Adrenal steroidogenesis

Dr Mohammad Waseem Kausar

Assistant Professor
IMDC , Biochemistry
Adrenocorticotropic Hormone
(ACTH, corticotropin)
The Adrenal Gland

Figure 18.16
 ADRENAL (SUPRARENAL) GLANDS

Location adrenal cortex

Cortex vs. medulla

adrenal medulla
Cortex = steroids
Medulla = catecholamines
adrenal gland
sympathetics
kidney
norepinephrine and epinephrine
fight-or-flight
The Adrenal Cortex Has Three
Distinct Layers.
 Adrenal cortex
 Synthesizes many steroids but 3 classes of
hormones; glucocorticoids,
mineralocorticoids and androgens
 Cortex divided into three layers
 Zona glomerulosa (produces mineralocorticoids)
 Zona fasciculate (produces glucocorticoids)
 Zona reticularis (produces androgens)
 ADRENAL CORTEX (ZONA GLOMERULOSA)

Mineralocorticoids (aldosterone)
Electrolyte and fluid balance
Aldosterone secretion in response to either:
high blood [K+] (hyperkalemia)
renin-angiotensin system
Actions:
decreased K+ reabsorption by kidneys
Increased Na+ reabsorption by kidneys
 ADRENAL CORTEX (ZONA FASCICULATA and
reticularis)

Glucocorticoids (cortisol, hydrocortisone, cortisone)

Stress  C-RF  ACTH  glucocorticoids
Actions:
Promote normal metabolism (increased glucose
availability)
Resistance to stress (increased alertness,
energy, blood pressure)
Anti-inflammatory (membrane stabilization)
 ACTH
 CRH controls its secretion from hypothalamus
 Two forms α and β
 ProOpiomelanocortin (POMC, "Big Mama") ant-
pitutary.
 Regulates the growth and function of adr-cortex
 ACTH stimulates the adrenal cortex. More
specifically, it stimulates secretion of
glucocorticoids such as cortisol
 has little control over secretion of aldosterone,
the other major steroid hormone from the
adrenal cortex
Corticotropin-releasing hormone
 corticoliberin, a polypeptide hormone  and 
neurotransmitter 
 involved in the stress response.
 41-amino acid peptide derived from a 191-
amino acid preprohormone.
 Marked reduction in CRH has been observed in
association with Alzheimer's disease, and
autosomal recessive hypothalamic corticotropin
deficiency has multiple and potentially-fatal
metabolic consequences like hypoglycemia and
hepatitis
 CRH is produced by (paraventricular nucleus) of
the hypothalamus and is released at the median
eminence from neurosecretory terminals of these
neurons into the primary capillary plexus of the
hypothalamo-hypophyseal portal system
 . The portal system carries the CRH to the anterior
lobe of the pituitary, where it
stimulates corticotropes to
secrete corticotropin (ACTH) and other biologically
active substances (for example β-endorphin)
ACTH is a single PP, containing 39 AA, ACTIVE CORE =1st 23 AA
from the N terminal while 24 -39 AA stabilizes the molecules and
varies in composition from species to species
Mechanism of action of ACTH
 METABOLIC ROLE OF
ACTH
 act on adrenal cortex & extra adrenal tissues
 affects both basal secretion & under stress
secretion of glucocorticoid.
 ACTH increases the synthesis & secretion from
adrenal cortex.
 ACTH has a profound changes in
1 adrenal structure
2 chemical composition
3 enzymatic activity
 Specific receptors on fascicularis
 It stimulates the synthesis & secretion of
Glucocorticoid
1, increases the transfer of cholesterol from
plasma lipoprotein into cells
2, cAMP, phosphorylation & activation of
cholesterol esterase thus free choles.
3, it promotes the binding of cholesterol to mito-
cyt- P450, which is required for hydroxylation.
4, it activates dehydrogenase of HMP to increase
the concentration of NADPH for hydroxylation
5 it activates the hormone sensitive lipase
lipolysis FFA
Feed back control of ACTH
Basic structure
Cholesterol side chain cleavage and basic steroid
hormone structure
Synthesis of three major classes of adr- steroid
 MINERALOCORTICOIDS
 Are C21 steroids
 Influences the metabolism of Na & K
 Chief is Aldosterone, others are
 Cortocosterone
 11- deoxycortisol
 11- deoxycorticosterone
 Metabolic roles of
ALDOSTERONE
 1, Na reabsorption
 From DCT, CT and loop
2, chloride ions reabsorption
 secondarily to Na
3, K excreation
(hypokalemia--- muscle paralysis)
4, effect on acid base balance(alkalosis)
5, effect on blood volume
 Metabolic role of the
Glucocorticoids
 Generally Anti-insulin
 Catabolic to peripheral tissues

 Anabolic to liver

 EFFECT ON CHO
 Hyperglycemia

 Decreased glucose uptake by muscles, adipocites and lymphoid

tissues by inhibiting membrane transport

Rate of gluconeogenesis as much as 6- to 10-fold in liver.
• induces key enzymes of gluconeogenesis
• Increasing protein catabolism in extrahepatic tissues by synthesis of
amino acid catabolic enzymes like transaminases
• Decreasing amino acids incorporation in proteins
.
 Cont-
 effect on lipid metabolism
• Net effect increase FFA and GLYCEROL
• Lipolysis by activating hormone sensitive TG lipase
 effect on protein metabolism
 In extrahepatic tissues it is catabolic to proteins
 In liver it is anabolic by
1, inc- A A uptake
2, inc- incorporation of A A into ribosomal proteins
3, inc- m-RNA , inc- plasma proteins
4, inc- urea synthesis by inc- necessary enzymes
 ACTH pathophysiology
 Weak MSH like activity ----- hyper pigmentation
 Excessive production by pituitary or by tumor
results in Cushing’s syndrome. Manifestation are
due to excessive adrenal steroids includes
1,negative nitrogen, K+ and Phosphorus balance
2,sodium retention------- hypertention, oedema
3,diabetes mellitus
4,inc- FFA
5,dec- lymp.
Muscular atrophy, truncal obesity
 Enzymatic deficiency
 Congenital defect ; dec- cortisol secretion
and CAH
1, Gene defect for protein in gonads and
adrenals, for movement of cholesterol into
mitoc-.(cause of sever CAH)
2,. Cholesterol desmolase def-.
fatal in utero b/c placenta can not synthesis
progesterone
 Common defects are
 21 β hydroxylase def-.  11 β hydroxylase def-
90–95 % cases of CAH. 1% of cases
Virilization( ACTH) virilization ( ACTH)+
Enough gluco & minera- Excess sec- of 11-
Sustain life deoxy cortisol &11-
In sever cases deoxy corticosterone
Masculinization salt & water retention
Female pseudohermo-. hypertensive
Salt loosing