Stromal-Epithelial Cell Communication in the Female Reproductive Tract

  • Paul S. Cooke
  • David L. Buchanan
  • Takeshi Kurita
  • Dennis B. Lubahn
  • Gerald R. Cunha
Part of the Contemporary Endocrinology book series (COE, volume 9)


The female reproductive organs undergo well-characterized structural and functional changes during the estrous or menstrual cycles and the establishment and maintenance of pregnancy. These reproductive tract changes are primarily under the control of hormones such as estrogens, specifically estradiol 17-β (E2), and progesterone (P). Owing to the critical role of E2 and P in the normal functioning of the female reproductive tract, as well as the role of these hormones in the etiology and progression of various diseases of the reproductive organs, it is important to understand the cellular and molecular mechanisms by which these hormones act.


Keratinocyte Growth Factor Epithelial Proliferation Female Reproductive Tract Uterine Epithelium Mouse Uterus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Cunha GR, Alarid ET, Turner T, Donjacour AA, Boutin EL, Foster, BA (1992) Normal and abnormal development of the male urogenital tract: role of androgens, mesenchymal-epithelial interactions, and growth factors. J Andrology 13:465–475.Google Scholar
  2. 2.
    Cunha GR, Horn YK (1996) Role of mesenchymal interactions in mammary gland development. J Mammary Gland Biol Neoplasia 1:21–35.PubMedCrossRefGoogle Scholar
  3. 3.
    Wessels NK (1977) Tissue Interactions and Development, Benjamin/Cummings, Menlo Park, CA.Google Scholar
  4. 4.
    Finn CA, Martin J (1967) Patterns of cell division in the mouse uterus during early pregnancy. J Endocrinol 39:593–597.PubMedCrossRefGoogle Scholar
  5. 5.
    Martin L (1980) Estrogens, anti-estrogen and the regulation of cell proliferation in the female reproductive tract in vivo, In: Estrogens in the Environment (McLachlan JA, ed.), Elsevier/North-Holland, New York, pp. 103–130.Google Scholar
  6. 6.
    Martin L, Das R, Finn C (1973) The inhibition by progesterone of uterine epithelial proliferation in the mouse. J Endocrinol 57:549–555.PubMedCrossRefGoogle Scholar
  7. 7.
    Finn CA, Publicover M (1981) Hormonal control of cell death in the luminal epithelium of the mouse uterus. J Endocrinol 91:335–340.PubMedCrossRefGoogle Scholar
  8. 8.
    Weitlauf HM (1994) Biology of implantation, In: The Physiology of Reproduction, Volume 1, 2nd Ed, (Knobil E, Neill JD, eds.), Raven, New York, pp. 391–440.Google Scholar
  9. 9.
    Clark BF (1973) The effect of oestrogen and progesterone on uterine cell division and epithelial morphology in spayed-hypophysectomized rats. J Endocrinol 56:341–342.PubMedCrossRefGoogle Scholar
  10. 10.
    Lydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes AR, Montgomery CA, et al. (1995) Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Development 9:2266–2278.PubMedCrossRefGoogle Scholar
  11. 11.
    Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O (1993) Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci USA 90:11,162-11,166.CrossRefGoogle Scholar
  12. 12.
    Rosa DG, Velardo JT (1959) Histochemical localization of vaginal oxidative enzymes and mucins in rats treated with estradiol and progesterone. Ann NY Acad Sci 83:122–144.PubMedCrossRefGoogle Scholar
  13. 13.
    Saunders PTK, Maguire SM, Gaughan T, Millar MR (1997) Expression of oestrogen receptor beta (ERβ) in multiple rat tissues visualized by immunohistochemistry. J Endocrinol 154:R12–R16.CrossRefGoogle Scholar
  14. 14.
    Ohta Y, Sato T, Iguchi T (1993) Immunocytochemical localization of progesterone receptor in the reproductive tract of adult female rats. Biol Reprod 48, 205–213.PubMedCrossRefGoogle Scholar
  15. 15.
    Cunha GR, Shannon JM, Vanderslice KD, Sekkingstad M, Robboy SJ (1982) Autoradiographic analysis of nuclear estrogen binding sites during postnatal development of the genital tract of female mice. J Steroid Biochem 17:281–286.PubMedCrossRefGoogle Scholar
  16. 16.
    Bigsby RM, Cunha GR (1986) Estrogen stimulation of deoxyribonucleic acid synthesis in uterine epithelial cells which lack estrogen receptors. Endocrinology 119:390–396.PubMedCrossRefGoogle Scholar
  17. 17.
    Casimiri V, Tath NC, Parvey H, Psychoyos A (1980) Effect of sex steroids on rat endometrial epithelium and stroma cultured separately. J Steroid Biochem 12:293–298.PubMedCrossRefGoogle Scholar
  18. 18.
    Iguchi T, Uchima FDA, Ostrander PL, Bern HA (1983) Growth of normal mouse vaginal epithelial cells in and on collagen gels. Proc Natl Acad Sci USA 80:3743–3747.PubMedCrossRefGoogle Scholar
  19. 19.
    Cooke PS, Buchanan DL, Young P, Setiawan T, Brody J, Taylor J, et al. (1997) Stromal estrogen receptors (ER) mediate the mitogenic effect of estradiol on uterine epithelium. Proc Natl Acad Sci USA 94:6535–6540.PubMedCrossRefGoogle Scholar
  20. 20.
    Couse JF, Curtis SW, Washburn TF, Lindzey J, Golding TS, Lubahn DB, et al. (1995) Analysis of transcription and estrogen insensitivity in the female mouse after targeted disruption of the estrogen receptor gene. Mol Endocrinol 9:1441–1454.PubMedCrossRefGoogle Scholar
  21. 21.
    Cooke PS, Buchanan DL, Lubahn DB, Cunha GR (1998) Mechanism of estrogen action: lessons from the ERKO mouse. Biol Reprod (in press).Google Scholar
  22. 22.
    Sundstrom SA, Komm BS, Ponce-de-Leon H, Yi Z, Teuscher C, Lyttle CR (1989) Estrogen regulation of tissue-specific expression of complement. J Biol Chem 264:16,941-16,947.Google Scholar
  23. 23.
    Pentecost BT, Teng CT (1987) Lactotransferrin is the major estrogen inducible protein of mouse uterine secretions. J Biol Chem 262:10,134-10,139.Google Scholar
  24. 24.
    Yamashita S, Newbold RR, McLachlan JA, Korach KS (1990) The role of the estrogen receptor in uterine epithelial proliferation and cytodifferentiation in neonatal mice. Endocrinology 127:2456–2463.PubMedCrossRefGoogle Scholar
  25. 25.
    Brenner RM, McClellan MC, West NB (1988) Immunocytochemistry of estrogen and progestin receptors in the primate reproductive tract, In: Steroid Receptors in Health and Disease. (Moudgil VK, ed.), Plenum, New York, pp. 47–70.Google Scholar
  26. 26.
    Kurita T, Young P, Brody J, Lydon JP, O’Malley BW, Cunha GR (1998) Stromal progesterone receptors mediate the inhibitory effects of progesterone on estrogen-induced uterine epithelial proliferation. Endocrinology (submitted).Google Scholar
  27. 27.
    Cunha GR, Young P, Hem YK, Cooke PS, Taylor JA, Lubahn DB (1997) Elucidation of a role of stromal steroid hormone receptors in mammary gland growth and development by tissue recombination experiments. J Mammary Gland Biology and Neoplasia 2:393–402.CrossRefGoogle Scholar
  28. 28.
    Stumpf W, Sar M (1976) Autoradiographic localization of estrogen, androgen, progestin, and glu-cocorticosteroid in “target tissues” and “non-target tissues”, In: Receptors and Mechanism of Action of Steroid Hormones (Pasqualini J, ed.), Marcel Dekker, New York, pp. 41–84.Google Scholar
  29. 29.
    Schmidt W, Katzenellenbogen B (1979) Androgen-uterine interactions: an assessment of androgen interaction with the testosterone and estrogen receptor systems and stimulation of uterine growth and progesterone reseptor synthesis. Mol Cell Endocrinol 15:91–108.PubMedCrossRefGoogle Scholar
  30. 30.
    Lindzey J, Korach KS (1997) Developmental and physiological effects of estrogen receptor gene disruption in mice. Trends Endocrinol Metabol 8:137–145.CrossRefGoogle Scholar
  31. 31.
    Cunha GR, Young P (1991) Inability of Tfm (testicular feminization) epithelial cells to express androgen-dependent seminal vesicle secretory proteins in chimeric tissue recombinants. Endocrinology 128:3293–3298.PubMedCrossRefGoogle Scholar
  32. 32.
    Mahendroo MS, Cala KM, Landrum CP, Russell DW (1997) Fetal death in mice lacking 5α-reductase type 1 caused by estrogen excess. Mel Endocrinol 11:917–927.CrossRefGoogle Scholar
  33. 33.
    Kollar EJ (1983) Epithelial-mesenchymal interaction in the mammalian integument. Tooth development as a model for instructive induction, In: Epithelial-Mesenchymal Interactions in Development (Sawyer RH, Fallen JF, eds.), Praeger, New York, pp. 27–50.Google Scholar
  34. 34.
    Saxen L, Karkinen-Jaaskelainen, Lehtonen E, Nordling S, Wartiovaara J (1976) Inductive tissue interactions, In: The Cell Surface in Animal Embryogenesis and Development, (Poste G, Nicolson GL, eds.), Elsevier/North Holland, New York, pp. 331–408.Google Scholar
  35. 35.
    Cunha GR, Young P, Brody JR (1989) Role of uterine epithelium in the development of myometrial smooth muscle cells. Biol Reprod 40:861–871.PubMedCrossRefGoogle Scholar
  36. 36.
    Cunha GR, Battle E, Young P, Brody JR, Donjacour A, Hayashi N, Kinbara H (1992) Role of epithelial-mesenchymal interactions in the differentiation and spatial organization of visceral smooth muscle. Epithelial Cell Biol 1:76–83.PubMedGoogle Scholar
  37. 37.
    Lejeune B, Leroy F (1980) Role of the uterine epithelium in inducing the decidual cell reaction. Prog Reprod Biol 7:92–101.Google Scholar
  38. 38.
    Xie J, Haslam SZ (1997) Extracellular matrix regulates hormone-ependent proliferation of mouse mammary epithelial cells. Endocrinology 138:2466–2473.PubMedCrossRefGoogle Scholar
  39. 39.
    Choe YS, Shim C, Choi D, Lee CS, Lee KK, Kim K (1997) Expression of galectin-1 mRNA in the mouse uterus is under the control of ovarian steroids during blastocyst implantation. Mol Reprod Dev 48:261–266.PubMedCrossRefGoogle Scholar
  40. 40.
    Singer CF, Marbaix E, Kokorine I, Lemoine P, Donnez J, Eeckhout Y, et al. (1997) Paracrine stimulation of interstitial collagenase (MMP-1) in the human endometrium by interleukin-1 alpha and its dual block by ovarian steroids. Proc Natl Acad Sci USA 94:10,341-10,345.Google Scholar
  41. 41.
    Nelson KG, Takahashi T, Bossert NL, Walmer DK, McLachlan JA (1991) Epidermal growth factor replaces estrogen in the stimulation of female genital-tract growth and differentiation. Proc Natl Acad Sci USA 88:21–25.PubMedCrossRefGoogle Scholar
  42. 42.
    Mukku VR, Stancel GM (1985) Regulation of epidermal growth factor receptor by estrogen. J Biol Chem 260:9820–9824.PubMedGoogle Scholar
  43. 43.
    Horn YK, Young P, Wiesen JF, Miettinen PJ, Derynck R, Werb Z, et al. (1998) Uterine and vaginal organ growth requires epidermal growth factor receptor (EGFR) signaling from stroma. Endocrinology (in press).Google Scholar
  44. 44.
    Zarnegar R, Michalopoulos G (1995) The many faces of hepatocyte growth factor: from hepatopoiesis to hematopoiesis. J Cell Biol 129:1177–1180.PubMedCrossRefGoogle Scholar
  45. 45.
    Pepper MS, Soriano JV, Menoud PA, Sappino AP, Orci L, Montesano R (1995) Modulation of hepatocyte growth factor and c-met in the rat mammary gland during pregnancy, lactation, and involution. Exp Cell Res 219:204–210.PubMedCrossRefGoogle Scholar
  46. 46.
    Sugawara J, Fukaya T, Murakami T, Yoshida H, Yajima A (1997) Hepatocyte growth factor stimulates proliferation, migration, and lumen formation of human endometrial epithelial cells in vitro. Biol Reprod 57:936–942.PubMedCrossRefGoogle Scholar
  47. 47.
    Aaronson SA, Bottaro DP, Miki T, Ron D, Finch PW (1990) Keratinocyte growth factor: a fibroblast growth factor family member with unusual target cell specificity. Ann NY Acad Sci 638:62–77.CrossRefGoogle Scholar
  48. 48.
    Sugimura Y, Foster BA, Rubin JS, Finch PW, Aaronson SA, Hayashi N, et al. (1996) Keratinocyte growth factor (KGF) replaces testosterone in the ductal branching morphogenesis of the rat ventral prostate. Int J Develop Biol 40:941–951.Google Scholar
  49. 49.
    Koji T, Chedid M, Rubin JS, Slayden OD, Csaky KG, Aaronson SA, Brenner RM (1994) Progesterone-dependent expression of keratinocyte growth factor mRNA in stromal cells of the primate endometrium: keratinocyte growth factor as a progestomedin. J Cell Biol 125:393–401.PubMedCrossRefGoogle Scholar
  50. 50.
    Imagawa W, Cunha GR, Young P, Nandi S (1994) Keratinocyte growth factor and acidic fibroblast growth factor are mitogens for primary cultures of mammary epithelium. Biochem Biophys Res Comm 204:1165–1169.PubMedCrossRefGoogle Scholar
  51. 51.
    Ulich TR, Yi ES, Cardiff R, Yin S, Bikhazi N, Biltz R, et al. (1994) Keratinocyte growth factor is a growth factor for mammary epithelium in vivo. The mammary epithelium of lactating rats is resistant to the proliferative action of keratinocyte growth factor. Am J Pathol 144:862–868.Google Scholar
  52. 52.
    Horn YK, Young P, Thomson AA, Cunha GR (1998) Keratinocyte growth factor (KGF) injected into female mouse neonates stimulates uterine and vaginal epithelial growth. Endocrinology (submitted).Google Scholar
  53. 53.
    Murphy LJ, Ghahary A (1990) Uterine insulin-like growth factor-1: Regulation of expression and its role in estrogen-induced uterine proliferation. Endocrine Rev 11:443–453.CrossRefGoogle Scholar
  54. 54.
    Ghahary A, Chakrabarti S, Murphy LJ (1990) Localization of the sites of synthesis and action of insulin-like growth factor-I in the rat uterus. Mol Endocrinol 4:191–195.PubMedCrossRefGoogle Scholar
  55. 55.
    Bhattacharyya N, Ramsammy R, Eatman E, Hollis VW, Anderson WA (1994) Protooncogene, growth factor, growth factor receptor, and estrogen and progesterone receptor gene expression in the immature rat uterus after treatment with estrogen and tamoxifen. J Submicrosc Cytol Pathol 26:147–162.PubMedGoogle Scholar
  56. 56.
    Kapur S, Tamada H, Dey SK, Andrews GK (1992) Expression of insulin-like growth factor-I (IGF-I) and its receptor in the peri-implantation mouse uterus, and cell-specific regulation of IGF-I gene expression by estradiol and progesterone. Biol Reprod 46:208–219.PubMedCrossRefGoogle Scholar
  57. 57.
    Baker J, Hardy MP, Zhou J, Bondy C, Lupu F, Bellvé AR, et al. (1996) Effects of an Igf1 gene null mutation on mouse reproduction. Mol Endocrinol 10:903–918.PubMedCrossRefGoogle Scholar
  58. 58.
    Rajkumar K, Dheen T, Krsek M, Murphy LJ (1996) Impaired estrogen action in the uterus of insulin-like growth factor binding protein-1 transgenic mice. Endocrinology 137:1258–1264.PubMedCrossRefGoogle Scholar
  59. 59.
    Roberts AB, Sporn MB (1993) Physiological actions and clinical applications of transforming growth factor-beta (TGF-β). Growth Factors 8:1–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Chen HL, Yelavarthi KK, Hunt JS (1993) Identification of transforming growth factor-beta 1 mRNA in virgin and pregnant rat uteri by in situ hybridization. J Reprod Immunol 25:221–233.PubMedCrossRefGoogle Scholar
  61. 61.
    Takahashi T, Eitzman B, Bossert NL, Walmer D, Sparrow K, Flanders KC, et al. (1994) Transforming growth factors beta 1, beta 2, and beta 3 messenger RNA and protein expression in mouse uterus and vagina during estrogen-induced growth: a comparison to other estrogen-regulated genes. Cell Growth Differ 5:919–935.PubMedGoogle Scholar
  62. 62.
    Rotello RJ, Lieberman RF, Purchio AJ, Gerschenson LE (1991) Coordinated regulation of apoptosis and cell proliferation by transforming growth factor beta 1 in cultured uterine epithelial cells. Proc Natl Acad Sci USA 88:3412–3415.PubMedCrossRefGoogle Scholar
  63. 63.
    Chegini N, Zhao Y, Williams RS, Flanders A (1994) Human uterine tissue throughout the menstrual cycle expresses transforming growth factor-beta 1 (TGF beta 1), TGF beta 2, 22 TGF beta 3, and TGF beta type II receptor messenger ribonucleic acid and protein and contains [125I]TGF beta 1-binding sites. Endocrinology 135:439–449.PubMedCrossRefGoogle Scholar
  64. 64.
    Daniel CW, Robinson SD (1992) Regulation of mammary growth and function by TGFβ. Mol Reprod Develop 32:145–151.CrossRefGoogle Scholar
  65. 65.
    Ethier SP, Van de Velde RM (1990) Secretion of a TGFβ-like growth inhibitor by normal rat mammary epithelial cells in vitro. J Cell Physiol 142:15–20.PubMedCrossRefGoogle Scholar
  66. 66.
    Nelson KG, Takahashi T, Lee DC, Luetteke NC, Bossert NL, Ross K, et al. (1992) Transforming growth factor-alpha is a potential mediator of estrogen action in the mouse uterus. Endocrinology 131:1657–1664.PubMedCrossRefGoogle Scholar
  67. 67.
    Adachi K, Kurachi H, Homma H, Adachi H, Imai T, Sakata M, et al. (1995) Estrogen induces epidermal growth factor (EGF) receptor and its ligands in human fallopian tube: involvement of EGF but not transforming growth factor-α in estrogen-induced tubal cell growth in vitro. Endocrinology 136:2110–2119.PubMedCrossRefGoogle Scholar
  68. 68.
    Pflug BR, Dionne C, Kaplan DR, Lynch J, Djakiew D (1995) Expression of a Trk high affinity nerve growth factor receptor in the human prostate. Endocrinology 136:262–268.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Paul S. Cooke
  • David L. Buchanan
  • Takeshi Kurita
  • Dennis B. Lubahn
  • Gerald R. Cunha

There are no affiliations available

Personalised recommendations