Ectopic Hormones - Production, Symptoms, Diagnosis and Treatment

What Are Ectopic Hormones?

Ectopic hormones are hormones derived from tumors of the tissues that are normally not associated with hormone production. Production of these hormones is generally not considered normal; in fact, it is considered harmful to the homeostasis of the body. Ectopic hormones cause dysregulation of various metabolic functions that are dependent on these hormones. An example of an ectopic hormone is the production of parathyroid hormone-related protein (PTHrP) by a squamous cell carcinoma.

Moreover, peptides produced by neuroendocrine tumors are the most common form of ectopic hormone production. Neuroendocrine cells are dispersed evenly throughout the body, especially in the lungs, pancreas, thyroid gland, gastrointestinal tract, breast, prostate, and skin. There is another type of ectopic hormone production in which hormone-producing cells whose machinery has been co-opted to produce another hormone. An example of this other type of ectopic hormone production of adrenocorticotropin (ACTH) hormone by neuroendocrine tumors. These ectopic hormones present several signs and symptoms, which is collectively known as paraneoplastic syndrome.

What Are the Common Examples of Ectopic Hormones?

Some common examples of ectopic hormones are:

• Pancreatic islet cell carcinomas are sometimes found to be secreting ACTH (adrenocorticotropic hormone), which is usually secreted by the pituitary gland.

• Inappropriate secretion of ACTH by small cell carcinoma of the lungs.

• The most prevalent example of ectopic hormone secretion is a peptide hormone known as the parathyroid hormone-related peptide, which is secreted by almost ten percent of malignant tumors and causes hypercalcemia (called hypercalcemia of malignancy).

What Are the Clinical Syndromes Caused by Ectopic Hormone Production?

1. Cushing's Syndrome: Cushing's syndrome, also known as ectopic Cushing's syndrome, in this case, is primarily caused by cancer of small cells of the lungs, pancreatic carcinomas, neural tumors, and thymoma. The ectopic hormones produced are ectopic adrenocorticotropic hormones (ACTH) or ACTH-like substances.

2. Syndrome of Inappropriate Antidiuretic Hormone: It is mainly caused by small cell lung cancer, and the ectopic hormone produced is an ectopic antidiuretic hormone (ADH).

3. Hypercalcemia: Hypercalcemia is the increased concentration of calcium in the blood, and hypercalcemia due to ectopic hormone production is mainly caused due to lung cancer (squamous cell), breast cancer, renal cancer, bladder cancer, multiple myeloma, ovarian cancer, and squamous cell carcinoma (of lungs, head, neck, and esophagus).

4. Hypoglycemia: Hypoglycemia is the reduced blood sugar level caused due to ectopic hormone production and is mainly caused by fibrosarcoma (rare, soft tissue cancer) and hemangiopericytoma (rare tumor involving blood vessels and soft tissues). And the ectopic hormone produced is an ectopic parathyroid-hormone-related peptide, tumor necrosing factor, and interleukin-1 family.

5. Hyperaldosteronism: It is primarily caused by non-Hodgkin's lymphoma, ovarian cancer, and pulmonary cancer. The ectopic hormone formed is ectopic aldosterone.

Why Does Ectopic Hormone Production Occur?

Multiple theories explain the production of ectopic hormones by tumors:

• One theory suggests that some fundamental changes occur at the genomic level that allows new gene expression of the tissue. Therefore, neoplastic changes cause some genes to be switched on and some genes to be switched off.

• Another theory suggests that the neoplastic cell is derived from a stem cell that was capable of expressing the gene at an early developmental stage but is later suppressed and that following neoplastic transformation, the cells undergo de-differentiation and regain some of their developmental properties.

• One more theory suggests that some widely expressed genes that are transcribed but not translated under normal conditions may be amplified and translated due to the action of different promoters.

How Is Ectopic Corticotropin (ACTH) Produced?

The main cells responsible for ectopic ACTH production are:

• Bronchus cells (oat-cell).

• Carcinoma of gastrointestinal tract and lungs.

• Thymus cells.

• Thyroid cells.

• Pancreatic islets.

• Pheochromocytoma.

• Parotid.

• Parathyroid.

• Stomach.

• Gallbladder.

• Kidneys.

• Colon.

• Prostate.

• Ovaries.

• Testes.

• Breasts.

It has been suggested that all ACTH-producing cells have the same structural properties and even have a common origin. Unlike the normal Cushing's syndrome, ectopic ACTH syndrome is more common in males and causes muscle weakness and marked hypokalemic alkalosis. Hyperglycemia (increased blood sugar levels), edema (swelling), and hyperpigmentation of the skin are other common symptoms caused by ectopic production of beta-MSH (another polypeptide). With ectopic hormone formation, large amounts of ACTH-like substances are produced, which causes bilateral adrenal hyperplasia, which cannot be suppressed by Dexamethasone.

How Is Ectopic Production of Parathyroid Hormone-Like Protein Associated With Hypercalcemia?

The ectopic production of parathyroid hormone-like protein is associated with hypercalcemia, and humoral factors produced by the cancer cells act on the affected individual's bones and kidneys, leading to impaired bone resorption and calcium excretion. Ectopic hormone hypercalcemia may be challenging to differentiate from hyperparathyroidism. This condition is common in males who are clinically ill without any history of bone diseases. However, alkaline phosphatase levels may be elevated in some cases without bone involvement, which does not happen in hyperparathyroidism.

How Does Syndrome of the Inappropriate Antidiuretic Hormone Occur Due to Ectopic Hormone?

The syndrome of the inappropriate antidiuretic hormone due to ectopic hormone occurs mainly due to small cell lung cancer. However, it may also occur due to cerebellar hemangioblastoma, pituitary adenoma, pancreatic cancer, and lymphoma. Ectopic production of the inappropriate antidiuretic hormone causes overhydration in the body that may lead to drowsiness, irritability, confusion, and disorientation. In addition, dilutional hyponatremia is present along with low chloride levels and concentrated urine.

How Does Hypoglycemia Occur?

Tumor-induced hypoglycemia is a rare but severe complication of cancer. Three different syndromes have been identified:

1. Insulin production by islets cells malignancy.

2. Insufficient gluconeogenesis (the process of generation of glucose from certain non-carbohydrate carbon substrates. This is commonly seen in patients with complete replacement of hepatic parenchyma by the tumor, interfering with the enzymatic production of glucose.

3. Increased concentration of insulin-like growth factor (a peptide that activates the insulin receptor).

How Is the Presence of Ectopic Hormones Diagnosed?

Ectopic hormone secretion is diagnosed through a combined approach of imaging tests along with blood tests (arteriovenous sampling). Blood examinations will measure a hormone concentration gradient across the tissues (and so it will also establish the source of the hormone).

What Is the Treatment for Ectopic Hormone and Their Syndromes?

The primary treatment modality for the treatment of ectopic hormones is to treat the underlying cause of these abnormal hormone productions, which is generally a tumor. Mentioned below are the various ways of treating them:

1. Surgical removal of the tumor causing ectopic hormone production.

2. Drug-induced suppression of the tumor.

3. In some cases, when the tumor cannot be surgically removed, the whole gland may be removed. For example, adrenal glands are removed.

4. In case of inappropriate antidiuretic hormone production, the first line of treatment is to restrict the fluid intake in the body.

5. Antineoplastic chemotherapy.

Conclusion:

Ectopic hormones are clinically defined as the abnormal production of hormones by tumors of the tissues that are otherwise not associated with their production. This excess hormone secretion is harmful to the body and interferes with the metabolic functioning of the body and the normal homeostasis of the body. Ectopic hormone production can cause several clinical syndromes, including Cushing's syndrome, hypercalcemia, inappropriate antidiuretic hormone, hypoglycemia, and hyperaldosteronism. The treatment of ectopic hormone production is generally surgical removal of the tumor or drug-induced suppression of the tumor.