Adrenal Disorder

role of adrenal glands:

water and electrolyte homeostasis, regulation of blood pressure, carbohydrate and fat metabolism, physiologic response to stress, sexual development and differentiation

what are the 2 most common conditions associated with adrenal gland dysfunction?

adrenal insufficiency (Addison disease) and adrenal/glucocorticoid excess (Cushing syndrome)

where are the adrenal glands located?

on the upper segment of the kidneys

what are the adrenal glands made up of?

the cortex and inner medulla

what portion of the adrenal gland releases epinephrine and norepinephrine to regulate the sympathetic nervous system?

medulla.

what are the three zones of the adrenal cortex?

zona glomerulosa, zona fasciculata, zona reticularis.

what hormones are produced in the zona glomerulosa

mineralocorticoid hormones - aldosterone, 19-hydroxy-corticosterone, corticosterone, and deoxycorticosterone

which hormone promotes renal sodium retention and potassium excretion

aldosterone

what is aldosterone’s role in the RAAS system?

renin signals production and release of aldosterone in response to decreased vascular volume and renal perfusion

what does the zona fasciculata produce?

glucocorticoid hormone - cortisol

what is the role of cortisol

responsible for maintaining homeostasis of carbohydrates, protein, and fat metabolism; also plays a role in the body’s response to stress

which hormone increases during physiologic stress?

cortisol

when is cortisol secreted?

secreted with circadian rhythm

how much cortisol is produced in our bodies every day?

8-25 mg/day

what is cortisol converted to via the liver?

cortisone (inactive metabolite)

when is cortisol highest?

first thing in the morning (5-6 AM)

what does the zona reticularis produce?

androgens - androstenedione and dehydroepiandrosterone (DHEA)

T/F: androgens are the precursors to testosterone and estrogen

true

T/F: only a small amount of testosterone and estrogen directly produced by adrenal glands

true

describe the process of hormone release between hypothalamus, pituitary gland, and adrenals

hypothalamus releases CRH which signals the anterior pituitary gland to release ACTH (corticotropin) which signals the adrenal glands to release cortisol; when sufficient or excess cortisol is reached, negative feedback exerted on secretion of CRH and ACTH to decrease overall cortisol production

normal range of cortisol

5-25 mcg/dL

normal range for aldosterone

5-15 ng/dL

normal range for ACTH

15-80 ng/L

examples of glucocorticoids:

cortisol, cortisone, and cortisterone

examples of mineralocorticoids

adlosterone and deoxycorticosterone

which region of the adrenal gland secretes glucocorticoids

zona fasciculata

what region of the adrenals secretes mineralocorticoids

zona glomerulosa

what do glucocorticoids do in the body?

along with carb/fat/protein metabolism/homeostasis, they stimulate gluconeogenesis, anti-inflammatory and are helpful in injury/pain

why are glucocorticoids anti-inflammatory and helpful in injury/pain

inhibit release of pro-inflammatory molecules and prevent activation of immune cells

mineralocorticoid’s role in electrolyte/water balance

reabsorption of sodium and water, and excretion of potassium and protons

T/F: mineralocorticoids have minimal effects on inflammatory/pain

true

what is primary adrenal insufficiency (Addison’s disease)?

adrenal glands unable to produce cortisol; typically, autoimmune which causes destruction of the adrenal cortex; may also have reduction in aldosterone and androgen production

what is secondary adrenal insufficiency

pituitary gland dysfunction leading to decreased production and secretion of ACTH = decreased cortisol; aldosterone is unaffected

what is tertiary adrenal inefficiency

disorder of the hypothalamus resulting in decreased production and release of CRH which decreases pituitary ACTH production and release; aldosterone unaffected

what is the procedure for an unstimulated serum cortisol measurement test

measure serum cortisol at 6-8 AM

what would be the findings in an unstimulated serum cortisol measurement if patient had adrenal insufficiency?

serum cortisol < 3 mcg/dL

how are rapid ACTH stimulation tests done?

measure serum cortisol 30-60 minutes after administering cosyntropin 250 mcg IM or IV

what would be the findings in a rapid ACTH stimulation test if patient had adrenal insufficiency?

serum cortisol concentration < 18-20 mcg/dL; if measurement of serum cortisol is low, measure ACTH, aldosterone, and renin to differentiate between primary, secondary, or tertiary

how are insulin tolerance tests done?

administer insulin IV to induce hypoglycemia (confirm BG < 40 mg/dL), then measure serum cortisol during symptomatic hypoglycemia

what would be the findings in an insulin toelrance test if patient had adrenal insufficiency?

serum cortisol concentration < 18 mcg/dL is indicative of secondary adrenal insufficiency

how are overnight metyrpone tests done?

administer metyrapone at midnight, then measure serum cortisol at 8 AM the next day

what would be the findings in an overnight metyrapone test if patient had adrenal insufficiency?

normal response is decrease in serum cortisol to < 5 mcg/dL, and increase in 11-deoxycortisol to > 7 mcg/dL; response is not seen in adrenal insufficiency which distinguishes between normal individuals and those with secondary adrenal insufficiency

how are plasma ACTH concentration tests done?

measure plasma ACTH

why are plasma ACTH concentration tests done?

in primary insufficiency, hypercortisolism leads to elevated ACTH concentration via positive HPA axis feedback

what would be the findings in a plasma ACTH concentration test if patient had adrenal insufficiency?

primary: elevated plasma ACTH

secondary or tertiary: plasma ACTH low or inappropriately normal

how are plasma aldosterone concentrations done

measure plasma aldosterone from same blood samples as those used in ACTH stimulation test

why are plasma aldosterone concentration tests done?

patients with primary insufficiency may experience reduction in aldosterone production

what would be the findings in a plasma aldosterone concentration test if patient had adrenal insufficiency?

primary: low plasma aldosterone

secondary or tertiary: aldosterone is normal > 5 ng/dL

how are plasma renin concentrations or activity done

measure plasma renin concentration or activity

why is plasma renin concentration or activity done

mineralocorticoid deficiency occurs in primary, but not usually in secondary or tertiary

what would be the findings in a plasma renin concentration or activity test if patient had adrenal insufficiency?

primary: elevated plasma renin

secondary or tertiary: normal

how to take glucocorticoids:

take with food to minimize GI upset

CI of glucocorticoids

live vaccines and serious systemic infections

warnings for use of glucocorticoids

adrenal suppression - HPA axis suppression may lead to adrenal crisis and death; if taking longer than 14 days, must taper slowly

what can glucocorticoids cause?

immunosuppression, psychiatric disturbances, Kaposi sarcoma, worsening of CHF, diabetes, hypertension, osteoporosis

long term side effects of glucocorticoids:

anxiety, depression, delirium, hypothyroidism, acne, glaucoma, cataracts, fat deposits in face (moon face), abdomen, and upper back (buffalo hump), pink-purple stretch marks on abdomen, thighs, breasts, easy bruising, growth retardation and muscle wasting in arms and legs, infection, impaired wound healing, GI bleeding, esophagitis, ulcers, poor bone health, and in women: hair growth on face and menstrual period changes

how to treat primary adrenal insufficiency with glucocorticoids

hydrocortisone 15-25 mg daily into 1-2 divided doses; with the highest dose being administered in the morning upon awaking and the second dose in the early afternoon ~2 hours after lunch

alternative treatment options or primary adrenal insufficiency with glucocorticoids

cortisone acetate 20-35 mg daily into 2 divided doses

prednisone 3-5 mg/day once to twice daily (optimized in those with non-adherence)

T/F: dexamethasone is not recommended to treat primary adrenal insufficiency due to long-acting effect/difficulty titrating

true

what are the broad treatment options for primary adrenal insuffiency

glucocorticoid replacement ± mineralocorticoid replacement

how to treat primary adrenal insufficiency if patient also has low aldosterone

add on fludrocortisone 0.05 to 0.1 mg once daily in the morning (titrate up to 0.2 mg daily); Do not sodium restrict

what are some indications to increase the dose of fludrocortisone in primary adrenal insufficiency

hypotension, dehydration, hyponatremia/salt craving, hyperkalemia

how to treat secondary or tertiary adrenal insufficiency

glucocorticoid therapy with oral hydrocortisone or another agent, lower doses are often required, and mineralocorticoid therapy with fludrocortisone therapy is generally NOT needed

what is the leading cause of hypercortisolism (Cushing syndrome)?

chronic supraphysiologic doses of corticosteroids; other drugs with glucocorticoid activity such as megestrol and medroxyprogesterone

what can Cushing syndrome lead to if left untreated

cardiovascular disease, cardiac hypertrophy, and osteoporosis

how does ACTH independent hypercortisolism occur

ACTH-secreting adenoma or CRH-secreting adenoma; ACTH secreting pituitary adenoma raising plasma ACTH and cortisol

how does ACTH-dependent hypercortisolism occur

excessive cortisol secretion by the adrenal glands or exogenous glucocorticoid administration; plasma ACTH will not be elevated; elevate cortisol levels suppress ACTH secretion via negative feedback loop

T/F: to get diagnosed with hypercortisolism you must have 2 positive tests

true

what are the findings in 24-hour urinary-free cortisol tests in Cushing’s?

elevated urinary-free cortisol (value dependent on assay)

how are overnight dexamethasone suppression test (DST) done

administer 1 mg PO dexamethasone at 11 PM then measure plasma cortisol at 8-9 AM

what are the findings of overnight DST in Cushing’s

plasma cortisol < 1.8 mcg/dL is NOT suggestive of Cushing syndrome

how are late-night salivary cortisol tests done

collect salivary cortisol at 11 PM

what are the findings of late-night salivary cortisol tests in Cushings

elevated results

broad treatment options for Cushing’s syndrome:

stop offending agent gradually for exogenous, reverse hypercortisolism and prevent complications (medications in endogenous), and surgical resection for endogenous tumor

how to treat exogenous hypercortisolism disease

taper the patient off the offending agent; abrupt discontinuation can result in adrenal insufficiency and/or exacerbate current condition

which patients receiving steroids should receive a steroid taper when treating exogenous hypercortisolism

patients receiving doses of 5-7.5 mg of prednisone (or equivalent) for over 3 weeks or more ORR patients receiving 40 mg of prednisone (or equivalent) for 1 week or more

how to taper in patients receiving chronic supraphysiologic doses for adrenal insufficiency

gradually taper to 20 mg of prednisone or equivalent per day in the morning, then decrease to every other day, then stop when physiologic dose is reached (5-7.5 mg of prednisone/day)

how long can it take to have recovery of HPA axis after stopping offending agents of hypercortisolism

may take up to 1-year

when is treatment indicated for endogenous hypercortisolism

ACTH-secreting tumor cannot be localized, control cortisol level prior to surgery, not surgical candidates, failed surgery or relapsed, having Cushing disease awaiting effect of pituitary radiation

T/F: adrenal steroidogenesis inhibitors will inhibit enzymes to decrease the synthesis of cortisol

true

which drugs can be used for endogenous hypercortisolism

PO ketoconazole, IV etomidate, PO mifepristone, PO metyrapone, and SC pasireotide

MOA of PO ketoconazole

inhibitor of adrenal steroidogenesis; also inhibits cholesterol synthesis

ADRs of PO ketoconazole

generally well tolerated but may see symptoms of adrenal insufficiency, gynecomastia, decreased libido, impotence, or hepatotoxicity

comments regarding PO ketoconazole

effective in majority of causes with rapid improvement seen; monitor efficacy with urinary cortisol; monitor LFTs for hepatotoxicity; useful in women with hirsutism and those with hyperlipidemia (HLD); not useful in those taking PPIs, ATC, H2RAs, or with achlorhydria; strong CYP3A4 inhibitor and potential for QTc prolongation and dysrhythmia drug interactions

MOA of IV etomidate

inhibitor of adrenal steroidogensis

ADRs of IV etomidate

injection site pain, N/V, myoclonus, hypotension

comments on IV etomidate

general anesthetic; reserved for patients with more severe symptoms and in emergency settings

MOA of PO mifepristone

antagonizes glucocorticoid receptors (peripheral glucocorticoid antagonist)

ADRs of PO mifepristone

N/V, fatigue, HA, hypokalemia, arthralgia, peripheral edema, HTN, dizziness, decreased appetite, endometrial hypertrophy, prolonged QTc interval, abortifacient and embryotoxic

comments of PO mifepristone

FDA approved for control of hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing syndrome who have T2DM or glucose intolerance and failed or are not candidates for surgery; increases cortisol and ACTH levels via antagonism of negative feedback of ACTH secretion; requires cautious use as cannot use cortisol or ACTH levels to monitor, efficacy, limited clinical experiences; quicker relative effectiveness inhibits CYP3A4

MOA for PO metyrapone

inhibitor of adrenal steroidogenesis, also suppresses aldosterone synthesis

ADRs of PO metyrapone

generally, well tolerated but may see hirsutism, acne, adrenal insufficiency, GI intolerance, rash, hypokalemia, edema, HTN

comments on PO metyrapone

used in Cushing disease, ectopic ACTH syndrome and adrenal carcinoma; also used as a test to diagnose adrenal insufficiency

MOA of SC pasireotide

somatostatin analog - binds to somatostatin receptor over-expressed in corticotroph tumor cells, inhibiting ACTH secretion

ADRs of SC pasireotide

hyperglycemia, GI pain, N/D, A, fatigue, bradycardia, QTc prolongation, LFT elevation, cholelithiasis, pituitary hormone inhibition

comments on SC pasireotide

FDA approved for treatment of adult patients with Cushing disease for whom pituitary surgery is not an option or has failed. Measure response based on 24-hour urinary-free cortisol level and/or improvement in signs/symptoms

what drugs need to be used when patients get transsphenoidal pituitary microsurgery

treatment of choice - requires exogenous glucocorticoids for months due to HPA axis suppression

which drugs do patients need if they get pituitary irradiation

requires cortisol-lowering treatment

which drugs do patients need if they get a bilateral adrenalectomy

lifelong glucocorticoid and mineralocorticoid treatment - 100% cure rate

what drugs do patients need to take if they have an unilateral laroscopic adrenalectomy

glucocorticoids before and after surgery due to atrophy and HPA axis suppression