Steroidogenic enzyme and key decidualization marker dysregulation in endometrial stromal cells from women with versus without endometriosis.
Identification of mechanisms underlying endometriosis pathogenesis will facilitate understanding and treatment of infertility and pain associated with this disorder. Herein, we investigated the expression of steroidogenic pathway enzymes and key decidualization biomarkers in endometrial tissue and in eutopic endometrial stromal fibroblasts (hESFs) from women with vs. those without endometriosis, and subsequently treated in vitro with 8-bromo-cAMP (8-Br-cAMP) or progesterone (P4). Real-time quantitative PCR, immunohistochemistry, ELISA, and radiometric aromatase activity assay were used. The results demonstrate significantly increased (14.5-fold; P=0.037) expression of aromatase in eutopic endometrium of women with disease. In 8-Br-cAMP-treated hESF from eutopic endometrium of women with endometriosis, the balance in estradiol (E2) and P4 biosynthetic and metabolizing enzymes is disturbed (decreased HSD3B1 and HSD17B2, and increased HSD17B1 and aromatase), with the equilibrium being shifted towards an E2-enriched milieu. However, hESF from the same group of women treated with P4 did not demonstrate such responsiveness. Lower expression of IGFBP1 and prolactin mRNA and protein was observed in hESF from women with vs. those without endometriosis in response to 8-Br-cAMP, but not P4, suggesting a blunted response of these decidual biomarkers to activation of the PKA pathway in eutopic endometrium in women with disease. The dichotomy of 8-Br-cAMP regulation of select steroidogenic enzymes leading to an enriched E2 milieu within the endometrium and a blunted response of decidual biomarkers to this decidualizing agent of hESF from women with endometriosis suggests resistance to full decidualization of the stromal fibroblasts and mechanisms underlying implantation failure and the pathophysiology of this disorder.
Aghajanova
L
L
Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, California 94143, USA.
Hamilton
A
A
Kwintkiewicz
J
J
Vo
K C
KC
Giudice
L C
LC
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000328:Adult; D001141:Aromatase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D003656:Decidua / Q000201:enzymology / Q000378:metabolism; D004715:Endometriosis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000096:biosynthesis; D004960:Estradiol Dehydrogenases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism; D008875:Middle Aged; D011374:Progesterone / Q000096:biosynthesis / Q000494:pharmacology; D011388:Prolactin / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
D018970:Insulin-Like Growth Factor Binding Protein 1; D012333:RNA, Messenger; D015124:8-Bromo Cyclic Adenosine Monophosphate; D011374:Progesterone; D004958:Estradiol; D011388:Prolactin; D004960:Estradiol Dehydrogenases; D001141:Aromatase