Expression of vascular endothelial growth factors and their receptors in human endometrium from women experiencing abnormal bleeding patterns after prolonged use of a levonorgestrel-releasing intrauterine system.

BACKGROUND Menstrual bleeding disturbances are a common initial complaint among users of the levonorgestrel-releasing intrauterine system (LNG-IUS). In this study, women who experienced bleeding disturbances recurring after a previous period of problem-free use and who therefore wanted removal of their LNG-IUD were investigated. Vascular endothelial growth factors (VEGFs) and their receptors are thought to be involved in normal endometrial angiogenesis. The aim of the study was to elucidate the possible association of these VEGF and receptors with bleeding disturbances among users of LNG-IUS. METHODS Endometrial biopsies were obtained from users of the LNG-IUS who complained of bleeding disturbances (n = 17) and from women without such problems (n = 14). The endometrial expression of these VEGFs and their receptors was analysed using immunohistochemistry. RESULTS Endometrial endothelial cells from LNG-IUS users with menstrual bleeding disturbances exhibited significantly higher immunoreactivity for VEGFR-1 and VEGFR-3 than those from women without bleeding disturbances. Stromal cells showed significantly lower immunoreactivity for VEGF-A in samples from LNG-IUS users with bleeding disturbances than in those without. CONCLUSION Changes in the expression of these angiogenic growth factors and their receptors in LNG-IUS-exposed endometrium might be involved in the formation of fragile and dysfunctional blood vessels that subsequently give rise to bleeding disturbances.

[1]  A. Pinol,et al.  Menstrual bleeding patterns in untreated women. Task Force on Long-Acting Systemic Agents for Fertility Regulation. , 1997, Contraception.

[2]  L. Xiaoqun,et al.  The effect of a levonorgestrel-releasing intrauterine device on human endometrial oestrogen and progesterone receptors after one year of use , 1999 .

[3]  J. Folkman,et al.  Angiogenic factors. , 1987, Science.

[4]  Y. Hirata,et al.  Molecular cloning of a novel vascular endothelial growth factor, VEGF-D. , 1997, Genomics.

[5]  K. Williams,et al.  Estrogen receptor beta, but not estrogen receptor alpha, is present in the vascular endothelium of the human and nonhuman primate endometrium. , 2001, The Journal of clinical endocrinology and metabolism.

[6]  Stephen K. Smith.  Regulation of angiogenesis in the endometrium , 2001, Trends in Endocrinology & Metabolism.

[7]  M. Olovsson,et al.  Expression of the angiogenic growth factors VEGF, FGF-2, EGF and their receptors in normal human endometrium during the menstrual cycle. , 2001, Molecular human reproduction.

[8]  D. Charnock-Jones,et al.  The effect of progestins on vascular endothelial growth factor, oestrogen receptor and progesterone receptor immunoreactivity and endothelial cell density in human endometrium. , 2000, Human reproduction.

[9]  R. Luoto,et al.  Length of use and symptoms associated with premature removal of the levonorgestrel intrauterine system: a nation‐wide study of 17,360 users , 2000, BJOG : an international journal of obstetrics and gynaecology.

[10]  P. Zhu,et al.  A morphometric study on the endometrial activity of women before and after one year with LNG-IUD in situ. , 1995, Contraception.

[11]  K. Alitalo,et al.  Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[12]  D. Charnock-Jones,et al.  Expression of vascular endothelial growth factor (VEGF)-D and its receptor, VEGF receptor 3, as a prognostic factor in endometrial carcinoma. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[13]  G. Krikun,et al.  Effects of norplant on endometrial tissue factor expression and blood vessel structure. , 2000, The Journal of clinical endocrinology and metabolism.

[14]  I. Mackenzie,et al.  In-vivo angiogenesis and progestogens. , 2002, Human reproduction.

[15]  L. Mattsson,et al.  Intrauterine administration of levonorgestrel 5 and 10 microg/24 hours in perimenopausal hormone replacement therapy. A randomized clinical study during one year. , 1997, Acta obstetricia et gynecologica Scandinavica.

[16]  G. Lecce,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society Presence of Estrogen Receptor � in the Human Endometrium through the Cycle: Expression in , 2022 .

[17]  T. Quinn,et al.  Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[18]  M. Olovsson,et al.  Expression of the vascular endothelial growth factors B and C and their receptors in human endometrium during the menstrual cycle , 2002, Acta obstetricia et gynecologica Scandinavica.

[19]  K. Alitalo,et al.  A novel vascular endothelial growth factor, VEGF‐C, is a ligand for the Flt4 (VEGFR‐3) and KDR (VEGFR‐2) receptor tyrosine kinases. , 1996, The EMBO journal.

[20]  J. Suvisaari,et al.  Detailed analysis of menstrual bleeding patterns after postmenstrual and postabortal insertion of a copper IUD or a levonorgestrel-releasing intrauterine system. , 1996, Contraception.

[21]  S. Wu,et al.  The effect of intrauterine devices, the stainless steel ring, the copper T220, and releasing levonorgestrel, on the bleeding profile and the morphological structure of the human endometrium--a comparative study of three IUDs. A morphometric study of 96 cases. , 1989, Contraception.

[22]  V. Odlind,et al.  Health effects of long-term use of the intrauterine levonorgestrel-releasing system. A follow-up study over 12 years of continuous use , 1999 .

[23]  T. Luukkainen,et al.  Ovarian function in amenorrheic and menstruating users of a levonorgestrel-releasing intrauterine device. , 1984, Fertility and sterility.

[24]  M. Iruela-Arispe,et al.  Endometrial Endothelial Cells Express Estrogen and Progesterone Receptors and Exhibit a Tissue Specific Response to Angiogenic Growth Factors , 1999, Microcirculation.

[25]  N. Ferrara,et al.  Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. , 1989, Biochemical and biophysical research communications.

[26]  P. Rogers,et al.  Endometrial vasculature in Norplant users. , 1996, Human reproduction.

[27]  Kuldip Singh,et al.  The effect of a levonorgestrel-releasing intrauterine system on angiogenic growth factors in the endometrium. , 2003, Human reproduction.

[28]  J. Fiddes,et al.  The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. , 1991, The Journal of biological chemistry.

[29]  E. Lehtonen,et al.  The ultrastructure of human endometrium is altered by administration of intrauterine levonorgestrel. , 1998, Human reproduction.

[30]  W. Wood,et al.  Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[31]  J. Bertram,et al.  Angiogenesis occurs by vessel elongation in proliferative phase human endometrium. , 2002, Human reproduction.

[32]  P. Rogers,et al.  Endometrial microvascular density during the normal menstrual cycle and following exposure to long-term levonorgestrel. , 1993, Human reproduction.

[33]  V. Odlind,et al.  Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. , 1994, Contraception.

[34]  T. Maruo,et al.  Effects of levonorgestrel-releasing intra-uterine system on the expression of vascular endothelial growth factor and adrenomedullin in the endometrium in adenomyosis. , 2003, Human reproduction.

[35]  F. Raga,et al.  Expression of mRNA for vascular endothelial growth factor transmembraneous receptors Flt1 and KDR, and the soluble receptor sflt in cycling human endometrium. , 1999, Molecular human reproduction.

[36]  K. Alitalo,et al.  Vascular endothelial growth factor-C and its receptor VEGFR-3 in the nasal mucosa and in nasopharyngeal tumors. , 2000, The American journal of pathology.

[37]  E. Tschachler,et al.  Lymphatic endothelium and Kaposi's sarcoma spindle cells detected by antibodies against the vascular endothelial growth factor receptor-3. , 1998, Cancer research.

[38]  H Ueno,et al.  The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. , 1992, Science.

[39]  S. Smith.  Angiogenesis, vascular endothelial growth factor and the endometrium. , 1998, Human reproduction update.

[40]  Douglas Hanahan,et al.  Signaling Vascular Morphogenesis and Maintenance , 1997, Science.

[41]  L. Giudice,et al.  Growth factors and growth modulators in human uterine endometrium: their potential relevance to reproductive medicine. , 1994, Fertility and sterility.

[42]  I. Fraser,et al.  The effect of high-dose medium- and long- term progestogen exposure on endometrial vessels. , 1995, Human reproduction.

[43]  G. Rybo,et al.  Levonorgestrel‐releasing intrauterine device in the treatment of menorrhagia , 1991 .

[44]  I. Fraser,et al.  Precise measurements of intrauterine vascular structures at hysteroscopy in menorrhagia and during Norplant use. , 1998, Human reproduction.

[45]  E. Coutinho,et al.  Ovarian function after seven years' use of a levonorgestrel IUD , 1995, Advances in contraception : the official journal of the Society for the Advancement of Contraception.

[46]  J. Cheng,et al.  The effect of a levonorgestrel-releasing intrauterine device on human endometrial oestrogen and progesterone receptors after one year of use. , 1999, Human reproduction.

[47]  B. Kasinath,et al.  The type 2 vascular endothelial growth factor receptor recruits insulin receptor substrate-1 in its signalling pathway. , 2002, The Biochemical journal.

[48]  K. Alitalo,et al.  Vascular endothelial growth factor B, a novel growth factor for endothelial cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[49]  P. Rogers,et al.  Endometrial angiogenesis , 2004, Angiogenesis.