Pituitary Flashcards
Adjuctive therapy in patients with persistent acromegaly.
1. Preferred first line?
2. second line? MOA? Monitoring caveat?
3. more refractory/challenging disease
- first-gen SS receptor ligands, octreotide and lanreotide. Increase to max tolerated dose to achieve IGF-1.
- Pegvisomant. MOA - competes with endogenous GH for binding at its receptor and blocks peripheral IGF1 production. Therefore, cannot monitor GH.
- Pasireotide (AE of glycemic disturbance)
Best management of persistent acromegaly after surgery for the following indications:
1. most RAPID response for tumor shrinkage and biochemical control.
2. Common AE?
3. Besides acromegaly, what other disease can it be used for?
- PASIREOTIDE ( somatostatin receptor ligand); it normalizes IGF-1 and may result in tumor shrinkage. Pegvisomant does not control tumor growth.
- Common AE is HYPERGLYCEMIA.
- Can also be used for Cushing disease (it decreases cortisol and ACTH)
- Treatment for all forms of endogenous Cushing syndrome?
- MOA?
- What levels actually rise during treatment?
- MIFEPRISTONE
- glucocorticoid receptor blocker
- cortisol and ACTH
MOA of somatostatin/SS analog
inhibits both GH and TSH. Therefore, can use in acromegaly and TSH secreting tumors. Can also reduce tumor size.
After TSS for acromegaly, a fasting GH concentration [ ] suggests a complete remission even without the requirement for an oral glucose tolerance test
less than 0.4 ng/ml
Isolated ACTH deficiency
1. most common cause
- prolonged exogenous glucocorticoid therapy. An isolated ACTH deficiency is extremely rare, except in hypophysitis associated with immune checkpoint inhibitors.
for glucocorticoid induced secondary AI, recovery of HPA axis can be reevaluated after glucocorticoid is stopped. Monitor with early morning serum cortisol and ACTH. A rise in ACTH is the first sign of axis recovery.
Patients with symptoms of AI and a morning serum cortisol in the range 3 and 15 ug/dl require what form of dynamic testing?
cosyntropin stim test or an insulin tolerance test
- What is the most common origin of clinically nonfunctioning pituitary adenomas
- what immunohistochemical positivity do they demonstrate?
- what transcription factor is expressed?
- if tumor growh recurrence occurs, what is the next best step?
- gonadotrope
- FSH and/or LH (stain for BETA subunits)
- Steroidogenic factor 1 (SF-1)
- Radiation therapy. Stereotactic radiotherapy is the best choice.
- Anticonvulsant drugs that lead to a false positive dex suppression test
- MOA?
- alternative testing for Cushings?
- carbamazepine, phenytoin, phenobarbital
- these drugs induce CYP3A4 enzyme, leading to increased dexamethasone metabolism. Always measure dex level simultaneously.
- late night salivary cortisol
what are sources of a FALSE-POSITIVE dexamethasone suppression test?
- use of anticonvulsant drugs (carbamazepine, phenytoin, phenobarbital) “car pheny phen”
- oral estrogen
- rifampin
- pioglitazone
Test with 24 hour urine free cortisol or late night salivary cortisol
DDx for pituitary stalk thickening
- congenital
- inflammatory - hypophysitis, sarcoidosis, granulomatosis with polyangiitis
- neoplastic - Langerhans cell histiocytosis, geminoma, lymphoma, metastatic disease
Langerhans cell histiocyctosis (LCH)
1. present in what patient demographic
2. classic presentation
2. what other organs are involved besides the pituitary?
- young males
- isolated central diabetes insipidus
- bones (in 60% of the cases). Therefore, get a skeletal survey if suspicious for LCH (safe and inexpensive) to obtain a confirmatory bone biopsy. In smokers, pulmonary involvement can be seen.
Macimorelin GH-stimulation test
1. what is macimorelin and what is it used for?
2. MOA?
3. normal test is?
3. pitfalls?
- a ghrelin agonist. Tests for GH deficiency.
- Stimulates GH secretion by acting directly on somatotroph cells.
- GH > 2.8 ng/ml
- in postradiation hypopoituitarism, if early in the disease, Macimorelin GH stim test may be falsely normal (since radiation can take > 5 years to cause problems).
What are the tests for GH defiency and cutoff values for a positive test?
- insulin tolerance test (gold standard). Peak GH < 5.
- Macimorelin stim test. Peak GH < 2.8. May not detect eary GH deficiency after radiation.
- Glucagon stim test. Peak GH < 3.0 (normal BMI) or < 1 (BMI greater than 30).
- GHRH + arginine test –> may not detect early GH deficiency after radiation
IgG4-related hypophysitis
1. what is it?
2. characteristics?
3. responds to?
4. what demographic is mostly affected
- an immune-mediated disease, often systemic
- infiltration of IgG4-positive plasma cells and lymphocytes, and fibrosis that can affect any organ
- glucocorticoids
- old men
Distinguish between a thyrotropinoma and THRB-related resistance to thyroid hormone:
1. SHBG
2. Serum alpha subunit
3. TRH stim test (absent/attenuated or exaggerated?)
4. pituitary MRI
metastasis to the sella commonly presents with?
central diabetes insipidus
how does lymphocytic hypophysitis present?
AI and central DI
how does neurosarcoidosis present?
central DI
POU1F1 gene (a transcription factor)
1. important for the development of?
- Somatotroph, thyrotroph, and lactotroph lineages. Therefore, deficiencies in GH, TH, PRL occurs in a pathogenic variant of this gene.
“Puffy Tho grew milky breasts”
What is the most common cause of congenital combined pituitary hormone deficiency? (GH, TSH, LH, FSH)
PROP1
“Proper Tho grew fish legs”
Patients with pathogenic variants in TBX19 (TPIT) present with?
isolated ACTH deficiency (the TBX19 gene product is needed for differentiation of corticotroph cells)
(think of a boxer/pitbull with AI)
If 3 or more pituitary axes are deficient, is a stim test needed to assess for GH deficiency?
NO
- severe hyponatremia following pituitary surgery is usually due to?
- treatment of moderate to severe hyponatremia following pituitary surgery (most rapid normalization)?
- when is demeclocycline used?
- SIADH
- TOLVAPTAN (an oral vasopressin receptor antagonist); hypertonic saline can also be used, usually at a rate of 0.5 to 1.0 mL/kg body weight per hour
- for patients with CHRONIC, symptomatic hyponatremia, such as that associated with malignancy. It causes partial nephrogenic diabetes insipidus
Hint that a tumor is not actually a prolactinoma
a discrepancy in the size vs PRL level. Also if tumor is not shrinking but PRL is decreasing with D2 agonist (can be d/t stalk effect)
- GH may metabolize?
- In patients on oral estrogens, what to do with GH dose?
- GH therapy may affect glucose in what way?
1a. cortisol –> relative adrenal insufficiency (therefore, increase hydrocortisone dose)
1b. free T4 –> therefore increase levothyroxine dose.
2. increase GH dose to maintain a steady IGF-1 level (can consider switching to transdermal estrogen to bypass liver and first pass effect and reduce impact of estrogen on GH dose).
3. 3. May lead to hyperglycemia
- what is the hook effect?
- next step?
- When the assay reads a low/normal/slightly elevated PRL level (instead of it being extremely high) due to a high analyte concentration.
- re-measure prolactin after dilution to rule out macroprolactinoma/hook effect
Familial Isolated Pituitary Adenoma Syndrome (FIPA)
1. clinica features?
2. method of inheritance
3. gene affected
- early onset acromegaly and a large pituitary tumor
- autosomal dominant
- aryl hydrocarbon receptor interacting protein (AIP), likely a tumor suppressor gene. “Second hit” hypothesis. Each of an affected patient’s children has a 50% chance of having inherited the pathogenic variant
Diagnosis of acromegaly
1. what test is the gold standard? GH cutoff?
2. Once acromegaly is diagnosed, what is the next step?
3. If the previous study is unrevealing, then?
- The oral glucose suppression test. GH cutoff 0.4-1 ng/ml depending on the guideline
- Obtain a pituitary MRI
- obtain a GHRH level (to look for the presence of a GHRH-secreting neuroendocrine tumor elsewhere in the body)
**in ESRD, GH may fail to suppress
The co-occurrence of suprasellar and pineal lesions is highly suggestive of?
a germinoma
best test to screen for Cushing syndrome in pregnancy?
Salivary cortisol. Urine free cortisol increases in pregnancy
for Cushing disease,
1. when an obvious pituitary adenoma (>/= 6 mm) is seen on imaging, what is the best next step in management?
2. when an adenoma is smaller or not obviously visible? What gradient indicates that ACTH secretion is pituitary-dependent?
- refer to a pituitary surgeon
- IPSS. When a central-to-peripheral ACTH gradient is > 2 at baseline and > 3 after CRH or desmopressin injection.
Histochemical markers for the following lineages:
1. gonadotroph (FSH/LH)
2. somatotroph/lactotroph/thyrotroph (GH/PRL/TH)
3. corticotroph (ACTH)
- SF-1 (“SF is FSH/LH backwards”)
- Pit-1 (think of Tho who grew milky breasts in a big pit)
- Tpit
In patients with prolactinomas, what are predictors of remission?
cabergoline x 2 yrs on 0.5 mg weekly (or 0.25 mg twice weekly), PRL 5.4 or less, max tumor diam of 3.1 mm
Possible causes of hyperthyroxinemia with nonsuppressed TSH (8)
- Increased TBG (oral estrogen or pregnancy)
- lab assay interference (rule out second)
- thyroxine replacement therapy (including poor adherence)
- medications (rule out first)
- nonthyroidal illness
- TSH secreting pituitary adenoma
- resistance to thyroid hormone
- disorders of thyroid hormone transport or metabolism
How do the following lab assay interference confound TFT results?
1. heterophilic or antiiodothyronine antibodies; familial dysalbuminemic hyperthyroxinemia
2. heterophilic or human antianimal antibodies; Macro-TSH
- falsely elevated free thyroid hormones
- falsely nonsuppresed TSH
Do you follow GH and IGF1 in pregnancy in a patient with acromegaly?
NO. Stop meds for acromegaly and monitor clinically (pituitary MRI w/o contrast for vision symptoms or worsening h/a).
effects of carbamazepine/oxarbazepine (antiseizure meds) on:
1. dex suppression test
2. TFTs?
3. patient on DDAVP
- false positive dex suppression test due to CYP3A4 inducer
- low FT4 but normal TSH. Patient is clinically euthyroid
- watch for hyponatremia since carbamazepine can enhance desmopressin’s effects (increase sensitivity of the renal tubules to endogenous and exogenous vasopressin)
What is the pattern of recovery of the HPA axis after successful surgery for Cushing disease?
order of recovery:
1. ACTH
2. cortisol ( > 15 is full recovery and ok to stop HC; 10-15 do cosyntropin stim test)
3. DHEAS (high only if Cushing’s disease recurs)
check early morning serum cortisol and ACTH (before the HC dose) every 8-12 weeks
post TSS, what are the criteria for starting DDAVP in the first DI phase (3)?
significant polyuria (greater than 250 ml/hr), elevated serum sodium, pt can’t keep up with urine output
give DDAVP in single doses due to impending SIADH phase
remember: phase post TSS is: DI-SIADH-DI, but not always
In a patient with a history of childhood-onset GHD, should reinitiating GH therapy be done in the following:
1. isolated GH deficiency and a normal pituitary MRI
2. GH deficiency and multiple hormone deficiencies, with structural lesions; those with proven genetic causes.
- need to do a GH stim test first. Reinitiation of therapy without a stim test is not appropriate
- a low IGF-1 level 1 at least 1 month off GH therapy is sufficient documentation of persistent GHD without additional provocative testing
what is the most common pituitary deficit after radiation-induced pituitary damage?
GH deficiency
Particularly in males, GH deficiency can be present despite normal serum IGF-1 levels
In severe or longstanding primary hypothyroidism, what can be seen on pituitary MRI?
pituitary hyperplasia due to thyrotoroph-cell hyperplasia.
Hyperprolactinemia can be seen due to TRH stimulation (TRH stimulates both TSH and PRL to be released). PRL will decrease after treatment of hypothyroidism.
Carney complex:
- form of inheritance. Associated with what gene?
- clinical features?
- A.D.; protein kinase A type 1 alpha regulatory subunit gene (PRKAR1A)
- GH excess or acromegaly, Cushing syndrome due to primary pigmented nodular adrenocortical disease, and large-cell calcifying Sertoli-cell tumors in males. Thyroid nodules are also seen.
neuroendocrine manifestation: pigmented lesions of the skin and mucosa, CARDIAC MYXOMAS
What is the pituitary imaging finding in histiocytosis?
an enhancing posterior sellar mass
treatment for very aggressive prolactinoma/pituitary carcinoma refractory to cabergoline/bromocriptine, surgery, and stereotactic radiosurgery?
temozolomide
common cancers causing pituitary mets
breast, renal cell, lung;
when the pituitary mass is fast growing, think of mets
- What are symptoms of GH deficiency?
- How to diagnose?
- cutoff value to diagnose GHD?
- change in body composition (increase in abdominal girth, change in well-being with fatigue and worsening cognitive function including short-term memory), lower bone density, and cardiovascular risk.
- glucagon-stimulation test
- Endo Society Guidelines: <1 ng/ml; Acromegaly consensus group: <0.4 ng/ml
- somatostatin analogs (octreotide, lanreotide, and pasireotide) decrease?
- which of these worsen glucose tolerance?
- GH and IGF-1; therefore improve insulin resistance.
- PASIREOTIDE (decreases GLP-1 and glucose insulinotropic peptide)
True or False: oral contraceptive use is safe in women with microadenomas and there is minimal risk of tumor enlargement
TRUE
- True or False: More than 2/3 of children with idiopathic isolated GH deficiency diagnosed by conventional criteria have normal GH secretion as adults
- Before continuing GH treatment in these patients, what should be done?
- TRUE
- GH-stimulation test one month after stopping GH. If GH deficiency is documented to still be present, resume GH treatment at a lower dosage than that used in childhood
Pregnant woman with a sellar mass. MRI shows contrast enhancement. Dx?
lymphocytic hypophysitis
Patient with history of cancer and/or histiocytosis:
- MRI findings?
- associated clinical finding?
- hypOenhancing mass
2. diabetes insipidus
pituitary adenomas:
1. typical MRI feature?
- hypOenhancing
rarely associted with diabetes insipidus
cystic lesion on pituitary MRI. Ddx?
Rathke cyst
mifepristone:
- MOA?
- used in the treatment of?
- what is NOT recommended measurements to be used for dosage adjustment during mifepristone treatment? How should dosage be adjusted?
- a glucocorticoid receptor blocker. Therefore, cortisol and ACTH levels may actually rise during treatment
- all forms of Cushing syndrome
- cortisol and ACTH.
The dosage should be adjusted solely based on clinical parameters of the activity of Cushing syndrome while avoiding symptoms of adrenal insufficiency
Tx of acromegaly:
- how often is lanreotide given?
- for pegvisomant to be considered as first-line therapy, how often is administration?
- monthly
- daily; this has the highest likelihood of normalizing IGF-1 level. Since it is a GH receptor antagonist, GH cannot be used to monitor tx efficacy.
Women on oral estrogen require what change in GH replacement to normalize serum IGF-1 compared to women on transdermal estrogen or no estrogen?
A 2-3 times higher GH replacement.
Therefore, if a woman switches from oral to transdermal estrogen, GH dose should be decreased to one-half or one-third of the original dosage.
What is one of the absolute contraindications to GH therapy?
an active malignancy
- What is the gold standard for assessing GH reserve? What is the caveat?
- an insulin tolerance test. HOWEVER, caution in a patient with a history of cranial surgery because of concerns regarding possible seizure induction by hypoglycemia.
- -> An alternative test is a GLUCAGON-STIMULATION TEST
DDx for: acute onset hypopituitarism in adolescence or young adulthood
craniopharyngioma –> calcification within the lesion
OR
germinoma (germ-cell tumors) –> co-occurrence of suprasellar and pineal lesions
most likely dx in a pregnant woman with diffuse pituitary enlargement
Pituitary hyperplasia
MRI without GAD (or noncon MRI), since this is what you would order in pregnancy, shows focal enhancement rather than diffuse enhancement with GAD.
management of prolactinoma during pregnancy
- visual field testing (not routine for microprolactinoma)
- MRI without gad
do not follow PRL since it increases during pregnancy
- monomeric prolactin - size
- macroprolactin - size
- if suspicious for macroprolactin/falsely elevated prolactin, what is the next step?
- 23-kDa
- 150-kDa
- polyethylene glycol (PEG) - can determine % monomeric and macroprolactin
