Anterior Pituitary and Adrenal Disorders

Question 1

Outline the hypothalamic-pituitary-adrenal (HPA) axis

Answer 1

Inputs to the hypothalamic parvocellular nuclei lead to an increase in corticotropin-releasing hormone (CRH) into the hypophyseal portal veins.

CRH stimulates the corticotrophs of the anterior pituitary to increase the release of ACTH into the pituitary capillary beds.

CRH also stimulates the synthesis of new ACTH by activating gene transcription for the precursor molecule proopiomelanocortin (POMC) and its post translational processing to ACTH and other byproducts.

ACTH stimulates the release of cortisol by binding to the melanocyte type-2 receptor (MC2R) in the adrenal cortex (zona fasciculata and zona reticularis).

^ Cortisol —I CRH secretion from Hypoth.
^ Cortisol —I ACTH secretion Pit.

Question 2

Remind me, does cortisol travel freely in circulation or bound to a carrier protein?

Answer 2

Bound (it is a steroid. Steroids are non-polar and thus are mostly [95%] bound in circulation)

Question 3

Your pt has excessive production of ACTH and you notice their skin is hyperpigmented recently. What is going on here?

Answer 3

ACTH contains the sequence for melanocyte stimulating hormone (MSH) within it. When ACTH is over produced, MSH is also overproduced.

Question 4

What is going on in Cushing’s Syndrome?

Answer 4

Defined as a state of glucocorticoid excess.
Caused by:
Endogenous production of cortisol by the adrenal gland
- ACTH dependent Cushing’s synd.
::Caused by excess ACTH secretion by pituitary corticotroph tumors or
::ectopic ACTH production, usually from neuroendocrine tumors
-ACTH independent Cushing’s synd.
::Caused by autonomous adrenal overproduction of cortisol, usually due to a benign, solitary adrenal adenoma or
:: by exogenous admin. of glucocorticoids (e.g. to treat autoimmune conditions or other inflammatory conditions)

Question 5

What are the signs and symptoms of Cushing’s syndrome?

Answer 5

Weight gain
Hyperphagia
Proximal muscle weakness
Easy bruising
Violaceous striae (belly stretch marks)
Growth retardation in children
Decreased bone mineral density
Psychiatric disturbances

Question 6

Describe one of the first derangements that occurs in Cushing’s syndrome.

Answer 6

Failure of cortisol production/release to drop to a low point between 2300-0100.

Question 7

Describe the tests used to Dx Cushing’s Syndrome.

Answer 7

24 hr free urine cortisol
Late night salivary cortisol
1-mg overnight dexamethasone suppression test*
Longer low dose DST (2mg/day for 48 hrs)

CT scan for pit. tumor

Question 8

What is the most common cause of primary adrenal insufficiency?

Answer 8

Autoimmune destruction of the adrenal cortex
Histology: lymphocytic infiltration
Pts are likely to have other endocrine glands affected as well

Question 9

What do you suspect would happen to ACTH and CRH levels if the adrenal cortex was destroyed or otherwise rendered ineffective?

Answer 9

ACTH and CRH levels would increase do do a lack of negative feedback from the adrenal cortex.

Question 10

What do you suspect would happen to ACTH levels during a secondary adrenal insufficiency.

Answer 10

ACTH levels would be reduced because the source of the secondary adrenal insufficiency is a somehow damaged pituitary gland, which produces inadequate levels of ACTH.

Question 11

___________ should be expected in any pt with acute, unexplained volume depletion and shock.

Answer 11

Acute adrenal insufficiency (adrenal crisis)

Hyperkalemia, acidosis, and hypoglycemia may also be accompanying.

Question 12

Why would you see hyperpigmentation in primary adrenal insufficiency?

Answer 12

Primary adrenal insufficiency would cause an increase in circulating levels of ACTH and thus MSH because the body is trying, unsuccessfully, to stimulate the adrenal cortex to produce more cortisol.

Question 13

Describe some signs and symptoms of cortisol deficiency.

Answer 13

Signs: Hyperpigmentation, slight decrease in BP (unless cortisol deficiency is complete)

Symptoms: Fatigue, nausea, anorexia, weight loss, abdominal pain, athralgias, low grade fever.

Question 14

Describe some signs and symptoms of aldosterone deficiency.

Would renin levels be high or low?

Answer 14

Signs: Hypotension, dehydration

Symptoms:Salt craving, postural dizziness.

Renin levels would be high

Question 15

Describe some signs and symptoms and lab findings of adrenal androgen insufficiency.

Answer 15

Signs: Decreased pubic/axillary hair (only in women b/c men produce testosterone in the testes, too)

Symptoms: Decreased libido

Lab: would see low serum DHEA and DHEAS levels

Question 16

How do you Dx adrenal insufficiency?

Answer 16

Standard ACTH stimulation test: 
-draw baseline cortisol levels
-admin bolus ACTH
-check cortisol at 30 and 60 mins
\::cut-off for adequate peak serum cortisol is 18 mcg/dL

Question 17

Describe congenital adrenal HYPERplasia

Answer 17

AR disorder
Involves defects in the steroidogenic pathway, glucocorticoid negative feedback and control of adrenal growth.
Discovered at birth and characterized by hyperplastic adrenal cortex.
Can also express in adolescence or adulthood as non-classic CAH

Question 18

Describe the mutations in the CYP gene that cause congenital adrenal hyperplasia.

Answer 18

Defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol accounts for 95% of cases of CAH. This conversion is mediated by 21-hydroxylase due to mutations in the CYP21A2 gene. Thus, you will find elevated plasma levels of 17-hydroxyprogesterone in CAH due to 21-hydroxylase deficiency.

Question 19

CAH due to 21-hydroxylase deficiency results in one of two clinical syndromes in females: #1
Girls as neonates present with: #2
Why? #3

Answer 19

1) A salt losing form or a non salt losing form.
2) Genital ambiguity.
Enlarged clitoris.
Normal internal female repro. organs
Common urethral/vaginal orifice
May present with a salt-losing crisis at 1-2 wks of age
3) Failure to produce cortisol causes a loss of negative feedback on the fetal pituitary which produces more ACTH to stimulate the adrenal cortex –> adrenal cortical hypertrophy —> more androgens —> genital ambiguity.

Question 20

CAH due to 21-hydroxylase deficiency results in one of two clinical syndromes in males: #1
Boys as neonates present with: #2
Why? #3

Answer 20

1) Salt losing adrenal crisis or early signs of puberty (non-salt losing)
2) Newborn males show no overt signs of CAH, although phallic enlargement and scrotal hyperpigmentation is sometimes present.
3) Excessive levels of ACTH produced –> ^ androgen production

Question 21

How do you Dx congenital adrenal hyperplasia?

Answer 21

elevated levels of 17-hydroxyprogesterone in the serum b/c 21-hydroxylase not present to convert it to deoxycortisol

Question 22

Describe non-classic CAH.

Describe the Dx.

Answer 22

There is enough 21-hydroxylase activity to produce normal levels of cortisol and aldosterone BUT at the expense of too much androgen production.
Affected females do not have ambiguous genitalia.
Presents later in life with androgen excess.
Clinical features in late adulthood:
Premature pubarche
acne
accelerated bone age
female hirsutism, acne, menstrual irreg.
Some men may present with infertility and testicular masses.
Dx same as classic CAH (check 17-hydroxyprogesterone levels). Confirm with ACTH stimulation.

Question 23

Review: increased aldosterone activity via ENaC channels in the apical membrane of renal tubules results in loss of this ion:

Answer 23

Potassium. Due to net electronegative charge in lumen of tubule from Na+ reabsorption, which is favorable for K+ secretion in to the lumen and thus, loss in the urine.
Bonus: also results in metabolic alkalosis (due to loss of H+ in urine)

Question 24

What are the leading causes of primary hyperaldosteronism?

Answer 24

Bilateral idiopathic hyperaldosteronism (60-70%)
Unilateral aldosterone producing adenomas (30-40%)
Familial hyperaldosteronism
Pure aldosterone-secreting adrenocortical carcinomas and ectopic aldosterone-secreting tumors.

Question 25

Describe the clinical features of primary hyperaldosteronism.
How is it Dx’d?
Tx?

Answer 25

Hypertension
Hypokalemia
Metabolic alkalosis
Mild hypernatremia
Hypomagnesemia 
Muscle weakness
CV risks

Dx: PLASMA K+ to screen. Renin:Ald ratio is definitive.
Simultaneous measurement of morning aldosterone levels and renin activity. Aldosterone should be high (>15 ng/dL). Renin should be very low. Ratio of aldosterone:renin of >30 has a 90% sensitivity and specificity for primary hyperaldosteronism

Then do CT of adrenal gland to determine pathological cause. Can show either solitary adrenal adenoma or diffuse bilateral adrenal hyperplasia (affects treatment).

Tumor: resect
Diffuse hyperplasia: spirinolactone or other K+ sparing diuretic.

Question 26

Prolactinomas are classically associated with this dysfunction:

Answer 26

Sexual dysfunction (decreased libido) by suppressing LH/FSH

Question 27

What should be co-administered with levothyroxine when treating hypothyroidism?

Answer 27

Glucocorticoids, to prevent adrenal insufficiency due to a sudden increase in metabolism and higher demand for cortisol.

Question 28

Describe the blood supply of the anterior and posterior pituitary.

Answer 28

Anterior pituitary = dense capillary network of pituitary portal venous plexus formed from hypophyseal portal veins, which drain into the petrosal sinuses to jugulars; *lacks major arterial supply
Posterior pituitary = fed by the inferior hypophyseal artery; drains to posterior hypophyseal veins

Question 29

What is hypopituitarism and what causes it?

Answer 29

• the reduced secretion of pituitary hormones
• can be from disease of hypothalamus (no releasing hormones) or pituitary (no hormones)
• most common cause is from surgical resection of the pituitary
• pituitary-based causes: infarct (i.e., Sheehan syndrome), mass lesions (e.g., non-functional adenomas), infiltrative lesions (e.g., lymphocytic hypophysitis), or radiation
• hypothalamus-based causes: mass lesions (e.g., craniopharyngiomas, mets), radiation, infiltrative lesions (e.g., sarcoidosis), trauma (e.g., skull base fracture), infections (e.g., TB, meningitis)

Question 30

Clinical features and treatment of hypopituitarism.

Answer 30

Depends on which hormone is deficient:
• ACTH: Adrenal insufficiency
• TSH: Hypothyroidism
• Gonadotropin: Hypogonadism
• GH: Failure to thrive and short stature in children; most adults are asymptomatic, but some may experience fatigue/weakness and decreased quality of life
• Prolactin: Failure of lactation
• ADH: Diabetes insipidus 

Treatment includes a sum of the treatment of each of the individual pituitary hormone deficiencies (HRT)

Question 31

What is hyperpituitarism and what causes it?

Answer 31

• the increased secretion of pituitary hormones

- functional adenomas are the most common cause

Question 32

Clinical features and treatment of hyperpituitarism.

Answer 32

Depends on which hormone is in excess:
• ACTH: Cushing’s disease
• TSH: Hyperthyroidism; tx with surgical resection
• GH: kids –> gigantism; adults –> acromegaly; tx with resection for microadenomas and decompression for macroadenomas, +/- somatostatin analog
• Prolactin: can be asx, or: hypogonadism, abnormal menstruation, infertility, galactorrhea, bone loss 2/2 sex steroid hormone attenuation; tx with DA receptor agonists

Question 33

Diagnosis of:

• GH excess
• prolactinoma
• TSH-secreting adenoma

Answer 33

• GH excess: person is big, elevated IGF-1, elevated GH following OGTT (remember pulsatile/stimulated release), then MRI
• prolactinoma: A single measurement of serum prolactin level above the upper limit of normal (usually 250mcg/L) confirms the diagnosis.
• TSH-secreting adenoma - elevated T4 level and elevated or non suppressed TSH level, confirm with MRI.