(M) Lec 4: Adrenal Glands (Intro & Cortisol) Flashcards
The adrenal glands are:
1. ____ in shape
2. Located ____ each kidney
3. Composed of distinct but conjoined glands, the outer adrenal ____ and the inner adrenal ____
- Pyramidal
- Above
- Cortex; Medulla
Structure and Synthesis of Cortical Hormones
The cortical hormones are composed of a basic structure known as a ____ ring, a 17C skeleton derived from cholesterol
Cyclopentanoperhydrophenanthrene (CP) Ring
Structure and Synthesis of Cortical Hormones
What is the parent cell of all steroid hormones?
Cholesterol
Structure and Synthesis of Cortical Hormones
G cells are able to convert cholesterol to ____ which is the precursor substance for androgens, cortisol, and aldosterone
Pregnenolone
Structure and Synthesis of Cortical Hormones
Cholesterol is converted to pregnenolone by what enzyme?
Cholesterol Desmolase
Structure and Synthesis of Cortical Hormones
- The cortical hormones are synthesized from what type of cholesterol?
- The cortical hormones will be delivered to the adrenals where it will be taken up by what receptors?
- LDL
- LDL Receptors
Structure and Synthesis of Cortical Hormones
The secretion of adrenal glucocorticoids (cortisol) and androgens (sex hormones) is regulated by the ____ hormone which is under the control of another hormone called, ____
- Adrenocorticotrophic hormone (ACTH)
- Corticotropin-Releasing Hormone (CRH); from the hypothalamus
Structure and Synthesis of Cortical Hormones
The mineralocorticoid secretion is controlled by the ____ system
Renin-Angiotensin-Aldosterone System (RAAS)
Cortisol has a hyper-____ effect but glucose is still elevated because it is a ____ agent
- Hyperinsulin
- Hyperglycemic
Structure and Synthesis of Cortical Hormones
Regulated by the ACTH, CRH, RAAS, or Neither?
1. Mineralocorticoids (aldosterone)
2. Glucocorticoids (cortisol)
3. Androgens (sex hormones)
4. Secretion of an adrenal hormone from the pituitary gland
5. Epinephrine and Norepinephrine
- RAAS
- ACTH
- ACTH
- CRH
- Neither (adrenal medulla)
What are the 2 stimulants of CRH?
- Low cortisol levels (positive feedback)
- Stress
The Adrenal Cortex
This zone makes up 10% of the adrenal cortex and is able to produce mineralocorticoids (aldosterone/salts)
Zona Glomerulosa (G-zone)
The Adrenal Cortex
This zone makes up 75% of the adrenal cortex and is able to produce glucocorticoids (cortisol/glucose)
Zona Fasciculata (F-zone)
The Adrenal Cortex
This zone makes up 15% of the adrenal cortex and is able to produce weak androgens (sex hormones)
Zona Reticularis (R-zone)
- The principal and most important glucocorticoid produced by the adrenal cortex
- Its synthesis is regulated by ACTH from the pituitary gland
Cortisol
Cortisol circulates as predominantly bound to this corticosteroid binding globulin
Transcortin
- If cortisol promotes lipolysis and gluconeogenesis, it (increases/decreases) blood glucose levels during stress
- Cortisol functions in a (positive/negative) feedback loop as the only adrenal hormone that inhibits ACTH secretion
- Increases
- Negative
- Cortisol is a valuable therapeutic agent for ____ conditions such as RA, SLE, and MS
- Cortisol exhibits a diurnal secretion pattern with the highest levels observed in the ____ while the lowest levels are observed in the ____
- Inflammatory
- Early morning (6-7AM); Night (11PM-12MN)
Urinary Metabolites of Cortisol
- Measured by the PORTER SILBER method
- Phenylhydrazine in H2SO4 produces a ____ end color
17-Hydroxycorticosteroid (Yellow)
Urinary Metabolites of Cortisol
- Measured by the ZIMMERMAN reaction
- Meta-dinitrobenzene undergoes the Norymberski oxidation procedure to produce a ____ end color
17-Ketogenic Steroids (Reddish Purple)
Cortisol as a Sample
- If collecting serum, use a ____ top tube
- If collecting plasma, use an ____ tube
- Aside from blood, what are the 2 other sample types?
- Red
- EDTA
- 24H urine and Saliva
Cortisol as a Sample
This type of cortisol is a sensitive indicator of adrenal hyperfunction
Urine Free Cortisol
Cortisol as a Sample
Blood samples should be drawn at this time as it is when the cortisol level reaches its equilibrium level or value in the blood (consider the diurnal pattern of cortisol)
8 to 10AM
Cortisol as a Sample
Match the Specimen to the Testing Method:
1. Serum and Saliva Cortisol
2. Urine Free Cortisol
3. Alternative to the routine method
4. Reference method
A. HPLC-MS/MS
B. Immunoassay
C. LC-MS/MS
D. GC-MS/MS
- (B) - Immunoassay
- (D) - GC-MS/MS
- (C) - LC-MS/MS
- (A) - HPLC-MS/MS
Clinical Disorders of Cortisol
- A form of hypercortisolism primarily caused by the excessive production of cortisol and ACTH (although it is ACTH independent)
- Also caused by the overuse of corticosteroidal drugs
- Manifestations include: truncal obesity, hirsutism, a “buffalo hump,” and others
Cushing’s Syndrome
Clinical Disorders of Cortisol
A type of Cushing’s Syndrome caused by depression and excessive alcohol intake
Pseudo-Cushing’s
Tests for Cushing’s Syndrome
Screening or Confirmatory?
- 24H urinary free cortisol
- Overnight dexamethasone suppression test
- Midnight salivary test
Screening
Tests for Cushing’s Syndrome
Screening or Confirmatory?
- Low dose dexamethasone suppression test
- Midnight plasma cortisol
- CRH stimulation test
Confirmatory
Tests for Cushing’s Syndrome
- The most specific and sensitive screening test for adrenal hyperfunction
- A positive result is a urine free cortisol level of more than (>) 120 µg/day
24-hour urinary free cortisol
Tests for Cushing’s Syndrome
What causes a false positive (+) in the 24-hour urinary free cortisol?
Urine cortisol level of greater than (>) 3L
Tests for Cushing’s Syndrome
- 1mg of dexamethasone (which suppresses ACTH) is orally given between 11pm to 12 midnight
- Blood is collected the following day between 8am to 9am (urine may also be tested for 17-OHCS)
- Negative result: cortisol is less than (<) 1.8µg/dL
- Positive result: cortisol levels are not suppressed
Overnight/Rapid Dexamethasone Suppression Test
Tests for Cushing’s Syndrome
- There is a cotton roll or sponge roll that the patient needs to lightly chew so that saliva will accumulate in the cotton
- Must be collected between 11pm to 12mn
Midnight Salivary Test
Tests for Cushing’s Syndrome
- 0.5mg of dexamethasone (which suppresses ACTH) is orally given every 6 hours for 48 hours
- 24-hour urine and serum samples are collected
- Negative result: cortisol is less than (<) 1.8µg/dL and urine free cortisol is less than (<) 10µg/24 hours on the second day of the dose
- Positive result: serum and urine cortisol levels are not suppressed
Low-Dose Dexamethasone Suppression Test
Tests for Cushing’s Syndrome
- Day 1: 8mg of dexamethasone (which suppresses ACTH) is given between 11pm to 12mn
- Plasma is collected at 8am
- Day 2: 2mg is administered every 6 hours for 48 hours
- 24 hour urine free cortisol is measured
High-Dose Dexamethasone Suppression Test
Tests for Cushing’s Syndrome
This test differentiates ACTH-dependent hypercortisolism from ACTH-independent (ectopic) hypercortisolism
High-Dose Dexamethasone Suppression Test
Tests for Cushing’s Syndrome
What is the source of the hypercortisolism if serum cortisol is less than (<) 5µg/dL or if it is suppressed by more than (>) 50% from the baseline?
Pituitary Gland (ACTH-dependent)
Tests for Cushing’s Syndrome
- The gold standard for determining the source of ACTH production
- IPS ACTH and blood ACTH are measured
Inferior Petrosal Sinus Sampling (IPSS)
Tests for Cushing’s Syndrome
What is the source of ACTH production if:
- IPS ACTH and blood ACTH ratio is > 2:1
- IPS ACTH and blood ACTH ratio is > 3:1 (after CRH stimulation)
Pituitary Gland
Tests for Cushing’s Syndrome
- This directly measures the amount of midnight (lowest) plasma cortisol
- Positive result: cortisol level is greater than (>) 5.0 ug/dL
Midnight Plasma Cortisol
Types of Adrenal Insufficiency
- There is a destruction of over 90% of the adrenal cortex leading to decreased cortisol production
- Leads to aldosterone deficiency as well
- There is excess ACTH release due to the negative feedback mechanism
Primary Hypocortisolism
Diseases of Primary Hypocortisolism
- Presents with hypotension, hyponatremia, hyperkalemia, weight loss, and hyperpigmentation
- Due to autoimmune adrenalitis, TB, and HIV/AIDS
- The hyponatremia and hyperkalemia are caused by low aldosterone levels which is responsible for sodium retention
Addison’s Disease
Note: ACTH communicates with the MSH to produce pigmentation
Diseases of Primary Hypocortisolism
What is the pathognomonic feature of Addison’s Disease?
Presence of F21-hydroxylase autoantibodies (21-OH-AA)
Diseases of Primary Hypocortisolism
What is the screening test for Addison’s Disease and what are the interpreptations for a positive result?
- Screening test: ACTH Stimulation
- Positive result: Increased ACTH with decreased cortisol and aldosterone (no changes)
Types of Adrenal Insufficiency
- Due to hypothalamic-pituitary insufficiency with a loss of ACTH
- There is no problem with the mineralocorticoid (aldosterone) secretion
- Presents with absence of hyperpigmentation
- Caused by pituitary tumors/surgeries, Sheehan’s syndrome, and bacterial infections
Secondary Hypocortisolism
Diseases of Secondary Hypocortisolism
What is the screening test for Secondary Hypocortisolism and what are the interpreptations for a positive result?
- Screening test: ACTH Stimulation
- Positive result: Delayed response to stimulation (decreased ACTH and cortisol)
Types of Adrenal Insufficiency
- Related to defective hypothalamic release of corticotropin-releasing hormone (CRH) with decreased production of ACTH
- Mostly drug-induced or caused by the overuse of synthetic glucocorticoids
- Can be caused by hypothalamic tumors or surgeries, bacterial infections, or can be drug-induced
Tertiary Hypocortisolism
Diseases of Tertiary Hypocortisolism
What are the levels of cortisol, ACTH, and CRH in tertiary hypocortisolism?
All decreased
Diagnostic Tests for Hypoadrenalism/Adrenal Insufficiency
- This determines the capacity of the adrenal gland to increase hormone production in response to stimulation
- Requires the administration of 250ug of Cosyntropin (IV or IM)
- Negative result: cortisol levels greater than (>) 18-20µg/dL at any time of the day
- Positive result: cortisol levels less than 18µg/dL
ACTH/Cosyntropin (synthetic ACTH) Stimulation Test
Diagnostic Tests for Hypoadrenalism/Adrenal Insufficiency
- This measures the ability of the pituitary gland to respond to declining levels of circulating cortisol
- Is performed when ACTH stimulation test results are normal
Metyrapone Test
Diagnostic Tests for Hypoadrenalism/Adrenal Insufficiency
The Metyrapone Test blocks the ____ enzyme which does the ff.:
- Increases ____ by greater than 7µg/dL
- Decreases ____ by less than 5µg/dL
- 11B-hydroxylase
- 11-deoxycortisol
- Cortisol
Diagnostic Tests for Hypoadrenalism/Adrenal Insufficiency
- The confirmatory test for hypoadrenalism
- The gold standard for differentiating secondary from tertiary hypoadrenalism
- Used to confirm a borderline response to the ACTH stimulation test
Insulin Tolerance Test
Diagnostic Tests for Hypoadrenalism/Adrenal Insufficiency
- Hypoglycemia is induced by administering 0.05 U/kg of insulin (a natural stessor for the body)
- Negative result: cortisol levels are greater than 18-20µg/dL at anytime of the day
- Positive result: cortisol levels are still decreased
Insulin Tolerance Test
Diseases of the Adrenal Gland
- Results from deficiency of 21-hydroxylase, 11B-hydroxylase, and 3B hydroxysteroid dehydrogenase isomerase
- 24-hour urinary free cortisol is not a consistent sample as this disease affects newborns
- Manifestations include: atypical sexual development, hirsutism, infertility, and salt wasting
Congenital Adrenal Hyperplasia (CAH)
Diseases of the Adrenal Gland
What are the 2 definitive tests for Congenital Adrenal Hyperplasia?
- 17-OHP (17-hydroxyprogesterone) measurement in amniotic fluid
- Genotyping of cells from chorionic villous sampling
Types of Congenital Adrenal Hyperplasia
- Most common form
- Elevated levels of 17alpha-hydroxyprogesterone (17-OHP) and urinary excretion of pregnanetriol are indicative of this disorder
- Symptoms caused by excess androgen levels are: virilization, infertility, amenorrhea, and hirsutism
21-Hydroxylase Deficiency
Types of Congenital Adrenal Hyperplasia
What gene is defective in 21-Hydroxylase Deficiency?
CYP21
Types of Congenital Adrenal Hyperplasia
What 2 tests are used for 21-Hydroxylase Deficiency?
- ACTH Stimulation Test
- 17A-Hydroxyprogesterone Test
Types of Congenital Adrenal Hyperplasia
- Second most common form
- Increased levels of 11-deoxycortisol are indicative of this disorder
- Associated with virilization and hypertension
11B-Hydroxylase Deficiency
Types of Congenital Adrenal Hyperplasia
This deficiency results in:
- An elevated ratio of 17 alpha-hydroxylpregnenolone
- An increased ratio of DHEA to androstenedione
- Characterized by pseudohermaphroditism in females and incomplete masculinization in males
3B Hydroxysteroid Dehydrogenase Isomerase Deficiency
Types of Congenital Adrenal Hyperplasia
Characterized by the inability to convert:
- 17 alpha-hydroxypregnenolone to DHEA
- 17 alpha-hydroxyprogesterone to androstenedione
- In females, there is absence of menstruation and defective ovarian maturation
- In males, there is pseudohermaphroditism
C-17,20-Lyase/17 Alpha-Hydroxylase Deficiency
