Extracellularly signal-regulated kinase activity in the human endometrium: possible roles in the pathogenesis of endometriosis.
BACKGROUND
Endometriosis is an estrogen-dependent disease characterized by the presence of endometrial tissue outside of the uterine cavity, causing pelvic pain and infertility in 10% of reproductive-aged women. It is unclear why ectopic endometrium remains viable in only a subset of women. ERK1/2 plays key intracellular roles in activating cellular survival and differentiation processes.


OBJECTIVE
We sought to determine ERK1/2 activity in patients with endometriosis and its possible roles in regulating endometrial cell survival.


METHODS
ERK1/2 phosphorylation and expression throughout the menstrual cycle were evaluated in vivo in normal and endometriotic human endometrium, and in vitro techniques assessed the steroidal regulation of ERK1/2 and its effect on endometrial cell survival.


RESULTS
Total ERK1/2 remained constant in normal and endometriotic endometrium throughout the menstrual cycle. Phospho-ERK1/2 was high in the late proliferative and secretory phases in normal endometrium (P < 0.05). In endometriotic glandular cells, there was no cyclical variation in phospho-ERK1/2. In endometriotic stromal cells, there was also a reduction in phospho-ERK1/2 variation, with higher levels in the early-mid secretory phase (P < 0.05). In cultured endometrial stromal cells (ESCs), estrogen plus progesterone increased ERK1/2 phosphorylation within 15 min (P < 0.05). Although estrogen alone did not induce ERK1/2 phosphorylation in normal ESCs, there was a significant response to estrogen in ESCs isolated from eutopic endometriotic endometrium (P < 0.05). ERK1/2 inhibition in ESCs reduced proliferation and increased apoptosis (P < 0.05).


CONCLUSIONS
Abnormally high levels of ERK1/2 activity may be involved in endometriosis, possibly by stimulating endometrial cell survival.
Murk
William
W
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520-8063, USA.
Atabekoglu
Cem S
CS
Cakmak
Hakan
H
Heper
Aylin
A
Ensari
Arzu
A
Kayisli
Umit A
UA
Arici
Aydin
A
D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004715:Endometriosis / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism; D004717:Endometrium / Q000201:enzymology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011374:Progesterone / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D014591:Uterine Diseases / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism
D004791:Enzyme Inhibitors; D005419:Flavonoids; D011374:Progesterone; D004958:Estradiol; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one