GnRH II as a possible cytostatic regulator in the development of endometriosis

BACKGROUND GnRH II is the second form of GnRH and is widely distributed in peripheral tissues of the female reproductive tract as well as in the central nervous system. In the present study, we studied the possible implication of GnRH II in endometriosis. METHODS Effects of GnRH II on 5-bromo-2'-deoxyuridine (BrdU) uptake by cultured endometriotic stromal cells were examined. Effects of GnRH II on interleukin (IL)-1beta-induced expression of cyclooxygenase (COX)-2 and IL-8 were also studied. mRNA levels of GnRH I, GnRH II, type I GnRH receptor and type II GnRH receptor were determined by real-time quantitative RT-PCR in endometrial tissues of women with or without endometriosis and in endometriotic tissues. RESULTS GnRH II dose-dependently suppressed BrdU uptake by endometrial stromal cells. Treatment with IL-1beta markedly increased mRNA levels of COX-2 and IL-8 in endometrial stromal cells and IL-8 protein secretion by these cells, while these increments were significantly suppressed by supplementation with GnRH II. The mRNA levels of GnRH II were lower in endometrial and endometriotic tissues of women with endometriosis than in endometrial tissues of women without endometriosis, both in the proliferative phase and the secretory phase. In addition, as for GnRH I, type I GnRH receptor and type II GnRH receptor, the mRNA levels were lower in endometrial tissues of women with endometriosis than in those without endometriosis in the secretory phase. CONCLUSIONS In the light of the demonstrated antiproliferative and anti-inflammatory effects of GnRH II on endometrial stromal cells, the lower expression of GnRH II in eutopic and ectopic endometrium of women with endometriosis suggests that endogenous GnRH II-mediated cytostatic regulation may be impaired in the development of endometriosis.

[1]  T. Nett,et al.  Gonadotropin-releasing hormone and its receptor in normal and malignant cells. , 2004, Endocrine-related cancer.

[2]  Y. Taketani,et al.  Possible Pathophysiological Roles of Mitogen‐Activated Protein Kinases (MAPKs) in Endometriosis , 2004, American journal of reproductive immunology.

[3]  D. Endo,et al.  Human Type II GnRH Receptor Mediates Effects of GnRH on Cell Proliferation , 2004, Zoological science.

[4]  G. Emons,et al.  Antiproliferative effects of the GnRH antagonist cetrorelix and of GnRH-II on human endometrial and ovarian cancer cells are not mediated through the GnRH type I receptor. , 2004, European journal of endocrinology.

[5]  M. Motta,et al.  The biology of gonadotropin hormone-releasing hormone: role in the control of tumor growth and progression in humans , 2003, Frontiers in Neuroendocrinology.

[6]  P. Leung,et al.  Regulatory effects of gonadotropin-releasing hormone (GnRH) I and GnRH II on the levels of matrix metalloproteinase (MMP)-2, MMP-9, and tissue inhibitor of metalloproteinases-1 in primary cultures of human extravillous cytotrophoblasts. , 2003, The Journal of clinical endocrinology and metabolism.

[7]  M. Tesone,et al.  Effect of GnRH analogues on apoptosis and release of interleukin-1beta and vascular endothelial growth factor in endometrial cell cultures from patients with endometriosis. , 2003, Human reproduction.

[8]  Y. Taketani,et al.  Possible roles of thrombin-induced activation of protease-activated receptor 1 in human luteinized granulosa cells. , 2003, The Journal of clinical endocrinology and metabolism.

[9]  Ming-Yih Wu,et al.  The Role of Cytokines in Endometriosis * , 2003, American journal of reproductive immunology.

[10]  P. Leung,et al.  Differential regulation of gonadotropin-releasing hormone (GnRH)I and GnRHII messenger ribonucleic acid by gonadal steroids in human granulosa luteal cells. , 2003, The Journal of clinical endocrinology and metabolism.

[11]  Adam J Pawson,et al.  A transcriptionally active human type II gonadotropin-releasing hormone receptor gene homolog overlaps two genes in the antisense orientation on chromosome 1q.12. , 2003, Endocrinology.

[12]  R. Millar.  GnRH II and type II GnRH receptors , 2003, Trends in Endocrinology & Metabolism.

[13]  M. Tesone,et al.  Gonadotropin-releasing hormone agonist induces apoptosis and reduces cell proliferation in eutopic endometrial cultures from women with endometriosis. , 2002, Fertility and sterility.

[14]  P. Leung,et al.  The effects of gonadotropin-releasing hormone (GnRH) I and GnRH II on the urokinase-type plasminogen activator/plasminogen activator inhibitor system in human extravillous cytotrophoblasts in vitro. , 2002, The Journal of clinical endocrinology and metabolism.

[15]  Y. Taketani,et al.  Cellular mechanisms of growth inhibition of human epithelial ovarian cancer cell line by LH-releasing hormone antagonist Cetrorelix. , 2002, The Journal of clinical endocrinology and metabolism.

[16]  Tatsuo Yamamoto,et al.  Increased Expression of Cyclooxygenase‐2 in Local Lesions of Endometriosis Patients , 2002, American journal of reproductive immunology.

[17]  G. Emons,et al.  Expression of gonadotropin-releasing hormone II (GnRH-II) receptor in human endometrial and ovarian cancer cells and effects of GnRH-II on tumor cell proliferation. , 2002, The Journal of clinical endocrinology and metabolism.

[18]  N. Auersperg,et al.  Expression and antiproliferative effect of a second form of gonadotropin-releasing hormone in normal and neoplastic ovarian surface epithelial cells. , 2001, The Journal of clinical endocrinology and metabolism.

[19]  S. McColl,et al.  Ectopic endometrial cells express high concentrations of interleukin (IL)-8 in vivo regardless of the menstrual cycle phase and respond to oestradiol by up-regulating IL-1-induced IL-8 expression in vitro. , 2001, Molecular human reproduction.

[20]  K. L. Sharpe-Timms,et al.  Endometrial Anomalies in Women with Endometriosis , 2001, Annals of the New York Academy of Sciences.

[21]  Y. Taketani,et al.  Evidence for the expression of interleukin (IL)-18, IL-18 receptor and IL-18 binding protein in the human endometrium. , 2001, Molecular human reproduction.

[22]  Hyoung-Song Lee,et al.  Expression of the second isoform of gonadotrophin-releasing hormone (GnRH-II) in human endometrium throughout the menstrual cycle. , 2001, Molecular human reproduction.

[23]  S. Igarashi,et al.  Distribution of cyclooxygenase-2 in eutopic and ectopic endometrium in endometriosis and adenomyosis. , 2001, Human reproduction.

[24]  M. Grayson,et al.  Action of chicken II GnRH on the human placenta. , 2001, The Journal of clinical endocrinology and metabolism.

[25]  M. Mueller,et al.  Immunobiology of endometriosis. , 2001, Fertility and sterility.

[26]  C. Tai,et al.  Differential regulation of two forms of gonadotropin-releasing hormone messenger ribonucleic acid in human granulosa-luteal cells. , 2001, Endocrinology.

[27]  Y. Taketani,et al.  Evidence for the presence of angiogenin in human follicular fluid and the up-regulation of its production by human chorionic gonadotropin and hypoxia. , 2000, The Journal of clinical endocrinology and metabolism.

[28]  T. Tamaya,et al.  Gonadotropin-releasing hormone analog repairs reduced endometrial cell apoptosis in endometriosis in vitro. , 2000, American journal of obstetrics and gynecology.

[29]  P. Viganò,et al.  Expression of GnRH receptor gene in human ectopic endometrial cells and inhibition of their proliferation by leuprolide acetate , 2000, Molecular and Cellular Endocrinology.

[30]  S. Quenby,et al.  Peritoneal fluid concentrations of interleukin-8 in women with endometriosis: relationship to stage of disease. , 1998, Human reproduction.

[31]  N. Terakawa,et al.  Pathogenetic significance of increased levels of interleukin-8 in the peritoneal fluid of patients with endometriosis. , 1998, Fertility and sterility.

[32]  J. Eisen,et al.  Second gene for gonadotropin-releasing hormone in humans. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Y. S. Yang,et al.  Decrease in interferon gamma production and impairment of T-lymphocyte proliferation in peritoneal fluid of women with endometriosis. , 1996, American journal of obstetrics and gynecology.

[34]  P. Rogers,et al.  Cell proliferation is increased in the endometrium of women with endometriosis. , 1995, Fertility and sterility.

[35]  S. Sealfon,et al.  Cloning and characterization of the human GnRH receptor , 1993, Molecular and Cellular Endocrinology.

[36]  Y. Taketani,et al.  Comparison of cytokine levels and embryo toxicity in peritoneal fluid in infertile women with untreated or treated endometriosis. , 1992, American journal of obstetrics and gynecology.

[37]  P. Seeburg,et al.  The complete nucleotide sequence of the human gonadotropin-releasing hormone gene. , 1989, Nucleic acids research.