Progesterone Receptor Isoform A But Not B Is Expressed in Endometriosis

Abstract

We previously demonstrated that 17beta 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-alpha 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.

Endometriosis and the neoplastic process

“…At the tissue level, endometriosis may resist the antiproliferative effect of progesterone by the predominant expression of the inhibitory PR-A isoform instead of the stimulatory PR-B isoform (Attia et al 2000).…”

Disturbed estrogen and progesterone action in ovarian endometriosis

“…The data on expression of PRs are also rather controversial: Misao et al (1999) have reported significantly higher levels of PRB mRNA in ovarian endometriosis samples compared to the normal endometrium. Attia et al (2000) have reported that PRB was not expressed in non-ovarian endometriosis, while Bukulmez et al (2008) detected three isoforms PRC, PRB and PRA in ovarian endometriomas. In contrast, our results showed no significant differences in mRNA levels of PRAB (Fig.…”

The density of nervous fiber and nucleus isoforms expression of estrogen and progesterone receptors in eutopic endometrium in patients with peritoneal endometriosis: pregnancy outcomes

“…Показано, что ПР-A и ПР-B экспрессируются преимущественно в эутопическом эндометрии у больных эндометриозом, но у больных с наступившей беременностью уровень экспрессии не отличался от такового у больных с ненаступившей беременностью [10]. Дополнительно анализ эутопи-ческого эндометрия с использованием иммуноблот-тинга у больных эндометриозом показал равное ко-личественное присутствие ПР-A и ПР-B, преоблада-ющее в стромальных клетках [14].…”

“…Прогесте-рон вызывает децидуализацию эндометрия и готовит эндометрий для нидации эмбриона, проявляя дей-ствие через прогестероновый рецептор А и прогесте-роновый рецептор В (ПР-A, ПР-B соответственно), экспрессия обоих рецепторов выражена в эндоме-трии во всех фазах менструального цикла [33]. О раз-личиях в экспрессии ЭР и ПР и их изоформ в эуто-пическом эндометрии при эндометриозе сообща-лось ранее [10,11,30]. Кроме того, показано, что экспрессия ЭР-альфа и ПР-B в стромальных клетках эктопического эндометрия была снижена, возмож-но, за счет резистентности к прогестерону при эндо-метриозе [16].…”