SM_175b: Hypothalamus-Pituitary Pathophysiology Flashcards
Congenital malformations related to ____ can lead to hypothalamic dysfunction
Congenital malformations related to hypothalamic dysfunction can lead to hypothalamic dysfunction
- Other etiologies: hydrocephalus, tumors, trauma, infiltrative disease, inflammation / infection
Septo-optic dysplasia involves mutations in ____, ____, ____, or ____ and can lead to ____
Septo-optic dysplasia involves mutations in HESX1, SOX2, SOX3, or OTX2 and can lead to hypothalamic dysfunction
- Absent septum pellucidum, agenesis of corpus callosum, optic nerve dysplasia, hypothalamic developmental dysfunction, hypopituitarism
Craniopharyngiomas cause varying degrees of ____, ____, and ____
Craniopharyngiomas cause varying degrees of hypopituitarism, hyperprolactinemia, and diabetes insipidus
- Cysts lined with squamous epithelium and contain serous or oily fluid
- Nodular, lobular well-demarcated cystic mass often with rim enhancement on MRI
- Predominantly suprasellar with intrasellar component
- Often cause headaches and visual field defects and may cause hydrocephalus
Describe sellar masses
Sellar masses
- Pituitary adenomas
- Cell rest tumors
- Benign lesions
- Metastatic tumors
- Aneurysms
- Primitive germ cell tumors
- Gliomas
- Granulomatous lesions
Describe differential diagnosis of thickened hypothalamic-pituitary stalk
Thickened hypothalamic-pituitary stalk DDx
- Langerhans cells histiocytosis (histiocytosis X)
- Sarcoidosis
- Dysgerminoma
- Infundibulohypophysitis
- Metastasis
- Tuberculosis
- Lymphoma
- Infundibuloma
Langerhans cell histiocytosis presents in ___ with ____
Langerhans cell histiocytosis presents in middle age with osteolytic lesions especially in jaw
- May be pulmonary interstitial disease: get DLCO
- Treat with alkylating agents, focal irradiation, vinca alkaloids
Sarcoidosis involves ____ and ____
Sarcoidosis involves CSF pleiocytosis and increased ACF levels
- May be isolated to CNS
- Treat with steroids
Dysgerminoma usually produces ____ and is ____
Dysgerminoma usually produces hCG and is very radiosensitive
- Measure hCG in CSF
___ tuberculosis leads to progressive dysfunction
Hypothalamic tuberculosis leads to progressive dysfunction
____ and ____ can lead to hypothalamic dysfunction
TBI and aneurysms can lead to hypothalamic dysfunction
Radiation can reduce levels of ____ including ____, ____, ____, and ____
Radiation can reduce levels of hypothalamic hormones including TSH, ACTH, LH / FSH, and GH
Hypothalamic disease manifests as ____, ____, ____ and ____
Hypothalamic disease manifests as hypopituitarism, disordered vasopressin regulation, hyperprolactinemia, and other
- Midline structural defects occur if hypopituitarism is due to transcription factor mutation
- Hyperprolactinemia is failure of dopamine to reach pituitary
- Food intake and temp regulation difficulties
____ causes congenital hypogonadotropic hypogonadism and is associated with ____
Kallmann’s syndrome causes congenital hypogonadotropic hypogonadism and is associated with anosmia
- Mutation in gene for protein that facilitates migration of GnRH and olfactory neurons from olfactory placode to anterior septal region of hypothalamus (GnRH) and olfactoty bulbs (olfactory neurons)
Acquired hypogonadotropic hypogonadism may be caused by ____, ____, and ____ and is usually ____
Acquired hypogonadotropic hypogonadism may be caused by stress / illness, weight loss, and increased exercise and is usually functional and reversible
Precocious puberty is ____ caused by ____
Precocious puberty is early puberty (< 8 in girls, < 10 in boys) caused by early gonadotropin secretion
- Rarely: hamartoma secreting GnRH, dysgerminoma secreting hCG
- Central (hypothalamic) vs peripheral (gonad, adrenal)
Hyperprolactinemia is usually caused by ____ but can also be caused by ____
Hyperprolactinemia is usually caused by prolactin-secreting pituitary adenomas but can also be caused by decreased dopamine getting to normal lactrotrph cells to inhibit prolactin secretion
- Hypothalamic tumors or infiltrative disease
- Medications which block dopamine generation or dopamine receptor: antipsychotics, verapamil, metoclopramide
Integration of signals in ____ cause increase in food intake
Integration of signals in lateral hypothalamus cause increase in food intake
- Damage to this area causes lack of appetite and weight loss
Feedback signals in ____ cause decrease in food intake
Feedback signals in ventromedial hypothalamus cause decrease in food intake
- Damage to this area causes obesity
Anorexia is associated with by hormonal abnormalities including ____, ____, and ____
Anorexia is associated with by hormonal abnormalities including hypogonadotropic hypogonadism (amenorrhea), early satiety, and temperature dysregulation (hypothermia)
- Hormonal abnormalities reversible with weight gain
Hypopituitarism can be caused by ____
Hypopituitarism can be caused by congenital defects
- Isolated gonadotropin deficiency: GnRH deficiency (Kallmann’s) ± anosmia, gene mutations in gonadotropins or GnRH receptors
- Isolated growth hormone deficiency: GH gene mutations, gene mutations in GHRH and GH receptors
- Isolated ACTH and TSH deficiencies: gene mutations, receptor gene mutations
- Multiple hormone deficiencies: Pit1 and Prop1 transcription factor gene mutations
- Embryopathies: congenital midline defects, gene mutations in various transcription factors
Acquired defects causing hypopituitarism include ____, ____, ____, and ____
Acquired defects causing hypopituitarism include tumors, apoplexy / infarction / hemorrhage, empty sella syndrome, and hypophysitis
- Tumors: pituitary, hypothalamic
- Apoplexy / infarction / hemorrhage: Sheehan’s syndrome
- Empty sella syndrome
- Hypophysitis: usually associated with pregnancy
Dwarfism of Sindh is a ____
Dwarfism of Sindh is a genetic syndrome of GHRH receptor mutation
Pituitary transcription factors including ____, ____, ____, and ____ may be mutated
Pituitary transcription factors including Pit-1, PROP-1, HESX1, and others may be mutated
Describe mass effects of sellar lesions
Sellar lesion mass effects
- Headache
- Visual field defects
- Cranial nerve palsies
- Hypopituitarism
- Diabetes insipidus
- Rare effects: temperature dysregulation, dysregulation of food intake
Describe the order to loss of hormones after pituitary injuries
Loss of hormones after pituitary injuries
- GH
- LH / FSH
- ACTH / TSH
Describe symptoms and signs of pituitary apoplexy
Pituitary apoplexy
- Headache
- Altered consciousness
- Visual symptoms: visual field defects, CN palsies (III, IV, V1, V2, VI)
- Stiff neck
- Fever
- Nausea and vomiting
- Hypotension
- Hypopituitarism common, SIADH/DI rare
Sheehan’s syndrome is ____
Sheehan’s syndrome is pituitary necrosis occurring within a few hours of delivery and generally associated with obstetric hemorrhage
- Hypotension thought to cause occlusive vasospasm resulting in ischemic necrosis of pituitary
- Acute within 30 days of delivery, have < 10% of tissue left: hypotension, tachycardia, failure to lactate
- Chronic: presents months to years later with varying degrees of hypopituitarism
- May have partial to complete diabetes insipidus
Empty sella syndrome commonly presents with ____
Empty sella syndrome commonly presents with hypopituitarism
- Primary or secondary
Describe pituitary hormone deficiencies
Pituitary hormone deficiencies
- Prolactin
- Growth hormone
- Gonadotropins (LH and FSH)
- TSH
- ACTH
Hyporpolactinemia is associated with ____ and ____
Hyporpolactinemia is associated with failure of postpartum lactation and loss of other hormones
- Sheehan’s syndrome: pituitary infarction in association with peripartum obstetric hemorrhage
- Lymphocytic hypophysitis: inflammatory destruction of pituitary often with ACTH loss
- Other mass lesions of the sella
____ may present with increased fat mass, decreased muscle mass, decreased energy, and poor quality of life
Adult GH deficiency syndrome may present with increased fat mass, decreased muscle mass, decreased energy, and poor quality of life
Common etiologies of childhood GH deficiency are ____, ____, and ____
Common etiologies of childhood GH deficiency are idiopathic, organic, and septo-optic dysplasia
Insulin induced hypoglycemia causes _____ GH release
Insulin induced hypoglycemia causes increased GH release
(inverse)
Describe testing and treatment for GH deficiency
GH deficiency testing
- ITT, Arg / GHRH, Arg / L-dopa, Arginine, L-dopa
- IGF-1 levels not useful
- Treatment: starting dose of 150-300 ug/day, usual final dose needed 5-10 ug/kg/dat, want IGF-1 levels in middle of normal range
Growth hormone insensitivity syndrome (Laron’s syndrome) results from a ____ causing ____
Growth hormone insensitivity syndrome (Laron’s syndrome) results from a defective GH receptor causing an inability to generate IGF-1
- Recessive gene
- IGF lower than in GH deficiency
Gonadotropin deficiency has ____ and ____ manifestations
Gonadotropin deficiency has prepubertal and postpubertal manifestations
- Prepubertal: failure to go through puberty
- Postpubertal: lack of libido / impotence / infertilitty / decreased hair growth / osteoporosis in men, lack of libido / oligo/amenorrhea / infertility / osteoporosis in women
Describe diagnosis and treatment of gonadotropin deficiency
Gonadotropin deficiency
- Diagnosis: measure LH, FSH, estradiol, testosterone
- Common: mass lesions, reversible (exercise, weight), idiopathic
- Treatment: testosterone for men, cyclic estrogen / progesterone for women, stimulate gonad with gonadotropins for fertility
TSH deficiency manifests as ____
TSH deficiency manifests as secondary hypothyroidism
TSH deficiency diagnosis involves ____ and treatment involves ____
TSH deficiency diagnosis involves low thyroid hormones and lack of elevation of TSH and treatment involves l-thyroxine
ACTH deficiency manifests as ___
ACTH deficiency manifests as secondary hypoadrenalism
- Lose cortisol and adrenal androgens
- Aldosterone relatively normal
- Na+ low from lack of cortisol and K+ normal because aldosterone is normal
____ deficiency is the most important homrone deficiency due to an inability to respond to ____ which may result in death
ACTH deficiency is the most important homrone deficiency due to an inability to respond to stress which may result in death
ACTH deficiency diagnosis involves ____ and treatment involves ____
ACTH deficiency diagnosis involves low cortisol and ACTH and treatment involves replacing hydrocortisone first
Pituitary tumors may manifest as ____ or ____
Pituitary tumors may manifest as mass effects of oversecretion syndromes
- Mass effects: headache, visual field defects, CN palsies, and hypopituitarism
- PRL: prolactinoma
- GH: acromegaly
- ACTH: Cushing’s disease
- TSH: hyperthyroidism
- LH / FSH: none
- Nonfunctioning
Microadenoma is ____ in greatest dimension
Microadenoma is < 1 cm in greatest dimension
Macroadenoma is ___ in greatest dimension, can be ____, and has ____ extension
Macroadenoma is > 1 cm in greatest dimension, can be invasive or noninvasive, and has extrasellar extension
Inherited forms of pituitary adenomas include ____, ____, and ____
Inherited forms of pituitary adenomas include familial isolated pituitary adenoma (FIPA) syndrome, multiple endocrine neoplasia (MEN) type 1, and Carney complex
- FUPA: germline mutation in gene for aryl hydrocarbon receptor-interacting protein (tumor suppressor)
- MEN type 1: mutation in menin (tumor suppressor)
- Carney complex: mutation in type 1A subunit of Protein Kinase A (PRKAR1A)
Describe principles of evaluation for pituitary adenomas
Pituitary adenomas principles of evaluation
- Establish that a hormone excess syndrome exists: exclude other potential causes, demonstrate nonsuppressibility of homrone oversecretion
- Image pituitary / hypothalamic area with MR or CT: may need visual field testing
- Evaluate for other mass effects if macroadenoma: hypopituitarism
Pituitary adenoma treatment includes ____, ____, and ____
Pituitary adenoma treatment includes surgery, irradiation, and medical therapy
Describe regulation of prolactin secretion
Prolactin secretion regulation
- Hypothalamus secretes TRH and VIP
- Pituitary secretes prolactin
- Acts on breast
- Positive feedback on hypothalamus via spinal afferent pathways (suckling)
Describe clinical manifestations of hyperprolactinemia
Hyperprolactinemia clinical manifestations
- Men: decreased libido, erectile dysfunction, gynecomastia, galactorrhea, infertility, osteopenia
- Women: oligo-amenorrhea / infertility, galactorrhea, estrogen deficiency, osteopenia, diminished lipido / dyspareunia
- Acne / hirsutism
____ may result from hyperprolactinemia
Hypogonadism may result from hyperprolactinemia
____ is a ____ that is most useful for the treatment of prolactinomas
Cabergoline is a dopamine agonist that is most useful for the treatment of prolactinomas
- Efficacy in normalizing prolactin levels: 80-90%
- Efficacy in shrinking tumors
- Can also use bromocriptine
Prolactin levels and pituitary size ___ during normal pregnancy due to ___
Prolactin levels and pituitary size increase during normal pregnancy due to lactotroph hyperplasia
- Concerns in patients with prolactinomas: dopamine agonist use safe, macroadenomas increase, nursing does not increase tumo size but cannot nurse while taking dopamine agonists that suppress prolactin
Describe growth hormone regulation
Growth hormone regulation
- Hypothalamus secretes GHRH
- Pituitary secretes GH
- Liver and bones secrete IGF-1 and negatively feedback on pituitary and hypothalamus
____ is involved in the pathogenesis of acromegaly
IGF-1 is involved in the pathogenesis of acromegaly
Acromegaly involves a ____ due to a ____ mutation
Acromegaly involves a constitutively activated adenyl cyclase due to a GSP mutation
- Mutations found in alpha sunit of guanine nucleotide binding stimultory regulatory protein (Gs) that couples the GHRH receptor to adenyl cyclase in pituitary GH-secreting adenomas in about 40% of patients with acromegaly
- Mutations result in unregulated, high activity of adenyl cyclase and secretion of GH and cell proliferation
- Tumors with mutation are not significantly different from those without mutations with respect to size, GH levels, invasiveness, and curability
Acromegaly involves many ____ and decreases ____
Acromegaly involves many comorbidities and decreases survival
Diagnostic testing for acromegaly involves ____, ____, and ____
Diagnostic testing for acromegaly involves
- Inability to suppress GH levels during an oral glucose tolerance test
- Elevated serum IGF-1 level (age matched)
- MRI to identify location and size of tumor (60% macroadenomas)
Acromegaly treatment involves ____ or ____
Acromegaly treatment involves surgery and medical therapy
- Microadenomas easier to cure than macroadenomas
- Dopamine agonists: cabergoline
- Somatostatin analogs: octreotide, lantreotide (better)
- GH receptor antagonist: pegvisomant
Describe the mechanism of hGH binding and signal transduction
hGH binding and signal transduction mechanism
- hGH has two binding sites, each of which bind identical cell surface receptor
- Both sites bind, dimerizing the receptor
- Signal transduction occurs
- IGF-1 produced
Describe action of Pegvisomant (GH receptor antagonist)
Pegvisomant (GH receptor antagonist)
- Site-2 binding disrupted by substituting an amino acid with a long side-chain in G120 position
- Site-1 binding to GH receptor enhanced, preventing hGH from binding to receptor, greately increasing potency of GH antagonist
- Functional dimerization prevented
- Signal transduction does not occur
- IGF-1 production does not occur
Cushing’s syndrome is ____
Cushing’s syndrome is hypercortisolism
TSH producing pituitary adenoma causes ____ and may be treated with ____ or ____
TSH producing pituitary adenoma causes hyperthyroidism and may be treated with ablative treatment or octreotide / lantreotide
Gonadotroph adenomas occur in ____ who are ____, have a ____, and have ____
Gonadotroph adenomas occur in males who are > 40 years of age, have a normal past history of gonadal function, and have enormous pituitary size
- Visual field defects, hypopituitarism and hypogonadism, hyperprolactinemia, and extrasellar extension on CT or MIR
- Can make isolated alpha and beta subunits or intact LH or FSH
Clinically nonfunctioning pituitary adenomas include ____ and ____
Clinically nonfunctioning pituitary adenomas include asymptomatic and symptomatic
- Asymptomatic: present as incidental finding on MRI that has been done for other reason
- Symptomatic: mass effects (visual field defects, headaches, hypopituitarism), primary therapy is surgery
Indications for radiotherapy for pituitary adenomas include ____, ____, and ____
Indications for radiotherapy for pituitary adenomas include prolactinomas, GH / ACTH / TSH secreting pituitary adenomas, and clinically nonfunctioning adenomas
- Medical therapies: prolactinoma, acromegaly, Cushing’s, TSH secreting tumors
Diabetes insipidus is ____ and presents as ____ and ____
Diabetes insipidus is deficiency of vasopressin secretion or action and presents as polyuria and polydipsia
- Polyuria: large volume of dilute urine as a result of failure of vasopressin to act on the kidney to promote water resorption
- Polydipsia: increased thirst and/or fluid intake as a result of the rise in serum osmolality brought on by the excessive urinary losses of water
Central diabetes insipidus is caused by ____
Central diabetes insipidus is caused by primary deficiency
- Destruction of neurohypophysis
- Increased degradation of placenta
Nephrogenic diabetes insipidus is ____ caused by ____
Nephrogenic diabetes insipidus is resistance to antidiuretic action of AVP caused by defective V2 receptor signaling
____ can treat central diabetes insipidus
DDAVP can treat central diabetes insipidus
- Urine output decreases to normal
- Thirst and fluid intake also decrease rapidly commensurate with urine output
- Water retention and resultant fall in serum Na+ is minimal
Excessive vasopressin secretion / action may ____ and ____, but these have no effect if ____ and ____ are ____
Excessive vasopressin secretion / action may raise urine osmolality and reduce urine output, but these have no other effect if thirst and water intake are reduced proportionately as they normally area
Normal or increased water intake in the setting of increases vasopressin secretion / action will result in ____ and ____
Normal or increased water intake in the setting of increases vasopressin secretion / action will result in hyponatremia and symptoms of water intoxication (nausea, headache, confusion, death)
Primary cause of excess vasopressin may lead to ____, ____, or ____ hyponatremia
Primary cause of excess vasopressin may lead to SIADH, ectopic, or eutopic hyponatremia
- SIADH: no known stimulus to ADH secretion
- Ectopic: tumors making vasopressin
- Eutopic (neurohypophysis): strokes, head trauma, and other acute illnesses
Secondarily excess vasopressin may cause ____ hyponatremia
Secondarily excess vasopressin may cause multiple types of hyponatremia
- Secondary: known non-osmotic stimulus
Describe treatment of hyponatremia
Hyponatremia treatment
- Decreased effective volume -> restrict water intake and increase cardiac output
- Hypovolemic -> stop losses and replace deficits with blood or saline
- Euvolemic (known cause): restrict water intake and treat cause
- Euvolemic (SIADH): restrict fluids
