Hypothalamic-Pituitary autoimmunity and related impairment of hormone secretions in chronic fatigue syndrome

CBS

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https://pubmed.ncbi.nlm.nih.gov/34254637/

Hypothalamic-Pituitary autoimmunity and related impairment of hormone secretions in chronic fatigue syndrome

Annamaria De Bellis, 1, 2, Giuseppe Bellastella, 2, 3, Vlenia Pernice, 2, Paolo Cirillo, 2, Miriam Longo, 2, 3, Antonietta Maio, 2, Lorenzo Scappaticcio, 2, Maria Ida Maiorino, 2, 3, Antonio Bellastella, 4, Katherine Esposito, 2, 5, Jose G Montoya, 6

Abstract

Context: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a severe chronic illness which reduces the quality of life. A potential role of neuroendocrine autoimmune dysfunction has been hypothesized.

Objective: To investigate the occurrence of anti-pituitary (APA) and anti-hypothalamic (AHA) antibodies and possible related hypothalamic/pituitary dysfunctions in ME/CSF patients.

Design, setting, patients and other participants: This is a case-control study conducted in University Hospital setting (Stanford, Naples). Thirty women with ME/CSF (Group 1) diagnosed according to Fukuda, Canadian, and IOM criteria, at Stanford University, were enrolled and compared with 25 age-matched healthy controls.

Main outcome measures: APA and AHA were detected by immunofluorescence; moreover, we investigated hormonal secretions of anterior pituitary and respective target glands and plasma and urinary osmolality. Both APA and AHA titers were assessed and the prevalence of pituitary hormone deficiencies was also investigated.

Results:
Patients in Group 1 showed a high prevalence of AHA (33%) and APA (56%) and a significant lower levels of ACTH/cortisol, and GH peak/IGF1 vs controls (all AHA/APA negative). Patients in Group 1A (13 patients positive at high titers, ≥1:32) showed ACTH/cortisol and GH peak/ IGF1 levels significantly lower and more severe forms of ME/CFS with respect to patients in Group 1B (7 positive at middle/low titers,1:16-1:8) and 1C (10 Ab negative patients).

Conclusions: Both AHA and/or APA at high titers associated with hypothalamic/pituitary dysfunction suggest that hypothalamic/pituitary autoimmunity may play an important role in the manifestations of ME/CFS, especially in its more severe forms.

Keywords: ME/CFS; Pituitary; autoimmunity; hypothalamus; pituitary dysfunction.
 

Gingergrrl

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I sent this research study to both my main doctor and my endocrinologist b/c it significantly pertains to my current situation. Both were very interested in the study and said that they would be happy to order tests for these autoantibodies for me if I can figure out how!

As far as we can tell, these autoantibodies are only tested within a research study and are not available through any commercial lab in the US. Does anyone know if it is possible to test for these autoantibodies outside of research? I am thinking about contacting Stanford to try to find out as soon as I have time.
 

dylemmaz

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As far as we can tell, these autoantibodies are only tested within a research study and are not available through any commercial lab in the US. Does anyone know if it is possible to test for these autoantibodies outside of research? I am thinking about contacting Stanford to try to find out as soon as I have time.
dr montoya replied to someone on twitter saying he doubts you can get these tests performed in the US, but that he’d do some inquiring to double check
 

Gingergrrl

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dr montoya replied to someone on twitter saying he doubts you can get these tests performed in the US, but that he’d do some inquiring to double check
Do you have the Twitter link? I’m not a member of Twitter and can never find these things! My guess is that Dr. Montoya is right and this testing does not currently exist in the US outside of research. I truly think I have anti pituitary autoantibodies based on my blood work of the past year (but am waiting on results of some blood work I just did a few days ago).
 

dylemmaz

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Do you have the Twitter link? I’m not a member of Twitter and can never find these things! My guess is that Dr. Montoya is right and this testing does not currently exist in the US outside of research. I truly think I have anti pituitary autoantibodies based on my blood work of the past year (but am waiting on results of some blood work I just did a few days ago).

hope that helps!
 

junkcrap50

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I truly think I have anti pituitary autoantibodies based on my blood work of the past year (but am waiting on results of some blood work I just did a few days ago).
Still?? Or do you think you have new ones? I thought you cured or fixed all of your autoantibodies with Rituximab + IVIG and the conditions they caused? Did your treatment only target/cure a partial number of autoantibodies?
 

Gingergrrl

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Still?? Or do you think you have new ones? I thought you cured or fixed all of your autoantibodies with Rituximab + IVIG and the conditions they caused? Did your treatment only target/cure a partial number of autoantibodies?
This is a complicated issue and I don’t know for sure if I have anti-pituitary autoantibodies without access to the test in the research study (from the article in this thread). IVIG & Rituximab put me into remission from LEMS (Lambert Eaton Myasthenic Syndrome), from POTS, and from MCAS. And to clarify so there is no confusion, it turned out that ME/CFS was never my diagnosis after all.

But, I am dealing w/endocrine problems which may or may not be autoimmune. Actually the Hashimoto’s is autoimmune but that is fully controlled w/thyroid med and not a big deal. The big issue that my doctors are trying to figure out is why I've had undetectable ACTH on blood tests for over a year leading me to be unable to taper off Cortef (hydrocortisone).

Initially they thought I had pituitary suppression (most likely due to autoimmunity or inflammation). But now my endocrinologist is wondering if I could have a benign adrenal tumor or hyperplasia (although he thinks this is unlikely) and I just did some new blood tests w/a different lab to get further info (but the results are not back yet).

I don’t want to take this thread off track (unless my situation would be helpful to others)? It would be extremely helpful if I could be tested for pituitary autoantibodies in the study (but that seems too good to be true to be able to access the testing outside of a research study)! I would pay privately for whatever it costs.

Edited to Add: I was also wondering if anyone knows how to access the full article re: the research study?
 
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CBS

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I sent this research study to both my main doctor and my endocrinologist b/c it significantly pertains to my current situation. Both were very interested in the study and said that they would be happy to order tests for these autoantibodies for me if I can figure out how.

As far as we can tell, these autoantibodies are only tested within a research study and are not available through any commercial lab in the US. Does anyone know if it is possible to test for these autoantibodies outside of research? I am thinking about contacting Stanford to try to find out as soon as I have time.
Hi Gingergrrl,
I figured I didn't have much more to say about CFS research until this study either was published or failed and was forever forgotten.
These tests are not available commercially as far as I know. Dr. De Bellis has been working in this area for a couple decades and she is THE world's expert in this area (and shipping samples in the appropriate cold-chain packaging while making sure that Italian customs doesn't destroy your samples - IS NOT FOR THE FAINT OF HEART).
The APA and AHA tests on their own don't tell you how to treat anything. They tell you that there has been some autoimmune process in either the pituitary of the hypothalamus. And the level of antibodies can give you some idea as to the intensity of the activity.
The treatment for patients in this study should be based upon their actual hormone deficiencies but the testing needs to be specific for CENTRAL hormone issues (low ACTH, not low cortisol, low TRH or TSH, not low T4, etc.).
Testing for central endocrine (pituitary/hypothalamus) deficiencies can be tricky as it almost always involves stressing critical systems involved in homeostasis which makes many doctors very anxious (and for many who don't, it should). Treatment needs to be done with just as much care.
A careful review of "end organ" abnormalities (think odd cortisol levels with the adrenal representing the end organ in the CRH/ACTH/Cortisol system, TSH levels dropping over time but still technically within the normal range) should be your guide.
Most endocrinologists are not well versed in these tests. Endocrinologists specializing in pituitary/hypothalamic function are not common but they are out there. Tests are being developed that are safe and more easily interpreted (co-peptin for central diabetes insipidus).
This study strongly suggests a mechanism and an area of treatment but you can test and treat without access to APA or AHA tests. Lastly, Dr. De Bellis is not (to my knowledge) equipped or capable of processing a large number of samples outside of the research setting. I hope this helps.
 
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Gingergrrl

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@CBS Thank you for your PM’s and I am going to reply as soon as I can. I actually remember chatting w/you re: endocrine issues by PM many years ago (maybe 2014 or 2015)?!! But that was before I even knew my proper diagnosis & treatment and before my current mess! I did not even make the connection that it was you who posted this article until right now! 🤦🏻‍♀️ Thank you again and of everything I’ve dealt with medically, the endocrine stuff is the most challenging for me to grasp.
 

CBS

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@CBS Thank you for your PM’s and I am going to reply as soon as I can. I actually remember chatting w/you re: endocrine issues by PM many years ago (maybe 2014 or 2015)?!! But that was before I even knew my proper diagnosis & treatment and before my current mess! I did not even make the connection that it was you who posted this article until right now! 🤦🏻‍♀️ Thank you again and of everything I’ve dealt with medically, the endocrine stuff is the most challenging for me to grasp.
Save those chats, they might be worth something some day (some of my best work) - ;)
 

Gingergrrl

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Save those chats, they might be worth something some day (some of my best work) - ;)
I am going to attempt to find the old PM’s and re-read them (re: the endocrine issues) and then reply to the new PM’s re: this thread and the research article.

I’ve gotten so behind w/PM’s that I am truly embarrassed about it (and I had several very kind & smart people give me feedback re: my current ACTH/Cortisol problem and my plan is to reply to every PM now matter how long it takes me 🤦🏻‍♀️)!
 

CBS

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I am going to attempt to find the old PM’s and re-read them (re: the endocrine issues) and then reply to the new PM’s re: this thread and the research article.

I’ve gotten so behind w/PM’s that I am truly embarrassed about it (and I had several very kind & smart people give me feedback re: my current ACTH/Cortisol problem and my plan is to reply to every PM now matter how long it takes me 🤦🏻‍♀️)!
Please don't feel any pressure to respond, especially within some time period. I know how hard it is to be so sick. Just start with our conversation in August, 2016 (it's concise). It basically outlines what was found in this paper (but the paper is a lot more exciting). Once you see what we've all been battling, I think you'll find it easier to be alot less hard on yourself for less important things like getting behind on responses to PM's.
 

Gingergrrl

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Please don't feel any pressure to respond, especially within some time period. I know how hard it is to be so sick. Just start with our conversation in August, 2016 (it's concise). It basically outlines what was found in this paper (but the paper is a lot more exciting). Once you see what we've all been battling, I think you'll find it easier to be alot less hard on yourself for less important things like getting behind on responses to PM's.
Thank you for being so patient & kind and I am definitely going to re-read the old PM's before I reply. I am actually in remission (for lack of a better word!) from multiple autoimmune illnesses but it is this endocrine stuff that is causing so much confusion & grief for me right now. My doctors are working under the assumption that the endocrine problems (in my case) are also autoimmune since it makes the most logical sense given my entire history. But we don't know for sure and that it why the article you posted was so striking to me. I will explain more by PM so I do not take this entire thread off-track with my specific situation.
 

Gingergrrl

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@LiLaLu This is the thread that I mentioned re: the article about pituitary autoantibodies. I wanted to tag you to make it easier to find but please do not worry about replying here! :hug:
 

Gingergrrl

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Hi Gingergrrl, I figured I didn't have much more to say about CFS research until this study either was published or failed and was forever forgotten.
@CBS, I wanted to reply to this thread first before I reply to the PM's. I am so glad that this study was finally published and that you were able to post it here for others to read! Thank you again :)

These tests are not available commercially as far as I know. Dr. De Bellis has been working in this area for a couple decades and she is THE world's expert in this area (and shipping samples in the appropriate cold-chain packaging while making sure that Italian customs doesn't destroy your samples - IS NOT FOR THE FAINT OF HEART).
This matches w/everything I've researched and these tests are not commercially available in the US as far I as can tell. I was not familiar with Dr. De Bellis before this study and am so glad to have learned about the connection between Italy & Stanford on this issue. And I agree w/you that it sounds impossible to ship a blood sample to Italy for this test and have it get there in time and intact! Someone mentioned to me that this kind of testing might also be available in Germany and I was wondering if you were familiar w/this?

The APA and AHA tests on their own don't tell you how to treat anything. They tell you that there has been some autoimmune process in either the pituitary of the hypothalamus. And the level of antibodies can give you some idea as to the intensity of the activity.
That completely makes sense but I think it would be useful to know if there is an autoimmune issue w/the hypothalamus and/or pituitary (vs. an adrenal issue) or another potential cause of the disruption to the HPA axis. Especially in someone like me who has a history of obscure autoantibodies at the core of their illness.

Have you heard of people doing imaging (MRI or CT scan) of the pituitary in order to see if there is inflammation (separate from the blood testing for the autoantibodies)? I did not do imaging b/c I am allergic to contrast dye and my doctor felt that it would not be useful without the dye (and that even WITH the dye, it still might not show anything if the inflammation was very small). I also assume that there might be people who test sero-negative for the autoantibodies but still have an autoimmune process going on?

Did the study find that the level of autoantibodies always correlated with the intensity of the activity? I was curious b/c with some autoantibodies, this is not the case. And I also agree w/you that knowing if you have the autoantibodies might simply be "academic" and would not change the treatment (meaning that the person would continue on a steroid like hydrocortisone for life).

The treatment for patients in this study should be based upon their actual hormone deficiencies but the testing needs to be specific for CENTRAL hormone issues (low ACTH, not low cortisol, low TRH or TSH, not low T4, etc.). Testing for central endocrine (pituitary/hypothalamus) deficiencies can be tricky as it almost always involves stressing critical systems involved in homeostasis which makes many doctors very anxious (and for many who don't, it should). Treatment needs to be done with just as much care.
I completely agree w/this (that the treatment would be individualized for each patient depending on their actual hormone deficiency in regard to their CENTRAL end-organ hormone issue). This is precisely what my doctors are still trying to figure out in my case. My ACTH has been "undetectable" on all blood tests from June 2020 to the present (approx one year). So there is definitely an issue w/my ACTH production (separate from my ACTH being suppressed by Cortef/hydrocortisone).

I spent over 2 yrs tapering off Cortef/hydrocortisone but after only one week, I had to go back on it as I was starting to have the symptoms of an adrenal crisis. And recently, my endocrinologist wondered if I could have a benign adrenal tumor or hyperplasia (b/c my Cortisol level was not undetectable like the ACTH). It was "low" but it was within the normal range. But I had wondered if the Cortisol blood test was actually measuring the hydrocortisone that I had taken the day before since I am a slow metabolizer (in general). I have now re-done the tests (with a different lab) and am waiting for the results.

I also wanted to ask you, is there a commercial test in the US for Corticotropin-releasing hormone (CRH)? I have never been tested for this by any doctor which makes me think that it is not tested in the US (or maybe anywhere)? But it would be interesting to see if there is an issue w/this part of the HPA Axis (vs. the pituitary).

A careful review of "end organ" abnormalities (think odd cortisol levels with the adrenal representing the end organ in the CRH/ACTH/Cortisol system, TSH levels dropping over time but still technically within the normal range) should be your guide.
Absolutely and this is exactly what I am trying to figure out. It seems like either way, the end result is supplementing with Cortef/hydrocortisone. But it would be helpful to know exactly what the problem is.

Most endocrinologists are not well versed in these tests. Endocrinologists specializing in pituitary/hypothalamic function are not common but they are out there. Tests are being developed that are safe and more easily interpreted (co-peptin for central diabetes insipidus).
My endocrinologist is very good and I am so appreciative that he is investigating this vs. telling me that everything is "normal" like so many doctors might do (when it is clearly not normal to have undetectable ACTH)! But if the core issue is pituitary vs. adrenal then the treatment would be different moving forward.

This study strongly suggests a mechanism and an area of treatment but you can test and treat without access to APA or AHA tests. Lastly, Dr. De Bellis is not (to my knowledge) equipped or capable of processing a large number of samples outside of the research setting. I hope this helps.
Thank you for confirming this and I promise not to contact Dr. De Bellis and bug her :rofl:! But if I ever find a way, I want to do these blood tests some day!
 
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CBS

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@CBS, I wanted to reply to this thread first before I reply to the PM's. I am so glad that this study was finally published and that you were able to post it here for others to read! Thank you again :)
There is a lot more important detail in the full text copy. If this might be important to you. reading the full article is worthwhile. Better yet, have your endocrinologist read it.
I need to make clear that nothing nor no-one was holding the study up. It was finally published after 7 years because that is how long this type of research takes. Present ideas, critique ideas, lit reviews to see what's been done and how a project might build on past work, etc. Searching for funding, drafting final proposals, IRB approvals. etc.
 

Gingergrrl

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There is a lot more important detail in the full text copy. If this might be important to you. reading the full article is worthwhile. Better yet, have your endocrinologist read it. I need to make clear that nothing nor no-one was holding the study up. It was finally published after 7 years because that is how long this type of research takes. Present ideas, critique ideas, lit reviews to see what's been done and how a project might build on past work, etc. Searching for funding, drafting final proposals, IRB approvals. etc.
@CBS I would love to read the full copy of the article (and show it to my endocrinologist) and I really appreciate this! I also wanted to tell you that I finally had a chance tonight to search through all of my old PM's and was able to find the PM's w/you from 2015 & 2016 (in addition to the recent PM's that you sent me re: this article). I am going to reply via PM but wanted to let you know that the info that you sent me back then was incredibly relevant to my current situation and I am embarrassed to admit that I did not understand it at all back then but I do now.

I think you might be spot on re: "central adrenal insufficiency" (meaning the problem is w/the hypothalamus or pituitary production of hormones and not at the adrenal level) and also it is not secondary adrenal insufficiency from taking Cortef/hydrocortisone. This is something that I am planning to pursue depending upon the results of my most recent blood work. I am wondering if central adrenal insufficiency is always (or often?) autoimmune?

I checked w/my endocrinologist today b/c it's been over a week since I did the blood work but the lab has not even sent him any partial results! He said that this is concerning (that the lab might've made a mistake :mad:) and he is going to check tomorrow. I truly hope this is not the case b/c I am not certain that I can tolerate not taking Cortef (hydrocortisone) again for 24-hours (which I had to do prior to doing the blood tests).

I am certain that this endocrine issue is the final piece of the medical puzzle that needs to be solved (in my case) and I really appreciate your help :hug:.