6 Endo adrenal glands

where are adrenal glands located?

sit atop each kidney

how are adrenal glands divided?

according to function- cortex and medulla

what are the zones of the cortex?

zona glomerulosa, zona fasciulata, zona reticularis

what does zona glomerulosa do?

aldosterone synthesis (mineralocorticoids)

what does zona fasciculata do?

corticosteroid synthesis (glucocorticoid)

what does zona reticularis do?

androgen synthesis (glucocorticoid)

what are parts of the medulla?

autonomic nervous tissue (sympathetic function)

catecholamine production/release, particularly epinephrine

what does synthesis of steroid hormones start with?

cholesterol → glucocorticoids + mineralcorticoids

what is an example of a glucocorticoid?

cortisol

what is the pathway to cortisol release?

CRH from hypothalamus controls ACTH synthesis and release from pituitary gland which stimulates production of cortisol from adrenal cortex

cortisol feedback to inhibit both CRH and ACTH production

what are functions of cortisol?

maintains BP by arterial/arteriole muscular tone and sodium retention (increases intravascular volume)

metabolic control by increasing appetite, glucose production by multiple mechanisms (at expense of protein and glycogen stores)

immune/inflammatory regulation by inhibiting lymphocyte action (immunosuppression during acute stress to prevent overreactive immune response)

osteoclast stimulation during acute stress

what are the 2 major androgens produced in the adrenal cortex?

dehydroepiandrosterone (DHEA), androstenedione

what are the major adrenal androgens converted into?

testosterone

what important role do the adrenal androgens play?

muscle mass, bone growth/mineralization and libido

does an overproduction of adrenal androgens have a significant consequence in men and women?

no significant consequence in men

in women it can result in acne, hirsutism and infertility

what is the main mineralcorticoid?

aldosterone

how is aldosterone produced?

in response to renin-angiotensin pathway

what is the RAA system?

low intravascular volume or low serum osmolality/low sodium stimulates renin production in juxtaglomerular cells of kidney

renin cleaves angiotensinogen into angiotensin I which is converted to angiotensin II

angiotensin II stimulates adrenal cortex to produce aldosterone

what type of agents are angiotensin II and aldosterone?

potent vasoconstrictor agents

what are aldosterone functions?

maintaining normal sodium and potassium concentrations and extracellular volume which causes sodium retention, potassium excretion and acid excretion in the collecting ducts of the nephrons

what is the adrenal medulla?

specialized part of the sympathetic nervous system that secretes epinephrine and norepinephrine

what are epinephrine (adrenaline) and norepinephrine (noradrenaline) produced and secreted in response to?

nervous stimulation

what increases the conversion of norepinephrine to epinephrine?

cortisol (paracrine function of cortisol)

how does the adrenal medulla function?

under stress or deviations from normal conditions

differs from the rest of the sympathetic nervous system that is involved in minute to minute fine regulation of most physiological process

what are epinephrine functions?

fight or flight, negative feedback via CNS-located alpha-2 receptors

what are results of fight or flight?

increased cardiac output, BP, blood glucose, sweating

decreased blood flow to non-vital tissues

dilated pupils

what does negative feedback via CNS-located alpha-2 receptors do?

decreases sympathetic outflow

what are adrenal disorders?

adrenal insufficiency (hypoadrenalism)

glucocorticoid (cortisol) excess

hypoaldosteronism

hyperaldosteronism

pheochromocytoma

what is adrenal insufficiency?

low cortisol, aldosterone

primary or secondary

what is primary adrenal insufficiency?

destruction/dysfunction of the adrenal cortex

what is secondary adrenal insufficiency?

decreased secretion of ACTH

can be from lesion anywhere along the hypothalamic-pituitary axis

can be caused by medical care- removal of the corticosteroids after long duration of tx (hypothalamus-pituitary-adrenal-axis “shut-off” with extended use)

how does critical illness affect hypothalamic-pituitary-adrenal axis?

becomes down-regulated with critical illness

similar to what happens to hypothalamic-pituitary-thyroid axis

what are the two main causes of addison’s disease?

autoimmune destruction of cortex by anti-adrenal antibodies (80% of causes)

TB

what is an example of adrenal insufficieny?

addison’s disease

who is autoimmune destruction of cortex by anti-adrenal antibodies more common in?

women

what can we measure with autoimmune destruction of cortex by anti-adrenal antibodies?

21-hydroxylase antibodies in serum

how much of the adrenal gland does TB involve?

entire gland

what do we see on CT scan for TB?

visible calcifications

what are rare causes of addison’s disease?

adrenal hemorrhage (sepsis, anticoagulation issues)

adrenoleukodystrophy, amyloidosis, histoplasmosis

congenital adrenal hyperplasia

meds (metyrapone, ketoconazole)

familial glucocorticoid deficiency

hemochromatosis

HIV

malignancy, metastasis, lymphoma

sarcoidosis

what are sx of primary adrenal insufficiency?

weakness, fatigue, wt loss

“lassitude”

hyperpigmentation (primary)- overproduction of ACTH, ACTH has melanin activity

vague abdominal complaints (diarrhea, constipation)

dizziness, hypotension, postural hypotension, syncope

musculoskeletal pain

sluggish mentation

salt craving

what are lab abnormalities of primary adrenal insufficiency?

hyponatremia (cortisol deficiency → increased ADH → hyponatremia)

hyperkalemia (d/t mineralcorticoid/aldosterone deficiency)

mild hyperchloremic acidosis (d/t low aldosterone)

hypoglycemia (decreased gluconeogenesis)

low cortisol (AM draw)

low plasma aldosterone levels

high plasma renin levels (compensatory to low aldosterone)

what is addisonian crisis?

acute adrenal insufficiency typically induced by stress (severe illness, trauma, surgery)

emergency situation due to insufficient cortisol → acute deterioration

what are sx of addisonian crisis?

fever, n&v, hypoglycemia, orthostatic hypotension, heart failure, shock, coma

what must we check if we suspect addisonian crisis?

plasma ACTH, serum cortisol, serum glucose, BUN/Cr and electrolytes, obtain blood cultures

what is the tx for addisonian crisis?

while waiting on results tx is started with IV hydrocortisone and IV fluids (normal saline, if hypoglycemic present use NS + dextrose)

tx electrolyte abnormalities and hypoglycemia if needed

start broad spectrum abx until culture results received

what is ACTH (cosyntropin) test?

measure serum cortisol level (8am)

if low/indeterminate do a rapid ACTH stimulation test

pt given 250mcg ACTH

pre and post serum cortisol levels drawn

how do we differentiate between primary vs secondary/tertiary hypoaldrenalism?

measure ACTH level

secondary: lack of pituitary ACTH

tertiary: lack of CRH from hypothalamus

how long is adrenal insufficiency tx?

typically lifelong

what is the tx for adrenal insufficiency?

replace glucocorticoid and mineralocorticoid activity (hydrocortisone will replace both, prednisone and fludrocortisone combo)

stress dose steroid required for states of increased stress (surgery, illness, double hydrocortisone maintenance dose)

MUST monitor for sx of over or under replacement (fatigue may indicate under tx, neutrophilia and lymphocytopenia may indicate over replacement)

what is an example of corticosteroid excess?

cushing’s syndrome and disease

what is cushing’s disease?

disorder of the pituitary gland (adenoma) which leads to excess ACTH produced leading to excess cortisol

results in hyperplastic adrenal glands, excess production of adrenal androgens (leads to hirsutism)

what can cushing’s disease be caused by (rare)?

rare cases can be due to non-pituitary source of excessive ACTH or ACTH-like protein that appears similar to cushing’s disease (small cell CA, neuroendocrine tumors)

what are types of cushing’s syndrome?

endogenous and exogenous

what is endogenous cushing’s syndrome?

increased cortisol production by adrenal cortex

independent of ACTH stimulation (ACTH levels usually low)

what is exogenous cushing’s syndrome?

most commonly iatrogenic = excess/prolonged corticosteroid use

what are sx of cushing’s syndrome?

central obesity, muscle wasting, hirsutism, acne, balding, purple striae, hyperpigmentation, thin extremities, moon facies, buffalo hump, superficial wound infections, poor wound healing, sexual dysfunction, menstrual irregularities, kidney stones, glaucoma, depression, sleep disturbances, impaired memory

what are associated complications (morbidity)?

osteoporosis, metabolic syndrome, htn

what may we be looking for when we find dx of cushing’s syndrome?

PCOS, htn, DM, incidental pituitary or adrenal mass

what are labs seen with cushings?

elevated a1c, elevated wbc, lymphocytopenia, hypokalemia (excess cortisol can act on mineralocorticoid receptors → increase aldosterone → Na retention and K loss), hyperlipidemia

what is the dx work up for cushing’s syndrome?

testing for hypercortisolism (need 2 out of 3):

lack of cortisol diurnal variation

reduced cortisol suppression with dexamethasone

increased 24 hr urine free cortisol

what is the 1st test for cushing’s syndrome?

late night (10-11pm) salivary cortisol level

useful for ACTH-dependent hypercortisolism

> 250ng/dL = abnormal

must avoid smoking, chewing tobacco, eating licorice which can falsely elevate levels

what is the 2nd test for cushing’s syndrome?

overnight dexamethasone suppression test

what is the overnight dexamethasone suppression test?

dexamethasone 1mg given at 11pm

serum cortisol level collected at 8am following morning (normal is < 1.8 mcg/dL)

what does normal overnight dexamethasone suppression test exclude?

cushing’s syndrome

what can affect overnight dexamethasone suppression test?

antiseizure meds

estrogen (pregnancy, BCP, HRT) can decrease dexamethasone suppressibility

cushing’s disease may require high dose dexamethasone (2mg) to cause suppression

do ectopic ACTH tumors suppress dexamethasone levels?

no

what is the 3rd test for cushing’s syndrome?

24 hour urine free cortisol and creatinine

what is 24 hour urine free cortisol and creatinine?

Typically used to confirm hypercortisolism if high late-night salivary cortisol or abnormal dexamethasone suppression test

High 24 hr urine free cortisol = > 50mcg/day

Can be increased in pregnancy

what do we do once hypercortisolism is confirmed?

measure plasma ACTH and/or DHEAS

determine if ACTH dependent or independent

adrenal mass vs pituitary lesion?

what is the probable cause of low plasma ACTH and low DHEAS?

adrenal tumor

increased levels are produced by pituitary or ectopic ACTH-secreting tumor

what else can we use instead of ACTH to determine cushings?

DHEAS since secretion is ACTH dependent

what does it mean if DHEAS is low?

implies ACTH is low → ACTH-independent hypercortisolism

what is imaging we can get for ACTH-independent cushing’s syndrome?

CT of adrenals can detect mass/adrenal adenoma/carcinoma (adrenocortical carcinoma tend to be larger)

what is imaging we can get for ACTH-dependent cushing’s syndrome?

MRI of pituitary gland

what can we do for evaluation for ectopic source of ACTH?

CT of chest and abdomen (lung- carcinoid or small cell CA, thymus, pancreas, adrenals)

what is the tx for cushing’s?

tx associated abnormalities- hypokalemia, htn, osteopenia, screen for infections, prevention/tx

what is the tx for cushing’s disease due to pituitary lesion?

transsphenoidal surgical resection

screen for secondary hypothyroidism 1-2 weeks post surgery

may require replacement with hydrocortisone or prednisone + florinef until endogenous pituitary-adrenal axis “re-awakens” (resection can lead to hypoadrenalism)

can develop adrenal insufficiency/cortisol withdrawal syndrome

if surgery unsuccessful, may require bilateral adrenalectomy (immediate remission)

will require LIFELONG steroid replacement

what is the tx for ectopic ACTH-secreting tumor?

surgically resected (if unable → bilateral adrenalectomy)

what is the tx for benign adrenal adenomas?

laparoscopic resection, may require adrenalectomy

what is the tx for adrenocortical carcinoma?

surgical resection

what do we do for cushing’s if surgery not successful or pt declines?

medical management:

osilodrostat- reduces cortisol synthesis (blocks adrenal enzyme 11b- hydroxylase)

ketoconazole- inhibits adrenal steroid production (? effectiveness, SE of liver toxicity)

mitotane- kills off adrenal tissue; approved for adrenocortical carcinoma

what is another term for hypoaldosteronism?

renal tubular acidosis type 4

what is hypoaldosteronism characterized by?

hyperkalemia

metabolic acidosis (hyperchloremic)

absence of a secondary cause (such as K-sparing diuretics, excessive K supplementation, ACE-I/ARBs)

Na wasting only clinically apparent in infants

what is hypoaldosteronism etiology?

aldosterone synthesis impairment, renal response to aldosterone impairment, renal release impairment (not releasing renin)

what causes aldosterone synthesis impairment?

Primary adrenal insufficiency (Addison’s)

Congenital adrenal hyperplasia

Isolated aldosterone synthase deficiency

Heparin administration

what causes renal response to aldosterone impairment?

Meds (amiloride, spironolactone, triamterene, trimethoprim, pentamidine)

Tubulointerstitial disease of nephrons

Pseudo-hypoaldosteronism

Distal chloride shunt

what causes renal disease impairment (not releasing renin)?

Renal disease (ex. DM nephropathy)

Volume expansion (seen in acute glomerulonephritis)

how many forms of aldosterone synthesis hereditary defects?

2

what are characteristics of aldosterone synthesis issues due to hereditary defects?

both auto-recessive inheritance

nearly indistinguishable except for loci of point mutations

infants present with recurrent dehydration, salt wasting and failure to thrive

what are causes of aldosterone synthesis issues?

type 1 and 2

CAH (congenital adrenal hyperplasia)

heparin (direct toxic effect on zona glomerulosa cells)

severe illness (adrenal insufficiency in critically ill)

how does spironolactone affect aldosterone?

blocks aldosterone receptors

how do amiloride, trimethoprim, triamterene affect aldosterone?

close sodium channels and collecting ducts on luminal side which blocks action of intracellular aldosterone

what causes pseudo-hypoaldosteronism?

receptor defects or channel defects

what does type 1 pseudo-hypoaldosteronism look like?

hypoaldosteronism but with high serum aldosterone level

what is common with type 2 pseudo-hypoaldosteronism?

associated htn

is hyporeninemic hypoaldosteronism common?

yes

what is hyporeninemic hypoaldosteronism?

impaired release of renin leading to decreased aldosterone production

what is hyporeninemic hypoaldosteronism related to?

renal insufficiency (DM nephropathy, chronic interstitial nephritis, acute glomerulonephritis)

can be due to meds (NSAIDs, ACE-I/ARBs, cyclosporin)

may also be seen with HIV infection

how do we dx hyporeninemic hypoaldosteronism?

hyperkalemia

check serum renin, aldosterone and cortisol levels (low renin and low aldosterone with NORMAL CORTISOL levels, if aldosterone and cortisol both low, think adrenal insufficiency or CAH)

evaluate urine Na levels (can see persistently high urine Na despite restricted Na diet due to the aldosterone deficiency/resistance)

how do we tx primary adrenal insufficiency?

Mineralocorticoid and glucocorticoid replacement