Progestin-Dependent Human Endometrial Protein: A Marker for Monitoring Human Endometrial Function

  • Sharad G. Joshi
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 230)


Progesterone (P), which is the major secretory product of the corpus luteum (CL) is the key hormone of pregnancy. CL defects that cause P to be secreted for too brief a period or at too low a rate are associated with an underdeveloped or inadequate endometrium which is incapable of supporting pregnancy. Some investigators, therefore, have recommended the use of exogenous P support in chronic CL defect patients who wish to conceive. However, the mechanisms by which P regulates endometrial function are poorly understood and there is no suitable, non-invasive method to monitor in individual patients the endometrial response to either endogenous or exogenous progesterone. We therefore initiated a search for progesterone-dependent endometrial protein(s) which might serve as a marker to assess effects of progestin therapy on endometrial function, and which might also afford insight into the mechanism of P action. We have detected a hormone-dependent endometrial protein designated “progestagen-associated (or -dependent) endometrial protein” or PEP. PEP is a glycoprotein (molecular weight~47,000) which is synthesized in the endometrial glands and secreted into the blood. Its synthesis increases dramatically during pregnancy, as indicated by a more than 1000-fold greater PEP concentration in the decidua. PEP is not synthesized by the immature placenta, but binds to placental cell membranes. In normally cycling women, the serum PEP concentration increases in an exponential manner during the late luteal phase. In cycling infertile women, a direct relationship was found to exist between serum PEP levels they attained in the late luteal phase and their endometrial development, the serum levels being subnormal in women with inadequate endometrium. Menstrual cycles that are anovulatory or with a CL-defect are associated with low luteal phase serum PEP levels. In both pre- and post-menopausal women, serum PEP levels increase following a progestin challenge, demonstrating that PEP is indeed a progestin-dependent protein. Very low luteal phase serum PEP levels are encountered in some women who do not conceive following in vitro fertilization and embryo transfer (IVF/EF), suggesting that endometrial inadequacy is a major cause of failure in this procedure. In patients who undergo ovarian stimulation by exogenous hormones but do not conceive following IVF/ET, luteal phase serum PEP levels are markedly higher in those who receive luteal phase P support than those with no support. In women in whom implantation occurs following IVF/ET, serum PEP levels increase sharply as early as day 5 post-oocyte aspiration and with a doubling time of 2.49+1.71 (Mean +SE) days. PEP levels peak within 4 weeks of conception. The levels remain more or less steady during 10–12 weeks post conception and rapidly decline thereafter. PEP was also detected in the peritoneal fluid (PF) of women. In women with moderate to severe endometriosis, PEP concentration in PF is 10-fold higher than in those women with mild endometriosis or control subjects. In some patients with primary endometrial cancer, the treatment with a progestin results in a significant change in the PEP concentration in the endometrial tumor and/or serum. From these studies, we conclude that progestin-stimulated human endometrium synthesizes a specific protein, namely PEP. Although the role of PEP in pregnancy is totally unknown, determinations of PEP in serum or PF offers a practical means to assess endometrial responses to endogenous and exogenous progesterone and progestins in infertile women, habitual aborters, endometriosis patients and patients with endometrial hyperplasias or neo-plasias. This method is minimally invasive, quantitative, and simple enough to be used on a repetitive basis in large scale clinical trials.


Endometrial Cancer Luteal Phase Corpus Luteum Endometrial Cancer Patient Late Luteal Phase 
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  1. 1.
    J. Arias-Stella, Gestational endometrium, in: “The Uterus,” H. J. Norris, A. T. Hertig, and M. R. Abell, ed., Williams & Wilkins Co., Baltimore (1973).Google Scholar
  2. 2.
    A. J. Csapo, M. O. Pulkkinen, B. Ruttner, J. P. Sauvage, and W. G. Wiest, The significance of human corpus luteum in pregnancy maintenance, Am. J. Obstet. Gynecol. 112: 1061 (1972).PubMedGoogle Scholar
  3. 3.
    G. W. Jones, The luteal phase defect, Fertil. Steril. 27: 351 (1976).PubMedGoogle Scholar
  4. 4.
    J. L. H. Horta, J. G. Fernandez, B. DeLeon, and V. Cortes-Gallegos, Direct evidence of luteal insufficiency in women with habitual abortions, Obstet. Gynecol. 49: 705 (1977).PubMedGoogle Scholar
  5. 5.
    H. M. Beier, Uteroglobin—a hormone sensitive endometrial protein involved in blastocyst development, Biochem. Biophys. Acta 160: 289 (1968).PubMedGoogle Scholar
  6. 6.
    D. B. Laster, A pregnancy-specific protein in the bovine uterus, Biol. Reprod. 16: 682 (1972).CrossRefGoogle Scholar
  7. 7.
    S. G. Joshi, K. M. Ebert, and D. P. Swartz, Detection and synthesis of a progestagen-dependent protein of the human endometrium, J. Reprod. Fertil. 59: 273 (1980).PubMedCrossRefGoogle Scholar
  8. 8.
    S. G. Joshi, K. M. Ebert, and R. A. Smith, Properties of the progestagen-dependent protein of the human endometrium, J. Reprod. Fertil. 59: 287 (1980).PubMedCrossRefGoogle Scholar
  9. 9.
    J. E. Mazurkiewicz, J. F. Bank, and S. G. Joshi, Immunocytochemical localization of a progestagen-associated endometrial protein in the human decidua, J. Clin. Endocrinol. Metab. 52: 1006 (1981).PubMedCrossRefGoogle Scholar
  10. 10.
    S. G. Joshi, J. F. Bank, and D. H. Szarowski, Radioimmunoassay for a progestagen-associated protein of the human endometrium, J. Clin. Endocrinol. Metab. 52: 1185 (1981).PubMedCrossRefGoogle Scholar
  11. 11.
    R. S. Raikar, J. F. Bank, and S. G. Joshi, Progestagen-associated human endometrial protein — Detection and binding in immature placenta, in: “Pregnancy proteins in animals,” J. Hau, ed., Walter de Gruyter, Berlin (1986).Google Scholar
  12. 12.
    R. G. Sutcliffe, S. G. Joshi, W. F. Paterson, and J. F. Bank, Serological identity between human alphauterine protein and human progestagen-dependent endometrial protein, 65: 207 (1982).Google Scholar
  13. 13.
    R. G. Sutcliffe, The search for new fetal proteins, Protides Biol. Fluids24: 543 (1976).Google Scholar
  14. 14.
    M. Julkunen, R. S. Raikar, S. G. Joshi, H. Bohn, and M. Seppala, Placental Protein 14 and PEP are immunologically indistinguishable, Human Reproduction (UK) 1: 7 (1986).Google Scholar
  15. 15.
    H. Bohn, W. Kraus, and W. Wickler, New soluble placental tissue proteins: Their isolation, characterization, localization and quantification, in: “Immunology of Human Placental Proteins,” A. Klopper, ed., Placenta, Suppl. 4, Praeaer, East Bourne, pp. 67–81 (1982).Google Scholar
  16. 16.
    I. A. Masler and R. Ansbacher, Effects of progesterone on decidual prolactin production by organ cultures of human endometrium, Endocrinologyl 118: 2101 (1986).Google Scholar
  17. 17.
    I. A. Masler, P. Powers-Craddock, and R. Ansbacher, Decidual prolactin production by organ cultures of human endometrium: Effects of continuous and intermittent progesterone treatment, Biol. Reprod. 34: 741 (1986).CrossRefGoogle Scholar
  18. 18.
    D. Shoupe, F. J. Montz, O. A. Kletzky, and G. S. DeZerega, Prolactin molecular heterogenecity: Response to thyrotropin-releasing hormone stimulation of Concanavalin A-bound and -unbound immunoassayable prolactin during human pregnancy, Am. J. Obstet. Gynecol. 147: 482 (1983).PubMedGoogle Scholar
  19. 19.
    U. J. Lewis, R. N. P. Singh, Y. N. Sinha, and H. P. Vanderlaan, Glycosylated human prolactin, Endocrinologyl 116: 359 (1985).PubMedCrossRefGoogle Scholar
  20. 20.
    M. B. Braverman, A. Bagni, D. DeZiegler, T. Dem, and E. Gurpide, X Isolation of prolactin producing cells from first and second trimester decidua, J. Clin. Endocrinol. Metab. 58:521 (1984),Google Scholar
  21. 21.
    M. A. McRae, G. R. Newman, S. M. Walker, and B. Jasani, Immunohistochemical identification of prolactin and 24K protein in secretory endometrium, Fertil. Steril. 45: 643 (1986).PubMedGoogle Scholar
  22. 22.
    D. A. Kletzky, F. Rossman, S. I. Bertolli, L. D. Piatt, and D. R. Mishell, Dynamics of human chorionic gonadotropin, prolactin and growth hormone in serum and amniotic fluid throughout normal human pregnancy, Am. J. Obstet. Gynecol. 151: 878 (1975).Google Scholar
  23. 23.
    Y. N. Sinha, T. A. Gilligan, and D. W. Lee, Detection of a high molecular weight variant of prolactin in human plasma by a combination of electrophoretic and immunologic techniques, J. Clin. Endocrinol. Metab. 58: 752 (1984).PubMedCrossRefGoogle Scholar
  24. 24.
    L. J. Heffner, D. A. Iddenden, and C. R. Lyttle, Electrophoretic analyses of secreted human endometrial proteins: Identification and characterization of luteal phase prolactin, J. Clin. Endocrinol. Metab. 62: 1288 (1986).PubMedCrossRefGoogle Scholar
  25. 25.
    D. W. Lee and E. Markoff, Synthesis and release of glycosylated prolactin by human decidua in vitro, J. Clin. Endocrinol. Metab.Google Scholar
  26. 26.
    S. G. Joshi, R. A. Smith, and D. K. Stokes, A progestagen dependent endometrial protein in human amniotic fluid, J. Reprod. Fertil. 60: 317 (1980).PubMedCrossRefGoogle Scholar
  27. 27.
    S. G. Joshi, J. F. Bank, E. S. Henriques, A. Makarachi, and G. Matties, Serum levels of a progestagen-associated endometrial protein during menstrual cycle and pregnancy, J. Clin. Endocrinol. Metab. 55: 642 (1982).PubMedCrossRefGoogle Scholar
  28. 28.
    E. Radwanska and G. I. M. Dwyer, Plasma progesterone estimation in infertile women and in women under treatment with Clomiphene and chorionic gonadotrophin, J. Obstet. Gynecol. Br. Commonw. 81: 107–112 (1974).Google Scholar
  29. 29.
    A. C. Wentz, Physiological and clinical considerations in luteal phase defects, Clin. Obstet. Gynecol. 22: 169 (1979).Google Scholar
  30. 30.
    S. G. Joshi, R. Rao, E. R. Henriques, R. S. Raikar, and M. Gordon, Luteal phase concentrations of a progestagen-associated endometrial protein (PEP) in the serum of cycling women with adequate or inadequate endometrium, J. Clin. Endocrinol. Metab. 63: 1247 (1986).PubMedCrossRefGoogle Scholar
  31. 31.
    S. G. Joshi, G. Lavy, R. S. Raikar, A. H. DeCherney, and M. Gordon, Secretion of the progestin-dependent protein following IVF/ET, presented at the 42nd Ann. Meeting, Am. Fertil. Soc., Sept. 27- Oct. 2, 1986, Toronto, Canada, Abstract no. 229 (submitted for publication).Google Scholar
  32. 32.
    J. C. Weed, P. C. Arquembourg, Endometriosis: Can it produce an autoimmune response resulting in infertility?, Clin. Obstet. Gynecol. 23: 885 (1980).PubMedCrossRefGoogle Scholar
  33. 33.
    S. G. Joshi, N. M. Zamah, R. S. Raikar, V. C. Buttram, E. S. Henriques, and M. Gordon, Serum and peritoneal fluid proteins in women with and without endometriosis, Fertil. Steril. 46: 1077 (1986).PubMedGoogle Scholar
  34. 34.
    C. E. Ehrlich, R. E. Cleary, and P. C. M. Young, The use of progestin receptors in the management of recurrent endometrial cancer, in: “Endometrial Cancer,” M. G. Brush, R. J. B. King, and R. W. Tyler, eds., Bailliere Tindall, London (1978).Google Scholar
  35. 35.
    E. I. Kohorn, Gestagens and endometrial carcinoma, Gynecol. Oncol. 4: 398 (1976).PubMedCrossRefGoogle Scholar
  36. 36.
    E. C. Reifenstein, The treatment of advanced endometrial cancer with hydroxyprogesterone caproate, Gynecol. Oncol. 2: 377 (1974).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • Sharad G. Joshi
    • 1
  1. 1.Department of Obstetrics and Gynecology, and BiochemistryAlbany Medical CollegeAlbanyUSA

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