Acromegaly/ Prolactinoma/ DI/ Ant hypopituitarism Flashcards
why can acromegaly be accompanied by amenorrhea and galactorrhea?
- GH stimulates the PRL receptor (they are both in the cytokine superfamily of JAK-STAT receptor pathways)
- the GH adenoma may cosecrete PRL
- the acromegalic tumor may push on pituitary stalk –> block DOPA –> loss of inhibition of PRL secretion
** increased PRL results in decreased gonadotropin release
what acts on PRL stimulation?
stimulated by TRH
inhibited by DOPA
(can also be stimulated by GH due to same JAK/STAT receptor)
What can cause carpal tunnel? specifically three endocrine causes?
see + Tinel’s sign
“median trap”
- **Myxedema (hypoTH)
- Edema
- **Diabetes
- Infiltration (sarcoid, fibrosis)
- Amyloid
- Neoplasms
- Trauma
- RA
- **Acromegaly
- Pregnancy
sx of acromegaly?
- increased hat/glove size
- increased sweating, weakness,
- amenorrhea and galactorrhea (high PRL levels)
- pain in low back, hips, knees
- Tinel’s sign (carpal tunnel)
- change in bite
- chest pain, dyspnea
- frontal bossing
- deep voice
- velvety ski (acanthosis nigricans), skin tags
- goiter
- tongue, hands, feet enlarged
which h/a are worse w/ coughing, assoc. w/ nausea and worse upon rising?
tension h/a –> sign of pituitary tumor causing mass effects
Cowden’s disease can be confused with acromegaly… why?
= multiple hamartoma syndrome
- mutation in PTEN tumor suppressor
- Trichelemmomas (neoplasms of hair follices), oral papillomatosis, umbilicated palmer papules (keratosis) - skin bumps
- increased hat size
- breast, thyroid, colon, and renal cell cancers
lab tests in acromegaly?
- elevated FBS >126 (due to elevated IGF-1)
Order:
- glucose
- elevated PRL
- BUN (if kidneys are dysfunctional, they can elevate IGF-1 on their own)
- AST,ALT (liver is responsible for some IGF secretion)
- Ca2+, P- (check for MEN1)
- T4, TSH (see if TSH is messed up)
- Cortisol (see if ACTH is involved)
- Uosm/Posm (normal is 1 to 3; <1 indicates possible DI)
- serum GH 2 hours post 75 mg glucose
which value of Uosm/Posm indicates DI?
normal is 1 to 3
if <1, can indicate DI
glucose suppression test? memorize the values
used for GH: administer 75 mg of glucose - would normally suppress GH - but see that GH doesn’t drop in pt. w/ acromegaly
** Administration of 75 g of glucose syrup in a patient with acromegaly will show:
inability to suppress GH to less than 1 ng/mL (10 mcg/mL) **
GH produces lipolysis that yields increased liver acetyl Co A and therefore increased gluconeogenesis, followed by increased conversion of lactate and glycerol to glucose. Also free fatty acids block glucose uptake by muscle and fat cells. (insulin blocks these effects of GH). Thus GH is a slow acting counter-regulatory hormone like cortisol.
when see GH secreting tumor, what do you need to check?
P-/Ca2+ levels
pituitary adenoma can be caused by MEN1 syndrome, which also causes
- hyperparthyroidism
- pancreatic neoplasms
causes of acromegaly?
- Microadenoma with somatotroph mutation*
- Macroadenoma
- Ectopic GH or GHRH production (carcinoid, pancreas, lung, ovary, breast, lymphoma)
- mutation of the alpha subunit of GTP-binding protein resulting in stimulatory Gs subunit
with increased cyclic AMP producing GH secretion
what can acromegaly be associated with?
- MEN 1 (hyperparthyroidism causing hypercalcemia, pancreatic cancer causing peptic ulcer/hypoglycemia, pituitary adenoma) ** know this **
- MuCune-Albright syndrome
- Carney complex
assoc. complications of GH secreting adenoma?
- Pressure effects (headache, visual alterations,etc)
- Additional hormone production (Prolactin production; TSH production, etc)
- Interference with other hormones (decreased ACTH, TSH, etc)
tx of GH secreting adenomas?
3 options:
- surgery
- radiotherapy
- drugs:
1. Dopamine agonists (Bromocryptine, Cabergoline)
2. SST analogues (Ocreotide, Lanreotide) * watch for gallstones
3. Pegvisomat (GHR antabonist) * watch for liver fn. abnormalities!
how do you determine where GH is coming from?
Before surgery to remove an adenoma, must do a GHRH assay
- If have oat cell carcinoma (small cell carcinoma): see elevated GHRH
- if have pituitary adenoma, GHRH will be supressed
long term follow up in cases of GH Adenomas? ** know this **
follow GH and IGF-1 levels and do a glucose load when suspicious (GH should suppress to <1)
Goals of treatment:
- GH level under 1 ng/mL
- Glucose-suppressed GH under 0.4 ng/mL
how does dopamine work to suppress PRL?
Dopa activates inhibitory G protein –> decreased cAMP –> decreases PRL secretion
sx of prolactinoma?
microadenoma:
- amenorrhea, galactorrhea, low back pain (increased PRL –> decreased GNRH and LH –> decreased estrogen = osteoporosis and amenorrhea)
- hirsutism, acne (decreased estrogen = decreased sex hormone binding globulin SHBG = increased free testosterone and DHEAS = hirsuitism and acne)
macroadenoma:
- vomiting, nausea
- bitemporal diplopia
how can hypothyroidism and kidney disease increase PRL levels?
- hypothyroidism –> increased TRH –> stimulates PRL –> hyperprolactinemia
- Kidney disease: decreased excretion of PRL –> increased level of PRL in blood
Endocrine causes of hyperPRL?
see amenorrhea and galactorrhea
- pituitary adenoma (disrupts dopamine inhibition, prolactinoma of cosecretes GH and PRL)
- hypothalamic disease: high levels of TRH –> stimulates PRL release
- hypothroidism: high levels of TRH –> stimulates PRL release
- pregnancy
Drug causes of hyperPRL?
- CNS acting meds (hydroxyzine, risperidone)
- antihypertensives (verapamil, reserpine, alpha methyldopa)
- sex hormones (oral contraceptives, estrogen)
- certain H2 blockers (metoclopromide, cimetidine, rantidine)
- protease inhibitors
- opiates
other causes for hyperPRL?
- cirrhosis
- exercise
- macroprolactinoma
- nipple stimulation
- REM sleep
- renal failure
- SLE
- stress
what level of PRL do you think its prolactinoma?
over 200, if under 200 then think of drugs or other causes of hyperPRL
20-100 would usually indicate another cause such as meds or chest wall stimulation
whats expected in male w/ hyperPRL?
loss of libido, impotence, bitemporal hemianopsia (usually late presenting)
when to do pituitary MRI w/ hyperPRL?
on patients w/out pregnancy, hypothyroidism, drug induced hyperPRL
NOTE: normal pituitary does increase in size during pregnancy
What do you suspect if a patient with a high level (>200 ng/mL) of
prolactin and a negative MRI has no symptoms?
Macroprolactinemia – may need to precipitate IgGs with polyethylene glycol and remeasure.
- Macroprolactin is a physiologically inactive form of prolactin found in a small proportion of people.
- It is in fact prolactin bound to IgG.
- Macroprolactin is important, as some laboratory assays will detect it as prolactin, leading to a falsely elevated prolactin result.
- This can lead to a misdiagnosis of hyperprolactinaemia in some people, especially those with other symptoms, such as infertility or menstrual problems.
- polyethylene glycol, that can be added to remove macroprolactin from a suspicious sample.
- The sample can then be re-analysed to see if the prolactin levels are still high.
if macroadenoma is present, what other testing should be performed?
Screen for pituitary insufficiency – cortisol, T4, etc
Treatment for hyperPRL?
- Bromocriptine (Parlodel) - Beware of D1 receptor side effects, ie nausea, fatigue, psychiatric symptoms.
* *Cabergoline (Dostinex) 0.5 mg twice weekly at bedtime Dopamine agonist to D2 receptor. May be used during pregnancy, especially with a macroadenoma. - Surgery
- Radiation
Postpartum cardiomyopathy (PPCM)?
cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy
** some women develop cardiac hypertrophy and heart failure d/t role of PRL
sx of hypopituitarism?
causes: adenoma, infarct, “empty sella”
- “personality changes”
- Loss of TRH: weakness, lethargy, coldness, fine wrinkling of skin, thinned hair
- Loss of FSH/LH: decreased libido, full body hair loss, amenorrhea, atrophic testicles
- Loss of ACTH: paleness, decreased energy, decreased mm. mass, hypoglycemia, mm and soft tissue wasting
- Loss of GH: decreased growth in children
- Loss of PRL: no lactation
Posterior pituitary:
- may see DI (loss of ADH)
order of hormone loss w/ pituitary insufficiency?
GLTA: Girls love TA’s
- GH: decreased sense of well being; decreased mm. and bone mass; increased central fat; decreased CO; increased cholesterol
- FSH/LH: fine wrinkling of skin, decreased libido, hair loss, gynecomastia, atrophic testicles, vaginal dryness, alopecia
- TSH: fatigue, constpiation, dry skin, puffiness, alopecia (Queen Anne’s sign); cold intolerance, weight gain, increased cholesterol
- ACTH (most important!): weakness, fatigue, low grade fever, orthostasis, loss of sex hair, pallor, hypoglycemia, abdominal pain, nausea, vomiting, w/l, low Na+, normal K+
causes of anterior pituitary failure?
VINDICATE:
Vascular:
- pituitary apoplexy (bleeding into pituitary)
- Sheehan’s (ischemia of pituitary d/t blood loss or shock of pregnancy)
- carotid aneurysm, subarachnoid hemorrhage, ischemic stroke
- SS disease
- DM
Infection/Infiltrative:
- syphilis, TB,
Infiltration:
- sarcoid, langerhans histiocytosis, Wegeners, leukemia/lymphoma, hemocrhomatotis
Neoplastic disorder:
- adenoma (watch for 3 P’s)
- Mets
- craniopharyngioma
Degenerative state
Idiopathic:
1. ** Empty sella syndrome (intrasellar herniation - obese, hypertensive female)
Congenital:
- Kallman syndrome: GNRH stays in nose
Trauma:
- surgery, head trauma, irradiation
Endocrine:
- hypothalamic of pituitary disease, MEN 1
tests to assay for deficiency of anterior pituitary hormones?
- Testosterone, FSH, LH:
- male: low 8 am testosterone and nonelevated LH
- female: low estradiol w/ non-elevated FSH - ACTH, Cortisol, DHEA levels:
- cortisol deficiency: 8 am cortisol < 85 mcg/L)
- stimulation test may be needed: insulin induced hypoglycemia (GH <5ng/mL is positive test)
low IGF-1 ? ??
lower than 85 mcg/L
8 am cortisol indicating addisons?
8 am cortisol <3 ug/dL
abnormal ACTH stimulation test?
cortisol <18ug/dL = adrenal insufficiency
why low BP and sodium seen in pituitary insufficiency?
low thyroxine and low cortisol –> decreased CO and increased ADH secretion
furthermore cortisol is unable to produce epinephrine
causes of euvolemic hyponatremia?
- hypothyroidism (low T4)
- adrenocorticotropin deficiency (low cortisol)
why low glucose in pituitary insufficiency?
counterregulary hormones that help keep glucose from dropping too low:
- epinephrine
- glucagon
- cortisol
- GH
hormone replacement for pit insuffic?
TQ: need to replace cortisone first, then thyroid
- hydrocortisone
- thyroxine
- testosterone
- GH
** thyroxine increases clearance of cortisol, so could cause adrenal crisis if not given first
** GH not normally given: GH increases conversion of T4 to T3: so when no GH, results in increased levels of T4 - giving GH may unmask TSH deficiency
** GH replacement may expose central adrenal insufficiency by inducing cortisol to
cortisone conversion.
What if the replacement of cortisol resulted in polyuria?
This could unmask a true panhypopiturarism because cortisol increases GFR (through improved CO and ECV), allowing the absence of ADH* (if also deficient) to manifest itself with polyuria.
this is a question on the test – pt has an accident has hypopituitariasm – replace cortisol results in polyuria – have unmasked ADH deficiency b/c need cortisol to maintain GFR rate
*Central DI does not usually occur with anterior pituitary failure. When it does, consider hypophysitis, metastatic cancer, or sarcoidosis
hemochromatosis
can cause pituitary failure
- see diabetes, gray skin, joint pain, dilated CM, heart rhtym disturbances, addisonism, cirrhosis, hyperpigmentation
Empty sell syndrome
sella looks empty on MRI, but is actually filled with CSF –> can result in hypopituitarism
sx of DI?
- polyuria, polydipsia
- elevated serum sodium
- increased serum uric acid
- 24 hour urine collection shows Uosm/Posm<100
PP vs DI?
Serum uric acid will be high in DI and low on PP. BUN is low in both DI and PP.
** V1 receptors cause uric acid excretion, so if ADH is present and working, serum UA should be low, ie, high UA = low or absent ADH effect.
serum osmolality:
2(Na+) + glucose/18 (+ BUN/2.8)
In DI see increased serum sodium (>140) in PP these is decreased serum sodium (< 1 only in complete central and renal DI.
This corrects to > 1 with addition of DDAVP only in central DI.
causes of polyuria and polydipsia?
- Cortisol excess: cushings, steroid drugs
- DI (Uosm/Posm < 1, often Uosm lower than 100)
- DM (Uosm/Posm>1)
- recovery from renal failure (urea)
- ions: hyperCa2+ hypoK+
- Parkinson’s
- psychogenic polydipsia
- Enzyme: vasopressinase (autoimmune DI)
- Drugs: lithium, demeclocycline, cis-platinum
Central DI?
ADH = 0
Uosm 50%
partial CDI:
ADH <1.5
Uosm: 300-800 w/ water restriction
Uosm increases 10-50% w/ addition of DDAVP
psychogenic polydipsia?
- ADH levels are <10% with addn of DDAVP
Nephrogenic DI?
- ADH >5
- Uosm: 5
- Uosm is 300-800 w/ water restriction
- addiction of DDAVP increases Uosm only <10%
when do you see pituitary stalk thickening on MRI?
Autoimmune, sarcoid of histiocytosis X causing DI
causes of central DI?
- Ischemia/Sheehan’s
- Infection (syphilis, TB)
- Sarcoid, amyloid, hemochromatotis
- tumors/mets
- hypothalamic or pituitary disease
- trauma or irradiation
treatment for central DI?
Desmopressin acetate 0.05 mg BID orally – to 0.4 mg q 8 hours. Resistant to vasopressinase. Can use nasal prep. Watch for suicide.
Hydrochlorthizide 50-100 mg daily
causes for nephrogenic DI?
SS disease, pyelonephritis, amyloid/sarcoid, myeloma, polycystic kidneys, corticosteroids, **lithium!!!
