|Year : 2019 | Volume
| Issue : 1 | Page : 56-57
Use of granulocyte colony-stimulating factor in recurrent implantation failures
U Nagashree, Sumana Manohar
IVF Department, Apollo Women's Hospital, Chennai, Tamil Nadu, India
|Date of Web Publication||11-Mar-2019|
Apollo Women's Hospital, Shafi Mohammed Raod, Thousand Lights, Chennai - 600 006, Tamil Nadu
Source of Support: None, Conflict of Interest: None
In spite of significant advances in ART, recurrent implantation failures (RIFs) and miscarriages are challenging. These could be attributed to unfavorable endometrium/poor embryo quality. Regular priming with estrogen is done to improve endometrial thickness. Despite these, RIF and miscarriages most probably account for some immune-related problems too, normally classified as unexplained infertility. Several research groups reported increase in endometrial thickness and immunomodulatory functions of granulocyte colony-stimulating factor (GCSF) during in vitro fertilization cycles, in terms of achieving higher clinical pregnancy rates. More studies should be done in this context before resorting to gestational surrogacy. We report one such case of recurrent miscarriage and RIF which resulted in a successful pregnancy after intrauterine GCSF instillation into uterine cavity.
Keywords: Granulocyte colony-stimulating factor, Immunomodulator, recurrent implantation failures
|How to cite this article:|
Nagashree U, Manohar S. Use of granulocyte colony-stimulating factor in recurrent implantation failures. Apollo Med 2019;16:56-7
| Introduction|| |
G-CSF is a glycoprotein with haematopoietic lineage- specific cytokine produced by cells of bone marrow, stromal cells, endothelial cells, monocytes, macrophages. The imbalance in immune response due to T-helper 1 and T-helper 2 cell function, natural killer cell cytotoxixity; -HLA compatibility etc., are some of the causes for failures in embryo implantation and consequent recurrent miscarriages.
G-CSF administration appears to be associated with an increase in regulatory T-cells and dendritic cells; improves local immunity; has a positive impact on cellular adhesion pathway and enhances endometrial vascular remodeling; thereby creating a favourable environment for implantation.
| Case Report|| |
A 35-year-old female, a resident of Tanzania, with a history of secondary infertility came for further management in September 2015 after been investigated in a private hospital. She was suggested in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) in view of decreased ovarian reserve.
She is married for 3 years. She conceived spontaneously after 3 months of marriage and had spontaneous abortion at 3 months of gestation for which suction and evacuation was done. The next was a spontaneous pregnancy in 2014; diagnosed as blighted ovum on Transvaginal scan. Suction and evacuation was done for the same. She did not conceive after that.
There was no relevant medical and surgical history.
Routine basic investigations were normal.
- Follicle-stimulating hormone – 9 mIU/ml
- Luteinizing hormone – 5 mIU/ml
- Anti-Müllerian hormone (AMH) – 0.09
- Transvaginal sonography – Seedling fibroid.
Transvaginal sonography showed a seedling fibroid of 1 x 1 cm; both ovaries with only one follicle and endometrial thickness of 5mm on day 2 of cycle. In view of decreased AMH; ICSI was suggested. As the patient insisted that her eggs be used for the procedure; she was started on Antagonist protocol.
There was no improvement in the size or number of follicles though. Only one oocyte was retrieved; ICSI performed and the same implanted with ET of 8-mm thickness with no success.
In the next cycle, she had no evidence of any follicles on scan, so was suggested for a donor oocyte program.
She underwent fresh ET with donor oocytes after endometrial preparation but with no success.
With a history of repeated miscarriages and implantation failures, it was evident that she did not have a favorable endometrium for implantation.
We tried granulocyte colony-stimulating factor (GCSF), popularly available as FILGRASTIM 300 mcg. We instilled GCSF into the uterine cavity 1 day before the frozen ET in February 2016. The endometrium increased by 3 mm on the day of transfer. Her B-HCG was positive. Her 8-week early pregnancy ultrasound revealed dichorionic diamniotic gestation with single viable fetus. She continued her pregnancy in Tanzania and was under follow-up with us through mails. She recently delivered a term healthy male child by cesarean section.
| Discussion|| |
GCSF is a glycoprotein and possess growth factor and cytokine functions. It stimulates neutrophilic granulocyte proliferation and differentiation. GCSF is expressed and produced by decidual cells. C-FMS acts as a receptor to GCSF which is expressed by trophoblastic cells. Implantation, embryo, and fetal development involves various immunological mechanisms. GCSF stimulates secretion of various endogenous cytokines and activates various endocrine pathways.
Tanaka et al.'s study concluded that GCSF acts in autocrine and paracrine fashion and promotes decidualisation of endometrial cells. Various studies have shown that it acts on decidual macrophages and affects implantation by stimulating neutrophilic granulocyte proliferation and differentiation., It causes dendritic cell recruitment and T-regulatory cell activation and stimulates various proangiogenic factors.
A study was conducted in Germany in 2002 on the role of GCSF in achieving a higher live birth rate on patients with 4 % recurrent miscarriages. Focusing on subgroup of recurrent miscarriage patients with GCSF treatment, more patients receiving GCSF delivered healthy baby (72%) compared to placebo/normal patients receiving aspirin, cortisone, and LMWH.
A pregnancy rate of 47% was achieved after GCSF administration, 27% in recurrent miscarriage patients with alternate medication. G-CSF has multiple effects on immune system like induction of Th2 (Pan et al. 1995), inhibition of NK cells (Schlahsa et al. 2011), and blood mononuclear cells (Kitabayashi et al. 1995; Sugita et al. 2003).
Presuming immunological factor might be main reason for recurrent miscarriage and implantation; these patients could benefit concerning immunomodulatory functions of GCSF.
Many studies are still going on – To assess the effectiveness of GCSF in improving the ovarian response in IVF cycles of poor responders. A study conducted between July and December 2011 showed an increase in number of retrieved oocytes which used GCSF. There was also increased number of mature oocytes and embryos in the same in comparison to preceding cycles without GCSF in the same group. Data suggest that G-CSF is involved in follicle development and may be a predictor of IVF outcome.
There are studies which suggest good endometrial thickness affecting the outcome of IVF and embryo implantation. Many studies suggest a definite increase in endometrial thickness after 48 h of G-CSF instillation in uterine cavity. It increases ET and ongoing clinical pregnancy rates. Studies indicate improvement in pregnancy rates when G-CSF is administered in patients with thin endometrium at the time of ET.
| Conclusion|| |
GCSF would be a valuable tool to help pregnancy rates among infertile women undergoing IVF-ET cycles, irrespective of their past ET and past treatment failures. However, a definitive conclusion is yet to be made regarding its role in recurrent implantation failures and recurrent miscarriages refractory to conventional treatments. Hence, further studies are needed to conclusively show the effects of GCSF treatment.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Tanaka T, Miyama M, Masuda M, Mizuno K, Sakamoto T, Umesaki N, et al.
Production and physiological function of granulocyte colony-stimulating factor in non-pregnant human endometrial stromal cells. Gynecol Endocrinol 2000;14:399-404.
Loke YW, King A, Burrows TD. Decidua in human implantation. Hum Reprod 1995;10 Suppl 2:14-21.
Barash A, Dekel N, Fieldust S, Segal I, Schechtman E, Granot I, et al.
Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro
fertilization. Fertil Steril 2003;79:1317-22.
Rutella S, Zavala F, Danese S, Kared H, Leone G. Granulocyte colony-stimulating factor: A novel mediator of T cell tolerance. J Immunol 2005;175:7085-91.
Salmassi A, Schmutzler AG, Schaefer S, Koch K, Hedderich J, Jonat W, et al.
Is granulocyte colony-stimulating factor level predictive for human IVF outcome? Hum Reprod 2005;20:2434-40.
Gleicher N, Vidali A, Barad DH. Successful treatment of unresponsive thin endometrium. Fertil Steril 2011;95:2123.e13-7.