SM_183b: Adrenal Cortex Physiology and Pathophysiology Flashcards
Three types of steroid hormones are ____, ____, and ____
Three types of steroid hormones are mineralocorticoids (C21), glucocorticoids (C21), and androgens (C19)
Mineralocorticoids are produced in the ____
Mineralocorticoids are produced in the zona glomerulosa
Glucocorticoids are produced in the ____
Glucocorticoids are produced in the zona fasciculata
Androgens are produced in the ___
Androgens are produced in the zona reticularis
____ is the main mineralocorticoid
Aldosterone is the main mineralocorticoid
____ is the main glucocorticoid
Cortisol is the main glucocorticoid
____ and ____ are the main androgens
Dehydroepiandrosterone and androstenedione are the main androgens
StAR is responsible for ____
StAR is responsible for substrate delivery to enzymes
P450scc converts ____ to ____
P450scc converts cholesterol to pregnenolone
(cholesterol side chain cleavage)
3-beta-HSD converts to ____ to ____
3-beta-HSD converts to prenenolone to progesterone
(3-beta oxidation)
P450c17 converts ____ to ____
P450c17 converts prenenolone to 17-OH-prenenolone
(17-alpha hydroxylation)
P450c17 also converts ____ to ____
P450c17 also converts prenenolone to dehydroepiandosterone
(17,20-lyase)
P450c21 converts ____ to ____
P450c21 converts 17-OH-progesterone to 11-deoxycortisol
(21-hydroxylation)
P450c11-beta converts ____ to ____
P450c11-beta converts 11-deoxycortisol to cortisol
(11-beta-hydroxylation)
P450c11AS converts ____ to ____
P450c11AS converts corticosterone to aldosterone
(18-hydrol/aldo synthesis)
11-beta-hydroxysteroid dehydrogenase type I and II are responsible for ____
11-beta-hydroxysteroid dehydrogenase type I and II are responsible for cortisol-cortisone interconversion
17-beta-hydroxysteroid dehydrogenase III converts ____ to ____
17-beta-hydroxysteroid dehydrogenase III converts androstenedione to testosterone
5-alpha-reductase converts ____ to ____
5-alpha-reductase converts testosterone to 5-alpha-dihydrotestosterone
Aromatase converts ____ to ____
Aromatase converts testosterone to estradiol
___ regulates adrenal hormones
HPA axis regulates adrenal hormones
Describe the proopiomelanocortin cascade
Proopiomelanocortin cascade
- alpha-MSH
- ACTH
- POMC processing in the pituitary (alpha-MSH)
a-MSH is expressed in ___
a-MSH is expressed in skin (keratinocytes, melanocytes)
ACTH is expressed in the ____
ACTH is expressed in the anterior pituitary
MCR-2 is the ____
MCR-2 is the ACTH receptor
(located in adrenal cortex, responsible for steroid production)
MCR-2 requires ____ for membrane display and function
MCR-2 requires MRAP (melanocortin 2 receptor accessory protein) for membrane display and function
Renin is released by the ____, ____, and ____
Renin is released by the
- Juxtaglomerular apparatus sensing lower BP
- Macula densa sensing decreased osmotic pressure
- Direct renal adrenergic input
Describe the RAAS
RAAS
- Angiotensinogen -> angiotensin I by renin
- Angiotensin I -> angiotensin II by ACE
- Angiotensin II promotes excretion of aldosterone
- Na, K decrease
- Na retentiona and volume expansion
(ACTH and serum K regulate aldosterone)
Aldosterone release is stimulated by ___, ___, and ___
Aldosterone release is stimulated by renin-angiotensin system, hyperkalemia, and ACTH
___ is the ligand for AT receptor type I and II
Angiotensin II is the ligand for AT receptor type I and II
AT receptor type I is expressed in the ____, ____, ____, and ____
AT receptor type I is expressed in the vasculature, heart, kidney, and adrenal pituitary
AT receptor type I is responsible for ____, ____, and ____
AT receptor type I is responsible for vasoconstriction, aldosterone synthesis, and vasopressin secretion
AT receptor type is ____ expressed and responsible for ____
AT receptor type is widely expressed and responsible for cell growth / differentiation
(incompletely understood)
Describe the action of nuclear receptors
Nuclear receptors
- Nuclear receptors bind steroid hormone (cortisol)
- COnformational change activates receptor protein
- Activated receptor-cortisol complex moves into nucleus
- Activated receptor-cortisol complex binds to regulatory region of target gene and activates transcription
Describe effects of cortisol
Cortisol effects
- Catabolic: decreased protein synthesis and amino acid uptake in extrahepatic tissues, amino acids diverted to gluconeogenesis in the liver, decreased growth hormone secretion and action
- Hyperglycemic: gluconeogenesis, glycogen deposition in liver, insulin antagonism in peripheral tissues
- Electrolytes: Na retention, K exceetion in kidney, gut and sweat glands
- Adipose tissue: redistribution of fat
- Erythropoietic: red cell mass
- Lympholytic: depresses all aspects of the immune response
- Anti-inflammatory
- CNS effects: stimulates appetite, mood modulation
Cortisol has ____ actions
Cortisol has catabolic actions
Cortisol decreases activation of ___ and ___
Cortisol decreases activation of T lymphocytes and macrophages (anti-inflammatory)
Describe effects of androgen
Androgen
- Hair growth: beard, pubic, axillary, body
- Central and temporal balding
- Sebum production -> acne
- Penile and clitoral growth
- Erythropoietic
- Anabolic (muscle mass)
- Anti-estrogen
- Voice changes
Cortisol increases at start of ___ while DHEAS increases in the ___
Cortisol increases at start of puberty while DHEAS increases in 20s
(earlier for females than maels)
Describe androgen testing
Androgen testing
- DHEAS, androstenedione, testosterone
- Immunometric assays for testosterone are not sufficiently accurate or sensitive to use in prepubertal boys and women
- Testosterone is highly protein bound to albumin and sex hormone binding globulin
- Low SHBG will lower total testosterone, bioavailable testosterone may be normal
____, ____, and ____ are effects of mineralocorticoids
Na+ retention, K+ excretion, and H+ excretion are effects of mineralocorticoids
11-beta-hydroxysteroid dehydrogenase type I is presents in the ____, ____, and ____ and converts ____ to ____
11-beta-hydroxysteroid dehydrogenase type I is presents in the liver, lung, and omental fat, and converts cortisone to cortisol
(can also convert cortisone back to cortisol)
(cortisone is inactive)
11-beta-hydroxysteroid dehydrogenase type II is presents in the ____ and converts ____ to ____
11-beta-hydroxysteroid dehydrogenase type II is presents in the kidney and converts cortisol to cortisone
(cortisone is inactive)
____ is an enzyme that inactivates cortisol, limiting renal mineralocorticoid receptor activation in normal conditions
11-beta-hydroxysteroid dehydrogenase type II is an enzyme that inactivates cortisol, limiting renal mineralocorticoid receptor activation in normal conditions
Describe causes of primary adrenal hypofunction
Primary adrenal hypofunction
- Autoimmune
- Infectious / granuloma (TB)
- Hemorrhage (bleeding diathesis)
- Metastases
- Genetic ACTH receptor or MRAP deficiency
Secondary adrenal hypofunction involves ____
Secondary adrenal hypofunction involves ACTH deficiency
(pituitary disease: tumor, granuloma, autoimmune, hemorrhage)
Congenital adrenal hyperplasia (mixed hypo and hyperfunction) occurs when ___
Congenital adrenal hyperplasia (mixed hypo and hyperfunction) occurs when genetic enzyme deficiencies lead to a defect of cortisol and excess of precursors
Describe clinical features of adrenal hypofunction
Adrenal hypofunction clinical features
- Cortisol hypofunction: anorexia, nausea, weakness, salt craving, hypoglycemia, hyponatremia, hyperkalemia, dehydration, and death (adrenal crisis is often precipitated by a medical stress)
- Aldosterone deficiency: hyponatremia, hyperkalemia, dehydration, hypotension
- Adrenal androgen deficiency: axillary and pubic hair loss, loss of libido (women)
- Excess ACTH (primary adrenal insufficiency, Addison’s disease) causes pigmentation
- Secondary adrenal insufficiency: cortisol and adrenal androgen deficiency but largely normal aldosterone secretion
____ adrenal insufficiency causes mucosal pigmentation
Primary adrenal insufficiency causes mucosal pigmentation
(excess ACTH)
Describe endocrine testing in adrenal insufficiency
Endocrine testing in adrenal insufficiency
- Basal plasma cortisol and ACTH
- Cosyntropin (synthetic ACTH) stimulation test
- Direct pituitary simulation tests for ACTH (insulin tolerance, CRH)
- Plasma aldosterone and renin
Describe cortisol testing for adrenal insufficiency
Cortisol testing for adrenal insufficiency
- Measure ACTH and morning cortisol to start
- Cortisol is highly protein bound to cortisol binding globulin: routine assays measure total (free + bound cortisol) so when CBG is abnormal there is not a normal reference range
- Moening cortisol should be > 10 ug/dL, less than 4 likely adrenal insufficiency
Insulin tolerance test involves measurement of ____
Insulin tolerance test involves measurement of blood glucose
(used to assess pituitary function, adrenal function, and insulin sensitivity)
____ is the most common cause of isolated hypoaldosteronism
Hyporeninemic hypoaldosteronism is the most common cause of isolated hypoaldosteronism
(type IV renal tubular acidosis)
(common complication of diabetes)
Describe therapy for adrenal hypofunction
Adrenal hypofunction therapy
- Replacement therapy with hydrocortisone = cortisol
- Replacement therapy with 9-alpha-fluorocortisol (fludrocortisone, a synthetic mineralocorticoid)
- Replacement of adrenal androgens not generally necessary
Describe clinical manifestations of Cushing’s syndrome
Cushing’s syndrome clinical syndrome
- Weight gain, redistribution of fat (trunk, face)
- Na retention, fluid retention, HTN
- K depletion, hypokalemia
- Ruddy complexion, purple striae
- Hyperphagia
- Depression, euphoria, inability to concentrate
- Osteoporosis
- Myopathy, muscle loss, weakness
Describe clinical manifestations of chronic hypercorticism (Cushing’s disease)
Chronic hypercorticism (Cushing’s disease)
- Centripetal obesity
- Buffalo hump
- Striae
- HTN
- Acne, hirsutism
- Echymoses
- Decreased CHO tolerance
- Myopathy
- Osteoporosis
Describe clinical manifestations of acute hypercorticism (ectopic ACH)
Acute hypercorticism (ectopic ACH)
- Weight loss
- Psychosis
- Pigmentation
- HTN
- Acne
- Hypokalemia alkalosis
- Hyperglycemia
- Weakness (hypokalemia)
- Polyuria - polydypsia (hypokalemic nephrophathy, hyperglycemia)
Describe etiologies of glucocorticoid excess (Cushing’s syndrome)
Glucocorticoid excess (Cushing’s syndrome) etiologies
- Pituitary ACTH secreting adenoma (Cushing’s disease)
- Adrenal tumor (adenoma, carcinoma)
- Nodular adrenal hyperplosia (macronodular can be due to aberrant receptor expression, micronodular can be part of Carney complex)
- Ectopic ACTH syndrome
- Exogenous steroid administration
- Ectopic CRH-producing tu]mor
Micronodular adrenal hyperplasia can be part of ____, which results from ____
Micronodular adrenal hyperplasia can be part of Carney complex, which results from mutation of a subunit of protein kinase A (autosomal dominant)
____ is most common cause of ectopic ACTH
Lung carcinoma is most common cause of ectopic ACTH
(also carcinoma of pancreas, thymoma, benign bronchial adenoma)
Hallmark of Cushing’s syndrome is ___
Hallmark of Cushing’s syndrome is non-suppressibility of excess hormone production
(glucocorticoid excess)
Describe diagnosis of Cushing’s syndrome (glucocorticoid excess)
Cushing’s syndrome (glucocorticoid excess)
- Biochemical confirmation: loss of diurnal rhythm of plasma cortisol, loss of suppressibility of steroid secretion, excessive production of steroids
- Specific diagnosis: AM cortisol and ACTH, 24 h urine free cortisol excretion, midnight salivary free cortisol, dexamethasone suppression test
- Localization procedures: pituitary, adrenal, ectopic (often obvious cancer source)
Primary selective mineralocorticoid excess is caused by ____ or ____
Primary selective mineralocorticoid excess is caused by aldosterone-producing adenoma and bilateral hyperplasia
HTN, hypokalemia, alkalosis
Secondary selective mineralocorticoid excess involves ___, ___, and ___
Secondary selective mineralocorticoid excess involves high renin (due to hypovolemia), hypokalemia, and alkalosis
Hypokalemia is ___ required to consider the diagnosis of hyperaldosteronism
Hypokalemia is NOT required to consider the diagnosis of hyperaldosteronism
Selective mineralocorticoid excess diagnostic tests are ____ and ____
Selective mineralocorticoid excess diagnostic tests are plasma renin and aldosterone
(urinary aldosterone)
Describe diagnostic testing for primary hyperaldosteronism
Primary hyperaldosteronism
- Renin suppressed and aldosterone high
- Renin not stimulatable (Na depletion, posture)
- Aldosterone not suppressible (Na loading)
Describe diagnostic testing for secondary hyperaldosteronism
Diagnostic testing for secondary hyperaldosteronism
- Renin and aldosterone high
- Renin and aldosterone suppressible (Na loading, volume repletion)
Describe clinical manifestations of androgen excess
Androgen excess clinical manifestations
- Hirsutism, acne, temporal / central balding
- Ruddy complexion, purple striae (together with glucocorticoid excess)
- Increased red cell mass
- Irregular periods
____ is the main therapy of adrenal hyperfunction
Stopping or minimizing exogenous steroids is the main therapy of adrenal hyperfunction
Congenital adrenal hyperplasia is caused by a ____, most often ____ but sometimes ____
Congenital adrenal hyperplasia is caused by a genetic deficiency in steroidogenic enzymes, most often 21-hydroxylase deficiency but sometimes 11-hydroxylase deficiency
(deficiency of cortisol and excess of precursors)
Describe pathophysiology of congenital adrenal hyperplasia
Congenital adrenal hyperplasia pathophysiology
- Cortisol deficiency
- ACTH overproduction
- Adrenal hyperplasia, excess production of precursor steroids, and shunting of precursors into non-blocked androgen pathway
Describe clinical manifestations of 21-hydroxylase deficiency congenital adrenal hyperplasia
21-hydroxylase deficiency congenital adrenal hyperplasia
- Girls: ambiguous genitalia
- Sodium wasting, shock
- Short stature, hirsutism, hypo/amenorrhea
Describe clinical manifestations of 11-hydroxylase deficiency congenital adrenal hyperplasia
11-hydroxylase deficiency congenital adrenal hyperplasia
- Girls: ambiguous genitalia
- Na retention, hypertension (11-deoxycorticosterone is a mineralocorticoid)
- Short stature
- Hirsutism
- Hypo/amenorrhea
Nonclassical congenital adrenal hyperplasia main symptoms are due to ____, is phenotypically similar to ____, and is most common in ____
Nonclassical congenital adrenal hyperplasia main symptoms are due to androgen excess, is phenotypically similar to polycystic ovarian syndrome, and is most common in Ashkenazi Jews / Hispanics
Endocrine therapy of congenital adrenal hyperplasia due to 21-hydroxylase deficiency is ____ and ____
Endocrine therapy of congenital adrenal hyperplasia due to 21-hydroxylase deficiency is replacing with cortisone (lowest dose) and replacing with fludrocortisone if necessary
A woman with historically regular cycles unexpectedly misses her menstrual period. Home pregnancy test is positive. She wishes to end the pregnancy, so her doctor prescribes mifepristone (RU-485). In addition to its desired progesterone receptor antagonist activity in the uterus, the hormone action producted in ___ of the adrenal gland will be most affected.
A woman with historically regular cycles unexpectedly misses her menstrual period. Home pregnancy test is positive. She wishes to end the pregnancy, so her doctor prescribes mifepristone (RU-485). In addition to its desired progesterone receptor antagonist activity in the uterus, the hormone action producted in zona fasciculata of the adrenal gland will be most affected.
(glucocorticoids)
