Anterior Pituitary and Adrenal Disorders Flashcards
Outline the hypothalamic-pituitary-adrenal (HPA) axis
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.
Remind me, does cortisol travel freely in circulation or bound to a carrier protein?
Bound (it is a steroid. Steroids are non-polar and thus are mostly [95%] bound in circulation)
Your pt has excessive production of ACTH and you notice their skin is hyperpigmented recently. What is going on here?
ACTH contains the sequence for melanocyte stimulating hormone (MSH) within it. When ACTH is over produced, MSH is also overproduced.
What is going on in Cushing’s Syndrome?
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)
What are the signs and symptoms of Cushing’s syndrome?
Weight gain Hyperphagia Proximal muscle weakness Easy bruising Violaceous striae (belly stretch marks) Growth retardation in children Decreased bone mineral density Psychiatric disturbances
Describe one of the first derangements that occurs in Cushing’s syndrome.
Failure of cortisol production/release to drop to a low point between 2300-0100.
Describe the tests used to Dx Cushing’s Syndrome.
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
What is the most common cause of primary adrenal insufficiency?
Autoimmune destruction of the adrenal cortex
Histology: lymphocytic infiltration
Pts are likely to have other endocrine glands affected as well
What do you suspect would happen to ACTH and CRH levels if the adrenal cortex was destroyed or otherwise rendered ineffective?
ACTH and CRH levels would increase do do a lack of negative feedback from the adrenal cortex.
What do you suspect would happen to ACTH levels during a secondary adrenal insufficiency.
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.
___________ should be expected in any pt with acute, unexplained volume depletion and shock.
Acute adrenal insufficiency (adrenal crisis)
Hyperkalemia, acidosis, and hypoglycemia may also be accompanying.
Why would you see hyperpigmentation in primary adrenal insufficiency?
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.
Describe some signs and symptoms of cortisol deficiency.
Signs: Hyperpigmentation, slight decrease in BP (unless cortisol deficiency is complete)
Symptoms: Fatigue, nausea, anorexia, weight loss, abdominal pain, athralgias, low grade fever.
Describe some signs and symptoms of aldosterone deficiency.
Would renin levels be high or low?
Signs: Hypotension, dehydration
Symptoms:Salt craving, postural dizziness.
Renin levels would be high
Describe some signs and symptoms and lab findings of adrenal androgen insufficiency.
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
How do you Dx adrenal insufficiency?
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
Describe congenital adrenal HYPERplasia
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
Describe the mutations in the CYP gene that cause congenital adrenal hyperplasia.
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.
CAH due to 21-hydroxylase deficiency results in one of two clinical syndromes in females: #1
Girls as neonates present with: #2
Why? #3
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.
CAH due to 21-hydroxylase deficiency results in one of two clinical syndromes in males: #1
Boys as neonates present with: #2
Why? #3
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
How do you Dx congenital adrenal hyperplasia?
elevated levels of 17-hydroxyprogesterone in the serum b/c 21-hydroxylase not present to convert it to deoxycortisol
Describe non-classic CAH.
Describe the Dx.
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.
Review: increased aldosterone activity via ENaC channels in the apical membrane of renal tubules results in loss of this ion:
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)
What are the leading causes of primary hyperaldosteronism?
Bilateral idiopathic hyperaldosteronism (60-70%)
Unilateral aldosterone producing adenomas (30-40%)
Familial hyperaldosteronism
Pure aldosterone-secreting adrenocortical carcinomas and ectopic aldosterone-secreting tumors.
