Ray's View Of Causes Of Vulvodynia

Tansia

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Jan 14, 2020
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75
Hi Guys,
I've asked Ray's about causes of vulvodynia and treatment for this disease. I was also interested if it could be related to estrogen and endometriosis. I've got a really nice explanation form Ray and would like to share it with you. Maybe you could also suggest other treatments that could help me as well or something that helped you?
That's Ray comment for my question:

Endometriosis is clearly the result of too much estrogen, and there are good reasons for thinking a similar imbalance is involved in vulvodynia. Estrogen increases the presence of mast cells, which are found increased in the painful area. Mast cells secrete a variety of proinflammatory and pain-inducing substances including histamine, serotonin, and renin, which is converted locally to angiotensin. Estrogen supports formation of all those. Low vitamin D, low calcium intake relative to phosphate, and low thyroid function contribute to the excess of estrogen relative to progesterone. Vitamin D, milk, cyproheptadine (antagonist to histamine and serotonin), thyroid, and angiotensin blockers (such as telmisartan or candesartan) should help to correct the condition.

J Pain. 2017 May;18(5):511-525. A Local Inflammatory Renin-Angiotensin System Drives Sensory Axon Sprouting in Provoked Vestibulodynia
Zhaohui Liao 1 , Anuradha Chakrabarty 1 , Ying Mu 1 , Aritra Bhattacherjee 1 , Martha Goestch 2 , Catherine M Leclair 2 , Peter G Smith 3
Free PMC article
Vestibulodynia is a form of provoked vulvodynia characterized by profound tenderness, hyperinnervation, and frequently inflammation within well-defined areas of the human vestibule. Previous experiments in animal models show that inflammatory hypersensitivity and hyperinnervation occur in concert with establishment of a local renin-angiotensin system (RAS). Moreover, mechanical hypersensitivity and sensory axon sprouting are prevented by blocking effects of angiotensin II on angiotensin II receptor type 2 (AT2) receptors. This case-control study assessed whether a RAS contributes to hyperinnervation observed in human vestibulodynia. Vestibular biopsies from asymptomatic controls or patients' nontender areas showed moderate innervation and small numbers of inflammatory cells. In women with vestibulodynia, tender areas contained increased numbers of mechanoreceptive nociceptor axons, T-cells, macrophages, and B-cells, whereas mast cells were unchanged. RAS proteins were increased because of greater numbers of T cells and B cells expressing angiotensinogen, and increased renin-expressing T cells and macrophages. Chymase, which converts angiotensin I to angiotensin II, was present in constant numbers of mast cells. To determine if tender vestibular tissue generates angiotensin II that promotes axon sprouting, we conditioned culture medium with vestibular tissue. Rat sensory neurons cultured in control-conditioned medium showed normal axon outgrowth, whereas those in tender tissue-conditioned medium showed enhanced sprouting that was prevented by adding an AT2 antagonist or angiotensin II neutralizing antibody. Hypersensitivity in provoked vestibulodynia is therefore characterized by abnormal mechanonociceptor axon proliferation, which is attributable to inflammatory cell-derived angiotensin II (or a closely related peptide) acting on neuronal AT2 receptors. Accordingly, reducing inflammation or blocking AT2 represent rational strategies to mitigate this common pain syndrome.
Perspective: This study provides evidence that local inflammation leads to angiotensin II formation, which acts on the AT2 to induce nociceptor axon sprouting in vulvodynia. Preventing inflammation and blocking AT2 therefore present potential pharmacological strategies for reducing vestibular pain.
Keywords: Vulvodynia; angiotensin II; cell culture; inflammation; neural plasticity; peripheral nociceptors; quantitative histology.

Ann Epidemiol. 2009 Nov;19(11):771-7.
Allergic reactions and risk of vulvodynia
Bernard L Harlow 1 , Wei He, Ruby H N Nguyen
Free PMC article
Purpose: A recent histological study of vestibular tissue from women with localized vulvodynia found universal presence of mast cells compared to no presence in vestibular tissue among controls. Since histamine is generated by mast cells, and mast cells contribute to the production of cytokines during chronic inflammation, we assessed the association between conditions that elicit a clinically relevant histamine response and vulvodynia.
Methods: We studied 239 women with and 239 women without vulvodynia to assess the influence of self-reported allergic reactions antecedent to first development of vulvar pain symptoms among cases, and a matched reference age among controls.
Results: Women with self-reported hives prior to first report of vulvar pain or reference age among controls were 2.5 times more likely to develop vulvodynia (95% confidence interval [CI], 1.7-4.4). Those reporting a history of allergic reactions to insect bites were 2.1 times more likely (95%CI, 1.1-4.0), and those reporting a history of seasonal allergies were 2.0 times (95%CI, 1.3-3.2) more likely to develop vulvodynia. Findings were similar in a restricted subset of clinically confirmed cases and matched controls.
Conclusions: An altered immuno-inflammatory response to environmentally induced allergic reactions may predispose women to the development of vulvodynia or may be markers of an already heightened immuno-inflammatory response.

Obstet Gynecol. 2011 Jun;117(6):1307-13. doi: 10.1097/AOG.0b013e31821c33dc.
Differences in primary compared with secondary vestibulodynia by immunohistochemistry
Catherine M Leclair 1 , Martha F Goetsch, Veselina B Korcheva, Ross Anderson, Dawn Peters, Terry K Morgan
Free PMC article
Objective: To assess whether primary and secondary vestibulodynia represent different pathologic pathways.
Methods: This was an analysis of archived vestibulectomy specimens from 88 premenopausal women with vestibulodynia (2002-2008). Patient records were reviewed to classify the type of vestibulodynia, duration of symptoms, and hormone status. Histologic sections were stained for hematoxylin and eosin to grade inflammation, S100 to highlight nerves, CD117 for mast cells, estrogen receptor α, and progesterone receptor. Differences between primary and secondary vestibulodynia were tested by t tests, chi-square analysis, and linear and logistic regression.
Results: Primary vestibulodynia showed significant neural hypertrophy and hyperplasia (P=.02, adjusted odds ratio [OR] 3.01, 95% confidence interval [CI] 1.2-7.6) and increased progesterone receptor nuclear immunostaining (P=.004, adjusted OR 3.94, CI 1.6-9.9) compared with secondary vestibulodynia. Estrogen receptor α expression was also greater in primary vestibulodynia when symptom diagnosis was less than 5 years (P=.004, adjusted OR 5.53 CI 1.71-17.91).
Conclusion: Primary and secondary vestibulodynia have significantly different histologic features, suggesting that they may have separate mechanistic pathways. Clinically, this may mean the discovery of distinct conditions.

17
Am J Obstet Gynecol. 2010 Jun;202(6):614.e1-8. doi: 10.1016/j.ajog.2010.01.028. Epub 2010 Apr 28.
Histologic and receptor analysis of primary and secondary vestibulodynia and controls: a prospective study
Martha F Goetsch 1 , Terry K Morgan, Veselina B Korcheva, Hong Li, Dawn Peters, Catherine M Leclair
Objective: The objective of the study was to assess the association between hormone receptor densities, pain nerves, and inflammation in vestibulodynia patients.
Study design: In a prospective study, tender and nontender biopsies from 10 primary and 10 secondary vestibulodynia patients were compared with biopsies in 4 nontender controls. Hormone receptors were evaluated using immunohistochemistry for estrogen receptor-alpha and -beta, androgen, and progesterone receptors. Inflammation, nerves, and mast cells were assessed histologically. Statistical analysis was by Fisher's exact test, analysis of variance, paired Student t test, and Wilcoxon rank test.
Results: Tender sites from primary vestibulodynia had increased nerve density compared with secondary and control biopsies (P = .01). Tender sites in secondary vestibulodynia had more lymphocytes than tender primary sites and control biopsies (P < .0001). Mast cells were increased in tender sites compared with nontender and controls. There were no differences in hormone receptor expression.
Conclusion: Markers of inflammation differed between primary and secondary vestibulodynia and controls.

Copyright 2010 Mosby, Inc. All rights reserved.

Obstet Gynecol. 2011 Jun;117(6):1307-13.
Differences in primary compared with secondary vestibulodynia by immunohistochemistry
Catherine M Leclair 1 , Martha F Goetsch, Veselina B Korcheva, Ross Anderson, Dawn Peters, Terry K Morgan
Free PMC article
Objective: To assess whether primary and secondary vestibulodynia represent different pathologic pathways.
Methods: This was an analysis of archived vestibulectomy specimens from 88 premenopausal women with vestibulodynia (2002-2008). Patient records were reviewed to classify the type of vestibulodynia, duration of symptoms, and hormone status. Histologic sections were stained for hematoxylin and eosin to grade inflammation, S100 to highlight nerves, CD117 for mast cells, estrogen receptor α, and progesterone receptor. Differences between primary and secondary vestibulodynia were tested by t tests, chi-square analysis, and linear and logistic regression.
Results: Primary vestibulodynia showed significant neural hypertrophy and hyperplasia (P=.02, adjusted odds ratio [OR] 3.01, 95% confidence interval [CI] 1.2-7.6) and increased progesterone receptor nuclear immunostaining (P=.004, adjusted OR 3.94, CI 1.6-9.9) compared with secondary vestibulodynia. Estrogen receptor α expression was also greater in primary vestibulodynia when symptom diagnosis was less than 5 years (P=.004, adjusted OR 5.53 CI 1.71-17.91).
Conclusion: Primary and secondary vestibulodynia have significantly different histologic features, suggesting that they may have separate mechanistic pathways. Clinically, this may mean the discovery of distinct conditions.

APMIS. 2015 May;123(5):452-6.
Mast cell infiltrates in vulvodynia represent secondary and idiopathic mast cell hyperplasias
Sigrid Regauer 1 , Barbara Eberz, Christine Beham-Schmid
Mast cell infiltrates in tissues of vulvodynia are common, but they have not been characterized for criteria of neoplastic mast cell disease or correlated with patient's concomitant diseases associated with increased mast cells. Formalin-fixed specimens of 35 patients with vulvodynia were evaluated immunohistochemically with antibodies to CD 3,4,8,20,117c and human mast cell tryptase, and for WHO-criteria of neoplastic mastocytosis (>25% spindled mast cell, CD25 expression, point mutations of the c-kit gene (D816V), and chronically elevated serum tryptase levels). Only 20/35 specimens showed a T-lymphocyte dominant inflammatory infiltrate on HE-stained sections, but all showed mast cells. 4/35 biopsies showed <10 mast cells/mm(2) , 15/35 specimens 40-60 mast cells/mm(2) and 16/35 specimens >60 mast cells/mm(2) (average 80/mm(2) ). Control tissue contained typically <10 mast cells/mm(2) . Spindling, CD25-expression, c-kit gene mutations, or increased serum tryptase levels were not detected. 26/35 (74%) patients had concomitant autoimmune diseases, psoriasis, atopy, various allergies, preceding infections. Independent of the subtype of vulvodynia, the majority of mast cell rich biopsies with >40 mast cells/mm(2) were classified as a secondary mast cell disorder reflecting an activated immune system in 75% of vulvodynia patients. Patients with increased mast cells may benefit from medical therapy targeting mast cells.
Keywords: CD25 expression; Vulvar pain; c-kit mutation D816V; mast cell activation; mast cell hyperplasia; spindled mast cells.

I haven't got an access to angiotensin blockers, is there something else I could use instead?
I'm following Ray's diet for over 18 months, but put a lot of weight and I'm trying to loose it now. I take progesterone, NDT thyroid - 1 grain, aspirin, K2, B3 and D - but my levels of vit D still low ( I take 12000 IU a day).
Thanks!
 
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You can take 50,000 units of vitamin D per day for a few weeks to raise your levels.

Should be helpful, if you can’t get cyproheptadine maybe you can get generic Benadryl or better yet ketotifen
 

Tansia

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You can take 50,000 units of vitamin D per day for a few weeks to raise your levels.

Should be helpful, if you can’t get cyproheptadine maybe you can get generic Benadryl or better yet ketotifen
Thanks @ecstatichamster . Will try 50,000 as 12000 did nothing for 6months. Hope that helps with the burning otherwise I will get crazy. I do have cypro and was taking it with some breaks. Now I try again.
 

Blossom

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There is a causal relationship with high oxalate consumption. While the tissue/histological aspects contribute to our understanding the reaction, high oxalates are being viewed as a cause. The low-oxalate diet - Vulval Pain Society
Thank you Tom. I was going to post this myself because it is what helped me the most. The only flare I’ve experienced since going low oxalate was after being on antibiotics.
 

Tansia

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Thank you Tom. I was going to post this myself because it is what helped me the most. The only flare I’ve experienced since going low oxalate was after being on antibiotics.
Thanks @Blossom. How much oxalates do eat a day? Would I have to wait long to see improvement with this diet?
 

Tom K

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I avoid the 'Healthy" foods: spinach, almonds, etc. Also of importance is to consume citric acid, which assists with eliminating oxalate before it does damage. Recent discoveries reveal that oxalate crystals, once believed only detrimental to kidney function, affects all our organs, including the thyroid.
 

Blossom

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Thanks @Blossom. How much oxalates do eat a day? Would I have to wait long to see improvement with this diet?
I eat basically none at this point but I’ve read that it’s highly advised to gradually reduce your intake. I didn’t know about the slow reduction when I first found the vulvar pain site and stopped cold turkey. I definitely saw dramatic results within the first month but started feeling better in a matter of days. I suffered with it for at least 4 years never knowing the cause and thinking it was menopause related. Sally K. Norton has some good free material on oxalate and the Facebook group called Trying Low Oxalate has an abundance of information in their files and units.
 

Tansia

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I eat basically none at this point but I’ve read that it’s highly advised to gradually reduce your intake. I didn’t know about the slow reduction when I first found the vulvar pain site and stopped cold turkey. I definitely saw dramatic results within the first month but started feeling better in a matter of days. I suffered with it for at least 4 years never knowing the cause and thinking it was menopause related. Sally K. Norton has some good free material on oxalate and the Facebook group called Trying Low Oxalate has an abundance of information in their files and units.
That's amazing it helps you! Will definitely give it a go, and thanks for the heads up about gradual approach. First thing that came to my mind about this diet was: Would I have to stop drinking coffee?
 

Tansia

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I'm just thinking out loud how oxalates are related to mast cells related inflammation?
 

Tansia

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I avoid the 'Healthy" foods: spinach, almonds, etc. Also of importance is to consume citric acid, which assists with eliminating oxalate before it does damage. Recent discoveries reveal that oxalate crystals, once believed only detrimental to kidney function, affects all our organs, including the thyroid.
Thanks. Now I'm looking for a good source on oxalates in foods. There's no good app for that.
 

Blossom

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That's amazing it helps you! Will definitely give it a go, and thanks for the heads up about gradual approach. First thing that came to my mind about this diet was: Would I have to stop drinking coffee?
Regular drip coffee is fine but tea is generally high.
 

somuch4food

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I'm just thinking out loud how oxalates are related to mast cells related inflammation?

My understanding is that oxalates cause inflammation which increases mast cells and then, you get into a vicious cycle where mast cells contribute to inflammation.

Oxalates can also be produced by the body from glycine/gelatin, fructose and ascorbic acid/vitamin C.
 

MatheusPN

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Thanks for sharing Tansia.
A topical anti-estrogen like aspirin, would be very effective, so...
 

Blossom

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Thanks for sharing Tansia.
A topical anti-estrogen like aspirin, would be very effective, so...
Do you know anyone who has applied aspirin to their vagina? I’m genuinely curious.
 

Tansia

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My understanding is that oxalates cause inflammation which increases mast cells and then, you get into a vicious cycle where mast cells contribute to inflammation.

Oxalates can also be produced by the body from glycine/gelatin, fructose and ascorbic acid/vitamin C.
Does it mean that by eating gelatin, fructose and vit C rich diet I will increase oxalates in my body?
 
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