The Relationship Between Androgens and Days per Month of Period Pain, Pelvic Pain, Headache, and TLR4 Responsiveness of Peripheral Blood Mononuclear Cells in Young Women with Dysmenorrhoea

Abstract

Purpose Women bear a disproportionate burden of persistent pain conditions when compared to men. To determine whether the hormonal environment affects the clinical experience of pain, as measured by the days per month of pelvic pain (DPelvicPM), period pain (DPeriodPM), headache (DHeadachePM) or the in vitro EC 50 for Interleukin-1β (IL-1β) release following TLR4 stimulation with Lipopolysaccharide from Peripheral Blood Mononuclear Cells (PBMCs). Findings were stratified according to use or non-use of the oral contraceptive pill. Patients and Methods Fifty-six women aged 16–35 years, with minimal or severe dysmenorrhea, and use or non-use of the OC, were enrolled. Blood was collected on two occasions in a single menstrual cycle: Days 1–2 and Days 7–10. Hormonal analysis for testosterone, dihydrotestosterone, dehydroepiandrosterone, Androstenedione, 3α-Androstanediol, 3β-androstanediol, estradiol, estrone, 17α-hydroxyprogesterone, progesterone, cortisol and sex-hormone binding globulin was undertaken using ultra-sensitive Liquid Chromatography Mass–Spectrometry (LC-MS). PBMCs were exposed to lipopolysaccharide (LPS) and the resulting Interleukin-1β output was determined. Results Non-users of the OC showed a strongly inverse correlation between a reducing free androgen index (FAI) and increasing DPelvicPM (p=0.0032), DPeriodPM (p=0.013), DHeadachePM (p=0.041). Non-users of the OC showed a significant increase in DPelvicPM (p=0.049) on Days 7–10. Modestly significant associations were found between reduced androgens and potentiated LPS-induced IL-1β (lower EC 50 ). Conclusion This is the first study to investigate the relationship between the hormonal environment and activation of the immune system in young women with dysmenorrhoea-related pain conditions. Low androgen levels were consistently associated with increased pain. Translational implications for the findings are discussed.

Circulating sex steroids and bladder pain sensitivity in dysmenorrhea

“…It has been hypothesized that increases in SHBG result in androgen sequestration, increasing pain sensitivity, but research on the trajectory of estradiol and SHBG over time is needed to clarify whether increased SHBG is compensatory or contributes to worsening pain trajectories. 55 A handful of small studies have attempted to explore the relationship between sex steroids and pain sensitivity explicitly but have obtained different results from our study. A study of 11 healthy participants 56 reported that the only relationship between pain sensitivity and sex steroids was estradiol and thermal pain (r ¼ 0.33, p ¼ 0.06).…”

“…By definition, 31 DYSB participants reported experimental bladder pain greater than 15 on a 0-100 VAS at first urge, and they had pain levels similar to BPS participants (Table 2). Participants with DYSB reported nearly as much pain at first urge (32 [24,48]) as BPS participants (43 [34,55]; p ¼ 0.091), but had significantly more bladder capacity (256 [1,94,345] vs. 192 [89,235]; p ¼ 0.018). Notably, both DYSB and BPS participants had significantly more pain at first urge than control participants (Table 2).…”

Androgens, Endometriosis and Pain

“…In a group of healthy women, Bartley and Fillingim (1) found higher testosterone levels to be anti-nociceptive, and higher estrogen levels to be mildly nociceptive. To our knowledge, our research is the first to document an inverse correlation between levels of testosterone and the experience of pain in young women (5). This article outlines our recent research findings and how androgens can influence pain at different stages of life and when different pathologies are present.…”

“…Our work, as published in the Journal of Pain Medicine ( 5 ), investigated the relationship between serum levels of 10 steroid hormones and the subjective experience of dysmenorrhea-related pelvic pain symptoms ( 5 ). We used high sensitivity liquid chromatography mass spectrometry (LC-MS) assays to measure serum levels at 2 stages of a single menstrual cycle, Day 1–2 (when estrogen is baseline) and Day 7–10 (when estrogen peaks).…”

“…Finally, we explore the potential for androgens to provide a therapeutic benefit in women and what role they may have in future treatment pathways. pain symptoms (5). We used high sensitivity liquid chromatography mass spectrometry (LC-MS) assays to measure serum levels at 2 stages of a single menstrual cycle, Day 1-2 (when estrogen is baseline) and Day 7-10 (when estrogen peaks).…”