Firstly, let me say that I have no intention of advising you how to lose or gain weight! Rather, I’d like to discuss what factors might be involved and why people with NETs might lose or gain weight either at diagnosis or after treatment. Clearly I can talk freely about my own experience and associated weight issues. If nothing else, it might help some in thinking about what is causing their own weight issues.
I wrote a patient story for an organisation over 3 years ago and it started with the words “Did you mean to lose weight”. Those were actually the words a nurse said to me after I nonchalantly told her I thought I’d lost some weight (….about half a stone). I answered the question with “no” and this response triggered a sequence of events that led to all the stories in all the posts in this blog (i.e. my diagnosis).
I annoyingly can’t remember at which point I started to lose the weight but I was initially reported to have Iron Deficiency Anemia due to a low hemoglobin result and my subsequent iron test (Serum Ferritin) was also low and out of normal range. This, combined with the weight loss, the GP was spot on by referring me to a clinic. The sequence of events during the referral led to a diagnosis of metastatic NETs (Small Intestine Primary). If I had been a betting man, I would have put money on my GP thinking “Colorectal Cancer”. So my adage “If your doctors don’t suspect something, they won’t detect anything” applies.
I can also tell you that I weigh myself most days at the same time using the same scales. Weight loss or gain needs to be recorded. Clearly 2 or 3 pounds is nothing to worry about, I found you could put on or lose that amount in a day, depending on time of weighing and food intake. I’m looking for downwards or upwards trends of 7lbs or more (3kg).
Why did I lose weight?
The drop from 12st to 11st was clearly something to do with the anemia symptom (the NETs). But after diagnosis, I had major surgery about 10 weeks later. When I left the hospital after my 19 day stay, I was a whole stone lighter (14 lbs or 6.3 kg). I guess 3 feet of intestine, the cecum, an ascending colon, a bit of a transverse colon together with an army of lymph nodes and other abdominal ‘gubbins’ actually weighs a few pounds.
However, add the gradual introduction of foods to alleviate pressure on the ‘new plumbing’, and this is also going to have an effect on weight. I remember my Oncologist after the surgery saying to use full fat milk – the context is lost in memory but I guess he was trying to help me put weight back on. I also vividly remember many of my clothes not fitting me after this surgery. In fact, since 2010, I’ve actually dropped 2 trouser sizes and one shirt/jumper size. I did spend a lot of time in the toilet over the coming months, so I guess that also had an impact! However, what I wasn’t aware of was the side effect of my surgery. I started to put on some weight in time for my next big surgery – a liver resection. The average adult liver weighs 1.5 kg so I lost another 1 kg in one day based on a 66% liver resection.
However, what was also going on was something that took me a while to figure out – malabsorption and vitamin/mineral deficiency. My new ‘plumbing’ wasn’t really as efficient as my old one, so the malabsorption. issues caused by a lack of terminal ileum was slowly starting to have an effect. The commencement of Lanreotide in Dec 2010 added to this complication. That knowledge led me to understand some of the more esoteric nutritional issues that can have a big effect on NET patients and actually lead to a host of side effects that might be confused with one of the several NET syndromes. What it also confirmed to me was that I could still eat foods I enjoy without worrying too much about the effect on my remnant tumours or the threat of a recurrence of my carcinoid syndrome, something I was experiencing prior to and after diagnosis.
Armed with the ‘consequences of NETs’ knowledge, I did eventually adjust my diet and my weight has now ‘flat-lined’ at around 10 st 7 lbs (give or take 1 or 2 lbs fluctuation). Amazingly, the same weight I was when I left hospital after major surgery, looking thin and gaunt and not very well at all! The difference to day is that I have adapted to my new weight and look fit and healthy.
I actually lost another half a stone (7 lbs or 3.5 kg) in 2014 whilst training for an 84 mile charity walk – many commented that I looked thin and gaunt despite being extremely fit from all the training. Perspectives. It took several months to put the weight back on but at least I knew what had caused the loss and then subsequent gain.
I don’t have any appetite issues although I try to avoid big meals due to a shorter gut, so I snack more. With the exception of the 4 months of intense training for the 84 mile hike, I cannot seem to lose or gain weight. As my current weight is bang in the middle of the BMI green zone (healthy), I’m content.
Why do NET patients lose weight?
That’s a tricky one but any authoritative resource will confirm fairly obvious things such as (but not limited to) loss of appetite and side effects of cancer treatments. NETs can be complex so I resorted to researching the ISI Book on NETs, a favourite resource of mine. I wanted to check out any specific mentions of weight and NETs whether at diagnosis or beyond. Here’s some of the things I found out:
Carcinoid Syndrome. Weight loss is listed but not as high a percentage as I thought – although it tends to be tied into those affected most with diarrhea.
Gastrinoma/Zollinger-Ellison Syndrome. Up to half of these patients will have weight loss at diagnosis.
Glucagonoma. 90% will have weight loss.
Pheochromocytoma. Weight loss is usual.
Somatostatinoma. Weight loss in one-third of pancreatic cases and one-fifth in intestinal cases.
VIPoma. Weight loss is usual.
MEN Syndromes. One of the presentational symptoms can be weight loss.
Secondary Effects of NETs.
Many NETs can result in diabetes (particularly certain pNETs) and as somatostatin analogues can inhibit insulin, it could push those at borderline levels into formal diabetic levels (including any type of NET using long term somatostatin analogues). In people with diabetes, insufficient insulin prevents the body from getting glucose from the blood into the body’s cells to use as energy. When this occurs, the body starts burning fat and muscle for energy, causing a reduction in overall body weight.
It must be emphasised that there will always be exceptions and the above will not apply to every single patient with one of the above.
Suggested reading for putting weight back after surgery
An excellent reference document produced by Royal Free Hospital, authored by Tara Whyand and distributed via the NET Patient Foundation – hints and tips for different types of NET by anatomy: click here
What about weight gain?
You always associate weight loss with cancer patients but there are some types of NETs and associated syndromes which might actually cause weight gain. Here’s what I found from ISI and other sources (as mentioned):
Cushing’s Syndrome. Centripetal weight gain is mentioned. (Centripetal – tends to the centre of the body). I also noted that Cushing’s Syndrome tends to be much more prevalent in females. Cushing’s syndrome comprises the signs and symptoms caused by excessive amounts of the hormone cortisol (hypercortisolism) or by an overdosage of drugs known as glucocorticoids.
Insulinoma. Weight gain occurs in around 40% of cases, because patients may eat frequently to avoid symptoms. However, according to an Insulinoma support group site, I did note that after treatment (some stability), things can improve.
Again, it must be emphasised that there will always be exceptions and the above will not apply to every single patient with one of the above. As in weight loss scenarios, the Secondary Effects of NETs can have an effect.Hypothyroidism is another potential issue and weight gain is a listed symptom. I just been diagnosed with hypothyroidism this year but I was not gaining weight!
The NETs Jigsaw
Like anything in NETs, things can get complex. So it is entirely possible that weight loss or weight gain is directly caused by NETs, can be caused by side effects/secondary effects of treatment, and it’s also possible that it could be something unrelated to NETs (Dr Liu “Even NET patients get regular illnesses“). I guess some people might have a good idea of the reason for theirs – my initial weight loss was without doubt caused by the cancer and the post diagnostic issues caused by the consequences of the cancer.
I guess that weight loss or weight gain can be a worry. I also suspect that people might be happy to lose or gain weight if they were under/over weight before diagnosis (every cloud etc). However, if you are progressively losing weight, I encourage you to seek advice soonest or ask to see a dietician (preferably one who understands NETs).
Edit: I changed my blood thinner in May 2017 and lost 2kg (4 pounds) after 6 months.
Edit: I started Creon at the beginning of 2018 (read about this here) and almost immediately put on 2kg (4 pounds) to offset the 2kg loss from 6 months prior. However, no real change after 3 months of Creon (March 2018).
Edit: I was recently diagnosed with Hypothyroidism, one of the symptoms can be weight gain. Clearly that has not applied to me. Hyperthyroidism is the opposite condition where weight loss is a symptom.
Edit: Due to a bad chest infection in June 2018 and due to the consequences of the effects of that illness and most likely the treatments undergone, I have dropped three quarters of a stone (~10lbs). My lightest weight for over 30 years. To me that is a significant loss of weight in such a short space of time. Currently trying to put it back on again – I need the weight!
Edit: 4 Sep 2018. After the 10lbs (~4.5kg) loss following the chest infection, people who see me regularly have noticed the visible difference. I’m still struggling to get back beyond 10st after 2 months. I’m monitoring this really closely.
Edit: 28 Nov 2018. I’m back at 10st after increasing my dosage of Creon.
Edit: 10 Jan 2019. I’m back at 10st 3lbs, my approximate weight before the chest infection. It’s taken 7 months and the recent acceleration coincides with Creon dose increase.
Edit 7th Feb 2019. Changed from Creon to Nutrizym.
Edit: 17 Mar 2019. It appears my trouser waist size is back to 32″. Is the use of Pancreatic Enzymes making me eat more, or getting more nutrients through, or making me eat food which makes me put on weight?
For those wishing to see the output from an online discussion with Tara Whyand on the subject of ‘Weight’ issues for NET patients – please see this link inside my closed Facebook group.
In my article ‘Ever wonder what caused your NET’, I concluded that currently, the only known scientifically explained causes for NETs were hereditary/genetic in nature. This is mostly associated with those who have MEN syndromes (yes, they are a syndrome not a type of tumour) and a few other less common types of NET including Pheochomocytoma/Paraganglioma (Pheo/Para) and Medullary Thyroid Carcinoma (MTC) (the familial version of MTC is often referred to as FMTC). However, please note this does not mean that all those diagnosed with pancreatic, parathyroid, pituarity, Pheo/Para and MTC tumours, will have any hereditary or genetic conditions, many will simply be sporadic tumors.
In recent years, it has become increasingly apparent that a number of Neuroendocrine tumours arise as a result of germline genetic mutations and are inherited in an autosomal dominant pattern. The number of genes implicated is increasing.
Apparently, 5-10% of Gastroenteropancreatic NETs (GEP NETs) are estimated to have a hereditary background. Hereditary syndromes associated with these include Multiple Endocrine Neoplasia (MEN), Von Hippel Lindau (VHL), Neurofibromatosis Type 1 (NF1), Tuberous Sclerosis (TS) and others. People who have a genetic condition may present with the tumors (perhaps along with an associated functional hormone syndrome) and so the genetic condition if there is one, may not be known at this point.
How will I know if I am affected?
Some people do worry about this, often because of what they find on the internet including inside patient forums. I suspect some people already know via family connections and as an example (there are many), I guess if you have 2 tumors found in (say) parathyroid and pancreas, it should at least raise a suspicion for MEN1 and be investigated.
Many people say how do I know, how do I check and this is obviously a delicate subject. Of course, your first port of call should be your NET specialist if you suspect or know of any connection.
Thus why I was interested in a paper published in Springer Link – titled “When should genetic testing be performed in patients with neuroendocrine tumours.” When reading, you’ll find it’s actually much more than that! Check it out here:
When should genetic testing be performed in patients with neuroendocrine tumours?
In this review, the authors examined the features which may lead a clinician to suspect that a patient may have an inherited cause of a NET and they outlined which underlying conditions should be suspected. They also discussed what type of screening may be appropriate in a variety of situations. If there is a way to identify which patients are likely to have a germline mutation, this would enable clinicians to counsel patients adequately about their future disease risk, and allows for earlier detection of at-risk patients through family screening. There’s a couple of minor errors in the text but I’ve contacted the authors who also agreed they should have included the pituitary.
The authors focused on presentations of NETs of the gastrointestinal system, chromaffin cell tumours (Pheochromocytoma and Paraganglioma) and Medullary Thyroid Carcinoma. Pituitary tumors (normally associated with MEN1), were not considered in scope for the review. Interesting thought, the review includes news of a move by endocrinologists to reclassify ‘Pituitary Adenomas’ as Pituitary NETs (PitNETs). Read the abstract here. This would appear to be in line with a gradual shift from the benign nomenclature associated with certain NETs to the ‘malignant’ potential of these type of tumors. The abbreviation is also in line with others, e.g. pNET, SiNET, etc. A useful reminder that we must stop using the term ‘Carcinoid‘ as this is regressing this extremely useful initiative to highlight the malignant potential of all NETs.
There also appears to be some linkage to the study looking at the possibility of familial Small Intestine NETs (SiNETs). You can read more about a US registered trial here (with apologies for use of the now defunct term ‘Carcinoid‘).
This is a complex subject and the text above is very basic. If you wish to dig further, the quoted reference is a good read. Just to emphasise, it’s aim is to provide advice about when to recommend genetic testing for NETs, and in doing so provides some useful reference information. Please also note they are finding new genetic links all the time so there could be some omissions of recently discovered genes but the article remains good enough as a primer on the subject. It’s broken down into 4 distinct tumor groupings:
Until I was diagnosed with metastatic Neuroendocrine Cancer, I didn’t have a clue about hormones – it’s one of those things you just take for granted. However, hormones are vital to human health (male and female) and it’s only when things go wrong you suddenly appreciate how important they are ……..like a lot of other things in life I suppose! The presence of over-secreting hormones (often called peptides throughout) is useful to aid diagnosis albeit it often means the tumours have metastasized. It’s also a frequent indication that the person has an associated NET syndrome.
This is a really complex area and to understand the hormone problems associated with Neuroendocrine Cancer, you need to have a basic knowledge of the endocrine and neuroendocrine systems. I’ve no intention of explaining that (!) – other than the following high level summary:
Glands in the endocrine system use the bloodstream to monitor the body’s internal environment and to communicate with each other through substances called hormones, which are released into the bloodstream. Endocrine glands include; Pituitary, Hypothalmus, Thymus, Pineal, Testes, Ovaries Thyroid, Adrenal, Parathyroid, Pancreas.
A Hormone is a chemical that is made by specialist cells, usually within an endocrine gland, and it is released into the bloodstream to send a message to another part of the body. It is often referred to as a ‘chemical messenger’. In the human body, hormones are used for two types of communication. The first is for communication between two endocrine glands, where one gland releases a hormone which stimulates another target gland to change the levels of hormones that it is releasing. The second is between an endocrine gland and a target organ, for example when the pancreas releases insulin which causes muscle and fat cells to take up glucose from the bloodstream. Hormones affect many physiological activities including growth, metabolism, appetite, puberty and fertility.
The Endocrine system. The complex interplay between the glands, hormones and other target organs is referred to as the endocrine system.
The Neuroendocrine System. The diffuse neuroendocrine system is made up of neuroendocrine cells scattered throughout the body. These cells receive neuronal input and, as a consequence of this input, release hormones to the blood. In this way they bring about an integration between the nervous system and the endocrine system (i.e. Neuroendocrine). A complex area but one example of what this means is the adrenal gland releasing adrenaline to the blood when the body prepares for the ‘fight or flight’ response in times of stress, ie, for vigorous and/or sudden action.
Hormones – the NET Effect
At least one or more hormones will be involved at various sites and even within certain syndromes, the dominant and offending hormone may differ between anatomical tumour sites. For example, NETs of the small intestine may overproduce serotonin and other hormones which can cause a characteristic collection of symptoms currently called carcinoid syndrome. The key symptoms are flushing,diarrhea and general abdominal pain, loss of appetite, fast heart rate and shortness of breath and wheezing. The main symptom for me was facial flushing and this was instrumental in my eventual diagnosis. The fact that I was syndromic at the point of diagnosis made it easier to discover, albeit the trigger for the investigation was a fairly innocuous event. Other types of NETs are also affected by the overproduction of hormones including Insulinomas, Gastrinomas, Glucagonomas, VIPomas, Somatostatinomas, and others. These can cause their own syndromes and are not part of carcinoid syndrome as some organisations incorrectly state. For more on NET syndromes – Read Here.
So are hormones horrible?
Absolutely not, they are essential to the normal function of the human body. For example if you didn’t have any of the hormone Serotonin in your system, you would become extremely ill. On the other hand, if your glands start secreting too much of certain hormones, your body could become dysfunctional and in some scenarios, this situation could become life threatening. So hormones are good as long as the balance is correct. NET patients with an oversecreting tumor may be classed as “functional”.
Functional tumors make extra amounts of hormones, such as gastrin, insulin, and glucagon, that cause signs and symptoms.
Nonfunctional tumors do not make extra amounts of hormones. Signs and symptoms are caused by the tumor as it spreads and grows. Many NET patients are deemed to be “non-functioning” with normal hormone levels. It’s also accurate to say that many can move from one stage to the other.
Location Location Location
It’s accurate to say that the type and amount of hormone secretion differs between locations or sites of the functional tumor and this can also create different effects. The division of NETs into larger anatomical regions appears to differ depending on where you look but they all look something likes this:
Foregut NETs: In the respiratory tract, thymus, stomach, duodenum, and pancreas. This group mostly lack the enzyme aromatic amino decarboxylase that converts 5-HTP (5-Hydroxytryptophan – a precursor to serotonin) to serotonin (5-HT); such tumours tend to produce 5-HTP and histamine instead of serotonin.
The Pancreas is a particularly prominent endocrine organ and can produce a number of different syndromes each with their associated hormone oversecretion – although many can be non-functional (at least to begin with), (see below for more detail). It’s also possible to see predominantly serotonin secreting tumors in places such as the pancreas (although what you would call that type of NET is open for debate).
Lung NETs rarely produce serotonin, but may instead secrete histamine causing an ‘atypical’ carcinoid syndrome with generalized flushing, diarrhea, periorbital oedema, lacrimation and asthma. They may also produce adrenocorticotropic hormone (ATCH) or corticotropin-releasing factor (CRP), resulting in an ectopic Cushing’s syndrome. Please note the respiratory tract and thymus are not really anatomically pure ‘Foregut’ – but in NETs, grouped there for convenience.
Gastric (Stomach) NETs. Gastrin is the main hormone but there can also be histamine producing an atypical carcinoid syndrome effect.
Midgut NETs: In the small intestine, appendix, and ascending colon. For example, serotonin secreting tumors tend to be associated with carcinoid syndrome which tends to be associated with midgut NETs and this is normally the case. Many texts will also tell you that a syndrome only occurs at a metastatic stage. Both are a good rule of thumb but both are technically incorrect. For example, ovarian NETs can have a form of carcinoid syndrome without liver metastasis (tends to be described as atypical carcinoid syndrome).
Hindgut NETs (transverse, descending colon and rectum) cannot convert tryptophan to serotonin and other metabolites and therefore rarely cause carcinoid syndrome even if they metastasise to the liver.
Less Common Locations – there are quite a few less common NET locations which may involve less common hormones – some are covered below including the key glands contributing to NETs.
Unknown Primary? – One clue to finding the primary might be by isolating an offending hormone causing symptoms.
The key NET hormones
I used the example of Serotoninabove because it is the most cited problem with NET Cancer although it does tend to be most prevalent in midgut tumors. Serotonin is a monoamine neurotransmitter synthesized from Tryptophan, one of the eight essential amino acids (defined as those that cannot be made in the body and therefore must be obtained from food or supplements). About 90% of serotonin produced in the body is found in the enterochromaffin cells of the gastrointestinal (GI) tract where it is used mainly to regulate intestinal movements amongst other functions. The remainder is synthesized in the central nervous system where it mainly regulates mood, appetite, and sleep. Please note there is no transfer of serotonin across the blood-brain barrier.
Alterations in tryptophan metabolism may account for many symptoms that accompany carcinoid syndrome. Serotonin in particular is the most likely cause of many features of carcinoid syndrome as it stimulates intestinal motility and secretion and inhibits intestinal absorption. Serotonin may also stimulate fibroblast growth and fibrogenesis and may thus account for peritoneal and valvular fibrosis encountered in such tumours; serotonin, however, it is said not to be associated with flushing. The diversion of tryptophan to serotonin may lead to tryptophan deficiency as it becomes unavailable for nicotinic acid synthesis, and is associated with reduced protein synthesis and hypoalbuminaemia; this may lead to the development of pellagra (skin rash, glossitis, stomatitis, confusion/dementia).
Serotonin is also thought to be responsible for ‘right sided’ heart disease (Carcinoid Heart Disease). It is thought that high levels of serotonin in the blood stream damages the heart, leading to lesions which cause fibrosis, particularly of the heart valves. This generally affects the right side of the heart when liver metastases are present. The left side of the heart is usually not affected because the lungs can break down serotonin. Right sided heart failure symptoms include swelling (edema) in the extremities and enlargement of the heart.
Whilst serotonin can be measured directly in the blood, it’s said to be more accurate to measure 5HIAA (the output of serotonin) via blood or urine, the latter is said to be the most accurate.
Tackykinins include Substance P, Neurokinin A, Neuropeptide K and others. They are active in the enterochromaffin cells of the GI tract but can also be found in lung, appendiceal and ovarian NETs, and also in Medullary Thyroid Carcinoma and Pheochromocytomas. They are thought to be involved in flushing and diarrhea in midgut NETs. The most common tachykinin is Substance P, which is a potent vasodilator (substances which open up blood vessels). Telangiectasias are collections of tiny blood vessels which can develop superficially on the faces of people who have had NETs for several years. They are most commonly found on the nose or upper lip and are purplish in color. They are thought to be due to chronic vasodilatation.
Histamine is a hormone that is chemically similar to the hormones serotonin, epinephrine, and norepinephrine. After being made, the hormone is stored in a number of cells (e.g., mast cells, basophils, enterochromaffin cells). Normally, there is a low level of histamine circulating in the body. However (and as we all know!), the release of histamine can be triggered by an event such as an insect bite. Histamine causes the inconvenient redness, swelling and itching associated with the bite. For those with severe allergies, the sudden and more generalized release of histamine can be fatal (e.g., anaphylactic shock). Mast cell histamine has an important role in the reaction of the immune system to the presence of a compound to which the body has developed an allergy. When released from mast cells in a reaction to a material to which the immune system is allergic, the hormone causes blood vessels to increase in diameter (e.g., vasodilation) and to become more permeable to the passage of fluid across the vessel wall. These effects are apparent as a runny nose, sneezing, and watery eyes. Other symptoms can include itching, burning and swelling in the skin, headaches, plugged sinuses, stomach cramps, and diarrhea. Histamine can also be released into the lungs, where it causes the air passages to become constricted rather than dilated. This response occurs in an attempt to keep the offending allergenic particles from being inhaled. Unfortunately, this also makes breathing difficult. An example of such an effect of histamine occurs in asthma. Histamine has also been shown to function as a neurotransmitter (a chemical that facilitates the transmission of impulses from one neural cell to an adjacent neural cell).
In cases of an extreme allergic reaction, adrenaline is administered to eliminate histamine from the body. For minor allergic reactions, symptoms can sometimes be lessened by the use of antihistamines that block the binding of histamine to a receptor molecule. Histamine is thought to be involved with certain types and locations of NET, including Lung and foregut NETs where they can cause pulmonary obstruction, atypical flush and hormone syndromes.
Histamine, another amine produced by certain NETs (particularly foregut), may be associated with an atypical flushing and pruritus; increased histamine production may account for the increased frequency of duodenal ulcers observed in these tumours.
Kallikrein is a potent vasodilator and may account for the flushing and increased intestinal mobility.
Although prostaglandins are overproduced in midgut tumours, their role in the development of the symptoms of carcinoid syndrome is not well established but triggering peristalsis is mentioned in some texts.
Bradykinin acts as a blood vessel dilator. Dilation of blood vessels can lead to a rapid heartbeat (tachycardia) and a drop in blood pressure (hypotension). Dilation of blood vessels may also be partly responsible for the flushing associated with carcinoid syndrome.
Gastrin is a hormone that is produced by ‘G’ cells in the lining of the stomach and upper small intestine. During a meal, gastrin stimulates the stomach to release gastric acid. This allows the stomach to break down proteins swallowed as food and absorb certain vitamins. It also acts as a disinfectant and kills most of the bacteria that enter the stomach with food, minimising the risk of infection within the gut. Gastrin also stimulates growth of the stomach lining and increases the muscle contractions of the gut to aid digestion. Excess gastrin could indicate a NET known as a Gastric NET (stomach) or a pNET known as Gastrinoma (see pancreatic hormones below).
Calcitonin is a hormone that is produced in humans by the parafollicular cells (commonly known as C-cells) of the thyroid gland. Calcitonin is involved in helping to regulate levels of calcium and phosphate in the blood, opposing the action of parathyroid hormone. This means that it acts to reduce calcium levels in the blood. This hormone tends to involve Medullary Thyroid Carcinoma and Hyperparathyroidism in connection to those with Multiple Endocrine Neoplasia. Worth also pointing out the existence of Calcitonin Gene-Related Peptide (CGRP) which is a member of the calcitonin family of peptides and a potent vasodilator. Please note that hypothyroidism is often a side effect of NETs or treatment for NETs – please click here to read about the connection.
HPA AXIS – It’s important to note something called the HPA axis when discussing pituitary hormones as there is a natural and important connection and rhythm between the Hypothalamus, Pituitary and the Adrenal glands. However, I’m only covering the pituitary and adrenal due to their strong connection with NETs.
Adrenocorticotropic hormone (ATCH) is made in the corticotroph cells of the anterior pituitary gland. It’s production is stimulated by receiving corticotrophin releasing hormone (CRH) from the Hypothalamus. ATCH is secreted in several intermittent pulses during the day into the bloodstream and transported around the body. Like cortisol (see below), levels of ATCH are generally high in the morning when we wake up and fall throughout the day. This is called a diurnal rhythm. Once ACTH reaches the adrenal glands, it binds on to receptors causing the adrenal glands to secrete more cortisol, resulting in higher levels of cortisol in the blood. It also increases production of the chemical compounds that trigger an increase in other hormones such as adrenaline and noradrenaline. If too much is released, The effects of too much ATCH are mainly due to the increase in cortisol levels which result. Higher than normal levels of ATCH may be due to:
Cushing’s disease – this is the most common cause of increased ATCH. It is caused by a tumor in the pituitary gland (PitNET), which produces excess amounts of ATCH. (Please note, Cushing’s disease is just one of the numerous causes of Cushing’s syndrome). It is likely that a Cortisol test will also be ordered if Cushing’s is suspected.
A tumour outside the pituitary gland, producing ATCH is known as an ectopic ATCH. With NETs, this is normally a pNET, Lung/Bronchial/Pulmonary NET or Pheochromocytoma.
Adrenaline and Noradrenline
These are two separate but related hormones and neurotransmitters, known as the ‘Catecholamines’. They are produced in the medulla of the adrenal glands and in some neurons of the central nervous system. They are released into the bloodstream and serve as chemical mediators, and also convey the nerve impulses to various organs. Adrenaline has many different actions depending on the type of cells it is acting upon. However, the overall effect of adrenaline is to prepare the body for the ‘fight or flight’ response in times of stress, i.e. for vigorous and/or sudden action. Key actions of adrenaline include increasing the heart rate, increasing blood pressure, expanding the air passages of the lungs, enlarging the pupil in the eye, redistributing blood to the muscles and altering the body’s metabolism, so as to maximise blood glucose levels (primarily for the brain). A closely related hormone, noradrenaline, is released mainly from the nerve endings of the sympathetic nervous system (as well as in relatively small amounts from the adrenal medulla). There is a continuous low-level of activity of the sympathetic nervous system resulting in release of noradrenaline into the circulation, but adrenaline release is only increased at times of acute stress. These hormones are normally related to adrenal and extra adrenal NETs such as Pheochromocytoma and Paraganglioma. Like serotonin secreting tumours, adrenal secreting tumours convert the offending hormone into something which comes out in urine. In fact, this is measured (amongst other tests) by 24 hour urine test very similar to 5HIAA (with its own diet and drug restrictions). It’s known as 24-hour urinary catacholamines and metanephrines. Worth noting that adrenaline is also known as Epinephrine (one of the 5 E’s of Carcinoid Syndrome).
This is a steroid hormone, one of the glucocorticoids, made in the cortex of the adrenal glands and then released into the blood, which transports it all round the body. Almost every cell contains receptors for cortisol and so cortisol can have lots of different actions depending on which sort of cells it is acting upon. These effects include controlling the body’s blood sugar levels and thus regulating metabolism acting as an anti-inflammatory, influencing memory formation, controlling salt and water balance, influencing blood pressure. Blood levels of cortisol vary dramatically, but generally are high in the morning when we wake up, and then fall throughout the day. This is called a diurnal rhythm. In people who work at night, this pattern is reversed, so the timing of cortisol release is clearly linked to daily activity patterns. In addition, in response to stress, extra cortisol is released to help the body to respond appropriately. Too much cortisol over a prolonged period of time can lead to Cushing’s syndrome. Cortisol oversecretion can be associated with Adrenal Cortical Carcinoma (ACC) which can sometimes be grouped within the NET family.
Other hormones related to ACC include:
Androgens (e.g. Testosterone) – increased facial and body hair, particularly females. Deepened voice in females.
Estrogen – early signs of puberty in children, enlarged breast tissue in males.
Aldosterone – weight gain, high blood pressure.
Adrenal Insufficiency (Addison’s Disease) occurs when the adrenal glands do not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. For this reason, the disease is sometimes called chronic adrenal insufficiency, or hypocortisolism.
Parathyroid hormone (PTH) is secreted from four parathyroid glands, which are small glands in the neck, located behind the thyroid gland. Parathyroid hormone regulates calcium levels in the blood, largely by increasing the levels when they are too low. A primary problem in the parathyroid glands, producing too much parathyroid hormone causes raised calcium levels in the blood (hypercalcaemia – primary hyperparathyroidism). You may also be offered an additional test called Parathyroid Hormone-Related Peptide (PTHrP). They would probably also measure Serum Calcium in combination with these type of tests. The parathyroid is one of the ‘3 p’ locations often connected to Multiple Endocrine Neoplasia – MEN 1
Pancreatic Hormones (Syndromes)
Pancreatic neuroendocrine tumors form in hormone-making cells of the pancreas. You may see these described as ‘Islet Cells’ or ‘Islets of Langerhans’ after the scientist who discovered them. Pancreatic NETs may also be functional or non-functional:
Functional tumors make extra amounts of hormones, such as gastrin, insulin, and glucagon, that cause signs and symptoms.
Nonfunctional tumors do not make extra amounts of hormones. Signs and symptoms are caused by the tumor as it spreads and grows.
There are different kinds of functional pancreatic NETs. Pancreatic NETs make different kinds of hormones such as gastrin, insulin, and glucagon. Functional pancreatic NETs include the following:
Gastrinoma: A tumor that forms in cells that make gastrin. Gastrin is a hormone that causes the stomach to release an acid that helps digest food. Both gastrin and stomach acid are increased by gastrinomas. When increased stomach acid, stomach ulcers, and diarrhea are caused by a tumor that makes gastrin, it is called Zollinger-Ellison syndrome. A gastrinoma usually forms in the head of the pancreas and sometimes forms in the small intestine. Most gastrinomas are malignant (cancer).
Insulinoma: A tumor that forms in cells that make insulin. Insulin is a hormone that controls the amount of glucose (sugar) in the blood. It moves glucose into the cells, where it can be used by the body for energy. Insulinomas are usually slow-growing tumors that rarely spread. An insulinoma forms in the head, body, or tail of the pancreas. Insulinomas are usually benign (not cancer).
Glucagonoma: A tumor that forms in cells that make glucagon. Glucagon is a hormone that increases the amount of glucose in the blood. It causes the liver to break down glycogen. Too much glucagon causes hyperglycemia (high blood sugar). A glucagonoma usually forms in the tail of the pancreas. Most glucagonomas are malignant (cancer).
Pancreatic Polypeptide (PPoma). A pancreatic polypeptide is a polypeptide hormone secreted by the pancreatic polypeptide (PP) cells of the islets of Langerhans in the endocrine portion of the pancreas. Its release is triggered in humans by protein-rich meals, fasting, exercise, and acute hypoglycemia and is inhibited by somatostatin and intravenous glucose. The exact biological role of pancreatic polypeptide remains uncertain. Excess PP could indicate a pNET known as PPoma.
Other types of tumors: There are other rare types of functional pancreatic NETs that make hormones, including hormones that control the balance of sugar, salt, and water in the body. These tumors include:
VIPomas, which make vasoactive intestinal peptide. VIPoma may also be called Verner-Morrison syndrome, pancreatic cholera syndrome, or the WDHA syndrome (Watery Diarrhea, Hypokalemia (low potassium)and Achlorhydria).
Somatostatinomas, which make somatostatin. Somatostatin is a hormone produced by many tissues in the body, principally in the nervous and digestive systems. It regulates a wide variety of physiological functions and inhibits the secretion of other hormones, the activity of the gastrointestinal tract and the rapid reproduction of normal and tumour cells. Somatostatin may also act as a neurotransmitter in the nervous system.
Having certain syndromes can increase the risk of pancreatic NETs.
Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Multiple endocrine neoplasia type 1 (MEN1) syndrome is a risk factor for pancreatic NETs.
Signs and symptoms of pancreatic NETs
Signs or symptoms can be caused by the growth of the tumor and/or by hormones the tumor makes or by other conditions. Some tumors may not cause signs or symptoms. Check with your doctor if you have any of these problems.
Signs and symptoms of a non-functional pancreatic NET
A non-functional pancreatic NET may grow for a long time without causing signs or symptoms. It may grow large or spread to other parts of the body before it causes signs or symptoms, such as:
A lump in the abdomen.
Pain in the abdomen or back.
Yellowing of the skin and whites of the eyes.
Signs and symptoms of a functional pancreatic NET
The signs and symptoms of a functional pancreatic NET depend on the type of hormone being made.
Too much gastrin may cause:
Stomach ulcers that keep coming back.
Pain in the abdomen, which may spread to the back. The pain may come and go and it may go away after taking an antacid.
The flow of stomach contents back into the esophagus (gastroesophageal reflux).
Too much insulin may cause:
Low blood sugar. This can cause blurred vision, headache, and feeling lightheaded, tired, weak, shaky, nervous, irritable, sweaty, confused, or hungry.
Too much glucagon may cause:
Skin rash on the face, stomach, or legs.
High blood sugar. This can cause headaches, frequent urination, dry skin and mouth, or feeling hungry, thirsty, tired, or weak.
Blood clots. Blood clots in the lung can cause shortness of breath, cough, or pain in the chest. Blood clots in the arm or leg can cause pain, swelling, warmth, or redness of the arm or leg.
Weight loss for no known reason.
Sore tongue or sores at the corners of the mouth.
Too much vasoactive intestinal peptide (VIP) may cause:
Very large amounts of watery diarrhea.
Dehydration. This can cause feeling thirsty, making less urine, dry skin and mouth, headaches, dizziness, or feeling tired.
Low potassium level in the blood. This can cause muscle weakness, aching, or cramps, numbness and tingling, frequent urination, fast heartbeat, and feeling confused or thirsty.
Cramps or pain in the abdomen.
Weight loss for no known reason.
Too much somatostatin may cause:
High blood sugar. This can cause headaches, frequent urination, dry skin and mouth, or feeling hungry, thirsty, tired, or weak.
Steatorrhea (very foul-smelling stool that floats).
Yellowing of the skin and whites of the eyes.
Weight loss for no known reason.
Too much pancreatic polypeptide may cause:
an enlarged liver.
Clearly the presenting symptoms will give doctors a clue to the oversecreting hormone (see list above). Excessive secretions or high levels of hormones and other substances can be measured in a number of ways. For example:
Well known tests for the most common types of NET include 5-Hydroxyindoleacetic Acid (5-HIAA) 24 hour urine test which is also measured by a blood draw. Note: -tumor markers can be measured simultaneously e.g. Chromogranin A (CgA) blood test and/or Pancreastatin as there can very often be a correlation between tumour mass and tumour secreting activity. CgA / Pancreastatin is a blood test which measures a protein found in many NET tumour cells. These marker tests are normally associated with tumour mass rather than tumour functionality.
By measuring the level of 5-HIAA in the urine or blood, healthcare providers can calculate the amount of serotonin in the body (5-HIAA is a by-product of serotonin). 5-HIAA test is the most common biochemical test for carcinoid syndrome or the degree of how ‘functional’ tumours are. If you’ve understood the text above, you can now see why there are dietary and drug restrictions in place prior to the test.
Pancreatic Hormone testing. There are other tests for other hormones and there is a common test which measured the main hormones seen in NETs. It may be called different things in different countries, but in UK, it’s known as a ‘Fasting Gut Hormone Profile‘.
Scratching the surface here so for a comprehensive list of marker tests for NETs, have aread here.
Treatment for Over-secreting Hormones
Of course, reducing tumour bulk through surgery and other treatment modalities, should technically reduce over-secretion (I suspect that doesn’t work for all). Other treatments may have the dual effect of reducing tumour burden and the effects of hormone oversecretions.
One of the key treatment breakthroughs for many NET cancer patients, is the use of ‘Somatostatin Analogues’ mainly branded as Octreotide (Sandostatin) or Lanreotide (Somatuline). People tend to associate these drugs with serotonin related secretions and tumours but they are in actual fact useful for many others including the pancreatic NETs listed above. Patients will normally be prescribed these drugs if they are displaying these symptoms but some people may be more avid to the drug than others and this may influence future use and dosages. This is another complex area but I’ll try to describe the importance here in basic terms. Somatostatin is a naturally occurring protein in the human body. It is an inhibitor of various hormones secreted from the endocrine system (some of which were listed above) and it binds with high affinity to the five somatostatin receptors found on secretory endocrine cells. NETs have membranes covered with receptors for somatostatin. However, the naturally occurring Somatostatin has limited clinical use due to its short half-life (<3 min). Therefore, specific somatostatin analogues (synthetic versions) have been developed that bind to tumours and block hormone release. Thus why Octreotide and Lanreotide do a good job of slowing down hormone production, including many of the gut hormones controlling emptying of the stomach and bowel. It also slows down the release of hormones made by the pancreas, including insulin and digestive enzymes – so there can be side effects including fat malabsorption.
The recent introduction of Telotristat Ethyl(XERMELO) is interesting as that inhibits a precursor to serotonin and reduces diarrhea in those patients where it is not adequately controlled by somatostatin analogues.
Other than the effects of curative or cytoreductive surgery, some NETs may have very specialist drugs for inhibiting the less common hormone types. This is not an exhaustive list.
Worth also noting that oversecreting hormones can contribute to a phenomenon known as Carcinoid Crisis – read more here. For catacholamine secreting tumors (Pheochromocytoma/Paraganglioma), this may be known as Intraoperative Hypertensive Crisis
Sorry about the long article – it’s complex and you should always consult your specialist about issues involving hormones, testing for hormones and treating any low or high scores.