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.

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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

Musings on mullerian

This is purely my conjecture based on my readings. The literature refers to peritoneal endometriosis,  ovarian endometriosis,  and deep infiltrating endometriosis. Current theory points to defects when our pelvic organs are developed (Mullerianosis) that leave stem cells in the wrong place. This might also explain why other mullerian disorders such as adenomyosis are frequently seen in endometriosis patients as well.  These stem cells are acted upon by hormones (puberty) to develop as glands and stroma and begin the process of making nerves and blood vessels to support itself - as any good stem cell should. However that tissue should not be in those wrong sites and an inflammatory response happens.  Factors from the environment (food, physical activity,  stress,  etc) play a role in presentation of illness. This is why diet etc might affect symptoms but will not rid the person of the lesions. The different locations of stem cells left behind might influence how they are acted upon by hormones and affect their presentation and the ability to extract them all (trying to spare the ovarian tissue for fertility). https://www.hindawi.com/journals/ogi/2013/527041/abs/

The literature also refers to different stages of the lesions based on color - clear,  white,  tan,  red,  black. The different stage can produce different effects on the amount of pain and inflammation it causes.

Symptoms of endometriosis review

Author(s) [Ref.]	Year	Results for symptoms	Results for signs
Valle [14]	2002	Pelvic pain that often is worse just before and during menstruation, hypermenorrhea, premenstrual staining, dyspareunia, suprapubic pain, dysuria, hematuria, painful defecation (dyschezia), lower back pain.	Local tenderness in cul de sac or uterosacral ligaments, adnexal enlargement or tenderness, pelvic masses.
Spaczynski and Duleba. [15]	2003	Chronic pelvic pain consists of dysmenorrhea, intermenstrual pain, and dyspareunia.	Bluish implants typical of endometriosis or red, hypertrophic lesions bleeding on contact, usually in the posterior fornix. lateral cervical displacement, cervical stenosis. Retroversion, decreased or absent mobility of uterus and tenderness. Tender masses, nodules, and fibrosis appreciated on palpation of the upper vagina, cul-de-sac, uterosacral ligaments, or rectovaginal septum.
Kennedy et al. [16]	2005	Severe dysmenorrhea, deep dyspareunia, chronic pelvic pain, ovulation pain, cyclical or perimenstrual symptoms (e.g. bowel or bladder associated) with or without abnormal bleeding, infertility and chronic fatigue.	Pelvic tenderness, a fixed retroverted uterus, tender uterosacral ligaments or enlarged ovaries on examination. The diagnosis is more certain if deeply infiltrating nodules are found on the uterosacral ligaments or in the pouch of Douglas, and/or visible lesions are seen in the vagina or on the cervix. The findings may, however, be normal.
Mounsey et al. [17]	2006	Pelvic pain, back pain, dyspareunia, dysmenorrhea loin pain, dyschezia, pain with micturition and infertility.	Tender nodules in the posterior vaginal fornix, uterine motion tenderness, a fixed and retroverted uterus, or tender adnexal masses.
Denny and Mann. [18]	2007	Pain around menstruation, dyspareunia, dyschezia, cyclical dysuria and extreme fatigue.	Not discussed.
Amer [19]	2008	Dysmenorrhoea, dyschezia, hematochezia, dysurea, haematurea, dyspareunia, chronic pelvic pain, heavy and/or irregular periods, premenstrual spotting, infertility.	Tenderness on cervical movement, thickening and tenderness of the uterosacral ligaments, fullness or mass in the pouch of Douglas (POD), fixation and retroversion of the uterus, rectovaginal nodule. Adnexal (or even a pelvi-abdominal) mass in women with large endometriomas.
Luisi et al. [2]	2009	Severe dysmenorrhea, deep dyspareunia, chronic pelvic pain, ovulation pain, cyclical or perimenstrual symptoms with or without abnormal bleeding, infertility and chronic fatigue.	Not discussed.
Giudice. [20]	2010	Chronic pelvic pain (lasting ≥6 months), dysmenorrhea, dyspareunia, deep pelvic pain, and lower abdominal pain with or without back and loin pain. The pain can be continuous, and it can be dull, throbbing, or sharp, and exacerbated by physical activity. Bladder- and bowel associated symptoms (nausea, distention, and early satiety) are typically cyclic. Burning or hypersensitivity symptoms that are suggestive of a neuropathic component (infrequently).	A pelvic mass, immobile pelvic organs, and rectovaginal nodules.
Altman and Wolcyzk. [21]	2010	Chronic pelvic pain, dysmenorrhea, dyspareunia, infertility, back pain, dyschezia, rectal pain, diarrhea, constipation, dysuria, hematuria, infertility, chronic fatigue and psychosocial stressors.	Palpable tender nodules in the cul-de-sac or uterosacral ligaments; localized tenderness in the cul-desac, uterosacral ligaments, or rectovaginal septum; pain with uterine movement; enlarged or tender adnexal masses; and fixation of adnexa or uterus in a retroverted position. Red, blue, or hemorrhagic nodules may also be visualized on the external genitalia, vagina, or cervix.
Okeke and Ikeako. [9]	2011	Dysmenorrhea, dyspareunia, menorrhagia and infertility.	Not discussed.
Koninckx et al. [22]	2012	Hypogastric pain, especially dysmenorrhea, deep dyspareunia, severe chronic pain, mictalgia, and dyschezia.	Not discussed.
Acién and Velasco [23]	2013	Dysmenorrhea (during and at the end of menstruation), deep dyspareunia, chronic pelvic pain, and infertility premenstrual spotting for 2–4 days, headache, irritability, or premenstrual tension syndrome.	Not discussed.
Carneiro M M et al. [24]	2013	Dysmenorrhea, dyspareunia, dyschezia, gastrointestinal symptoms, chronic pelvic pain, infertility.	Pelvic tenderness, a fixed retroverted uterus, tender uterosacral ligaments or enlarged ovaries, uterosacral nodularity.
Schrager et al. [25]	2013	Debilitating pelvic pain, dysmenorrhea, dyspareunia, and decreased fertility.	Not discussed.
Mehedintu et al. [26]	2014	Severe dysmenorrhea, non-cyclical chronic pelvic pain, dysfunctional uterine bleeding, infertility, dyspareunia, painful defecation during menstruation, urinary tract symptoms and gastrointestinal symptoms	Not discussed.
Bhattacharjee et al. [27]	2014	Dysmenorrhea, deep dyspareunia, infertility, abnormal uterine bleeding, non-cyclic pain, menstrual cycle abnormalities, constipation, chronic fatigue, heavy or long uncontrollable menstrual periods with small or large blood clots, gastrointestinal problems including diarrhea, bloating and painful defecation, extreme pain in legs and thighs, back pain, mild to extreme pain during intercourse, pain from adhesions which may bind an ovary to the side of the pelvic wall, or they may extend between the bladder and the bowel, uterus, extreme pain with or without the presence of menses, premenstrual spotting, mild to severe fever, headaches, depression, hypoglycemia and anxiety.	Non-specific pelvic tenderness, localized tenderness in the pouch of Douglas, thickened nodular uterosacral ligaments, fixed retroverted uterus, palpable fixed cystic adnexal mass or an obliterated pouch of Douglas, masses, fixity of organs, displacements of cervix & presence of nodules in the rectovaginal pouch or uterosacral ligaments, nodularity or tenderness in the uterosacral ligament, bluish or red powder burn lesions may be seen in the cervix or posterior fornix of the vagina (which may be tender or bleed on touch), bluish nodules in the posterior fornix, a fixed retroverted tender uterus or a firm fixed pouch of Douglas.

https://bmcwomenshealth.biomedcentral.com/articles/10.1186/s12905-015-0196-z