Effect of intrauterine granulocyte-colony stimulating factor administration on in vitro fertilization outcome in women with moderate-to-severe endometriosis: An RCT

Abstract Background Nearly 25-50% of infertile women have endometriosis. There are reports of disorders in the expression of granulocyte colony-stimulating factor (G-CSF) receptors in women with endometriosis. Objective To examine the effect of intrauterine administration of G-CSF in in vitro fertilization (IVF) cycles on the fertility rate of infertile women with moderate-to-severe endometriosis. Materials and Methods This clinical trial was conducted on 66 infertile women with moderate-to-severe endometriosis, undergoing IVF and intracytoplasmic sperm injection (ICSI). The participants were allocated into two groups via simple randomization: the G-CSF (n = 27) and control (n = 39) groups. In the G-CSF intervention group, on the oocyte pick-up day, immediately after an ovarian puncture, 300 μg of G-CSF was injected through a transcervical catheter under abdominal ultrasound guide to visualize flushing into the uterine cavity. Women in the control group received no intervention. The two groups were evaluated for clinical pregnancy. Results No significant difference was noted in the demographic characteristics of the two groups. The rate of clinical pregnancy was 28.2% in the control group and 25.9% in the G-CSF group, indicating no significant difference (p = 0.83). Conclusion The results showed that the intrauterine injection of G-CSF had no effects on pregnancy in women with stage-3/4 endometriosis undergoing IVF.


Introduction
Endometriosis is defined as a disorder in which endometrial tissue is present outside the uterine cavity. This disorder occurs in about 5-10% of the female population and 25-50% of infertile women (1). However, the etiology of endometriosis is not yet clear (2). Strong biological evidence suggests Considering the high prevalence of endometriosis in infertile women and the possible effects of this disorder on endometrial receptivity, this study was conducted to examine the effect of intrauterine administration of G-CSF in IVF cycles on the fertility rate of infertile women with moderate-to-severe endometriosis.

Design
This single-center randomized controlled clinical trial was conducted at the Arash Women's Hospital, Tehran, Iran between January 2019 and September 2019.

Study population
This study included a total of 66 infertile women with endometriosis, who underwent IVF/ICSI for

Random allocation, concealment, and blinding
After the doctor declared the eligibility of patients, the type of intervention was determined by the gynecologist assistant using simple randomization, dividing the patients into either the G-CSF or no-intervention groups. In this method, the RANDBETWEEN function in the Excel program was used to generate a random number between one and two. This was repeated 66 times. Blinding for patients was not possible because the patients were aware of the type of intervention. Evaluation of the final results was done by a physician who was blind to the intervention type. A statistician who was blind to the allocation analyzed the results.

Intervention
The long gonadotropin-releasing hormone    (Table II). Also, after excluding women with canceled IVF due to cysts (based on the per-protocol analysis), the rate of clinical pregnancy was not significantly different between the two groups (control group: n = 11, 33.3%; G-CSF group: n = 7, 29.2%; p = 0.73).

Discussion
This study showed that the intrauterine However, the mechanism of action of G-CSF must be clarified in clinical studies of G-CSF in reproductive medicine (14).
A review of the literature revealed that no study has yet examined the effectiveness of intrauterine G-CSF injection in women with endometriosis receiving IVF. In a study in 2011, a new option for the treatment of thin endometrium was introduced.
Intrauterine injection of G-CSF increased the endometrial thickness in four IVF patients who did not respond to conventional treatments, and all of these women became pregnant (15). Other studies failed to find significant effects in women with a thin endometrium (16,17).
Conversely, some studies have shown that routine use of G-CSF for women with a normal endometrium undergoing IVF does not have a positive effect on the IVF outcomes (6,18). In the present study, intrauterine administration of G-CSF was performed in women with endometriosis.
We did not observe any significant differences between the two groups in terms of chemical or clinical pregnancy rates. Many studies have reported lower pregnancy rates in women with endometriosis compared to healthy controls (19).
An inverse correlation has been found between the success rate of IVF and stage-3/4 endometriosis (20). Moreover, IVF studies have shown that women with advanced endometriosis have a poorer ovarian reserve, lower-quality embryos and oocytes, and weaker implantation (21

Conclusion
In conclusion, G-CSF may have no significant effect on endometrial function in women with endometriosis. The pregnancy rate is generally affected by factors, such as maternal age, number of embryos, and number of high-quality embryos transferred, which were similar in the two groups.
Overall, the design of this study (a single-blind randomized clinical trial) is its major strength.
This study also had some limitations, such as