Distinguished anatomists such as Galen, da Vinci, and Vesalius omitted the adrenal
glands in their descriptions of the retroperitoneum.
Bartholomaeus Eustachius was the first to describe them in mid-16th century
In mid-19th century Thomas Addison, an English physician, described a series of
patients with the condition of adrenal insufficiency that now carries his name
Charles Brown-Sequard, through a series of animal experiments demonstrated that
bilateral adrenalectomy uniformly resulted in death, suggesting that the adrenals
were indispensable to the survival of the host
William Osler was the first to report treatment of Addison disease with hormonal
replacement in 1896. He administered crude extract from adrenals of pigs to a
patient with Addison disease and produced significant weight gain in this one
In the ensuing half-century “adrenalin” was discovered, and its production was
localized to the adrenal medulla (Oliver and Sharpey-Schafer, 1895).
The ability of adrenaline to produce a sustained rise in blood pressure was
subsequently determined (Abell and Crawford, 1897). Moreover, the failure of this
substance, later termed “epinephrine” to sustain life following bilateral
adrenalectomy underscored the complexity and multifunctionality of the adrenal
gland and established Addison disease as an ailment of the adrenal cortex (Scott,
1990; Porterfield et al, 2008).
Discovery and isolation of cortisol from the adrenal gland in the 1930s and
subsequent work on its use to treat rheumatoid arthritis produced a 1950 Nobel
Prize in Physiology and Medicine for Edward Kendall, Philip Hench, and Tadeus
Reichstein (Scott, 1990).
Aldosterone was ultimately isolated from the bovine adrenal in 1952 (Grundy et al,
The latter part of the 20th century witnessed a rapid transformation in our
understanding and treatment of adrenal disorders lead by pioneers such as Jerome
Conn, Lawson Wilkins, Grant Liddle, and Earl Sutherland
The adrenal gland consists of
Adrenal cortex and medulla are two embryologically and functionally distinct units.
The cells of the cortex arise from coelomic epithelium (mesoderm).
Cortex - Mesoderm
The cells of the medulla are derived from the neural crest (ectoderm).
Medulla - Neuroectoderm
Derived from intermediate mesoderm of urogenital ridge
Formed during 2nd month by a proliferation of coelomic epithelium. The cells of
the cortex arise from the coelomic epithelium, that lies in the angle between the
developing gonad and the attachment of the mesentery (Figs 18.3A. B). Cells pass
into the underlying mesenchyme between the root of the dorsal mesogastrium and
Beginning in the 5th week of gestation, mesenchymal cells located at the urogenital
ridge and the root of mesentery proliferate ( form Fetal Adrenal Cortex). The
cells are large and acidophil. They surround cells of medulla.
The proliferating tissue, which extends from T6 to T12, is soon disorganized
Invasion of neural crest cells and
Development of venous sinusoids
The venous sinusoids are joined by capillaries, which arise from adjacent
mesonephric arteries and penetrate the cortex in a radial manner.
During the 6th and 7th weeks of gestation additional mesothelial cells surround
fetal cortex they will later form Adult Adrenal Cortex. These cells are smaller.
When proliferation of coelomic epithelium stops, cortex is enveloped by a
mesenchymal capsule which is derived from the mesonephros.
By the end of the 8th week of gestation the mesothelial cells forming the cortex are
encapsulated by connective tissue and have separated from peritoneal mesothelium.
Derived from Neural Crest Cells (from somites 18-24), located in adjacent
Neural Crest Cells are similar to postganglionic sympathetic neurons. Pre-ganglionic
sympathetic neurons terminate in relation to them
They migrate into medial aspect of fetal cortex by 9th week of gestation
They continue to invade cortex until they achieve a central position surrounding
the adrenal vein by 18th week of gestation
THIS EMBRYOLOGIC RELATIONSHIP EXPLAINS THE BROWN STIPPLING OF
Adrenals In The Neonate
Each gland weighs 4 g; avg weight of two glands is 9 g (average in adult is 7-
Adrenals are relatively very large at birth
Constitute 0.2% of entire body weight, compared with 0.01% in adult
Fetal adrenal gland is twice the weight of an adult adrenal gland, but has not
Left gland is heavier and larger than right, as in the adult
Cortex is thicker than in adult and medulla is small.
Fetal cortex begins to atrophy and will be completely resorbed by 12 months of
age. Fetal cortex undergoes rapid involution during first two years after birth.
The glands involute rapidly
Each gland loses 25% of its mass
Average weight of both glands is
5 g by end of 2nd wk
4 g by 3 months
As the fetal cortex is being resorbed, the zona glomerulosa and fasciculata of
the adult cortex continue to develop, but the zona reticularis will not complete
differentiation until 3 years of age, reflecting the relative late importance of
sex steroid production by this part of cortex
Birth weight is not regained until puberty
Adrenals In The Neonate
U/l adrenal agenesis
Rare and often a/w U/l renal agenesis (Incidental)
Adrenal gland development occurs normally in the absence of ipsilateral renal unit
development, mal-rotation, or mal-ascent. In these cases, the adrenal glands are
often discoid in shape and located in their normal position within the
Adrenal cortical tissue may be present at various ectopic sites.
The entire adrenal may be ectopic and may lie deep to the capsule of the kidney.
It may be fused to the liver or the kidney.
Results from incomplete separation of primitive adrenal mesoderm from adjacent
organs such as the liver or kidney,
Results in partial or complete incorporation of the gland into the adjacent organ.
Accessory Adrenal Tissue (Adrenal Rests)
Can be composed of cortical/medullary tissues
Due to the close proximity of adrenal and genitourinary development, adrenal rests
can be found anywhere along the path of gonadal descent within the
Although adrenal rests can be found in up to 50% of neonates, the tissue typically
atrophies and is found in only approximately 1% of adults
In cases of congenital adrenal hyperplasia (CAH), adrenal rest within testis may
become hyperplastic and present as a testicular mass. THIS IS AN IMPORTANT
CONSIDERATION PRIOR TO PERFORMING AN ORCHIECTOMY FOR A TESTICULAR
MASS IN PATIENTS WITH CAH.
Congenital Adrenal Hyperplasia (overdevelopment of cortex)
MC abnormality of adrenal development
Occurs in 1:5000-1:15000 births.
Deficiencies in enzymes required for synthesis of cortisol.
In 90% of cases cause is deficiency of enzyme 21-hydroxylase accumulation
of 17-hydroxyprogesterone is converted to androgens. levels of androgens
increase by several hundred times
In female it may cause Pseudohermaphroditism
Female embryos and foetuses undergo external genital masculinisation ranging
from clitoral hypertrophy to formation of a phallus and scrotum
Child may be mistaken for a male
Masculinisation of brain has also been suggested
In male this leads to Adrenogenital Syndrome
Do not cause any changes in external genitalia
Very early development of secondary sexual characters
Precocious masculinisation and accelerated growth
Anatomy was first described in 1563
They are paired retroperitoneal organs composed of a cortex and medulla
Contained in its own sub-compartment within Gerota’s fascia
Gross examination reveals
Cortex = spiculated, mustard yellow colour
Medulla = central, brown colour
Weight ~ 4 - 5 g each
Length = 4 - 6 cm
Width = 2 - 3 cm
Right adrenal gland is triangular in shape
Left adrenal gland is crescent shaped
They may sit either immediately superior to kidney, “capping” the upper pole, or
superio-medially to upper pole, “cradled” by kidney just above renal vessels.
Located within Gerota fascia at level of 11th and 12th ribs
Gerota’s fascia connects them to upper pole of kidney
Located cephalad to upper pole of kidneys and anterior to crus of diaphragm
The right adrenal gland tends to lie more cephalad than the left adrenal gland
Right adrenal is bounded
Anteriorly = Liver
Posterior = Diaphragm
Superior = Diaphragm
Inferio-laterally = Right Kidney
Medially = IVC
Medial aspect of the gland is often retrocaval
Right adrenal vein enters IVC in a posterolateral position
Left adrenal gland is bounded
Anteriorly = Stomach, Pancreas (Body), Splenic Vessels
Posteriorly = Diaphragm
Superiorly = Spleen
Inferiorly = Kidney
Medially = Aorta
Left adrenal is more elongated than right and will lie in a more superomedial
position to the kidney. This tends to place the gland closer to the left renal hilum,
and these structures must be accounted for during dissection.
Close juxtaposition of these organs to adrenal explains why lesions of adjacent
organs, such as leiomyomas of greater curvature of stomach, may be confused for
an adrenal mass.
Receives blood @ 7cc/gm/min
3 arterial sources of flow: (IPS-ARMI)
Branches from Inferior Phrenic Artery Superior Adrenal A.
Direct visceral branches from Aorta Middle Adrenal A.
Branches from I/L Renal Artery Inferior Adrenal A.
The main adrenal arteries branch to form a subcapsular plexus
From subcapsular plexus
Some branches continue directly to medulla
Others form sinusoids to cortex
Medullary veins coalesce to form adrenal vein
Adrenal vein is surrounded by medullary tissue within the gland.
Single main vein on each side
Most important surgical structure
Right adrenal vein
Drains directly into post IVC
Left adrenal vein
Long as compared to right adrenal vein
Joined by Inferior Phrenic vein prior to draining into Left Renal Vein
The overlapping of both arterial and venous anatomy makes partial adrenalectomy
possible with little risk of subsequent adrenal infarction
Preganglionic sympathetic fibers from sympathetic trunk directly to
Postganglionic fibers from splanchnic ganglia
Parasympathetic to adrenal cortex and medulla
Not well defined
Branches from Vagus nerve may be present
Right Para-caval Lymph Nodes
Left Para-aortic Lymph Nodes
Is divided into 3 zones in the adult gland:
Is divided onto 4 zones in the fetal gland:
The three zones of the permanent adult cortex constitutes only 20% of the fetal
The remaining zone (fetal cortex) comprises up to 80% of gland’s size during
Each adrenal gland is enclosed within a fibrous capsule
Directly beneath the capsule is the cortex, which comprises three zones:
Zona Glomerulosa (Outermost Layer)
Small polyhedral cells with scant eosinophilic cytoplasm and dark round
Broad layer of large pale cells arranged in vertical columns beneath
Zona Reticularis (Innermost layer)
Round dark staining cells
Adrenal Cortex: Steroid Hormone Production
The cortex is divided into three regions:
Hormones produced by the adrenal cortex are referred to as corticosteroids.
Sex hormones (Androgens)
Synthesized from cholesterol–steroid ring
Zona Glomerulosa: Mineralocorticoids
Zona Fasciculata: Glucocorticoids
Zona Reticularis: Androgens
Hormones of the Adrenal Cortex
• All adrenal cortex hormones are steroid
• Not stored, synthesized as needed
C = O
Common precursor = Cholesterol
Low-density lipoprotein (LDL) serves as primary source of cholesterol to adrenals
Steroid hormone receptors are absent on cellular membranes of target tissues.
Instead, steroids diffuse passively into cell bind to their respective receptors
intracellularly direct binding of hormone receptor complex to target DNA
Gene transcription is modulated.
Ratios and types of enzymes in each zone of the adrenal cortex vary, resulting
in different hormonal products for each region
Mineralocorticoids (ZG) = 100 to 150 mcg/d
Glucocorticoids (ZF) = 10 to 20 mg/d
Androgens (ZR) = >20 mg/d
Zona Glomerulosa (ZG)
Outermost region of adrenal cortex - just below the adrenal capsule
Secretes Mineralocorticoids. The naturally synthesized Mineralocorticoid of most
importance is Aldosterone.
Aldosterone = 10 human Mineralocorticoid
Only zone of adrenal gland that contains enzyme Aldosterone synthase (CYP11B2).
As a result sole source of Aldosterone
Mineralocorticoids are aptly termed as they are involved in regulation of
electrolytes in ECF.
Zona Fasciculata (ZF)
Middle zone – between the glomerulosa and reticularis
Site of Glucocorticoid production due to expression of 17α-hydroxylase, 21
hydroxylase, and 11β-hydroxylase enzymes
Primary secretion is Glucocorticoids. Glucocorticoids, as the term implies, are
involved the increasing of blood glucose levels. However they have additional
effects in protein and fat metabolism.
Cortisol = 10 Glucocorticoid in humans
Its secretion is under tight control of ACTH. Production of cortisol by adrenal follows
a strict circadian schedule. Majority of cortisol is secreted in the early morning
Glucocorticoids are essential to life and modulate complex physiologic pathways
that include metabolism, immunity, maintenance of intravascular volume, regulation
of blood pressure, and complex modulation of CNS with significant effects on mood,
sleep, and potentially memory
Cortisol and ACTH are a part of a classic hormonal negative feedback system that
features hypothalamus, pituitary gland and adrenal.
Some androgen synthesis also occurs in zona fasciculata
Zona Reticularis (ZR)
Innermost zone of adrenal cortex – between fasciculata and medulla
Primary secretion is androgens.
Presence of 17α-hydroxylase and 17,20-lyase production of
Dehydroepiandrosterone (DHEA), sulphated DHEA (DHEA-S) and Androstenedione
Adrenal Androgens exhibit ~ same effects as male sex hormone (testosterone).
Adrenal Androgen secretion appears to be under control of ACTH, and, like cortisol,
exhibits circadian patterns
DHEA, DHEA-S, and Androstenedione comprise the greatest portion of steroid
hormone that is produced by the adrenals (>20 mg/day), but appear to be the
least important for adult physiologic homeostasis
However, pharmacologic manipulation of adrenal androgen production remains a
viable and increasingly targeted strategy for advanced prostate cancer
NB.: Overlap in secretions of Androgens and Glucocorticoids exist b/w ZF and ZR
Adrenal medulla comprises less than 10% of total adrenal mass.
Embryologically derived from pheochromoblasts (Neuroectoderm)
Differentiate into modified neuronal cells
More gland than nerve
Functions of Adrenal Medulla
It is an integral part of autonomic nervous system (extension of Sympathetic NS)
Acts like sympathetic ganglion (Acts as a peripheral amplifier)
Activated by same stimuli as the sympathetic nervous system (examples – exercise,
cold, stress, hemorrhage, etc.)
Chromaffin cells of medulla are innervated by preganglionic sympathetic fibers of
T11 to L2, making them analogous to cells of the sympathetic ganglia.
These substances, collectively known as catecholamines, are produced from the
amino acid tyrosine and modulate the systemic stress response. Hormones are
secreted and stored in medulla and released in response to appropriate stimuli
Effects of these catecholamines are mediated through their binding to
Adrenoreceptors located on target organs. The nature of these effects depend on
the adrenoreceptor subtypes located and stimulated on a particular end organ
Enzyme phenylethanolamine-Nmethyl transferase (PNMT), which catalyzes the
conversion of norepinephrine to epinephrine, is relatively unique to the adrenal
medulla (the brain and organ of Zuckerkandl also express this enzyme).
The function of this enzyme is potentiated by the presence of Glucocorticoids,
thereby creating one of the few physiologic links between the adrenal cortex and
Localization of PNMT to the adrenal medulla explains why the gland is the primary
source of systemic epinephrine, despite the presence of similar chromaffin cells
elsewhere in the sympathetic nervous system
Similar to the physiology that controls norepinephrine release at synaptic nerve
terminals, the storage and release of adrenal catecholamines involves intracellular
vesicles. Liberation of these vesicles through exocytosis results in release of adrenal
catecholamines into the blood stream
Majority of adr catecholamine metabolism occurs at site of production
Important for clinical purposes :
Vanillyl Mandelic Acid
Catechol-O-Methyl Transferase (COMT)
Mono Amine Oxidase (MAO)
Methylation of Epinephrine by COMT = Metanephrine
Methylation of Norepinephrine by COMT = Normetanephrine
Large amounts present in the liver and kidneys
Majority of adrenal catecholamine metabolites are methylated by COMT within the
cells of the adrenal medulla
> 90% of Metanephrine and ~ 20% of normetanephrine in blood stream are
derived from the adrenal medulla.
Therefore a measurable rise in the level of these metabolites is very useful when
diagnosing potential pheochromocytoma.
In the urine, the majority of these metabolites are excreted in a sulfonated form.
MAO and other enzymes subsequently convert catecholamine metabolites to VMA
VMA is the primary catecholamine metabolic end product
VMA is largely formed by liver
Nonadrenal catecholamines from sympathetic nervous system are also similarly
converted to VMA
Exclusively synthesized in ZG
Essential for life
Functions of Aldosterone
Regulates electrolyte metabolism by stimulating epithelial cells of distal nephron to
reabsorb Na+ and Cl−, while secreting H+ and K+
Promotes Sodium retention and Potassium elimination by kidney
Expands ECF volume
Aldosterone exerts the 90% of the Mineralocorticoid activity. Cortisol also have
Mineralocorticoid activity, but only 1/400th that of Aldosterone
Aldosterone increases renal tubular (principal cells) reabsorption of sodium &
secretion of potassium
Although Aldosterone levels have a profound effects on total body Na+,
concentration of the ion does not change, whereas reabsorption of sodium is
accompanied by reuptake of free water. Therefore Aldosterone primarily affects
total body volume and not sodium concentration
Excess Aldosterone ↑ ECF volume & arterial pressure, but has only a small effect on
plasma sodium concentration
Excess Aldosterone causes hypokalemia & muscle weakness, & too little Aldosterone
causes hyperkalemia & cardiac toxicity
Excess Aldosterone increases tubular (intercalated cells) hydrogen ion secretion, with
resultant mild alkalosis
Electrolyte balance in epithelial cells of the submaxillary salivary glands and the
large intestine are also under Mineralocorticoid control (? physiologic importance)
Aldosterone stimulates sodium & potassium transport in sweat glands, salivary
glands, & intestinal epithelial cells
a steroid hormone
essential for life (acute)
responsible for regulating Na+ reabsorption in the distal tubule and the cortical
target cells are called “principal (P) cell”
stimulates synthesis of more Na/K-ATPase pumps
Renal and circulatory effects … covered (ECF volume regulation, sodium and
potassium ECF concentrations)
Promotes reabsorption of sodium from the ducts of sweat and salivary glands
during excessive sweat/saliva loss.
Enhances absorption of sodium from the intestine esp. colon. – absence leads to
Regulation of Aldosterone secretion:
Primarily regulated by
Angiotensin II through Renin-angiotensin-aldosterone system (RAAS)
Directly by serum potassium levels
Primary stimulus for release of Aldosterone is Angiotensin II
Other: ACTH, low serum Na, elevated K, JGA via low kidney perfusion
Rise in ACTH can also increase Aldosterone (much less potent stimulus). For this
reason ZG is the only region of cortex that does not atrophy upon pituitary failure
ANP = main inhibitor, providing an imp link b/w cardiac, adrenal and renal
Somatostatin, dopamine, and others may also play a role
Regulation of Aldosterone Release
Direct stimulators of release
Increased extracellular K+
Indirect stimulators of release (RAAS)
Decreased blood pressure
Decreased macula densa blood flow
Angiotensin II can
water & salt
Aldosterone: Role in Diseases
Complete failure to secrete Aldosterone leads to death (dehydration, low blood
Hyperaldosterone states: Contribute to hypertension associated with increased
Glucocorticoids (including cortisone and cortisol)
Plasma bound to corticosteroid binding globulin (CGB) or transcortin
Essential for life (long term)
The net effects of cortisol are catabolic
Prevents against hypoglycemia
Produced in the middle layer of the adrenal cortex
Promote normal cell metabolism
Help resist long-term stressors
Released in response to increased blood levels of ACTH
Physiological Actions of Cortisol
Promotes breakdown of skeletal muscle protein
Enhances fat breakdown (Lipolysis)
Suppresses immune system
Breakdown of bone matrix (high doses)
Anti-inflammatory Effects of Cortisol
Reduces phagocytic action of white blood cells
Suppresses allergic reactions
Wide spread therapeutic use
Effect on Blood Cells and Immunity
Decrease production of eosinophils and lymphocytes
Suppresses lymphoid tissue systemically therefore decrease in T cell and antibody
production thereby decreasing immunity
Decrease immunity could be fatal in diseases such as tuberculosis
Decrease immunity effect of cortisol is useful during transplant operations in
reducing organ rejection.
Effect of cortisol on protein metabolism
Reduction of protein storage in all cells except those of liver – ↑ protein catabolism
& ↓ protein synthesis
Cortisol increases liver & plasma proteins
Mobilizes amino acids from non hepatic cells, thus increase blood amino acid level.
↑ amino acid transport to liver cells & ↓ transport of amino acids into other cells
Physiological Actions of Cortisol
Permissive Effects of Cortisol on Development
Cortisol is required for normal development
Permissive role in final maturation of many organs
Required for synthesis of digestive enzymes, surfactant
Required for skeletal growth in children
Body Responses to Stress
Permissive effect on glucagon
Memory, learning and mood
Skeletal muscle breakdown
Lipolysis, calcium balance
Physiological Actions of Cortisol
Cortisol and Chronic Stress
Prolonged exposure to high cortisol levels can lead to break down of muscle,
excessive epinephrine release, hyperglycemia, weakening of bone, destruction of
the immune system, inhibition of reproductive function, and other complications.
Physiological Actions of Cortisol
Mechanism of Cortisol Action
The actions of cortisol are mediated through the Glucocorticoid receptor.
Intracellular receptor in steroid receptor superfamily
Stimulates transcription of target genes by interaction of bound receptor with GRE
in 5’ flanking region.
Inhibits transcription of some genes by interaction of receptor with AP1 (jun/fos
dimer), decreasing AP1-mediated gene expression.
Hormone Effects on
Cortisol release is regulated by ACTH
Release follows a daily pattern – circadian
Negative feedback by cortisol inhibits the secretion of ACTH and CRH
Enhanced release can be caused by:
Extreme heat and cold
Exercise to the point of exhaustion
Extreme mental anxiety
Regulation Of Cortisol Secretion
Mechanism of Action
• receptor mediated – adrenergic receptors
• peripheral effects are dependent upon the
type and ratio of receptors in target tissues
Norepinephrine +++++ ++
Epinephrine ++++ ++++
Relative effects of epinephrine and norepinephrine on and adrenergic receptors.
Differences between Epinephrine and
Epinephrine >> norepinephrine – in terms of cardiac stimulation leading to greater
cardiac output ( stimulation).
Epinephrine < norepinephrine – in terms of constriction of blood vessels – leading to
increased peripheral resistance – increased arterial pressure.
Epinephrine >> norepinephrine –in terms of increasing metabolism Epi = 5-10 x
Norepi. = 100% normal
Effects of Epinephrine
Gets you ready to fight or run
Heightens your senses, tenses your muscles, openings
breathing passages, etc.
In response to stress
Take less than 30 seconds to kick in and last several
Effects of Epinephrine
- glycogenolysis in liver and skeletal
- mobilization of free fatty acids
- increased metabolic rate
• can lead to hyperglycemia
• O2 consumption increases
Mechanism: Norepinephrine Release and Recycling
Review of Efferent Pathways: Motor and Autonomic
Stimulates the “fight or fight” reaction
Increased plasma glucose levels
Increased cardiovascular function
Increased metabolic function
Decreased gastrointestinal and genitourinary function