Abstract
Progestogens are used clinically for contraception, to control excessive menstrual bleeding and to oppose oestrogen in hormone replacement therapy. The use of intrauterine levonorgestrel (LNG) is however, associated with endometrial atrophy and decidualisation of the stroma. In this study, we aimed to identify genes whose expression is modulated by LNG either alone or in combination with progesterone. Thus endometrial stromal cells were stimulated with progesterone, LNG or LNG and progesterone. Poly-A RNA was isolated and used to probe expression arrays. The expression of a number of genes was altered on exposure to LNG or LNG and progesterone. Alteration of expression patterns was confirmed using semi-quantitative RT-PCR and western blot analysis. In particular, the protease activated receptor-1 (PAR-1) gene that encodes a receptor for thrombin was down regulated. This is the first demonstration that PAR-1 is down regulated by the progestogen LNG in human endometrium. Alteration in the expression levels of this receptor may affect both growth and haemostatic activity within the endometrium and may account for the observed morphological effects seen in users of intrauterine LNG delivery devices.
Similar content being viewed by others
References
Lahteenmaki P, Rauramo I, Backman T. The levonorgestrel intrauterine system in contraception. Steroids 2000; 65: 693–7.
Riphagen FE. Intrauterine applications of progestins in hormone replacement therapy: A review. Climateric 2000; 3: 199–211.
Nilsson CG, Haukkamaa M, Vierola H, Luukkainen T. Tissue concentrations of levonorgestrel in women using a levonorgestrel-releasing IUD. Clin Endocrinol (Oxf) 1982; 17: 529–36.
Silverberg SG, Haukkamaa M, Arko H et al. Endometrial morphology during long-term use of levonorgestrel-releasing intrauterine devices. Int J Gynecol Pathol 1986; 5: 235–41.
Salmi A, Pakarinen P, Peltola AM et al. The effect of intrauterine levonorgestrel use on the expression of c-JUN, oestrogen receptors, progesterone receptors and Ki-67 in human endometrium. Mol Hum Reprod 1998; 4: 1110–5.
Luo H, Zhu P, Xu R et al. Inhibition of DNA synthesis in isolated human endometrial cells by a levonorgestrel-releasing intrauterine device. Anal Quant Cytol Histol 1999; 21: 409–12.
Critchley HO, Wang H, Kelly RW et al. Progestin receptor isoforms and prostaglandin dehydrogenase in the endometrium of women using a levonorgestrel-releasing intrauterine system. Hum Reprod 1998; 13: 1210–7.
Rutanen EM, Salmi A, Nyman T. mRNA expression of insulin-like growth factor-I (IGF-I) is suppressed and those of IGF-II and IGF-binding protein-1 are constantly expressed in the endometrium during use of an intrauterine levonorgestrel system. Mol Hum Reprod 1997; 3: 749–54.
Pekonen F, Nyman T, Lahteenmaki P et al. Intrauterine progestin induces continuous insulin-like growth factor-binding protein-1 production in the human endometrium. J Clin Endocrinol Metab 1992; 75: 660–4.
Murphy LJ, Ghahary A. Uterine insulin-like growth factor-1: Regulation of expression and its role in estrogen-induced uterine proliferation. Endocr Rev 1990; 11: 443–53.
Rutanen E, Hurskainen R, Finne P, Nokelainen K. Induction of endometrial plasminogen activator-inhibitor 1: A possible mechanism contributing to the effect of intrauterine levonorgestrel in the treatment of menorrhagia. Fertil Steril 2000; 73: 1020–4.
Satyaswaroop PG, Bressler RS, de la Pena MM et al. Isolation and culture of human endometrial glands. J Clin Endocrinol Metab 1979; 48: 639–41.
Fernandez-Shaw S, Shorter SC, Naish CE et al. Isolation and purification of human endometrial stromal and glandular cells using immunomagnetic microspheres. Hum Reprod 1992; 7: 156–61.
Wells M. Female genital tract. In Underwood JC (ed): General and Systemic Pathology, Edinburgh: Churchill Livingstone 1996; 551–84.
Nierodzik ML, Bain RM, Liu LX et al. Presence of the seven transmembrane thrombin receptor on human tumour cells: Effect of activation on tumour adhesion to platelets and tumor tyrosine phosphorylation. Br J Haematol 1996; 92: 452–7.
Macfarlane SR, Seatter MJ, Kanke T. Proteinase-activated receptors. Pharmacol Rev 2001; 53: 245–82.
Arena CS, Quirk SM, Zhang YQ et al. Rat uterine stromal cells: Thrombin receptor and growth stimulation by thrombin. Endocrinology 1996; 137: 3744–9.
Lockwood CJ, Krikun G, Aigner S et al. Effects of thrombin on steroid-modulated cultured endometrial stromal cell fibrinolytic potential. J Clin Endocrinol Metab 1996; 81: 107–12.
Haslinger B, Mandl-Weber S, Sitter T. Thrombin suppresses matrix metalloproteinase 2 activity and increases tissue inhibitor of Down regulation of PAR-1 by levonorgestrel in endometrium 97 metalloproteinase 1 synthesis in cultured human peritoneal mesothelial cells. Perit Dial Int 2000; 20: 778–83.
Fernandez-Patron C, Martinez-Cuesta MA, Salas E et al. Differential regulation of platelet aggregation by matrix metalloproteinases-9 and-2. Thromb Haemost 1999; 82: 1730–5.
Klein-Soyer C, Duhamel-Clerin E, Ravanat C et al. PF4 inhibits thrombin-stimulated MMP-1 and MMP-3 metalloproteinase expression in human vascular endothelial cells. C R Acad Sci III 1997; 320: 857–68.
Hampton AL, Nie G, Salamonsen LA. Progesterone analogues similarly modulate endometrial matrix metalloproteinase-1 and matrix metalloproteinase-3 and their inhibitor in a model for long-term contraceptive effects. Mol Hum Reprod 1999; 5: 365–71.
Osteen KG, Keller NR, Feltus FA et al. Paracrine regulation of matrix metalloproteinase expression in the normal human endometrium. Gynecol Obstet Invest 1999; 48(Suppl 1): 2–13.
Marbaix E, Vekemans M, Galant C et al. Circulating sex hormones and endometrial stromelysin-1 (matrix metalloproteinase-3) at the start of bleeding episodes in levonorgestrel-implant users. Hum Reprod 2000; 15(Suppl 3): 120–34.
Jones RL, Critchley HO. Morphological and functional changes in human endometrium following intrauterine levonorgestrel delivery. Hum Reprod 2000; 15(Suppl 3): 162–72.
Cunningham MA, Rondeau E, Chen X et al. Protease-activated receptor 1 mediates thrombin-dependent, cell-mediated renal inflammation in crescentic glomerulonephritis. J Exp Med 2000; 19: 455–62.
Jenkins AL, Howells GL, Scott E et al. The response to thrombin of human neutrophils: Evidence for two novel receptors. J Cell Sci 1995; 108: 3059–66.
Herkert O, Kuhl H, Sandow J et al. Sex steroids used in hormonal treatment increase vascular procoagulant activity by inducing thrombin receptor (PAR-1) expression: Role of the glucocorticoid receptor. Circulation 2001; 104: 2826–31.
Rogers PA, Lederman F, Plunkett D et al. Bcl-2, Fas and caspase 3 expression in endometrium from levonorgestrel implant users with and without breakthrough bleeding. Hum Reprod 2000; 15(Suppl 3): 152–61.
Rodriguez GC, Walmer DK, Cline M et al. Effect of progestin on the ovarian epithelium of macaques: Cancer prevention through apoptosis? J Soc Gynecol Invest 1998; 5: 271–6.
Tao XJ, Tilly KI, Maravei DV et al. Differential expression of members of the bcl-2 gene family in proliferative and secretory human endometrium: Glandular epithelial cell apoptosis is associated with increased expression of bax. J Clin Endocrinol Metab 1997; 82: 2738–46.
Vaskivuo TE, Stenback F, Karhumaa P et al. Apoptosis and apoptosis-related proteins in human endometrium. Mol Cell Endocrinol 2000; 165: 75–83.
Perino A, Quartararo P, Catinella E et al. Treatment of endometrial hyperplasia with levonorgestrel releasing intrauterine devices. Acta Eur Fertil 1987; 18: 137–40.
Popovici RM, Kao LC, Giudice LC. Discovery of new inducible genes in in vitro decidualized human endometrial stromal cells using microarray technology. Endocrinology 2000; 141: 3510–3.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hague, S., Oehler, M., MacKenzie, I. et al. Protease activated receptor-1 is down regulated by levonorgestrel in endometrial stromal cells. Angiogenesis 5, 93–98 (2002). https://doi.org/10.1023/A:1021510723157
Issue Date:
DOI: https://doi.org/10.1023/A:1021510723157