Normetanephrine Testing 101: Top Tests And Understanding Results

Normetanephrine is a biomarker that helps healthcare practitioners detect certain rare tumors such as pheochromocytomas and paragangliomas. 

Normetanephrine testing is generally ordered when a person has symptoms of high catecholamine (epinephrine and norepinephrine) production, including persistent high blood pressure that doesn’t respond well to treatment, unexplained episodes of rapid heart rate, anxiety, severe headaches, sweating, or palpitations. 

These symptoms, especially if they occur in combination or come on suddenly and severely, can raise suspicion of an adrenal or neuroendocrine tumor.

Understanding normetanephrine levels and knowing how to understand these results are key steps in diagnosing catecholamine-related conditions and determining the right treatment approach.

In this article, we will dive into what normetanephrine is, when testing should be done, and how to understand the results. 

We will also discuss next steps for patients and practitioners when normetanephrine levels are either high or low, as well as further functional medicine lab testing options to consider if normetanephrine results are low in a symptomatic patient.

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What is Normetanephrine?

Normetanephrine is a metabolite, or breakdown product, of norepinephrine, one of the body’s primary stress hormones. 

Norepinephrine is important in the "fight-or-flight" response, regulating blood pressure, heart rate, and stress levels. When norepinephrine is used by the body, it is metabolized into normetanephrine, which circulates in the blood until it is excreted through the urine.

Causes of High Normetanephrine

Normetanephrine testing is usually done when there is concern for a pheochromocytoma or a paraganglioma.

Pheochromocytoma: A Rare Adrenal Gland Tumor 

Normetanephrine is particularly important in diagnosing pheochromocytoma, a rare tumor that forms in the adrenal glands, which are located above the kidneys. 

These tumors cause an overproduction of the stress hormones norepinephrine and epinephrine, causing symptoms like high blood pressure, rapid heart rate, anxiety, and excessive sweating. 

Both normetanephrine and metanephrine (a metabolite of epinephrine) are important biomarkers for pheochromocytomas. 

Experts agree that normetanephrine and metanephrine testing is more sensitive for detecting pheochromocytoma than the catecholamines epinephrine and norepinephrine testing; while catecholamine production fluctuates, their metabolites including normetanephrine are continuously produced. 

Pheochromocytomas can be life-threatening if left untreated, as the excessive production of norepinephrine and epinephrine can lead to severe cardiovascular issues. 

Paraganglioma: A Rare Neuroendocrine Tumor 

Paragangliomas are rare, usually non-cancerous tumors that form from neuroendocrine cells found outside the adrenal glands. These neuroendocrine cells are part of the nervous system and help regulate body functions. 

Unlike pheochromocytomas, which develop in the adrenal glands, paragangliomas can appear along nerve pathways in areas like the head, neck, chest, or abdomen. These tumors can produce too much norepinephrine, which leads to high levels of normetanephrine.

Symptoms of paragangliomas often include high blood pressure, headaches, a racing heart, sweating, and anxiety or panic attacks. Sometimes, if the tumor isn't producing hormones, it may cause other symptoms like a lump in the neck, difficulty swallowing, or changes in voice. 

To diagnose paragangliomas, doctors measure normetanephrine levels in blood or urine and use imaging tests like CT scans or MRIs. 

Treatment often involves surgery to remove the tumor, and in some cases, additional treatments like radiation or medication may be needed to manage symptoms or prevent the tumor from coming back.

When to Order Normetanephrine Testing

Normetanephrine testing is typically ordered when a healthcare practitioner suspects a pheochromocytoma or paraganglioma. 

Key Symptoms of Pheochromocytoma or Paraganglioma

Clinical signs and symptoms that might cause a practitioner to order normetanephrine testing include:

• Persistent high blood pressure (especially if it is resistant to medication)

• Unexplained anxiety, rapid heart rate, or excessive sweating

• Headaches, particularly if they are associated with high blood pressure

• Symptoms of autonomic nervous system imbalance (e.g., dizziness, fatigue, flushing)

Types of Normetanephrine Tests

There are two main types of normetanephrine tests that healthcare providers can order: blood testing and urine testing. Each test has its specific advantages, and the choice of test may depend on the patient’s symptoms and clinical scenario.

Blood Testing: Plasma-Free Normetanephrines

Plasma-free normetanephrine testing measures the amount of normetanephrine circulating in the blood. This test is often the first step in diagnosing pheochromocytomas because it provides an immediate snapshot of catecholamine metabolism in the body.

Many practitioners believe plasma normetanephrine testing is more accurate than urine testing, although the sensitivity levels are 99% and 97%, respectively. However, plasma testing may have fewer false positives than urine testing. 

How The Test Is Performed

To perform a plasma normetanephrine test, the patient should fast overnight and avoid caffeine, nicotine, and certain medications (e.g., acetaminophen, tricyclic antidepressants) that can interfere with results. 

After resting in a lying-down position for 20 minutes, blood is drawn through a forearm vein. 

Urine Testing: 24-Hour Urine Normetanephrines

Urine normetanephrine testing involves collecting urine over 24 hours to measure normetanephrine levels. 

This method is useful for capturing daily fluctuations in hormone production and is often preferred when the patient’s symptoms fluctuate throughout the day.

Urine testing may be preferred for patients whose symptoms are variable or who have hypertension or anxiety that comes and goes. It provides a more comprehensive view of how catecholamine production changes over the course of a full day.

Urine testing may also have a lower false-positive rate.

How The Test Is Performed 

To perform a 24-hour urine normetanephrine test, collect all your urine over a 24-hour period, starting with an empty bladder.

Each time you urinate, collect it in the provided container, store it in the refrigerator or a cooler, and avoid consuming foods, drinks, or medications that could affect results, such as caffeine, alcohol, and certain medications. 

After the 24-hour period, bring the labeled urine sample to your healthcare provider for analysis.

Understanding Normetanephrine Results

Understanding the results of normetanephrine tests is critical for diagnosing conditions like pheochromocytoma and adrenal imbalances. High or low normetanephrine levels can provide insight into adrenal function and guide next steps for treatment.

High Normetanephrine Levels

Elevated normetanephrine levels are most commonly associated with pheochromocytomas and paragangliomas. 

However, they can also be linked to other causes including 

• Stress

• Exercise

• Illness

• Alcohol and smoking

• Certain drugs and medications

High Normetanephrine Levels: Next Steps

Current guidelines state that elevations of normetanephrine or metanephrine that are 3-fold or more above the upper cutoffs are rare as false positives and should be treated with a high suspicion for pheochromocytoma and paraganglioma. These patients require an endocrinologist’s care.

Further testing such as imaging studies (MRI or CT scans) may be ordered to confirm the presence of a tumor, particularly in the setting of very high elevations. 

If a pheochromocytoma or paraganglioma is diagnosed, treatment options may include surgery, medications to control blood pressure, or lifestyle interventions to manage stress.

Low or Normal Normetanephrine Levels

Interestingly, some patients may have symptoms suggestive of a pheochromocytoma or paraganglioma but show low or normal normetanephrine levels. 

Other causes that require medical attention but will show low or normal metanephrine levels include:

• Hyperthyroidism/Thyroid Storm: an overactive thyroid causes anxiety, rapid heart rate, sweating, high blood pressure, headaches, and dizziness. Severe cases can mimic pheochromocytoma.

• Cushing’s Disease: excess cortisol leads to high blood pressure, anxiety, headaches, and autonomic imbalance, often with weight gain around the abdomen and face.

• Anxiety or Panic Disorder: these can cause rapid heart rate, sweating, dizziness, and headaches but usually not persistent high blood pressure. 

• Autonomic Dysregulation (POTS): autonomic nervous system issues cause dizziness, fatigue, faintness, rapid heart rate, sweating, headaches, and many other manifestations. Resistant hypertension is less common.

• Primary Hyperaldosteronism: excess aldosterone (another adrenal hormone) results in resistant hypertension, headaches, dizziness, and fatigue due to electrolyte imbalances.

• Obstructive Sleep Apnea: causes resistant hypertension, morning headaches, and fatigue, with stress responses like rapid heart rate and anxiety.

• Medication-Induced Hypertension: stimulants, decongestants, and corticosteroids can elevate blood pressure and cause anxiety, sweating, and dizziness.

• Carcinoid Syndrome: episodic flushing, rapid heart rate, and autonomic symptoms due to serotonin release.

Next Steps: Functional Medicine Lab Testing Options to Consider When Normetanephrine is Low

When normetanephrine levels are low and other serious medical causes have been ruled out, further testing can help uncover underlying conditions and imbalances:

Comprehensive Thyroid Panel 

Thyroid function is closely linked to adrenal health, and assessing the thyroid is important for patients with symptoms of hyper- and hypothyroidism, which can mimic other adrenal issues. 

A thyroid panel evaluates TSH, T4, T3, and antibodies for a full thyroid health picture.

Comprehensive Cardiometabolic Testing 

Evaluating cardiometabolic health is key for everyone, and especially for people with symptoms like hypertension, headaches and palpitations. 

This includes in-depth lipid panels, blood sugar assessment, and cardiovascular risk markers. 

Adrenal Stress Index (ASI) 

The ASI measures cortisol and DHEA levels throughout the day, giving a clear picture of how the body handles stress. 

By mapping the diurnal rhythm of cortisol, as well as reporting DHEA levels, the ASI provides a good view of adrenal health.

Micronutrient Testing 

Key nutrients like magnesium, B vitamins, and vitamin C are critical for adrenal function, and deficiencies can impair stress resilience. 

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Key Takeaways

• Normetanephrine is a key biomarker used to assess adrenal function, detect rare tumors like pheochromocytomas and paragangliomas, and may help to understand stress response.

• Testing is typically ordered when patients show symptoms of high catecholamine production such as high blood pressure, rapid heart rate, anxiety, sweating, or headaches, especially if these symptoms occur suddenly or in combination.

• High normetanephrine levels often indicate pheochromocytomas or paragangliomas, while low levels in symptomatic people may suggest other conditions like thyroid issues, anxiety disorders, or medication-induced symptoms, which require further diagnostic testing.