Adrenal/Pituitary Flashcards
What conditions results from hyperfunction of the adrenal glands?
Cushings syndrome
Hyeraldosteronism
What conditions result from hypofunction of the adrenal glands?
Primary adrenal insufficiency- addisons disease
Secondary adrenal insufficiency
What is the adrenal gland regulation and function?
- Hypothalamus releases corticotropin releasing hormone (CRH)
- Stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary
- ACTH stimulates the adrenal gland to release cortisol (also releases aldosterone and androgens)
- As cortisol levels rise it inhibits further release of CRH and ACTH through negative feedback
- Renin is released from the kidney (In response to ↓ blood pressure, salt depletion, CNS excitation)
- Conversion of angiotensinogen to angiotensin I then II stimulates aldosterone synthesis (Renal sodium and water retention and increased BP occur as a result of aldosterone secretion)
- Negative feedback to turn off renin release
What is involved with cushings syndrome?
↑adrenal function =↑cortisol production
Excess of cortisol in the plasma- hypercortisolism
What is the cause of Cushing’s Syndrome?
ACTH-dependent:
Pituitary tumor: excess ACTH secretion
Stimulates adrenal glands to secrete excess cortisol
Ectopic disease: ACTH secretion from another tumor
ACTH-independent: abnormal adrenocortical tissues (ACTH is functioning fine but you are still releasing too much cortisol)
Adrenal adenoma: benign
Adrenal carcinoma
Exogenous Steroids
What is the clinical presentation of Cushing’s Syndrome?
- Altered Fat Distribution- Central obesity
- Purple striae along the lower abdomen
- Facial rounding- “moon face”
- Supraclavicular fat pads
- Fat accumulation in the dorsocervical area- “buffalo hump”-Fat accumulation over chest & abdomen
- Hypertension
- Glucose intolerance
- Muscle weakeness
- Osteoporosis
- Psychiatric changes
- Gonadal dysfunction- Amenorrhea
How is Cushing’s syndrome diagnosed (confirmation)?
- Elevated urinary free cortisol- confirms hypercortisolism
- Plasma ACTH concentrations determine the etiology
Pituitary dependent
Ectopic ACTH
Adrenal Adenoma
Adrenal Carcinoma
What is the treatment of choice for Cushing’s syndrome?
Dependent on the etiology
Surgery is the treatment of choice
Transphenoidal removal of the pituitary tumor
Removal of the adrenal glands
Patient will require life-long treatment with glucocorticoids and mineralcorticoids
Steroidogenic inhibitors (Metyrapone (Metopirone®))- indications
Used for non-surgical candidates with cushings disease
Steroidogenic inhibitors (Metyrapone (Metopirone®)) - MOA
Steroidogenic inhibitors: inhibit synthesis and secretion of cortisol from the adrenal gland
Metyrapone (Metopirone®)- MOA
inhibits 11-hydroxylase activity in the adrenal cortex
Sudden drop in cortisol levels can result in an increase in plasma ACTH levels → increased androgenic and mineralcorticoid levels
Metyrapone (Metopirone®) (steroidogenic inhibitor)- indications
Used for Ectopic ACTH (something is causing the release of ACTH and it cant be reverse and these people are not candidates for surgery)
Metyrapone (Metopirone®) (steroidogenic inhibitor)- adverse effects
N/V
Hypertension
Alopecia
Hirsutism
Aminoglutethimide (Cytadren®) (steroidogenic inhibitor)- MOA
inhibits conversion of cholesterol to pregnenolone in adrenal glands
Blocks conversion of androstenedione to estrone and estradiol in the peripheral tissues
↓ production of cortisol, aldosterone, and estrogens
Aminoglutethimide (Cytadren®) (steroidogenic inhibitor)- Indications
Used for ectopic ACTH syndrome
Aminoglutethimide (Cytadren®) (steroidogenic inhibitor)- Adverse effects
N/V
Sedation
Hypothryoidism- blocks synthesis of thyroxine
Can cause problems with amenorrhea and fertility due to estrogen suppression
Ketoconazole (Nizoral) (Steroidogenic inhibitors)- MOA
imidazole antifungal agent
Also inhibits androstenedione synthesis
Ketoconazole (Nizoral) (Steroidogenic inhibitors)- Indications
Used for adrenal adenoma
Ketoconazole (Nizoral) (Steroidogenic inhibitors)- Adverse effects
Hepatotoxicity (need to monitor LFTs)
Gynecomastia (due to decreased testosterone levels)
Nausea
Ketoconazole (Nizoral) (Steroidogenic inhibitors)- drug interations
Inhibits CYP3A4, 1A2, 2C9, 2D6, 2A6
Ketoconazole (Nizoral) (Steroidogenic inhibitors)- absorption
Absorption requires an acidic pH
Administer 2 hours before antacids to reduce chance of decreased absorption
What are the adrenolytic agents?
Mitotane (Lysodren®)
Mitotane (Lysodren®) (adrenolytic agents)- MOA
cytotoxic drug that results in atrophy of the adrenal cells
Mitotane (Lysodren®) (adrenolytic agents)- indications
Used for adrenal carcinoma
Mitotane (Lysodren®) (adrenolytic agents)- adverse effects
Severely suppresses adrenal function (need to monitor urinary free cortisol)
N/V- administer w/ food
Lethargy and somnolence
Hypercholesterolemia
What causes primary hyperaldosteronism?
Abnormality is within the adrenal cortex
Aldosterone producing adenoma
Bilateral adrenal hyperplasia (BAH)
What do you screen with to detect primary hyperaldosteronism?
Screen with plasma aldosterone to plasma-renin activity ratio.
What causes secondary hyperaldosteronism?
Stimulation of the zona glomerulosa by an extraadrenal factor Usually the RAAS Other causes Excessive potassium intake Pregnancy CHF Cirrhosis Renal artery stenosis
What are the signs and sx of hyperaldosteronism?
Hypertension Hypervolemia Hypokalemia Hypernatremia- Leads to fluid retention Muscle weakness Fatigue Headache
What is the treatment for hyperaldosteronism?
Surgery if the cause is an adenoma
Spironolactone is the drug of choice : Aldosterone antagonist
Interferes with testosterone biosynthesis
What are the monitoring parameters with spirolactone?
Blood Pressure
Sodium and potassium
SCr
What are the adverse effects of spirolactone?
Hyperkalemia
Gynecomastia
Eplerenone (Inspra)
Hyperaldosteronism treatment
aldosterone antagonist
Less affinity for other steroid receptors
Use as an alternative for patients who can’t tolerate the anti-androgenic side effects of spironolactone
Monitor: Na, K, blood pressure, and renal function
Amiloride
Hyperaldosteronism treatment
potassium sparing diuretic
Not as effective as the aldosterone antagonists
Monitor: Na, K, blood pressure, and renal function
Typically need another agent for additional blood pressure control
What is Primary hypofunction of the adrenal gland (adrenal insufficiency) (addison’s disease) due to?
Destruction of the adrenal cortex
Deficiency in cortisol, aldosterone and androgens
What is secondary hypofunction of the adrenal gland (adrenal insufficiency) due to?
Suppression of the HPA axis from exogenous steroid use
ACTH deficiency
Deficiency in cortisol and androgens
Not mineralcorticoids
Which pathways does primary adrenal insufficiency block?
The glucocorticoids (cortisol) and mineralcorticoid (aldosterone)
What are the signs and sx of adrenal insufficiency?
- Weakness/fatigue
- Anorexia- Weight loss
- N/V, abdominal pain
- Can lead to adrenal crisis
- Hypotension- Postural dizziness
- Salt craving
- Hyperpigmentation
- Muscle/Joint symptoms
- Sexual dysfunction
What are the laboratory findings of chronic primary adrenal insufficiency?
Hyponatremia
Hyperkalemia
Hypercalcemia
Azotemia
How is adrenal insufficiency usually diagnosed?
COSYNTROPIN STIMULATION TEST FOR DIAGNOSIS
Cosyntropin is synthetic ACTH
In normal adrenal function you would expect plasma cortisol levels to rise after stimulation by ACTH
Administer 250 mcg cosyntropin IV or IM, draw serum cortisol levels at baseline and then at 30-60 minutes post dose
An increase in serum cortisol level ≥ 18 mcg/dL rules out adrenal insufficiency
What is another test that can be done for adrenal insufficiency diagnosis but is more specific and sensitive?
Low dose cosyntropin test
1 mcg cosyntropin IV with a baseline serum cortisol and a 30 minute post dose serum cortisol
Requires a more carefully timed sample
Administered IV
More sensitive than the 250 mcg dose test
Which side of the pathway needs replaced in primary adrenal insufficiency?
Both
What is the goal of treament with adrenal insufficiency?
Goal is to mimic endogenous cortisol production
What is diurnal variation?
More cortisol is produced in the early morning than in the evening (very little cortisol is produced from 6pm-3am)
What is the treatment for adrenal insufficiency?
Glucocorticoid replacement is needed in primary and secondary adrenal insufficiency
Endogenous secretion is ~5-10 mg/m2 of cortisol
Equivalent to 5 mg prednisone or 20 mg hydrocortisone
Short-acting glucocorticoid regimens:
Hydrocortisone
15-30 mg/day divided BID
Give ~ 2/3 of the total daily dose in the morning and 1/3 in the afternoon
What are the alternative glucocorticoid regimens?
Cortisone 25 mg in the am 12.5 in the pm
Prednisone 5 mg in the am 2.5 mg in the pm
Dexamethasone 0.5 mg in the am 0.25 mg in the pm
Prednisone and dexamethasone have longer half-lives
When should glucocorticoids be given?
In the morning.
Glucocorticoids- Dose adjustment
-Use lowest dose possible and titrate up
-Monitor symptoms every 6 to 8 weeks
-Signs of glucocorticoid excess: reduce the dose
Body fat redistribution
Mood changes/sleeping difficulty
Glucose intolerance
Muscle weakness
-If presenting signs and symptoms of adrenal insufficiency don’t resolve: increase the dose
-If patient feels symptoms at a certain time of day, can adjust dosing intervals
What is a mineralcorticoid replacement drug?
Fludrocortisone (Florinef)
Fludrocortisone (Florinef)- Indication
Only necessary in PRIMARY insufficiency (Addison’s disease)
Goal: prevent hyponatremia, hyperkalemia, intravascular volume depletion
What are the signs of an insufficient mineralcorticoid dose (Fludrocortisone (Florinef))?
Hypotension
Hyponatremia
Hyperkalemia
What are the signs of excess mineralcorticoid dose (Fludrocortisone (Florinef))?
Hypertension
Edema
Hypokalemia
What is suppressed with long term use of high dose glucocorticoids?
The hypothalamus pituitary axis
What needs to be replaced in secondary adrenal gland insufficiency?
Glucocorticoids (Cortisol)
What occurs in secondary adrenal insufficiency?
Suppression of the hypothalamic-pituitary-adrenal (HPA) axis
One way of doing this Is by administering high doses of glucocorricoids for a long time like in those with cancer.
Long-term suprapysiologic doses of glucocorticoids
After treatment is stopped the adrenal glands can’t generate enough cortisol on their own (HPA axis has been suppressed by the steroids they were receiving and doesn’t realize it needs to make its own hormones?)
Risk for HPA axis suppression
↑ potency = ↑ risk of suppression
Dexamethasone>prednisone>hydrocortisone
Supraphysiologic doses
What are the signs and sx after glucocorticoid withdrawl?
Malaise, myalgias, weakness, fatigue, anorexia
What is the risk factor associated with glucorticoid use in secondary adrenal insufficiency?
Duration of therapy is a risk factor
Low risk when therapy is < 1 week (Even if high dose steroids)
How are glucocorticoids tapered?
Glucocorticoid tapering – no evidence based guidelines
↓ prednisone (or equivalent) by 2.5-5 mg q 3-7 days until you reach 5-10 mg/day
Switch to am hydrocortisone or alternate day dosing
Either use morning cortisol levels to determine adrenal suppression or a very gradual
When is it okay to stop the use of glucocorticoids and when do you still need to continue tapering?
- If am cortisol >20 mcg/dL the HPA axis has recovered (means you can discontibue the exogenous steroids)
- If am cortisol < 3 mcg/dL the HPA axis is still suppressed
- If am cortisol 3-20 mcg/dL use another test: cosyntropin stim test
What is the adverse effects of withdrawl of glucocorticoids?
Flare-up of underlying disease
Acute adrenal insufficiency- symptoms of withdrawl=symptoms of adrenal insufficiency
What are the general adverse effects of chronic glucocorticoids use?
- Weight gain
- Increased appetite
What are the CNS adverse effects of chronic glucocorticoids use?
- Mood changes- euphoria -> depression
- Psychosis (rare)
What are the opthamology adverse effects of chronic glucocorticoids use?
- Cataracts: later in life (children would show up with them later in life, but more risky for the elderly)
- Glaucoma due to increased intraocular pressure
What are the CV adverse effects of chronic glucocorticoids use?
- HTN
- Dyslipidemia (Increased TC, LDL, TG)
What are the heme adverse effects of chronic glucocorticoids use?
- Immunosuppression
- Infection
- Impaired wound healing
What are the GI adverse effects of chronic glucocorticoids use?
- Peptic ulcer disease
- Controversial, may occur more w/ NSAID use
- Suppression of response to H. Pylori
What are the bone adverse effects of chronic glucocorticoids use?
- Osteoporosis: inhibition of bone formation (DEXA scan to assess bone mineral density) (>5mg/day of prednisone equivalent for >3mo tx needs preventative bisphosphonate therapy plus 1500mg elemental calcium & 800-1200 units vit. D/Day)
- Aseptic Necrosis Hip
- Growth suppression (PO steroids in asthma and kids w/ cancer)
- Myopathy
What are the endocrine adverse effects of chronic glucocorticoids?
-Cushing’s syndrome
-Adrenal suppression (not seen until steroid is taken away)
-Glucose Intolerance/Diabetes mellitus (DM)/Exacerbation of DM (↓ insulin sensitivity
↑ gluconeogenesis)
- Mineralcorticoid ADR- kidney and RAA system
What are the skin adverse effects of chronic glucocorticoids use?
- Acne
- Easy bruising (loss if collagen support for blood vessels)
- Thin skin (atrophy of epidermal and dermal skin layers)
- Striae (atrophy of the subcutaneous tissue)
What should you counsel patients on that are taking glucocorticoids?
- TAKE THEM WITH FOOD
- NEVER STOP STEROID THERAPY ABRUPTLY
- Carry or wear a medical ID (patients on chronic glucocorticoids or those with adrenal insufficiency)
- Ensure daily calcium intake is adequate
- Adverse reactions
How long does a patient have to be taking a steroid for them to have to taper before stoping?
Anyone taking a steroid for longer than a week cannot stop the steroid abruptly and needs to taper
What causes acute adrenal insufficiency (adrenal crisis)?
Trauma, surgery, illness or stress activate the HPA axis
Increased CRH → ACTH →cortisol production
What are the signs and sx of acute adrenal insufficiency (adrenal crisis)?
SHOCK
Coma
N/V, weakness, lethargy
Patients with adrenal insufficiency require stress doses of glucocorticoids in the above situations
What is the inpatient tx for acute adrenal insufficiency (Adrenal crisis)?
Hydrocortisone 100mg IV push followed by continuous infusion or 100mg Q6-8° x 48 hrs, then taper
IV fluids (D5NS)
BP support
Fludrocortisone (kinda like aldosterone it’s a mineral corticoid) if needed to decrease potassium levels
What should you educate patients about for adrenal crisis?
Emergency situations- can precipitate an adrenal crisis
Injury with substantial blood loss or a fracture
N/V and inability take PO medications
Unresponsive patient
Patients with primary adrenal insufficiency should wear a medical alert bracelet
Patients should carry an injectable glucocorticoid (100 mg hydrocortisone or 4 mg dexamethasone)
What hormones is the anterior pituitary responsible for?
- Growth hormone (GH or somatropin)
- Prolactin
- Adrenocorticotropic hormone (ACTH)
- Thyroid stimulating hormone (TSH)
- Luteinizing hormone (LH)
- Follicle-stimulating hormone (FSH)
What hormones is the posterior pituitary responsible for?
- Oxytocin
- Vasopresin (antidiuretic hormone)
What is an excess production of GH typically due to a GH-secreting pituitary adenoma?
Growth hormone (GH) excess Acromegaly
What are the sx of acromegaly?
Slow onset of symptoms- overtime Soft tissue overgrowth High mortality risk Cardiovascular Respiratory Neoplastic disease
How is GH excess (acromegaly) diagnosed?
Oral glucose tolerance test followed by a GH level
GH level >1 mcg/L
Elevated IGF-1 levels
Why should you start with an oral glucose tolerance test followed by a GH level?
Give oral glucose tolerance test first to distinguish if the elevated growth hormone level is related to patient not having sugars right now. GH takes up sugars so you need to double to take it up so if glucose is too low then you might have a higher GH so you need to do that
*Tried typing this in class while she was talking doesn’t make much sense now but i feel like its important ahhah
What is the treatment for GH excess (acromegaly)?
Surgery (First line treatment)
Pharmacologic treatment (Done only while patient is waiting for surgery or if there are contraindications)
Somatostatin analogs
More potent GH secretion inhibitors than endogenous somatostatin
Dopamine agonists
Decrease GH production
GH receptor antagonist
Blocks the effects of GH on target tissue
Octreotide (Sandostatin®, Sandostatin LAR®)- Indication
Somatostatin Analog
FIRST LINE THERAPY FOR GH EXCESS (ACROMEGALY)
Octreotide (Sandostatin®, Sandostatin LAR®)- Adverse effects
Nausea, diarrhea Hyperglycemia Arrhythmias Hypothyroidism Cholelithiasis
Bromocriptine (Parlodel®) & Ergot alkaloid- Indications
Dopamine agonists
Used in treatment of growth hormone excess (acromegaly)
Bromocriptine (Parlodel®) & Ergot alkaloid- clinical response
Clinical response seen after 4-8 weeks of therapy (clinical effect)
Reduces GH levels within 1-2 hours (clad effect)
Bromocriptine (Parlodel®) & Ergot alkaloid- Adverse effects
N/V- most common
Headache
Dizziness
Hypotension
Pegvisomant (Somavert®) - MOA
GH receptor antagonist
Binds to GH receptors on the cell surface
Pegvisomant (Somavert®) - indications
FDA approved for acromegaly as 2nd line therapy. (Only used after starting other meds and they aren’t working very successfully)
Pegvisomant (Somavert®) - response
Response is seen in 2 weeks
Pegvisomant (Somavert®) - adverse effects
Nausea, diarrhea
AST, ALT elevations
Monitor liver function tests during treatment
What is the post common presentation of GH deficiency?
Short stature
What is involved with short stature?
> 2 SD below the population mean and lower than the third percentile for height in a specific age group
Prominence of the forehead
Immaturity of the face
Central obesity
Can also occur with other conditions not associated with GH deficiency
What is GH deficient (GHD) short stature?
True lack of GH (children are usually born with an average birth weight)
Is GH insufficiency a congenital or acquired disorder?
Acquired
Recombinant GH- Indications
- First line for children with GHD short stature
- Improves growth velocity in the first year of treatment
Other FDA Indications
- Turner’s syndrome
- Prader-Willi’s syndrome
- Children with chronic renal insufficiency
- Idiopathic short stature
- Adult GH deficiency
- Short-bowel syndrome
- AIDS wasting syndrome
What do all recombinant GH products contain?
Somatropin
What are the 11 products available for recombinant GH?
Genotropin Humatrope Norditropin Nutropin Nutropin AQ Nutropin Depot- once or twice montly injection Omnitrope Saizen Serostim Tev-Tropin Zorbtive
*Don’t have to memorize in test she will indicate that it is a GH recombinant
Recombinant GH- Route
All given IM or SC
Continue therapy until growth velocity decreases to <2.5 cm/year after puberty
Recombinant GH- Adverse effects
- Well tolerated
- Slipped capital femoral epiphysis
- Idiopathic intracranial hypertension
What are the recombinant insulin-;like-growth factor-1 (IGF-1) drugs?
Mescasermin (Increlex®) Mescasermin rinfabate (Iplex®)
Mescasermin (Increlex®), Mescasermin rinfabate (Iplex®) (recombinant insulin-;like-growth factor-1 (IGF-1))- Indications
Approved for children with short stature due to primary IGF-1 deficiency
Mescasermin (Increlex®), Mescasermin rinfabate (Iplex®) (recombinant insulin-;like-growth factor-1 (IGF-1))- adverse effects
HYPOGLYCEMIA- INSULIN LIKE EFFECTS
Dizziness
Arthralgias
What is hyperprolactinemia?
Persistent prolactin levels > 20 mcg/L
Affects women of reproductive age
Incidence < 1%
What is the etiology for hyperprolactinemia?
Prolactinomas
Drug-induced
What does 10x ↑Prolactin levels inhibit?
10x ↑Prolactin levels inhibit gonadotropin secretion and sex-steroid synthesis
Increased risk of osteoporosis
Make sure to tx this
What are the DA antagonists that cause drug induced hyperprolactinemia?
Antipsychotics
Phenothiazines (promeclizine aka phenergen)
Metoclopramide
What is the other drug that causes drug induced hyperprolactinemia?
Verapamil
What are the prolactin stimulators that cause drug induced hyperprolactinemia?
Methyldopa Reserpine SSRIs Estrogens/Progestins Protease inhibitors Benzodiazepines TCAs MAO-I H2-receptor antagonists Opioids
What are the signs and sx of hyperprolactinemia in females?
Anovulation Oligomenorrhea or ameorrhea Infertility Galactorrhea Decreased libido Hirsutism Acne
What are the signs and sx of hyperprolactinemia in males?
Erectile dysfunction Infertility Decreased muscle mass Galactorrhea Gynecomastia
Bromocriptine (Parlodel®)- MOA
Stimulates hypothalamic dopamine receptors
Bromocriptine (Parlodel®)- indications
Hyperprolactinemia tx
Treatment of infertility due to hyperprolactinemia
Use barrier contraceptive method until prolactin levels are normalized
Reduce dose to minimum therapeutic dose before attempting to become pregnant
Bromocriptine (Parlodel®)- ADRs
N/V- most common
Headache
Dizziness
Hypotension
Cabergoline (Dostinex®)- MOA
long-acting dopamine agonist
Cabergoline (Dostinex®)- Indications
First line for prolactinomas
Better efficacy than bromocriptine
Treatment of infertility
Little data on use in pregnancy
Few observational studies have not shown detrimental effects on the pregnancy or fetus
Cabergoline (Dostinex®)- ADRs
Adverse effects – similar to bromocriptine
Possibly a lower incidence
Reports of valvular heart disease when used in high doses (2 mg/day) for long-term therapy
What are the monitoring parameters for those receiving hyperprolactinemia treatment?
- Serum prolactin concentrations q 3-4 weeks after the initiation of drug therapy
- Evaluate clinical signs and symptoms
- Once serum levels are normalized, monitor every 6-12 months
