Histamine, excess estrogen and interstitial cystitis: is there a link?
Dr Janice Joneja says definitely - yes.

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Dr Janice Joneja, a world expert on histamine intolerance, has created an easy-to-read guide to help you understand whether you might be histamine intolerant, and, if so, what you can do about it.
From Amazon here in the US – $7.72
From Amazon here in the UK – £5.99


Question:

I am a 41 year old female from Vancouver Island, British Columbia.

I have a question regarding a possible link between histamine intolerance, interstitial cystitis (IC), and estrogen. I was diagnosed with IC at the age of 23 after 3 bouts of real UTIs and then multiple yeast infections due to the antibiotics used. Before I developed this I had not had a period for 4 years due to an eating disorder, and it was only after I started to ovulate again and the infections that I developed IC. I was in unrelenting pain for 12 years, but noticed it started to calm down around 4 years ago. I also had a sharp drop in libido. I was taking Prometrium for the last 8 years for insomnia and that seemed to help my bladder pain as well.

 I recently tried to take estrogen for my libido and my bladder pain and frequency increased almost immediately. I noticed I would sneeze like crazy, have itchy eyes, be angry at nothing and then the IC would act up. If I took the estrogen concurrently with Loratidine the pain was reduced. I wonder if I am having a very strong histamine response to estrogen and if that it was what caused my IC to be so bad during my highest estrogen reproductive years. It is my understanding the estrogen receptors line the bladder walls and that estrogen causes mast cell degranulation releasing histamine.

Is it possible that some people with IC are really very histamine intolerant and that their estrogen is driving their pain? This might explain why such a large proportion of IC patients are female. An intolerance to my own estrogen also might explain why my mood is so awful on it and why when I hit puberty my personality changed, and not for the best.

Also, does progesterone quell histamine release?

Dr Joneja says:

Interstitial cystitis (IC) is usually defined as a sterile (no evidence of an infective micro-organism) bladder condition occurring primarily in females. Its characteristic symptoms include frequent urination, frequent wakening to urinate during the night (nocturia), and pain, often severe, in the pubic region. IC symptoms are often worse during ovulation and stress.  The most prevalent theories to explain the pathophysiology of IC appear to be altered bladder lining and increased number of activated bladder mast cells. 

The first step of the disease is thought to be the loss of the glycosaminoglycan (GAG) mucous layer, which acts as a protective barrier in the intact lining of the bladder.   Reasons for the loss of this protective layer include inflammation, which might result from recurrent or chronic bladder infections among other causes.  A defective bladder glycosaminoglycan (GAG) layer could allow penetration of allergens, chemicals, food preservatives, drugs, toxins, and bacteria, all of which can activate bladder mast cells.

Mast cells have been studied extensively for their involvement in allergic reactions, where they secrete numerous powerful mediators such as histamine, enzymes, leukotrienes and prostaglandins in response to immunoglobulin E (IgE) and specific allergens. (You can buy all of Dr Joneja's books here in the UK or here in the US and you can buy DAO supplements here in the UK or here in the US.)

  However, they are also triggered by neuropeptides and have been found in close contact with neurons in the lining of the digestive tract and bladder.  In conditions such as irritable bowel syndrome (IBS) and bladder conditions such as IC, mast cells appear to be activated by agents such as allergens and other triggers (listed above) which enter via a non-intact barrier lining, as well as by neurogenic factors.

When mast cells are degranulated (release their store of inflammatory chemicals) by allergic or neurogenic activation, the enzyme tryptase can be detected and is an indicator that mast cells are involved in the reaction.  In IC, urine tryptase is elevated, confirming the role of mast cells in the condition.  Mast cell-derived enzymes can cause tissue damage, which further exacerbates the situation by allowing the ingress of additional mast cell activating factors. 

Mast cell activation is known to be enhanced by estradiol, which is a specific form of estrogen.  Human bladder mast cells express estrogen receptors, which means that estrogen can attach to molecules on the mast cell surface and aid in the degranulation process and release of the stored inflammatory mediators.  In contrast, bladder mast cells have very few receptors for progesterone.  Research has indicated that progesterone has an inhibitory effect on the release of histamine from mast cells, even when they are stimulated by allergens or other molecules that trigger degranulation.   This research tends to explain the worsening of IC symptoms during ovulation, when estrogen levels rise, and to some extent the decrease in symptoms of allergy during pregnancy when estrogen is lower and progesterone predominates.

Furthermore, acute psychological stress leads to mast cell degranulation via neurotransmitters. Please see my article on “stress” here.  These findings suggest that IC could be a syndrome with neural, immune, and endocrine components, in which activated mast cells play a central role.  In this respect it might be considered that interstitial cystitis should be included in the catalogue of mast cell activation disorders (MCAD).

So, with that explanation, you will be able to understand why you have experienced the reactions you report as a consequence of your frequent UTIs, estrogen supplements, as well as undoubted psychological stress. It is not possible for you to be intolerant of your own estrogen, as you seem to suspect, so that should not be a concern for you.

Of course, the next question is, “What can be done about all this to offer you some relief of your distressing symptoms?”

First of all it is important for you to avoid increasing your estrogen levels by supplemental estrogen.  The symptoms you experienced when you did try this were definitely a result of mast cell degranulation and release of histamine, as well as other mediators.

 Histamine and other mediators released from mast cells are the cause of the miserable symptoms of the condition because mast cells are central to the inflammatory process in IC.  Reducing the level of histamine in your body by avoiding all sources of histamine that you can control by following a histamine-restricted diet will afford you a measure of relief.  However, because other mediators in addition to histamine are involved, controlling histamine alone will not completely alleviate your symptoms.  Nevertheless I would recommend a trial on my histamine-restricted diet as recommended in “Dealing with Food Allergies” and the consumer handout of “The Health Professional’s Guide”.

You can buy all of Dr Joneja's books here in the UK or here in the US and you can buy DAO supplements here in the UK or here in the US.

A few years ago I started a trial study with members of the interstitial cystitis support group in Vancouver.  A number of the participants reported significant relief of their symptoms on a histamine-restricted diet.  Unfortunately at that time I was not in a position to conduct a randomised placebo-controlled trial which of course is required for any serious research study.  Nevertheless, the results were sufficiently encouraging for me to continue to advise sufferers of IC to try a histamine-restricted diet as part of their management of the condition.  To help in my research, please let me know if this improves your symptoms.

Augmenting the dietary management with supplemental diamine oxidase (DAO), the enzyme that breaks down excess histamine might help to further reduce the histamine level.  A DAO supplement called HistamAid can be obtained in Canada on-line at http://88healthproducts.com/product/histamaid-88/ . Please understand that DAO alone will not reduce your histamine level sufficiently; it must be used as an adjunct to a histamine-restricted diet to provide optimal effects.

A small number of preliminary studies are suggesting that healing of the barrier cell layer of the bladder by replenishing the GAG in the lining of the bladder might help reduce access by foreign agents such as allergens and other mast cell activating factors.  So far the best results were obtained with 0.2% chondroitin sulphate.  It might be a good idea for you to speak to your doctor about trying this approach.

References:

Muñoz-Cruz S, Mendoza-Rodríguez Y, Nava-Castro KE, Yepez-Mulia L, Morales-Montor J.
Gender-related effects of sex steroids on histamine release and FcεRI expression in rat peritoneal mast cells. J Immunol Res 2015. Volume 2015, Article ID:351829.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417946/pdf/JIR2015-

Theoharides TC, Pang X, Letourneau R, Sant GR. Interstitial Cystitis: A Neuroimmunoendocrine Disorder. Neuroimmunomodulation: molecular aspects, integrative systems, and clinical advances. Annals of the New York Academy of Sciences, 1998;840: 619–634.

Vasiadi M1, Kempuraj D, Boucher W, Kalogeromitros D, Theoharides TC. Progesterone inhibits mast cell secretion. Int J Immunopathol Pharmacol. 2006 Oct-Dec;19(4):787-794.

Vliagoftis H1, Dimitriadou V, Boucher W, Rozniecki JJ, Correia I, Raam S, Theoharides TC. Estradiol augments while tamoxifen inhibits rat mast cell secretion. Int Arch Allergy Immunol. 1992;98(4):398-409.

You can buy all of Dr Joneja's books here in the UK or here in the US.

January 2016


Purse

Dr Janice Joneja, a world expert on histamine intolerance, has created an easy-to-read guide to help you understand whether you might be histamine intolerant, and, if so, what you can do about it.
From Amazon here in the US – $7.72
From Amazon here in the UK – £5.99


If you found this article interesting you can find a number of other articles on histamine intolerance both by Dr Joneja and others here, reports on histamine research here and a Q & A section on histamine with Dr Joneja here.

For many, many other articles on every type of food allergy and intolerance click here; for coeliac disease and other food related conditions, go here.

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Dr Janice Joneja, Ph.D., RDDr. Janice Joneja is a researcher, educator, author, and clinical counsellor with over thirty years of experience in the area of biochemical and immunological reactions involved in food allergy and intolerances. Dr. Joneja holds a Ph.D. in medical microbiology and immunology and is a registered dietitian (RD). 

She has been a member of the faculty at several Canadian universities, starting her career as an Assistant Professor in the Department of Microbiology, Faculty of Science, and in the Faculty of Dentistry, at the University of British Columbia, Vancouver. Since 2001 Dr. Joneja has been a faculty member in the School of Biomedical and Molecular Sciences, at the University of Surrey, in England, teaching in the M.Sc. course in Nutritional Medicine.  For 12 years she was head of the Allergy Nutrition Program at the Vancouver Hospital and Health Sciences Centre.

Dr. Joneja is the author of six books and a dietetic practice manual on food allergy, a textbook on Irritable Bowel Syndrome, and several distance education courses. Her most recent books include “The Health Professional’s Guide to Food Allergies and Intolerances”, “Dealing with Food Allergies”, and “Dealing with Food Allergies in Babies and Children”.  Dr. Joneja’s work has been published in peer-reviewed scientific and medical journals, as well as in popular magazines.  She is a respected lecturer at universities, colleges and hospitals internationally, and regularly appears on television and radio call-in shows as an expert in her field.

Dr. Joneja is President of Vickerstaff Health Services, Inc., a practice that provides counselling for people suffering from all aspects of adverse reactions to food, and resources for the professionals and care-givers who support them.

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