SM_183b: Adrenal Cortex Physiology and Pathophysiology

Question 1

Three types of steroid hormones are ____, ____, and ____

Answer 1

Three types of steroid hormones are mineralocorticoids (C21), glucocorticoids (C21), and androgens (C19)

Question 2

Mineralocorticoids are produced in the ____

Answer 2

Mineralocorticoids are produced in the zona glomerulosa

Question 3

Glucocorticoids are produced in the ____

Answer 3

Glucocorticoids are produced in the zona fasciculata

Question 4

Androgens are produced in the ___

Answer 4

Androgens are produced in the zona reticularis

Question 5

____ is the main mineralocorticoid

Answer 5

Aldosterone is the main mineralocorticoid

Question 6

____ is the main glucocorticoid

Answer 6

Cortisol is the main glucocorticoid

Question 7

____ and ____ are the main androgens

Answer 7

Dehydroepiandrosterone and androstenedione are the main androgens

Question 8

StAR is responsible for ____

Answer 8

StAR is responsible for substrate delivery to enzymes

Question 9

P450scc converts ____ to ____

Answer 9

P450scc converts cholesterol to pregnenolone

(cholesterol side chain cleavage)

Question 10

3-beta-HSD converts to ____ to ____

Answer 10

3-beta-HSD converts to prenenolone to progesterone

(3-beta oxidation)

Question 11

P450c17 converts ____ to ____

Answer 11

P450c17 converts prenenolone to 17-OH-prenenolone

(17-alpha hydroxylation)

Question 12

P450c17 also converts ____ to ____

Answer 12

P450c17 also converts prenenolone to dehydroepiandosterone

(17,20-lyase)

Question 13

P450c21 converts ____ to ____

Answer 13

P450c21 converts 17-OH-progesterone to 11-deoxycortisol

(21-hydroxylation)

Question 14

P450c11-beta converts ____ to ____

Answer 14

P450c11-beta converts 11-deoxycortisol to cortisol

(11-beta-hydroxylation)

Question 15

P450c11AS converts ____ to ____

Answer 15

P450c11AS converts corticosterone to aldosterone

(18-hydrol/aldo synthesis)

Question 16

11-beta-hydroxysteroid dehydrogenase type I and II are responsible for ____

Answer 16

11-beta-hydroxysteroid dehydrogenase type I and II are responsible for cortisol-cortisone interconversion

Question 17

17-beta-hydroxysteroid dehydrogenase III converts ____ to ____

Answer 17

17-beta-hydroxysteroid dehydrogenase III converts androstenedione to testosterone

Question 18

5-alpha-reductase converts ____ to ____

Answer 18

5-alpha-reductase converts testosterone to 5-alpha-dihydrotestosterone

Question 19

Aromatase converts ____ to ____

Answer 19

Aromatase converts testosterone to estradiol

Question 20

___ regulates adrenal hormones

Answer 20

HPA axis regulates adrenal hormones

Question 21

Describe the proopiomelanocortin cascade

Answer 21

Proopiomelanocortin cascade

1. alpha-MSH
2. ACTH
3. POMC processing in the pituitary (alpha-MSH)

Question 22

a-MSH is expressed in ___

Answer 22

a-MSH is expressed in skin (keratinocytes, melanocytes)

Question 23

ACTH is expressed in the ____

Answer 23

ACTH is expressed in the anterior pituitary

Question 24

MCR-2 is the ____

Answer 24

MCR-2 is the ACTH receptor

(located in adrenal cortex, responsible for steroid production)

Question 25

MCR-2 requires ____ for membrane display and function

Answer 25

MCR-2 requires MRAP (melanocortin 2 receptor accessory protein) for membrane display and function

Question 26

Renin is released by the \_\_\_\_, \_\_\_\_, and \_\_\_\_

Answer 26

Renin is released by the * Juxtaglomerular apparatus sensing lower BP * Macula densa sensing decreased osmotic pressure * Direct renal adrenergic input

Question 27

Describe the RAAS

Answer 27

RAAS 1. Angiotensinogen -\> angiotensin I by renin 2. Angiotensin I -\> angiotensin II by ACE 3. Angiotensin II promotes excretion of aldosterone 4. Na, K decrease 5. Na retentiona and volume expansion (ACTH and serum K regulate aldosterone)

Question 28

Aldosterone release is stimulated by \_\_\_, \_\_\_, and \_\_\_

Answer 28

Aldosterone release is stimulated by renin-angiotensin system, hyperkalemia, and ACTH

Question 29

\_\_\_ is the ligand for AT receptor type I and II

Answer 29

Angiotensin II is the ligand for AT receptor type I and II

Question 30

AT receptor type I is expressed in the \_\_\_\_, \_\_\_\_, \_\_\_\_, and \_\_\_\_

Answer 30

AT receptor type I is expressed in the vasculature, heart, kidney, and adrenal pituitary

Question 31

AT receptor type I is responsible for \_\_\_\_, \_\_\_\_, and \_\_\_\_

Answer 31

AT receptor type I is responsible for vasoconstriction, aldosterone synthesis, and vasopressin secretion

Question 32

AT receptor type is ____ expressed and responsible for \_\_\_\_

Answer 32

AT receptor type is widely expressed and responsible for cell growth / differentiation (incompletely understood)

Question 33

Describe the action of nuclear receptors

Answer 33

Nuclear receptors 1. Nuclear receptors bind steroid hormone (cortisol) 2. COnformational change activates receptor protein 3. Activated receptor-cortisol complex moves into nucleus 4. Activated receptor-cortisol complex binds to regulatory region of target gene and activates transcription

Question 34

Describe effects of cortisol

Answer 34

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

Question 35

Cortisol has ____ actions

Answer 35

Cortisol has catabolic actions

Question 36

Cortisol decreases activation of ___ and \_\_\_

Answer 36

Cortisol decreases activation of T lymphocytes and macrophages (anti-inflammatory)

Question 37

Describe effects of androgen

Answer 37

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

Question 38

Cortisol increases at start of ___ while DHEAS increases in the \_\_\_

Answer 38

Cortisol increases at start of puberty while DHEAS increases in 20s (earlier for females than maels)

Question 39

Describe androgen testing

Answer 39

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

Question 40

\_\_\_\_, \_\_\_\_, and ____ are effects of mineralocorticoids

Answer 40

Na+ retention, K+ excretion, and H+ excretion are effects of mineralocorticoids

Question 41

11-beta-hydroxysteroid dehydrogenase type I is presents in the \_\_\_\_, \_\_\_\_, and ____ and converts ____ to \_\_\_\_

Answer 41

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)

Question 42

11-beta-hydroxysteroid dehydrogenase type II is presents in the ____ and converts ____ to \_\_\_\_

Answer 42

11-beta-hydroxysteroid dehydrogenase type II is presents in the kidney and converts cortisol to cortisone (cortisone is inactive)

Question 44

\_\_\_\_ is an enzyme that inactivates cortisol, limiting renal mineralocorticoid receptor activation in normal conditions

Answer 44

11-beta-hydroxysteroid dehydrogenase type II is an enzyme that inactivates cortisol, limiting renal mineralocorticoid receptor activation in normal conditions

Question 45

Describe causes of primary adrenal hypofunction

Answer 45

Primary adrenal hypofunction * Autoimmune * Infectious / granuloma (TB) * Hemorrhage (bleeding diathesis) * Metastases * Genetic ACTH receptor or MRAP deficiency

Question 46

Secondary adrenal hypofunction involves \_\_\_\_

Answer 46

Secondary adrenal hypofunction involves ACTH deficiency (pituitary disease: tumor, granuloma, autoimmune, hemorrhage)

Question 47

Congenital adrenal hyperplasia (mixed hypo and hyperfunction) occurs when \_\_\_

Answer 47

Congenital adrenal hyperplasia (mixed hypo and hyperfunction) occurs when genetic enzyme deficiencies lead to a defect of cortisol and excess of precursors

Question 48

Describe clinical features of adrenal hypofunction

Answer 48

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

Question 49

\_\_\_\_ adrenal insufficiency causes mucosal pigmentation

Answer 49

Primary adrenal insufficiency causes mucosal pigmentation (excess ACTH)

Question 50

Describe endocrine testing in adrenal insufficiency

Answer 50

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

Question 51

Describe cortisol testing for adrenal insufficiency

Answer 51

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

Question 52

Insulin tolerance test involves measurement of \_\_\_\_

Answer 52

Insulin tolerance test involves measurement of blood glucose (used to assess pituitary function, adrenal function, and insulin sensitivity)

Question 53

\_\_\_\_ is the most common cause of isolated hypoaldosteronism

Answer 53

Hyporeninemic hypoaldosteronism is the most common cause of isolated hypoaldosteronism (type IV renal tubular acidosis) (common complication of diabetes)

Question 54

Describe therapy for adrenal hypofunction

Answer 54

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

Question 55

Describe clinical manifestations of Cushing's syndrome

Answer 55

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

Question 56

Describe clinical manifestations of chronic hypercorticism (Cushing's disease)

Answer 56

Chronic hypercorticism (Cushing's disease) * Centripetal obesity * Buffalo hump * Striae * HTN * Acne, hirsutism * Echymoses * Decreased CHO tolerance * Myopathy * Osteoporosis

Question 57

Describe clinical manifestations of acute hypercorticism (ectopic ACH)

Answer 57

Acute hypercorticism (ectopic ACH) * Weight loss * Psychosis * Pigmentation * HTN * Acne * Hypokalemia alkalosis * Hyperglycemia * Weakness (hypokalemia) * Polyuria - polydypsia (hypokalemic nephrophathy, hyperglycemia)

Question 58

Describe etiologies of glucocorticoid excess (Cushing's syndrome)

Answer 58

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

Question 59

Micronodular adrenal hyperplasia can be part of \_\_\_\_, which results from \_\_\_\_

Answer 59

Micronodular adrenal hyperplasia can be part of Carney complex, which results from mutation of a subunit of protein kinase A (autosomal dominant)

Question 60

\_\_\_\_ is most common cause of ectopic ACTH

Answer 60

Lung carcinoma is most common cause of ectopic ACTH (also carcinoma of pancreas, thymoma, benign bronchial adenoma)

Question 61

Hallmark of Cushing's syndrome is \_\_\_

Answer 61

Hallmark of Cushing's syndrome is non-suppressibility of excess hormone production (glucocorticoid excess)

Question 62

Describe diagnosis of Cushing's syndrome (glucocorticoid excess)

Answer 62

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)

Question 63

Primary selective mineralocorticoid excess is caused by ____ or \_\_\_\_

Answer 63

Primary selective mineralocorticoid excess is caused by aldosterone-producing adenoma and bilateral hyperplasia HTN, hypokalemia, alkalosis

Question 64

Secondary selective mineralocorticoid excess involves \_\_\_, \_\_\_, and \_\_\_

Answer 64

Secondary selective mineralocorticoid excess involves high renin (due to hypovolemia), hypokalemia, and alkalosis

Question 65

Hypokalemia is ___ required to consider the diagnosis of hyperaldosteronism

Answer 65

Hypokalemia is NOT required to consider the diagnosis of hyperaldosteronism

Question 66

Selective mineralocorticoid excess diagnostic tests are ____ and \_\_\_\_

Answer 66

Selective mineralocorticoid excess diagnostic tests are plasma renin and aldosterone (urinary aldosterone)

Question 67

Describe diagnostic testing for primary hyperaldosteronism

Answer 67

Primary hyperaldosteronism * Renin suppressed and aldosterone high * Renin not stimulatable (Na depletion, posture) * Aldosterone not suppressible (Na loading)

Question 68

Describe diagnostic testing for secondary hyperaldosteronism

Answer 68

Diagnostic testing for secondary hyperaldosteronism * Renin and aldosterone high * Renin and aldosterone suppressible (Na loading, volume repletion)

Question 69

Describe clinical manifestations of androgen excess

Answer 69

Androgen excess clinical manifestations * Hirsutism, acne, temporal / central balding * Ruddy complexion, purple striae (together with glucocorticoid excess) * Increased red cell mass * Irregular periods

Question 70

\_\_\_\_ is the main therapy of adrenal hyperfunction

Answer 70

Stopping or minimizing exogenous steroids is the main therapy of adrenal hyperfunction

Question 71

Congenital adrenal hyperplasia is caused by a \_\_\_\_, most often ____ but sometimes \_\_\_\_

Answer 71

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)

Question 72

Describe pathophysiology of congenital adrenal hyperplasia

Answer 72

Congenital adrenal hyperplasia pathophysiology 1. Cortisol deficiency 2. ACTH overproduction 3. Adrenal hyperplasia, excess production of precursor steroids, and shunting of precursors into non-blocked androgen pathway

Question 73

Describe clinical manifestations of 21-hydroxylase deficiency congenital adrenal hyperplasia

Answer 73

21-hydroxylase deficiency congenital adrenal hyperplasia * Girls: ambiguous genitalia * Sodium wasting, shock * Short stature, hirsutism, hypo/amenorrhea

Question 74

Describe clinical manifestations of 11-hydroxylase deficiency congenital adrenal hyperplasia

Answer 74

11-hydroxylase deficiency congenital adrenal hyperplasia * Girls: ambiguous genitalia * Na retention, hypertension (11-deoxycorticosterone is a mineralocorticoid) * Short stature * Hirsutism * Hypo/amenorrhea

Question 75

Nonclassical congenital adrenal hyperplasia main symptoms are due to \_\_\_\_, is phenotypically similar to \_\_\_\_, and is most common in \_\_\_\_

Answer 75

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

Question 76

Endocrine therapy of congenital adrenal hyperplasia due to 21-hydroxylase deficiency is ____ and \_\_\_\_

Answer 76

Endocrine therapy of congenital adrenal hyperplasia due to 21-hydroxylase deficiency is replacing with cortisone (lowest dose) and replacing with fludrocortisone if necessary

Question 77

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.

Answer 77

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)