Adrenal Glands: Anatomy, Hormones, Regulation, and Dysfunction

Adrenal Glands Overview

U22201, P22180
Dr. Sassan HafiziTHIS LECTURE

• Anatomy and cytology of the adrenal gland
• Adrenal hormones
• Adrenal hormone regulation pathways
• Adrenal dysfunction in disease
• Hormone overproduction
• Hormone deficiency
• Pharmacological interventionADRENAL GLANDS

Hypothalamus
Adrenal:
Pituitary-
Parathyroids
ad-, "near" or "at"
Thyroid
Adrenals
+
Pancreas
Ovaries
(female)
Testes
(male)
renes, "kidneys“ADRENAL GLANDS

Adrenal Gland Anatomy

Adrenal
glands
Inferior phrenic
arteries
Kidney
LEFT ADRENAL GLAND
Celiac trunk
Right superior
suprarenal arteries
RIGHT ADRENAL
GLAND
Left middle suprarenal artery
Right middle
suprarenal artery
Left inferior suprarenal artery
Right inferior
suprarenal artery
Left suprarenal vein
Right renal artery
Left renal artery
Right renal vein
Left renal vein
Superior mesenteric artery
Inferior vena cava
Abdominal aorta

• Located superior to the kidneys (suprarenal)
• Each: 9cm3; 4-6g
• Well supplied with blood from aorta, renal & phrenic arteries
  . Highest rate of blood flow in the bodySTRUCTURE OF ADRENAL GLAND

Adrenal Gland Structure

• Cortex (outer region)
  . 80-90%
  . Derived from mesoderm
  . 3 regions (zona)
  Capsule
  Adrenal
  cortex
  Adrenal
  medulla
  (b) Section through left adrenal gland
• Medulla (inner)
  . 10-20%
  . Derived from ectoderm
  . Modified post-ganglionic neurons
• intimately connected to sympathetic nervous systemADRENAL GLAND - CLOSE-UP

Adrenal Gland Subdivisions

Capsule
Capsule
Adrenal cortex:
Adrenal
cortex
Zona glomerulosa
secretes
mineralocorticoids,
mainly aldosterone
Adrenal
medulla
(b) Section through left adrenal gland
Zona fasciculata
secretes
glucocorticoids,
mainly cortisol
Zona reticularis
secretes androgens
Adrenal medulla
Chromafrin cells secrete
epinephrine and
norepinephrine (NE)
LM
50x
(d) Subdivisions of the adrenal glandADRENAL CORTEXADRENAL CORTEX - ANATOMIC & FUNCTIONAL ZONATION

• Zona glomerulosa
  . Abundant smooth ER, lipid droplets
• Mineralocorticoids (aldosterone)
  . affect mineral homeostasis
• Zona fasciculata
  . Abundant smooth ER, lipid droplets
• Glucocorticoids (cortisol)
  . affect glucose homeostasis
• Zona reticularis
  . Androgens (DHEA)
  . have masculinising/virilising effects
  capsule
  L
  glomerulosa
  Cortex
  fasiculata
  reticularis
  Medulla
  . "Salt, stress and sex" - the three S's of the adrenal
  ·Relatively little storage of hormones; active synthesis requiredSTEROIDS

Steroid Hormones

Steroid Ring Structure

Derivatives of perhydrocyclopentanophenanthrene ring:
21
22
24
26
18
20
25
12
23
11
17
19
13
C
D
9
14
9
A
B
1
8
H
H
2
7
A
B
4
6
3
5
7
6
Derived from Cholesterol - natural precursor of all steroid hormones
.Comes from LDL in blood
Steroid synthesis
I
(in fat droplets)
O
HO
Cholesterol
R-C-O
Fatty acid
chain
Cholesterol ester
.4-ring structure
·Carbons numbered
C
D
16
10
8
15
3
5
4
27CORTICOSTEROID MOLECULAR STRUCTURES

Corticosteroid Molecular Structures

• Aldosterone
  · (mineralocorticoid)
  OH
  O
  O
  HO
  H
  H
  Ȟ
• Cortisol
  · (glucocorticoid)
  O
  OH
  HO
  "OH
  H
  H
  O
• Dehydroepiandrosterone (DHEA)
  · (androgen)
  C
  H
  II
  HOSummary of Hormones by Chemical Class

Hormone Classification

Summary of Hormones by Chemical Class

CHEMICAL CLASS
HORMONES
SITE OF SECRETION
LIPID-SOLUBLE
Steroid hormones
CH2OH
Il C=0
H-C
HO-
Aldosterone
Aldosterone, cortisol, and androgens.
Adrenal cortex.
Kidneys.
Testes.
Ovaries.
Thyroid hormones
I
Iエ ー
HO
O
C-C-COOH
H
NH2
Triiodothyronine (T3)
Gas
Nitric oxide (NO).
Endothelial cells lining blood vessels.
WATER-SOLUBLE
Amines
CH-CH2 -NH2
OH
HO
Norepinephrine
Peptides and proteins
Glutamine
Isoleucine
I
1
Asparagine
Tyrosine
Cysteine-S-S-Cysteine
1
Proline
Leucine
-
Glycine
-
Oxytocin
NH2
Eicosanoids
HO
COOH
OH
A leukotriene (LTB4)
Epinephrine and norepinephrine (catecholamines).
Melatonin.
Histamine.
Serotonin.
All hypothalamic releasing and inhibiting hormones.
Oxytocin, antidiuretic hormone.
Human growth hormone, thyroid-stimulating hormone,
adrenocorticotropic hormone, follicle-stimulating hormone,
luteinizing hormone, prolactin, melanocyte-stimulating
hormone.
Insulin, glucagon, somatostatin, pancreatic polypeptide.
Parathyroid hormone.
Calcitonin.
Dastrin, secretin, cholecystoOInin, OIP
(glucose-dependent insulinotropic peptide).
Erythropoietin.
Ceptin.
Prostaglandins, leukotrienes.
Adrenal medulla.
Pineal gland.
Mast cells in connective tissues.
Platelets in blood.
Hypothalamus.
Posterior pituitary.
Anterior pituitary.
Pancreas.
Parathyroid glands.
Thyroid gland (parafollicular cells).
Stomach and small intestine
(enteroendocrine cells).
Kidneys.
Adipose tissue.
All cells except red blood cells.
Calcitriol.
Testosterone.
Estrogens and progesterone.
T3 (triiodothyronine) and T4 (thyroxine).
Thyroid gland (follicular cells).
I
OH
1GLUCOCORTICOIDSHORMONE SYNTHESIS IN THE CORTEX

Hormone Synthesis in the Adrenal Cortex

Glucocorticoid Synthesis Pathway

In smooth ER
21
Inner boundary membrane
18 17
C
2019
19
A
5
HO
0
Cholesterol
CYPIIAI
Side chain
cleavage
CH,
CH,
Č=O
5
0
C=O
3
LOH
CYPI7
CYPI7
DHEA
sulphate
HO
HO
HO
Pregnenolone
17a-Ol/Pregnenolone
Dehydroepiandrosterone (DHEA)
3B-HBD
2
CH
CH3
T
3
C=O
0
C=O
5
LOH
CYPI7
CYPI7
0
0
Progesterone
17c-OH Progesterone
Androstenedione
CYP21A2
6
CH2OH
C=O
4
CH,OH
C=O
LOH
0
Deoxycorticosterone
11-Deoxycortisol
CYPIIBI
CYPIIBI
6
CH,OH
C=O
C=O
HO
HO
LOH
0
Corticosterone
Cortisol
CYPIIB2
6
CH,OH
C=O
ORCHI
HO
0
Aldosterone
Intermembrane compartment
Matrix
8
B
In mitochondrion
Outer boundary
membrane
Cristae
0
4
CHỊOHHORMONE SYNTHESIS IN THE CORTEX - Glucocorticoids

Glucocorticoid Synthesis in Mitochondria

21
1817
15
19
8
A
15
HO
1
Cholesterol
CYPIIAI
Side chain
cleavage
CH,
ÇH,
C=O
C=O
3
LOH
DHEA
TYPIZ
CYPI
sulphate
HO
HO
HO
Pregnenolone
17a-OH Pregnenolone
Dehydroepiandrosterone (DHEA)
3B-HBD
2
CH,
CH3
T
C=O
3
C=O
5
LOH
TYPI7
CYPI
0
Progesterone
17c-OH Progesterone
Androstenedione
CY 21A2
6
CH2OH
4
CH,OH
Ċ=O
LOH
Deoxycorticosterone
11-Deoxycortisol
CYPIIBI
CYPLIBI
6
CH2OH
4
CHỈOH
Č=0
HO
HO
LOH
0
Corticosterone
Cortisol
CYPIIB2
6
CH,OH
C=O
HO
Om CHI
Aldosterone
In smooth ER
B
In mitochondrion
C=OSTEROID HORMONE RECEPTORS - INTRACELLULAR

Steroid Hormone Receptors

Intracellular Receptor Mechanism

1
Agonist
2
Agonist
3
Agonist
4
Agonist
Na
Na
1
G-Protein
Activation
L
Phosphorylation
of Tyrosines on
Key Signaling
Molecules
L
Transport to
the Nucleus
Activation of
conductance
L
Generation
of Second
Messenger
-
Activation of
Cell
Signaling
1
Activation of
transcription
and translation
1
Activation of
Cell SignalingGLUCOCORTICOID RECEPTOR -
MECHANISM OF ACTION

Glucocorticoid Receptor Action

• For a steroid hormone to affect gene
  transcription, its receptor must:
  . Bind to the hormone (lipophilic)
  . Dimerise to form a homodimer
  · Migrate from cytosol to nucleus
  . Bind to glucocorticoid response elements
  (GRE) in promoter of specific genes
  . Activate/repress expression of certain genes
  · Modify inflamm/metabolic/immune
  response
• Glucocorticoid receptor is a zinc-finger
  transcription factor
  Glucocorticoid
  extracellular
  cytoplasm
  GR
  GR
  GR
  GRE
  DNA helix
  NucleusCORTISOL

Cortisol Hormone

Cortisol Properties and Metabolism

O
OH
HO
"OH
H
工
O

• Essential glucocorticoid for life
• Produced in zona fasciculata and reticularis
• In plasma, 75% bound to corticoisteroid-binding globulin
  (CBG)
  . Only unbound is biologically active
• Resistance to stress - makes nutrients available for ATP
  production
• Affects glucose, protein, fat metabolism:
  . Stimulates liver cells to synthesise glucose from non-
  carbohydrates & thereby blood glucose concentrations -
  (gluconeogenesis)
  . Inhibits synthesis of fat and protein in tissues
  . Promotes use of fatty acids (lipolysis) as energy source for
  gluconeogenesis, decreasing the use of glucoseCORTISOL

Cortisol Effects on Body Systems

O
OH
HO
"OH
H
工
O

• Raises 1 blood pressure by vasoconstriction
• Anti-inflammatory
  . reduces release of histamine from mast cells & basophils
  . decreases capillary permeability
  · depresses phagocytosis
• Immunosuppressive
  . Reduces lymphocyte numbers
  · Reduced antibody production
• Also has mineralocorticoid activity (less than
  aldosterone)CORTISOL REGULATION

Cortisol Regulation

Cortisol Regulation Pathway

• Emotion, stress, trauma
  stimulates corticotropin-
  releasing hormone (CRH)
  from hypothalamus
• CRH regulates
  adrenocorticotrophic
  hormone (ACTH) from
  anterior pituitary
• ACTH stimulates cortisol
  production from adrenal
• Cortisol inhibits ACTH from
  pituitary
• negative feedback
  HYPOTHALAMUS
  Stimulated by
  Corticotropin-
  Releasing Hormone
  (CRH)
  Į Plasma Cortisol Level, Hypoglycemia
  Pyrogen, and Stress
  Suppressed by
  t Plasma Glucocorticoid Level
  ANTERIOR PITUITARY
  - AVP
  Corticotropin
  (ACTH)
  Cortisol
  Angiotensin
  ADRENAL
  GLAND
  Aldosterone
  Cortisol
  Androgens
  LIVER
  KIDNEY
  17-Hydroxysteroids
  Free Cortisol
  17-KetosteroidsCORTISOL SECRETION - CIRCADIAN PATTERN

Cortisol Circadian Rhythm

• Cortisol secretion pattern episodic and variable
• Rhythm over 24h-period, independent of environmental variables.
  .
  Also called diurnal rhythms
• Main clock in suprachiasmatic nucleus in hypothalamus
  operates via clock and per genes switched on & off
• Affects CRH, ACTH levels
• Cortisol episodes follow ACTH secretion by 15-30 min
  · burst in early am (an hour after awaken)
  · rest of day brief bursts (7-15 episodes)
  . increased release with coffee consumption
  · increased during sleep stage when protein is being recycled
  . increases with increased exercise time & intensity
• Rhythm upset by time shifting (eg. jetlag)
• Some diseases get no rhythm e.g. Cushing's or stressDISEASES OF ADRENAL CORTEX -
  HYPERCORTISOLISM (OVERPRODUCTION)

Adrenal Cortex Diseases

Hypercortisolism (Cushing's Syndrome)

Cushing's syndrome
Emotional disturbance
Enlarged sella turcica
Moon facies
Osteoporosis
Cardiac hypertrophy
(hypertension)
Buffalo hump
Obesity
Adrenal tumor or
hyperplasia
Thin, wrinkled skin
Abdominal striae
Amenorrhea
Muscle weakness
Purpura
Skin ulcers
(poor wound healing)
Causes

• Primary disorder of adrenal (e.g. tumour)
  .
  "Cushing's syndrome"
• Secondary overactivity due to overproduction
  of ACTH from pituitary (e.g. tumour)
  . "Cushing's disease"
  . Thus, should measure ACTH concn in blood
• Also caused by patient hormone treatment
  · "iatrogenic" (physician-caused) hypercortisolism
  Treatment
• Remove tumour
• Metyrapone, aminoglutethimide, Trilostane,
  ketoconazole
  .
  Interfere with steroid biosynthesisDISEASES OF ADRENAL CORTEX -
  HYPOCORTISOLISM (DEFICIENCY)

Hypocortisolism (Addison's Disease)

Addison's disease

• Lethargy
• Weakness
• Weight loss
• Î Serum K+, V Na+
• Decreased blood pressure
• Impaired elimination of water
• Increased pigmentation
  · Vague abdominal pains
• Vomiting
• Anaemia
• Feeble heart action
• Irritable stomach
• Hypoglycaemia
  Causes
• Adrenocortical failure
• Deficiency of both cortisone and aldosterone
• Main cause is autoimmunity
  Treatment
• Replacement therapy with oral:
• hydrocortisone
• fludrocortisone (synthetic mineralocorticoid)
  O
  overproduction of ACTH