Progesterone Stops Abortion
Immunological action aids in the maintenance of pregnancy, say two experts
Progesterone-through its immunological action-holds the key to the maintenance of pregnancy, and this, according to Prof. Julia Szekeres-Bartho of the University of Hungary, is the principle behind the use of dydrogesterone in preventing pregnancy loss.
"It is well known that in most mammalian species, progesterone is indispensable in the maintenance of gestation. It affects various phases of the immunoresponse in vitro and is able to prolong the survival of allogenic skin grafts, if administered in high concentrations," said Bartho in a symposium organized by Solvay Pharma Philippines.
In the same forum, Prof. Mazen Yousef El-Zibdeh, senior consultant OB-gynecologist at the Islamic Hospital in Amman, Jordan, said the use of progesterone for treatment of infertility and threatened abortion, rests on its action on luteal phase defect (LPD), inflammatory mediators, and immunomodulation.
Bartho said the percentage of progesterone receptor positive cells increases as pregnancy progresses. In the peripheral blood of a woman at risk for premature pregnancy termination, the percentage of these positive receptor lymphocytes is lower than in healthy pregnant women.
The presence of the fetus as an antigenic challenge activates the lymphocytes and progesterone receptors of the pregnant woman. Progesterone then binds to its receptor-mediated molecule. A 34-kilo Dalton (kD) mediator molecule called progesterone induced blocking factor or PIBF is produced.
PIBF has various biological affects on cytokine balance, natural killer activity, and arachidonic acid metabolism through which it exerts an antiabortive effect, explained Bartho. However, the production of PIBF depends on the presence of intact progesterone receptors. Thus, even if progesterone is present, if the progesterone receptor is blocked, PIBF won't be produced.
Bartho said that most important among the immunological effects of progesterone is its action on the Th1 and Th2 cytokines. Th1 cytokines, which increase cell-mediated responses and decrease humoral responses, are deleterious to pregnancy. On the other hand, Th2 cytokines, which increase antibodies production and depress cell-mediated responses, are favorable to pregnancy. Bartho said that during pregnancy, lymphocytes develop progesterone receptors, and if progesterone binds to these receptors PIBF is produced. "PIBF action on the cytokine balance favors Th2 dominance and low NK activity, resulting in normal pregnancy outcome. On the other hand, if progesterone receptors are blocked by antiprogesterone, progesterone cannot bind to its receptor and no PIBF would be produced," she explained
El-Zibdeh cited three modes of action of progesterone. One is on LPD, a recognized cause of infertility and early pregnancy loss in 23 to 35 percent of women with recurrent abortion. Progesterone also regulates inflammatory mediators. Stabilizing the endometrium is necessary in the early stages of trophoblastic penetration and villous formation. El-Zibdeh said progesterone deficiency or withdrawal has been found to destabilize the endometrium by significant elevation of interleukin-8, cyclooxygenase-2, and monocyte chemoattractant protein-1. Progesterone also acts as an immunomodulator to prevent alloimmune rejection of the fetus.
Unexplained
Recurrent abortion (RA) or loss of three or more consecutive pregnancies affects one percent of all women. Theoretically, the risk of RA is 0.34 percent.
El-Zibdeh noted that while RA has many causes, the cause is unexplained in 40 to 50 percent of cases. He said this is where the role of progesterone turns significant, citing a prospective study by the Islamic Hospital, which found that among women who took dydrogesterone, 85.4 percent had viable pregnancy while 14.6 percent had an abortion.
Based on the results, El-Zibdeh said that a great deal of recurrent abortions may be due to immuno-endocrinology cause in which progesterone might help in establishing adequate immune response in the early stage of pregnancy. He noted that both dydrogesterone and hCG showed reduction in the incidence of RA without significant side effects.
El-Zibdeh presented another study that used dydrogesterone to prevent threatened abortion in women at risk because of previous abortion and treatment for infertility, stillbirth, or congenitally abnormal infant; paternal or maternal genetic defects; and age (older than 35 for the mother 53 for the father). The results showed that patients given dydrogesterone twice daily from the day the patients presented with bleeding to one week after bleeding stopped had significantly reduced risk of abortion (17.5 percent vis-à-vis 25 percent in the untreated group).
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