Pelvic pain is more than period pain (dysmenorrhea)
One in 5 women suffer severe period pain (dysmenorrhoea), often from their early teens. Many (but not all) of these women also have a condition called Endometriosis.
Dysmenorrhoea itself means pain with periods. It is usually caused by the release of prostaglandin chemicals in the uterus that make the muscle of the uterine wall contract strongly. However, the bigger picture of period pain involves more than the uterus.
In some women with dysmenorrhoea pain becomes more complicated over time, and a range of additional symptoms may develop (Table 1). These symptoms may become persistent and present on more days per month. The full article describing the symptoms often found in women with dysmenorrhoea is available at the following link: jpr-179409-the-co-morbidities-of-dysmenorrhea-a-clinical-survey-compar-111418
For women with pre-existing severe period pain, the insertion of an intrauterine device may go smoothly, or may be associated with an increase in their pain, especially in the first few months after insertion. While this pain often settles over a few months, for some women it does not settle.
Alyra Biotech’s goal is to develop products that prevent the transition from severe period pain to chronic pelvic pain.
Toll-Like Receptor 4, Menstruation and Pain Symptoms in Women
Alyra Biotech has already completed pre-clinical, cell receptor, human blood and end-user research. The next logical step is to demonstrate that modulation of the immune system within the uterus can reduce pain in women. In 2024, Alyra Biotech successfully completed a first-in-human trial of our lead device. This cohort will expand with a further 90 participants in 2025.
Pain conditions of the bladder and bowel are common. Irritable Bowel Syndrome affects between 7% and 21% of Americans with 2 in 3 of those affected being female, while 0.3% suffer the more severe Inflammatory Bowel Disorders. Bladder Pain Syndrome, also called Interstitial Cystitis affects between 3 and 8 million American women with 5 in 6 of those affected being female. These disorders are associated with increased immune activation and central sensitization. Although this cannot be tested in humans, it is anticipated that they also include activation of the glial cells within the dorsal horn of the spinal cord
As with other pain conditions, current treatments are available. However, adverse effects and the need to take these medications daily make them unappealing to young women.
Following preclinical research demonstrating that activation of the immune system in the uterus results in excessive activation of spinal glial cells within the dorsal horn of the spinal cord (a condition seen in chronic pain), Alyra Biotech began development of intrauterine devices that will turn down this activation and thus reduced chronic pain. It is anticipated that these devices will also improve symptoms of an irritable bowel or painful bladder as the nerve supply to all three organs converges on the same segments of the spinal cord: Jobling P. Female Reproductive Tract Pain- targets challenges and outcomes
Our products use intrauterine administration of immune inhibitors to treat bladder and bowel symptoms by reducing spinal glial activation within the dorsal horn.
Medical conditions of the central nervous system that are more common in women
Women are over-represented in populations with conditions of the central nervous system associated with inflammation and activation of the innate immune system. These conditions may present in 3 ways:
- Certain medical conditions affecting the central nervous system are present in both men and women, but are known to be more frequent in females. For example, migraine headache occurs three times as commonly in women than men, affecting approximately 18% of women compared with 6% of men in the United States.
- Certain medical conditions occur only in the luteal phase of the menstrual cycle. For example, Premenstrual Syndrome (PMS) and Premenstrual dysphoric disorder (PMDD) describe a variety of affective, behavioural and somatic symptoms that occur in the luteal phase of the menstrual cycle during a woman’s reproductive years.
- Certain medical conditions may be present throughout the menstrual cycle, but be exacerbated in the days prior to a menstrual period. For example, established psychiatric diagnoses including persistent depressive disorder, major depressive disorder, bipolar disorder and anxiety disorders may be exacerbated premenstrually in a proportion of women.
Where there is an inflammatory component to the medical condition, with activation of circulating immune cells and associated cytokine release, a reduction in immune activation holds promise for effective management.
Our Lead Device
Although women using a levonorgestrel-releasing intrauterine device have reduced menstrual blood flow, a proportion of women using these devices report increased pain following insertion of their intrauterine device. Overall, between 4 and 14% of women request premature removal of the device, mostly due to pain. Even where the device is well tolerated, and menstrual pain is reduced, additional pain symptoms and pain-associated symptoms may persist. This is because these symptoms are associated with excess glial activation in the glial cells of the spinal cord. Our novel, non-opioid, products add an immune inhibitor to an intrauterine device to reduce this effect.
Patient Resources
The Pelvic Pain Foundation of Australia http://www.pelvicpain.org.au
References
- Bush D, Evans S, Vancaillie T. “The 6 Billion Woman and the $600Million Girl: The Pelvic Pain Report,” 2011. http://www.fpm.anzca.edu.au/Pelvic_Pain_Report_RFS.pdf
- K N Dodds, E A H Beckett, S F Evans, P M Grace, L R Watkins, and M R Hutchinson. “Glial Contributions to Visceral Pain: Implications for Disease Etiology and the Female Predominance of Persistent Pain.” Translational Psychiatry 6, no. 9 (September 13, 2016): e888. https://doi.org/10.1038/tp.2016.168
- Evans, Jemma, and Lois A. Salamonsen. “Inflammation, Leukocytes and Menstruation.” Reviews in Endocrine & Metabolic Disorders 13, no. 4 (December 2012): 277–88. https://doi.org/10.1007/s11154-012-9223-7.
- Evans Sf, Brooks TA, Esterman Aj, Hull Ml, and Rolan Pe. “The Comorbidities of Dysmenorrhea: A Clinical Survey Comparing Symptom Profile in Women with and without Endometriosis.” Journal of Pain Research, 2018, 3181–3194. https://doaj.org/article/d9e23b1430ff4d9386b56d3d2a2f6296.
- Jobling, Phillip, Kate O’Hara, and Susan Hua. “Female Reproductive Tract Pain: Targets, Challenges, and Outcomes.” Frontiers in Pharmacology 5 (2014). https://doi.org/10.3389/fphar.2014.00017.
- Hardi, Gemma, Susan Evans, and Meredith Craigie. “A Possible Link between Dysmenorrhoea and the Development of Chronic Pelvic Pain.” The Australian & New Zealand Journal of Obstetrics & Gynaecology 54, no. 6 (December 2014): 593–96. https://doi.org/10.1111/ajo.12274.
- Khan, K. N., M. Kitajima, K. Hiraki, A. Fujishita, T. Ishimaru, and H. Masuzaki. “Escherichia Coli in Menstrual Blood: An Association with Bacterial Endotoxin and Toll-like Receptor 4 (TLR4)-Mediated Growth of Endometriosis.” Journal of Reproductive Immunology 71, no. 2 (2006): 152–153. https://doi.org/10.1016/j.jri.2006.08.030.
- Khan, Khaleque Newaz, Akira Fujishita, Michio Kitajima, Koichi Hiraki, Masahiro Nakashima, and Hideaki Masuzaki. “Intra-Uterine Microbial Colonization and Occurrence of Endometritis in Women with Endometriosis †.” Human Reproduction 29, no. 11 (2014): 2446–2456. https://doi.org/10.1093/humrep/deu222.
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