Serotonin – the NET effect

A team of researchers from Case Western Reserve University School of Medicine have used high-powered microscopes for the first time to view serotonin activating its receptor

Background

I’d never heard of Serotonin until I was diagnosed with Neuroendocrine Cancer in 2010.  It is frequently discussed, often with contrasting views from the respondents. One common assumption/question is that it is responsible for many things that can go wrong with NET Cancer patients who have serotonin-producing tumours. “It’s the hormones” is an easy assumption to make or an easy answer to give in response to a complex set of circumstances.  It’s difficult to get a definitive answer and the science behind the behaviour of our hormones isn’t really 100% tied down.

You may see serotonin referred to as a ‘neurotransmitter’, a ‘chemical’ and a ‘hormone’ – this is complex but it is my understanding that it just adds context in respect the role/location of the serotonin, e.g. chemical and hormone are essentially synonymous and are endocrine related whereas neurotransmitter is concerned with the nervous system (the neuro in neuroendocrine) and the brain (more on this below). Consequently, I’ll keep this as basic as I can (author’s note on completion – it was not easy!).

Serotonin and NETs

One thing which is widely accepted and agreed…… Serotonin is definitely involved in Neuroendocrine Tumours, in particular, those resulting in carcinoid syndrome which can manifest as a number of symptoms including but not limited to flushing and diarrhea.  Although serotonin is one of the main ‘hormones’ released in excess by certain NETs (mainly midgut), it is not thought to be the main culprit behind some of the symptoms produced by Carcinoid Syndrome.  For example, flushing, the most common symptom (and a cardinal one) is thought to be caused by a number of hormones/peptides – too many to list but the main ones are histamine (particularly foregut), tachykinins (Substance P), bradykinins, prostaglandins …….. and I’m sure serotonin’s in there too!  It does, however, appear to be massively guilty in causing carcinoid syndrome diarrhoea, desmoplasia, and carcinoid heart issues.

Where does Serotonin come from?

Serotonin’s technical name is 5-hydroxyltryptamine (5-HT).  It is converted from 5-Hydrotryptophan (5-HTP) which is also known as oxitriptan. 5-HTP is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of serotonin (…..and melatonin) from tryptophan. Tryptophan is interesting as that brings in one of the missing pieces of the jigsaw – food!  Tryptophan cannot be manufactured in the body, it must be brought in via diet. There is no serotonin in food, it is only manufactured in the body.

Tryptophan in food enters the body and serotonin is created by a biochemical conversion process which combines tryptophan (essentially a protein) with tryptophan hydroxylase (TPH), a chemical reactor. I suspect other substances might be involved in that process.

While serotonin cannot cross the blood-brain barrier, tryptophan can, and almost all of it is converted to serotonin. Just to emphasise that NET dietitians do not say to avoid foods containing tryptophan other than at the time of marker testing (see below and nutrition Blog 4).

Are you happy with your serotonin?

Serotonin Inhibitors

The introduction of Somatostatin analogues (SSAs) such as Octreotide and Lanreotide, help reduce the secretion of “tumour-derived serotonin”  by binding to its receptors on the outside of the cell.  If you ever wondered why receptors are important, please check out my blog on this subject (click here).

TPH is actually very interesting as this is how Telotristat Ethyl (XERMELO) is able to help with the symptoms of Carcinoid Syndrome diarrhea which is not adequately controlled by SSAs or where patients are unable to be treated by somatostatin analogues for whatever reason. It’s a potent inhibitor of TPH which will disrupt the manufacturing of tumour-derived serotonin.  There is also evidence that it can help reduce the effects or halt the growth of the fibrosis leading to carcinoid heart disease.  Slight digression but useful to aid/enhance understanding at this point.  Read about Telotristat Ethyl here.

Serotonin and the Brain

There is constant discussion and assumption that serotonin-producing tumours are somehow causing depression, anxiety and rage.  If you think about the role of serotonin, to my simple way of thinking, there doesn’t appear to be any concrete evidence to back up this suspicion. Certain NETs can overproduce serotonin in the gut but the issues concerning depression and anxiety are normally associated with low levels of serotonin in the brain.

I know many people with cancer who suffer from depression, anxiety and rage but they do not have serotonin-producing tumours.  What they do have is a life threatening and/or life changing condition which is bound to have an effect on mind as well as body.  Serotonin is a natural substance found in the body and not just there to service NETs.  If you didn’t have any, you wouldn’t be able to get out of bed according to one of my ‘favs’ Dr Gene Woltering.

Serotonin is separately manufactured in the brain (~10%) and in the gastrointestinal tract (~90%).  The serotonin in the brain must be manufactured in the brain, it cannot be directly increased or reduced external to the brain, i.e. it cannot be directly reinforced by gut serotonin (peripheral serotonin). It follows that ‘brain serotonin’ and ‘gut serotonin’ are held in separate stores, they are manufactured in those stores and remain in those stores – there is no cross-pollination. This is managed by something called the blood-brain-barrier (BBB). Therefore, excess serotonin from NETs does not infiltrate the brain. As low-level of ‘brain serotonin’ is often linked to depression, it also follows that it’s possible to have high levels of serotonin in the gut but low levels in the brain.

My simple way of thinking about such things is that low levels of tryptophan in the brain might be contributing to low levels of serotonin in the brain.

Measuring Serotonin levels

Measuring levels of serotonin is important in both diagnosis and management of certain NETs – although it’s probably sensible to test all potential NET patients during diagnosis when the type of tumour is not yet known.  Testing for tumour markers will differ between countries and within countries but the most common standard for testing Serotonin appears to be 5-HIAA (5-hydroxyindoleacetic acid) either via a 24-hour urine test or via a plasma version (mainly used in USA but now creeping into UK).  5-HIAA is the output (metabolite) of 5-HT (Serotonin). Not to be confused with the less reliable ‘serum serotonin’ which is a different test.

Another frequently asked question about serotonin tests is whether they are testing the amount in the brain or the gut. The answer is …… they are testing the levels in the blood. Furthermore, if you are measuring serotonin as an indicator for Carcinoid Syndrome, it has to be remembered that the majority of serotonin is in the gut, so even if serotonin levels in the brain were being measured alongside the gut levels, it would not majorly influence the result. It also has to be remembered that serum serotonin and 5HIAA are not absolute tests, they are not 100% sensitive, they are simply indicators of a potential problem. There are methods of measuring brain serotonin but it is very complex and beyond the purposes of this blog.  However, I would just add that it is the reuptake of Serotonin in the brain (plus some other stuff) that can cause depression, not the actual level or amount in the brain.

I intentionally did not mention the other common test (Chromogranin A) or other markers as they are measuring different things but you can read about in my Testing for Markers blog.

Summary

I did say it was a difficult jigsaw!

Thanks for reading

Ronny

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16 thoughts on “Serotonin – the NET effect”

  1. Hi Ronnie, I stumbled across your page when I got the result of my chromogranin A blood test (90), did the 5HIAA urine test (awaiting results) and hot called for an urgent Tektrotyd scan – ALL my symptoms point to a neuroendocrine tumour (I have felt ill for about 7 years). I have all the symptoms of carcinoid syndrome. However scan results are clear, no tumours. But I’m baffled – why is my CgA high and why do I feel so ill? Any advice to give? I wish you well in your journey – you are very inspiring!

    1. I see this a lot Lisa. Unfortunately with many cancers “tissue is the issue” and to do a biopsy (currently), you need to ‘see’ a tumour to biopsy. It’s possible you don’t have a NET as the symptoms tend to be vague and similar to many everyday conditions – I would say flushing is pretty cardinal BUT it’s not like a wet hot flash you would get in menopause nor it is sweating, it’s dry as a rule of thumb. Check out my article “I bet my flush beats yours” to see the differential diagnoses for flushing. Your CgA is not actually that high – are you taking PPIs (anti acid medications) ? That will skew CgA – a blood test called Pancreastatin is better and not affected by PPIs, if that is the case. It will be useful to see the results of the octreoscan (I had to google tektroyd!). If you have working receptors, it should light up where there is an excess secretion (but even then it needs careful interpretation). Can you let me know the results when you get it? A gallium 68 PET is the newer version of octreoscan.

    2. Thanks for your response. I have dry flushing (no sweating) triggered by alcohol, chocolate, spicy food, stress, and sometimes is so bad I get a massive drop in blood pressure, violent vomiting, diarrhoea, immense cramping pain in right side then feel dreadful and can’t eat for 2-3 days. Keep being diagnosed with IBS but am so fatigued, B12 and vitamin D deficient, joint pain, hypoglycaemic, thyroiditis, just generally been feeling very unwell past 7 years. Seeing consultant next Wednesday so will let you know what 5HIAA result was and what scans showed. Thank you so much!

  2. I was dx’d in 2015 and Had small intestine resection. Since then my Serotonin level has been > 2000, Last test was 2250. I was wondering what the long term effects of serotonin typically are. I see things like hyper sensitivity to cold, muscle weakness, and hyper reflexivity. I have heard of Telotristat Ethyl (XERMELO) might be able to lower this. My Net Dr mentioned this back in May 2017 but my last visit in Dec 2017, made no mention of it. But did talk about PRRT and possibility of being approved early in 2018. We depend on these Net Dr’s but they are so busy, I think my Doc has been a little scattered..

    1. Hi Jeff. What was your 5HIAA score? You didn’t mention the unit of measure for serotonin, presumably the figure you gave is not normal, i.e. it’s out of range? XERMELO is approved for inadequate control of carcinoid syndrome diarrhea (this would indicate it’s for diarrhea caused by abnormal levels of serotonin rather than caused by surgery (i.e. shorter bowel etc)). Apparently it does lower 5HIAA results (the output of serotonin). Check out my article on XERMELO https://ronnyallan.com/2016/03/31/telotristat-ethyl-xermelo-an-oral-treatment-for-carcinoid-syndrome-diarrhea-not-adequately-controlled-by-somatostatin-analogues/ I would say one of the biggest long term risks of elevated serotonin is carcinoid heart disease – https://ronnyallan.com/2015/06/02/neuroendocrine-cancer-dont-break-my-heart/ however, these risks are lowered by the use of somatostatin analogues

  3. Really interesting. At oncology appointments I only have blood taken which is immediately put on ice. Do you think that’s the plasma version test you mention? Haven’t done a 24 hour urine for a while. Also Ronnie. What are your thoughts on fatigue? Disease vs treatment as the cause. It drives me crazy. Thanks.

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    1. The blood in ice is probably Chromogranin A (CgA) which is measuring tumour bulk rather than function. As for fatigue, am working on a post stay tuned. However, it’s a common problem and even doctors gave difficulty fixing it. I have some ideas.

  4. What are your thoughts on discontinuing an SSRI for 72 hours prior to the 5-HIAA test? Is it necessary to do so? My GI doctor said I didn’t need to stop them, but I’ve read conflicting information. I’d rather not have to stop them if possible, but I don’t want to mess up my test results either.


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  5. This is good stuff. I have been wondering why I wasn’t tripping over myself with happiness if my body produces too much Serotonin and why I don’t feel more sad with my Lanreotide injections. I have been curious if this injection interferes with the 5-HTP test results? Would it also interfere with a Gallium scan’s results? Should one stop injections before such tests?

    1. Thanks for commenting. I tried to put over that the two stores of serotonin in the GI tract and the brain were independent of each other, mainly to dispell the myth that the excess serotonin from NET tumours (specifically carcinoid) does not go zooming straight into the brain. I did not want to focus on serotonin issues associated with depression and treament for that (SSRIs etc) as it is even more technical (and beyond my understanding) and would perhaps complicate my focus on the specific serotonin NET issues, which in comparison are straightforward (kinda !).

      As for somatostatin analogues leading up to a Octreotide scan or Gallium 68, there is a protocol for that which I will try to find for you. Re the 5-HTP test, why do you get this? Is it a blood serum test.

  6. I have read that excess serotonin can also cause agitation. I immediately calmed down when my tumors were removed. Lanreotide is helping also

    1. Do you mean brain serotonin or gut serotonin? In respect brain serotonin, excess would not be a NET issue and I wanted to avoid discussing illnesses such as serotonin syndrome as this is up related to NETS.

      1. I suppose the agitation is from brain serotonin but it’s interesting that I feel more calm since my gut serotonin is lower. It’s still above average but lower than prior to surgery. Perhaps it’s due to some other cause.

      2. Maybe you’re feeling more calm because you’ve had treatment? If you’re also taking a somatostatin analogue, that will lower gut serotonin too.

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