Estradiol is Pro-Nociceptive and Associated with a Small-Fiber Neuropathy Among Premenopausal Women with Sickle Cell Disease

Vaso-occlusive crisis (VOC) pain episodes often occur with menses and concurrent hormonal contraceptive use may reduce their frequency. This study tested the hypothesis that among women with sickle cell disease (SCD), sex hormones are associated with pain detection thresholds. Women with SCD aged minimum 18 years with regular menses, and without acute illnesses, pregnancy, oophorectomy, or hormonal contraceptive use within three months prior were included. Pain detection thresholds for heat (HPT) and pressure (PPT), and serum estradiol, progesterone and testosterone were measured at follicular and luteal phases. The Adult Sickle Cell Quality-of-Life Measurement Information System assessed quality-of-life and VOC frequency and severity scores. Generalized linear mixed models were performed, including the day of the cycle standardized by cycle length. Among 125 participants, neither the day nor phase of the menstrual cycle was associated with PPT or HPT. In multivariate analyses, worse VOC scores (<i>β</i> = 1.7) and severe genotype (<i>β</i> = -46.0) were associated with higher and lower trapezius PPT, respectively. Older age was associated with lower forearm HPT (<i>β</i> = -0.1). Among leg measurements, ovulatory cycles (<i>β</i> = -1.1) and hydroxyurea use (<i>β</i> = -1.2) were associated with lower HPT, while worse VOC scores (<i>β</i> = 0.1) were associated with higher HPT. Higher estradiol was associated with lower HPT at the leg (<i>β</i> = -0.02), with an interaction with the cycle day (<i>β</i> = 0.001) predicting lower thresholds earlier in the cycle for the same estradiol level. Estradiol is associated with a time-varying, length-dependent small-fiber neuropathy among SCD women; and may be a potential therapeutic target and biomarker for SCD pain.