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MS2 Endocrine > 10/6- Diseases of the Anterior Pituitary 2 > Flashcards

10/6- Diseases of the Anterior Pituitary 2 Flashcards

1
Q

What does the HPA axis refer to?

A

Hypothalamo-pituitary-adrenal axis

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2
Q

Describe the HPA axis in terms of cortisol

A
  • Hypothalamus CRH (corticotropin releasing hormone)
  • Pituitary ACTH (adreno-corticotropic hormone)
  • Adrenal cortisol
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3
Q

What is ACTH?

  • Half life
  • Source
  • Other products
A

Adrenocorticotropin

  • 39 AA peptide
  • Plasma half life < 20 min
  • Derived from POMC (pro-opiomelanocortin)

Other POMC products:

  • a-MSH
  • B-MSH
  • Lipotropins
  • Etc
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4
Q

Cortisol is a glucocorticoid.

What are some synthetic glucocorticoids?

A
  • Prednisone
  • Methylprednisone
  • Dexamethasone
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5
Q

What is Cushing’s syndrome?

A
  • 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
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6
Q

What is the basic model of steroid receptors?

A
  • Conformation change
  • Nuclear translocation
  • Dimerization
  • DNA binding
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7
Q

What are common signs/symptoms of Cushing’s disease?

A

- 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
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8
Q

What is seen here, characteristic of Cushing’s disease?

A
  • Cushingoid facies
  • Round, red face (plethora)
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9
Q

What is seen here, characteristic of Cushing’s disease?

A
  • Truncal obesity with supraclavicular and dorsocervical fat pads
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10
Q

What is the characteristic body mass/distribution in Cushing’s?

A

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
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11
Q

What are skin changes in Cushing’s?

A

Skin atrophy

Ecchymoses

  • 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)

Hyperpigmentation

  • “Dusky”
  • Light or trauma exposed areas: pro-opiomelanocortin, ACTH

Acanthosis

  • Insulin resistance
  • Diabetes mellitus
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12
Q

What glucose level changes are seen in Cushing’s?

A

Elevated glucose

- Increased hepatic glucose output

  • More muscle AAs available as a substrate to make glucose (gluconeogenesis)

- Decreased glucose uptake into tissues (insulin resistance)

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13
Q

What affect does Cushing’s syndrome have on the adrenals?

A

Hyperandrogenism

  • Adrenal androgen synthesis is increased by ACTH
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14
Q

How does Cushing’s cause hypertension?

A

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

  • hypokalemia
  • hypernatremia
  • metabolic alkalosis

Increased vascular reactivity to vasoconstrictors

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15
Q

What is seen in Cushing’s in regards to gonadal function?

A

Gonadal dysfunction:

  • Decreased sex hormone production
  • GnRH pulsatility affected
  • androgen feedback in women?
  • Oligo- and amenorrhea Impotence/decreased libido
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16
Q

With glucocorticoid therapy, there is an increased fracture risk when?

  • Due to what?
  • How does this tie in with renal effects?
A

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
  • nephrolithiasis
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17
Q

T/F: Cushing’s syndrome involves increased infections

A

True

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18
Q

How does Cushing’s syndrome cause increased infections?

A

Inhibition of inflammatory cytokines

  • Decreased fever, signals to fight infection

Fungal/yeast, bacterial

Phagocytes

  • Decreased neutrophil adhesion molecules so less accumulation at sites of infection
  • Decreased macrophage phagocytosis

T cells

  • Opportunistic infections (PCP, TB)
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19
Q

What are some psychiatric disorders seen in Cushing’s syndrome?

A

Insomnia

  • Lack of diurnal rhythm

Cognitive impairment

Depression

  • Family history at higher risk

Emotional lability

Euphoria, hypomania

Psychosis

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20
Q

Long term glucocorticoid excess may cause what?

A
  • Cataracts
  • Glaucoma
  • Gastritis and peptic ulcer disease
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21
Q

What is exogenous hypercortisolism/what causes it?

A

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
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22
Q

What can cause endogenous hypercortisolism (broad categories)?

A

ACTH- dependent

  • Pituitary (65-75%)
  • Ectopic (10-15%)

ACTH- independent

  • Adrenal (15-20%)
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23
Q

Ectopic ACTH (and or CRH), what are the common tumor sources? Uncommon?

A

Neuroendocrine (common)

  • Bronchial & thymic carcinoid
  • Small cell lung cancer
  • Medullary
  • Thyroid Cancer
  • Pheochromocytoma
  • Pancreatic islet tumors
  • Gastrinoma

Uncommon

  • Neuroblastoma
  • Breast
  • Prostate
  • Ovarian ca
24
Q

What can produce ACTH independent Cushing’s?

A

- Adrenal adenoma

- Adrenocortical carcinoma

  • Macronodular hyperplasia
  • Micronodular disease
  • Primary pigmented nodular adrenocortical disease (Carney complex)
25
Q

T/F: Imaging should be one of the first things done to help diagnose with Cushing’s.

A

False

  • Pituitary adenomas are found in 10-20% of people; not conclusive
26
Q

What are some tests for Cushing’s (clinical features)?

A

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)
  • Salivary
27
Q

T/F: AM or random cortisol can be used if other tests are not available

A

False!

Unless extremely high, this really can’t help; diurnal variation is too great

28
Q

When is serum cortisol lowest?

A

Midnight

29
Q

Describe the 2 day low dose dex suppression test

A
  • 48 hrs of Dex (0.5 mg every 6 hrs) will suppress cortisol
  • To “pass” test, cortisol should be < 1.8 mcg/dL
30
Q

What is Pseudo-Cushing’s?

  • Symptoms
A

Depression

  • Abnormal CRH secretion
  • Abnormal Circadian rhythms -> hypercortisolism

Obesity

  • Overnight DST positives

Alcohol

  • Interference with metabolism and steroidogenic pathways (11B-HSD)
31
Q

What test can be done to distinguish Cushing’s and Pseudo-Cushing’s?

A

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
32
Q

What do you think/do if:

  • Hypercortisolism is confirmed
  • Am ACTH is undetectable
  • Low ACTH levels
A

Image adrenals

  • Adrenal CT (4 mm)
33
Q

What do you think/do if:

  • Hypercortisolism is confirmed
  • Am ACTH is > 20 pg/mL
  • High ACTH levels
A

Image pituitary

  • MRI pituitary protocol (Gad enhanced)
34
Q

How to determine pituitary vs. ectopic ACTH?

A

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!
35
Q

Treatment for Cushing’s disease?

A

Transphenoidal resection

36
Q

Next step for ectopic Cushing’s?

A

Image thorax, neck, abdomen

37
Q

Describe CRH stimulation

A
  • 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.
38
Q

48 hours of Dex (2 mg every 6 hrs) will do what to cortisol? ACTH?

A

Suppress

  • Cortisol to < 5
  • ACTH to < 5
39
Q

Cushing’s disease confirmed if it ___ with CRH and ___ with high dose dexamethasone

A

Cushing’s disease confirmed if it stimulates with CRH and suppresses with high dose dexamethasone

40
Q

Ectopic Cushing’s disease though if it ____ with CRH and ___ with high dose dexamethasone

A

Ectopic Cushing’s disease though if it cannot be stimulated with CRH and does not suppress with high dose dexamethasone

41
Q

What should you do if you get discordant results?

A

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

42
Q

Pearl for MRI in diagnosis of Cushing’s

A

Gad enhanced mRI is max 60% sensitive in identifying a pituitary adenoma in suspected CD

43
Q

What are treatment options for Cushing’s disease?

A

Surgical removal

  • Transsphenoidal
  • Craniotomy for larger invasive tumors

Adrenalytic Rx

  • Ketoconazole
  • Metyrapone (available only on compassionate grounds)
  • Aminoglutethamide (not available anymore in US)
  • Mitotane (destroys adrenal tissue – adrenocortical carcinoma)
  • NEW!!! Mifipristone (RU486) – glucocorticoid receptor antagonist

Radiation

  • EBRT
  • Gamma knife

Adrenalectomy

  • Risk for Nelson’s disease (radiation of sella first)
44
Q

What is Nelson’s disease?

A
  • Uncontrolled growth of residual ACTH producing pituitary tumor due to lack of feedback by cortisol
  • Hyperpigmentation
45
Q

What can cause hypopituitarism?

A

Vascular:

  • Peripartum hypoTN with infarction (Sheehan’s)
  • Pituitary apoplexy

Iatrogenic

  • External beam radiation

Infectious/Inflammatory/Infiltrative:

  • Granulomatous diseases (Sarcoidosis, eosinophilic)
  • Langerhan’s cell histiocytosis
  • TB
  • Fungal infections
  • Hemachromatosis

Neoplastic

  • Pituitary adenoma
  • Craniopharyngiomas
  • Metastastic carcinoma
  • Meningiomas
  • Germinomas
  • Hematologic (leukemia, lymphoma infiltration)

Congential

  • Mutations of pituitary developmental TFs

Autoimmune

  • Lymphocytic hypophysitis

Trauma/surgery

  • Car accident
  • Craniotomy
  • Transphenoidal resection of pituitary adenoma
46
Q

What is pituitary apoplexy? Cause?

A

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
  • Cysts
47
Q

Treatment for pituitary apoplexy?

A
  • 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.
48
Q

What are endocrine manifestations of post-pituitary apoplexy?

A

(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 (?%)
49
Q

What are ways to assess pituitary hormone deficiencies: H-P-A axis

A
  • Insulin Tolerance Test (ITT)
  • ACTH stimulation test, cortisol levels
50
Q

What are ways to assess pituitary hormone deficiencies: GH axis

A
  • ITT
  • GHRH-arginine stimulation
  • Glucagon stimulation
51
Q

What are ways to assess pituitary hormone deficiencies: H-P-G axis?

A
  • LH, FSH
  • Testosterone or estrogen
52
Q

What are ways to assess pituitary hormone deficiencies: H-P-T axis?

A
  • TSH
  • T4
53
Q

What are ways to assess pituitary hormone deficiencies: Prolactin

A

Prolactin

54
Q

What is the insulin tolerance test (ITT) and how does it work?

A

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:

  • Cortisol
  • GH
  • (ACTH)

Give pt dextrose or PO orange juice

55
Q

How should ITT be interpreted?

A
  • 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

56
Q

How should hormone replacement be managed for hypo-pituitary function?

A
  • Adrenal: hydrocortisone divided doses (e.g. 20 mg in the morning, 10 mg in the afternoon)
  • Thyroid: daily T4 replacement
  • Gonadal
  • Testosterone (patch, gel, injection)
  • Estrogen/progesterone
  • GH (case by case basis)
  • Diabetes insipidus: DDAVP

MS2 Endocrine (25 decks)

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