appears to be no obvious
defects in the structure and function of the oviduct that
impede fertility.
D. Ovary
In most mammals, differentiation of the bipotential fetal
gonad to an ovary in the genotypic female occurs later in
gestation than differentiation of the testis in the male (111).
The factors involved in development and differentiation of
the ovary are not well understood, although the process does
not appear to be dependent on the presence of primordial
germ cells (111). The appearance of follicles and the onset of