175. Hypothalamus-Pituitary Pathophysiology Flashcards
Septo-Optic Dysplasia
- cause
- findings
Craniopharyngioma
- what is it
- MRI
- where
- signs, sx
SOD: mutations in HESX1, SOX2/3, OTX2
Absent septum pellucidum, agenesis of corpus callosum, optic nerve dysplasia, hypothalamic developmental dysfx, hypopituitarism
CP: cysts lined with squamous epithelium contain serous/oily fluid
MRI: nodular, lobular, well-demarcated cystic mass with rim enhancement
Location: suprasellar with some intrasellar component
signs: varying degrees of hypopituitarism, hyperPRL (less DA), DI
Sx: headaches, visual field defects, hydrocephalus
DDx of Thickened Hypothalamic Stalk
- 3 key infiltrative diseases with key signs
- other causes
- Langerhans Cell Histiocytosis (Histiocytosis X)
- eosinophilic granuloma presents in middle age
- may have pulmonary interstitial disease (get diffusing capacity)
- cause osteolytic lesions, esp in jaw
- tx: alkylating agents, focal irradiation, alkyloids - Sarcoidosis
- can be isolated to CNS - CSF has pleiocytosis and HIGH ACE LEVELS
- tx: steroids - Dysgerminoma
- often makes HCG - can measure in CSF, usually sensitive to radio/chemo-tx
Other: infundibulohypophysitis, metastases, tuberculosis, lymphoma, infundibuloma (tumor in stalk itself)
Effects of the following on hypothalamus fx
- Traumatic Brain Injury
- Aneurysmal SAH
- Radiotherapy
- TBI: 30% have hormone deficiency (usually LH/FSH, or ACTH, or GH)
- SAH: 55% have hormone deficiency (ACTH > GH > ACTH + GH > TSH)
- Radiotherapy: stereotactic type has less radiation to surrounding tissue (gamma knife, LINAC, proton beam), conventional type does not, over time leads to loss of hypothalamus (progressive hormone deficiencies)
What are 4 manifestations of hypothalamic disease
- Hypopituitarism
- Disordered AVP Regulation
- HyperPRL (failure of DA to reach pit)
- Other hypothalamic dysfx if large/bilateral (changes in food intake and temperature dysregulation)
Hypogonadotrophic Hypogonadism
- Causes
Precocious Puberty: definition, types
HyperPRL: cause
Hypo Hypogonad: Congenital - Kallman’s syndrome (mutation in gene facilitating olfactory/GnRH neuron migration), causing anosmia; idiopathic
Acquired - usually functional/reversible due to stress/illness, weight loss, excessive exercise (suppress GnRH)
PP: puberty <8 girls or <10 boys; central (hypothalamic = high GnRH) vs. peripheral (gonad/adrenal high # receptors), more common in girls than boys
HyperPRL: usually due to PRL-secreting adenoma, or reduced DA getting to PRL cells to block PRL secretion (hypothalamic tumors, infiltrative disease, meds blocking DA)
What is the role of hypothalamus in Energy Balance?
What hormone abnormalities manifest in Anorexia Nervosa?
Lateral Hypothalamus: stim increases food intake (damage decreases appetite, causing weight loss - difficult b/c need to damage BOTH sides)
Ventromedial Hypothalamus: stim decreases food intake (damage causes obesity)
AN: weight loss causes
- hypogonadotropic hypogonadism (amenorrhea)
- early satiety
- temperature dysregulation (hypothermia)
hormone abnormalities reversible with weight gain
What are the causes of the following congenital defects resulting in hypopituitarism?
- Isolated Gonadotropin Deficiency
- Isolated GH Deficiency
- Isolated ACTH + TSH Deficiency
- Multiple Hormone Deficiency
- Embryopathy
What transcription factor mutations cause specific hormone deficiencies?
Gonadotropin: GnRH deficiency (Kallman’s - anosmia), other mutations in LH/FSH, GnRH receptors, LH-R/FSH-R, can be acquired (less GnRH from weight loss, exercise, stress, illness)
GH: mutations in GH, GHRH, GH receptors (dwarfism in GHRH receptor mutations)
ACTH + TSH: hormone/receptor gene mutations
Multiple Hormone: Pit1 and Prop1 transcription factor mutations
Embryopathy: congenital midline defects due to mutations in various transcription factors (SOX2/3, OTX2, HESX1)
Pit1: GH, TSH, PRL deficiency
Prop1: GH, TSH, PRL, FSH/LH deficiency
HESX1: variable deficiencies (GH, TSH, ACTH, FSH/LH, AVP) in assoc w/ midline brain abnormalities and optic nerve hypoplasia
What are symptoms of mass effect?
Pituitary Apoplexy: what is it, sx, What is Sheehan’s syndrome?
Mass Effect: HA, visual field defect, CN palsies, hypopituitarism, DI (rare: temp dysregulation, food intake dysregulation if LARGE)
hormones lost in order of GH - LH/FSH - ACTH/TSH (least to most necessary)
Pit Apoplexy: necrosis with partially empty sella
sx: HA, altered consciousness, visual field deficits, CN palsies (3,4,6,V1,V2), stiff neck, fever, N/V, hypotension, hypopituitarism
Sheehan’s syndrome: special case of pit apoplexy, pit necrosis within hrs of delivery assoc with hypotension from obstetric hemorrhage (ischemic necrosis of pit)
sx: Acute (hypotension, tachycardia, failure to lactate (low PRL)), Chronic (variable hypopituitarism)
May have partial to complete DI
Empty Sella Syndrome
- prevalence
- types (primary vs secondary)
prevalence increases with age
Primary: no hx of predisposing event, due to diaphragmatic defect, benign intracranial HTN, congenital embryopathy, asx infarction, autoimmune
Secondary: hx of infection, surgery, radiation, hypophysitis
1/3 pts have hypopituitarism
Hypoprolactinemia
- sx
GH deficiency
- sx, etiology, dx, tx for kids and adults
- tx
HypoPRL: failure of postpartum lactation, idiopathic and rare, assoc with other hormone loss, no tx
GH deficiency
Kids: sx: fall off growth curve
Eti: idiopathic (majority), other: craniopharyngioma, CNS tumor, irradiation, septo-optic dysplasia
tx: GH supplement (better than IGF1)
Adults: sx: high fat mass, low muscle mass, low energy, fatigue, low quality of life
Eti: 52% due to pit tumor, then craniopharyngioma
dx: observe changes in GH due to ins-induced hypoglycemia (GH should rise)
Tx: GH (EXPENSIVE)
For GH insensitivity syndrome - defective GH receptor (Laron’s Syndrome) need to tx with IGF-1 (less effective than GH but these pts will not respond to GH)
Gonadotropin Deficiency
- sx prepubertal vs postpubertal
- dx
- etiology
- tx
TSH Deficiency
- sx
- dx
- tx
Gonad: prepubertal (failure to go through puberty)
Postpubertal - men (less libido, impotence, infertility, less hair growth, osteoporosis), women (less libido, oligo-amenorrhea, infertility, osteoporosis)
Dx: measure LH/FSH (low) and E, T (target organ hormone)
Eti: mass lesions, reversible cause (exercise, weight loss), idiopathic
Tx: Men (testosterone) women (E/P), fertility (stim gonad with gonadotropins
TSH: sx: secondary hypoparathyroidism
Dx: low T3/T4 AND lack of TSH elevation (UNCOMMON)
Tx: levothyroxine (adjust dose based on T4 levels)
ACTH Deficiency
- sx
- Dx
- Etiology
- tx
sx: secondary hypoadrenalism: low corstisol, low adrenal androgens (normal aldo due to RAAS) = low Na, normal K (low cortisol, normal aldo)
Causes INABILITY TO RESPOND TO SRESS (life threatening deficiency!!!)
Dx: low cortisol and low ACTH, less response to hypoglycemia (chronic - low cortisol response to synthetic ACTH due to atrophy; normal response if acute)
Eti: prior GC tx - can suppress HPA axis for up to 1 year; late loss in mass lesions and rarely idiopathic
tx: ALWAYS replace ACTH FIRST WITH HYDROCOTISONE (even if other hormones deficient REPLACE. ACTH. FIRST.)
Types of Inherited Adenomas
- give the mutations and presenting signs of the following
1. Familial Isolated Pituitary Adenoma (FIPA) Syndrome
2. Multiple Endocrine Neoplasia Type 1 (MEN 1)
3. Carney Complex
FIPA: mutations in AIP tumor suppressor gene, causes GH + PRL producing tumors, large tumors presenting in childhood
MEN1: mutation in menin tumor suppressor gene, occurs in pituitary, parathyroid, pancreatic tumors
Carney Complex: mutation in PRKAR1A, causes GH producing adenoma, pigmented nodular adrenocortical disease (cushing’s syndrome), skin pigmentation, myxomas, schwannoma
Hyperprolactinemia
- sx in women and men
- why do these sx occur?
- cause of hypothalamic hyperPRL
- tx
- role in pregnancy
women: oligo-amenorrhea, infertility, galactorrhea, ESTROGEN deficiency, osteopenia (low E), low libido, acne/hirsutism
men: less libido, erectile dysfx, gynecomastia, galactorrhea, infertility, osteopenia
Hypogonadism: high PRL alters GnRH pulsations, interferes with LH/FSH action, interferes with feedback
Hypothalamic hyperPRL: failure of DA to reach pit. due to craniopharyngioma, stalk section, hypothalamic disease, nonfx adenoma, empty sella
Tx: DA agonists to block PRL (bromocriptine, cabergoline) - CAN SHRINK TUMOR! (Better than surgery)
Pregnancy: lactotroph hyperplasia causes increased PRL and pit size (concerning for prolactinoma pts), DA agonists safe in pregnancy but NOT when breastfeeding
Acromegaly
- what mutation occurs in the tumor?
- sx/comorbidities
- dx
- tx
Gs protein alpha subunit mutation - couples GHRH receptor to adenylate cyclase = unregulated high adenylate cyclase activity and secretion of GH/cell proliferation
Sx: gigantism (if growth plates open), large hands/feet, macroglossia
CV - HTN, cardiomyopathy, vascular disease
Brain - HA, cerebrovascular events
Hypogonadism (due to hypopituitarism)
MSK - arthritis (increased weight, cartilage abnormally produced and abnormally structured)
GI - colon polyps, glucose intolerance/DM (GH works against insulin)
Lung - sleep apnea
Life Expectancy - DECREASES BY 10 YEARS
Dx: inability to suppress GH during oral glu tolerance test (high glu should lower GH)
Elevated serum IGF1
MRI for tumor size/location, visual field test
Macro - evaluate for hypopituitarism
Tx: surgery (more successful with micro than macro)
medical: DA agonist (cabergoline), SS analog (octreotide, lanreotide), GH antagonist (pegvisomant) - blocks receptor dimerization
