anatomy and physiology of adrenal cortex . detail of artery and venous supply along with histological differences of adrenal cortex . detail of biosynthesis of adrenocorticosteroids. reaction of biosynthesis of cortisol , androgen and aldosterone in different region ie. zona fasciculata, zona reticularis and zona glomerulosa respectively. biochemical function of cortisol and aldosterone along with structures. congenital adrenal hyperplasia.
2. Adrenal Gland
Anatomy
Located on top of the kidneys near the
spine, just beneath the last rib and
extending down about an inch.
Also known as suprarenal glands.
Shape: pyramidal (usually right
adrenal is pyramidal, whereas the left
is shaped more like a half moon)
Size: 2- 3 cm wide, 4- 6 cm long, and
about 1 cm thick.
Weigh: 6-10 g.
3. Venous drainage
Adrenal veins are present for each gland:
The right adrenal vein enters directly into the venacava at an acute angle, whereas the left
adrenal vein enters into the left renal vein.
Arterial blood supply:
(1) Superior adrenal artery from the
inferior phrenic artery (a branch of
the aorta);
(2) Middle adrenal artery, which is
directly from the aorta; and
(3) Inferior adrenal artery, a branch
of the renal artery.
(1)
(2)
(3)
4. Structurally and functionally they consists of:
1. Outer Adrenal cortex (80-90%)–
glandular tissue derived from embryonic mesoderm
2. Inner Adrenal medulla (10-20%)–
formed from neural ectoderm, can be considered a modified sympathetic
ganglion
5. The Adrenal Cortex
The cortex is divided into 3 regions:
zona glomerulosa(10 to 15% of the cortex)
zona fasciculata(up to 75% of the cortex)
zona reticularis(5 to 10% of the cortex)
• These secrete different hormones that
carry out specific functions throughout
body
6. Biosynthesis Of Adrenocorticosteroid
All steroid hormones have in common the 17 carbon
cyclopentanoperhydrophenanthrene nucleus.
Additional carbons can be added at positions 10 and 13 or as a side chain attached
to C17.
7. Cholesterol is Precursor
Uptake of cholesterol by the adrenal cortex is mediated by the LDL
receptor.
With long-term stimulation of the adrenal cortex by ACTH, the number of
LDL receptors increases.
Much of the cholesterol in the adrenal is esterified and stored in
cytoplasmic lipid droplets.
Trophic stimuli such as ACTH in the zona fasciculata and zona reticularis,
and elevated cytosolic Ca++ in the zona glomerulosa, cause increased
synthesis of the steroidogenic acute regulatory protein (StAR)protein
within minutes.
StAR protein involved in cholesterol transfer across the mitochondrial membrane.
Biosynthesis of Adrenocorticosteroid
8.
9. In the mitochondria, a cytochrome P450 side chain cleavage enzyme (P450scc)
converts cholesterol to Pregnenolone and isocaproaldehyde
Desmolase- a cytochrome P450 mixed-function oxidase
NAPDH and O2 required
Rate limiting reaction
Pregnenolone migrates into the DOC migrates back into the
mitochondrion
Biosynthesis of Adrenocorticosteroid
10. In the zona glomerulosa
Pregnenolone is converted to
progesterone by the action of two C
enzymes
3-beta-hydroxysteroid dehydrogenase
type 2 and Δ 4,5 isomerase.
CYP17 (17-α-hydroxylase) activity is
not expressed
Progesterone is hydroxylated at the C21
position by CYP21(21-Alpha hydroxylase)
to form 11 deoxycorticosterone (DOC)
which is an active (Na+-retaining)
mineralocorticoid.
DOC migrates back into the mitochondrion
where CYP11B2 (Aldosterone synthase)
catalyzes the conversion of DOC ultimately to
aldosterone
11. In the zona glomerulosa
Aldosterone diffuses out of the mitochondrion into the
cytoplasm and across the cell membrane to enter the
circulation.
Aldosterone secretion rate per day is 100 to 150 µg,
with some estimates varying up to 200 µg.
CYP11B2 catalyzes the conversion of
DOC ultimately to aldosterone
CYP11B2 (aldosterone synthase)
enclose three enzymatic activities:
(i) 11-β-hydroxylase
(ii) 18-hydroxylase
(iii) 18-hydroxydehydrogenase
12. Pregnenolone is transferred to smooth endoplasmic
reticulum (ER)
and converted to 17-OH-pregnenolone catalysed by the enzyme
17-α-hydroxylase.
Conversion of 17-OH pregnenolone to 17-OH
progesterone
achieved by two enzymes, 3 β-OH-steroid dehydrogenase and
Δ4,5-isomerase.
17-OH-progesterone to 11-deoxycortisol:
Catalysed by the enzyme 21-α-hydroxylase present in
endoplasmic reticulum (ER).
Finally 11-deoxycortisol is transferred to mitochondrion
where it is acted by the enzyme 11-β-hydroxylase and
is converted to ‘cortisol’.
Normal cortisol secretion rate is 6 to 14 mg/m2per 24 hours.
In adults, this is approximately 10 to 20 mg/d.
In the Zona Fasciculata
13. In the Zona Reticularis
The major androgen or androgen precursor
produced by the adrenal cortex
Dehydroepiandrosterone (DHEA).
Most 17 hydroxypregnenolone follows the
glucocorticoid pathway,
But a small fraction is subjected to oxidative
fission and removal of the two-carbon side chain
through the action of 17,20-lyase and form DHEA.
3-beta-hydroxysteroid dehydrogenase and ∆5,4-
isomerase convert the weak androgen DHEA into
the more potent androstenedione.
Small amounts of androstenedione are also formed in the
adrenal by the action of the lyase on 17α hydroxyprogesterone.
Negligible amounts of testosterone, dihydrotestosterone (DHT), and
estradiol are secreted by the cortex.
15. Adrenocortical Hormones In The Circulation
90 to 98% Steroid hormones are bound to specific carrier proteins or albumin.
Steroids that are sulfated circulate unbound in the plasma.
Aldosterone is carried primarily by albumin.
Cortisol, corticosterone, and 17-hydroxyprogesterone occupy most of the binding
sites on corticosteroid-binding globulin (CBG; transcortin)
CBG- a 58 kDa, 383 amino acid alpha-1 globulin.
16. 80 - 90% of cortisol is carried by corticosteroid-binding globulin (CBG)
7% of cortisol is loosely bound to albumin
1 to 2% is unbound (free).
When total cortisol rises as in Cushing syndrome, the increased proportion of
plasma free cortisol readily spills into the urine, increasing the urinary free
cortisol (UFC) excretion.
The half-life of cortisol is longer (60 to 80 minutes) than the half-life of
aldosterone (20 to 30 minutes).
Because more cortisol than aldosterone is bound to CBG,
Adrenocortical Hormones In The Circulation
17. Dehydroepiandrosterone (DHEA)and its sulfated form,
DHEA-S, and estradiol are predominantly carried by albumin.
In contrast, testosterone and dihydrotestosterone (DHT) are carried by
sex hormone–binding globulin (SHBG)
Adrenocortical Hormones In The Circulation
18. Mechanism of action of Adrenocorticosteroids
Upon hormone binding, the receptor dissociates from the heat shock protein and translocates to
the nucleus. In the nucleus, the hormone-receptor complex binds to a DNA sequence called a
hormone response element (HRE), which triggers gene transcription and translation. The
corresponding protein product can then mediate changes in cell function.
19. Mineralocorticoid
The naturally synthesized mineralocorticoid of most importance is
aldosterone.
Other compounds with mineralocorticoid activity include:
11-desoxycorticosterone (DOC),
18-hydroxycorticosterone,
corticosterone, and
Cortisol
Mineralocorticoids bind to the mineralocorticoid receptor (MR)
in the distal convoluted tubule and collecting duct of the
nephron, the colon, and the salivary glands
to promote sodium reabsorption
and potassium & hydrogen ion excretion.
Aldosterone stimulates:
Epithelial sodium channel (ENaC) activity via serum and
glucocorticoid-induced kinase (SGK) and K-ras,
Increases expression ofmitochondrial ATP-producing genes,
and stimulates the basolateral Na+/K+-ATPase pump.
20. Effects Of Aldosterone
Important in the regulation of salt ("mineral") balance
and blood volume.
In the kidneys
Aldosterone acts on the distal convoluted tubule(DCT)
& the collecting tubule(CT)
by increasing the reabsorption of sodium and
the excretion of both potassium and hydrogen
ions.
It is responsible for the reabsorption of about 2% of
filtered glomerular filtration rates.
Effects of aldosterone in sodium retention are important
for the regulation of blood pressure.
Enhances absorption of sodium from the intestine especial. colon. –
absence leads to diarrhea.
21. Mechanism of Na+ Selective Reabsorption in renal DCT cells
Aldosterone regulates Na+, K+ ATPase activity in human renal distal tubules cells through mineralocorticoid
receptor
22. Aldosterone production and secretion are controlled through
the Renin-angiotensin-aldosterone system
Direct stimulators
increased extracellular K+
decline in sodium concentration
ACTH
Indirect stimulators
decreased blood pressure
decreased macula densa blood flow
These stimulus influences juxtaglomerular cells for renin
secretion via beta1-adrenoreceptors.
Renin, an aspartyl protease (M.W. 42,000), acts on the Leu -Val bond
at the amino terminus of angiotensinogen form angiotensin I
ACE present in lungs splits off the carboxy terminal dipeptide
angiotensin I to yield the highly active angiotensin II
Regulation Of Aldosterone
25. GLUCOCORTICOIDS
• Glucocorticoids bind to the glucocorticoid receptor (GR) and have a major role in
regulation of glucose metabolism.
• Cortisol is major Glucocorticoids and other are
• 11-deoxycorticosterone
• Corticosterone
• Cortisone
26. Function of Cortisol
Cortisol’s most important job is to help the body respond to stress.
Effects on carbohydrate metabolism
Increase gluconeogenesis (PEPCK)
Inhibits uptake and utilization of glucose by extrahepatic tissue
Increase hepatic glycogenosis (Glycogen synthase)
Hyperglycemic effect
Effects on Lipid metabolism
increase TG hydrolysis in adipose tissue
Increase FFA
Effects on Protein metabolism
promotes transcription and protein biosynthesis in liver
catabolic effect in extrahepatic tissue (muscle, adipose tissue,
bone)
27. Effects of glucocorticoids on fuel metabolism.
• Stimulate lipolysis in
adipose tissue
• Release of amino acids
from muscle protein.
In liver
• stimulate
gluconeogenesis and
the synthesis of
glycogen.
• The breakdown of liver
glycogen is stimulated
by epinephrine.
28.
29. Effects of Cortisol
Cortisol helps in maintaining vascular tone and cardiac output,
and stabilize lysosomal membranes.
Cortisol suppress hypersensitivity responses by inhibiting the
production of histamine by basophils and mast cells.
Cortisol prevents the Development of Inflammation by Stabilizing
Lysosomes and by Other Effects.
Cortisol decreases both migration of white blood cells into the
inflamed area and phagocytosis of the damaged cells
Cortisol suppresses the immune system, causing lymphocyte
reproduction to decrease markedly.
T lymphocytes are especially suppressed
Cortisol attenuates fever mainly
because cortisol reduces the release of interleukin-1 from the
white blood cells
30. Cortisol has anti-inflammatory properties that include effects on the
microvasculature, cellular actions, and the suppression of inflammatory cytokines
(the so-called immune-adrenal axis)
31. Regulation Of Cortisol Release
Cortisol is controlled through a traditional hypothalamic-
pituitary- end organ negative feedback system
Hypothalamus produces corticotropin-releasing hormone
(CRH) that stimulates the pituitary gland to secrete
adrenocorticotropin hormone (ACTH).
Corticotropin-releasing hormone (CRH) is released by :
Stress (pain, trauma, surgery, and hemorrhage, severe
anxiety and major depression.)
exercise, and
hypoglycemia.
ACTH then stimulates the adrenal glands to make and
release cortisol hormones into the blood.
Cortisol release follows a circadian rhythm and a negative
feedback by cortisol inhibits the secretion of ACTH and
CRH.
32. Cortisol is controlled through a traditional hypothalamic – pituitary -end organ
negative feedback system
SCN-suprachiasmatic nucleus
PVN-paraventricular nucleus
35. Glucocorticoids
Common Therapeutic Uses Of
Glucocorticoids
o Bronchial asthma.
o Chronic bronchitis.
o Emphysema.
o Sarcoidosis.
o Ulcerative colitis.
o Crohn’s disease.
o SLE, cerebral edema.
o Skin diseases.
o Hodgkin’s disease
Adverse Effects Of
Glucocorticoids
Hypertension.
Peptic ulcer, pancreatitis.
Insomnia, depression and
psychosis.
Amenorrhea.
Hyperglycemia.
Osteoporosis.
Pathological fractures.
Cataract.
36. Adrenal Androgens
The adrenal androgens:
Dehydroepiandrosterone (DHEA),
Dehydroepiandrosterone sulfate (DHEA-S)
Androstenedione
They provide androgenic effects through their peripheral conversion to
testosterone, which binds to the androgen receptor (AR)
37. In males, adrenal androgens, such as DHEA and androstenedione: less
important as testosterone is a much more potent androgen.
In women : has important role in producing axillary and pubic hair.
Women with Turner syndrome are an excellent example of the effects of
adrenal androgens in women.
Androgens are also the precursor of all estrogens
38. Biochemical functions
Effect on protein metabolism:
RNA synthesis( transcription)
Protein synthesis( translation)
Rapid growth of musculo-skeletal system associated with puberty.
Muscle mass (Androgens promote the enlargement of skeletal muscle cells)
Effect on carbohydrate and fat metabolism:
Glycolysis
Production of D-fructose from D-glucose by seminal vesicles
Fatty acid synthesis
Effects on mineral metabolism- Androgens promote :
Mineral deposition and bone growth
Renal reabsorption of Na+, Cl- and water.
39. Regulation Of Adrenal Androgens
The regulation of adrenal androgen synthesis and secretion remains poorly
understood.
But, the best characterized regulator of androstenedione and DHEA
secretion is ACTH
as CYP17(17,20-lyase & 17-hydroxylase) is regulated by ACTH.
Sympathetic innervation of the zona reticularis may also regulate adrenal
androgen secretion.
40. Metabolism of Adrenal Steroids
The liver is the major site of steroid metabolism via P450 enzyme systems, with the
kidney playing less of a metabolic role but an important excretory role.
Clearance of steroid hormones involves
hydroxylation,
dehydrogenation,
reduction of double bonds,
conjugation to sulfates or glucuronides.
The reduction in steroid concentrations increases their solubility and provides functional sites (such
as hydroxyl groups)
for their conjugation to sulfate or glucuronic acid.
This increases their solubility in urine, promoting their excretion & app. 90% of conjugated
steroids are excreted by the kidney.
41. Metabolism of Aldosterone
Aldosterone is reduced to tetrahydroaldosterone.
Glucuronidation produces tetrahydroaldosterone 3 glucuronide, which can
be excreted by the kidney.
Only ≈0.5% of aldosterone is excreted unchanged in the urine.
42. Metabolism of Cortisol
• Cortisone is formed from cortisol via 11
beta-hydroxysteroid dehydrogenase type
2(HSD11β2)
• Reduction of the double bonds at
carbons 4-5 yields dihydrocortisol and
dihydrocortisone (DHE).
• Reduction of the ketone groups at carbon
3 results in tetrahydrocortisol (THF) and
tetrahydrocortisone (THE),
• which account for ≈50% of cortisol
excretion.
• Further metabolism of THF and THE
produces alpha and beta cortol and
cortolone (the cortoic acids),
• which account for ≈30% of cortisol
excretion.
Cortisone
cortisol
Dihydrocortisol Dihydrocortisone
20-beta-hydroxysteroid dehydrogenase
cortol cortolone
delta(4)-5- beta reductase or delta(4)-5-alpha reductase
43. • 11 beta-hydroxyetiocholanolone
and 11- ketoetiocholanolone,
• representing ≈10% ofcortisol
excretion
• ≈ 1% of cortisol is normally
excreted as free cortisol or
cortisone.
• Minor cortisol metabolites include
• 20 alpha hydroxycortisol
• 20 beta-hydroxycortisol
• 6 betahydroxycortisol
Metabolism of Cortisol
44. DHEA is sulfated to DHEA-S
.
7α HydroxyDHEA or
16αHydroxyDHEA by
Hdroxylase
Alternatively, 17-ketosteroid
reductase reduces the ketone
at carbon 17 to a hydroxyl
group, yielding androstenediol
from DHEA
Metabolites of the adrenal
androgens are glucuronidated
or sulfated for urinary
excretion
Metabolism of Adrenal Androgens
45. Congenital Adrenal Hyperplasia (CAH)
Congenital adrenal hyperplasia (CAH) is a group of autosomal
recessive disorders characterized by impaired cortisol synthesis.
Results from the deficiency of one of the five enzymes required
for the synthesis of cortisol in the adrenal cortex.
In CAH, defects in the enzymes necessary for cortisol production
lead to cortisol deficiency;
cortisol deficiency results in a disinhibition of the negative
feedback on CRH and ACTH production.
As a consequence, CRH and ACTH levels rise,
inducing adrenal hyperplasia and a forward push in
steroidogenesis, as the body tries to compensate and
normalize cortisol production.
50. Congenital lipoid adrenal hyperplasia
Most severe form of CAH in which the synthesis of all gonadal and adrenal
cortical steroids is markedly impaired.
Lipoid CAH may be caused by a defect in either the steroidogenic acute
regulatory protein (StAR) or the P450scc(Desmolase) ( Fujieda, 2003 ).
Pathologically, the adrenal cortex shows marked accumulation of
cholesterol and other lipids,
which is the primary distinguishing feature from congenital adrenal hypoplasia.
Diagnosis is made by the presence of
extremely low cortisol and aldosterone concentrations,
elevated ACTH and plasma renin activity.
51. Feature 21-Hydoxylase
deficiency
11β-Hydoxylase
deficiency
17-Hydroxylase
deficiency
3β-Hydroxysteroid
deficiency
Lipoid
hyperplasia
Aldosterone
synthase
deficiency
Defective gene CYP21 CYP11B1 CYP17 HSD3B2 StAR CYP11B2
Incidence 1:15 000 1:100 000 Rare Rare Rare Rare
Ambiguous
genitalia
+ (Female) + (Female) + (Male) + (Male) + (Male) Normal
Absent puberty
(female)
Mild in female Absent
puberty
(female)
Laboratory
findings
↑ plasma 17-
OHP and
pregnanetriol
↑ serum DOC and
11-deoxycortisol
↑ serum DOC, 18-
OH DOC, B and 18-
OHB
↑ serum 17OH-
pregnenolone,
pregnenolone and
DHEA
All serum
and plasma
steroids are
decreased
↑ serum B, 11-
DOC and 18-
OHB
Greatly ↑ urinary
pregnanetriol and
17-KS
↑ urinary 17-OHCS
and 17-KS
↑ urinary 17-KS
↑ Δ5/Δ4 serum and
urinary steroids
Glucocorticoids ↓ ↓ ↓ ↓ ↓ Normal
Mineralocortico
ids
↓ ↑ ↑ ↓ ↓ ↓
Androgens ↑ ↑ ↓ ↓ male, ↑ female ↓ Normal
Congenital Adrenal Hyperplasia