MODULE 11: ENDOCRINE SYSTEM

Adrenal Glands
04/03/2020
ANATOMY & PHYSIOLOGY

TABLE OF CONTENTS

I. ANATOMY OF THE ADRENAL GLAND .........................................................................1

A. BLOOD SUPPLY ...................................................................................................1
II. ADRENAL CORTEX AND CORTICOSTEROIDS..............................................................2
A. THREE LAYERS OF THE ADRENAL CORTEX ..........................................................2
B. SYNTHESIS AND FATE OF CORTICOSTEROIDS .....................................................2
III. MINERALOCORTICOIDS............................................................................................3
A. ALDOSTERONE VS. CORTISOL .............................................................................3
B. MECHANISM OF ALDOSTERONE ACTION ..........................................................4
C. REGULATION OF ALDOSTERONE SECRETION .....................................................4
E. EFFECTS OF ALDOSTERONE ................................................................................4
IV. GLUCOCORTICOIDS..................................................................................................5
A. ACTIONS OF GLUCOCORTICOIDS ........................................................................5 Figure 1. Zones of the Adrenal Cortex
V. ADRENAL SEX STEROIDS ...........................................................................................6
A. PRODUCTION OF SEX STEROIDS .........................................................................6 Table 1. Comparison between Adrenal Cortex and Adrenal Medulla
B. ADRENAL ANDROGEN REGULATION ..................................................................7
VI. ADRENAL MEDULLA .................................................................................................7 Adrenal Cortex Adrenal Medulla
A. SYNTHESIS ..........................................................................................................8
B. ACTIONS OF CATECHOLAMINES ........................................................................8 Origin Intermediate mesoderm Neural crest ectoderm
C. METABOLISM OF CATECHOLAMINES .................................................................8
QUICK REVIEW ..............................................................................................................8 No neural innervation
SUMMARY OF PROCESSES ......................................................................................8 Innervation/ Sympathetic nervous
REVIEW QUESTIONS ...............................................................................................8 Regulation system
REFERENCES..................................................................................................................9 Hormonal stimulation
REQUIRED ...............................................................................................................9
SUPPLEMENTARY....................................................................................................9 Steroids
Catecholamines
FREEDOM SPACE...........................................................................................................9 Secretion (mineralocorticoids,
(epinephrine and
glucocorticoids, and
norepinephrine)
adrenal androgens)

LEARNING OBJECTIVES
A. BLOOD SUPPLY
(1) Anatomy Arterial Supply
(2) Hormones secreted by the adrenal gland
• Derives its blood supply from the following:
a. Synthesis and secretion
b. Regulation & Inferior Phrenic Artery
o Branches into the superior phrenic arteries
c. Biologic activity
d. Metabolism & Aorta (Abdominal)
o Near the level of the origin of the SMA
o Branches into the middle suprarenal arteries
T/N: This trans is taken mainly from the 2023 Trans (12.06 Adrenal Glands) & Renal Artery
and Guyton and Hall’s Medical Physiology 13th edition. o Branches into the inferior suprarenal arteries
Venous Drainage
I. ANATOMY OF THE ADRENAL GLAND • Right adrenal vein
• Lies in the retroperitoneum o Short
• On the superior poles of each kidney o Drains directly into the inferior vena cava
• Left adrenal vein
• Also known as suprarenal glands
o Merges with the inferior phrenic vein
• Each gland weighs approximately 4 grams
• Common phrenic vein
• Divided into two parts:
o Drains into the left renal vein
o Adrenal medulla
§ Central 20% of the gland
§ Secretes norepinephrine and epinephrine in response to
sympathetic stimulation
o Adrenal cortex (outer)
§ Covered by an outer fibrous capsule
§ Subdivided into three layers:
Þ Zona glomerulosa (outer)
Þ Zona fasciculata
Þ Zona reticularis (inner)
§ Secretes corticosteroids

Figure 2. Blood Supply of Adrenal Gland

Transcribed by TG 18: Baloloy, Chong, de Dios, Diones, Estampador, Noceda, Villaret

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Checked by TG 6: Angeles, Argona, Cruz, Go, Kosca, Mallillin, Paderon, Yao 1 of 9
 II. ADRENAL CORTEX AND CORTICOSTEROIDS o The Steroidogenic Acute Respiratory Protein (stAR) then transports
cholesterol from the outer to the inner mitochondrial membrane
• Corticosteroids are a class of steroid hormones produced in the adrenal
(mitochondrial matrix)
cortex
• Once it enters the inner mitochondrial membrane, cholesterol is cleaved
• Major types:
by the enzyme desmolase (cytochrome P450 side chain cleavage enzyme)
o Mineralocorticoids
to form pregnenolone
§ See Mineralocorticoids section
o Desmolase is dependent on ACTH levels
o Glucocorticoids
o The conversion of cholesterol to pregnenolone is rate limiting step in
§ Have effects that increase blood glucose concentration
the eventual formation of adrenal steroids
§ Have additional effects on carbohydrate, fat and protein
metabolism
§ Cortisol as the principal glucocorticoid
o Adrenal Androgens
§ Same effects in the body as testosterone

T/N: The three layers of the adrenal cortex was not thoroughly discussed in
the handout. This subsection was taken from Guyton and Hall.

A. THREE LAYERS OF THE ADRENAL CORTEX

Zona Glomerulosa
• Lies just underneath the capsule that constitutes 15% of the adrenal
cortex
• Secretion: aldosterone (main mineralocorticoid)
• Enzyme: aldosterone synthase
• Stimulates secretion: extracellular fluid concentrations of angiotensin II
and potassium Figure 3. Synthesis of Steroid Hormones from Cholesterol in the Adrenal
Cortex
Zona Fasciculata
• Middle and widest zone Functional Zonation of Enzyme Synthesis
• 75% of the adrenal cortex • Aldosterone secretion is confined to zona glomerulosa because of the
• Secretion : glucocorticoids (cortisol, corticosterone) and small amounts of restricted expression of aldosterone synthase, but it cannot synthesize
adrenal androgens and estrogens cortisol
• Regulates secretion: hypothalamic-pituitary axis via adrenocorticotropic • The synthesis of cortisol is limited to the layer with 17 a-hydroxylase
hormone (ACTH) • In the zona reticularis, high levels of cytochrome B5 confer 17,20-lyase
Zona Reticularis activity on CYP17A1 and androgen production
• Inner zone of the cortex o Sulfotransferase converts DHEA to DHEAS
• Secretion: adrenal androgens (dehydroepiandrosterone and
androstenedione), small amounts of estrogens, and some glucocorticoids Binding Proteins and Half-Life
• Regulates secretion: ACTH and cortical androgen-stimulating hormone • Steroid hormones are not stored
(released from the pituitary) o They are synthesized as needed unlike peptide hormones and is
formed immediately when ACTH stimulus is received
Table 2. Hormones Produced by the Adrenal Cortex o The stimulation will cause rapid synthesis and complete degradation
ADRENAL CORTEX afterwards
Zona Glomerulosa Zona Fasciculata Zona Reticularis o Therefore, binding proteins are important to lengthen half-life of
Mineralocorticoids Glucocorticoids Sex Steroids steroid hormones
• Aldosterone • Cortisol • DHEA • Binding of adrenal steroids to plasma proteins may serve as a reservoir to
• Deoxycorticosterone • Corticosterone • Androstenedione lessen rapid fluctuations in free hormone concentrations
• Androgens and • Estrogens o Helps ensure a relatively uniform distribution of adrenal hormones to
Estrogens • Glucocorticoids the tissues

Table 3. Corticosteroids Table 4. Binding Proteins and Half-Life of Principal Corticosteroids

Adrenal Sex Aldosterone Cortisol Androgen
Mineralocorticoid Glucocorticoid Layer
Steroids
Zona glomerulosa Zona fasciculata Zona reticularis
Function Salt and water Adrenal Produced
Metabolism
balance androgen % Binding
60% 90-95% Low affinity
Layer
produced Zona glomerulosa Zona fasciculata Zona reticularis Cortisol binding
Binding globulin
Regulation RAAS ACTH ACTH
Protein Plasma Proteins (Transcortin) Albumin

B. SYNTHESIS AND FATE OF CORTICOSTEROIDS Albumin

Cholesterol DHEA: 15-30

• Precursor of steroidogenesis (process of forming steroids) Half-Life minutes
20 minutes 60-90 minutes
• Sources of cholesterol DHEAS: 7-10
o Small amounts of cholesterol from de novo acetyl coenzyme A hours
o 80% from LDL in the circulating plasma
o HDL cholesterol Metabolism of Adrenal Steroids
Steps of Steroidogenesis • The adrenal steroids are degraded mainly in the liver and conjugated to
• Transfer of cholesterol to mitochondria glucuronic acid and to a lesser extent sulfates
o Sterol Carrier Protein (SCP-2) transports cholesterol from the o These substances are inactive and do not have mineralocorticoid or
cytoplasm to the outer mitochondrial membrane glucocorticoid activity

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 o 25% of these conjugates are excreted in the bile and then into the
feces III. MINERALOCORTICOIDS
o The remaining conjugates (75%) formed by the liver enter the
& Type of adrenocortical hormones secreted by the adrenal cortex
circulation but are not bound to plasma proteins are highly soluble in
& Affect the electrolytes (the “minerals”) of the extracellular fluid,
the plasma and filtered readily by the kidneys and excreted into the
especially sodium and potassium
urine
• Aldosterone is the major mineralocorticoid secreted by the adrenal gland
Regulation of Adrenal Steroids o Other steroids such as, corticosterone, deoxycorticosterone and
• Aldosterone synthesis and secretion is under the renin-angiotensin- cortisol can also act as mineralocorticoids
aldosterone system (RAAS)
o Important in the Zona Glomerulosa A. ALDOSTERONE VS. CORTISOL
o Stimulated by:
• In terms of mineralocorticoid activity: aldosterone is 3000 times greater
§ Low blood pressure
than that of cortisol
§ Low plasma sodium concentration
• In terms of plasma concentration: cortisol is 2000 times greater than that
§ Low blood volume
of aldosterone
§ Blood loss
• Aldosterone is the major mineralocorticoid secreted by the adrenal gland
o Renin converts Angiotensinogen to Angiotensin I à Angiotensin
o Aldosterone synthesis through Aldosterone Synthase
converting enzyme (ACE) in the lungs converts Angiotensin I à
§ Enzyme found only in the zona glomerulosa
angiotensin IIà stimulates adrenal cortex à aldosterone production
§ Converts corticosterone to aldosterone
and secretion
o Recall: Aldosterone increases sodium and water reabsorption

Figure 4. RAAS System of the Adrenal Gland

• Cortisol synthesis and secretion is under the hypothalamic pituitary

adrenal axis Figure 6. Aldosterone Synthesis
o Important in Zona Fasciculata and Zona Reticularis
• Cortisol, corticosterone, and deoxycorticosterone can also act as a
o Stimulated by:
mineralocorticoid
§ Stress
o Can also bind to mineralocorticoid receptors with high affinity, but is
§ Hypotension
still NOT considered as the major mineralocorticoid
§ Fever
o The renal epithelial cells contain the enzyme 11β-HSD21, which
§ Hypoglycemia
converts cortisol (active) to cortisone (inactive)
§ Exercise
§ Cortisone does NOT avidly bind to mineralocorticoid receptors
§ Physiological stress
Þ Hence, even if cortisol plasma concentration is high, cortisol does
o Hypothalamusà Cortico-releasing Hormone (CRH)à Anterior
Pituitaryà ACTH productionà Cortisol production NOT normally exert significant mineralocorticoid effects
o As a negative feedback, glucocorticoids inhibit POMC transcription in o Inactivation is reversible
the anterior pituitary and CRH mRNA synthesis and secretion in the
hypothalamus

Figure 7. Conversion of Cortisol to Cortisone

Figure 5. Hypothalamic Pituitary Adrenal Axis

1 11β-HSD2: 11Beta- Hydroxysteroid Dehydrogenase type 2

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 B. MECHANISM OF ALDOSTERONE ACTION

Figure 9. Regulation of Aldosterone Secretion

Inhibitory Agents
• Atrial natriuretic hormone
Figure 8. Mechanism of Action of Aldosterone in an Epithelial Cell • High sodium concentration
• Due to its lipid solubility in the cellular membranes, aldosterone diffuses o High concentration of aldosterone in the plasma can transiently
readily to the interior of the tubular epithelial cells decrease sodium loss into the urine to as little as a few milliequivalents
o In the cytoplasm of the tubular cells, aldosterone combines with a a day
highly specific cytoplasmic mineralocorticoid receptor • Potassium deficiency
o The aldosterone-receptor complex diffuses into the nucleus inducing o Excessive secretion of aldosterone may cause a serious decrease in
one or more specific portions of DNA to form mRNA related to the potassium concentration
process of sodium, potassium and hydrogen transport o May lead to severe muscle weakness caused by alteration of the
§ Sodium Potassium Adenosine Triphosphatase electrical excitability of the nerve and muscle fiber membranes which
Þ principal part of the pump for sodium and potassium exchange prevents transmission of normal action potentials
at the basolateral membrane of the renal tubular cells
§ Epithelial Sodium Channel D. EFFECTS OF ALDOSTERONE
• Result: Increased sodium reabsorption and potassium secretion
Table 6. Genomic and Non-Genomic Actions of Aldosterone
C. REGULATION OF ALDOSTERONE SECRETION GENOMIC ACTIONS NON-GENOMIC ACTIONS
Intracellular receptors Cell membrane receptors
Table 5. Stimulatory and Inhibitory Agents of Aldosterone Secretion mRNA à protein formation Second messenger systems
STIMULATORY AGENTS INHIBITORY AGENTS Enzymes or membrane transport Formation of cAMP in vascular
Increased in potassium Atrial natriuretic hormone proteins involved in sodium and smooth muscle cells and epithelial
concentration in the ECF potassium transport cells
Low blood volume, sodium loss High sodium concentration No immediate effect Few seconds or minutes
à Activation of RAAS system
ACTH Potassium deficiency Table 7. Effects of Aldosterone
SWEAT GLANDS AND INTESTINAL
RENAL SYSTEM
SALIVARY GLANDS EPITHELIAL CELLS
Stimulatory Agents
Collecting tubules Colon
• Increased potassium ion concentration in the extracellular fluid greatly and principal cells
increases aldosterone secretion Enhanced Na+ and H2O
o Rising serum potassium levels depolarize the glomerulosa cell Increased number of Increased
absorption in the
membranes stimulating opening of voltage-sensitive calcium channels activity of basolateral reabsorption of NaCl
intestine, preventing
§ Result in an influx of calcium stimulating aldosterone production Na+/K-ATPase pumps and secretion of K+
loss of Na+ in the stool
• Increased angiotensin II concentration in the extracellular fluid greatly Increased sodium
increases aldosterone secretion Sweat glands:
permeability of Increased potassium
o Angiotensin II binds to a G-protein coupled receptor, angiotensin I Conserve body salt in
luminal plasma excretion
receptor, on zona glomerulosa cells hot environments
membrane
§ Results in increased aldosterone secretion by increasing
Increased luminal Salivary glands:
transcription of CYP11B2 gene Unabsorbed NaCl &
plasma membrane Conserve salt when
• Increased ACTH2 secretion will increase aldosterone secretion H2O can lead to
potassium excessive saliva are
o Done by stimulating early pathways of adrenal steroidogenesis, but has diarrhea
permeability lost
no effect on CYP11B2 gene transcription or enzyme activity
§ Chronic continuous ACTH has no effect or an inhibitory effect on
aldosterone production because of receptor downregulation Renal System
& Increased sodium ion concentration in the extracellular fluid very slightly • Main principle: Increased Na+ reabsorption and K+ secretion followed by
decreases aldosterone secretion H2O reabsorption
& Potassium ion concentration and renin-angiotensin system are by far the • Aldosterone acts on:
most potent in regulating aldosterone secretion o Principal Cells
§ Found in the distal convoluted tubule and collecting ducts in the
kidney
§ Upregulation of ENaC channels increases the permeability of the
cell to sodium thereby causing reabsorption
§ Sodium will then be pumped out of the cell through the Na+/K+
ATPase towards the tubular lumen and secreted in the urine

2 ACTH: Adrenocorticotropic Hormone

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 § Amiloride inhibits ENaC but does not act on the mineralocorticoid
receptor
o Intercalated Cells
§ Found in the cortical collecting tubule
§ Affects hydrogen balance in the system thereby affecting the acid-
base balance of the body
§ Renal collecting tubules secrete hydrogen ions in exchange for
sodium
§ The hydrogen ions get pumped out of the vascular system and into
the urine, decreasing hydrogen ion concentration in the ECF and
causing metabolic alkalosis
IV. GLUCOCORTICOIDS
• ACTH and cortisol are secreted in a pulsatile manner, following the
circadian rhythm
o Circadian rhythm is dependent on day-night and sleep-wake patterns
o Levels are highest upon waking, decline throughout the day, and are
lowest in the evening
Figure 10. Circadian Rhythm of Cortisol Secretion
• Stress stimulates CRH release from the paraventricular nucleus
o CRH leads to increased POMC gene expression, corticotrope
hypertrophy, and thus ACTH release
• ACTH binds to melanocortin 2 receptors (M2CR) in zona fasciculata cells
to increase steroidogenesis and thus cortisol synthesis and secretion
o Acutely, rapid increase in StAR protein gene expression stimulates
steroidogenesis
§ Increase in stAR-mediated cholesterol delivery to the CYP11A1
enzyme in the inner mitochondrial membraneà enzyme-mediated
conversion of cholesterol to pregnenolone
o Chronically, ACTH-mediated increase in the transcription of genes
encoding steroidogenic enzymes and their co-enzymes leads to the
increased synthesis of all steroidogenic CYP enzymes
• ACTH also increases synthesis of LDL and HDL receptors, as well as HMG-
CoA reductase
• Long-term stimulation (weeks to months) by ACTH increases secretory
activity and adrenal weight through hyperplasia and hypertrophy
• Cortisol is a lipid-soluble steroid hormone that is able to diffuse through
the cell membrane
• Cortisol binds to glucocorticoid-receptor α in the cytosol
o This binding leads to a dissociation of heat shock proteins, which then
activates the steroid receptor complex
o The dimerized GR-ligand (steroid receptor) complex translocates to
the nucleus and binds to a specific DNA sequence known as the
glucocorticoid response elements
§ This can either stimulate or repress gene transcription
Figure 11. Mechanism of Cortisol Action
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• Most of the metabolic effects of cortisol are not immediate and require
45-60 minutes for proteins to be synthesized and another several hours
to days be fully developed
• Glucocorticoids in high concentrations can have nongenomic effects on cell
membrane ion transport
A. ACTIONS OF GLUCOCORTICOIDS
• At least 95% of the glucocorticoid activity results from the secretion of
CORTISOL.
o A small amount of glucocorticoid activity is provided by
CORTICOSTERONE.
2 95% is the result of endogenous cortisol and/or exogenous
hydrocortisone and 4% is from corticosterone (12.06, ASMPH 2023).
Increase Blood Glucose Concentration
Liver
• Cortisol increases hepatic glucose output
o Increased gluconeogenesis (12.07, ASMPH 2022)
2 Breaks down glycogen deposition (12.07, ASMPH 2022)
2 Aids in Amino Acid Delivery (12.07, ASMPH 2022)
Muscles
• Increases protein catabolism
• Decreases protein synthesis
o Overall catabolism promotes mobilization of amino acids to provide
gluconeogenic precursors
o Cortisol mobilizes amino acids derived from muscles
• Inhibits glucose uptake and mobilization
Adipose Tissue
• Inhibits glucose uptake and mobilization
o “Insulin Resistance” (12.07, ASMPH 2022)
2 Increased Lipolysis (12.07, ASMPH 2022)
2 Release of free fatty acids (12.06, ASMPH 2023)
Stimulate Adipocyte Differentiation
• Promotes adipogenesis
• Stimulates deposition of visceral or central adipose tissue
• Increase in total circulating cholesterol & triglycerides
Causes catabolic changes in Muscle, Skin, and Connective Tissue
• Inhibits epidermal cell division
• Reduce synthesis & production of collagen
• Causes atrophy of type II muscle fibers
• Reduce Muscle protein synthesis
Causes negative calcium balance
• Inhibits osteoblast formation
• Inhibits intestinal calcium absorption
• Increases renal calcium excretion
Exerts Anti-Inflammatory effects and Immunosuppression
• Cortisol:
o stabilizes the lysosomal membrane
§ Most of the proteolytic enzymes are released in greatly decreased
quantity
o Diminishes the formation of prostaglandins, histamine, leukotriene
which leads to:
§ lessen vasodilation
§ decreased capillary permeability
§ reduced mobility of white blood cells
o Decreases migration of white blood cells into the inflamed area and
phagocytosis of the damaged cells
• Glucocorticoids reduce lymphocyte counts acutely by redistribution of the
lymphocytes from the intravascular space to the spleen, lymph nodes &
bone marrow
• Eosinophils counts rapidly fall
• Inhibition of monocyte differentiation into macrophages
• Macrophage phagocytic & cytotoxic activity decreases
• Fever attenuation
5 of 9
 o Dehydroepiandrosterone sulfate (DHEAS9)
§ Detectable at age 6
o Dehydroepiandrosterone (DHEA10)
§ A crucial precursor for sex steroid biosynthesis
§ Exerts androgenic or estrogenic activity after conversion
by 3-beta-hydroxysteroid dehydrogenase in the adrenal gland
• Adrenal androgens represent an important component of circulating
androgens in premenopausal women
o Responsible for axillary and pubic hair development which starts at 8
years old
o Increase libido in women only
§ In men, this contribution is much smaller because of the testicular
production of testosterone.
§ The testis is still the major source of testosterone in men.
2 Since there is no testis in women, they rely on adrenal androgens.
o The adrenal contribution of sex steroids in men is crucial only in
patients with Congenital Adrenal Hyperplasia.
• Adrenal androgens peak in mid 20s and declines with age
Figure 12. Normal Inflammatory Process (Left) and Anti-Inflammatory • Although ACTH stimulates adrenal androgen, the latter does not exert
Process (Right). (12.06, ASMPH 2023) negative feedback on ACTH or CRH11
2 Exogenous Cortisol is used as a pain reliever (12.06, ASMPH 2023).
Table 9. Production of Major Sex Hormones in Males
Peripheral
Sex steroids in Testicular Adrenal
T/N: The next section concerning the effects of glucocorticoids is not Conversion
men Secretion (%) Secretion (%)
included in the handout distributed during the CoVid-19 Extreme Enhanced (%)
Community Quarantine (EECQ) but is included in the Batch 2022 and 2023 Testosterone 95 <1 <5
trans. This section was included under the discretion of the transing team. DHT < 20 <1 80
Estradiol < 20 <1 80
Estrone <2 <1 98
Inhibition of immune system DHEAS < 10 90 -
2 Macrophage: decreased activity
2 Neutrophilia: high levels of neutrophil but do not migrate to infection site 2 From 12.06, ASMPH 2023 Doc said during the lecture:
2 Eosinopenia: Decreased number of eosinophils; for treatment of asthma o Testosterone is the major hormone coming from the testis
and allergies § Testicular secretion is the major source of testosterone
2 Lymphocyte: apoptosis (95%)
2 Lymphocyte redistribution: § Adrenal secretion is less than 1%
o T-Lymphocytes are more affected § Peripheral conversion is less than 5%
o Attenuation (Reduction) of fever because of IL-1 inhibition o Dihydrotestosterone (DHT) is mainly from the peripheral conversion
2 Immunoglobulins: decreased synthesis (80%) because of 5-alpha-reductase
2 Cytokines: Decreased synthesis § 5-alpha-reductase is not present in testis, only in the peripheral
Other Effects tissues (hair follicles, prostate, genital skin)
• Suppress thyroid axis through decrease in TSH3 secretion o Estradiol is also mainly from peripheral conversion
• Inhibits GnRH4 pulsatility & release of LH5 & FSH6 o DHEAS is mainly from adrenals
• Inhibits ADH7 secretion § This is why when you have excess adrenal androgen secretion, you
• Induces differentiation & maturation of type II alveolar cells measure your DHEAS to confirm (not your testosterone levels)
2 Inhibits Thyroxine 5-deiodinase (enzyme essential in thyroid hormone
production). (12.06, ASMPH 2023) T/N: The next sections concerning the production of adrenal sex steroids
and adrenal androgen regulation are not included in the handout
Table 8. Glucocorticoids, Anti-inflammatory and salt retention action factors. distributed during the CoVid-19 Extreme Enhanced Community Quarantine
Anti-Inflammatory Salt Retention (EECQ) but is included in the Batch 2022 and 2023 trans. This section was
Action Action included under the discretion of the transing team.
Cortisol 1 1
Corticosterone 0.3 15
Aldosterone 0.3 3000 A. PRODUCTION OF SEX STEROIDS
Deoxycorticosterone 0.2 100
Prednisone 3 0.75
Prednisolone 3 0.75
Methylprednisolone 6.2 0.5
Dexamethasone 26 0
Fludrocortisone 12 125

V. ADRENAL SEX STEROIDS

2 Adrenal sex steroids are produced in the zona reticularis.
• Begins to appear and becomes functional at age 5 to 6
• Production of adrenal sex steroids (DHEA, androstenedione, and some Figure 13. Sex Steroid Production and Conversion (12.06, ASMPH 2023)
testosterone) is stimulated by ACTH8
• Major secretory products of Zona Reticularis • Adrenal gland produces DHEAS, DHEA, Androstenedione (A), and 11-
hydroxyandrostenedione (11OHA)

3 TSH: Thyroid Stimulating Hormone 8 ACTH: Adrenocorticotropic hormone

4 GnRH: Gonadotropin-releasing Hormone 9 DHEAS: Dehydroepiandrosterone sulfate
5 LH: Luteinizing Hormone 10 DHEA: Dehydroepiandrosterone
6 FSH: Follicle Stimulating Hormone 11 CRH: Corticotropin-releasing hormone
7 ADH: Anti-Diuretic Hormone

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 o These adrenal sex steroids will diffuse into the blood vessels and go to
the peripheral tissues.
• No 17-alpha-hydroxylase or absent 21-alpha-hydroxylase which
• In the peripheral tissues, androstenedione will be converted to
testosterone by 17-beta-hydroxysteroid dehydrogenase
• Eventually, by virtue of the 5-alpha-reductase, this testosterone will then
be converted to the active dihydrotestosterone (DHT12).
• This takes place in the prostate, hair follicle, and genital skin.
• Conversion of DHEA and DHEAS also happens in the peripheral tissues.
o (RECALL: major secretory products of Zona Reticularis)
• If you want to determine if the high testosterone level is coming from the
testis or from the adrenal, you get the blood level of DHEAS.
o When it is elevated, excess testosterone might be from the adrenal
gland.
• When there is a primary genital problem or testicular tumor producing
excess testosterone, DHEAS might be suppressed (or low).
B. ADRENAL ANDROGEN REGULATION
CASE: CONGENITAL ADRENAL HYPERPLASIA (CAH)
normally produces cortisol
o Thus, there is no cortisol production.
o No cortisol production sends feedback (Doc said negative
feedback) to the pituitary, asking it to produce more ACTH
o The pituitary will then produce ACTH
o ACTH will stimulate zona fasciculata to produce cortisol, but the
absence of the enzyme for this production will prevent it from
doing so
o ACTH also stimulates zona reticularis, which leads to production
of adrenal androgens (given that the zona reticularis enzymes are
intact); this preferential increase in adrenal androgen secretion
will lead to the development of ambiguous genitalia
§ Virilizing symptoms (development of male characteristics)
evident in females due to excess adrenal androgens
§ These adrenal androgens do not send negative feedback
to ACTH (loophole), so more and more adrenal androgens are
further secreted leading to the clinical manifestations of CAH
o Negative feedback is sent to the reproductive hormones FSH and
LH, thereby causing decreased or absence of secondary sexual
characteristics in women.
§ No estrogen and progesterone due to inhibition of FSH and LH
by the excess adrenal androgens

SOURCE: (12.06, ASMPH 2023)

Figure 14. Adrenal Androgen Regulation Disorders

• Zona reticularis exhibit atrophic change under conditions of little or no
ACTH (just like zona fasciculata)
o However, other factors besides ACTH regulate adrenal androgen
function.
• ACTH stimulates adrenal androgen production because of increased
cholesterol conversion to pregnenolone, but androgens do not exhibit
negative feedback on ACTH
o Known as the “loophole” in endocrine physiology
o End products (DHEAS, testosterone, estrogen) do not send negative
feedback to ACTH-producing cells or CRH- producing cells in the
hypothalamus
o These products exert negative feedback on LH- and FSH- producing
cells instead, and not on ACTH
Figure 15. Ambiguous Genitalia
VI. ADRENAL MEDULLA
• Adrenomedullary cells are called Chromaffin Cells because they stain
brown with chromium salts
o Cytoplasmic granules turn dark when stained with chromic acid because
of the oxidation of epinephrine and norepinephrine to melanin
2 Chromaffin Cells
o Modified postganglionic axons
o Main Function: Synthesize Epinephrine and Norepinephrine
§ Norepinephrine can also be synthesized in axons (synaptic vesicles)

Table 10. Epinephrine vs. Norepinephrine

Epinephrine Norepinephrine
Adrenal medulla and
Source Adrenal medulla peripheral
sympathetic nerves
Contribution of
100% ~30%
adrenal medulla
Secretion of adrenal
80% 20%
medulla

12 DHT: Dihydroestosterone

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 A. SYNTHESIS
Figure 16. Synthesis of Catecholamines
• Catecholamines are synthesized from Tyrosine
o Tyrosine is derived from ingested food or synthesized from
phenylalanine in the liver
o Enters neurons & chromaffin cells by active transport
• Tyrosine is converted to DOPA by Tyrosine Hydroxylase, the rate-limiting
step in catecholamine synthesis
o Increased intracellular levels of catecholamines downregulate the
activity of tyrosine hydroxylase
o Transcription of tyrosine hydroxylase is stimulated by glucocorticoids,
kinases
• Aromatic L-Amino Acid Decarboxylase catalyzes the decarboxylation of
DOPA to dopamine
• Dopamine is actively transported into vesicles to be hydroxylated to
norepinephrine by Dopamine Hydroxylase
• In the adrenal medulla, norepinephrine is released from the granules into
the cytoplasm, where the cytosolic enzyme Phenylethanolamine N-
methyltransferase converts it to epinephrine
B. CATECHOLAMINE SECRETION
T/N: This section of the trans is taken from the 2023 Trans (12.06 Adrenal
Glands)
Figure 17. Summary of the Activation of Catecholamine Secretion
• Stressful stimuli trigger adrenal medullary catecholamine secretion by
stimulating the preganglionic fibers of the sympathetic nervous system,
which synapse within the adrenals
• Preganglionic neurons (specifically the axons from the splanchnic nerve)
release acetylcholine upon activation
o Directly innervates the adrenal medulla
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o RECALL: unlike the adrenal cortex which has no innervations because it
is regulated by hormones
• Acetylcholine binds to post-junctional nicotinic cholinergic receptors in the
tissue
o Increases the activity of enzymes involved in the catecholamine
synthesis (Tyrosine Hydroxylase and Dopamine β- hydroxylase)
o Depolarizes the cells
• Depolarization of the adrenomedullary glands activates voltage-gated
calcium channels
o Causes chromaffin cells to release their granules, which contain
catecholamines
§ Process: exocytosis of the secretory vesicles
o Epinephrine and norepinephrine are released into the blood perfusing
the glands and carried throughout the body
C. ACTIONS OF CATECHOLAMINES
• Increase in myocardial contractility & cardiac conduction velocity
• Increase in heart rate and blood pressure
• Bronchodilation
• Decrease gastrointestinal motility & secretion
• Relaxation of urinary bladder
• Pupillary dilatation
• CNS stimulation
• Decrease insulin action, increase glucagon action
D. METABOLISM OF CATECHOLAMINES
Figure 18. Metabolism of Catecholamines
• Norepinephrine and epinephrine are metabolized by catechol-O-
methyltransferase (COMT) and monoamine oxidase (MAO)
o MAOs are found at the outer mitochondrial membrane
o COMTs are found outside the neural tissue
• Intermediate products: Normetanephrine and Metanephrine
o These metabolites are detectable in the blood and in the urine
• Final product: Vanillylmandelic Acid (VMA)
• Almost 90% of catecholamines released at the sympathetic synapses are
taken up locally by the nerve endings and it is recycled in the cell bodies
o Catecholamine reuptake by the sympathetic nerves
o Metabolism via sulfation and conjugation then by renal excretion
• Most of the metabolism occurs on the same cell in which they are
synthesized
QUICK REVIEW
SUMMARY OF PROCESSES
STEROIDOGENESIS
1) Transfer of cholesterol to mitochondria
2) Conversion of cholesterol to pregnenolone via enzyme desmolase
CORTISOL SYNTHESIS
1) ACTH binds to M2CR on zona fasciculata cells
2) StAR protein is rapidly expressed
3) Cholesterol is delivered to CYP11A1 in the inner mitochondrial membrane
via StAR proteins
4) CYP11A1 converts cholesterol to pregnenolone
REVIEW QUESTIONS
1. T/F: Aldosterone synthesis and secretion is under the HPA axis.
8 of 9
2. Which among the following is a potent regulator of aldosterone secretion? & ASMPH Batch 2023. 05/09/2019. 12.06: Adrenal Glands lectured by Julie
a) Angiotensin I concentration Anne L. Gabat, MD, FPCP, DPSEDM.
b) Potassium ion concentration
c) Sodium ion concentration
d) Calcium ion concentration IMPORTANT LINKS
e) ACTH concentration
Errata Tracker: https://tinyurl.com/2024YL5ErrataTracker11
3. T/F: StAR converts cholesterol to pregnenolone Trans Feedback Form: https://tinyurl.com/2024YL5TransFeedbackForm

4. In congenital adrenal hyperplasia, the absence of cortisol is compensated FREEDOM SPACE

for by the ACTH stimulation of zona reticularis which increases cortisol
production. ACTH also stimulates zona fasciculata leading to the
development of ambiguous genitalia.
a) First statement is true, second statement is false.
b) First statement is false, second statement is true.
c) Both statements are true.
d) Both statements are false.

5. Which of the following statement is TRUE about glucocorticoids?

a) Glucocorticoids increase glycolysis
b) It increases both protein synthesis and catabolism.
c) Cortisol inhibits glucose uptake and mobilization
d) It inhibits amino acid delivery in the stomach Hindi Bala ang Gamot
A political caricature from twitter by @sabadontt
6. The following are effects of glucocorticoids EXCEPT: #MassTestingNowPH
a) Inhibit differentiation and maturation of alveolar type II cells #NoToVIPTesting
b) Promote Gluconeogenesis #BigasHindiRehas
c) Stimulate adipogenesis #TulongHindiKulong
d) Causes atrophy of type II muscles #EndCoVid19

7. Isabella is making Mamela and Mamita a summary of the inhibition actions

of glucocorticoids. Which of the following should Isabella NOT include?
a) Epidermal Cell Division
b) Lipolysis
c) Release of Gonadotropin-releasing hormone
d) Production of thyroxine
e) Macrophage activity

ANSWERS:
1F, 2B, 3F, 4D, 5C, 6A, 7B

EXPLANATIONS:
1. F – Aldosterone synthesis and secretion is under the RAAS.
2. B. Potassium Ion Concentration
3. F - StAR transports cholesterol to CYP11A1 which converts it to
pregnenolone
4. D. Both statements are false– Cortisol production does not occur due to
the absence of 17- alpha-hydroxylase or absent 21-alpha-hydroxylase.
Also, Cortisol is secreted in the zona fasciculata not reticularis.
5. C. Inhibit glucose update and mobilization – A is incorrect because
glucocorticoids increase gluconeogenesis (therefore it should decrease
glycolysis because they are opposite processes). B is incorrect
glucocorticoids increase protein catabolism ONLY. D is incorrect because
it actually promotes amino acid delivery.
6. A. Inhibit differentiation and maturation of type II alveolar cells –
Glucocorticoids induces rather than inhibits the said process. The
remaining choices are truthful statements.
7. B. Lipolysis – Glucocorticoids promote lipolysis. D is false because
glucocorticoids depress thyroid activity by suppressing TSH. The thyroid
cannot produce both T3 (Triiodothyronine) and T4 (Thyroxine).

REFERENCES
REQUIRED
& Guyton, A.C., & Hall, J.E. (2016). Guyton and Hall Textbook for Medical
Physiology. Philadelphia, PA: Elsevier, Inc.
& Adrenal Glands Lecture Handout. (04/01/2020).

SUPPLEMENTARY
& ASMPH Batch 2022. 04/13/2018. 12.07: Adrenal Glands lectured by
Abigail Uy-Canto, MD, FPCP, DPSEDM.

YL5: 11.05 ENDOCRINE SYSTEM: Adrenal Glands 9 of 9