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