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Department of Obstetrics-Gynecology, University of Texas Southwestern Medical Center (G.R.A., K.Z., A.J., B.R.C.), Dallas, Texas 75235; Department of Pathology, University of Colorado Health Sciences Center (D.E.), Denver, Colorado 80262; and Department of Obstetrics and Gynecology, University of Illinois at Chicago (S.E.B.), Chicago, Illinois 60612
Address correspondence and requests for reprints to: Serdar E. Bulun, M.D., Department of Obstetrics-Gynecology, University of Illinois at Chicago, 820 South Wood Street, M/C 808, Chicago, Illinois 60612. E-mail: sbulun{at}uic.edu
We previously demonstrated that 17ß hydroxysteroid dehydrogenase type
2, the enzyme that inactivates estradiol to estrone, is expressed in
luteal eutopic endometrium in response to progesterone but not in
simultaneously biopsied peritoneal endometriotic tissue. This molecular
evidence of progesterone resistance, together with the clinical
observation of resistance of endometriosis to treatment with
progestins, led us to determine the levels of progesterone receptor
(PR) isoforms PR-A and PR-B in eutopic endometrial and extra-ovarian
endometriotic tissues. It was proposed that progesterone action on
target genes is mediated primarily by homodimers of PR-B, whereas the
truncated variant PR-A acts as a repressor of PR-B function.
Immunoprecipitation, followed by Western blot analysis, was performed
to detect bands specific for PR-A and PR-B in paired samples of
endometriotic and eutopic endometrial tissues simultaneously biopsed
from 18 women undergoing laparoscopy during various phases of the
menstrual cycle. PR-B was present in 17 of 18 eutopic endometrial
samples, and its level increased in the preovulatory phase, as
expected, whereas PR-A was detected in all samples (n = 18) with a
similar, but less prominent, cyclic variation in its levels. In
endometriotic samples, however, no detectable PR-B could be
demonstrated, whereas PR-A was detected in all samples (n = 18),
albeit in much lower levels and without any cyclic variation in
contrast with the eutopic endometrium. Levels of PR-A and PR-B in
endometriotic and eutopic endometrial tissues were determined and
compared after normalization to total protein and estrogen receptor-
levels. Using RNase protection assay, we also demonstrated indirectly
that only PR-A transcripts were present in endometriotic tissue samples
(n = 8), whereas both PR-A and PR-B transcripts were readily
detectable in all eutopic endometrial samples (n = 8). This was
indicative that failure to detect PR-B protein in endometriotic tissues
is due to the absence of PR-B transcripts. We conclude that
progesterone resistance in endometriotic tissue from laboratory and
clinical observations may be accounted for by the presence of the
inhibitory PR isoform PR-A and the absence of the stimulatory isoform
PR-B.
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