Role of granulocyte colony-stimulating factor in human reproduction

Elham Naghshineh, Maryam Eftekhar, Naghshineh E, Parisa Khani
Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences · 2018 · vol. 23(1) , pp. 7 · doi:10.4103/jrms.jrms_628_17 · PMID:29456564 · PMC5813296 · W2793926872
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⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

This review summarizes the multifaceted roles of granulocyte colony-stimulating factor in human reproduction, including ovulation, endometrial receptivity, and improving pregnancy loss.

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⚙ AI-generated deep summary by claude@2026-07, 2026-07-09 · read from full text ⓘ

This review examines the role of granulocyte colony-stimulating factor (G-CSF) in human reproduction, synthesizing evidence from studies of normal menstrual cycles, ovarian stimulation, luteinized unruptured follicle (LUF) syndrome, poor responders, IVF/ICSI outcomes, endometrial receptivity, recurrent implantation failure, and recurrent spontaneous abortion. Across the paper, G-CSF is described as a cytokine that regulates neutrophil production and also acts through its receptor on multiple reproductive and immune cell types, with reported associations between higher serum/follicular fluid G-CSF levels and improved oocyte/implantation outcomes, alongside some conflicting findings (e.g., no benefit in women with normal endometrial thickness or in polycystic ovary syndrome). A limitation explicitly inherent to the review is that it summarizes heterogeneous study designs and outcomes rather than presenting one unified experimental test of efficacy. This paper is centrally about endometriosis — it discusses reported roles of G-CSF in improving endometriosis pathophysiology and notes G-CSF as a factor in the genesis of early endometriotic lesions.

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Abstract

As new research reveals, granulocyte colony-stimulating factor (G-CSF) plays an effective role in pregnancy success, considering that it not only affects the embryo implantation and ovarian function but also it promotes endometrial thickening and improves the pathophysiology of endometriosis, which all fundamentally lead to reducing pregnancy loss. In this review, we focus on the role of G-CSF in human reproduction. We summarized its role in ovulation, luteinized unruptured follicle syndrome, poor responders, improving repeated in vitro fertilization failure, endometrial receptivity and treatment of thin endometrium, and recurrent spontaneous abortion.
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The

Recently, the potential role of serum and follicular fluid (FF) G-CSF, which is a noninvasive biomarker of oocyte competence and embryo choice IVF cycles, is being suggested. In fact, G-CSF level in both serum and FF is the main predictor of IVF outcome.[ 15 16 ] Lédée et al . and others demonstrated that, in subsequent implantation, the follicular G-CSF was highly predictive. Their results showed that the follicular level of G-CST had higher discriminatory power than embryo morphology for prediction of ongoing pregnancy (0.77 [0.69–0.83], P = 0.001 vs. 0.66 [0.58–0.73], multivariate logistic regression analysis).[ 17 ] In contrast, a study by Kahyaoglu et al . confirmed that levels of G-CSF concentration in both serum and follicular microenvironment in polycystic ovary syndrome women have no correlation with good ovarian response or clinical pregnancy rates.[ 11 ]

Role

G-CSF is necessary for many items such as mobilization and recruitment of lymphocytes, uterine dendritic cells, and macrophages. G-CSF plays a vital role as an endometrial remodeling factor for implantation window. G-CSF prepares endometrium in only a few days for some reasons such as suppressing any immune aggression to present an embryo and allow sufficient endometrial receptivity.[ 32 ] Successful implantation needs some items including a good quality embryo, a receptive endometrium, and a good embryo transfer method. The normal thickness of the endometrium, which is between 7 and 14 mm in the secretary phase, is a key element for a successful pregnancy in IVF cycles.[ 26 ] Shapiro et al . showed that if endometrium thickness is less than 6mm, pregnancy will not happen.[ 33 ] Al-Ghamdi et al . concluded that thin endometrium is associated with more miscarriage.[ 34 ] A wide variety of treatments has been used to enhance endometrium thickness such as extended estradiol, low-does aspirin, vaginal treatment by vitamin E, L-arginine and sildenafil citrate, intrauterine administration of bone marrow stem cells, and progenitor cells.[ 35 ] Kunicki et al . showed that endometrium thickness in the patient with extremely thin endometrium can be increased using G-CSF when other methods failed to improve it. Improving endometrial thickness after administering of G-CSF will probably increase the chance of pregnancy.[ 36 ] Tehraninejad et al . understood that infusion of G-CSF in the endometrial cavity is a safe and effective method for increasing endometrial thickness in patients with thin and unresponsive endometrium.[ 16 ] Apparently, chronically unresponsive thin endometrium, which was resistant to traditional remedies, such as increased E2 support and sildenafil could be affected positively by endometrial perfusion with G-CSF. An increased spurt in endometrial thickness can be noticed during 48–72 h of G-CSF administration.[ 6 ] For frozen embryo transfer (FET) cycles, the endometrium is consistently prepared with estrogen and progesterone supplementation.[ 37 ] Gleicher et al . showed that G-CSF is a beneficial remedy in FET cycles for patients suffering from the unresponsive, inadequate, and thin endometrium.[ 38 ] Eftekhar et al . failed to demonstrate that G-CSF potentially improves endometrial thickness; however, it was claimed that it will possibly improve chemical and clinical pregnancy rate of the infertile women suffering from thin endometrium in FET cycle.[ 39 ] Li et al . failed to indicate the potential role of G-CSF in improving embryo implantation and clinical pregnancy rate of the infertile women with thin endometrium.[ 10 ] Mishra et al . showed that G-CSF led to a very small increase in endometrial thickness in women dealing with persistent thin endometrium although no improvement in their pregnancy rates was noticed.[ 40 ]

What

Bone pain, general fatigue, headaches, insomnia, anorexia, nausea, and/or vomiting are considered as some side effects of treatments with G-CSF. Moreover, dyspnea, chest pain, hypoxemia, diaphoresis, anaphylaxis, syncope, and flushing are some other it's adverse effects.[ 43 ]

Intro

Some cells such as fibroblasts, monocytes, macrophages, endothelial cells, stromal cells, and bone marrow cells make a special cytokine called granulocyte colony-stimulating factor (G-CSF).[ 1 ] G-CSF has some functions; however, its major role is to stimulate the neutrophils proliferation and their differentiation in the bone marrow. Besides, their release to the bloodstream is under control of G-CSF. Actually, in mature neutrophils, phagocytosis and oxidative process are boosted by G-CSF.[ 2 ] In 1983, G-CSF was found in mice for the first time and later in 1986, and it was purified in human G-CSF (hG-CSF).[ 3 ] hG-CSF has a specific receptor (G-CSF receptor) which is located on the surface of some cells such as myeloid progenitor cells, myeloid leukemia cells, mature neutrophils, platelets, monocytes, lymphoid cells, some T-cells, and B-cells.[ 4 ] Even several nonhemato cells, for example, endothelial cells, placenta cells, trophoblastic cells, the fetomaternal interface, and granulose luteinized cells include such a receptor that h G-CSF's activities are mediated through it.[ 5 ] As new research reveals, G-CSF plays an effective role in pregnancy success, considering that it not only affects the embryo implantation and ovarian function but also it promotes endometrial thickening and improves the pathophysiology of endometriosis, which all fundamentally lead to reducing pregnancy loss.[ 6 7 8 ] In fact, since G-CSF improves implantation, it is presented as an essential item for implantation and even it is a remedy for implantation failure.[ 9 ] In general, human decidual macrophages, ovulation, and ovarian function are impacted by G-CSF. Furthermore, it influences granulosa cell functions (granulocyte-macrophage-CSF [GM-CSF]), as well as, improving ovarian stimulation in poor responders, and even it is predictive of in vitro fertilization (IVF) outcome. In addition, it is considered as a biomarker for oocytes/embryos that are potentially able to implant. Even the number of unexpected repeated pregnancy loss reduces by G-CSF. Furthermore, G-CSF is known as a key factor in the genesis of early endometriotic lesions and autoimmunity suppressor.[ 6 ] Furthermore, it was claimed that serum G-CSF was kept at the high level during pregnancy. Fetal chorionic villous and maternal decidual tissues release G-CSF in the first trimester and during it.[ 10 ] In this review, we focus on the role of G-CSF in human reproduction. We summarized its role in ovulation, luteinized unruptured follicle (LUF) syndrome, poor responders, improving repeated IVF failure, endometrial receptivity, and recurrent spontaneous abortion.

Conclusion

Oocyte maturation, endometrial receptivity, development of preimplantation embryos, and trophoblast invasion are affected and promoted by G-CSF. Evidently, it increases the pregnancy rate in ART treatment, especially in patients who had RIF and it decreases the abortion rate in patients with RSA, and even it reduces preterm birth of preeclampsia. Nil. There are no conflicts of interest.

Granulocyte

Recurrent miscarriage's definition (RM) is the occurrence of three or more clinically detectable pregnancy losses in the first trimester. RM is as frequent as 1% in women with reproductive age. In general, the recognized causes of RM are many. Take the example of parental chromosomal defects, mainly reciprocal or Robertsonian translocations, infections, endocrinological cause (thyroid disease, diabetes, and polycystic ovaries), uterine abnormalities, antiphospholipid antibody syndrome, and other autoimmune conditions.[ 41 ] Surprisingly, over 40% of RM cases remain unexplained. However, for such cases, possible causes seem to be immune dysfunction or alloimmune response. RM could be caused due to an imbalance in the Th1/Th2 system. The great part is that, during pregnancy in the uterine tissues of Th1 cytokine production, they act as a cytotoxic one instead of Th2 cytokine production and have an immune suppression role. The negative parts are about rejecting the embryonic allograft.[ 8 ] Scarpellini and Sbracia use recombinant G-CSF (RG-CSF) as a way of treatment for couples with RM. Sixty-eight women with RM of unknown cause and being treated with intravenous human immunoglobulin were accidentally chosen to be treated by either Rg-CSF or placebo. Women in the treated group received a dose of 1 g (100,000 IU) kg/day of Filgrastim (Neupogen, Dompe, Italy) starting from the 6 th day of ovulation until the end of menstruation or even the end of the 9 th week of pregnancy. Another group named placebo group contained 33 women receiving saline exactly the same administration and period of time, the way treated group had received. It was detected that, in G-CSF group, 29 out of 35 (82.8%) women delivered a healthy infant, whereas, in the placebo group, live birth rate was 48.5% (16 out of 33) ( P = 0.0061).[ 8 ] Santjohanser et al . performed a retrospective cohort study in women with RM undergoing ART. One hundred and twenty-seven women (199 cycles) with RM (at least 2 early miscarriages), 49 (72 cycles) receiving G-CSF, and 78 (127 cycles) who were controls received either no medication (subgroup 1) or cortisone, intravenous immunoglobulin, or low molecular weight heparin (subgroup 2) undergoing ART for IVF/intracytoplasmic sperm injection were analyzed. They showed that the number of early miscarriages was significantly higher in the G-CSF group as compared to the subgroups (G-CSF 2.67 ± 1.27, subgroup 1: 0.85 ± 0.91, subgroup 2: 0.64 ± 0.74).[ 42 ]

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