ENDOCRINE PHYSIOLOGY

Module 3

The Adrenal Gland

CORE KNOWLEDGE

 HYPO/HYPERPITUITARISM
 GIGANTISM, ACROMEGALY, PROLACTINEMIA,
 DIABETES INSIPIDUS & SIADH
 DIABETES MELLITUS
 HYPO/HYPERTHYROIDISM (MYXOEDEMA, CRETINISM,
THYROIDITIS, THYROTOXICOSIS)
 HYPER/HYPO PARATHYROIDISM
 HYPER/HYPO CORTISOLISM
 CUSHING’S DISEASE/SYNDROME
 ADDISON’S DISEASE
 HYPER/HYPO ALDOSTERONISM
 PHAEOCHROMOCYTOMA
 HORMONES RELATED TO STRESS

Prof. Dr. Hamdan Noor

March, 2017

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Module 3: The Adrenal Gland

1. General introduction to Hormones of the Adrenal Gland

2. Functional Anatomy and Histology of the Adrenal Gland

3. Overview of Adrenal Hormones Related to Stress

4. Adrenal Medullary Hormones - Catecholamines

4.1. Synthesis and secretion of catecholamines
4.2. Adrenergic receptors and mechanism of action of catecholamines
4.3. Physiologic effects of medullary hormones
4.4. Overview of adrenal medullary disorders

5. Adrenalcortical Steroids
5.1. Types of adrenal steroids
5.2. Biosynthesis of steroid hormones
5.3. Mechanism of action of steroid hormones
5.4. Mineralocorticoids
5.5. Glucocorticoids

6. Summary

7. Conclusion

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Learning Outcomes:
After working through this Module you should be able to:

1. Describe the gross anatomy and microanatomy of the adrenal gland including the
functional zones (one medullary and three cortical zones), innervation, and blood supply
and the principal hormones secreted from each zone.
2. Describe the adrenal medullary hormones in terms of their chemistry, biosynthesis,
origin, target cells, regulation of release, mechanism of action and the effect of over and
under secretion of the hormones.
3. Describe the adrenal cortical hormones in terms of their chemistry, biosynthesis, origin,
target cells, regulation of release, mechanism of action and the effect of over and under
secretion of the hormones.
4. Describe the interactions of adrenal medullary and cortical hormones in response to
stress.

Additional objectives:
1. Identify the functional zones (one medullary and three cortical zones), innervation, and blood supply of the
adrenal glands and the principal hormones secreted from each zone.
2. Describe the biosynthesis of the adrenal steroid hormones (glucocorticoids, mineralocorticoids, and androgens)
and the key structural features that distinguish each class.
3. Describe the cellular mechanism of action of adrenal cortical hormones.
4. Identify the major actions of glucocorticoids on metabolism and the target organs on which they are produced.
5. Describe the actions of glucocorticoid hormones in injury and stress.
6. Describe the components of the neuroendocrine axis that control glucocorticoid secretion and describe how
factors in the internal and external environment influence the neuroendocrine axis.
7. Identify the causes and consequences of a) over-secretion and b) under-secretion of glucocorticoids and
adrenal androgens.
8. List the major mineralocorticoids and identify their biological actions and target organs or tissues.
9. Name the physiological stimuli that cause increased mineralocorticoid secretion. Relate these stimuli to
regulation of sodium and potassium excretion. List the factors can modulate the secretory response and
explain how they are detected.
10. Identify the causes and consequences of a) over-secretion and b) under-secretion of mineralocorticoids.
11. Diagram the negative feedback control of aldosterone secretion.
12. Identify the chemical nature of catecholamines, their biosynthesis, mechanism of transport within the blood,
and how they are degraded and removed from the body. Identify how the structure of norepinephrine differs
from epinephrine.
13. Describe the biological consequences of activation of the adrenal medulla and identify the target organs or
tissues for catecholamines along with the receptor subtype that mediates the response. Understand the
mechanism by which epinephrine and norepinephrine can produce different effects in the same tissues.
Explain the change in the ratio of epinephrine to norepinephrine release from the adrenal medulla during
sympathetic activation (fight and flight), or in prolonged food deprivation.
14. Name the key stimuli causing catecholamine secretion. List the factors that can modulate a) the secretory
response and b) the responses of target tissues.
15. Describe the interactions of adrenal medullary and cortical hormones in response to stress.
16. Identify disease states caused by an over-secretion of adrenal catecholamines.

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Learning Resources:

Notes in this Module

Boron and Boulpaep, Ch. 46
Widmaier, Raaf and Strang (Vander’s Human Physiology) Ch. 11
Marieb. Ch. 17
Tortora and Derrickson. Ch. 18
Guyton and Hall. Ch. 74
Ganong. Ch.18
Patricia E. Molina Endocrine Physiology, 2nd Edition (Access Medicine)

Terms to Know:

Please list down all the terms that you need to know and write down their meaning.

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1. General introduction to Hormones of the Adrenal Gland
In Module 1 we mention three series of hormones that are involved in the hypothalamo-pituitary-
adrenal, hypothalamo-pituitary-thyroidal, and hypothalamo-gonadal axis respectively (please
recall the hormones involved). In Module 2 we explore the hormones of the hypothalamus and
pituitary, focusing on those that are not involved in the axis. In this module, we focus on the
hypothalamo-pituitary-adrenal (HPA) axis (Fig. 3.1) and discuss in detail the hormones of the
adrenal gland.

Activity 3.1: The HPA axis

State the three main axes of

the endocrine system

Which cells in the

hypothalamus secrete
neurohormone that triggers
the HPA axis? What is this
neurohormone?

Which cells of the anterior

pituitary have the receptors
for the hypothalamic
neurohormone to continue
with the HPA axis?

What is the main pituitary

hormone involved with the
HPA axis?

How is the adrenal cortex

involved in the HPA axis?

Fig 3.1. The HPA axis

When you think about the adrenal glands, you should think about stress (elaborated in Module
6). Stress can take many forms: taking an examination, recovering from a broken bone, running
away from an invading army, or maintaining proper levels of energy substrates in the face of
even mild starvation. How does our body respond to stressors? The various receptors that are
activated by stressors transmit the information to the hypothalamus.

Essentially, there are two main outputs from the hypothalamus (Fig 3.2):

• Neural signals to the sympathetic nervous system - the (lateral) hypothalamus, via
multineuronal pathways project to the spinal cord, where the cells that drive the
sympathetic nervous system are located. The sympathetic nervous system stimulates or
inhibits various organs of the body commensurate with the fight or flight responses via

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 the neurotransmitter norepinephrine. In addition, the sympathetic nervous system also
stimulates the adrenal medulla to produce epinephrine.

• Endocrine signals to/through the pituitary – The parvocellular nucleus secrete CRH
which stimulates ACTH release by the corticotrophs of the anterior pituitary. ACTH
binds to its receptor in adrenal cortex resulting in secretion of cortisol. Cortisol acts on
many organs to alter metabolism in tandem with the fight or flight responses.

The adrenal gland produces three major classes of hormones, each of which aids in dealing with
the multitude of small and large stresses faced by people almost daily:
• Glucocorticoids e.g. cortisol
• Mineralocorticoids e.g. aldosterone
• Catecholamines e.g. epinephrine and norepinephrine.

Activity 3.2: Introduction to adrenal hormones

Recall the three series of hormones that are involved in the hypothalamo-pituitary-adrenal axis, the
hypothalamo-pituitary-thyroidal axis, and the hypothalamo-pituitary-gonadal axis, respectively.
Briefly describe the functions of each hormone in the series.

Briefly describe the function of the hypothalamus as an endocrine gland and as a neuronal control
centre in the central nervous system. Relate it with stress response to the external and internal
environmental stimuli.

Briefly describe the hormones of the adrenal gland in terms of coping with stress.

In summary, the hormones of the adrenal gland are secreted via stimulation by the nervous
system and the endocrine system. The adrenal medulla is stimulated by the sympathetic nervous
system whereas the adrenal cortex is stimulated by the hormone (ACTH) released by the anterior
pituitary. The nervous system pathway is depicted in Fig. 3.2.

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 A5 noradrenergic cell group;
C1, C1 adrenaline cell group
IML, intermediolateral cell column;
LH, lateral hypothalamic area;
LC, locus coeruleus;
PVN, paraventricular nucleus;
RN, medullary raphe nuclei;
SG, sympathetic ganglion;
V, varicosities of the postganglionic
neuron.

Fig. 3.2. Humoral (hypothalamo-pituitary-adrenal axis) and neuronal (hypothalamus-brain stem-

sympathetic preganglionic) projections from the hypothalamus to the adrenal medulla and sympathetic
ganglia.

In this module we’ll discuss the adrenal hormones in terms of the chemical nature, the synthesis
and secretion, the mechanism of action and the abnormalities associated with hyper- and hypo-
secretion of the hormones.

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2. Functional Anatomy and Histology of the Adrenal Gland

The two adrenal glands are located immediately anterior to the kidneys, encased in a connective
tissue capsule and usually partially buried in an island of fat (Fig. 3.3). Like the kidneys, the
adrenal glands lie beneath the peritoneum (i.e. they are retroperitoneal).

Fig 3.3. The anatomy and histology of the adrenal gland

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 Fig. 3.4: Anatomy and
histology of the adrenal
gland.

An adrenal gland sits on top

each kidney. The adrenal
gland is actually two glands-
the cortex and the medulla.

The adrenal cortex

comprises three layers that
surround the medulla. The
outermost layer (zona
glomerulosa) contains the
granulosa cells that secrete
aldosterone, and the two
inner layers of cortex (zona
fasciculata and zona
reticularis) synthesize cortisol
and sex steroids.

The blood supply enters the

cortex in the subcapsular
region and flows through
anastomotic capillary beds
while coursing through both
the cortex and the medulla.

The adrenal medulla

contains chromaffin cells that
secrete epinephrine and a
small amount of
norepinephrine. It is richly
innervated by preganglionic
sympathetic fibres.

Fig 3.4. Anatomy and histology of the adrenal gland

Inspection of an adrenal gland that has been sectioned reveals two distinct regions (Fig. 3.4):

• An inner medulla, which is a source of the catecholamines (epinephrine and

norepinephrine). The chromaffin cell is the principle cell type. The medulla is richly
innervated by preganglionic sympathetic fibers and is, in essence, an extension of the
sympathetic nervous system.

• An outer cortex, which secretes several classes of steroid hormones (glucocorticoids and
mineralocorticoids, plus a few others). Histologic examination of the cortex reveals three
concentric zones of cells (zona glomerulosa, zona fasciculate and zona reticularis) that
differ in the major steroid hormones they secrete.

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Despite their organization into a single gland, the medulla and cortex are functionally different
endocrine organs, and have different embryological origins. The medulla derives from ectoderm
(neural crest), while the cortex develops from mesoderm. The utility, if any, of having them
together in one discrete organ is not obvious.

The vascular supply to the adrenal medulla is also unusual. The medulla receives vascular input
from vessels that begin in a subcapsular plexus of the adrenal cortex. The vessels then branch
into capillary network in the cortex only to merge into small venous vessels that branch into a
second capillary network within the medulla. This portal blood supply exposes the adrenal
medulla to the highest concentration of glucocorticoids and mineralocorticoids before the blood
is distributed to all somatic tissues.

Activity 3.3. Functional anatomy of the adrenal gland

• Describe the location of the adrenal glands.

• Describe the blood supply to the adrenal glands. What is the significance of the two
capillary networks connecting the cortex and the medulla?

• Describe the innervations of the adrenal gland. What is the significance of sympathetic
innervations of the medulla?

• Describe the cells of the adrenal cortex and adrenal medulla that are involved in the
synthesis and secretion of adrenal hormones. What special features of the cells contribute
to the ability of the cells to produce the specific hormones?

• Compare and contrast the adrenal medulla and the adrenal cortex in terms of
development, anatomy and histology, hormones synthesized and secreted, stimulation of
hormone secretion and signal transduction mechanisms.

• Based on the vascularisation and innervations of the adrenal gland, predict how hormone
production by the cortex and medulla is regulated.

In summary, the adrenal gland consists of adrenal medulla and adrenal cortex which are have
distinct embryological origins. The adrenal medulla produces catecholamines (mainly
epinephrine from the chromaffin cell) and the adrenal cortex produces mineralocorticoid (from
zona glomerulosa), glucocorticoid (from zona fasciculata) and androgen (from zona reticularis).

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3. Overview of Adrenal Hormones Related to Stress
Adrenal hormones are associated with stress (Module 6). Stress is defined as physiologic and
behavioral responses to intrinsic (internal) and extrinsic (external) factors (aka stressors) that
threaten homeostasis, psychological status and physical wellbeing.

Stress could be acute or chronic.

Acute stress is the most common form of stress. It comes from demands and pressures of the
recent past and anticipated demands and pressures of the near future. Acute stress is thrilling and
exciting in small doses, but too much is exhausting. E.g. physical exercise, accident,
examination, etc. Fortunately, acute stress symptoms are recognized by most people. Because it
is short term, acute stress doesn't have enough time to do the extensive damage associated with
long-term stress.

Chronic stress is the grinding stress that wears people away day after day, year after year.
Chronic stress destroys bodies, minds and lives. It wreaks havoc through long-term attrition. For
example, the stress of poverty, of dysfunctional families, of being trapped in an unhappy
marriage or in a despised job.

Fig. 3.5 depicts how our body responds to psychological (extrinsic) stress. The direct effects are
on the autonomic nervous system, the endocrine system and the immune system. In this module,
we’ll focus on the effect of stress on the endocrine system, especially via the hypothalamo-
pituitary-adrenal (HPA) axis.

Fight or freight reactions Reduced resistance

Fig. 3.5. Body response to psychological (external) stress

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From endocrinologial view, our body copes with stress by releasing hormones, mainly from the
adrenal gland. The adrenal medulla releases epinephrine and norepinehrine in response to
acute stress, and the physiological effects of the hormones get the body ready for the “fight or
flight” reactions. On the other hand, the adrenal cortex releases glucocorticoid and
mineralocorticoid in response to stress, and the physiological effects of the hormone include
those that supply the body cells with necessary materials to survive.

Fig. 3.6. Stress and hormones. Stressful stimuli cause the hypothalamus to activate the adrenal
medulla via sympathetic nerve impulses and the adrenal cortex via hormonal signals. The medulla
mediates short term responses to stress by secreting catecholamines (epinephrine and norepinephrine).
The cortex controls more prolonged responses by secreting steroid hormone.

Activity 3.4: Stress and hormones

• What is the meaning of stress? Using examples, compare and contrast between acute stress and
chronic stress. How does our body respond to stress in terms of hormone production? What
good does this do to our body? Predict how hormones play their roles in coping with stress.
• What are the three major classes of hormones that are useful in dealing with the multitude of small
and large stresses faced people almost daily? What do these hormones do?
• Describe the short term and long term response of the body to stress.
• How does your body cope with stress physiologically?

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4. Adrenal Medullary Hormones: Catecholamines
Cells in the adrenal medulla synthesize and secrete norepinephrine and epinephrine. In
humans, roughly 80% of the catecholamine output is epinephrine. Following release into blood,
these hormones bind adrenergic receptors on target cells, where they induce essentially the same
effects as direct sympathetic nervous stimulation.

4.1. Synthesis and secretion of catecholamines

Chromaffin cells of the adrenal medulla are the only ones that have the enzyme for synthesizing
epinephrine. Synthesis of catecholamines begins with the amino acid tyrosine, which is taken
up from the circulation by chromaffin cells in adrenal medulla and converted to norepinephrine
and epinephrine through the following steps (Figs. 3.6 and 3.7):

Fig. 3.7. Cellular view of catecholamine synthesis in chromaffin cell.

Fig. 3.8. Catecholamine synthesis pathway.

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Norepinephine and epinephrine are stored in electron-dense granules which also contain ATP
and several neuropeptides (Fig. 3.7). Secretion of these hormones is stimulated by acetylcholine
released from preganglionic sympathetic fibers innervating the medulla (Fig. 3.8). Many types
of "stressors" stimulate such secretion, including exercise, hypoglycemia and trauma. Following
secretion into blood, the catecholamines bind loosely to and are carried in the circulation by
albumin and perhaps other serum proteins.

Chromaffin cells are the structural and functional equivalents of the postganglionic neurons in
the sympathetic nervous system. The preganglionic sympathetic fibres of the splanchnic nerves,
which release acetylcholine are the principle regulators of adrenomedullary hormone secretion.

Fig. 3.9: Anatomical

analogy between cells of
the adrenal medulla
and the sympathetic
postganglionic neurons.

Note that the particular

postganglionic fibre
(dashed red line) has
effects on one specific
effector organ, such as
the heart. In contrast,
cells of the adrenal
medulla, because they
secrete epinephrine into
the blood, are able to
influence the activity of
various effector organs
throughout the body.

Explain how secretion of

epinephrine (from the
adrenal medulla) and
norepinephrine (from
preganglionic nerve
endings) are regulated.

Fig. 3.9. Sympathetic activation of adrenal medulla and other organs.

Activity 3.5: Regulation of epinephrine secretion

What is so special about the chromaffin cells in terms of catecholamine synthesis? Hint: they
have enzymes for the synthesis of catecholamine. Starting with tyrosine, describe how
catecholamines are synthesized in the chromaffin cells. Name the enzymes involved.

Compare and contrast between cholinergic and adrenergic receptors. How does Ach stimulate
epinephrine secretion from the chromaffin cells of the adrenal medulla? Begin with stressful
stimuli processed by the brain cells.
Hint: Fig. 3.9 .. Nicotinic receptor  depolarization  activating voltage gated Ca2+ channels 
entry of Ca2+  exocytosis of vesicles containing epinephrine.

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 Fig. 3.10. Cellular view of catecholamine synthesis.

Mechanism of catecholamine secretion (Fig. 3.10)

The catecholamines are stored in chromaffin granules in the chromaffin cells. The most
important stimulus for catecholamine secretion is acetylcholine (Ach) derived from the
splanchnic nerve (preganglionic sympathetic nerve). Ach binds to nicotinic Ach receptor
(nAChR) that leads to membrane depolarisation due to Na+ entry. The action potential produced
then activates voltage operated Ca2+ channels (VOCC) allowing entry of Ca2+. Ca2+ facilitates
exocytosis of chromaffin granules, releasing the catecholamine

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4.2. Adrenergic Receptors and Mechanism of Action of Catecholamines

The physiologic effects of epinephrine and norepinephrine are initiated by their binding to
adrenergic receptors on the surface of target cells. These receptors (Table 3.1) are prototypical
examples of seven-pass transmembrane proteins that are coupled to G proteins which stimulate
or inhibit intracellular signaling pathways.

Table 3.1. Adrenergic receptors

Receptor Effectively G protein Effect of Ligand Location
Binds Binding
Alpha1 Epinephrine, Gq Increased free All cells that are to be stimulated
Norepinphrine calcium by sympathetic nervous system
except heart, adipocyte, renal JGA
that have β1 receptor
Alpha2 Epinephrine, Gi Decreased cyclic Platelets, pre synaptic membrane,
Norepinphrine AMP insulin producing cells.
Beta1 Epinephrine, Gs Increased cyclic AMP
Heart, adipocyte, renal JGA
Norepinphrine
Beta2 Epinephrine Gs Increased cyclic AMP All cells that are to be inhibited by
sympathetic nervous system except
platelets, pre synaptic membrane,
insulin producing cells that have α2
receptor

Complex physiologic responses result from adrenal medullary stimulation because there are
multiple receptor types which are differentially expressed in different tissues and cells (Table
3.1). In stress response, some organs are stimulated (e.g. the heart beats faster, the pupils dilate,
blood vessels to GIT contract) to help in the fight or flight reaction while some others that are not
involved in the fight or flight reaction are inhibited (blood vessels to skeletal muscle dilates,
bronchial smooth muscles relax).

The alpha and beta adrenergic receptors and their subtypes were originally defined by
differential binding of various agonists and antagonists and, more recently, by analysis of
molecular clones.

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Fig. 3.11. Catecholamine receptors. The 1, 2, and DA-1 receptors all interact with Gs, which activates adenylyl
cyclase (AC) and raises levels of cyclic AMP (cAMP). The α2 and DA-2 receptors interact with Gi, which inhibits AC.
Additionally, the 1 receptor interacts with Gq, which activates phospholipase C (PLC), which in turn converts
phophoinositides in the cell membrane to inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). ATP, adenosine
triphosphate; DA, dopamine

Activity 3.6: Mechanism of action of epinephrine

• How is an increase in cAMP or cytosolic Ca2+ related to the final physiological response of the
target cells to catecholamines?
• Describe the mechanism of action of epinephrine/norepinephrine on target cells starting with
receptor activation.

In summary, catecholamines released by the adrenal medulla exerts their effects on the target
tissues by binding to the adrenergic receptors located in many types of body cells. The response
of a target tissue depends on the type of adrenergic receptor present on the tissue.

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4.3. Physiologic Effects of Medullary Hormones

In general, circulating epinephrine and norepinephrine released from the adrenal medulla have
the same effects on target organs as direct stimulation by sympathetic nerves, although their
effect is longer lasting. Additionally, of course, circulating hormones can cause effects in cells
and tissues that are not directly innervated. The physiologic consequences of medullary
catecholamine release are justifiably framed as responses which aid in dealing with stress.
These effects can be predicted to some degree by imagining what would be needed if, for
example, you were attacked by a dog. A listing of some major effects mediated by epinephrine
and norepinephrine are:

• Increased rate and force of contraction of the heart muscle: this is predominantly an
effect of epinephrine acting through β1 receptors in the pacemaker and cardiac myocyte.
• Constriction of blood vessels: norepinephrine, in particular, causes widespread
vasoconstriction through α1 receptors, resulting in increased total peripheral resistance
(TPR) and hence arterial blood pressure. Exception: dilation of blood vessels to skeletal
muscle via β2 receptors in response to stress.
• Dilation of bronchioles: via β2 receptor, assists in pulmonary ventilation.
• Stimulation of lipolysis in fat cells: via β3 (modified β1). This provides fatty acids for
energy production in many tissues and aids in conservation of dwindling reserves of
blood glucose.
• Increased metabolic rate: oxygen consumption and heat production increase throughout
the body in response to epinephrine. Medullary hormones also promote breakdown of
glycogen in skeletal muscle to provide glucose for energy production.
• Dilation of the pupils: particularly important in situations where you are surrounded by
danger under conditions of low ambient light.
• Inhibition of certain "non-essential" processes: an example is inhibition of
gastrointestinal secretion and sexual activity.

Common stimuli for secretion of adrenomedullary hormones include exercise, hypoglycemia,

hemorrhage and emotional distress.

Activity 3.7: Mode of action of catecholamines

For each of the physiological responses listed above, use a diagram to explain the signal transduction
mechanisms involved.

Rule of thumb:
• All tissues that are to be stimulated by epinephrine and NE have α1 receptors except
the heart, JGA and lipocytes that have β1 receptors.

• All tissues that are to be inhibited by epinephrine and NE have β2 except

presynaptic nerve endings, platelets and insulin producing cells.

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Table 3.2. Physiologic Effects of Catecholamines on Adrenergic Receptors of Selected Tissues

Organ or Tissue Adrenergic Effect

Receptor
Heart (myocardium) 1 Increased force of contraction (inotropic)
1, 1 Increased rate of contraction (chronotropic)
1 Increased excitability (predisposes to arrhythmia)
1 Increased AV nodal conduction velocity
Blood vessels (vascular 1 Vasoconstriction, hypertension
smooth muscle) Vasodilation (to skeletal muscle)
2

Kidney (juxta-glomerular 1 Increased renin release

cells)
Gut (intestinal smooth 1 Increased sphincter tone (hyperpolarization);
muscle)
2 Decreased motility (relaxation)
Pancreas (B cells) 2 Decreased insulin release
Decreased glucagon release
Liver 1, 2

Adipose tissue
Skin (e.g. apocrine glands
on hands, axillas)
Lung (bronchial smooth
muscle)
Uterus (genitourinary
smooth muscle)
Increased glycogenolysis
Release of potassium
1, 3 Increased lipolysis
1 Increased sweating
2 Dilation of bronchi and bronchioles
1 Contraction
Relaxation
2

Bladder (genitourinary 1 Contraction

smooth muscle) Relaxation
2

Skeletal muscle 2 Vasodilation

Increased glycogenolysis
Increased release of lactic acid
Platelets 2 Aggregation

CNS Increased alertness, anxiety, fear

Peripheral nerves (pre 2 Decreased norepinephrine release
synaptic)
Hair 1 Hair stand
Eye 1 Pupil dilate
2 Flattened lens for far vision
Blood vessels to skin 1 constrict

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Fig. 3.12.
Summary of the
principle effects of
epinephrine on
energy metabolism.

The primary effects

of epinephrine are to
stimulate
glycogenolysis in
the liver and muscle,
and lipolysis in
adipose tissue. The
net result is an
increase in blood
glucose and blood
fatty acid
concentrations.

When does this

occur?

Fig. 3.12. Cellular view of catecholamine synthesis.

Summary of actions of sympathetic nervous system, including epinephrine secreted by the

adrenal medulla, during stress:

1. Increased hepatic and muscle glycogenolysis (provides a quick source of glucose)

2. Increased breakdown of adipose tissue triglyceride (provides a supply of glycerol for
gluconeogenesis and of fatty acids for oxidation)
3. Decreased fatigue of skeletal muscle by increasing its blood flow.
4. Increased cardiac function (e.g. increased heart rate and contractility).
5. Diverting blood from viscera to skeletal muscle by means of vasoconstriction in the
former beds and vasodilation in the latter.
6. Increased lung ventilation by stimulating brain breathing centres and dilating airways.

Other hormones that are usually released during stress are aldosterone, ADH, GH, glucagon, and
beta-endorphin (which is released from the anterior pituitary with ACTH).

Activity 3.8: Epinephrine and energy metabolism

How is epinephrine involved in energy metabolism? Explain the molecular mechanism involved
starting from receptor activation until the final response is achieved. State the significance of this
phenomenon in stress.

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4.4. Overview of Adrenal Medullary Disorders

Pheochromocytoma is an uncommon tumor of adrenal medullary tissue that causes production

of excessive amounts of catecholamines. Patients typically present with sustained or episodic
hypertension or with a syndrome characterized by episodic palpitations, tachycardia, chest pain,
headache, anxiety, blanching, excessive sweating, hyperglycemia, and glycosuria. Surgical
resection of the tumor is the treatment of choice and usually cures the hypertension.
Classically, pheochromocytoma manifests as spells with the following 4 characteristics:
• Headaches
• Palpitations
• Diaphoresis
• Severe hypertension

Typical patterns of the spells are as follows:

• Frequency may vary from monthly to several times per day
• Duration may vary from seconds to hours
• Over time, spells tend to occur more frequently and become more severe as the tumor
grows

The following may also occur during spells:

• Tremor
• Nausea
• Weakness
• Anxiety, sense of doom
• Epigastric pain
• Flank pain
• Constipation

Clinical signs associated with pheochromocytomas include the following:

• Hypertension: Paroxysmal in 50% of cases
• Postural hypotension: From volume contraction
• Hypertensive retinopathy
• Weight loss
• Pallor
• Fever
• Tremor
• Neurofibromas
• Tachyarrhythmias
• Pulmonary edema
• Cardiomyopathy

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5. Adrenalcortical Hormones (Adrenal Steroids)

5.1. Types of adrenal steroids

The adrenal cortex is a factory for steroid hormones. In total, at least two to three dozen different
steroids are synthesized and secreted from this tissue, but two classes are of particular
importance i.e. mineralocorticoid and glucocorticoid (Table 3.3).

Table 3.3. Classes of adrenal steroids

Class of Steroid Major Representative Physiologic Effects

Mineralocorticoids Aldosterone Na+, K+ and water homeostasis
Glucocorticoids Cortisol Glucose homeostasis and many others
Sex steroids Androgen Secondary sex characteristics

Additionally, the adrenal cortex produces some sex steroids, particularly androgens, a talent of
considerable importance in such diseases as congenital adrenal hyperplasia.

5.2. Biosynthesis of steroid hormone

Like all steroids, adrenal corticosteroids are synthesized from cholesterol through a series of
enzyme-mediated transformations.

Each of the three major pathways (mineralocorticoid, glucocorticoid, androgen) involves

sequential processing by a group of enzymes, some of which reside in endoplasmic reticulum
and others inside mitochondria. Hence, synthesis of steroids involves shuttling of the
intermediate compounds between these two organelles.

The first precursor for biosynthesis of steroid hormones in the adrenals, ovaries, and testes is
cholesterol (Fig. 3.13). In these endocrine glands, cholesterol can be synthesized de novo from
acetate by a complex series of reactions. Alternatively, it can be obtained directly from
circulating low-density lipoprotein (LDL) cholesterol.

Cholesterol can be converted to a variety of steroid hormones in the endocrine glands through
the action of specific enzymes. The first and rate-limiting reaction in the formation of steroid
hormones is the conversion of cholesterol to pregnenolone, which is stimulated by
adrenocorticotropin hormone (ACTH) in the adrenals and by LH in the ovaries and testes (Fig.
3.13). This reaction is complex and occurs in the mitochondria. It is catalyzed by the enzyme
C20-22-lyase (also referred to as C20-22-desmolase). Both the delivery of cholesterol to the
enzyme and the enzyme level are primarily under the control of tropic hormones (LH or ACTH)
using cyclic AMP or calcium as the intracellular messenger. Once pregnenolone is formed, it can
then be converted to progesterone, androgens, estrogens, and corticosteroids. For this reason,
pregnenolone is sometimes referred to as the “mother” steroid.

22
 Fig. 3.13: Uptake of cholesterol and synthesis of steroid hormones from cholesterol. The cholesterol needed
as the starting material in the synthesis of steroid hormones comes from two sources. Approximately 80% is
taken up as LDL particles via receptor-mediated endocytosis. The cell synthesizes the remaining cholesterol de
novo from acetyl coenzyme A (Acetyl CoA). LDL, low-density lipoprotein; VLDL, very-low-density
lipoprotein.

Although the adrenals, ovaries, and testes can all synthesize androgens, only the adrenals
produce corticosteroids. On the other hand, the ovaries and testes, but not the adrenals, can form
estrogens. This is due to activity of specific enzymes in each or the hormone producing cells
(Fig. 3.13). For example, since aromatase activity is not expressed in the adrenals, no estrogens
are formed. Instead, the adrenals form corticosteroids. They are formed by the mineralocorticoid
and glucocorticoid pathways. Transcription of 18-hydroxylase and 18-HSD gene is regulated
primarily by angiotensin II to produce aldosterone, whereas ACTH regulates 11β-
hydroxylase transcription to produce cortisol (Fig. 3.13).

ACTH influences steroid hormone secretion by both rapid short-term mechanisms that take place
within minutes and slower long-term actions. The rapid actions of ACTH include stimulation of
cholesterol delivery to the mitochondria where the P450scc (desmolase) enzyme is located.
ACTH also stimulates lipoprotein uptake into cortical cells. This increases the bio-availability
of cholesterol in the cells of the adrenal cortex.

The long term actions of ACTH include stimulation of the transcription of the genes coding for
steroidogenic enzymes, especially P450scc, steroid 11β-hydroxylase, and their associated
electron transfer proteins. This effect is observed over several hours.

Thus, ACTH stimulates mainly cortisol synthesis because it activates desmolase and 11β-
hydroxylase. Since cells of zona glomerulosa and reticularis do not have 11β-hydroxylase, only
zona fasciculata is stimulated by ACTH to secrete cortisol.

23
 ACTH

ACTH

Angiotensin II

Angiotensin II

Fig. 3.14. Synthesis of adrenal

corticoids

In summary, synthesis of the different steroids is not uniformly distributed through the cortex.
For example, the outermost group of cells (zona glomerulosa) synthesizes aldosterone, but
essentially no cortisol or androgens because those cells do not express the enzyme 17-α-
hydroxylase which is necessary for synthesis of 17-hydroxypregnenolone and 17-
hydroxyprogesterone. That enzyme is however present in cells of the inner zones of the cortex
(zona fasciculata and zona reticularis), which are the major sites of cortisol production. Thus,
ACTH is mainly responsible for the production of cortisol.

24
5.3. Mechanism of action of steroid hormone

Like all steroid hormones, cortisol and aldosterone bind to their respective receptors, and the
resulting hormone-receptor complexes bind to a hormone response element to modulate
transcription of responsive genes. Although the physiologic effects of these two steroid
hormones are distinctly different, their receptors are quite similar and, most interestingly, they
bind to the same consensus response element in DNA! How then is it possible to get hormone-
specific responses? (Please refer to Activity 3.9).

Fig. 3.15. Mechanism of action of steroid hormone

Activity 3.9: Types of adrenocorticosteroids

• Name the types of steroids produced by the adrenal gland. Describe their synthesis in the
cortical cells.
• What controls synthesis of steroid hormone? Explain the mechanism.
• How do steroid hormones from the adrenal cortex exert their effects during stress?

Next, we’ll look at the mechanism of action of specific adrenal steroids.

25
5.4. Mineralocorticoids

Removal of the adrenal glands leads to death within just a few days. Observation of such an
unfortunate subject would reveal several key derangements:

• The concentration of potassium in extracelluar fluid

becomes dramatically elevated
• Urinary excretion of sodium is high and the
concentration of sodium in extracellular fluid decreases
significantly
• Volume of extracellular fluid and blood decrease
• The heart begins to function poorly, cardiac output Fig. 3.16. Structure of
declines and shock ensues aldosterone

These phenomena are a direct result of loss of mineralocorticoid activity, and can largely be
prevented by replacement of salts and mineralocorticoids. Clearly, mineralocorticoids are acutely
critical for maintenance of life!

5.4.1. Mineralocorticoid Receptors

The principal steroid with mineralocorticoid activity is aldosterone (Fig. 3.17). Cortisol, the
major glucocorticoid, is said to have "weak mineralocorticoid activity", which is of some
importance because cortisol is secreted very much more abundantly than aldosterone. Another
way to state this is that a small fraction of the mineralocorticoid response in the body is due to
cortisol rather than aldosterone.

Activity 3.10: Receptor activation by adrenal steroids

The mineralocorticoid receptor binds both aldosterone and cortisol with equal affinity. Moreover, the
same DNA sequence serves as a hormone response element for the activated (steroid-bound) forms
of both mineralocorticoid and glucocorticoid receptors. An obvious question is: How can aldosterone
stimulate specific biological effects in this kind of system, particularly when blood concentrations of
cortisol are something like 2000-fold higher than aldosterone?

A large part of the answer is that, in aldosterone-responsive cells, cortisol is effectively destroyed,
allowing aldosterone to bind its receptor without competition. Target cells for aldosterone express the
enzyme 11-beta-hydroxysteroid dehydrogenase, which has no effect on aldosterone, but converts
cortisol to cortisone, which has only a very weak affinity for the mineralocorticoid receptor. In
essence, this enzyme "protects" the cell from cortisol and allows aldosterone to act appropriately.
Some tissues (e.g. hippocampus) express abundant mineralocorticoid receptors but not 11-beta HSD -
they therefore do not show responses to aldosterone because aldosterone is not present in quantities
sufficient to compete with cortisol.

26
5.4.2. Physiologic effects of Mineralocorticoids

Mineralocorticoids play a critical role in regulating concentrations of minerals - particularly

sodium and potassium - in extracellular fluids. As described above, loss of these hormones leads
rapidly to life-threatening abnormalities in electrolyte and fluid balance.

The major target of aldosterone is the distal tubule of the kidney, where it stimulates exchange of
sodium and potassium. Three primary physiologic effects result:

• Increased reabsorption of sodium: sodium loss in urine is decreased under aldosterone

stimulation.
• Increased reabsorption of water, with consequent expansion of extracellular fluid
volume. This osmotic effect is directly related to increased reabsorption of sodium.
• Increased renal excretion of potassium.

The cellular mechanism of action this hormone:

• Aldosterone stimulates transcription of the gene encoding the sodium-potassium ATPase,
leading to increased numbers of sodium pumps in the basolateral membranes of tubular
epithelial cells.
• Aldosterone also stimulates expression of a sodium channel which facilitates uptake of
sodium from the tubular lumen.
• Aldosterone also stimulates expression of a potassium channel which facilitates
secretion of potassium into the tubular lumen.

Aldosterone has effects on sweat glands, salivary glands and the colon which are essentially
identical to those seen in the distal tubule of the kidney. The major net effect is again to conserve
body sodium by stimulating its reabsorption or, in the case of the colon, absorption from the
intestinal lumen. Conservation of water follows conservation of sodium.

27
Activity 3.11: Mechanism
of action of aldosterone

• Describe how the ligand

(aldosterone) is released
from the adrenal cortex
and how is it transported
to the target cells.
• Name the target cells for
aldosterone.
• What kind of receptor is
complimentary to
aldosterone?
• What is the name of the
drug which is available to
compete with
aldosterone? When
would you use this drug?
What would be the effect
of this drug?
• Describe the signal
transduction mechanism
that occurs after receptor
activation. What are the
final physiological
responses of the target
cells?

Fig. 3.17. Mechanism of action of aldosterone.

Fig. 3.18: Cellular actions of aldosterone. The inset in A shows the upregulation of ENaC Na+ channels, based
on patch-clamp data from the rat cortical collecting tubule. N is the number of channels in the patch and P O is the
open probability

28
5.2.3. Control of Aldosterone secretion

Control over aldosterone secretion is truly multifactorial and tied into a spider web of other factors
which regulate fluid and electrolyte composition and blood pressure. If the major effects of
aldosterone are considered, it is rather easy to predict factors which stimulate or suppress
aldosterone secretion. The two most significant regulators of aldosterone secretion are:

• Concentrations of potassium ion in extracellular fluid: Small increases in blood levels

of potassium strongly stimulate aldosterone secretion.

• Angiotensin II: Activation of the renin-angiotensin system as a result of decreased renal

blood flow (usually due to decreased vascular volume) results in production of
angiotensin II, which stimulates aldosterone secretion.

Other factors which stimulate aldosterone secretion include ACTH (short-term stimulation only)
and sodium deficiency. Factors which suppress aldosterone secretion include atrial natriuretic
hormone (ANP), high sodium concentration and potassium deficiency.

Activity 3.12: Regulation of aldosterone

production

What are the two major factors that regulate

aldosterone secretion?

Describe the role of renin angiotensin system in

the regulation of aldosterone secretion 
regulation of Na+ and K+ levels.

Why is ACTH not a major factor in regulating

aldosterone secretion? Hint: Although desmolase
is stimulated by ACTH, the pregnenolone cannot
go through to form aldosterone because the
enzymes downstream (18 hydroxylase and 18-
HSD) are not activated. Thus very little
aldosterone production is stimulated by ACTH.
Aldosterone is activated by angiotensin II.

Why is cortisol not produced by zona glomerulosa?

Hint: because it does not have 17 α-hydroxylase to
convert pregnenolone through the glucocorticoid
pathways.

Describe the mechanism of regulation of

aldosterone secretion.

Describe the mechanism of action of aldosterone.

Hint: in the principal cell of the late distal tubule
and cortical collecting duct to stimulate Na+
reabsorption and K+ secretion.

Fig. 3.19: Control of aldosterone secretion. 29

5.2.4. Disease States involving mineralocorticoid

Primary hyperaldosteronism occurs because of excessive unregulated secretion of aldosterone

by the adrenal cortex. It is now thought to be the most common potentially curable and
specifically treatable cause of hypertension. Often it produces few symptoms. Most people have
high blood pressure which may cause poor vision or headaches. Occasionally there may be
muscular weakness, muscle spasms, tingling sensations, or excessive urination. Complications
include cardiovascular disease such as stroke, myocardial infarction, kidney failure, and
abnormal heart rhythms.
Primary hyperaldosteronism has a number of causes. About 66% of cases are due to enlargement
of both adrenal glands and 33% of cases are due to an adrenal adenoma (Conn’s syndrome) that
produces aldosterone. Other uncommon causes include adrenal cancer and an inherited disorder
called familial hyperaldosteronism.
Secondary hyperaldosteronism occurs because aldosterone secretion is stimulated by excessive
secretion of renin by the juxtaglomerular apparatus of the kidney. Secondary deficiency of
endogenous mineralocorticoids may occur when renin production is suppressed or deficient.
Renin production may be suppressed by the Na+ retention and volume expansion resulting from
exogenous mineralocorticoids (fludrocortisone acetate) or mineralocorticoid-like substances
(licorice or carbenoxolone). When this happens, hypertension, hypokalemia, and metabolic
alkalosis result. When renin production is deficient and unable to stimulate mineralocorticoid
production, Na+ loss, hyperkalemia, and metabolic acidosis occur.
Primary mineralocorticoid deficiency (hypoaldosteronism) may result from destruction of
adrenocortical tissue, defects in adrenal synthesis of aldosterone, inadequate stimulation of
aldosterone secretion, or resistance to the ion transport effects of aldosterone, such as are seen in
pseudohypoaldosteronism. Hypoaldosteronism is characterized by Na+ loss, with hyponatremia,
hypovolemia, and hypotension, and impaired secretion of both K+ and H+ in the renal tubules,
resulting in hyperkalemia and metabolic acidosis. Renin activity is typically increased.

30
5.5. Glucocorticoids

In contrast to loss of mineralocorticoids, failure to produce

glucocorticoids is not acutely life-threatening. Nevertheless, loss or
profound diminishment of glucocorticoid secretion leads to a state of
deranged metabolism and an inability to deal with stressors which,
if untreated, is fatal.

In addition to their physiologic importance, glucocorticoids are also

among the most frequently used drugs, and often prescribed for their
anti-inflammatory and immunosuppressive properties. Fig. 3.20. Structure of
cortisol
5.5.1. Glucocorticoid Receptors

The vast majority of glucocorticoid activity is from cortisol, also known as hydrocortisone.
Corticosterone, the major glucocorticoid in rodents, is another glucocorticoid.

Cortisol binds to the glucocorticoid receptor in the cytoplasm of all cells and the hormone-
receptor complex is then translocated into the nucleus, where it binds to its DNA response
element (HRE) and modulates transcription from a battery of genes, leading to changes in the
cell's phenotype.

Only about 10% of circulating cortisol is free. The remaining majority circulates bound to
plasma proteins, particularly corticosteroid-binding globulin (transcortin). This protein binding
likely decreases the metabolic clearance rate of glucocorticoids and, because the bound steroid is
not biologically active, tends to act as a buffer and blunt wild fluctuations in cortisol
concentration.

5.5.2. Physiologic Effects of Glucocorticoids

There seem to be no cells that lack glucocorticoid receptors and as a consequence, these steroid
hormones have a huge number of effects on physiologic systems. That having been said, it can
be stated that the best known and studied effects of glucocorticoids are on carbohydrate
metabolism and immune function.

Effects on metabolism

The name glucocorticoid derives from early observations that these hormones were involved in
glucose metabolism. In the fasted state, cortisol stimulates several processes that collectively
serve to increase and maintain normal concentrations of glucose in blood. These effects include:

• Stimulation of gluconeogenesis, particularly in the liver: This pathway results in the

synthesis of glucose from non-hexose substrates such as amino acids and lipids.
Enhancing the expression of enzymes involved in gluconeogenesis is probably the best
known metabolic function of glucocorticoids.

31
 • Mobilization of amino acids from extrahepatic tissues: These serve as substrates for
gluconeogenesis.
• Inhibition of glucose uptake in muscle and adipose tissue: A mechanism to conserve
blood glucose.
• Stimulation of fat breakdown in adipose tissue: The fatty acids released by lipolysis
are used for production of energy in tissues like muscle, and the released glycerol provide
another substrate for gluconeogenesis.

Activity 3.13: Mechanism of action of glucocorticoid

• Give an example of glucocorticoid.

• How does glucocorticoid activate the receptor? Explain the signal transduction involved until
the final physiological response is achieved.

Excessive glucocorticoid levels resulting from administration as a drug or

hyperadrenocorticolism have effects on many systems. Some examples include inhibition of
bone formation, suppression of calcium absorption and delayed wound healing. These
observations suggest a multitude of less dramatic physiologic roles for glucocorticoids.

Cardiovascular Actions
Cortisol reinforces its effects on blood glucose by its positive effects on the cardiovascular
system. Cortisol has permissive actions on catecholamines and thereby contributes to cardiac
output and blood pressure. Cortisol stimulates erythropoietin synthesis and hence increases red
blood cell production. Anemia occurs when cortisol is deficient, and polycythemia occurs when
cortisol levels are excessive.

Anti-inflammatory and Immunosuppressive Actions

Inflammation and immune responses are often part of the response to stress. However,
inflammation and immune responses have the potential for significant harm and may cause death
if they are not held in homeostatic balance. As a stress hormone, cortisol plays an important role
in maintaining immune homeostasis. Cortisol, along with epinephrine and norepinephrine,
represses the production of proinflammatory cytokines and stimulates the production of anti-
inflammatory cytokines

The inflammatory response to injury consists of local dilation of capillaries and increased
capillary permeability with resultant local edema and accumulation of white blood cells. These
steps are mediated by prostaglandins, thromboxanes, and leukotrienes. Cortisol
inhibits phospholipase A2, a key enzyme in prostaglandin, leukotriene, and thromboxane
synthesis. Cortisol also stabilizes lysosomal membranes, thereby decreasing release of the
proteolytic enzymes that augment local swelling. In response to injury, leukocytes normally
migrate to the site of injury and leave the vascular system. These effects are inhibited by cortisol,
as is the phagocytic activity of neutrophils, although release of neutrophils from bone marrow is
stimulated. Analogues of glucocorticoid are frequently used pharmacologically because of their
anti-inflammatory properties.

32
Cortisol inhibits the immune response, and for this reason glucocorticoid analogues have been
used as immunosuppressants in organ transplants. High cortisol levels decrease the number of
circulating T lymphocytes (particularly helper T lymphocytes) and reduce their ability to migrate
to the site of antigenic stimulation. Glucocorticoids promote atrophy of the thymus and other
lymphoid tissue. Although corticosteroids inhibit cellular-mediated immunity, antibody
production by B lymphocytes is not impaired.

Effects of Cortisol on the Reproductive Systems

Reproduction exacts a considerable anabolic cost on the organism. In humans, reproductive
behavior and function are dampened in response to stress. Cortisol decreases the function of the
reproductive axis at the hypothalamic, pituitary, and gonadal levels.

Effects of Cortisol on Bone

Glucocorticoids increase bone resorption. They have multiple actions that alter bone metabolism.
Glucocorticoids decrease intestinal Ca++ absorption and renal Ca++ reabsorption. Both
mechanisms serve to lower serum [Ca++]. As serum [Ca++] drops, secretion of parathyroid
hormone (PTH) increases, and PTH mobilizes Ca++ from bone by stimulating resorption of bone.
In addition to this action, glucocorticoids directly inhibit osteoblast bone-forming functions
(see Chapter 39). Although glucocorticoids are useful for treating the inflammation associated
with arthritis, excessive use will result in bone loss (osteoporosis).

Actions of Cortisol on Connective Tissue

Cortisol inhibits fibroblast proliferation and collagen formation. In the presence of excessive
amounts of cortisol, the skin thins and is more readily damaged. The connective tissue support of
capillaries is impaired, and capillary injury, or bruising, is increased.

Actions of Cortisol on the Kidney

Cortisol inhibits the secretion and action of antidiuretic hormone (ADH), and thus it is an ADH
antagonist. In the absence of cortisol, the action of ADH is potentiated, which makes it difficult
to increase free water clearance in response to a water load and increases the likelihood of water
intoxication. Although cortisol binds to the mineralocorticoid receptor with high affinity, this
action is normally blocked by inactivation of cortisol to cortisone by the enzyme 11β-HSD2.
However, the mineralocorticoid activity (i.e., renal Na+ and H2O retention, K+ and H+ excretion)
of cortisol depends on the relative amount of cortisol (or synthetic glucocorticoids) and the
activity of 11β-HSD2. Certain agents (such as compounds in black licorice) inhibit 11β-HSD2
and thereby increase the mineralocorticoid activity of cortisol. Cortisol increases the glomerular
filtration rate by both increasing cardiac output and acting directly on the kidney.

Actions of Cortisol on Muscle

When cortisol levels are excessive, muscle weakness and pain are common symptoms. The
weakness has multiple origins. In part, it is a result of the excessive proteolysis that cortisol
produces. High cortisol levels can result in hypokalemia (via mineralocorticoid actions), which
can produce muscle weakness because it hyperpolarizes and stabilizes the muscle cell membrane
and thus makes stimulation more difficult.

33
Actions of Cortisol on the Gastrointestinal Tract
Cortisol exerts a trophic effect on the GI mucosa. In the absence of cortisol, GI motility
decreases, GI mucosa degenerates, and GI acid and enzyme production decreases. Because
cortisol stimulates appetite, hypercortisolism is frequently associated with weight gain. The
cortisol-mediated stimulation of gastric acid and pepsin secretion increases the risk for
development of ulcers.

Psychological Effects of Cortisol

Psychiatric disturbances are associated with either excessive or deficient levels of
corticosteroids. Excessive corticosteroids can initially produce a feeling of well-being, but
continued excessive exposure eventually leads to emotional lability and depression. Frank
psychosis can occur with either excessive or deficient hormone. Cortisol increases the tendency
for insomnia and decreases rapid eye movement (REM) sleep. People who are deficient in
corticosteroids tend to be depressed, apathetic, and irritable.
Table 3.4. Effect of glucocorticoids

Target Tissue Effect Mechanism

Muscle Catabolic Inhibit glucose uptake and metabolism
Decrease protein synthesis
Increase release of amino acids, lactate
Fat Lipolytic Stimulate lipolysis
Increase release of FFAs and glycerol
Liver Synthetic Increase gluconeogenesis
Increase glycogen synthesis, storage
Increase glucose-6-phosphatase activity
Increase blood glucose
Immune Suppression Reduce number of circulating lymphocytes,
system monocytes, eosinophils, basophils
Inhibit T lymphocyte production of interleukin-2
Interfere with antigen processing, antibody production
and clearance
Anti-inflammatory Decrease migration of neutrophils, monocytes,
lymphocytes to sites of injury
Other Stimulate release of neutrophils from marrow
Interfere with neutrophil migration out of vascular
compartment
Cardiovascular Increase cardiac output
Increase peripheral vascular
tone
Renal Increase glomerular filtration
rate
Aid in regulating water,
electrolyte balance
Other Permissive action
Resistance to stress
Insulin antagonism Increase blood glucose

34
5.5.3. Control of Cortisol Secretion

Glucocorticoids are secreted in response to a single stimulator:

adrenocorticotropic hormone (ACTH) from the anterior pituitary.
ACTH is itself secreted under control of the hypothalamic peptide
corticotropin-releasing hormone (CRH). The central nervous
system is thus the commander and chief of glucocorticoid
responses, providing an excellent example of close integration
between the nervous and endocrine systems.

This fact sometimes makes it very difficult to assess

glucocorticoid levels, particularly in animals. Observing the
approach of a phlebotomist, and especially being restrained for
blood sampling, is enough stress to artificially elevate cortisol
levels several fold!

Cortisol secretion is suppressed by classical negative feedback

loops. When blood concentrations rise above a certain threshold,
cortisol inhibits CRH secretion from the hypothalamus, which Fig. 3.21. Regulation of
turns off ACTH secretion, which leads to a turning off of cortisol cortisol secretion
secretion from the adrenal. The on and off control on CRH
secretion results in pulsatile secretion of cortisol. Typically, pulse amplitude and frequency are
highest in the morning and lowest at night.

ACTH, also known as corticotropin, binds to receptors in the plasma membrane of cells in the
zona fasciculata and zona reticularis of the adrenal. Hormone-receptor engagement activates
adenyl cyclase, leading to elevated intracellular levels of cyclic AMP which leads ultimately to
activation of the enzyme systems involved in biosynthesis of cortisol from cholesterol.

Activity 3.14: Stimulation of

cortisol production

State the relationship between

CRH, ACTH and cortisol.

What is cortisol derived from?

Briefly explain the signal

transduction mechanism as a result
of ACTH receptor activation. What
is the final physiological outcome?

What is the major role of PKA in

cortisol synthesis?

Discuss the role of mitochondria in

cortisol synthesis.

Fig. 3.22. Stimulation of cortisol production

35
5.5.4. Disease States involving glucocorticoid

Hypersecretion

Adrenocortical hormone excess is termed Cushing's syndrome. Causes:

• Pharmacological use of exogenous corticosteroids is now the most common cause of
Cushing's syndrome.
• The next most prevalent cause is ACTH-secreting tumors.
• The form of Cushing's syndrome caused by a functional pituitary adenoma is
called Cushing's disease.
• The fourth most common cause of Cushing's syndrome is primary hypercortisolism resulting
from a functional adrenal tumor.

If the disorder is primary or if it is a result of corticosteroid treatment, secretion of ACTH will be

suppressed and increased skin pigmentation will not occur. However, if hypersecretion of the
adrenal is the result of an ACTH-secreting nonpituitary tumor, ACTH levels sometimes become
high enough to increase skin pigmentation.

Signs and symptoms of Cushing syndrome (Activity 3.14, Fig 3.23)

• Weight gain with a characteristic centripetal fat distribution and a "buffalo hump."
• The face will appear round aka moon face (fat deposition), and the cheeks may be reddened,
in part because of the polycythemia.
• The limbs will be thin as a result of skeletal muscle wasting (from increased proteolysis), and
muscle weakness will be evident (from muscle proteolysis and hypokalemia).
• Proximal muscle weakness is apparent, so the patient may have difficulty climbing stairs or
rising from a sitting position.
• The abdominal fat accumulation, coupled with atrophy of the abdominal muscles and
thinning of the skin, will produce a large, protruding abdomen.
• Purple abdominal striae are seen as a result of damage to the skin by the prolonged
proteolysis, increased intraabdominal fat, and loss of abdominal muscle tone. Capillary
fragility occurs because of damage to the connective tissue supporting the capillaries.
• Patients are likely to show signs of osteoporosis and poor wound healing.
• They have metabolic disturbances that include glucose intolerance, hyperglycemia, and
insulin resistance.
• Prolonged hypercortisolism can lead to manifestations of diabetes mellitus.
• Because of suppression of the immune system caused by glucocorticoids, patients are more
susceptible to infection.
• The mineralocorticoid activities of glucocorticoids and the possible increase in aldosterone
secretion produce salt retention and subsequent water retention that result in hypertension.
• Excessive androgen secretion in women can produce hirsutism, male pattern baldness, and
clitoral enlargement.

36
 Activity 3.15: Cushing syndrome

Discuss the pathophysiology of the signs

and symptoms of Cushing syndrome.

Hint:
Moon face:
Buffalo hump: increase fat deposition
Central obesity:

Hypertension: permissive actions on

catecholamines and thereby contributes to
cardiac output and blood pressure.

Purple abdominal striae: damage to the skin by

the prolonged proteolysis, increased
intraabdominal fat, and loss of abdominal
muscle tone. Capillary fragility occurs because
of damage to the connective tissue supporting
the capillaries

Thin arms and legs: skeletal muscle wasting

(increased proteolysis)

Poor wound healing: decreased immunological

function

Fig. 3.23. Cushing syndrome.

Hyposecretion

Addison's disease is primary adrenal insufficiency, with both mineralocorticoids and

glucocorticoids usually being deficient. The most prevalent cause of Addison's disease is
autoimmune destruction of the adrenal cortex. Because of the cortisol deficiency, ACTH secretion
increases.

Signs and symptoms:

• Elevated levels of ACTH can compete for MC1R in melanocytes and cause an increase in
skin pigmentation, particularly in skin creases, scars, and gums.
• The loss of mineralocorticoids results in contraction of extracellular volume, which produces
circulatory hypovolemia and therefore a drop in blood pressure.
• Because the loss of cortisol decreases the vasopressive response to catecholamines,
peripheral vascular resistance drops, thereby facilitating the development of hypotension.
• Individuals with Addison's disease are also prone to hypoglycemia when stressed or fasting,
and water intoxication can develop if excess water is ingested.
• Because cortisol is important for muscle function, muscle weakness also occurs in cortisol
deficiency.

37
• The loss of cortisol results in anemia, decreased GI motility and secretion, and reduced iron
and vitamin B12 absorption.
• Appetite decreases with cortisol deficiency, and this decreased appetite coupled with the GI
dysfunction predisposes these individuals to weight loss.
• These patients often have disturbances in mood and behavior and are more susceptible to
depression.

Activity 3.16: Addison

disease

Discuss the pathophysiology of

the signs and symptoms of
Cushing syndrome.

Skin hyperpigmentation:
increased ACTH  increased
melanin from POMC

Hypotension: volume
contraction due to low Na+

Gastrointestinal problems:
decreased motility and secretion

Weight loss: GI dysfunction and

loss of appetite.

Muscle weakness: reduced

muscle function

Anaemia: reduced
erythropoietin production

Fig. 3.24. Addison disease

Activity 3.17: Cortisol secretion

• Explain the mechanism of regulation of cortisol secretion.

• What is excess secretion of cortisol due to? What is the consequence?

38
Summary
• The adrenal gland is composed of a cortex that is of mesodermal origin and a medulla that is
of neuroectodermal origin. The cortex produces steroid hormones, and the medulla
produces catecholamines.
• The rate-limiting enzymes in medullary catecholamine synthesis are tyrosine hydroxylase
and dopamine β-hydroxylase, which are induced by sympathetic stimulation, and
phenylethanolamine-N-methyltransferase, which is induced by cortisol.
• Catecholamines increase serum glucose and fatty acid levels. They stimulate
gluconeogenesis, glycogenolysis, and lipolysis. Catecholamines increase cardiac output but
have selective effects on blood flow to different organs.
• Pheochromocytoma is a tumor of chromaffin tissue that produces excessive quantities of
catecholamines. Symptoms of pheochromocytoma are often sporadic and include
hypertension, headaches, sweating, anxiety, palpitations, chest pain, and orthostatic
hypotension.
• The adrenal cortex displays clear structural and functional zonation: the zona glomerulosa
produces the mineralocorticoid aldosterone, the zona fasciculata produces the glucocorticoid
cortisol, and the zona reticularis produces the weak androgens DHEA and DHEAS.
• Cortisol binds to the glucocorticoid receptor. During stress, cortisol increases blood glucose
by increasing gluconeogenesis in the liver and breaking muscle protein down to supply
gluconeogenic precursors. Cortisol also decreases glucose uptake by muscle and adipose
tissue and has permissive actions on glucagon and catecholamines. Cortisol has multiple
effects on other tissue. From a pharmacological point of view, the most important is the
immunosuppressive/anti-inflammatory effect.
• Cortisol is regulated by the CRH-ACTH-cortisol axis. Cortisol negatively feeds back at the
hypothalamus on both CRH-producing neurons and pituitary corticotropes. CRH is regulated
by several forms of stress, including proinflammatory cytokines, hypoglycemia, neurogenic
stress, and hemorrhage, and by diurnal input.
• The adrenal androgens DHEA, DHEAS, and androstenedione are androgen precursors. They
can be converted to active androgens peripherally and provide about 50% of circulating
androgens in women. In men, the role of adrenal androgens, if any, remains obscure. In
women, adrenal androgens promote pubic and axillary hair growth and libido. Excessive
adrenal androgens in women can lead to various degrees of virilization and ovarian
dysfunction.
• The zona glomerulosa of the adrenal cortex is the site of aldosterone production. Aldosterone
is the strongest naturally occurring mineralocorticoid in humans. It promotes Na+ and water
reabsorption by the distal tubule and collecting duct while promoting renal K+ and
H+ secretion. Aldosterone promotes Na+ and water absorption in the colon and salivary
glands. It also has a proinflammatory, profibrotic effect on the cardiovascular system and
causes left ventricular hypertrophy and remodeling.
• Major actions of angiotensin II on the adrenal cortex are increased growth and vascularity of
the zona glomerulosa, increased StAR and CYP11B2 enzyme activity, and increased
aldosterone synthesis.
• Major stimuli for aldosterone production are a rise in angiotensin II and a rise in serum [K+].
The major inhibitory signal is ANP.

39
• Addison's disease is adrenocortical insufficiency. Common symptoms include hypotension,
hyperpigmentation, muscle weakness, anorexia, hypoglycemia, and hyperkalemic acidosis.
• Cushing's syndrome results from hypercortisolemia. If the basis of the disorder is increased
pituitary adrenocorticotropin secretion, the disorder is called Cushing's disease. Common
symptoms of Cushing's syndrome include centripetal fat distribution, muscle wasting,
proximal muscle weakness, thin skin with abdominal striae, capillary fragility, insulin
resistance, and polycythemia.
• Congenital adrenal hyperplasia is caused by a congenital enzyme deficiency that blocks the
production of cortisol. The enzyme blockage results in elevated ACTH secretion, which
stimulates adrenal cortical growth and secretion of precursors produced before the block. 21-
Hydroxylase (CYP21B) deficiency is the most common form.

Fig 3.25. Metabolic response to cortisol

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Conclusion

Objectives Comment on achievement

1. Describe the gross anatomy and
microanatomy of the adrenal gland
including the functional zones (one
medullary and three cortical zones),
innervation, and blood supply of the
adrenal glands and the principal hormones
secreted from each zone.
2. Describe the adrenal medullary hormones
in terms of their chemistry, biosynthesis,
origin, target cells, regulation of release,
mechanism of action and the effect of over
and under secretion of the hormones.
3. Describe the adrenal cortical hormones in
terms of their chemistry, biosynthesis,
origin, target cells, regulation of release,
mechanism of action and the effect of over
and under secretion of the hormones.
4. Describe the interactions of adrenal
medullary and cortical hormones in
response to stress.

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