Effect of dydrogesterone on the hormonal profile and concentration of progesterone-induced blocking factor in pregnant women with threatened abortion

Abstract

Problem: The therapeutic value of progestogens in threatened abortion is still under debate. In the presence of sufficient progesterone levels during pregnancy, lymphocytes synthesize a mediator [progesterone-induced blocking factor (PIBF)] that is anti-abortive in mice. The aim of this study was to evaluate the effect of dydrogesterone on pregnancy outcome of threatened aborters.

Method of study: Twenty-seven threatened aborters were treated for 10 days with dydrogesterone (30-40 mg/day). Sixteen healthy pregnant controls received no treatment. Serum progesterone and estradiol concentrations as well as urine PIBF concentrations were measured by enzyme-linked immunosorbent assay (ELISA).

Results: Pregnancy outcomes in dydrogesterone-treated threatened aborters did not statistically differ from those in healthy controls. Serum progesterone concentrations in control patients, but not those in threatened aborters increased as pregnancy progressed. Following dydrogesterone treatment, initially low PIBF concentrations of threatened aborters significantly increased (P = 0,001) to reach the PIBF level found in healthy controls.

Keywords

dydrogesterone / early pregnancy / progesterone-induced blocking factor / threatening abortion

References

[1] Stites D.P., Bugbee S., Siiteri PK. Differential actions of progesterone and cortisol on lymphocyte and monocyte interaction during lymphocyte activation - relevance to immunosuppression in pregnancy. J Reprod Immunol 1983; 5:215-228.

[2] Piccinni M.P., Giudizi M.G., Biagiotti R., Beloni L., Giannarini L., Sampognaro S., Parronchi P., Manetti R., Annunziato F., Livi C., Romagnani S., Maggi E. Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established T cell clones. J Immunol 1995; 155:128-133.

[3] Choi B.C., Polgar K., Xiao L., Hill J.A. Progesterone inhibits in vitro embryotoxic Thl cytokine production to tropho-blast in women with recurrent pregnancy loss. Hum Reprod 2000; 15(Suppl. l):46-59.

[4] Szekeres-Bartho J., Kilar F., Falkay G., Csernus V., Torok A., Pacsa A.S. Progesterone-treated lymphocytes of healthy pregnant women release a factor inhibiting cytotoxicity and prostaglandin synthesis. Am J Reprod Immunol Microbiol 1985; 9:15-19.

[5] Szekeres-Bartho J., Autran B., Debre P., Andreu G., Denver L., Chaouat G. Immunoregulatory effects of a suppressor factor from healthy pregnant women s lymphocytes after progesterone induction. Cell Immunol 1989; 122:281-294.

[6] Szekeres-Bartho J., Par G., Dombay G.Y., Smart Y.C., Volgyi Z. The anti-abortive effect of PIBF in mice is manifested by modulating NK activity. Cell Immunol 1997; 177:194-199.

[7] Szekeres-Bartho J., Par G., Szereday L., Smart C.Y., Achacz I. Progesterone and non-specific immunological mechanisms in pregnancy. Am J Reprod Immunol 1997; 38:176-182.

[8] Szekeres-Bartho J., Szekeres G.Y., Debre P., Autran B., Chaouat G. Reactivity of lymphocytes to a progesterone receptor-specific monoclonal antibody. Cell Immunol 990; 125:273-283.

[9] Faust Z., Laskarin G., Rukavina D., Szekeres-Bartho J. Progesterone induced blocking factor inhibits degranula-tion of NK cells. Am J Reprod Immunol 1999; 42:71-75.

[10] Ng S.C., Gilman-Sachs A., Thaker P., Beaman K.D., Beer A. E., Kwak-Kim J. Expression of intracellular Thl and Th2 cytokines in women with recurrent spontaneous abortion, implantation failures after IVF/ET or normal pregnancy. Am J Reprod Immunol 2002; 48:77-86.

[11] Makhseed M., Raghupathy R., Azizieh F., Farhat R., Hassan N., Bandar A. Circulating cytokines and CD30 in normal human pregnancy and recurrent spontaneus abortions. Hum Reprod 2000; 15:2011-2017.

[12] Szereday L., Varga P., Szekeres-Bartho J. Cytokine production in pregnancy. Am J Reprod Immunol №7: 38:418-422.

[13] Sacks G.P., Redman C.W., Sargent I.L. Monocytes are primed to produce the TH1 type cytokine IL-12 in normal human pregnancy: an intracellular flow cytometric analysis of peripheral blood mononuclear cell. Clin Exp Immunol 2003; 131:490-497.

[14] Chaouat G. Innately moving away from the TH1/Th2 paradigm in pregnancy. Clin Exp Immunol 2003; 131:393-395.

[15] Szekeres-Bartho J., Wegmann T.G. A progesteronedependent immunomodulatory protein alters the Thl/Th2 balance. J Reprod Immunol 1996; 31:81-95.

[16] El-Zibdeh M.Y. Randomised clinical trial comparing the efficacy of dydrogesterone, human chorionic gonadothropin or no treatment in the reduction of spontaneous abortion. Gynecol Endocrinol 2001; 15:44.

[17] Polgar B., Nagy E., Miko E., Yarga P., Szekeres-Bartho J. Urinary Progesterone- Induced Blocking Factor concentration is related to pregnancy outcome. Biol Reprod 2004; 71:1699- 1705.

[18] Joachim R., Zenclussen A.C, Polgar B., Douglas A.J., Fest S., Knackstedt M., Klapp B.F., Arck P.C. The progesterone derivative dydrogesterone abrogates murine stress-triggered abortion by inducing a Th2 biased local immune response. Steroids 2003; 68:931-940.Milligan S.R., Finn C.A. Minimal progesterone support required for the maintenance of pregnancy in mice. Hum Reprod 1997; 12:602-607.

[19] Aksoy S., Celikkanat H., Senoz S., Gokmen P. The prognostic value of serum estradiol, progesterone, testosterone, and free testosterone levels in detecting early abortions. Eur J Obstct Gynecol Reprod Biol 1996; 67:5-8.

[20] Arck P. Stress and embryo implantation. J Gynecol Obstet Biol Reprod 2004; 33:S40-S42.

[21] Sotiriadis A., Papatheodorou S., Makrydimas G. Threatened miscarriage: evaluation and management. Br Med J 2004; 329:152-155.

[22] Oates-Whitehead R.M., Haas D.M., Carrier J.A. Progestogen for preventing miscarriage. Cochrane Database Syst Rev 2003; CD003511.

[23] Blois S.M., Joachim R., Kandil J., Margni R., Tometten M., Klapp B.F., Arck P.C. Depletion of CD8 + cells abolishes the pregnancy protective effect of progesteron substitution with dydrogesterone in mice by altering the Thl/Th2 cytokine profile. J Immunol 2004; 172:5893-5899.

[24] Raghupathy R., Mutawa E., Makhseed M., Azizieh F., Szekeres-Bartho J. Modulation of cytokine production by dydrogesterone in lymphocytes from women with recurrent abortion. Br J Obstet Gynecol in press.

RIGHTS & PERMISSIONS

Eсо-Vector