C-reactive protein and the menstrual cycle in females with sickle cell disease

• Females with sickle cell disease in the follicular phase of the menstrual cycle have higher C-reactive protein than in the luteal phase.

• Cyclic variations in inflammation with the menstrual cycle may contribute to perimenstrual vaso-occlusive pain patterns

Females with sickle cell disease (SCD) experience more frequent and severe vaso-occlusive episodes (VOEs) than males. Many also report perimenstrual timing of VOEs, suggesting cyclic variation in pain risk. C-reactive protein (CRP) is a robust inflammatory marker that is elevated at baseline in SCD patients and rises during VOEs. Cyclic patterns of inflammatory markers in females with SCD have not been previously examined. This study examines the relationship between CRP and menstrual cycle phase in females with SCD. Frozen plasma samples from reproductive-aged adult patients with SCD were analyzed. Estradiol, progesterone, and luteinizing hormone levels were measured in female patient samples to estimate menstrual cycle phase at time of collection. CRP levels were compared by SCD genotype, hydroxyurea treatment, female vs. male sex, and menstrual cycle phase in the female subgroup. CRP levels did not differ significantly by SCD genotype (SS vs. SC), hydroxyurea use, or sex. However, in females with SCD, CRP levels were significantly higher during the follicular phase compared to the luteal phase (8.80 [2.7-10.5] vs. 0.82 [0.6-2.1] mg/L, p=0.03). Although there were no differences in CRP levels in SCD patients by sex, genotype, or hydroxyurea use, our results suggest that females have cyclicity in inflammation across the menstrual cycle that may predispose them to VOEs during the follicular phase. Further study is needed to validate these findings prospectively and to correlate biomarker patterns with clinical symptoms.