Based on our knowledge, our study is the first study that evaluated the GCSF effect on patients with unexplained infertility that underwent IUI.The term of unexplained infertility is used for couples with normal semen analysis and the female infertility factor has not been identified. The living fetus and endometrium, as well as successful embryo-endometrium dialog is essential for successful implantation and pregnancy. Although it is endometrial receptivity process is not completely understood, but remodeling of endometrium at the time of window of implantation and local immune shift from adaptive (Type 1 T helper) to innate Type 2 T helper is vital for implantation. A balanced local immune system is required at the time of the window of implantation not only attach the fetus but also regulate the invasion phase. GCSF is a glycoprotein with growth factor and cytokine functions, which are produced in many tissues. Uzmaki and colleagues (1989) identified GCSF receptors in the membranes of human placenta and trophoblast cells and suggested that they probably played an important role in the fetal-placenta unit during human development . Also, GCSF was detected in endometrial cells, follicular cells, syncytotrophoblast, cytotrophoblast, stromal cells and embryonic membranes.
In our study, the subcutaneous GCSF injection independently improved the implantation, the pregnancy and live birth rates in patients with unexplained infertility underwent IUI with normal endometrium, but this was not statistically significant .It seems that the differences will significant if the sample size is increase. Although, our study evaluated the GCSF effect on patients with unexplained infertility that underwent IUI.Whereas, other studies examined the impact of GCSF on patients with repeated implantation failures that are rather similar to our study.
Our findings are in consistent with Scarpelliniet.al. (2012)which reported that GCSF was resulted in higher implantation rates in patients with repeated IVF failures , as well as, Aleyasinet.al. (2016), evaluated the effect of systemic administration of 300 µg GCSF by subcutaneous injection in patients with repeated IVF failure.Their findings have shown that GCSF significantly increased the pregnancy rate.
Also, Eftekhar and colleagues in an interventional study have shown that although with intra-uterine infusion of GCSF did not improve the endometrial thickness but significantly increased pregnancy rate in women with thin endometrium. Another study which conducted by the Eftekhar and colleagues, their findings have shown that in spite of fewer follicles and the fewer metaphase II oocytes in GCSF group, the implantation and pregnancy rates were more than the control group. They concluded that clinical pregnancies improved by intra-uterine administration of GCSF in oocyte puncture day.
In contrast to, Brade and colleagues (2014) examined the effect of GCSF on endometrial thickness and clinical pregnancy rate in patients who underwent IVF treatment and they have reported that GCSF did not improve the endometrial thickness and pregnancy rate.
It seems that the difference in the prescribed method, time of administration, age of participants, endometrial thickness and sample size maybe involve in the observed differences in these results. Scarpllini et al.(2012), Aleyasin et.al (2016) studies and our study have a higher sample size, the GCSF was administered systemic via subcutaneous, the study population was younger and had a normal endometrium[16, 12].Whereas, in the conflicting studies, GCSF was administered through intrauterine perfusion and had a smaller sample size and had thin endometrium. Our results showed that GCSF could play an important role in the implantation process and to maintain pregnancy. Salmassi et al. (2005) women underwent IVF treatment and observed that pregnant patients had a continuous increase in serum GCSF levels from day of embryo transfer to day of implantation to day of pregnancy confirmation, but the patients who were not pregnant, they showed a little increase in GCSF level, then its level significantly reduced by failure of implantation. These authors concluded that this cytokine played an important role in the pregnancy and maintained of pregnancy .Also, Rahmati and colleagues reported that infertile women with implantation failure had very low amounts of GCSF receptor in maternal-fetal interface. The interesting point was that stimulation with high dose of GCSF was able to increase expression of GCSF receptors in these patients.GCSF can affect reproductive, implantation and pregnancy through several mechanisms: GCSF induces the proliferation and invasion of trophoblast in pregnancy. GCSF also plays a key role in embryo implantation process through the regulation of fundamental genes which responsible for the embryo attachment, cell migration, tissue remodeling and angiogenesis. These events are inevitable for a successful implantation and placentation. Finally, GCSF is involved in adaptation changes that induce immune tolerance in pregnancy. Pregnancy is an immune challenge for the mother. GCSF shifts the T cell cytokine profile to TH2 responses and enhance the T regulatory cells producing IL10 and differentiation of the tolerant dendritic cells .These are important parts of immune regulation that occur before and after implantation in the uterus.
The main strengths of our study is randomized controlled trial and the first evaluation of GCSF effect on fertility in patients with unexplaned infertility whom treated by IUI. Other strengths of this study evaluated systemic administration and the dose of GCSF, which is easier, more tolerable, and more economical than repeatative doses or local infusion. However, this study has some limitations which should be considered in the interpretation of the results because of the nature of study, unblinded study was not used.