Plasma levels of stromal cell-derived factor-1 (CXCL12) and circulating endothelial progenitor cells in women with idiopathic heavy menstrual bleeding.

Study Question: Do plasma levels of stromal cell-derived factor-1 (CXCL12, sometimes termed SDF-1) and the numbers of circulating endothelial progenitor cells (EPCs), EPC colony-forming units (EPC-CFU) and mature endothelial cells (ECs) differ between women with idiopathic heavy menstrual bleeding of endometrial origin (HMB-E) and controls and are they related to plasma levels of other angiogenic growth factors?

Summary Answer: Angiogenesis is altered in women with HMB-E, characterized by a reduction in mean plasma levels of CXCL12, a low number of EPCs-CFUs and a high level of circulating ECs.

What Is Known Already: Plasma levels of CXCL12 are significantly higher during the proliferative than the secretory phase of the menstrual cycle in healthy women and exhibit a negative correlation with blood EPC-CFUs.

Study Design, Size, Duration: A prospective cohort study in a university hospital setting. Between 2008 and 2009 10 HMB-E patients were recruited from Karolinska University Hospital. Ten healthy women were also included in the analysis.

Participants/materials, Setting, Methods: Ten healthy control women and 10 HMB-E patients, all with regular menstrual cycles, provided 4 blood samples during a single menstrual cycle: 2 in the proliferative phase, 1 at ovulation and 1 in the secretory phase. We assessed plasma levels of CXCL12, vascular endothelial growth factor A(165) (VEGFA), basic fibroblast growth factor (bFGF) and granulocyte and granulocyte-macrophage colony-stimulating factors by ELISA. We counted circulating EPC-CFUs by culture, and ECs and EPCs by flow cytometry and immunostaining for cell surface markers.

Main Results And The Role Of Chance: Plasma levels of CXCL12 were significantly lower in HMB-E patients compared with control women (P < 0.0001), with a significant decrease (P = 0.013) between the proliferative phase and ovulation. VEGFA showed a trend towards the same decreasing pattern as CXCL12, although not statistically significant (P = 0.086), whereas systemic VEGFA levels in control women remained unchanged across the different phases of the menstrual cycle (P = 0.473). HMB-E patients had a lower number of EPC-CFUs compared with control women (P = 0.014), with a positive correlation between the level of CXCL12 and EPC-CFUs (r = 0.428; P = 0.047). Whilst the level of circulating endothelial cells in HMB-E patients was higher than in control women, this did not reach statistical significance. In contrast, the levels of the hematopoietic/EPC marker CD34 were significantly lower in HMB-E patients than control women (P < 0.020).

Limitations, Reasons For Caution: Small sample, unknown source of CXCL12, unknown balance between influx and efflux of EPCs from bone marrow and to the endometrium.

Wider Implications Of The Findings: Our results indicate that CXCL12 may play an important role in physiological angiogenesis in the endometrium, and that low and dysregulated levels of CXCL12 in women with HMB-E could affect vessel quality, integrity and repair.

Study Funding/competing Interest(s): Financial support was provided through the regional agreement on medical training and clinical research (ALF) between the Stockholm County Council and Karolinska Institutet (number 20110258). This study was also supported by grants from the Swedish Labor Market Insurance. The authors have no conflict of interest to declare.