Adrenal medulla: Catecholamines and serotonin and laboratory tests

Where is the adrenal medulla located?

It is the innermost part of the adrenal gland, surrounded by the adrenal cortex

What type of cells are found in the adrenal medulla?

Chromaffin cells, which secrete catecholamines

What hormones are secreted by chromaffin cells?

1. Epinephrine (adrenaline)

2. Norepinephrine (noradrenaline)

3. Dopamine

What stimulates the secretion of catecholamines?

Stimulation by the sympathetic neurons, activating the fight or flight response

What are chromaffin cells derived from?

They are modified postganglionic sympathetic neurons

What is the developmental origin of the adrenal medulla?

It develops from primordial neural crest stem cells

What do neural crest cells give rise to in adrenal medulla development?

They give rise to sympathetic cells, which differentiate into sympathoblasts or pheochromoblasts.

What are pheochromoblasts?

They are dividing embryonic sympathetic cells that mature into chromaffin cells

What type of organ is the adrenal medulla considered functionally?

It is a neuroendocrine organ—a glandular extension of the sympathetic division of the autonomic nervous system

What are catecholamines?

They are biological amines (amino acid derivatives) that contain a catechol group and an amine group

What amino acid are catecholamines derived from?

Phenylalanine, which is converted to tyrosine

What is the rate-limiting enzyme in catecholamine synthesis?

Tyrosine hydroxylase

How are catecholamines different from steroid hormones?

They are amino acid derivatives, not cholesterol based like steroids

What physiological role do catecholamines play?

They facilitate signaling for physiological processes, help maintain homeostasis, and mediate the flight or fight response

How does cortisol interact with catecholamines?

Cortisol induces epinephrine production in the adrenal medulla

What are the three naturally occurring catecholamines?

Norepinephrine, epinephrine, and dopamine

Where is norepinephrine mainly produced?

In the CNS and also in the adrenal medulla

What is the main catecholamine produced by the adrenal medulla?

Epinephrine (adrenaline).

Where is dopamine primarily produced?

In neurons and the kidneys

What is serotonin chemically classified as?

An indolamine, containing an indole ring and an amine group

What amino acid is serotonin derived from?

Tryptophan, through its metabolite 5-hydroxtryptamine

Where is serotonin mainly produced?

In enterochromaffin cells of the gut; it is also a neurotransmitter

Where is epinephrine (EPI) stored in the adrenal medulla?

In chromaffin granules

How are stored catecholamines released?

Through exocytosis triggered by nerve stimulation from efferent neurons

What enzyme converts norepinephrine to epinephrine?

Phenylethanolamine N-methyltransferase (PNMT) — found only in the adrenal medulla

What is the role of VMAT (Vesicular Monoamine Transporter)?

It transports catecholamines into vesicles for storage

What kind of organ is the adrenal medulla considered?

A neuroendocrine organ, part of the neuroendocrine system

How does the adrenal medulla receive signals to secrete catecholamines?

Through efferent axons, which deliver nerve signals to chromaffin cells

Where do efferent neurons deliver signals in the body?

To peripheral tissues, such as glands and muscles

What is the adrenal medulla’s role in stress?

It acts as a first responder, promoting the fight or flight response within seconds and mobilizing glucose for energy

What amino acid do catecholamines originate from?

Phenylalanine, which is converted to tyrosine in a tightly regulated process

What are the main catecholamines synthesized from the Catecholamine Synthesis pathway?

Dopamine, norepinephrine (NE), and epinephrine (EPI).

What is the precursor amino acid for serotonin?

Tryptophan

Where is serotonin primarily synthesized in the body?

In the enterochromaffin cells of the gut

What type of cells are responsible for catecholamine storage in the adrenal medulla?

Chromaffin cells, which contain catecholamine storage granules

What catecholamine is primarily secreted by the adrenal medulla?

Epinephrine.

What are the metabolic actions of epinephrine?

It is insulin-antagonistic and stimulates lipolysis, ketogenesis, thermogenesis, glycogenolysis, and gluconeogenesis.

What is the overall effect of epinephrine on blood glucose?

It increases blood glucose levels

What is the role of dopamine in the kidneys?

It regulates sodium excretion (natriuresis) and acts as an autocrine or paracrine substance to help control blood pressure and volume

Where are dopamine metabolites significantly produced outside the brain?

In the GI tract

What other physiological processes are influenced by dopamine?

It helps regulate mood and behavior

How do antidepressants relate to dopamine and serotonin?

They increase dopamine or serotonin levels, improving mood

: Can food influence dopamine levels?

Yes — dietary constituents can increase peripheral dopamine levels, contributing to the "feel good" effect after eating.

What is dopamine’s role in catecholamine biosynthesis?

It is the intermediate precursor for both norepinephrine (NE) and epinephrine (E).

What are the functions of serotonin?

They play a role in mood, sleep, appetite, and gastrointestinal motility

Where do most circulating and urinary dopamine and its metabolites come from?

From sources other than the brain, especially the GI tract

What is the principal dopamine metabolite in the brain?

Homovanillic acid (HVA).

What are two other key dopamine metabolites?

Dihydroxyphenylacetic acid (DOPAC) and dopamine sulfate (DA-SO₄).

What is the main source of urinary dopamine?

It is largely derived from renal metabolism of dopamine

Where is dopamine locally synthesized in the kidneys?

In the proximal convoluted tubule

What is the purpose of catecholamine degradation?

To excess catecholamines from the body

What are the three main methods for eliminating excess catecholamines?

1. Reuptake into secretory vesicles (by presynaptic neurons)

2. Uptake by non-neuronal cells, mainly in the liver

3. Enzymatic degradation in the synaptic cleft

Which two enzymes are involved in catecholamine inactivation?

1. COMT (Catechol-O-methyltransferase)

2. MAO (Monoamine oxidase)

What do COMT and MAO do?

They convert free catecholamines into inactive metabolites

How are catecholamine metabolites removed from the body?

They are filtered into the urine and excreted

Why is urine important for lab testing of catecholamines?

Because urine samples contain both free catecholamines and their metabolites, which are used for diagnosis

What condition is caused by excess catecholamine production in the adrenal medulla?

Medullary hyperfunction

What tumor is typically responsible for medullary hyperfunction in adults?

Pheochromocytoma

What cells give rise to pheochromocytomas?

Mature adrenal chromaffin cells

What do pheochromocytomas cause an increase in?

Catecholamine metabolites, including metanephrine, normetanephrine, and VMA.

What is metanephrine (MN) a metabolite of?

Epinephrine (EPI).

What is normetanephrine (NMN) a metabolite of?

Norepinephrine (NEPI).

What is homovanillic acid (HVA) the final metabolite of?

Dopamine.

What is vanillylmandelic acid (VMA) the final metabolite of?

Epinephrine or norepinephrine.

What is neuroblastoma?

A malignant embryonal tumor in children, derived from neural crest cells

What type of cells are involved in neuroblastoma?

Immature blast cells

What causes neuroblastoma?

Aquired gene changes during early development

What urinary metabolites are increased in neuroblastoma?

HVA and VMA.

How do catecholamine metabolite levels in neuroblastoma compare to pheochromocytoma?

Neuroblastoma shows more HVA and VMA, and less MN and NMN than pheochromocytoma.

What is sympathetic hyperactivity?

A syndrome characterized by increased acitivity of the sympathetic nervous system, typically in response to perceived danger or threat

What physiological system is activated during sympathetic hyperactivity?

The fight-or-flight system, a coping mechanism for danger.

What types of autonomic dysfunctions can cause sympathetic hyperactivity?

Traumatic brain injury (TBI) and stroke.

What emotional or psychological conditions can trigger sympathetic hyperactivity?

Panic attacks, psychosis, stress, and seizures.

What physiological stressors can also lead to sympathetic hyperactivity?

Hypoglycemia, injury, and infection.

What tumor is a known cause of sympathetic hyperactivity?

Pheochromocytoma, a catecholamine-producing tumor.

What drugs can increase sympathetic nervous system activity?

Decongestants, bronchodilators, appetite suppressants, and stimulants.

Why do MAO inhibitors cause sympathetic hyperactivity?

Because they prevent the breakdown of catecholamines, leading to excess levels

How does cortisol contribute to sympathetic hyperactivity?

It increases PNMT, the enzyme that converts norepinephrine to epinephrine.

How does thyroid hormone affect the sympathetic system?

It increases heart rate and enhances sympathetic responses.

What types of food can trigger catecholamine release?

Foods high in tyramine, such as imported beer, red wine, soy sauce, fermented foods, and aged meats.

What is the clinical concern with tyramine-containing foods?

They can induce catecholamine release, causing false-positive results or hypertensive episodes—especially in patients on MAO inhibitors.

What is an adrenal incidentaloma?

An adrenal mass, typically > 1 cm in diameter found incidentally during imaging in asymptomatic patients

What percentage of adrenal incidentalomas are nonfunctional?

About 80%.

How common are adrenal adenomas?

6%, with prevalence increasing with age.

What two key things should all adrenal lesions be evaluated for?

Malignancy and hormonal hypersecretion.

What is required before taking further steps in adrenal incidentaloma management?

Laboratory testing and pathology imaging assessment to rule out malignancy or functionality.

When should surgery be considered for an adrenal mass?

• If the mass is cancerous

• If it is a functioning (autonomously secreting) adenoma (producing cortisol, aldosterone, or catecholamines)

• If the size is ≥4 cm or if the mass is growing

What is a pheochromocytoma?

A tumor of mature chromaffin cells in the adrenal medulla that secretes catecholamines.

How is a pheochromocytoma identified in histology?

By the chromaffin reaction, where tissue shows a brown coloration due to oxidation of catecholamines.

What causes the chromaffin reaction in staining?

The reaction between catecholamines and bichromate (potassium dichromate) solution—this is why the cells are called chromaffin ("affinity for chromate").

What causes the symptoms in pheochromocytoma?

Elevated levels of epinephrine and norepinephrine, which are catecholamines.

What is the most common blood pressure presentation in pheochromocytoma?

Sustained hypertension, seen in 60–65% of cases.

What does paroxysmal hypertension mean, and how often does it occur?

It refers to sudden bursts of high blood pressure, occurring in about 25% of Pheochromocytoma cases.

Is it possible to have pheochromocytoma without hypertension?

Yes, in about 10% of cases, especially in those with an incidentaloma that is non-functioning.

What cardiovascular symptoms are associated with pheochromocytoma?

Tachycardia, palpitations, and chest pain.

What causes postural (orthostatic) hypotension in pheochromocytoma?

Intermittent catecholamine release, receptor downregulation, and desensitization.

What defines orthostatic hypotension?

A drop in blood pressure when moving from a sitting or lying position to standing.

What are some additional symptoms of pheochromocytoma?

• Diaphoresis (excessive sweating)

• Headache

• Nausea

• Weakness

• Nervousness

• Tremors

• Pallor

• Flushing

• Diarrhea

• Hyperglycemia due to anti-insulin effects (diabetogenic)

Why are metanephrines preferred over direct catecholamines for diagnosis?

Because metanephrines are more stable than their parent compounds, epinephrine (E) and norepinephrine (NE), which have very short half-lives (1–2 minutes).

Where are metanephrines formed?

In chromaffin cells, where COMT (catecholamine O-methyltransferase) metabolizes catecholamines—indicating functional chromaffin activity.