27 - 30 May 2005

NORMAL AND IMPAIRED DECIDUALIZATION OF HUMAN ENDOMETRIUM Jan Brosens [1], Birgit Gellersen [2] [1] Institute of Reproductive and Developmental Biology Imperial College London London UK [2] Endokrinologikum Hamburg Hamburg Germany

Remodelling of the endometrium during the menstrual cycle in response to ovarian hormones is a prerequisite for implantation of the developing embryo, the formation of the placenta, and maintenance of pregnancy. The mechanism by which progesterone controls the differentiation of human endometrial stromal cells, a process termed decidualisation, in the luteal phase of the menstrual cycle is not well understood.

Decidual transformation is first apparent in stromal cells surrounding the spiral arteries approximately ten days after the postovulatory rise in ovarian progesterone levels, indicating that the expression of decidua-specific genes is unlikely to be under direct transcriptional control of activated nuclear progesterone receptor (PR). In cultured primary endometrial stromal cells, the second messenger cyclic AMP (cAMP) is a much more potent inducer of decidualisation than progesterone, the latter serving to enhance the effect of cAMP.

We have identified a number of proteins that are induced by cAMP in cultured endometrial stromal cells and were able to show that these are also upregulated or activated in the stromal compartment in the luteal phase of the menstrual cycle, underscoring the relevance of cAMP-signaling in vivo. Among these proteins are transcription factors of very diverse nature, such as CCAAT/enhancer binding protein-beta (a basic region/leucine zipper factor), FOXO1a (a member of the forkhead/winged helix protein family), Stat5 (signal transducer and activator of transcription), PIASy (protein inhibitor of activated STAT y) and, most surprisingly, the tumour suppressor p53 [1-5].

Emerging evidence suggest that many of these ‘subsidiary’ transcription factors physically interact with PR, thereby modifying the genomic response to progesterone. A major advantage of this system is that a single hormonal signal (progesterone) can elicit a highly coordinated cascade of cellular responses [6].

A major disadvantage, however, is that a variety of aberrant signals can potentially disrupt the formation of these specific progesterone-dependent transcriptional complexes necessary for normal endometrial differentiation. Indeed, in-vivo and in-vitro studies have shown that the decidual process is impaired in the presence of pathological stimuli associated with pregnancy failure such as antiphospholipid antibodies, Th-1 cytokines, and androgen excess.

References:

1. Pohnke Y, Schneider-Merck T, Fahnenstich J, Kempf R, Christian M, Milde-Langosch, Brosens JJ, Gellersen B. Wildtype p53 protein is up-regulated upon cyclic AMP-induced differentiation of human endometrial stromal cells. J Clin Endocrinol Metab 2004;89:5233-44.

2. Zoumpoulidou G, Jones MC, de Mattos SF., Francis JM, Fusi L, Lee YS, Christian M, Varshochi R, Lam EW, Brosens JJ. Convergence of interferon-gamma and progesterone signaling pathways in human endometrium: role of PIASy (protein inhibitor of activated signal transducer and activator of transcription-y). Mol Endocrinol 2004;18:1988-99

3. Mak IY, Brosens JJ, Christian M, Hills FA, Chamley L, Regan L, White JO. Regulated expression of signal transducer and activator of transcription, Stat5, and its enhancement of PRL expression in human endometrial stromal cells in vitro. J Clin Endocrinol Metab 2002;87:2581-8.

4. Christian M, Zhang X, Schneider-Merck T, Unterman TG, Gellersen B, White JO, Brosens JJ. Cyclic AMP-induced forkhead transcription factor, FKHR, cooperates with C/EBP in differentiating human endometrial stromal cells. J Biol Chem 2002;277:20825-32.

5. Christian M, Pohnke Y, Kempf R, Gellersen B, Brosens JJ. Physical association of progesterone receptor and CCAAT/enhancer protein isoforms: Promoter dependent cooperation between PR-B and LIP, or LAP and PR-A in human endometrial stromal cells. Mol Endocrinol 2002;16:141-154.

6. Gellersen B, Brosens JJ. Cyclic AMP and progesterone receptor cross-talk in human endometrium: a decidualizing affair. J. Endocrinol 2003;178:357-72.

List of abstracts from the 3rd International Conference on the Female Reproductive Tract