Adrenal Glands:

Adrenal Cortex Hormones

 Anatomical position
The anatomical relations of the adrenal glands
Left Right
• Anterior Splenic vessels + pancreas Vena cava + right
lobe of liver
• Posterior Left crus of diaphragm Right crus of
diaphragm
• Inferior Upper pole of left kidney Upper pole of right
kidney
• Superior Stomach
 Anatomy, continued..
• Blood supply: Derived from a circle of arteries
arising from the superior, middle and inferior
arteries – capsular vessels, cortical vessels and
medullary arterioles
• Nerve supply: Splanchnic nerves
• Venous and lymphatic drainage: The central
vein of the right adrenal drains into the inferior
vena cava, while on the left, it drains into the
left renal vein.
 Micro-anatomy of adrenalin gland
• Two adrenal glands that lie anteriorly to kidneys.
• Each composed of 2 parts: an adrenal cortex and an
adrenal medulla.
• The adrenal medulla: inner portion, secretes
epinephrine and norepinephrine, by the
sympathetic nervous system stimulation;
- the two hormones also called catecholamines
involved in the “fight or flight” mechanism of
the nervous system.
• The adrenal cortex, outer portion and secretes a
variety of steroid hormones called corticorsteroids
• About 80% of the adrenal gland is composed of the
cortex which has three layers or zones:
1) Zona glomerulosa – the outermost region or
layer
2) Zona fasciculata – the middle and largest
portion
3) Zona reticularis – the innermost layer.
Micro anatomy continued..
 Steroid Hormones
 All steroid hormones are derived from cholesterol and differ only in the ring
structure and side chains attached to them.
 All steroid hormones are lipid soluble
• Steroid hormones: produced in the adrenal cortex, testis, ovary, and some
peripheral tissues (adipose tissue, the brain)
• All steroid hormones share a typical ring structure.
 Cholesterol is the precursor for human steroid
biosynthesis: Conversion to pregnenolone is the first step in steroid synthesis
from cholesterol, and is catalysed by the enzyme, desmolase (cytochrome P450scc, CYP11A1)
 Functions of Steroid Hormones

• Steroid hormones play important roles in:

- carbohydrate regulation (glucocorticoids)
- mineral balance (mineralocorticoids)
- reproductive functions (gonadal steroids)

• Steroids also play roles in inflammatory responses, stress responses,

bone metabolism, cardiovascular fitness, behavior, cognition, and
mood.
Histology of the adrenal gland
THE ADRENAL CORTEX
Layers (three)
 
• Corticosteroid- steroid hormone produced by the adrenal cortex.
• Most superficial cortical layer: zona glomerulosa, produces
mineralocorticoids (aldosterone)
• Middle cortical layer: zona fasciculata, produces glucocorticoids
(cortisol)
• Deepest cortical layer: zona reticularis, produces weak androgens
(e.g., dehydroepiandrosterone, adrenosterone)
Adrenal Steroid Hormones and Their Synthesis

• 1. The adrenal cortex synthesises and secretes steroid hormones.

• 2. Steroid secreting cells are filled with lipid droplets and mitochondria.
• 3. Functional zonation of the adrenal cortex occurs:
• a. zona glomerulosa secretes mineralocorticoids.
[aldosterone]
• b. zona fasciculata secretes glucocorticoids (cortisol).
• c. zona reticularis secretes androgens.
• 4. Adrenal cortex and medulla both respond in different ways to help
maintain homeostasis during times of physiological and psychological
stress.
BASIC SYNTHETIC PATHWAY OF STEROIDS
• 1. Cholesterol is the precursor for all adrenal and gonadal steroid hormones.
• 2. Cholesterol is derived primarily by uptake from plasma cholesterol, rather than by
synthesis in the adrenal gland.
• 3. Low-density lipoproteins (LDLs) are principal cholesterol transporters in plasma.
• 4. Cholesterol is converted to pregnenolone by cytochrome P450scc (desmolase) in
mitochondria.
• Pregnenolone exits mitochondria after it is synthesized.
• Pregnenolone is the precursor of all steroids in humans.
• 5. In the smooth endoplasmic reticulum, pregnenolone is converted to progesterone.
 Types of steroid hormones
• Glucocorticoids; cortisol is the major
glucocorticoid in humans
• Mineralocorticoids; aldosterone
• Androgens such as testosterone
• Estrogens, including estradiol and estrone
• Progestogens (also known a progestins) such
as progesterone
 Steroid hormones
• Are not packaged or stored, but synthesized and immediately released when
they are needed
• All steroids are derived from cholesterol, which is first converted to
pregnenolone
• Enzymes which produce steroid hormones from cholesterol are located in
mitochondria and smooth ER
• Steroids are lipid soluble and pass through cell membranes freely
• The way in which a cell responds to a steroid hormone depends on whether
the cell has enzymes that alter the steroid (for example, aromatase converts
testosterone to estradiol), whether the cell has a specific receptor for a
particular steroid, and if so which of the multiple forms of that receptor is
present. It also depends on the metabolic profile, protein content and
transcriptional activity of the cell.
Glucocorticoids (cortisol)
• They are produced in the zona fasciculata. The primary glucocorticoid released by the adrenal
gland in the human is cortisol; and corticosterone in many other animals. Its secretion is
regulated by the hormone ACTH (adrenocorticotrophic hormone) from the anterior pituitary.
Upon binding to its target, cortisol enhances metabolism in several ways:
• It stimulates the release of amino acids from the body- muscle protein wastage if too much
• It stimulates lipolysis, the breakdown of fat
• It stimulates gluconeogenesis, the production of glucose from newly-released amino acids and
lipids
• It increases blood glucose levels in response to stress, by inhibiting glucose uptake into muscle
and fat cells
• It strengthens cardiac muscle contractions
• It increases water retention
• It has anti-inflammatory and anti-allergic effects
GLUCOCORTICOID ACTION:
• 1. Examples of actions:
• a. cortisol at chronic high levels has a catabolic effect on muscle and adipose.
• b. cortisol promotes anabolic gluconeogenesis and glycogen storage in liver.
• c. cortisol suppresses all phases of inflammatory and allergic reactions.
• d. cortisol suppresses lymph node activity and immune response, causing atrophy.

• 2. Chronic cortisol secretion under stress leads to muscle wasting, hyperglycemia,

atrophy of the immune system, vascular derangements, gastrointestinal ulceration.
GLUCOCORTICOID PRODUCTION (cortisol)
(regulated by pituitary ACTH)
• 1. ACTH acts on membrane receptors to
stimulate cAMP and protein kinases.
• 2. This leads to the production of P450scc
(Cyp11A1) in zona fasciculate and 17a-
hydroxylase.
• 3. ACTH also stimulates hypertrophy and
hyperplasia of cortex
Mineralocorticoids
• They are produced in the zona glomerulosa of the adrenal gland. The primary
mineralocorticoid is aldosterone. Its secretion is regulated by the
oligopeptide angiotensin II (angiotensin II is regulated by angiotensin I, which
in turn is regulated by renin). Aldosterone is secreted in response to high
extracellular potassium levels, low extracellular sodium levels, and low fluid
levels and blood volume. Aldosterone affects metabolism in different ways:
• It increases urinary excretion of potassium ions
• It increases interstitial levels of sodium ions
• It increases water retention and blood volume
Androgens
• They are produced in the zona reticularis. The most important androgens include:
• Testosterone: a hormone with a wide variety of effects, ranging from enhancing
muscle mass and stimulation of cell growth to the development of the secondary
sex characteristics.
• Dihydrotestosterone (DHT): a metabolite of testosterone, and a more potent
androgen than testosterone in that it binds more strongly to androgen receptors.
• Androstenedione (Andro): an androgenic steroid produced by the testes, adrenal
cortex, and ovaries. While androstenediones are converted metabolically to
testosterone and other androgens, they are also the parent structure of estrone.
• Dehydroepiandrosterone (DHEA): It is the primary precursor of natural estrogens.
 Steroid hormones
• Steroid hormones are not water soluble so have to be carried in the blood
complexed to specific binding globulins.
• Corticosteroid binding globulin carries cortisol
• Sex steroid binding globulin carries testosterone and estradiol
• In some cases a steroid is secreted by one cell and is converted to the
active steroid by the target cell: an example is androgen which secreted by
the gonad and converted into estrogen in the brain.
Steroids can be transformed to active
steroid in target cell
 Cellular Localization of Cholesterol
Metabolism for Steroid Production
• The first enzymatic step in steroid synthesis is the conversion of
cholesterol into pregnenolone.

• The enzyme that catalyzes this reaction is located in the inner

mitochondrial membrane.

• Cholesterol must cross the outer membrane of the mitochondria to

reach the inner membrane and interior of the mitochondria in order to
be converted to pregnenolone. The StAR protein transports cholesterol
from the outer to the inner membrane.
Lipoid Congenital Adrenal Hypertrophy (Lipoid
CAH)
• Lipoid CAH is a genetic disease causing accumulation of cholesterol-
filled lipid droplets in adrenal gland cells and other steroid-producing
cells.
• There is a lack of production of all steroid hormones, including
adrenal steroids and sex hormones.
• Patients are often severely affected, with multiple problems
(electrolyte and metabolic disturbances, hypoglycaemia, sexual
ambiguity, among others)
• In some of these patients, there is a defective production of StAR
protein. This prevents efficient transfer of cholesterol from outer to
inner mitochondrial membrane and prevents pregnenolone
synthesis, even when desmolase (cytochrome P450scc, CYP11A1)
enzyme levels are normal.
Cytochrome P450scc (desmolase, or CytP450C11A1, or CYP11A1)

• Converts cholesterol to pregnenolone, the precursor of all human steroid

hormones.
• It is located in mitochondria. Cholesterol is transported to mitochondria to
be convereted to pregnenolone.
• Specifically, cholesterol has to be transported from the outer mitochondrial
membrane to the inner mitochondrial membrane in order to be a substrate
for this enzyme.
• This transfer of cholesterol is the control step for steroidogenesis.
• The transfer of cholesterol from outer to inner mitochondrial membrane is
controlled by the StAR protein (steroidogenic acute regulatory protein).
• Synthesis of the major steroid hormones secreted by the adrenal cortex
 Mineralcorticoids
• Aldosterone is the primary one and its most
important effect is its action on electrolyte balance.
• primary site of action,distal tubules of the kidney
nephron where it promotes Na+ retention into the
blood and enhances K+ elimination into the urine
filtrate
• If Na+ is retained, H20 is osmotically attracted to
Na+ and therefore is retained as well.
                                                                                                                                   

• Aldosterone actions in the kidney

                                                                                                   

• Control of aldosterone secretion

• Simplifed diagram illustrating the integrated actions of
aldosterone, arginine vasopressin (AVP) and atrial natriuretic
peptide (ANP) in the control of salt and water balance
Aldosterone is released due to:
1) Activation of the renin-angiotensin system in
the kidneys and related to a decrease in Na+
and decrease in BP.
2) Direct stimulation of the adrenal cortex by
increase in blood K+concentration
• This zone is relatively independent of the
anterior pituitary hormone influence of ACTH.
 Glucocorticoids
• The main glucocorticoid is cortisol,has an
important role in carbohydrate, fat and protein metabolism.
• Overall, cortisol main effect is to increase concentration of
blood glucose .
• In CHO metabolism, action includes
- increasing Gluconeogenesis
- Decrease utilization of glucose by cells
everywhere else in the body except the brain
• In general,cortisol has diabetogenic effect or increases
blood glucose.
• Occasionally, this could be great enough or 50% above
normal that it is called an Adrenal diabetes. Would only
weakly respond if given insulin.
                                                                                                          

• Diagrammatic outline of the synthesis of cortisol from cholesterol in the adrenal cortex
In protein metabolism, effect of cortisol includes:
1. stimulates protein degradation in all cells except
liver cells, i.e decrease protein anabolism, and
increase muscle protein & amino acid
catabolism.
- these amino acids are available for
gluconeogenesis at the liver.
- high cortisol, thus, make the muscle so weak.
2. promotes formation of proteins(anabolism)
by the liver which is opposite to the rest of the
body proteins
Summary on protein metabolism: ↓ muscle
proteins, ↑ liver proteins.
In lipid metabolism, effect of cortisol includes:
• Cortisol increases lipolysis or increased fatty acids in
the blood from adipose tissue. These fatty acids can
then be used for energy source
instead of glucose thereby conserving glucose for the
brain.
• Thus, in times of starvation, cortisol shifts the cells
from utilizing glucose for
• energy to using fats for energy and thereby conserving
glucose for the brain only
• Cortisol presence permits catecholamines to
induce vasoconstriction. If not, a person
lacking cortisol, may go into circulatory shock
(decrease in blood volume or blood pressure)
in a stressful situation that needs widespread
vasoconstriction.
 Anti-inflammatory and Immunosuppressive
Effect of cortisol
1) Anti-inflammatory - Synthetic glucocorticoids are being
administered to inhibit all steps in inflammation that are
actually very destructive, such as in rheumatoid arthritis.
They act to decrease inflammation and swelling and stabilize
capillary membranes. They don’t affect the underlying disease
process but merely suppress the body’s response to the disease.

2) Immunosuppression – Corticosteroids are also given to inhibit

the effects of the immune system by knocking out of
commission the white blood cells responsible for antibody
production and destruction of foreign cells. Useful in allergic
disorders and preventing organ transplant rejection
• Glucocorticoids inhibit the conversion of phosphatidyl choline to arachidonic acid by inducing the
production of lipocortin (now termed annexin) which inhibits phospholipase-A2 (PL-A2).
• They inhibit the production of inflammatory prostaglandins and thromboxanes by inhibiting
cycloxygenase (COX).
• They inhibit the production and action of leucotrines which are also formed from arachidonic acid
by lipo-oxygenase (L-O).
• They block cytokine (IL-1β) production, reduce the number of circulating T cells and so reduce
antibody production.
• x=inhibitory effects of glucocorticoids.
 Regulation of Cortisol release
• Two factors that can also influence the negative feedback are diurnal
variation in cortisol & stress.
• 1)Cortisol levels are highest in the morning and lowest at night. This
is
• primarily related to the sleep-wake cycle. They will be reversed in one
who works nightly and sleeps daily. This information is particularly
important to know:
1) when blood sample is taken;
2) the sleep cycle of person being sampled or swing shifts;
3) the effect of surgery time of day in helping the individual
handle the stress.
2)Stress can greatly affect levels of cortisol in
the blood. It can override, for example the
hypothalamic-pituitary axis of negative
feedback. The magnitude of the increase of
blood cortisol is proportional to the intensity
of the stressful stimulation. More stress –
more cortisol. Less stress- less cortisol.
• There is a circadian (diurnal) rhythm to
plasma cortisol levels, although it is probably
secreted all the time in varying amounts.
Levels are higher in the morning and lower at
night.
 Regulation of adrenal cortex activites

• Different nervous and hormonal actions

influence on the production or suppression of
adrenal cortex hormones
 A. SECRETION OF CRH AND ACTH
• ACTH is the trophic hormone of the zonae
fasciculata and reticularis and the major
regulator of cortisol and adrenal androgen
production
• ACTH in turn is regulated by the hypothalamus
and central nervous system via
neurotransmitters and corticotropin-releasing
hormone (CRH) and arginine vasopressin
(AVP).
B. ACTH EFFECTS ON THE ADRENAL CORTEX

ACTH stimulate
• rapid synthesis and secretion of steroids
• Chronic stimulation leads to adrenocortical
hyperplasia and hypertrophy
ACTH deficiency lead to
• decreased steroidogenesis and is accompanied by
adrenocortical atrophy
• decreased gland weight
• decreased protein and nucleic acid content.
 CIRCULATION OF CORTISOL & ADRENAL
ANDROGENS
• Cortisol and the adrenal androgens circulate
bound to plasma proteins
• The plasma half-life of cortisol (60–90
minutes)
 Transportations of Adrenal hormones

• Cortisol transport: 10% as a free, 75% binds

to corticosteroid-binding globulin (CBG,
transcortin) and the remaining bind to
albumin
• plasma free cortisol level is approximately 1
µg/dL
• androgens bind chiefly to albumin
• Androstenedione, DHEA, and DHEA sulfate
circulate weakly bound to albumin.
• testosterone is bound extensively to a specific
globulin, sex hormone-binding globulin
(SHBG).
• Bound steroids are biologically inactive; the
unbound or free fraction is active
• plasma proteins may provide a pool of
circulating cortisol by delaying metabolic
clearance, thus preventing more marked
fluctuations of plasma free cortisol levels
Reasons why therapeutic use should be limited:

1) Persons using have limited ability to resist

infections
2) Other undesirable effects can occur with the
good ones such as: Gastric ulcers b) ↑blood
pressure c) atherosclerosis d) menstrual irreg.
3) High levels of exogenous corticosteroids can lead
to irreversible atrophy of the cortisol-secreting
cells of the adrenal gland and later permanent
inability of the body to produce cortisol.
Factors affecting Metabolism steroids
 Pathologies associated with Adrenal cortex
hormone secretion
A) Oversecretion of Adrenal Cortex Hormones
1) 1o Hyperaldosteronism – Conn’s syndrome –hypersecreting
adrenal tumor of zona glomerulosa; ↑ aldosterone with no
negative feedback. High Na+ and H2O retention
(hypernatremia) and low plasma K+(hypokalemia) which leads
to ↑↑ BP

2) 2o Hyperaldosteronism – produced by any condition that

causes a chronic reduction in arterial blood flow to the kidneys,
thereby excessively activating the
renin-angiotensin system. Ex. Is atherosclerotic narrowing of
the renal arteries. Similar results as in #1 above.
3) Cushing’s Disease – Hypersecretion of cortisol, so see exagerated
effects of cortisol which includes glucose excess (hyperglycemia)
and protein shortage. The excess glucose is deposited as fat so see
“moonface”, “buffalo hump” (fat above the shoulder blades),
spindly legs, fat in facial area or strange redistribution of fat.
Diabetogenic effect. Glycosuria occurs and the conditonis called
an adrenal diabetes.
• Could be due to a) oversecretion of CRH or ACTH causing
overstimulation of the adrenal cortex; or, b)adrenal tumors that
uncontrollably secrete cortisol independent of ACTH;
or, c)ACTH-secreting tumors located in places other than the
pituitary, most commonly the lung.
• Cushing's syndrome: increased cortisol
• increased glucose, decreased K, decreased lymphs, decreased
eos may be noted
• Cushing's disease (pituitary adenoma or microadenoma):
increased ACTH
• Adrenal cortical adenoma or carcinoma: decreased ACTH
(maybe....)
• Ectopic ACTH production (i.e., oat cell carcinoma, carcinoid,
thymoma, pheochromocytoma) or CRF production (oat cell,
rarely others)
• Iatrogenic (glucocorticoid therapy)
4) Adrenal Androgen Hypersecretion – excess adrenal androgen secretion could
either be a virilizing adenoma in females with too much testosterone produced.
Will give the female overdeveloped male characteristics such as hirsutism,
deepening voice and more muscular arms and legs. In males, it may show up as a
feminizing adenoma with too much estrogen but is very rare. This would give
males more female characteristics such as breasts that are more developed.

• If ↑androgens occur in prepubertal boys, it may cause premature secondary sex

characteristics such as deep voice, beard, enlarged penis and a sex drive. This is
not a true puberty. There will be no sperm production or other gonadal activity
because the testes are still not functioning. If it occurs in adult males, no effect
will be seen. Inherited condition.
B) Insufficiency of Adrenal Cortex Hormones
1) Primary adrenal insufficiency – called Addison’s Disease –
Hyposecretion of cortisol but all hormones of the cortex are
undersecreting. Most commonly due to idiopathic atrophy of the
adrenal gland. Could be an antibody
(autoimmune) that is attacking the adrenal cortex.
Hypoglycemic,cortisol ↓ as well as aldosterone↓, ACTH
↑(darkens skin due to ↑MSH as well from the same precursor
and cell), lethargy, poor response to stress, mimics depression and
misdiagnosed at times. Will see hyperkalemia and hyponatremia
with hypotension and if aldosterone low enough, can be very life-
threatening.
↑CRH →↑ACTH→(atrophied adrenal gland)
↓cortisol ,↓aldosterone.
2. Secondary adrenal insufficiency – This may be
due to a pituitary or hypothalamus
• abnormality with only a decrease in cortisol.
ACTH does not cause the release of aldo.
• No ACTH →↓cortisol only
Addison's disease: decreased cortisol (or decreased
ability to produce cortisol)
• decreased glucose, increased K, increased BUN
(prerenal azotemia) may be noted
• Primary addisonism (autoimmune, TB , after
steroid Rx, etc.): increased ACTH
• Secondary addisonism (hypopituitarism):
decreased ACTH
Source of ACT DHE DHEA cortiso aldost
CRH renin Na K Causes5
pathology H A -S l erone
tumor of the
hypothala
hypothalamus (adenoma),
mus' low low low low low3 low low low low
antibodies, environment,
('tertiary)1
head injury
tumor of the pituitary
pituitary (adenoma), antibodies,
(secondary high2 low low low low3 low low low low environment, head injury,
) surgical removal6,
Sheehan's syndrome
tumor of the adrenal
adrenal (adenoma), stress,
glands high high high high low4 low high low high antibodies, environment,
(primary)7 Addison's, injury, surgical
removal

1 Automatically includes diagnosis of secondary (hypopituitarism)

2 Only if CRH production in the hypothalamus is intact
3 Value doubles or more in stimulation
4 Value less than doubles in stimulation
5 Most common, doesn't include all possible causes
6 Usually because of very large tumor (macroadenoma)
7 Includes Addison's disease
• Thank You !