In Vivo Assessment of the Regulation of Transforming Growth Factor Alpha, Epidermal Growth Factor (EGF), and EGF Receptor in the Human Endometrium by Medroxyprogesterone Acetate

Purpose: The present study evaluated the in vivo effect of medroxyprogesterone acetate (MPA) on the localization of immunoreactive transforming growth factor alpha (TGFα), epidermal growth factor (EGF), and their common receptor (EGF-R) in the human endometrium.

The study design was a randomized clinical trial enrolling 36 healthy women with regular menstrual cycles. The participants were randomly assigned into three groups: groups 1 (n = 11) and 2 (n = 17) received placebo and were submitted to endometrial biopsy during the proliferative and secretory phases of menstrual cycle, respectively; group 3 (n = 8) received MPA (10 mg/day) for 10 days followed by endometrial biopsy, which was performed during the secretory phase. Immunohistochemistry was used to localize TGFα, EGF, and EGF-R in the endometrial tissue.

TGFα was present markedly in the luminal and glandular epithelia but also in the periglandular stroma, with a distribution pattern similar in the three experimental groups. EGF immunostaing was equally distributed in epithelial and stromal layers of the endometrium and remained unchanged in endometrial samples from women treated with MPA compared to placebo. EGF-R was expressed only in the epithelium. The intensity of EGF-R immunostaining was higher in secretory than in proliferative endometrium and was further increased by administration of MPA (p < 0.05, chi-square test).

The present results suggest that the progestogen-induced in vivo differentiation of secretory endometrium does not require dramatic changes in the expression of EGF or TGFα, whereas EGF-R may be up regulated. Similar content being viewed by others

Irwin JC, Utian WH, Eckert RL: Sex steroids and growth factors differentially regulate the growth and differentiation of cultured human endometrial stromal cells. Endocrinology 1991;129:2385–2392 Haining RE, Cameron IT, van Papendorp C, Davenport AP, Prentice A, Thomas EJ, Smith SK: Epidermal growth factor in human endometrium: Proliferative effects in culture and immunocytochemical localization in normal and endometriotic tissues. Hum Reprod 1991;6:1200–1205 Taga M, Saji M, Suyama K, Minaguchi H: Transforming growth factor-alpha, like epidermal growth factor, stimulates cell proliferation and inhibits prolactin secretion in the human decidual cells in vitro. J Endocrinol Invest 1996;19:659–662 Haining REB, Schofield JP, Jones DSC, Rajput-Williams J, Smith SK: Identification of mRNA for epidermal growth factor and transforming growth factor-α present in low copy number in human endometrium and decidua using reverse transcriptase–polymerase chain reaction. J Mol Endocrinol 1991;6:207–214 Sakakibara H, Taga M, Saji M, Kida H, Minaguchi H: Gene expression of epidermal growth factor in human endometrium during decidualization. J Clin Endocrinol Metab 1994;79:223–226 Nelson KG, Takahashi T, Bossert NL, Walmer DK, Mclachlan JA: Epidermal growth factor replaces estrogen in the stimulation of female genital-tract growth and differentiation. Proc Natl Acad Sci USA 1991;88:21–25 Hansard LJ, Healy-Gardner BE, Drapkin AT, Bentley RC, McLachlan JA, Walmer DK: Human endometrial transforming growth factor-alpha: A transmembrane, surface epithelial protein that transiently disappears during the midsecretory phase of the menstrual cycle. J Soc Gynecol Invest 1997;4:160–166 Imai T, Kurachi H, Adachi K, Adachi H, Yoshimoto Y, Homma H, Tadokoro C, Takeda S, Yamaguchi M, Sakata M: Changes in epidermal growth factor receptor and the levels of its ligands during menstrual cycle in human endometrium. Biol Reprod 1995;52:928–938 Troche V, O’Connor DM, Schaudies RP: Measurement of human epidermal growth factor receptor in the endometrium during the menstrual cycle. Am J Obstet Gynecol 1991;165:1499–1503 Moller B, Rasmussen C, Lindblom B, Olovsson M: Expression of the angiogenic growth factors VEGF, FGF-2, EGF and their receptors in normal human andometrium during the menstrual cycle. Mol Hum Reprod 2001;7:65–72 Prentice A, Thomas EJ, Weddell A, Mcgill A, Randall BJ, Horne CHW: Epidermal growth factor receptor expression in normal endometrium and endometriosis: An immunohistochemical study. Br J Obstet Gynaecol 1992;99:395–398 Chegini N, Rossi MJ, Masterson BJ: Platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and EGF and PDGF β-receptors in human endometrial tissue: Localization and in vitro action. Endocrinology 1992;130:2373–2385 Huet-Hudson YM, Chakraborty C, De SK, Suzuki Y, Andrews GK, Dey SK: Estrogen regulates the synthesis of epidermal growth factor in mouse uterine epithelial cells. Mol Endocrinol 1990;4:510–523 Lockwood CJ: Regulation of plasminogen activator inhibitor 1 expression by interaction of epidermal growth factor with progestin during decidualization of human endometrial stromal cells. Am J Obstet Gynecol 2001;184:798–805 Noyes RW, Hertig AT, Rock J: Dating the endometrial biopsy. Fert Steril 1950;1:3–15 Reis FM, Maia AL, Ribeiro MF, Spritzer PM: Progestin modulation of c-fos and prolactin gene expression in the human endometrium. Fert Steril 1999;71:1125–1132 Horowitz GM, Scott RT, Drews MR, Navot D, Hofmann GE: Immunohistochemical localization of transforming growth factor-α in human endometrium, decidua, and trophoblast. J Clin Endocrinol Metab 1993;76:786–792 Reynolds RK, Talavera F, Roberts JA, Hopkins MP, Menon KMJ: Regulation of epidermal growth factor and insulin-like growth factor I receptors by estradiol and progesterone in normal and neoplastic endometrial cell cultures. Gynecol Oncol 1990;38:396–406 Watson H, Franks S, Bonney RC: Regulation of epidermal growth factor receptor synthesis by ovarian steroids in human endometrial cells in culture. J Reprod Fertil 1996;107:199–205 Singer GA, Strowitzki T, Rettig I, Kimmig R: Flow cytometric detection and binding studies of human endometrial stromal cell epidermal growth factor receptor in monolayer culture: Influence of progesterone. Mol Hum Reprod 1998;4:577–583 Camaggi CM, Strocchi E, Giovannini M, Angelelli B, Costanti B, Zebini E, Ferrari P, Pannuti F: Medroxyprogesterone acetate (MPA) plasma levels after multiple high dose administration in advanced cancer patients. Cancer Chemoth Pharmacol 1983;11:19–22 Gullic WJ: Prevalence of aberrant expression of the epidermal growth factor receptor in human cancers. Br Med Bull 1991;47:87–95 Chobotova K, Muchmore ME, Carver J, Yoo HJ, Manek S, Gullick WJ, Barlow DH, Mardon HJ: The mitogenic potential of heparin-binding epidermal growth factor in the human endometrium is mediated by the epidermal growth factor receptor and is modulated by tumor necrosis factor-alpha. J Clin Endocrinol Metab 2002;87:5769–5777 Roopa BA, Loganath A, Singh K: The effect of a levonorgestrel-releasing intrauterine system on angiogenic growth factors in the endometrium. Hum Reprod 2003;18: 1809–1819 Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Reis, F.M., Lhullier, C., Edelweiss, M.I. et al. In Vivo Assessment of the Regulation of Transforming Growth Factor Alpha, Epidermal Growth Factor (EGF), and EGF Receptor in the Human Endometrium by Medroxyprogesterone Acetate. J Assist Reprod Genet 22, 19–24 (2005). https://doi.org/10.1007/s10815-005-0816-x Received: Accepted: Issue date: DOI: https://doi.org/10.1007/s10815-005-0816-x