The progesterone receptor coactivator Hic-5 is involved in the pathophysiology of endometriosis.
Endometriosis is an estrogen-dependent disorder primarily associated with pelvic pain and infertility in up to 10% of women of reproductive age. Recent studies suggest that resistance to progesterone action may contribute to the development and pathophysiology of this disorder. In this study we examined the in vivo and in vitro expression and function of one progesterone receptor (PR) coactivator, Hic-5, in human endometrium and endometrial stromal fibroblasts (hESFs) from 29 women with and 30 (control) women without endometriosis. Hic-5 was highly expressed in stromal, but not epithelial, cells in women without endometriosis, in a cycle-dependent manner. In contrast, Hic-5 expression was not regulated during the menstrual cycle in hESFs from women with endometriosis and was significantly reduced in hESFs from women with vs. without disease. Hic-5 mRNA expression throughout the cycle in endometrium from control women, but not those with endometriosis, correlated with expression of PR. Hic-5 mRNA in hESFs was significantly up-regulated in control but not endometriosis hESFs after treatment in vitro with 8-bromoadenosine-cAMP for 96 h but only modestly after 14 d of progesterone treatment. Hic-5 silencing did not influence cAMP-regulated gene expression but affected genes regulated solely by progesterone (e.g. DKK1 and calcitonin). Together the data suggest that the proposed progesterone resistance in endometrium from women with endometriosis derives, in part, from impaired expression of the PR coactivator, Hic-5, in endometrial tissue and cultured endometrial stromal fibroblasts.
Aghajanova
Lusine
L
Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, California 94143, USA.
Velarde
Michael C
MC
Giudice
Linda C
LC
D000328:Adult; D002116:Calcitonin / Q000235:genetics; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004715:Endometriosis / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D004717:Endometrium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D060588:LIM Domain Proteins; D008597:Menstrual Cycle / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D011374:Progesterone / Q000494:pharmacology; D011372:Progestins / Q000494:pharmacology; D011388:Prolactin / Q000235:genetics; D034741:RNA, Small Interfering; D011980:Receptors, Progesterone / Q000819:agonists*; D055815:Young Adult
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C032231:IGFBP1 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D011372:Progestins; D034741:RNA, Small Interfering; D011980:Receptors, Progesterone; C490351:TGFB1I1 protein, human; D011374:Progesterone; D011388:Prolactin; D002116:Calcitonin; D000242:Cyclic AMP