How do you get endometriosis?

Short answer: no one really knows. Long answer: there are numerous theories as to why and when endometriosis develops although none of them have been proven conclusively. Some have big fancy names like retrograde menstruation (menstrual blood refluxing back into the body), metaplasia (residual embryonic cells that respond to hormones), or apoptosis suppression and alteration of endometrial cell fate. Or some go back to genetics, stem calls, immune dysfunction, or oxidative stress and inflammation. Endometriosis lesions can be found in embryos, thus highlighting that it can be laid down before birth. Studies do show there is a genetic component, with increased risks among those with relatives with endometriosis (for example in one study there was an 5.2 increased risk between sisters and 1.6 increased risk in cousins). The oldest theory of what causes endometriosis is that menstrual blood backflows into the pelvis and once there attaches and grows. However, this retrograde menstruation occurs in most individuals with a uterus, but only around 10% develop endometriosis. In addition, endometriotic lesions have distinct characteristics from that of regular endometrial tissue from the uterus.   

It matters how we get it, because some treatments are based on not only how endometriosis behaves and what relieves symptoms but also how it originates. While endometriosis’ origins continue to be an enigma, studies continue to highlight new information that can guide care in the future (see some studies below).

References

Crispi, S., Piccolo, M. T., D'avino, A., Donizetti, A., Viceconte, R., Spyrou, M., ... & Signorile, P. G. (2013). Transcriptional profiling of endometriosis tissues identifies genes related to organogenesis defects. Journal of cellular physiology, 228(9), 1927-1934. https://doi.org/10.1002/jcp.24358

Sourial, S., Tempest, N., & Hapangama, D. K. (2014). Theories on the pathogenesis of endometriosis. International journal of reproductive medicine, 2014. https://doi.org/10.1155/2014/179515

Rahmioglu et al. (2015. Genetics of Endometriosis. Woman’s Health. https://journals.sagepub.com/doi/pdf/10.2217/whe.15.41

 

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Theories on endometriosis from before birth:

●       Crispi, S., Piccolo, M. T., D'avino, A., Donizetti, A., Viceconte, R., Spyrou, M., ... & Signorile, P. G. (2013). Transcriptional profiling of endometriosis tissues identifies genes related to organogenesis defects. Journal of cellular physiology, 228(9), 1927-1934. https://doi.org/10.1002/jcp.24358

●       Laganà, A. S., Vitale, S. G., Salmeri, F. M., Triolo, O., Frangež, H. B., Vrtačnik-Bokal, E., ... & Sofo, V. (2017). Unus pro omnibus, omnes pro uno: a novel, evidence-based, unifying theory for the pathogenesis of endometriosis. Medical hypotheses, 103, 10-20. https://doi.org/10.1016/j.mehy.2017.03.032

●       Signorile, P. G., Baldi, F., Bussani, R., Viceconte, R., Bulzomi, P., D'Armiento, M., ... & Baldi, A. (2012). Embryologic origin of endometriosis: analysis of 101 human female fetuses. Journal of Cellular Physiology, 227(4), 1653-1656.  https://doi.org/10.1002/jcp.22888

●       Schuster, M., & Mackeen, D. A. (2015). Fetal endometriosis: a case report. Fertility and sterility, 103(1), 160-162. Retrieved from https://www.sciencedirect.com/science/article/abs/pii/S0015028214022274

 

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Genetics:

●       “… among sisters there was a 5.2-fold increase in the risk of being diagnosed with endometriosis”

European Society For Human Reproduction And Embryology. "Genetic Link To Endometriosis – Unique Icelandic Study Provides Further Proof." ScienceDaily. ScienceDaily, 5 March 2002. www.sciencedaily.com/releases/2002/02/020228073008.htm

●        “…primary difference was the finding that women who had relatives with endometriosis had more severe disease, defined as stages III to IV.”

Dun, E. C., Taylor, R. N., & Wieser, F. (2010). Advances in the genetics of endometriosis. Genome medicine, 2(10), 75. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988445/#!po=0.609756

●       “Endometriosis was found in 8/136 (5.9%) first-degree relatives of patients and in 4/134 (3.0%) first-degree relatives of controls in the real-case analysis”

Nouri, K., Ott, J., Krupitz, B., Huber, J. C., & Wenzl, R. (2010). Family incidence of endometriosis in first-, second-, and third-degree relatives: case-control study. Reproductive Biology and Endocrinology, 8(1), 85. https://pubmed.ncbi.nlm.nih.gov/20618992/

●       "...the study identified 19 genetic variants associated with endometriosis, and many of those variants are also associated with other serious health conditions such as ovarian cancer, cardiovascular disease and high cholesterol....In this case the study found several variants in genes involved in sex hormone metabolism, specifically the genes GREB1, FN1, KDR, CCDC170, ESR1, SYNE1, and FSHB." https://blog.23andme.com/23andme-research/endometriosis/

 

What is endometriosis?

             Technically speaking, endometriosis is “defined as the presence of endometrial glands and stroma like lesions outside of the uterus” (Parasar et al., 2017). This means that there is tissue similar to the lining of the uterus (“endometrial-like” thus “endometriosis”) present outside of the uterus. It is usually in the pelvic region but can be found throughout the body. This tissue that is outside of the uterus (endometriosis) is different in several ways from the tissue in the uterus in both how it is structured and how it behaves. This tissue outside of the uterus can cause pain, infertility, and organ dysfunction due to inflammation, invasion into other body areas, and scar tissue. The World Health Organization (2023) aptly states that endometriosis “is a chronic disease associated with severe, life-impacting pain during periods, sexual intercourse, bowel movements and/or urination, chronic pelvic pain, abdominal bloating, nausea, fatigue, and sometimes depression, anxiety, and infertility.” Endometriosis impacts approximately 1 in 10 individuals assigned female at birth and even has been found, although rarely, in individuals assigned male at birth. Symptoms are often dismissed as “bad cramps” leading to an average 10-year delay in diagnosis.

References

Parasar, P., Ozcan, P., & Terry, K. L. (2017). Endometriosis: epidemiology, diagnosis and clinical management. Current obstetrics and gynecology reports, 6(1), 34-41. https://link.springer.com/article/10.1007/s13669-017-0187-1

World Health Orgainzaiton. (2023). Endometriosis. https://www.who.int/news-room/fact-sheets/detail/endometriosis

 

Imbalanced sex hormones can affect fascia and pain

Follow up on a prior post of how hormones affect the whole body and that long term estrogen suppression may affect the whole body in many ways:

"Estrogens have long been known as a regulating factor of metabolism in tissues such as bone, muscle, cartilage, tendon and ligament, affecting the musculoskeletal functions [1]. The estrogen-beta receptor has also been described recently in the tissue of tendons and ligaments [2], and only in one of our recent works [3] the expression of sex hormone receptors was also demonstrated in the muscular fasciae....

...Lee and Park [12] described how musculoskeletal pain characteristics are caused by the severity of menstrual pain. Lee and Petrofsky [13] demonstrated that changes in plantar fascia elasticity during the menstrual cycle may involve sexual hormones in the increasing elasticity of human connective tissue.

Various trails have shown that women treated with aromatase inhibitors, which stop the production of estrogen in post-menopausal women, often experience joint pain and musculoskeletal aching. These manifestations may be reduced after cessation of therapy, and one explanation for these findings is that a rapid drop in estrogen levels enhances nociception [14]....

It is possible that women with hormonal dysfunctions may present a dysregulation of extracellular matrix production, causing stiffness, fibrosis and inflammation which create sensitization of fascial nociceptors [38,39]. This may explain why oral administration of estrogen (the dose of β-estradiol via oral administration is usually 50 pg/mL) may resolve myofascial pain in women."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6762168/

What happens with low estrogen states?

      An often used treatment for endometriosis is to lower the estrogen in a woman's body via hormonal suppression. Birth control can mimic a pregnancy state, while other treatments, such as gonadotrophin-releasing hormone agonists (GnRHa), can mimic a menopausal state. So what does estrogen do in the body and why do they want to lower it?

Estrogen not only affects the reproductive organs, but it also affects the heart and blood vessels, bones, breasts, skin, hair, mucous membranes, pelvic muscles, the urinary tract, and the brain (University of Rochester Medical Center Rochester, n.d.). All these different tissues have estrogen receptors (ER) on them that, when activated by estrogen, tell the cell how to behave. Endometriosis also has estrogen receptors. Estrogen, via these receptors (particularly ERα), cause an increase in endometriotic “lesion size, fluid volume, increased epithelial cell height, and epithelial cell proliferation” (Burns et al., 2012). The thought is that by decreasing estrogen, the endometriotic lesions can be “tamed”, so to speak. However, estrogen still has receptors in all those other tissues and has an important role in the functioning of those other areas.

             According to Medical New Today (De Pietro, 2018), low estrogenic states can have the following effects:

• Weak bones: Estrogen helps keep the bones healthful and strong. As estrogen levels decrease, bone loss may occur. For example, women who are post-menopausal are at an increased risk of developing osteoporosis and bone fractures.
• Painful intercourse: Estrogen can affect vaginal lubrication. If levels become too low, vaginal dryness can occur, which often leads to painful sex.
• Hot flashes: Hot flashes often happen during menopause due to low estrogen levels.
• Depression: Estrogen is thought to increase serotonin, which is a chemical in the brain that boosts mood. Estrogen deficiency may cause a decline in serotonin that contributes to mood swings or depression.
• Increase in urinary tract infections: Increased urinary tract infections may occur due to the thinning of the tissue in the urethra, which can develop with decreased estrogen.

The low estrogenic states induced by the medications can cause side-effects similar to menopause: “hot flashes/sweats, headache/migraine, decreased libido (interest in sex), depression/emotional lability (changes in mood), dizziness, nausea/vomiting, pain, vaginitis, and weight gain” (LupronDepot, n.d.). When estrogen is lowered to a chemically induced menopausal state for a long time, it can cause serious effects. “Regardless of the cause,…women who experience premature menopause (before age 40 years) or early menopause (between ages 40 and 45 years) experience an increased risk of overall mortality, cardiovascular diseases, neurological diseases, psychiatric diseases, osteoporosis, and other sequelae” (Shuster et al., 2010). The effect on bone health is why GnRHa medications are recommended as treatment for no longer than 12 months total therapy (two 6-month treatments)- “due to concerns about adverse impact on bone thinning” (LupronDepot, n.d.). This thinning of the bones “may not be completely reversible in some patients” (LupronDepot, n.d.). This should be considered when looking at long term options.

When looking at effectiveness of treatment with hormonal medications, then you might consider:

“Combined oral contraceptive pills (COCP), GnRHa and progestogens are equally effective in relieving endometriosis associated pelvic pain. COCP and progestogens are relatively cheap and more suitable for long-term use as compared to GnRHa. Long-term RCT of medicated contraceptive devices like Mirena and Implanon are required to evaluate their long-term effects on relieving the endometriosis associated pelvic pain.” (Wong & Lim, 2011)

           

References

Burns, K. A., Rodriguez, K. F., Hewitt, S. C., Janardhan, K. S., Young, S. L., & Korach, K. S. (2012). Role of estrogen receptor signaling required for endometriosis-like lesion establishment in a mouse model. Endocrinology, 153(8), 3960-3971. doi: 10.1210/en.2012-1294

De Pietro, M. (2018). What happens when estrogen levels are low?. Retrieved from https://www.medicalnewstoday.com/articles/321064.php#diagnosis

LupronDepot. (n.d.). Lupron Depot for endometriosis. Retrieved from https://www.luprongyn.com/lupron-for-endometriosis

Shuster, L. T., Rhodes, D. J., Gostout, B. S., Grossardt, B. R., & Rocca, W. A. (2010). Premature menopause or early menopause: long-term health consequences. Maturitas, 65(2), 161-166. doi: 10.1016/j.maturitas.2009.08.003

University of Rochester Medical Center Rochester. (n.d.). Estrogen's effects on the female body. Retrieved from https://www.urmc.rochester.edu/encyclopedia/content.aspx?ContentTypeID=85&ContentID=P00559

Wong, W. S. F., & Lim, C. E. D. (2011). Hormonal treatment for endometriosis associated pelvic pain. Iranian journal of reproductive medicine, 9(3), 163. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575749/

Vitamin B12 injections and pain

Vitamin B12 in low back pain: a randomised, double-blind, placebo-controlled study.

Randomized controlled trial

Mauro GL, et al. Eur Rev Med Pharmacol Sci. 2000 May-Jun.

Show full citation

Abstract

OBJECTIVES: The objective of this double-blind randomised, placebo-controlled study was to examine the efficacy and safety intramuscular vitamin B12 (Tricortin 1000) in the treatment of low back pain in patients with mechanical or irritative lumbago.

METHODS: 60 patients aged between 18 and 65 years with lumbago or sciatic neuritis of mechanical origin without need for surgical procedures were enrolled. Patients had to present with a proven medical history for back pain (lasting from 6 months to 5 years) and a pain intensity [as evaluated with a Visual Analogic Scale (VAS)] equal or greater than 60 mm. Efficacy primary end-point was evaluated by means of a visual analogic scale (VAS) and a Disability Questionnaire (DQ). Consumption of paracetamol during the study period was the secondary efficacy end-point.

RESULTS: Both treatment groups experienced a sharp decrease in pain and disability. However, comparison between groups at the end of the treatment period showed a statistically significant difference in favour of the active treatment both for VAS and DQ (p < 0.0001 and p < 0.0002, respectively). Consumption of paracetamol proved significantly higher in the placebo group than in the active treatment (p < 0.0001).

CONCLUSIONS: The efficacy and safety of parenteral Vitamin B12 in alleviating low back pain and related disability and in decreasing the consumption of paracetamol was confirmed in patients with no signs of nutritional deficiency.

PMID

 11558625 [Indexed for MEDLINE] https://www.ncbi.nlm.nih.gov/m/pubmed/11558625/ 

"MeCbl or its combined use with other agents has the potential analgesic effect in specific patients and animal models, for example, nonspecific low back pain; neck pain; diabetic neuropathic pain, subacute herpetic neuralgia, glossopharyngeal neuralgia, and trigeminal neuralgia. However, its mechanisms underlying the analgesic effect were poorly understood. On the basis of recent work, the possible mechanisms can be considered as follows. (1) MeCbl improved nerve conduction velocity; (2) MeCbl promoted injured nerve regeneration, recovering the neuromuscular functions in peripheral hyperalgesia and allodynia; and (3) MeCbl inhibited the ectopic spontaneous discharges from peripheral primary sensory neurons in neuropathic pain states. As a vitamin, MeCbl may be a potential candidate for treating peripheral neuropathy with good safety." https://www.hindawi.com/journals/np/2013/424651/ 

Local Injection of Methylcobalamin Combined with Lidocaine for Acute Herpetic Neuralgia 

Gang Xǔ, MD, Site Xu, BSc, Wei-Zhen Tang, BSc,Gang Xú, BSc, Chao Cheng, BSc, Jie Xu, BSc

Pain Medicine, Volume 17, Issue 3, March 2016, Pages 572–581,https://doi.org/10.1093/pm/pnv005

Published:

 

11 November 2015

Article history

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Abstract

Objective. To determine the efficacy of methylcobalamin combined with lidocaine for acute herpetic neuralgia.

Design. Randomized controlled trial with longitudinal analysis.

Subjects. The authors recruited 204 patients (>50 years) with T5-10 dermatomal acute herpetic neuralgia with rash onset within 7 days. Patients were divided into two groups based on the time of onset: immediate-early (IE, 1–3 days) and early stage (ES, 4–7 days) groups and then subdivided randomly into control (IE-Ctl, ES-Ctl) and treatment (IE-Tr, ES-Tr) groups.

Methods. Control groups received intramuscular methylcobalamin in addition to local lidocaine injection, while treatment groups received local methylcobalamin combined with lidocaine injection for 14 days. Treatment efficacy was assessed based on rash healing time, alteration in pain intensity, and interference with quality of life. Multilevel mixed modeling and survival analysis were employed to examine treatment responses.

Results. There was no significant difference in the rash healing time between IE and ES. The mean pain scores in IE-Tr (2.4 ± 0.7) and ES-Tr (1.3 ± 0.7) decreased significantly compared with those in the control groups. The median satisfactory response time was 6 days in ES-Tr and 11 days in IE-Tr. The benefit ratio for ES-Tr versus IE-Tr was 14.94. The subjects in IE-Tr and ES-Tr had higher quality of life scores (81.2 ± 6.9 vs 88.3 ± 8.6, respectively) than those in the control groups. The incidence of postherpetic neuralgia was 1.1% at 3 months.

Conclusions. Local methylcobalamin combined with lidocaine, optimally administered within 4–7 days of onset, may be an effective therapeutic option for acute herpetic neuralgia. https://academic.oup.com/painmedicine/article/17/3/572/1888790 

More genes related to endometriosis

"...the study identified 19 genetic variants associated with endometriosis, and many of those variants are also associated with other serious health conditions such as ovarian cancer, cardiovascular disease and high cholesterol....In this case the study found several variants in genes involved in sex hormone metabolism, specifically the genes GREB1, FN1, KDR, CCDC170, ESR1, SYNE1, and FSHB." https://blog.23andme.com/23andme-research/endometriosis/ 

Symptoms translates to less productivity

"Women who experienced 3 endometriosis symptoms concurrently lost a significantly greater number of employment hours because of absenteeism and presenteeism compared with those experiencing 1 or 2 symptoms (P < 0.001). Regression analyses showed that a range of endometriosis symptoms predicted employment and household losses because of presenteeism and absenteeism." 
http://www.jmcp.org/doi/10.18553/jmcp.2017.23.7.745