Neuroendocrine tumours (NETs) are complex malignancies that arise from neuroendocrine cells, which are integral components of the endocrine system. These cells produce hormones that regulate various bodily functions, including metabolism, growth, and digestion.
Hormonal imbalances can influence the development and progression of NETs. This creates a two-way relationship where hormone imbalances may lead to tumour growth, and the tumours can worsen the hormonal problems.
Neuroendocrine Cancer Australia (NECA), is dedicated to assisting individuals diagnosed with NETs and their loved ones. NECA offers a wealth of resources, educational programs, and advocacy efforts aimed at deepening the understanding of NETs, improving patient care, and encouraging research advancements. Patients can engage with NECA’s comprehensive support and information by calling the NET nurse line.
Understanding the role of hormones in the endocrine system
The endocrine system comprises a network of glands that secrete hormones directly into the bloodstream, orchestrating a range of physiological processes.
Neuroendocrine cells, dispersed throughout the body, act as intermediaries between the nervous and endocrine systems by releasing hormones in response to neural signals.
This intricate network ensures the maintenance of homeostasis and the regulation of critical functions such as metabolism, stress response, and digestion.
How hormonal imbalances can influence NET development
Abnormal hormone levels can create an environment conducive to the growth and development of NETs. These imbalances may trigger excessive neuroendocrine cell activity, leading to uncontrolled proliferation and tumour formation.
Excess hormone production and hyperplasia
Elevated levels of specific hormones can induce hyperplasia, an increase in the number of cells, within neuroendocrine tissues.
For example, chronic hypergastrinemia (excessive production of the hormone gastrin) can result in gastric neuroendocrine cell hyperplasia, potentially progressing to tumour development.
Hormonal feedback loop disruptions
The endocrine system relies on feedback mechanisms to regulate hormone levels. Disruptions in these loops can lead to persistent hormonal imbalances, fostering conditions that promote cancer growth.
Hormone-secreting tumours and secondary effects
Some NETs are functional, meaning they autonomously secrete hormones, leading to further systemic imbalances. This abnormal hormone production can exacerbate symptoms and create a cycle of endocrine disruption, complicating the clinical management of the disease. For example, insulinomas, a type of pancreatic NET, secrete excessive insulin, causing recurrent hypoglycemia and associated symptoms.
Specific hormones implicated in NETs
Certain hormones have been closely associated with the development and behaviour of NETs:
Gastrin
Excessive gastrin production is linked to gastrinomas that can cause Zollinger-Ellison syndrome. This syndrome is characterised by severe peptic ulcers and gastric acid hypersecretion, resulting from gastrin-induced stimulation of the stomach’s parietal cells.
Insulin and glucagon
Pancreatic NETs may secrete insulin or glucagon, leading to significant disturbances in glucose metabolism. Insulinomas result in hypoglycemia due to excessive insulin, while glucagonomas cause hyperglycemia by overproducing glucagon. These hormonal imbalances can manifest as dizziness, confusion, weight loss, and diabetes-like symptoms.
Serotonin
Certain NETs, particularly those originating in the gastrointestinal tract, can produce serotonin, leading to carcinoid syndrome. The excessive serotonin can also contribute to heart valve fibrosis, posing significant cardiovascular risks.
This condition manifests with symptoms such as:
- Flushing
- Diarrhoea
- Wheezing
ACTH and cortisol
Ectopic production of adrenocorticotropic hormone (ACTH) by some NETs can stimulate excessive cortisol release from the adrenal glands, resulting in Cushing’s syndrome. This syndrome is characterised by:
- Weight gain
- Hypertension
- Glucose intolerance
- Muscle weakness
- Osteoporosis
- Increased susceptibility to infections
Conditions that may lead to hormonal imbalance and NET risk
Several medical conditions predispose individuals to hormonal imbalances that can increase NET risk:
Multiple Endocrine Neoplasia (MEN) syndromes
MEN syndromes are genetic disorders causing tumours in multiple endocrine glands, leading to overproduction of various hormones and an elevated risk of developing NETs. MEN1 is associated with tumours in the parathyroid glands, pancreas, and pituitary gland.
Individuals with MEN1 have a higher chance for developing pancreatic NETs, such as gastrinomas and insulinomas.
Chronic inflammation or autoimmune disorders
Chronic inflammatory conditions, such as autoimmune atrophic gastritis, can lead to sustained hormonal imbalances and are linked to an increased risk of gastric NETs. The ongoing inflammation results in hypergastrinemia, promoting neuroendocrine cell proliferation. Patients with autoimmune atrophic gastritis often develop type I gastric NETs due to this mechanism.
Metabolic disorders
Metabolic conditions like diabetes mellitus have been associated with an increased incidence of pancreatic NETs. The interplay between insulin resistance, hyperglycemia, and chronic inflammation in diabetes may contribute to tumour development.
Studies have shown that patients with diabetes have a higher prevalence of pancreatic NETs compared to the general population.
Diagnostic challenges related to hormonal imbalances
Hormonal imbalances in neuroendocrine tumours (NETs) can make diagnosis particularly complex.
Because these tumours can secrete a wide variety of hormones, the symptoms they cause often mimic other, more common conditions, leading to misdiagnosis or delayed detection.
For many patients, this results in a prolonged period of uncertainty before a clear diagnosis is made.
Overlapping symptoms with other endocrine disorders
Many of the symptoms caused by functional NETs overlap with those seen in more common endocrine or metabolic disorders.
For example, fatigue, changes in weight, high blood pressure, anxiety, flushing, and gastrointestinal disturbances are often attributed to thyroid dysfunction, menopause, irritable bowel syndrome, or even stress.
Flushing: a hallmark of carcinoid syndrome caused by serotonin-secreting NETs, is sometimes mistaken for menopause or allergic reactions.
Diarrhoea, a common symptom in hormone-secreting tumours, may be misdiagnosed as inflammatory bowel disease or food intolerance.
These overlaps complicate the clinical picture and may prevent timely referral to a specialist or further investigations that would lead to a NET diagnosis.
Functional vs Nonfunctional NETs
Another key diagnostic hurdle lies in distinguishing between functional and non-functional NETs.
- Functional NETs secrete hormones that cause recognisable symptoms, which can eventually lead to diagnostic testing if a healthcare provider suspects a hormonal disorder.
- In contrast, non-functional NETs do not secrete hormones in clinically significant amounts.
These often remain silent until they grow large enough to cause symptoms through mass effect (such as pain, obstruction, or bleeding) or until they are discovered incidentally during scans for unrelated health concerns.
This diagnostic delay can mean that non-functional NETs are sometimes detected at more advanced stages, making early diagnosis and treatment more difficult.
Monitoring and managing hormonal imbalances in NET patients
Once a NET diagnosis is confirmed, monitoring hormonal imbalances becomes an essential part of treatment and long-term disease management.
Tracking hormone levels over time helps guide treatment decisions, assess tumour behaviour, and evaluate how well therapies are working.
For patients with functional NETs, managing hormone secretion is as important as controlling tumour growth.
Biomarkers and hormone testing
A range of blood and urine tests is available to monitor the hormonal activity of NETs. The most widely used biomarker is chromogranin A (CgA), a protein secreted by neuroendocrine cells. Although it is not specific to one hormone or tumour type, CgA can provide a general indication of tumour burden, particularly in well-differentiated NETs.
Other important markers include:
- 5-Hydroxyindoleacetic acid (5-HIAA): a breakdown product of serotonin, often measured in a 24-hour urine sample or via plasma to assess for carcinoid syndrome.
- Insulin and C-peptide: monitored in patients with insulinomas.
- Gastrin, glucagon, and vasoactive intestinal peptide (VIP): elevated in respective hormone-producing NETs.
- ACTH and cortisol: tested in patients with signs of ectopic Cushing’s syndrome.
These markers help identify the presence and severity of hormone-related symptoms and can be useful in detecting recurrence or disease progression.
Medical therapies to regulate hormone levels
Managing hormone secretion is a cornerstone of treatment for patients with functional NETs. The most commonly used class of medication is somatostatin analogues (SSAs), such as octreotide and lanreotide.
These drugs work by binding to somatostatin receptors on tumour cells, reducing hormone secretion and slowing tumour growth. SSAs are effective in alleviating symptoms of hormone overproduction, such as flushing, diarrhoea, and hypoglycaemia.
Other treatments may be considered depending on the hormone involved and the severity of symptoms.
In patients with advanced disease, treatments like peptide receptor radionuclide therapy (PRRT) or targeted therapies such as everolimus or sunitinib may also play a role in controlling hormone levels by reducing tumour mass or disrupting specific cellular pathways involved in hormone production.
Long-term management involves not only treating the underlying tumour but also controlling the systemic effects of hormone imbalances to improve quality of life. This includes careful nutritional management, psychological support, and regular surveillance through imaging and biomarker testing.
Further information and support for people diagnosed with NETs is available by calling the NECAÂ NET nurse line
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