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Purpose: We have previously shown that stress prior to induction worsens clinical presentation and inflammatory parameters in a rat model of endometriosis. This study was designed to examine whether stress during the development of endometriosis can affect the growth of endometriotic implants through nerve growth and immune alterations., Methods: Endometriosis was surgically induced in female Sprague-Dawley rats by suturing uterine horn implants onto the small intestine mesentery. Two weeks later, one group of rats (endo-stress) was subjected to a 10-day swim stress protocol. Controls had no stress (endo-no stress) or sutures only and stress (sham-stress). On day 60, all rats were killed and examined for the presence of endometriotic vesicles. The size of each vesicle was measured. The uterus and colon were removed and assessed for damage, cell infiltration, and expression of nerve growth factor (NGF), its receptors (p75 and Tropomyosin receptor kinase A (Trk-A)/pTrk-A), and calcitonin gene-related peptide, a sensory fiber marker. A differential analysis of peritoneal fluid white blood cell count was performed., Results: Stress significantly increased endometriotic vesicle size but not colonic damage and increased infiltration of mast cells. Significantly increased expression of NGF and its receptors was found in the uterus of animals with endometriosis receiving stress., Conclusions: Stress stimulates the development of ectopic endometrial vesicles in an animal model of endometriosis and increases inflammatory cell recruitment to the peritoneum. In addition, stress promotes nerve fiber growth in the uterus.

Studies have examined how endometriosis interacts with the nervous system, but little attention has been paid to opioidergic systems, which are relevant to pain signaling. We used the autotransplantation rat model of endometriosis and allowed to progress for 60 days. The brain was collected and examined for changes in endogenous opioid peptides, mu opioid receptors (MORs), and the N-methyl-d-aspartate subunit receptor (NR1) in the periaqueductal gray (PAG), since both of these receptors can regulate PAG activity. No changes in endogenous opioid peptides in met- and leu-enkephalin or β-endorphin levels were observed within the PAG. However, MOR immunoreactivity was significantly decreased in the ventral PAG in the endometriosis group. Endometriosis reduced by 20% the number of neuronal profiles expressing MOR and reduced by 40% the NR1 profiles. Our results suggest that endometriosis is associated with subtle variations in opioidergic and glutamatergic activity within the PAG, which may have implications for pain processing., (© The Author(s) 2016.)

We have previously shown detrimental effects of stress in an animal model of endometriosis. We now investigated whether the ability to control stress can affect disease parameters. Endometriosis was surgically induced in female Sprague-Dawley rats before exposing animals to a controllable (submerged platform) or uncontrollable (no platform) swim stress protocol. Corticosterone levels and fecal pellet numbers were measured as an indicator of stress. Uncontrollable stress increased the number and size of the endometriotic cysts. Rats receiving uncontrollable stress had higher anxiety than those exposed to controllable stress or no stress and higher corticosterone levels. Uncontrollable stressed rats had more colonic damage and uterine cell infiltration compared to no stress, while controllable stress rats showed less of an effect. Uncontrollable stress also increased both colonic and uterine motility. In summary, the level of stress controllability appears to modulate the behavior and pathophysiology of endometriosis and offers evidence for evaluating therapeutic interventions., (© The Author(s) 2014.)

Women with endometriosis have significant emotional distress; however, the contribution of stress to the pathophysiology of this disease is unclear. We used a rat model of endometriosis to examine the effects of stress on the development of this condition and its influence on inflammatory parameters. Female Sprague-Dawley rats were subjected to swim stress for 10 consecutive days prior to the surgical induction of endometriosis by suturing uterine horn implants next to the intestinal mesentery (endo-stress). Sham-stress animals had sutures only, and an endo-no stress group was not subjected to the stress protocol. At the time of sacrifice on day 60, endometriotic vesicles were measured and colons assessed for macroscopic and microscopic damage. Colonic tissue and peritoneal fluid were collected for inflammatory cell analysis. Endometriosis, regardless of stress, produced a decrease in central corticotropin-releasing factor immunoreactivity, specifically in the CA3 subregion of the hippocampus. Prior exposure to stress increased both the number and severity of vesicles found in animals with endometriosis. Stress also increased colonic inflammation, motility, myeloperoxidase levels, and numbers of mast cells. In summary, prior stress may contribute to the development and severity of endometriosis in this animal model through mechanisms involving cell recruitment (eg, mast cells), release of inflammatory mediators, and deregulation of hypothalamic-pituitary axis responses in the hippocampus.