Adrenocortical Hormones and Disorders

Introduction
The adrenal gland lies at the upper pole of each kidney, each is

 Pyramidal in shape

 Weight 4kg irrespective of sex, age and weight

Histologically, it consists of two layers, cortex and medulla. Cortex consists of three layers

i. Zona glomerulosa which produces aldosterone

ii. Zona fasciculata which produces cortisol and androgens

iii. Zona reticularis which produces cortisol and androgens

Regulation of adrenal hormones

1. Circadian rhythm

• Physiological events in the brain result in episodic cardiac secretion of CRH from the
hypothalamus with similar circadian variation in ACTH release

• The released ACTH then stimulates cortisol production , which provides negative feedback
inhibition of the CRH-ACTH axis

• The circadian rhythm of ACTH secretion under normal wake and sleep cycles produces higher
cortisol concentrations in the morning between 7 and 9am and lower concentration in late
evening and early morning between 11pm and 4am

ii. Physical stresses that elevate plasma cortisol concentrations and alter the circadian rhythm include

1. Trauma

2. Fever

3. Surgery

4. Hypoglycemia

5. Alcohol ingestion

6. Uncontrolled diabetes

7. Anorexia nervosa
Iii. Major depression and severe anxiety are psychological stresses that also elevate plasma cortisol
concentrations

iv. Prolonged suppression of ATCH by administration of glucocorticoids causes atrophy of the adrenal
cortex

With prolonged intense suppression, recovery of the HPA takes several days to a few months

Biochemistry of adrenocortical steroids

• Steroid hormones are synthesized primarily from cholesterol in the adrenal glands and gonads.
In most cases, cholesterol is acquired from the circulation in the form of low-density lipoprotein
(LDL) cholesterol.

• All steroidogenic cells, are capable of de novo synthesis of cholesterol from acetyl coenzyme A

• Steroidogenesis occurs in the mitochondria and endoplasmic reticulum

• The initial rate-limiting step in the transport of cholesterol for steroidogenesis is mediated by a
steroidogenic acute regulatory protein (StAR) that is regulated by aadrenocorticotropic
hormone (ACTH)

Adrenal Steroidogenesis

Cholesterol

cholesterol side chain

cheavage enzyme

Pregnenolone 17-Hydroxypregnenolone DHEA

3β-HSD 17-Hydroxylase 3β-HSD

Progesterone 17-Hydroxyprogesterone Androstenedione oestrone

- - - - -21-Hydroxylase- - - -

11-Deoxycorticosterone 11-Deoxycortisol Testosterone 17β oestradiol

- - - - -11-Hydroxylase- - - - -

Corticosterone Cortisol

Aldosterone
Glucocorticoids

• Cortisol is the major glucocorticoid synthensized from cholesterol in the zona fasciculata and
rreticularis of the adrenal cortex

• Cortisol is secreted within a few minutes after a rise in serum ACTH

• It is secreted at the rate of approximately 25mg/day

• Cortisol is principally bound to corticosteroid-binding globulin (CBG) and transported as such. In

the circulation. Other factors that affect cortisol secretion include age, drugs eg oestrogen
therapy and nutrition

• Cortisol is metabolized and conjugated in the liver to several inactive forms

• More than 95% of cortisol and its metabolite cortisone is conjugated to glucoronic acid and
excreted into the urine as a conjugate

• Less than 2% of cortisol is excreted in the urine unmetabolized as urinary free cortisol

• Glucocorticoids have major effects on carbohydrate, protein and lipid metabolism

Response to cortisol is catabolic in most tissues (muscle, skin, lymphoid, adipose, or connective tissue)
but anabolic in the liver where it stimulates gluconeogenesis. These result in protein catabolism and
hepatic glucose production, striae in the skin (thinning of the skin). Excess cortisol results in
hyperglycemia and muscle wasting.

Lipolysis and the release of free fatty acid cause a central distribution of fat to the face, neck and trunk
(truncal obesity).

 Glucocorticoids also have antiinflamatory properties and suppress the immune system.
Consequently, they are used therapeutically to treat inflammatory conditions such as
rheumatoid arthritis
 It also suppresses wound healing and scar formation
 Antagonizes Vit D to decrease calcium absorption. Combined with its proteolytic activity, this
results in decreased bone formation (osteoporosis)

Mineralocorticoids

 Aldosterone is the most potent naturally occurring mineralocorticoid

 Mineralocorticoids regulate salt homeostasis (Na conservation and K & H loss) and extracellular
fluid volume
 The zona glomerulosa uniquely contains the enzyme aldosterone synthase, an obligatory
enzyme in the synthesis pathway of aldosterone
 Other mineralocorticoids with varying degrees of potency include
o Deoxycorticosterone (DOC)
 o Corticosterone, and cortisol
 The primary control mechanism for the secretion of aldosterone involves the renin-angiotensin
system. Renin is a proteolytic enzyme synthesized and stored in the juxtaglomerular epithelial
cells of the afferent arterioles of the renal glomeruli
 It hydrolyzes its substrate, angiotensinogen, to produce a decapeptide known as angiotensin 1
 Angiotensin 1 is then rapidly converted to an octapeptide, angiotensin II, by a circulating
angiotensin-converting enzyme (ACE), which is found in abundance in the lungs, angiotensin II is
a potent vasoconstrictor and stimulates the cells of the zona gluimerulosa to produce
aldosterone
 Potassium stimulates aldosterone synthesis and release through a membrane depolarization
effect that opens up calcium channels in adrenal cells
 The mineralocorticoids stimulate Na pump causing Na retention and K excretion, metabolic
alkalosis and increased BP

Adrenal Androgens

 The adrenal glands secrete androgens, progesterone and estrogen, all of which are produced by
the gonads
 Adrenal androgens are synthesized in the zona fasciculate and/or reticularis from the precursor
substrate 17a-hydroxypregnenolone
 The adrenal androgens include
o Dehydroepiandrosterone (DHEA) and DHEA sulphate (most important)
o Androstenedione, and
o Testosterone
 The adult adrenal gland secrets approximately
o 6-8 mg/day of DHEA
o 8-16 mg/day of DHEA-S
o 1.5 mg/day of androstenedione, and
o 0.05 mg/day of testosterone
 ACTH partially regulates adrenal androgen production in adults
 Adrenal androgen production begins to increase around the age of 9-10yrs; peaks in the third
decade of life; and then gradually decreases; reaching low concentrations again in advanced age

 The androgens induce protein anabolism and development of male sexual characteristics

Disorders of the adrenal cortex

 Disorders of the adrenal cortex are classified as resulting from either hypofunction or
hyperfunction
 Hypofunction of the adrenal cortex;-
 Adrenal insufficiency(glucocorticoid deficiency)
 hypoaldosteronism
 Hyperfunction of the adrenal cortex;-
  Glucocorticoid excess
 Mineralocorticoid excess, and
 Androgen excess

Adrenal Insufficiency

 Adrenal insufficiency is classified as primary or secondary

 Primary hypoadrenalism refers to adrenal insufficiency occurring in the setting of adrenal
disease. There is jncrease plasma ACTH; secondary hypoadrenalism arises due to deficiency of
ACTH
 a major distinction between these two is that mineralocorticoid deficiency invariably
accompanies primary hypoadrenalism but does not occur in secondary hypoadrenalism because
only ACTH is deficient; renin-angiotensin-aldosterone axis is intact.

Causes of adrenal insufficiency

PRIMARY (increased plasma ACTH)

 Addison’s disease: autoimmune, tuberculosis, metastatic

carcinoma,amyloidosis,heamochromatosis
 Acute deficiency: Waterhouse-Friderichsen syndrome
Iatrogenic: adrenalectomy (bilateral)

Congenital adrenal Hyperplasia

 Specific enzyme defects in steroidogenesis

 2 1-hydroxylase, 1 1 p-hydroxylase
 17a-hydroxylase
 3 b-hydroxysteroid dehydrogenase

SECONDARY (decreased plasma ACTH)

 CRH deficiency: hypothalamic disease

 ACTH deficiency: pituitary disease
 Prolonged steroid administration
 Decreased ACTH adrenal atrophy

DECREASED CBG (normal plasma ACTH)

 Congenital
 Androgen therapy
 Protein-losing states: nephrotic syndrome, protein-losing enteropathy

PRIMARY ADRENAL INSUFFICIENCY/…

Also known as Addison disease:

 It results from progressive destruction or dysfunction of the adrenal glands caused by a local
disease process or systemic disorder, the entire cortex is affected in primary adrenal
insufficiency, all classes of adrenal steroids are deficient
 The onset of clinical manifestation is usually gradual, and the degree and severity of symptoms
depend on the extent of adrenal failure
 Early or mild expressions of primary adrenal insufficiency may not be evident unless the patient
is under stress

Clinical features of glucocorticoid deficiency include

1. Fatigue
2. Weakness
3. Weight losss
4. Gastrointestinal disturbance
5. Postprandial hypoglycemia
 Mineralocorticoid deficiency leads to dehydration with hypotension, hyponatremia and
hyperkalemia
 Excessive pituitary release of ACTH and related precursor peptides due to loss of the negative
feedback system, may cause hyperpigmentation of the skin and mucous membranes through
the action of melanocyte-stimulating hormones on melanocytes

ACUTE ADRENAL INSUFFICIENCY (ADDISONIAN CRISIS)

 It is medical emergency characterized by severe hypotension and shock, hyponatraemia and

hyperkalemia.
 It can occur in the following situations:
1) Withdrawal of glucocorticoid
2) Stress e.g trauma, surgical operation, infection,
3) Bilateral adrenalectomy e.g for two months
4) Adrenal injury e.g trauma, haemorhage (anticoagulant therapy), sepsis.
 Clinical features
Nausea and vomiting
Weight loss
Hypotension
The presence of adrenal hyperpigmentation raises a suspicion of primary adrenal insufficiency
 Treatment

Intravenous fluid

Synthetic ACTH

Intravenous hydrocortison
 Correct abnormal electrolyte findings

For severe hyperkalaemia (> 6mmol/L) -hydrocortisone, glucose and insulin or potassium
binding raisin, in order to rapidly lower serum potassium

SECONDARY AND TERTIARY ADRENAL INSUFFICIENCY

 In secondary and tertiary adrenal insufficiency, inadequate cortisol production may be due to
destructive processes in the hypothalamic and pituitary glands that result in the decreased
ability to secrete ACTH (secondary) or CRH (tertiary)