GnRH II as a Possible Cytostatic Regulator in the Development of Endometriosis

Both the classic form of the gonadotropin-releasing hormone receptor, GnRH I, and GnRH agonists reportedly have antiproliferative and apoptotic (programmed cell death) effects on cultured endometriotic cells as well as on some cancer cells from reproductive organs. The second form of GnRH receptors, GnRH II, is widely distributed in the central nervous system as well as in the female reproductive tract. The present investigators set out to learn whether GnRH II affects the proliferation of endometriotic stromal cells (ESCs) and whether it might have a role in the pathogenesis of endometriosis. Forty women with endometriosis who were having gynecologic surgery and 19 others without endometriosis were studied. GnRH II inhibited the incorporation of 5-bromo-2′-deoxyuridine (a reflection of mitosis) into DNA of ESC in a dose-dependent manner. The maximum effect was a 28% decrease of incorporation below control level. Treatment with interleukin-1β (IL-1β) markedly increased levels of mRNA for cyclooxygenase-2 and IL-8 in ESC as well as secretion of IL-8 protein by these cells. Supplemental GnRH II significantly inhibited these effects. Levels of GnRH II mRNA were lower in endometrial and endometriotic tissues from women with endometriosis than in endometrial tissues from unaffected women. Levels in endometriotic tissues were significantly reduced in the proliferative phase and tended to be low in the secretory phase when compared with those in endometrial tissues from women with endometriosis. Levels of mRNA for type I and type II GnRH receptors followed, for the most part, the same pattern as GnRH I. These findings suggest that GnRH II has antiproliferative and antiinflammatory effects on ESC. Observations of lower levels of expression of GnRH II in eutopic and ectopic endometrium from women having endometriosis indicate that, in this disorder, cytostatic mechanisms mediated by GnRH II may be impaired.