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 Neuroendocrine Cancer patients who have serotonin-producing tumours. To a certain extent, that’s true but statement such as “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 – the human body is extremely complex.
You may see serotonin referred to as a ‘neurotransmitter’, a ‘chemical’ and a ‘hormone’ – this is complex, but it is my understanding that it can add context in respect to the role/location of the serotonin, e.g. neurotransmitter is concerned with the central nervous system and the brain (the neuro in neuroendocrine), whereas chemical and hormone are essentially synonymous with the endocrine systems. Consequently, I’ll keep this as basic as I can (author’s note on completion – it was not easy!).
One more issue I frequently see is the assumption that all Neuroendocrine Cancers are hormonal via Serotonin which is patently incorrect. Serotonin is only one hormone involved in Neuroendocrine Cancer and is almost exclusively associated with the group of tumours once known by the ancient and misnomer term ‘carcinoid‘ thus the term ‘carcinoid syndrome’. However, the misuse of the term by doctors, advocate organisations and patients, spreads the myth that anyone who is symptomatic with Neuroendocrine Cancer has carcinoid syndrome and/or oversecretes serotonin, leading to unnecessary testing, worry, confusion and potentially unnecessary treatment. This adds to the issue I intend to cover below.
One thing which is widely accepted and agreed…… Serotonin is definitely involved in Neuroendocrine Tumours, particularly 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 typical 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 one is tachykinins (Substance P). According to a recent study from Europe, there is currently, insufficient evidence to link histamine, bradykinin, kallikrein, prostaglandins, motilin, and other putative mediators to Carcinoid Syndrome.
However, Serotonin does appear to be guilty in causing carcinoid syndrome diarrhoea, desmoplasia, and carcinoid heart issues.
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 from Tryptophan (often known as L-tryptophan) which is an amino acid (protein building blocks). L-tryptophan is called an “essential” amino acid because the body can’t make it on its own. It must be acquired from food. This makes Tryptophan very 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. It follows that there is no serotonin in food (incorrectly stated on many websites), it is only manufactured in the body via the complicated process just described. In simplistic terms, after absorbing Tryptophan from food, our bodies convert it to 5-HTP and then to serotonin, but it’s also involved in generating melatonin, and vitamin B6 (nicotinamide). Additionally, a small amount of Tryptophan is converted to B3 (Niacin) – the importance of this will be described later. Changes in the level of serotonin in the brain can alter mood. Melatonin is important for sleep and vitamin B6 is essential for energy metabolism
While serotonin cannot cross the blood-brain barrier, tryptophan can, and once there, almost all of it is converted to serotonin. Unlike, peripheral serotonin where only a small percentage is used to generate 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). When you look at the role of tryptophan in the manufacture of brain serotonin, this might have an adverse effect if there is insufficient tryptophan generated (see Serotonin and the Brain section below).
Tryptophan in food enters the body and serotonin is created by a biochemical conversion process that combines tryptophan (essentially a protein) with tryptophan hydroxylase (TPH), a chemical reactor. I suspect other substances might be involved in that process. There are two forms of tryptophan hydroxylase – TPH1 and TPH2, which are encoded on two independent genes. TPH1 is linked to peripheral serotonin while TPH2 is related to brain serotonin. This is the process exploited by Telotristat Ethyl (XERMELO) which is a drug able to help with the symptoms of Carcinoid Syndrome diarrhea (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. Read about Telotristat Ethyl (XERMELO) here.
It should also be noted that the precursor to serotonin, tryptophan, does pass through the BBB and it is therefore possible that tryptophan depletion in the gut and brain can lead to less availability of serotonin in the brain. There are two potential issues:
1. Tryptophan depletion can be caused by dietary restrictions i.e. lack of tryptophan foods. When tryptophan stores are low in the brain, they cannot be converted to serotonin. which may then cause lower availability of serotonin needed to carry out its brain function of regulating mood etc. It follows that foods containing tryptophan might be important for those with consistently elevated gut serotonin levels (except when testing 5HIAA when they are omitted from diet during testing (read more here). See below for some of the dangers of taking 5-HTP or Tryptophan supplements if also taking anti-depressants – always consult your NET Specialist in such matters.
2. The over-secretion of serotonin can lead to less availability of tryptophan. In carcinoid syndrome, functioning tumour cells indirectly depress niacin (B3) production by diverting tryptophan metabolism towards making serotonin and away from niacin. Malnourishment and diarrhea, frequently present in carcinoid syndrome patients, reduce the availability of niacin by decreasing the amount ingested and absorbed. In extreme cases, the decreased availability of niacin eventually results in very low niacin levels responsible for the development of a skin condition called pellagra. For this reason, many NET Dietitians recommend a Vitamin B supplement (e.g. B Complex)
Due to a number of advancements in diagnosis and treatment, in particular, the introduction of somatostatin analogues which help with hormone regulation, these issues are less common but NET patients with highly elevated 5HIAA should remain vigilant to the possibilities.
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).
5HIAA should not be confused with the less reliable ‘serum serotonin’ which is a different test and can be affected by a number of things including the use of anti-depressants (read here about this – a paid article but I wanted you to see the headline). I know many people also test for raw serotonin but many NET specialists say it’s an unreliable test given that serotonin levels are really just a ‘snapshot’ at one time and serotonin is known to spike throughout the day. Your doctor will normally request measurement of 5HIAA in a 24-hour urine collection in the first instance, with serotonin measurement being reserved for cases where the 5-HIAA result does not help. Urine 5HIAA is preferred because it is more stable and, since it is collected for 24 hours, there is more chance of identifying increased 5HIAA concentrations than excess serotonin that is only released intermittently. The 5HIAA blood version is also snapshot but it’s still reliable because the serotonin has taken time to convert to 5HIAA and so spikes of serotonin have been smoothed out to produce an accurate result.
It’s hard to diagnose a serotonin imbalance in the brain because there’s no way to accurately test the amount. Blood serotonin levels don’t necessarily reflect the levels in your brain. It also has to be remembered that serum serotonin and 5HIAA are not absolute tests, they are simply indicators of a potential problem.
I intentionally did not mention the other common test (Chromogranin A) or other markers as although there can sometimes be a correlation and rises and falls, they are measuring different things, but you can read about in my Testing for Markers blog.
Read more about 5HIAA by clicking here or on the picture below.
There is constant discussion and assumption that serotonin-producing tumours are somehow causing depression, anxiety, and rage. Not as simple as that and as most assumptions made in groups are misplaced, I wrote a totally separate article here focussed on brain serotonin. See “Serotonin – it’s a no-brainer!“
I did say it was a difficult jigsaw!
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