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

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  1 , Yuen Kwok  1 , Ann Solterbeck  2 , Carmen Pyragius  3 , Mary Louise Hull  4 , Mark R Hutchinson  1   5 , Paul Rolan  1
Affiliations

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 et al. J Pain Res. .

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.

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Conflict of interest statement

Susan F. Evans receives royalties from book authorship (Endometriosis and Pelvic Pain), has received payment from Pfizer and Bayer for educational presentations, is a shareholder in Alyra Biotech Pty Ltd (a company developing non-hormonal immune therapies for the management of pelvic pain) and Havah Therapeutics Pty Ltd (a company developing testosterone therapies for women with breast cancer), is involved in the development of novel treatments for pelvic pain; and has patents pending: PCT/AU2018/051383 and PCT/AU2020/050551, Alyra Biotech Pty Ltd. Paul E. Rolan is a shareholder in Havah Therapeutics, Alyra Biotech, Lipotek and iX Biopharma, a consultant to Bionomics and Novartis, and has received payment for educational presentations from Novartis and Seqirus. Ann Solterbeck is an employee of Statistical Revelations and reports personal fees from the University of Adelaide, during the conduct of the study. Mark R. Hutchinson is director of the Australian Research Council Centre of Excellence for Nanoscale BioPhotonics (CE140100003) and the recipient of an ARC Future Fellowship (FT180100565) and reports grants from Australian Research Council. His research program is supported by Novartis, Abbott, Pfizer and Regeneus, but these activities fall outside the submitted work. The authors report no other potential conflicts of interest for this work.

Figures

Figure 1
Figure 1
Enrolment flow chart for participant recruitment and study inclusion.
Figure 2
Figure 2
IL-1β release (Mean ± SEM) following LPS (TLR4) stimulation (12.5pg·mL to 10µg·mL) of PBMC’s obtained from controls: no OC (red circle, solid line), controls: OC (blue square, solid line), dysmenorrhea: no OC (red triangle, dotted line), dysmenorrhea: OC (blue upside down triangle, dotted line), pelvic pain: no OC (red diamond, dashed line), and pelvic pain: OC (blue cross, dashed line). A four-parameter logistic dose–response curve has been fitted to each graph; data obtained from Days 1–2 and Days 7–10 of each individual’s menstrual cycle.
Figure 3
Figure 3
Comparison between DPelvicPM and levels of Free Androgen Index according to day of testing (Days 1–2 or Days 7–10) and OC use (No OC, OC, or Combined).
Figure 4
Figure 4
Comparison between DPelvicPM and the Estradiol according to day of testing (Days 1–2 or Days 7–10) and OC use (No OC, OC, or Combined).
Figure 5
Figure 5
Comparison between DPeriodPM and the Free Androgen Index according to day of testing (Days 1–2 or Days 7–10) and OC use (No OC, OC, or Combined).
Figure 6
Figure 6
Comparison between EC50 and levels of cortisol according to day of testing (Days 1–2 or Days 7–10) and OC use (No OC, OC, or Combined).
See this image and copyright information in PMC

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