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

Susan F Evans; Yuen Kwok; Ann Solterbeck; Carmen Pyragius; Mary Louise Hull; Mark R Hutchinson; Paul Rolan

doi:10.2147/JPR.S279253

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

J Pain Res. 2021 Mar 3:14:585-599. doi: 10.2147/JPR.S279253. eCollection 2021.

Authors

Susan F Evans¹, Yuen Kwok¹, Ann Solterbeck², Carmen Pyragius³, Mary Louise Hull⁴, Mark R Hutchinson^{1

5}, Paul Rolan¹

Affiliations

¹ Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
² Statistical Revelations, Melbourne, Victoria, Australia.
³ School of Paediatrics & Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.
⁴ Robinson Research Institute, School of Pediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.
⁵ ARC Centre of Excellence for Nanoscale Biophotonics, University of Adelaide, Adelaide, South Australia, Australia.

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 EC₅₀ 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 EC₅₀).

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.

Keywords: IL-1β; dysmenorrhoea; oral contraceptive pill; pain; pelvic pain; testosterone.

Grants and funding

The study was part funded by the Australia New Zealand College of Anaesthetists (ANZCA) Research Foundation and the Australian Research Council (FT180100565).