What does the HPA axis refer to?
Describe the HPA axis in terms of cortisol
- Hypothalamus CRH (corticotropin releasing hormone)
- Pituitary ACTH (adreno-corticotropic hormone)
- Adrenal cortisol
What is ACTH?
- Half life
- Other products
- 39 AA peptide
- Plasma half life
- Derived from POMC (pro-opiomelanocortin)
Other POMC products:
Cortisol is a glucocorticoid.
What are some synthetic glucocorticoids?
What is Cushing's syndrome?
- Manifestation of glucocorticoid (cortisol) excess
- Multiple systems affected through the widespread effect of glucocorticoids on gene expression
- Receptors present in every cell in the body
What is the basic model of steroid receptors?
- Conformation change
- Nuclear translocation
- DNA binding
What are common signs/symptoms of Cushing's disease?
- Truncal obesity (96%)
- Moon facies (82%)
- Diabetes or IGT (80%)
- Gonadal dysfunction (74%)
- Hirsutism/acne (72%)
- Hypertension (68%)
- Muscle weakness/atrophy (64%)
- Skin atrophy and bruising (62%)
- Phenomenal striae (where there has been fat gained) Many others; most are non-specific
- None are pathognomonic
What is seen here, characteristic of Cushing's disease?
- Cushingoid facies
- Round, red face (plethora)
What is seen here, characteristic of Cushing's disease?
- Truncal obesity with supraclavicular and dorsocervical fat pads
What is the characteristic body mass/distribution in Cushing's?
Central adiposity with peripheral muscle wasting
- Weight gain and fat redistribution
- Increased appetite
- Increased central fat deposition (deposition in the abdomen, dorsocervical and supraclavicular areas as well as retrorobital and face)
- Muscle wasting and weakness catabolic
- Degradation of proteins
What are skin changes in Cushing's?
- Catabolism of proteins making up underlying subcutaneous connective tissue
- Leads to fragility and easy bruising (thin skin and fragile blood vessels)
Striae (> 1 cm in width)
- Caused by weight gain
- Violacious color due to thinning of subcutaneous layers of the skin (can see venous blood underneath)
- Light or trauma exposed areas: pro-opiomelanocortin, ACTH
- Insulin resistance
- Diabetes mellitus
What glucose level changes are seen in Cushing's?
- Increased hepatic glucose output
- More muscle AAs available as a substrate to make glucose (gluconeogenesis)
- Decreased glucose uptake into tissues (insulin resistance)
What affect does Cushing's syndrome have on the adrenals?
- Adrenal androgen synthesis is increased by ACTH
How does Cushing's cause hypertension?
Cortisol can activate the aldosterone receptor
- normally endogenous cortisol is inactivated by an enzyme in the kidney (11-b-hydroxy-dehydrogenase type 2). High levels of cortisol overwhelm the enzyme.
May be accompanied by
- metabolic alkalosis
Increased vascular reactivity to vasoconstrictors
What is seen in Cushing's in regards to gonadal function?
- Decreased sex hormone production
- GnRH pulsatility affected
- androgen feedback in women?
- Oligo- and amenorrhea Impotence/decreased libido
With glucocorticoid therapy, there is an increased fracture risk when?
- Due to what?
- How does this tie in with renal effects?
With glucocorticoid therapy, there is an increased fracture risk at 3 - 6 mo
- Increased bone resorption
- Positive effects on osteoclast activity
- Decreased gonadal hormones
- Decreased bone formation
- Inhibit osteoblasts
- Increased osteoblast apoptosis
- Muscle weakness
Decreased intestinal Ca absorption
Increased renal Ca excretion
- increased calcium mobilization from bone
- direct effects on kidney
T/F: Cushing's syndrome involves increased infections
How does Cushing's syndrome cause increased infections?
Inhibition of inflammatory cytokines
- Decreased fever, signals to fight infection
- Decreased neutrophil adhesion molecules so less accumulation at sites of infection
- Decreased macrophage phagocytosis
- Opportunistic infections (PCP, TB)
What are some psychiatric disorders seen in Cushing's syndrome?
- Lack of diurnal rhythm
- Family history at higher risk
Long term glucocorticoid excess may cause what?
- Gastritis and peptic ulcer disease
What is exogenous hypercortisolism/what causes it?
Medication induced CS
- Exogenous corticosteroids (glucocorticoids)
- Iatrogenic: oral, IM, IA, inhaled, topical eye and skin
- Megestrol acetate (Megace)
- Surreptitious glucocorticoid use (synthetic glucocorticoids in urine by HPLC/gas chromatography)
- "Herbal" medications
What can cause endogenous hypercortisolism (broad categories)?
- Pituitary (65-75%)
- Ectopic (10-15%)
- Adrenal (15-20%)
Ectopic ACTH (and or CRH), what are the common tumor sources? Uncommon?
- Bronchial & thymic carcinoid
- Small cell lung cancer
- Thyroid Cancer
- Pancreatic islet tumors
- Ovarian ca
What can produce ACTH independent Cushing's?
- Adrenal adenoma
- Adrenocortical carcinoma
- Macronodular hyperplasia
- Micronodular disease
- Primary pigmented nodular adrenocortical disease (Carney complex)
T/F: Imaging should be one of the first things done to help diagnose with Cushing's.
- Pituitary adenomas are found in 10-20% of people; not conclusive
What are some tests for Cushing's (clinical features)?
Decreased feedback inhibition -> O/N 1 mg Dexamethasone (synthetic steroid) suppression test
- "Low dose DST"
- Problems include pt variation in: absorption, compliance, and clearance
Over production -> 24 hr urine free cortisol (1 to 3x)
- Cyclical Cushing's
- Cortisol in urine means it's spilled over its protein binder; have very high amounts
Lack of diurnal rhythm -> midnight serum cortisol
- (not low at midnight)
T/F: AM or random cortisol can be used if other tests are not available
Unless extremely high, this really can't help; diurnal variation is too great
When is serum cortisol lowest?
Describe the 2 day low dose dex suppression test
- 48 hrs of Dex (0.5 mg every 6 hrs) will suppress cortisol
- To "pass" test, cortisol should be
What is Pseudo-Cushing's?
- Abnormal CRH secretion
- Abnormal Circadian rhythms -> hypercortisolism
- Overnight DST positives
- Interference with metabolism and steroidogenic pathways (11B-HSD)
What test can be done to distinguish Cushing's and Pseudo-Cushing's?
Dexamethasone suppressed CRH stimulation test
- 48 hrs of Dex (0.5 mg q 6hrs) will suppress normally in most Pseudo-Cushing's pts so there is no stimulation by 100 ug of CRH IV
- A CD patient will still respond to CRH because of aberrant feedback inhibition
- Serum cortisol > 1.4 ng/dL
What do you think/do if:
- Hypercortisolism is confirmed
- Am ACTH is undetectable
- Low ACTH levels
- Adrenal CT (4 mm)
What do you think/do if:
- Hypercortisolism is confirmed
- Am ACTH is > 20 pg/mL
- High ACTH levels
- MRI pituitary protocol (Gad enhanced)
How to determine pituitary vs. ectopic ACTH?
ACTH dependent causes you to do MRI; possible results:
- > 5mm adenoma
- Likely Cushing's disease
- NSx referral
- > 5 mm adenoma
- "Ectopic presentation"
- Normal or equivocal (under 5mm)
- Further testing!
Treatment for Cushing's disease?
Next step for ectopic Cushing's?
Image thorax, neck, abdomen
Describe CRH stimulation
- Injection of 1 mcg/kg CRH (to max 100 mcg) at time 0
- Test ACTH and cortisol levels 0, 15, 30, 45, 60 minutes
- A variety of cutoffs in the literature
- Human vs Ovine CRH
- Depending on sensitivity and specificity
- 50% rise in ACTH is often used with smaller responses by cortisol.
48 hours of Dex (2 mg every 6 hrs) will do what to cortisol? ACTH?
- Cortisol to
- ACTH to
Cushing's disease confirmed if it ___ with CRH and ___ with high dose dexamethasone
Cushing's disease confirmed if it stimulates with CRH and suppresses with high dose dexamethasone
Ectopic Cushing's disease though if it ____ with CRH and ___ with high dose dexamethasone
Ectopic Cushing's disease though if it cannot be stimulated with CRH and does not suppress with high dose dexamethasone
What should you do if you get discordant results?
Cushing's/ectopic is unclear; IPSS (Inferior Petrosal Sinus Sampling) should be used
- Central ACTH: peripheral ACTH > 2 baseline or > 3 CRH stimulated
- Lateralization > 1.4 (left)
Pearl: a normal person may show similar ratios.... only useful in proven hypercortisolism where ACTH should be suppressed at the pituitary level
Pearl for MRI in diagnosis of Cushing's
Gad enhanced mRI is max 60% sensitive in identifying a pituitary adenoma in suspected CD
What are treatment options for Cushing's disease?
- Craniotomy for larger invasive tumors
- Metyrapone (available only on compassionate grounds)
- Aminoglutethamide (not available anymore in US)
- Mitotane (destroys adrenal tissue – adrenocortical carcinoma)
- NEW!!! Mifipristone (RU486) – glucocorticoid receptor antagonist
- Gamma knife
- Risk for Nelson's disease (radiation of sella first)
What is Nelson's disease?
- Uncontrolled growth of residual ACTH producing pituitary tumor due to lack of feedback by cortisol
What can cause hypopituitarism?
- Peripartum hypoTN with infarction (Sheehan's)
- Pituitary apoplexy
- External beam radiation
- Granulomatous diseases (Sarcoidosis, eosinophilic)
- Langerhan's cell histiocytosis
- Fungal infections
- Pituitary adenoma
- Metastastic carcinoma
- Hematologic (leukemia, lymphoma infiltration)
- Mutations of pituitary developmental TFs
- Lymphocytic hypophysitis
- Car accident
- Transphenoidal resection of pituitary adenoma
What is pituitary apoplexy? Cause?
Hemorrhage into pituitary (often a lesion such as an adenoma that is already there)
- Acute, catastrophic (30% of "hemorrhagic" adenomas)
- Headache (90%)
- Visual disturbance (75%)
- N/V (60%)
- Silent asymptomatic (70% of "hemorrhagic" adenomas)
- Spontaneous "cures"
- Empty sella
Treatment for pituitary apoplexy?
- ICU Care
- IV fluids
- High dose IV corticosteroids – assume adrenal insufficiency
- Craniotomy and decompression of pituitary fossa (save vision!!!!)
- Post-op evaluation for pituitary hormone deficiencies (ITT) and appropriate hormone replacement.
What are endocrine manifestations of post-pituitary apoplexy?
(by percent deficiency)
1. GH (88% deficient)
2. H-P-Adrenal (66%)
3. Reproductive: sex steroids (85%), gonadotropins LH/FSH (58%)
4. H-P-thyroid (42%)
5. ADH- diabetes insipidus (3%, rare b/c lesion in anterior pituitary)
6. Prolactin (?%)
What are ways to assess pituitary hormone deficiencies: H-P-A axis
- Insulin Tolerance Test (ITT)
- ACTH stimulation test, cortisol levels
What are ways to assess pituitary hormone deficiencies: GH axis
- GHRH-arginine stimulation
- Glucagon stimulation
What are ways to assess pituitary hormone deficiencies: H-P-G axis?
- LH, FSH
- Testosterone or estrogen
What are ways to assess pituitary hormone deficiencies: H-P-T axis?
What are ways to assess pituitary hormone deficiencies: Prolactin
What is the insulin tolerance test (ITT) and how does it work?
Test for pituitary hormone deficiencies in the H-P-A axis
- Based on the counter-regulatory roles of insulin vs. cortisol and GH
- Need physician supervision and no history of seizure disorder
Run labs for:
Give pt dextrose or PO orange juice
How should ITT be interpreted?
- Plasma glucose should be 35-45 mg/dL
- Cortisol should be > 18-22 mcg/dL
- (ACTH should be > 150)
- GH should be > 5.1 ng/mL (9 ng/mL)
Glucagon stimulation (3 hrs) and GH should be > 3 ng/mL
How should hormone replacement be managed for hypo-pituitary function?
- Adrenal: hydrocortisone divided doses (e.g. 20 mg in the morning, 10 mg in the afternoon)
- Thyroid: daily T4 replacement
- Testosterone (patch, gel, injection)
- GH (case by case basis)
- Diabetes insipidus: DDAVP