Address for correspondence: Robert M. Bigsby, Ph.D., Department of Obstetrics and Gynecology, Indiana University School of Medicine, 975 West Walnut Street (IB360), Indianapolis, IN 46202-5121. Voice: 317-274-8970; fax: 317-278-2884.
rbigsby{at}iupui.edu
Early work with neonatal mice showed that estrogen receptor-negative
uterine epithelium responded to estrogen treatment. Since the
underlying mesenchymal cells were estrogen receptor-positive,
it was suggested that these cells mediated the hormonal response
through elaboration of a paracrine factor. Cell culture work
showed that mesenchymal cells produced soluble factors that
stimulate uterine epithelium, but hormonal regulation was absent
or minimal. The paracrine hypothesis of estrogen action has
been proved by the use of tissue recombinant studies in which
epithelium from estrogen receptor-alpha knockout mice was combined
with wild-type mesenchyme; estrogen stimulated the ER
-negative
epithelium if the underlying stromal cells were receptor-positive.
Also, it is hypothesized that there is a reciprocal paracrine
interaction during stimulation with progesterone and estrogen.
Accordingly, under progesterone dominance, the epithelium elaborates
factors that direct the underlying stroma to proliferate when
estrogen is administered. Although this hypothesis needs further
testing, it has been shown that the uterine epithelium is required
for stromal responsiveness to hormones. The question arises:
What are the factors that mediate the effects of the steroid
hormones in the uterus? Several peptide growth factors are regulated
by estrogen and/or progesterone. Use of knockout animals will
allow a determination of the role that these factors play in
the uterus. However, ablation of many of these growth factor
genes has proved lethal to the newborn animals, making it impossible
to study hormonal effects using standard techniques. Tissue
xenograft and tissue recombination studies offer a means of
defining the role of specific growth factors in uterine physiology.
