Medical Biochemistry II - Adrenal Function

Adrenal gland regions, functions, overall effect

Cortex (outer 90%): steroid hormones

Medulla (inner 10%): catecholamines

Disorders affect blood pressure and electrolyte balance

Zones of cortex, hormone produced, general function

Zona glomerulosa (G zone, outer 10%)

• Mineralcorticoids-salt

  • Aldosterone

Zona fasciculata (F zone, middle 75%)

• Glucocorticoids-sugar

  • Cortisol

Zona reticularis (R zone, inner 10%)

• Androgens-sex

  • Testosterone/estrogen precursors

Medulla hormones

catecholamines

Aldosterone function, specific changes, control system

Maintains Na and K balance, helping control BV and BP

Increased renal NA reabsorption = increased BV and BP

increased K excretion into urine = decreased serum K

increased H excreted into urine = metabolic alkalosis

Controlled by Renin-angiotensin system (RAS) and increased plasma K

RAS mechanism

Renin released from kidney in response to decreased BP or plasma Na

Renin converts angiotensinogen to angiotensin I

ACE (lungs) converts angiotensin I to angiotensin II

Angiotensin II increases BP

• Stimulates aldosterone release

• causes vasoconstriction

Tests for aldosterone

Plasma K

Plasma aldosterone (PA) - highest in AM

24-hr urine aldosterone - no diurnal variation

Plasma renin / plasma renin activity (PRA) - highest in AM

Isolated hypoaldosteronism, signs and symptoms, types

Decreased BP from decreased Na, hyperkalemia, mild metabolic acidosis

Primary (hyperreninemic) - Adrenal origin

• rare

Secondary (hyporeninism) - more common

• conditions that reduce renin production = decreased aldosterone (commonly CKD, often 2/2 DM)

Diagnosis of hypoaldosteronism, low vs high PRA meaning, confirmation test

Plasma aldosterone by immunoassay

low aldosterone + high PRA activity = primary (adrenal unresponsive to renin)

Low aldosterone and low PRA = secondary (reduced renin production)

Confirm using salt restriction stimulation test

Salt restriction should stimulate renin and aldosterone secretion

abnormal if aldosterone fails to increase

Hyperaldosteronism, signs and symptoms, types

Increased sodium and water retention = increased BP and peripheral edema

increased urinary K+ excretion = decreased serum K+ (muscle weakness)

Metabolic alkalosis

Primary (Conn’s syndrome)

• adrenal adenoma/hyperplasia = autonomous aldosterone increased

Secondary (more common)

• conditions that activate RAS = hyperreninemic states

Diagnosis of primary hyperaldosteronism, clinical suspicion, screening tests

suspicion: HTN, unprovoked hypokalemia, metabolic alkalosis

screening tests

• Plasma aldosterone (PA): elevated

• Aldosterone-to-Renin Ratio (ARR) - best screening test

  • Increased plasma aldosterone or decreased plasma renin

Confirming diagnosis of primary aldosteronism

24 hr urinary aldosterone w/ salt loading suppression

normal patient: salt loading = intravascular expansion = suppressed aldosterone secretion

primary aldosteronism: urinary aldosterone remains high

Description and functions of cortisol

primary glucocorticoid hormone involved in the metabolism of proteins, lipids, and carbohydrates

increases blood glucose (anti-insulin effect)

stimulates gluconeogenesis in the liver

High conc. = influence electrolyte balance and blood pressure by interacting with mineralocorticoid receptors (Cortisol is similar to aldosterone, at high conc. it can bind to aldosterone receptors and act as aldosterone)

Suppresses inflammation and immune responses

Regulation of cortisol synthesis

stimulated by

• ACTH

• Hypoglycemia

• Stress (stress hormone)

Suppressed by

• Increased glucocorticoids (endogenous or exogenous) via feedback inhibition of ACTH synthesis

• Increased plasma cortisol inhibits CRH and ACTH release

• Decreased plasma cortisol stimulates CRH and ACTH release

Diurnal rhythm of cortisol

Normal sleep cycle required for accurate rhythm

AM levels highest

PM levels lower (about half of AM levels)

Midnight lowest

Time of blood/urine/saliva draw is critical for interpretation

Disruptions: irregular sleep, disease, or conditions affecting cortisol production

Cortisol protein bindings and bioactivity

90% of serum cortisol is bound

10% is free = diffusible in tissue, biologically active, and regulates ACTH via feedback

Bound cortisol is metabolized and conjugates in the liver, excreted by the kidney

Free cortisol is excreted directly in urine, also present in saliva

Types of cortisol disorders

Hypocortisolism

• primary adrenal insufficiency (Addison’s disease)

• Secondary adrenal insufficiency

Hypercortisolism

• ACTH dependent Cushing’s syndrome

• ACTH independent Cushing’s syndrome

Laboratory tests for cortisol

Cortisol measurement

• Plasma (total = bound + free)

• Saliva (free)

• 24 hour urine (free cortisol)

Stimulation or suppression tests to confirm abnormal cortisol levels and determine cause

plasma aldosterone, Na, K, and renin

imagining: CT or MRI

Adrenal insufficiency, symptoms, etiology

Orthostatic hypotension, hypoglycemia

Chronic fatigue, weakness, anorexia

Impaired stress response = life threatening (Addisonian crisis)

Primary adrenal insufficiency (Addison’s disease): damaged adrenal glands due to autoimmune disease, infection, D/Os and or drugs

• Hyperpigmentation (Increased ACTH = Increased MSH)

• Aldosterone affected: Decreased sodium, increased potassium, increased renin

• Secondary adrenal insufficiency: inadequate ACTH secretions due to hypopituitarism

Important note about stopping corticosteroid therapy

Taper dose slowly when stopping therapy, pituitary and adrenal glands may not respond immediately = secondary aldosterone insufficiency

Establishing adrenal insufficiency, screening, confirmatory test

Plasma cortisol measured at 8 am

Confirmatory:

• ACTH stimulating test

• Synthetic ACTH analog (cortisol measured at baseline, 30 min, 60 min

• Interpretation:

• Cortisol remains low - primary adrenal insufficiency or long term secondary aldosterone insufficiency

• Cortisol rises = adrenal function normal and may indicate hypopituitarism

Differentiating primary vs secondary AI

Primary (Addison’s disease)

Increased plasma ACTH = hyperpigmentation

Aldosterone: decreased sodium, increased sodium

Treatment: replace cortisol and aldosterone

Secondary AI (hypopituitarism

Plasma ACTH: decreased = no hyperpigmenetation

Aldosterone and renin normal = serum Na and K normal

Cushing syndrome signs and symptoms

Increased BP, cortisol, glucose

Decreased potassium

loss of diurnal cortisol pattern

Cushingoid appearance: central obesity and moon face, buffalo hump (upper back fat pad), sings of hyperandrogenism (hirsutism, acne, baldness)

Osteoporosis, immune suppression, behavioral changes, purple striae on abdomen

Long term complications like DM1

Cushing’s syndrome etiology and treatment

ACTH-independent causes

• Iatrogenic: prolonged glucocorticoid therapy (most common)

• adrenal: adenoma, carcinoma, hyperplasia

ACTH-Dependent causes

• Cushing disease: ACTH-secreting pituitary tumors (secondary)

• ectopic ACTH syndrome: rare ACTH producing tumors

treatment options: Surgery, radiation, medications to suppress adrenal cortisol production

Cushing syndrome: diagnosis approach (3 screening, 4-5 determining)

rule out exogenous corticosteroids

screening

• 24-hr urinary free cortisol

• overnight low dose dexamethasone suppression test (DST)

• AM and PM plasma cortisol or late night salivary cortisol

Determing the cause of cortisol increase

• ACTH measurement (dependent vs independent testing)

• High dose dexamethasone suppression test (HDDST)

• CRH stimulation test

• Bilateral inferior petrosal sinus sampling (BIPSS)

• Radiologic imaging (CT/MRI) to locate tumors

24 urinary free cortisol test (UFC)

Preferred screening test

negates diurnal variation

limitations: plasma cortisol can be elevated by stress, medications, increased CBG, pulsatile secretions = less reliable than urine or salivary measurements

Low dose dexamethasone suppression test, purpose, usefulness, interpretation

Detects loss of normal cortisol suppression

Quick, widely used initial screen, good for R/O Cushing

Dexamethasone: synthetic cortisol analog, 30x more potent negative feedback

Interpretation: low cortisol (suppressed) normal response = Cushing’s excluded

Unchanged cortisol (not suppressed) suggests = Cushing’s syndrome

Late night serum or salivary cortisol testing, purpose, interpretation

Simple, convenient screening to detect loss of cortisol diurnal rhythm

Cushing’s Syndrome: repeated high late-night plasma or salivary cortisol (nighttime suppression lost)

Could be falsely elevated due to stress

ACTH purpose in diagnosis

Plasma ACTH: the most common test to differentiate adrenal (ACTH-independent) from pituitary/ectopic (ACTH-dependent) causes of cortisol excess

High-dose dexamethasone suppression test, purpose, interpretation

Differentiates the cause of ACTH dependent cushing’s syndrome: The pituitary vs. ectopic ACTH production

No suppression = ectopic ACTH

50% decrease in urinary free cortisol = suggests pituitary adenoma (Cushing’s disease)

Decrease 90% = nearly 100% specific for pituitary source, excludes ectopic ACTH

CRH stimulation test, purpose, function, interpretation

like HDDST, newer and more accurate

Distinguishes pituitary ACTH (Cushing’s disease) from ectopic ACTH

Interpretation:

ACTH increase followed by cortisol increase = anterior pituitary adenoma (Cushing’s disease)

No response = ectopic ACTH syndrome

Inferior petrosal sinus sampling, purpose, interpretation

Compares ACTH near the pituitary vs systemic circulation to localize ACTH hypersecretion = the most specific test for Cushing’s disease

performed after CRH stimulation

Blood sampled from inferior petrosal sinuses and peripheral vein

Interpretation (Petrosal sinus : ACTH ratio)

greater than 2-3 = pituitary source = Cushing’s disease

Less than 2 = no gradient = ectopic ACTH producing tumor

R-zone: androgens overview

Known as male hormones but present in both males and females at varying levels

Produced primarily by the adrenal glands, testes, and ovaries

women: adrenal glands are the major source

Men: testes are the major source (Mainly testosterone)

Adrenal gland production: produces most DHEA, all DHEAS, and some androstenedione

DHEAS is not secreted by ovaries or testes = marker of adrenal androgen secretion

Adrenal androgens, regulation and action

Secretion is regulated by ACTH, but they do not suppress ACTH secretion (no negative feedback)

Action: testosterone and its metabolite dihydrotestosterone (DHT) are the most biologically active androgens

Physiological effects:

Development and maintenance of male characteristics

puberty and reproductive function

Adrenal androgen excess

Women: infertility with virilizing (masculine) effects (hirsutism, acne, male-pattern baldness)

Men: Infertility but with feminizing or hypogonadal effects (from negative feedback on pituitary gonadotropins = decreased LH FSH production = decreased testosterone production

Hyperandrogenism: etiology and lab evaluation

Congenital Adrenal Hyperplasia (CAH)

Adrenal andorgen-secreting tumors

tests:

Best screening test: plasma or urine 17-ketosteroids (androgen breakdown products)

more specific tests: plasma DHEAS, testosterone

Congenital Adrenal Hyperplasia (CAH), what it causes, clinical features

Autosomal recessive disorders caused by mutations in steroidogenic enzyme genes

causes deficiency of an enzyme requires for the synthesis of cortisol and aldosterone = intermediates shunted to androgen production

decreased cortisol = increased ACTH = excess adrenal androgens

virilization (increased androgen effects)

salt wasting (Na loss due to decreased aldosterone)

Impaired stress response to trauma infections (a/w inadequate cortisol release)