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Endometriosis is a polygenic, estrogen-dependent, inflammatory disorder of uncertain aetiology associated with pain, infertility and reduced quality of life. While the positive association between endometriosis and estrogen is established, a suite of recent studies has demonstrated an inverse association between the presence of endometriosis lesions and levels of testosterone both prenatally and postnatally. The following narrative review provides new insights into the roles of testosterone in the aetiology, diagnosis, and management of endometriosis and associated symptoms, especially pain. A relatively short anogenital distance (AGD) is indicative of lower levels of testosterone during fetal development. A shorter AGD has recently been correlated with both a higher risk of developing endometriosis in adult life, and with known correlates of endometriosis including earlier onset of reproductive cycling, lower ovarian follicle number, lower postnatal testosterone, and premature ovarian insufficiency. During adult life, lower levels of testosterone are positively associated with key comorbidities of endometriosis, including days per month of pelvic pain and increased pain sensitivity. Biochemically, lower levels of testosterone are associated with higher levels of pro-inflammatory IL-1β and lower levels of β-endorphin. In rodents, prenatal administration of testosterone to females reduces their pain sensitivity in adulthood. The emerging convergent links of endometriosis with low prenatal and postnatal testosterone provide evidence of a centrally mediated effect beginning in early prenatal development, and persisting through adult life, with notable effects on pain sensitivity. They generate a novel conceptual framework for understanding, studying and treating this disorder, whereby endometriosis is mediated by a combination of high estrogen in endometrial tissue with low systemic and ovarian testosterone. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Dysmenorrhea is a common disorder that substantially disrupts the lives of young women. To determine whether there is evidence of activation of the innate immune system in dysmenorrhea and whether the degree of activation may be used as a biomarker for pain, we compared the responsiveness of peripheral blood mononuclear cells (PBMCs) to toll-like receptor (TLR) 2 or 4 stimulation. We also investigated whether this effect is modulated by the use of the oral contraceptive pill (OC). Patients and Methods: Fifty-six women aged 16– 35 years, with either severe or minimal dysmenorrhea, and use or non-use of the OC, were enrolled. PBMCs were collected on two occasions in a single menstrual cycle: the menstrual phase and the mid-follicular phase. PBMCs were exposed to lipopolysaccharide (LPS), a TLR4 agonist, and PAM3CSK4 (PAM), a TLR2 agonist, and the resulting interleukin-1beta (IL– 1β) output was determined. Statistical analysis compared the EC50 between groups as a measure of TLR responsiveness of PBMCs. Results: The key finding following LPS stimulation was a pain effect of dysmenorrhea (p=0.042) that was independent of use or non-use of OC, and independent of day of testing. Women with dysmenorrhea showed a large 2.15-fold (95% CI − 4.69, − 0.09) increase in IL– 1β release when compared with pain-free participants across both days. Conclusion: This is the first study to demonstrate an ex vivo immune relationship in women with dysmenorrhea-related pelvic pain. It provides evidence for the potential of immune modulation as a novel pharmacological target for future drug development in the management of dysmenorrhea. [ABSTRACT FROM AUTHOR]

Purpose: Dysmenorrhea is a common disorder that substantially disrupts the lives of young women. The frequency of 14 associated symptoms both within and outside the pelvis was determined. Patients and methods: Symptom questionnaires were completed by 168 women with dysmenorrhea, allocated to three groups based on their diagnostic status for endometriosis confirmed (Endo+), endometriosis excluded (Endo−), or endometriosis diagnosis unknown (No Lap). Those with endometriosis confirmed were further divided into current users (Endo+ Hx+) and non-users of hormonal treatments (Endo+ Hx–). Users of hormonal treatments were further divided into users (Endo+ Hx+ LIUCD+) and non-users (Endo+ Hx+ LIUCD–) of a levonorgestrel-releasing intra-uterine contraceptive device (LIUCD). The frequency and number of symptoms within groups and the effect of previous distressing sexual events were sought. Results: Women with and without endometriosis lesions had similar symptom profiles, with a mean of 8.5 symptoms per woman. Only 0.6% of women reported dysmenorrhea alone. The presence of stabbing pelvic pains was associated with more severe dysmenorrhea (P=0.006), more days per month of dysmenorrhea (P=0.003), more days per month of pelvic pain (P=0.016), and a diagnosis of migraine (P=0.054). The symptom profiles of the Endo+ Hx+ and Endo+ Hx– groups were similar. A history of distressing sexual events was associated with an increased number of pain symptoms (P=0.003). Conclusion: Additional symptoms are common in women with dysmenorrhea, and do not correlate with the presence or absence of endometriosis lesions. Our study supports the role of central sensitization in the pain of dysmenorrhea. The presence of stabbing pelvic pains was associated with increased severity of dysmenorrhea, days per month of dysmenorrhea, days per month of pelvic pain, and a diagnosis of migraine headache. A past history of distressing sexual events is associated with an increased number of pain symptoms. [ABSTRACT FROM AUTHOR]

The intriguing relationship between androgens, endometriosis and chronic pain continues to unfold. Determining this relationship is of crucial importance to gynecologists managing people with these conditions, as common treatments dramatically alter her hormonal profiles, with both intended and unintended consequences. Although they may be present in the same individual, there is a recognized disconnect between pain or pain-related symptoms, and the presence or extent of endometriosis lesions. Reduced androgen levels provide a potential mechanism to link the development of endometriosis lesions and the presence of chronic pain. This research paper expands the presentation of our research at the World Endometriosis Congress in 2021, subsequently published in the Journal of Pain Research which demonstrated a strong inverse relationship between androgen levels and days per month of pelvic and period pain. Here we extend and further explore the evidence for a role for androgens in the etiology and management of dysmenorrhea and pelvic pain in women, both with and without endometriosis. We explore the potential for inflammation to induce low androgen levels and consider ways in which clinicians can optimize levels of androgens when treating women with these conditions. This article prompts the question: Is it estrogens that predispose people to a life of pain, or androgens that are protective?, Competing Interests: SE receives royalties from book authorship, is a shareholder in Alyra Biotech Pty Ltd a company developing non-hormonal immune therapies for pelvic pain and Havah Therapeutics Pty Ltd a company developing testosterone therapies for women with breast cancer; and has patents pending: PCT/AU2018/051383 and PCT/AU2020/050551, Alyra Biotech Pty Ltd. PR 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. MRH 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, National Health and Medical Research Council, Meat and Livestock Australia, Air Force Office of Scientific Research, Defence Science Technology Group, and National Institutes of Health. His research program is supported by Novartis, Abbott, Pfizer and Regeneus, but these activities fall outside the submitted work. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Evans, Hull, Hutchinson and Rolan.)

Context: Despite extensive searches for novel noninvasive diagnostics, laparoscopy remains the reference test for endometriosis. Circulating miRNAs are purported endometriosis biomarkers; however, the miRNA species and their diagnostic accuracy differ between studies and have not been validated in independent cohorts., Objective: Identify endometriosis-specific plasma miRNAs and determine their diagnostic test accuracy., Setting: Two university-based, public hospitals and a private gynecology practice in Australia., Design and Participants: Four phases: (i) Explorative phase. Plasma miRNA menstrual cycle fluctuations were evaluated in women with endometriosis and asymptomatic controls (n = 16). (ii) Biomarker discovery. Endometriosis-specific plasma miRNAs were identified in (a) women with endometriosis and asymptomatic controls (n = 16) and (b) women with and without surgically defined endometriosis (n = 20). (iii) Biomarker selection. Plasma miRNAs with the best diagnostic potential for endometriosis were selected in a surgically defined selection cohort (n = 78). (iv) Biomarker validation. The diagnostic test accuracy of these miRNAs was calculated in an independent, surgically defined validation cohort (n = 119)., Results: Forty-nine miRNAs were differentially expressed in women with endometriosis. Nine maintained dysregulation in the selection cohort, but only three (miR-155, miR574-3p and miR139-3p) did so in the validation cohort. Combined, these three miRNAs demonstrated a sensitivity and specificity of 83% and 51%, respectively., Conclusion: Plasma miRNAs demonstrated modest sensitivity and specificity as diagnostic tests or triage tools for endometriosis. Other groups' findings were not replicated and accorded poorly with our results. Circulating miRNAs demonstrate diagnostic potential, but stringent, standardized methodological approaches are required for the development of a clinically applicable tool., (Copyright © 2019 Endocrine Society.)