Fatigue in Endometriosis

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Fatigue is a symptom of endometriosis and can be quite debilitating (Ramin-Wright et al., 2018). Taber’s Medical Dictionary (n.d.) defines fatigue as “an overwhelming sustained feeling of exhaustion and diminished capacity for physical and mental work.” Fatigue with an illness often does not improve with rest (Louati & Berenbaum, 2015). Endometriosis is an inflammatory disorder, and this inflammation can lead to fatigue. Inflammatory molecules, such as prostaglandins, cytokines, etc., contribute to fatigue as well as problems with “sleep, cognition, anxiety, and depression” (Poon et al., 2015; Zielinski, Systrom, & Rose, 2019). Chronic low-grade inflammation can cause a reduction in energy on the cellular level (Lacourt et al., 2018). Inflammation can lead to pain, sleep problems, stress, and depression….which can lead to more inflammation. In addition, hormones, “mainly estradiol,” can “promote the expression and release of pro-inflammatory factors” (García-Gómez et al., 2020). Endometriosis lesions have shown higher estrogen receptors as well as progesterone resistance (see Role of Estrogen Receptor in Endometriosis). Pain can lead to sleep problems, and sleep disorders can also cause more inflammation, leading to more pain and fatigue (Lacourt et al., 2018; Zielinski, Systrom, & Rose, 2019). On a good note: “melatonin therapy has been shown to attenuate inflammatory cytokines…thus could potentially be beneficial in combating fatigue” (Zielinski, Systrom, & Rose, 2019). Stress, even good stress, can take a toll on your body and mind. Chronic stress can lead to more inflammation which can contribute to feelings of fatigue (Zielinski, Systrom, & Rose, 2019). Inflammation can affect neurotransmitters which can affect both fatigue and mood (Zielinski, Systrom, & Rose, 2019).  Lee & Giuliani (2019) report that “depression and fatigue are associated with an increased activation of the immune system which may serve as a valid target for treatment.” They also note that “antidepressants have been shown to decrease inflammation” (Lee & Giuliani, 2019). So we see that many things can contribute to fatigue. Fatigue is difficult to treat, especially if the underlying cause is not addressed. Ramin-Wright et al. (2018) states that “as fatigue is experienced by numerous women with endometriosis, it needs to be addressed in the discussion of management and treatment of the disease. In addition to treating endometriosis, it would be beneficial to reduce insomnia, depression, pain and occupational stress in order to better manage fatigue.” It is also important to remember that fatigue is a symptom of many disorders, so do not automatically assume that endometriosis is the only cause of your fatigue- it’s important to rule out other causes too. Links: Prevalence: “…it has been shown that fatigue is one of the most intense and frequent symptoms (Hansen et al., 2013Touboul et al., 2013) as well as the symptom with highest associated distress (Lemaire, 2004). The prevalence of fatigue is significantly higher in patients with endometriosis compared to the general female population (Sinaii et al., 2002). Conversely, women with chronic fatigue syndrome often report endometriosis in their gynecological history (Boneva et al., 2011). In addition, patients with endometriosis suffer more often from stress (Hansen et al., 2013; van Aken et al., 2018). The impact of fatigue is vast as women’s educational performance is affected as well as playing sports and social activities (Gilmour et al., 2008Moradi et al., 2014). Although chronic fatigue is mentioned as one of the most debilitating symptoms of endometriosis, it is not widely known and discussed as such (Riazi et al., 2015)…. “In our study, the prevalence of frequent fatigue is more than doubled in women diagnosed with endometriosis compared to unaffected control women. Fatigue was associated with endometriosis, pain, insomnia, depression, and occupational stress. The association between endometriosis and frequent fatigue remained significant after controlling for the confounding effects of pain, insomnia, occupational stress, depression, BMI and motherhood. This finding supports an independent effect of endometriosis which cannot be attributed to disease symptoms. Our results show that endometriosis-related fatigue is a frequent symptom which should be addressed in medical care. While the current treatment and management of the disease focuses more on classic symptoms such as pain and infertility (Bernardi and Pavone, 2013Dunselman et al., 2014Vercellini et al., 2014), it is important to also address fatigue when treating patients with endometriosis.”
  • Boneva, R. S., Lin, J. M. S., Wieser, F., Nater, U. M., Ditzen, B., Taylor, R. N., & Unger, E. R. (2019). Endometriosis as a Comorbid Condition in Chronic Fatigue Syndrome (CFS): Secondary Analysis of Data From a CFS Case-Control Study. Frontiers in pediatrics7, 195. Retrieved from https://pubmed.ncbi.nlm.nih.gov/31179251/ 
“We found more than a third of women with CFS reported endometriosis as a comorbid condition. The endometriosis comorbidity was associated with chronic pelvic pain, earlier menopause, hysterectomy, and more CFS-related symptoms. However, endometriosis in women with CFS did not appear to further impact functioning, fatigue, inflammatory markers, or other laboratory parameters.” Inflammation as a contributing factor:
  • Louati, K., & Berenbaum, F. (2015). Fatigue in chronic inflammation-a link to pain pathways. Arthritis research & therapy17(1), 1-10. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593220/
“Fatigue is a frequent symptom in several inflammatory diseases, particularly in rheumatic diseases. Elements of disease activity and cognitive and behavior aspects have been reported as causes of fatigue in patients with rheumatoid arthritis. Fatigue could be associated with activity of inflammatory rheumatism. Indeed, biologic agents targeting inflammatory cytokines are effective in fatigue. Fatigue is also associated with pain and depressive symptoms. Different pathways could be involved in fatigue and interact: the immune system with increased levels of pro-inflammatory cytokines (interleukin-1 and −6 and tumor necrosis factor alpha), dysregulation of the hypothalamic-pituitary-adrenal axis and neurological phenomena involving the central and autonomic nervous systems. A pro-inflammatory process could be involved in pain and behavioral symptoms. Inflammation could be a common link between fatigue, pain, and depression.” “Chronic pain and fatigue often occur together — as many as three in four people with chronic, widespread musculoskeletal pain report having fatigue; and as many as 94 percent of people with chronic fatigue syndromes report muscle pain. Women make up the majority of patients with these conditions…”The differences in fatigue between males and females depends on both the presence of testosterone and the activation of ASIC3 channels, which suggests that they are interacting somehow to protect against fatigue,” Sluka said. “These differences may help explain some of the underlying differences we see in chronic pain conditions that include fatigue with respect to the predominance of women over men.”  Estrogen can potentiate the action of ASICs
  • Qu, Z. W., Liu, T. T., Ren, C., Gan, X., Qiu, C. Y., Ren, P., … & Hu, W. P. (2015). 17β-Estradiol enhances ASIC activity in primary sensory neurons to produce sex difference in acidosis-induced nociception. Endocrinology156(12), 4660-4671. Retrieved from https://pubmed.ncbi.nlm.nih.gov/26441237/ 
“E2 potentiated ASIC currents via an ERα and ERK1/2 signaling pathway. E2 also altered acidosis-evoked membrane excitability of dorsal root ganglia neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acidic stimuli. E2 potentiation of the functional activity of ASICs revealed a peripheral mechanism underlying this sex difference in acetic acid-induced nociception.”   Treatment: This study, while older, measured quality of life (which included fatigue) before and after treatment with laparoscopic excision.  “Patients with endometriosis were severely ill with significant pain and impairment of quality of life and sexual activity. Four months after radical laparoscopic excision for deep endometriosis there was significant improvement in all the parameters measured including their quality of life based on EuroQOL evaluation: EQ-SD (0.595:0.729, P = 0.002) and EQ thermometer (68.9:77-7, P = 0.008); SF12 physical score (44.8:51.9, P = 0.015); sexual activity (habit P = 0.002, pleasure P = 0-002 and discomfort P IO.001).”


García-Gómez, E., Vázquez-Martínez, E. R., Reyes-Mayoral, C., Cruz-Orozco, O. P., Camacho-Arroyo, I., & Cerbón, M. (2020). Regulation of inflammation pathways and inflammasome by sex steroid hormones in endometriosis. Frontiers in endocrinology10, 935. Retrieved from https://doi.org/10.3389/fendo.2019.00935 Lacourt, T. E., Vichaya, E. G., Chiu, G. S., Dantzer, R., & Heijnen, C. J. (2018). The high costs of low-grade inflammation: persistent fatigue as a consequence of reduced cellular-energy availability and non-adaptive energy expenditure. Frontiers in behavioral neuroscience12, 78. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932180/#:~:text=We%20propose%20that%20chronic%20low,rapid%20generation%20of%20cellular%20energy. Lee, C. H., & Giuliani, F. (2019). The role of inflammation in depression and fatigue. Frontiers in immunology10, 1696. Retrieved from https://doi.org/10.3389/fimmu.2019.01696 Louati, K., & Berenbaum, F. (2015). Fatigue in chronic inflammation-a link to pain pathways. Arthritis research & therapy17(1), 1-10. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593220/ Poon, D. C. H., Ho, Y. S., Chiu, K., Wong, H. L., & Chang, R. C. C. (2015). Sickness: From the focus on cytokines, prostaglandins, and complement factors to the perspectives of neurons. Neuroscience & biobehavioral reviews57, 30-45. Retrieved from https://www.sciencedirect.com/science/article/abs/pii/S0149763415002006 Ramin-Wright, A., Schwartz, A. S. K., Geraedts, K., Rauchfuss, M., Wölfler, M. M., Haeberlin, F., … & Leeners, B. (2018). Fatigue–a symptom in endometriosis. Human reproduction33(8), 1459-1465. Retrieved from https://academic.oup.com/humrep/article/33/8/1459/5040620?login=true Taber’s Medical Dictionary. (n.d.). Fatigue. Retrieved from https://www.tabers.com/tabersonline/view/Tabers-Dictionary/757231/all/fatigue Zielinski, M. R., Systrom, D. M., & Rose, N. R. (2019). Fatigue, sleep, and autoimmune and related disorders. Frontiers in immunology10, 1827. Retrieved from https://doi.org/10.3389/fimmu.2019.01827