Every now and again, I stumble upon research that I believe will absolutely shift a paradigm in a particular field. That happened this morning. Sprouted Innervation into Uterine Transplants Contributes to the Development of Hyperalgesia in a Rat Model of Endometriosis, published in PLOS One earlier this year, is groundbreaking. Results from this study suggest that endometriosis is a neuropathic pain disorder or in layman’s terms, a nerve disease. This finding will open entirely new directions for the diagnosis and treatment of endometriosis, if it is heeded.
A Rodent Model of Endometriosis
Researchers from Florida State University, transplanted small pieces of uterine or fat tissue next to the abdominal arteries of female rodents. The uterine tissue became vascularized and formed cysts, the fat did not. More importantly, the transplanted uterine tissue sprouted nerve connections (innervation), which led to vaginal hyperalgesia or increased sensitivity to pain. Over time, as the density of nerve fibers increased, researchers speculate that signals to central nervous system become hyperactive or sensitized to pain.
Interestingly, the density of nerve fiber innervation was not regulated by the size of the cyst, some large cysts located near the ovaries or peritoneum didn’t innervate at all or only minimally. Rather, nerve innervation developed according to the cyst’s proximity to densely innervated anatomical areas such as the rectovaginal septum and the uterosacral ligaments. This may explain why pain does not always correlate with the size of cysts or stage of endometrial disease. It appears that it is the degree innervation that determines the level pain.
Squelching the Pain of Endometriosis Before It Begins
If the innervation is associated with endometrial pain, it is possible that curtailing the nerve growth could eliminate, even prevent the pain, but only if this disease process is identified early enough.
In the rat model, innervation developed in phases. Within the first two weeks of the tissue implant, a cyst developed and initial sensory and sympathetic nerves sprouted. Over the next weeks, the nerve sprouts became functional and neurogenic inflammation developed. Finally, over weeks four and five, the cysts became wholly populated by functional sympathetic and sensory nerve fibers. Pain ensued. Researchers found that removing the cysts before they reached the functional stage prevented the development of neuropathic pain- the vaginal hyperalgesia.
Although it is not clear what the time course of cyst innervation would be in human women -for rats the entire estrous cycle is 4-5 days, significantly shorter than the female menstrual cycle- it is clear that efforts should be made to identify and diagnose endometriosis significantly sooner than is currently the average.
That would require investigating the causes of dysmenorrhea and not automatically attributing the pain with menstruation to normal premenstrual or menstrual cramping, as is so often the case. Currently, the average time to diagnose endometriosis is nine years. Research suggests that 90% of adolescent girls have dysmenorrhea and 25-38% of adolescent girls with chronic pelvic pain have endometriosis.
If cyst development stages could be identified in women and if endometriosis diagnosed earlier, then removing or treating cysts before fully innervated could prevent a lifetime of what we now know to be neuropathic pain.
Endometriosis, Hormones, Nerves and Neurons
Better yet, let’s determine what is causing the extra-uterine tissue growth and subsequent innervation in the first place. Though many are loathe to admit it, hormones are likely involved. In many regions of the brain hormones elicit and modulate neurogenesis. Research also demonstrates a role for hormones in spinal and peripheral nerve functioning. As results from this study suggest, hormones may also influence somatosensory nerve growth in the uterine and extra-uterine endometrial tissue. Understanding the role of hormones in the innervation of endometrial tissue could open up entirely new therapeutic options.