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Obstetrics and Gynecology
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Duphaston Role in Pregnancy
Lowers risk of spontaneous abortion through immunologic action
Immunomodulation holds the key to successful pregnancies among women susceptible to spontaneous abortion or miscarriage. This, according to experts, is the emerging view that could help "explain the unexplained" cause in at least 40 percent of pregnancy losses.
Most spontaneous abortion cases (50 to 60 percent) are attributed to structural chromosomal abnormalities of the fetus, infections, and maternal endocrinological and anatomical disorders.
However, in the remaining unexplained cases, "an abnormal immune response of the mother to the paternal antigens of the fetus has been proposed as an important factor."
The role of immunomodulation and dydrogesterone in the maintenance of pregnancy was the subject of discussion among Filipino obstetricians-gynecologists during a recent workshop organized by Solvay Pharma.
Interface
Presenting highlights of the immunology session in last year's World Congress on Gynecological Endocrinology, Dr. Susan Nagtalon, associate professor at the University of the East Ramon Magsaysay Memorial Medical Center, reviewed two theories on the etiology of pregnancy.
One views the fetus in an isolated environment where it independently makes the most out of its system to develop into a neonate and be delivered. The other suggests a fetal-maternal interface in which fetal and maternal factors work hand in hand for the full development of the fetus and the success of pregnancy.
However, not all things always work out well since about 15 percent of pregnancies result in spontaneous abortion. And in at least 40 percent of pregnancy losses, the cause could involve an immune response.
Dr. Nagtalon explained: "For a pregnancy to be successful, there is a need for maternal tolerance to the paternal or fetal antigens. The recognition of the pregnancy by the mother will incite an immunologic reaction in favor of the existence of the fetus in utero."
Because of paternal genetic contribution, the fetal placental unit acts as a semi-allograft. Consequently, there is a maternal immune response to the allogenic conceptus (trophoblast), which necessitates adaptation between the mother and the fetus.
The trophoblast, as distinguished from other tissues, has the ability to suppress abortogenic maternal B cell and T cell responses. The trophoblast induces an immunomo-dulation, and thus actively defends itself from the maternal immune attack.
Prior to implantation, there is a requirement for an increase in estrogen activity to enhance receptivity to the trophoblast. Adequate physiologic levels of progesterone will allow a trophoblast to attach to the maternal decidua (Figure 1).
The interface between trophoblast and the endometrium at the time of implantation is termed as the syncytiotrophoblast.
Dr. Nagtalon explained that the syncytiotrophoblast in contact with maternal blood in the intervillous space and the amnion chorion in contact with maternal decidua represent the fetal tissue most prone to immunologic reactions from maternal factors.
This is where progesterone exerts influence.
In the presence of fetal allograft, the syncytiotrophoblast will manifest trophoblast antigen HLA-G and the trophoblast lymphocyte cross-reactive antigens. This is what is produced when the embryo is introduced to the mother. The HLA antigen will not allow invasion by the natural killer cells to the cytotrophoblast, and destroy it. Meanwhile, the trophoblast cross-reactive antigens are important for the induction of the immunologic blocking factors.
Antibodies produced against lymphocytes or trophoblast antigens are essential in the regulation of trophoblast growth and successful maintenance of fetal well-being.
Protective Mediators
In cases where the maternal system is abnormal or abortogenic, it has been found that there is no production of the trophoblast antigen when the fetus is introduced to the maternal system. This could be related to the failure of producing blocking factors, eventually leading to pregnancy loss.
In the peripheral blood, and with physiologic progesterone concentration, the lymphocytes produce a 34 kD mediator protein known as progesterone-induced blocking factor (PIBF), which has major protective immunological properties. These include changing the balance of immune system modulating cytokines, the T-helper type 1 cells (Th1) cytokines, which are harmful to pregnancy, and T-helper type 2 cells (Th2) cytokines, which are protective (Figure 2).
The enhanced release of PIBF will intensify production of immunoglobulins and asymmetric antibodies. These blocking antibodies will also make room for growth and development of the fetus in utero. Macrophages produce immunotropic factors like the colony-stimulating factor 1 and the granulocyte colony-stimulating factor, the balance of which will favor fetal protection (Figure 3).
So in early pregnancy, the presence of fetal allograft will stimulate maternal response with dominance of the humoral antibody response, but this is very dependent on normal concentration of progesterone and other hormones. Failure of the adaptive immune system to recognize the conceptus in the graft and to intentionally initiate protective immunomodulation leads to alloimmune rejection of the fetus.
Thus, immunomodulation at the fetal-maternal interface, if understood, appreciated and properly managed, can assist the growing fetus and decrease the incidence of rejection.
Rationale for Duphaston
Dydrogesterone is a potent orally active progestogen similar to endogenous progesterone in molecular structure and pharmacological effect. It therefore has a high affinity for progesterone receptors. It has no androgenic effects (hirsutism, voice changes, acne, etc.) in the mother and no masculinizing effect on the female fetus, even in high doses and prolonged treatment.
Duphaston is a synthetic hormone very similar to the natural female sex hormone progesterone. It is the brand name for dydrogesterone. It has been used for many years for regulation of the menstrual cycle, treatment of premenstrual syndrome, hormone replacement therapy, and endometriosis. It has been recognized that progesterone deficiency has been the cause of early pregnancy loss.
Foreign studies have shown that progesterone can inhibit Th1 cytokines and upregulate Th2 cytokines. It has been suggested that dydrogesterone may be used therapeutically to reverse the Th1 bias. Dydrogesterone may be of potential use in shifting a harmful maternal reactivity to a state that is immunologically conducive to pregnancy.
It is known that the Th1 cytokines tumor necrosis factor-a (TNFa), Interferon-g (IFNg) and interleukin-2 (IL-2) induce abortion in mice. The cytokines TNFa and IFNg are involved in apoptosis of trophoblast cells and can also inhibit outgrowth. There appears to be a strong basis for the suggestion that normal successful pregnancy is brought about by a strong Th2 response, whereas Th1 response is antagonistic to pregnancy.
Women with unexplained recurrent spontaneous abortion (RSA) normally produced low le-vels of Interleukin-4. However, in the presence of dydrogesterone or progesterone, there was a remarkable increase in IL-4 levels.
Dydrogesterone had important effects in reversing the bias from Th1 to Th2 dominance. Ratios of Th1 to Th2 cytokines can be redirected towards a strong abortogenic Th1 bias and a more conducive Th2 bias.
"For a pregnancy to be successful, there is a need for maternal tolerance to the paternal or fetal antigens. The recognition of the pregnancy by the mother will incite an immunologic reaction in favor of the existence of the fetus in utero."
-Dr. Nagtalon
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