Cortical hormones

Noor Ullah
noor1.qau@gmail.com

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Cortical Hormones
•A hormone that is secreted by the anterior lobe of the pituitary gland and
controls the development and functioning of the adrenal cortex, including its
secretion of glucocorticoids and androgens
• Adrenal cortex
• Composed of 3 layers (zones):
• Outer zone (zona glomerulosa) produces aldosterone (mineralocorticoid)
• Middle zone (zona fasciculata) produces cortisol (glucocorticoid)
• Inner zone (zona reticularis) produces androgens
• These cells produce a group of hormones known as gonadocorticoids
• They are also regulated by ACTH
• Precursor androgens are turned into testosterone in testes and estrogen in
ovaries

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ADRENAL CORTEX: Zona Glomerulosa

• ‘Grape-like’ clusters of cells that lie just under the capsule

• Releases mineralocorticoids (steroid hormones of the adrenal cortex that
regulate electrolyte imbalance)
• Main mineralocorticoid = Aldosterone
• Aldosterone release is regulated by the renin-angiotensin-aldosterone system
• Aldosterone stimulates distal tubules of kidney to pump sodium across basal
membrane and thereby attract water
• In this way aldosterone helps us to conserve both sodium and water
• This raises extracellular fluid volume and hence blood pressure

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ADRENAL CORTEX: Zona Fasciculata
• The cells are arranged in cords (long rows) separated by capillaries
• Cells secrete Glucocorticoids
• Glucocorticoids are steroid hormones secreted by the adrenal cortex [corticosteroids] that affect the
metabolism of glucose, protein and fat
• Release of glucocorticoids is under the influence of adrenocorticotropic hormone [ACTH]
• ACTH is a hormone from the anterior pituitary gland that stimulates the adrenal cortex in response
to illness, injury, stress and ‘fight’ or ‘flight’ responses
• The main glucocorticoid in humans is CORTISOL which is responsible for 95% of all glucocorticoid
functions
• Cortisol raises blood glucose levels, thereby providing a source of energy for our responses to stress
(in the flight or fight reaction)
• Cortisol is also anti-inflammatory (‘Hydrocortisone’)
• (Cortex also produce corticosterone and cortisone – about 5% of its production)
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Main actions of cortisol
1. Gluconeogenesis (‘creation of new glucose’)
2. Providing resistance to stress
3. Anti-inflammatory
• Gluconeogenesis is the creation of new glucose from non-carbohydrate
sources i.e. the conversion of proteins and fat to glucose
• Glucocorticoids also promote the storage of glucose as glycogen and inhibit
glucose utilization (particularly in peripheral tissues)
• Both of these actions are essential for the maintenance of plasma glucose
levels especially during period of prolonged fasting and dieting
• Glucocorticoids promote lipolysis (breakdown of fat) and the consequent
release of free fatty acids into the blood for energy production
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CORTISOL: Providing resistance to stress
• When exposed to stress (e.g. trauma, hypoglycaemia, perceived life threatening
conditions )  anterior pituitary gland releases adrenocorticotrophic hormone (ACTH)
 adrenal cortex is stimulated to secrete glucocorticoids increase in available
glucose  making the body and brain more alert and provides the raw fuel for energy
production.
• CLINICAL POINT:
• If we are under constant stress we are continually breaking down fat for glucose.
• If we run away from the stressor we will use this fat up but if we do not the fat remains
in the blood stream and can damage blood vessels, narrowing them as fat deposits
lodge under the lining of the vessel walls.
• This can in turn lead to the formation of clots, and this, coupled with an already
increased blood coagulation can lead to potential for cerebrovascular accident (CVA –
‘stroke’) or heart disease

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Diurnal variation of cortisol levels

• In humans, the amount of cortisol present in the blood undergoes diurnal variation;
the level peaks in the early morning (around 8 am) and reaches its lowest level at
about midnight-4 am, or 3-5 hours after the onset of sleep.

• Cortisol levels are generally high in the morning as we wake from a prolonged period
of sleep, with an increase of up to 50% in the 20-30 minutes after waking.

• This is known as the ‘cortisol awakening response’.

• Then, as the day progresses, our cortisol levels naturally begin to drop in a fairly
constant and regular fashion that is termed as diurnal rhythm, ending up as low in the
late evening.
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Diurnal variation of cortisol levels

• This allows the body to keep a regular sleeping pattern, with the cortisol level
dropping for periods of sleep, then during the following morning.

• The body can also detect and change the timing and cycle of cortisol production
and release for certain individuals. replenishing

• A great example is those individuals who work on night shifts.

• In these cases, the pattern and timing of the release of cortisol is reversed to
allow for higher levels throughout the late evening and early morning hours.

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Regulation- HPA axis

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Adrenal Insufficiency (Addison’s Disease)

• Adrenal insufficiency (low cortisol) results from a primary adrenal problem (destruction
of 90% of the adrenal cortex) or is secondary to ACTH deficiency (abnormality at the
hypothalamic–pituitary level).

• Symptoms of deficiency can be vague and misleading.

• As cortisol is critical to normal glucose homeostasis and maintenance of vascular tone,

deficiency produces symptoms resembling failure to thrive, such as weakness, fatigue,
anorexia, nausea, diarrhea, and abdominal pain accompanied by physical findings such
as weight loss.

• Abnormal laboratory values include hyponatremia, hyperkalemia, hypercalcemia, pre

renal azotemia, and mild metabolic acidosis.
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Aetiology
• Autoimmune adrenalitis accounts for 70% of the cases of primary adrenal
insufficiency.
• TB (most common worldwide)
• infections – AIDS, fungal
• Adrenal haemorrhage (caused by sepsis, meningitis)
• Metastatic spread to adrenals
• Adrenalectomy
• Genetic/congenital defects
• Addison's = long term steroids leading to suppression of HPA axis

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Diagnosis of Adrenal Insufficiency
• Low baseline cortisol levels (8:00 AM) and an elevated ACTH greater than 200
pg/mL are suggestive of adrenal insufficiency.
• Random cortisol levels are only useful in excluding the diagnosis when elevated (>
20 ug/dL).
• Cosyntropin is a synthetic stimulator of cortisol and aldosterone secretion, which
tests the capacity of the adrenal gland to increase hormone production in response
to stimulation.
• It is safe and offers reliable results regardless of food intake or time of day.
• Lower serum concentrations of ACTH and cortisol are consistent with secondary
adrenal failure.
• Hypoglycemia is also a potent stimulator of cortisol secretion but potentially
dangerous.
• A stimulated free cortisol level less than 18 ug/dL indicates impaired adrenal
function.
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Diagnosis of Adrenal Insufficiency
• Following a blood draw for baseline cortisol, ACTH, and aldosterone levels,
Cosyntropin (IV/IM) is given.
• Repeat samples are drawn at 30 and 60 minutes post stimulation.
• The normal response after an ACTH injection is a rise in blood cortisol levels.
People with Addison’s disease and most people who have had secondary adrenal
insufficiency for a long time have little or no increase in cortisol levels. The
adrenal glands may be too damaged to respond to ACTH.
• The ACTH test may not be accurate in people who have had secondary adrenal
insufficiency for a shorter time because their adrenal glands have not yet shrunk
and can still respond to ACTH

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Diagnosis of Adrenal Insufficiency
• Metyrapone is used as an alternate diagnostic or confirmatory test for central
causes of adrenal insufficiency.
• Metyrapone administered orally at midnight will, in normal individuals, block 11
β-hydroxylase, increasing (11-deoxycortisol, 11-DOC) (> 7 ug/dL). while cortisol
decreases (<5 ug/dL).
• Patients suspected of having central adrenal insufficiency should be screened
with MRI of the brain to assess for pituitary disease unless they have a history of
chronic exogenous glucocorticoid use.

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Hypercortisolism
• Overproduction of CRH or of ACTH, adrenal glucocorticoid secretion and
exogenous intake cause hypercortisolism.
• Excess cortisol affects multiple systems, including immune (suppression, poor
healing), dermatologic (thin, friable tissue, wide purple Striae), vascular (vessel
fragility, ecchymoses), adipose (increased fat with redistribution to upper back
and central locations), muscle (wasting, proximal muscle weakness, heart failure),
neurologic (peripheral neuropathy, autonomic dysregulation), bone (loss), renal
(edema, HTN, calciuria), and metabolic (hyperglycemia and insulin resistance).
• Cortisol also has central nervous system actions, influencing pain perception and
sense of well-being.
• Clinical presentation of hypercortisolism is variable, with no single feature
common in all cases.

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Cushing’s syndrome

• Cushing's syndrome is a disorder that occurs when your body makes too much
of the hormone cortisol over a long period of time

• Cushing’s syndrome describes the array of signs and symptoms resulting from
excess glucocorticoid production or prolonged exogenous steroid use.

• The most common causes of Cushing’s syndrome are ACTH-secreting pituitary

adenoma (68%); autonomous cortisol production from an adrenal tumor (17%,
ACTH is suppressed); and excess ectopic ACTH or CRH production (15%, usually
malignant).

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Diagnosis of Cushing’s Syndrome
• Clinical symptoms are supported by laboratory findings of cortisol excess, loss of
diurnal rhythm, and suppression resistance (once exogenous glucocorticoid
administration is excluded because a universal diagnostic algorithm for Cushing’s
syndrome has not been established)
• (1) ACTH and cortisol are secreted in bursts and excess secretion may occur
episodically
• (2) each patient has unique metabolism, metabolites, and metabolic clearance
rates
• (3) stimulation and suppression thresholds often vary (non suppressible lesions
can occasionally be suppressed, and normal patients can display suppression
resistance)
• (4) compliance and accuracy issues regarding sample collection and processing
are common.
• Standard assessment tests for diagnosing Cushing’s syndrome are listed next.
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Diagnosis of Cushing’s Syndrome

• Urine free cortisol (and/or metabolites).

• Urine cortisol is a sensitive indicator of endogenous cortisolism.
• When serum cortisol exceeds the capacity of its carrier protein binding, free
cortisol levels rise rapidly, increasing the free cortisol filtered into the urine.
• This value may be erroneous with high urine volume (>3 L) because patients who
drink more than 5 L/day will have a 64% increase in urine cortisol.
• In contrast, urine 17-hydroxycorticosteroid (17-OHCS) excretion occurs at a
constant rate and is not affected by volume changes.
• A 24-hour urine free cortisol is the most sensitive (95%–100%) and specific
(98%) screen for excess cortisol production.
• A revised method, collecting overnight (10:00 PM–8:00 AM) urine samples for
cortisol factored by urinary creatinine, appears equally valid (specificity and
sensitivity of 97%–100%).
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Diagnosis of Cushing’s Syndrome

• Random plasma cortisol levels are of little value for the diagnosis of Cushing’s
syndrome.

• Levels in normal people vary widely during the day and overlap with levels found
in patients with Cushing’s syndrome.

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Determine if Diurnal Rhythm Is Lost (Late-Night Values Remain High)

• Plasma cortisol is highest between 6:00 and 8:00 AM and 50% to 80% lower
between 10:00 PM and 12:00 AM.
• Measuring late-night cortisol is justified by the fact that its normal evening nadir
is lost in Cushing’s syndrome and bilateral nodular hyperplasia but preserved in
obese and depressed patients.
• Ideally, a blood sample (for cortisol and ACTH) is drawn between 11:00 PM and
12:00 AM.
• Samples are stabilized, stored, and sent to the laboratory if the previously
determined urine cortisol is elevated.
• Late-evening saliva, serum free or serum total cortisol values may be more
reliable than urine cortisol for the diagnosis of Cushing’s syndrome.

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Hirsutism?

• Development of androgen-dependent terminal body hair in a woman in places

in which terminal hair is normally not found.

• Terminal body hairs are thick, dark, pigmented hairs normally seen in men on the
face, chest, abdomen and back

• A woman’s definition of hirsutism may differ depending on her ethnic origin and
her subjective view of normal body hair distribution
Hirsutism?

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Hirsutism- causes
• Increased production rate of androgens
• Found in nearly all hirsute women

• Usually testosterone, but serum testosterone might not be above the normal
range

• Increased conversion of testosterone to dihydrotestosterone in

peripheral tissue, including hair follicles
Hirsutism- causes
• Functional androgen excess disorders:
• Polycystic ovary syndrome (80%)
• Idiopathic hirsutism (10%)
• Specific identifiable disorders:
• Non-classic congenital adrenal hyperplasia
• Thyroid dysfunction
• Hyperprolactinaemia
• Hyperandrogenism, insulin resistance
• Virilising ovarian tumour
• Virilising adrenal tumour
• Hyperthecosis
• Cushing’s disease
• Acromegaly
• Drugs (danazol, testosterone, anabolic steroids, androgenic progestogens)
Idiopathic hirsutism
• Applies to women with hirsutism and no other clinical abnormalities
• No menstrual irregularity
• Serum androgens usually normal or only mildly elevated
• May be part of the PCOS spectrum
• Polycystic ovary syndrome (PCOS): Most common cause of androgen excess
• 6-8% women of reproductive age
• Evidence of hyperandrogenism and menstrual irregularity
• Rotterdam consensus criteria for diagnosis:
• 2 of the following:
1. Oligo-/amenorrhea
2. Clinical or biochemical hyperandrogenism
3. Characteristic appearance of ovaries by ultrasound
Physical examination
• Body habitus
• Hirsutism • Shape, weight, BMI

• Other signs of androgen excess • Breasts

• Galactorrhoea (milky nipple discharge)
• Acne, seborrhoea, temporal balding
• Skin
• Acanthosis nigricans
• Virilisation
• thin skin,
• Deep voice

• Android body shape

• BP
• Hypertension
• Frontal balding • Abdomen and pelvis
• Clitoromegaly (>10mm) • Mass lesions
Initial investigations

The clinical picture will determine the initial strategy

for investigations in women with hirsutism

Clinical picture Initial investigations

Long-standing hirsutism Serum testosterone

Long-standing hirsutism and irregular menstrual Serum testosterone, LH, FSH, prolactin
cycles

Short history of hirsutism or progressive hirsutism Serum testosterone,

Dehydroepiandrosterone (DHEA)
Further investigations
Planned according to clinical suspicion and results of
preliminary investigations
Indication Next investigations

Hirsutism + virilisation Transvaginal ultrasound to look for ovarian tumour

Testosterone >5nmol/L
DHEAS normal
Hirsutism + virilisation CT/MR adrenals to look for an adrenal tumour
Testosterone >5nmol/L
DHEAS elevated
Early-onset hirsutism Short Synacthen test to measure 17-
Testosterone >5nmol/L hydroxyprogesterone response or urine steroid
profiling to test for congenital adrenal hyperplasia

Clinical features of Low dose dexamethasone suppression test

Cushing’s syndrome