Transcript The Adrenal Cortex - Washington State University

The Adrenal Cortex
Basic principles of steroid endocrinology
• Steroid effects fall into 3 categories:
– Mineralocorticoid
– Glucocorticoid
– Androgen/Estrogen
• Small differences in steroid molecules
have large effects on activity
• Steroids act through nuclear receptors, so
their major effects involve changes in the
expression of particular genes
Major Corticosteroid Hormones
• Aldosterone – mineralocorticoid
• Cortisol (human); corticosterone (some
mammals) – glucocorticoid
• Adrenal androgens:
dehydroepiandrosterone (DHEA),
androstenedione, androstenediol,
Corticosteroid effects
Hormone
Actions/Effects
Aldosterone
Stimulates Na+ reabsorption and H+ and K+ secretion
in nephron; indirectly regulates ECF volume
Cortisol
Permissive for epi and glucagon
Stimulates lipolysis, protein catabolism and
gluconeogenesis
Essential for normal inflammatory and immune
responses; but immunosuppressive and
antiinflammatory at pharmacological doses; also
stimulates bone breakdown
Androgens
Masculinizing effect at high doses, especially during
prenatal development; postnatal effects probably
trivial for males but essential for sustaining sex
interest in females
Pathways of
adrenal steroid
biosynthesis
Important
points:
This reaction occurs in the
periphery, not in the
adrenal itself
multiple
reactions are
catalyzed by
the same
enzymes –
however, in
different
regions of the
cortex,
different parts
of the map
are favored.
Enzyme mutations are responsible for a number of
clinical syndromes: for example – 21 alpha
hydroxylase deficiency
• Leads to inadequate production of both
mineralocorticoid and glucocorticoid, but
excessive production of adrenal androgen
• Symptoms: salt-losing diuresis, increased
susceptibility to infection, premature
masculinizing puberty
• Adrenal hypertrophy occurs as a result of the
lack of feedback from cortisol – so ACTH levels
are elevated.
• Appropriate therapy: replacement cortisol
Control of ACTH secretion
• The hypothalamus releases CRH in
regular pulses, about every 20 min.
• Circadian rhythm: greatest secretion
(increased pulse amplitude) occurs in the
early morning before awakening
• Stress or hypoglycemia strongly stimulate
pulse amplitude.
• ADH also stimulates ACTH secretion.
What is stress, anyway?
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Emotional
Situational
Surgical
Forced exercise
Confinement/handling (animals)
Pain
Ultimately, physiologists have decided to define
stress as any stimulus that elevates ACTH
secretion.
Hyper and hypoadrenal syndromes
• Cushing’s Syndrome: excessive corticosteroid –
hypertension, hyperglycemia, hypokalemia, alkalosis,
characteristic pattern of fat loss from lower body and fat
deposition around neck and face. This syndrome is very
commonly iatrogenic.
• Addison’s Syndrome: hypotension, poor survival in
fasting, increased susceptibility to infection,
hyperkalemia, acidosis, potential for ‘Addisonian crisis’.
• Causes may be at level of hypothalamus, pituitary or
adrenal itself – diagnosis involves measurement of
ACTH levels
Post-translational processing of POMC in pituitary
corticotrophs
‘POMC’ is proopiomelanocortin. The primary gene product can be
clipped at different places to produce a variety of hormones. During
adult life, the major corticotroph products are ACTH and betalipotropin. During fetal life and in pregnant women, the pars
intermedia of the pituitary processes the gene product differently,
yielding gamma lipotropin, beta endorphin, and two versions of
melanocyte stimulating hormone.
Addison’s Syndrome hypoadrenalism
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Hypoglycemia
Hypotension
Poor resistance to infection
Fatigue, muscle weakness
Susceptibility to Addisonian crises
Hyperpigmentation – in primary
hypoadrenalism
Primary versus secondary
disease
• In primary hypoadrenalism, the adrenal
cortex is the site of the lesion and ACTH
levels are elevated, giving
hyperpigmentation.
• In secondary hypoadrenalism, the pituitary
or brain is the site of the lesion, and ACTH
levels are low.
Visible symptoms of Cushing’s syndrome
Symptoms of Hyperadrenalism
• Obesity – including characteristic fat
deposit on back of neck
• Skin changes
• Symptoms of androgen excess
• Muscle and bone loss
• Menstrual irregularity
• Hypertension
• Glucose intolerance