Menstrual cycle may drive inflammation in women with sickle cell disease

A marker linked to inflammation, C-reactive protein, may increase significantly during the follicular phase of the menstrual cycle in female patients with sickle cell disease (SCD), according to emerging research published today in Blood Vessels, Thrombosis & Hemostasis.  This observation provides insight into the pattern of painful vaso-occlusive events (VOEs), which are driven by inflammation, in female patients with the disorder.

We know both from the literature and anecdotally from our patients that women with SCD have VOEs that cluster around their menstrual periods. We wanted to examine the potential reason behind that. Our study is the first to examine the association between menstrual cycles and inflammation in female patients with SCD."

Jessica Wu, MD, study's lead author, resident physician, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania

"The menstrual cycle is often overlooked in research and clinical care, but can interact with health in important ways, as we are seeing in SCD," said the study's principal investigator, Andrea Roe, MD, MPH, an assistant professor of obstetrics and gynecology at the Perelman School of Medicine at the University of Pennsylvania. Dr. Wu, Dr. Roe, and their colleagues analyzed plasma samples in the Penn Medicine BioBank repository from individuals with a confirmed SCD diagnosis. After excluding samples from participants who were pregnant, hospitalized with a VOE, or treated at an emergency department or infusion center at the time of sample collection, 31 plasma samples were included in their analysis – 13 from female patients and 18 from male patients.

SCD, the most common inherited red blood cell disorder in the United States, is characterized by abnormally shaped blood cells. These cells can become lodged in the veins and block blood flow, leading to organ damage, infection, and episodes of severe pain throughout the body, known as VOEs, which can be so debilitating that people seek treatment at a hospital. Previous literature has shown that female patients with SCD have more frequent, severe VOEs, often around the time of their menstrual periods.

The researchers measured C-reactive protein in all samples and female sex hormones, including estradiol, progesterone, and luteinizing hormone, in samples from female patients. They compared C-reactive protein, clinical laboratory markers, and other biomarkers by patient sex, SCD genotype, hydroxyurea, and, in the cases of the 13 female patients, made the same comparisons between samples from the follicular and luteal phases of the menstrual cycle. A progesterone level of 1.75 ng/mL was used to define the occurrence of ovulation and cutoff between the follicular and luteal phases.

Among the 31 samples, the average concentration of C-reactive protein was 4.45 mg/L, with no significant differences observed based off SCD genotype or treatment with hydroxyurea. When Dr. Wu and her colleagues compared C-reactive protein between samples from female patients and male patients, they observed no significant difference (3.88 vs. 4.45 mg/L, p=0.89); however, when they compared C-reactive protein between samples taken during the follicular or luteal phases of the female patients, they observed higher median C-reactive protein in the follicular phase versus the luteal phase (8.80 vs. 0.82 mg/L, p=0.03).

"The amount of inflammation is significantly elevated in the follicular phase, or first half, of the menstrual cycle in female patients with SCD," said Dr. Wu. "This observation correlates with what we see in the literature, that this is the time in which this patient population has the most VOEs."

These results also mirror the trend seen in the menstrual cycles of the general population, though the magnitude of elevation is much greater in female patients with SCD than in those without SCD during the follicular phase (8.80 mg/L vs. 0.74 mg/L). The significant fluctuation of C-reactive protein in female patients with SCD could have clinical implications given the similar temporal pattern of VOEs, providing a target for intervention.

"Many hormonal contraceptives can suppress menstruation or suppress the hormone fluctuations that occur from cycle to cycle, so contraceptives could help these patients manage their pain crises," said Dr. Wu. "SCD is a really debilitating and painful disease. The more data we have about how it presents in female patients, the better we can counsel them on anticipating and managing their pain."

Dr. Wu cautioned that this research is still early and has several limitations, including its small sample size and cross-sectional, retrospective nature. Specifically, since each sample was from a singular time point in different individuals, menstrual phase comparisons in C-reactive protein (follicular vs. luteal phase) were unable to be performed within the same individual. Additionally, because VOEs evolve through different stages, the researchers could not confirm that the subjects were at their baseline inflammatory levels, even if they did not have symptoms of an acute VOE.

The researchers intend to validate their findings through further prospective studies with larger sample sizes and plan to explore menstrual patterns of other biomarkers associated with SCD, as well as correlation with clinical symptoms.