Adrenal glands

• Aka suprarenal glands

• Two functionally distinct parts:
- Cortex
- Medulla
Adrenal cortex
- Essential to life
- Produces three classes of hormones
 Glucocorticoids
 Mineralocorticoids
 androgens
• Adrenal medulla:
- Functionally part of sympathetic nervous
system
- Not essential to life
- Pathological importance associated mainly to
occurrence of rare catecholamine secreting
tumours
• Steroid hormones:
- Cyclopentanoperhydrophenathrene backbone

- Contain upto 21 carbon atoms

- differ from one another with regard to

 Introduction of double bonds
 Introduction of substituent groups
 Addition/ deletion of specific type of side chain
Biosynthesis of steroid hormones:
• Cholesterol undergoes cleavage with an elimination of a 6-carbon
fragment to form pregnenolone.

• Pregnenolone is the common precursor for the synthesis of all steroid

hormones.

• Conversion of cholesterol to pregnenolone is catalysed by cytochrome

P450 side chain cleavage enzyme. This reaction is promoted by ACTH.

• The enzymes-hydroxylases, dehydrogenases, isomerases and lyases

associated with mitochondria or endoplasmic reticulum-are responsible
for the synthesis of steroid hormones.
Glucocorticoids
- Cortisol (hydrocortisone)- most important
- Production- predominantly by zona fasciculata
- C21
- Effect- carbohydrate (counter regulatory hormone)/ amino acid/ fat
metabolism

- Corticosterone: (aldosterone precursor)- weak glucocorticoid activity;

- cortisone (from cortisol) and 11- dehydrocorticosterone- potential
glucocorticoid activity
• Many actions:

 Increase protein catabolism

 Increase hepatic glycogenesis

 Increase hepatic gluconeogenesis

 Increased lipolysis

 Maintain blood pressure via sensitising arterioles to action of norepinephrine

 Permissive effect on water excretion

 Inhibit inflammatory and immune responses

 Inhibit bone formation

• Circadian rythm- higher concn- morning;
lower- evening/ night
• Physical stress may alter circadian rythm-
trauma, fever, surgery, hypoglycemia,
starvation etc
Mineralocorticoids:
• Aldosterone- most potent
• Water/ electrolyte balance (sodium conservation/ potassium
loss)
• Zona glomerulosa- exclusively
• C21

• Other adernocorticosteroid with mineralocorticoid activity:

DOC, 18 hydroxy DOC, cortocosterone, cortisol
• Secretion:
- in response to angiotensin II ; produced in response to
activation of renin- angiotensin system by decrease in renal
blood flow or decrease in sodium ( hypovolemia indicator)- JG
cells- JG apparatus

- Direct stimulation by hyperkalemia

• Function:
- Stimulate reabsorption of sodium and excretion of potassium
and hydrogen ions in DCT
- Effect on sodium central role in ECF volume determination

• ACTH- no role in secretion; stimulates synthesis, by

stimulation cholesterol desmolase
• Androgens
- Predominantly by zona reticularis
- Androgens, estrogens, progensterone- secretion by gonads as well
- Precursor substrate- 17 alpha hydroxypregnenolone
- small quantity of:
 Dehydroepiandrosterone
 Androstenedione ( can be converted to testesterone in peripheral
tissues)

- Stimulate libido and development of pubic and axillary hair in females

- Weak androgens in comparison with testesterone, and have minor
physiological role in males
 Circulating forms
• Either as free hormones/ bound- carrier protein

• Cortisol binding globulin, albumin, sex hormone binding

globulin- produced by liver

• At physiological concn, 90- 98 %- bound to binding globulin

• High concn- albumin- more important transport protein

• Binding to globulins d/o both affinity and concn of hormones

 Metabolism:

- Major site- liver

- Kidney/ GIT- important metabolic transformation

- Biochemical steps to inactivate hormones:

 Introduction of additional OH group
 Dehydrogenation
 Reduction of double bond
 Conjugation of essential OH group to chemical moieties as
glucuronic acid, sulfate- water soluble form- excretion in
urine- most effficient way of excretion
 Measurement

Analytical methods
- Immunoassay
- HPLC
- GC-MS/ LC-MS

Choice of specimen:
- Urine – hormone/ metabolites- incompleteness of collection, altered renal
function

- Blood- basal level, dynamic tests (supression test, stimulation test)

- Saliva- reflection of free hormone fraction; reliable for some hormones-

cortisol, progesterone, estriol; non invasive stress free collection
- Free versus bound steroids
- Cortisol- urinary cortisol, diurnal variation, stress
- Aldosterone- renin; aldosterone: renin ratio; posture
• Basal peptide/ steroid hormone concentration
- ACTH/ corticosteroids/ androgens
- Renin
- Episodic secretion; circadian variation

• Stimulation tests- hyposecretion of adrenocortical hormones

documented
- ACTH/ CRH
- Volume depletion manoeuvres- sodium restricn, upright posture,
diuretic administration; furosemide stimulation

• Supression tests- hypersecretion of hormones

- Dexamethasone
- Salt loading- saline infusion, oral salt loading, mineralocorticoid
administration (fludrocortisone suppresion test)
 Disorders of adrenal gland
Hyperfunction:
• Cushing’s syndrome- glucocorticoid excess; mineralocorticoid,
androgen- may also be excessive
• Conn’s syndrome- mineralocorticoid excess

Hypofuction
• Addison’s disease
 Cushing’s syndrome
• Result of autonomous, excessive production of cortisol leading to classic symptoms
characteristic of disorder

• Truncal obesity(moon face, buffalo hump, protuberant abdomen)

• Thinning of skin, purple striae, excessive bruising
• Back pain(osteoporosis, vertebral collapse)
• Glucose intolerance

• Sodium retention- hypertension, potassium wasting-hypokalemic alkalosis (iatrogenic

disease- exception), muscle weakness

• Hirsuitism, menstrual irregularities

• Neruopsychiatric symptoms- euphoria, mania, depression
• Skin pigmentation- ACTH excess

• Edema, ocular changes, exophthalmos

Causes:
• Corticosteroid, ACTH treatment

• Pituitary hypersecretion of ACTH (Cushing’s disease)

• Adrenal adenoma
• Adrenal carcinoma

• Ectopic ACTH secretion by (nonendocrine) tumors- eg. Tumor of lung, gut,

ovaries

• Iatrogenic
• Endogenous disorders- ACTH dependent/ ACTH independent
• Screening test:
- Uncommon disorder; common symptoms; early / mild stage-
demonstration of excessive and autonomous cortisol
production differential dx
1. Urinary free cortisol- <300 nmo/24 h normal; collection,;poor
specificity- +ve in pseudo cushing, obesity
2. Overnight low dose dexamethasone test- 1mg midnight- meas
of serum cortisol in morning- < 50 nmol/l; low specificity
3. Examining circadian rythm of cortisol secretion- morning night
difference lost- nocturnal concn inappropriately raised
2300h or 2400 h- <100 nmol/l normal
Differential diagnosis
1. ACTH measurement
• Low-adrenal cause
• Moderately elevated- Cushing syndrome
• Markedly elevated- ectopic ACTH secreting tumors

2. High dose dexamethasone test

3. CRH test
4. Imaging techniques
 Adrenal fxn test results in cushing’s syndrome

Basal Low dose High dose CRH test Plasma

cortisol dexamethas dexamethas ACTH (ng/l)
(nmol/l) one one
suppressn supressn
test test
Cushing’s High No Supressn Response High (<200)
disease (<1000)) suppressn
Adrenal High No No No response Low
tumor (variable) suppressn suppressn

Ectopic ACTH Very high No No No response Very high

secretion (>1000) suppressn suppressn (>200)
 Pseudo Cushing syndrome
• Conditions that mimic Cushing syndrome
• Clinical/ some biochemical features
• Alcohol abuse, severe depression, severe
obesity
 Conn’s syndrome:

• Characterised by excessive production of

aldosterone
• Secretion: Autonomous
• Very rare, but treatable cause of hypertension
• c/f- mainly due to hypokalemia (occuring due
to renal loss)
Causes:
• Adrenal adenoma
• Bilateral hypertrophy of zona glomerulosa cells
• Adrenal carcinoma

Clinical features:
• Hypertension (consequence of aldosterone induced
sodium retention)
• Muscle weakness
• Polydipsia, polyuria and nocturia
Diagnosis:
• Screening:
- Aldosterone
- Aldosterone to renin ratio

• Confirmation/ exclusion:
- Saline infusion test/ fludocortisone suppression test

• Other findings:
- Increased sodium
- Decreased potassium
Secondary aldosteronism:
• Due to incresed renin activity
• Far more common than primary form
• Increased renin activity leads to increased aldosterone
concentrations
• Patient may/ may not be hypertensive

• Conditions associated:
- Congestive cardiac failure
- Cirrhosis of liver, with ascites
- Nephrotic syndrome
- Others: renal artery stenosis, renin secreting tumor
• Differentiation between primary and secondary
aldosteronism:
- Plasma sodium
- renin
 Addison’s disease
• Adrenal hypofunction
• Uncommon but life threatening condition

• Cause:
- Glucocorticoid treatment
- Autoimmune adrenalitis
- Tuberculosis
- Adrenalectomy
- Amyloidosis, hemochromatosis
• Clinical features:
- tiredness, weakness, lethargy
- Anorexia, nausea, vomiting
- Weight loss
- Postural hypotension
- Pigmentation (due to high ACTH)
- Loss of body hair
- Hypoglycemia, depression- less common
Secondary adrenal failure:
• Pituitary failure- decreased ACTH
• Other signs of hypopituitarism also present
• Abnormal pigmentation absent
Diagnosis
• Plamsa cortisol level (at 0900h)
- <50 nm0l/l- dxtic of adrenal failure
- >550 nmol/l- exclusion
- However, concn in majority cases lies in between

• ACTH stimulation test (screening test)

- Synacthen/ tetracosactide- cortisol measurement
- No response (increase in cortisol) in both primary or
secondary hypoadrenalism
• Distinction between primary/ secondary
adrenal failure:
- ACTH test: (high in primary and low/ low
normal in secondary adrenal failure)

- Long ACTH stimulation test

 Congenital adrenal hyperplasia
• A group of inherited metabolic disorders of adrenal steroid
hormone biosynthesis

• Clinical feature: d/o position of defective enzyme in synthetic

pathway- determines pattern of hormone and precursors
produced

• Enzyme block-
 Partial- marked/ subtle clinical features
 Complete- incompatible with life
CAH
• Congenital presence of disorder
• Adrenal hyperplasia-
due to compensatory ACTH response to cortisol deficiency

• “Adrenogenital syndrome”
Affects genitalia and secondary sex characteristics of newborn
Enzymes affected:
• 21 hydroxylase deficiency: around 95 % cause
• 11 beta hydroxylase deficiency:about 5% cause

• Others: (rare)
- Steroid 3 beta hydroxy dehydrogenase
- Cholesterol hydroxylase/ side chain cleavage enzyme
- 17 hydroxylase
- 18 hydroxylase
• Incomplete deficiency common than complete block-
maintenance of adequate cortisol by compensatory ACTH
secretion (adrenal hyperplasia)
• Substrate of enzyme, 17 OH- progesterone accumulates –>
increased formation of adrenal androgens
• Females-
 ambiguous genitalia (less common)
 Late onset CAH: early adulthood- hirsuitism, amenorrhoea,
infertility

• Males-
 Precocious puberty; accelerated growth
Complete enzyme deficiency:
• Less common
• life threatening condition; insufficient cortisol and
aldosterone to maintain homeostasis

Diagnosis:
- 17 OH progesterone
- Genetic analysis
Adrenal medulla:
• Production of Catecholamines
• No clinical sequel from decreased adrenal
medullary activity- not essential to life

• tumor of medullary gland - phaeochromocytoma-

excessive production of catecholamines
• Extramedullary phaeochromocytoma- 10%
• Mostly benign (90%)
Aromatic L amino acid decarboxylase
• hypertension and other clinical features
related to sympathetic activity (headache,
palpitation, pallor, tremor, sweating)
• Rare, treatable cause of hypertension
• Diagnosis:
- Measurement of urinary/ plasma catecholamines
- Plasma free metanephrines
- Urinary VMA

- Imaging technique- locate tumor

- Clonidine suppression test