169. Hypothalamic-Pituitary Pathophysiology Flashcards
Caused by:
- h/o infarction, surgery, irradiation of tumor
- medical therapy of tumor
- end stage of hypophysitis
Results in hypopituitarism, rare visual defects, CSF in sella turcica
Secondary Empty Sella Syndrome
Clinical manifestations d/t direct or associated hormone effects
Women:
- oligo-amenorrhea/infertility
- galactorrhea
- estrogen deficiency
- osteopenia
- diminished libido/dyspareunia
- acne/hirsutism
Men:
- decreased libido
- ED
- gynecomastia
- galactorrhea
- infertility
- osteopenia
Hyperprolactinemia
Medical therapy for acromegaly
Cabergoline - dopamine agonist
Octreotide, lanreotide - somatostatin analogs
Pegvisomant - GH Receptor antagonist
Resistance to ADH
- defective V2 receptor signaling
- congenital defect
Caused by:
- drugs
- hypercalciuria
- hypokalemia
- mutation of V2 receptor
- Aquaporin 2 mutation
Nephrogenic Diabetes Insipidus
Over 90% in women Associated w/ multiple hormonal abnormalities:
- Hypogonadotrophic hypogonadism (amenorrhea)
- Early satiety
- Temp dysregulation (hypothermia)
Hormonal abnormalities reversible w/ weight gain
Anorexia nervosa
Dopamine agonists used to treat hyperprolactinemia
Efficacious in normalizing prolactin levels
Efficacious in shrinking tumors
Cannot nurse while on these medications d/t suppressed prolactin
Cabergoline and bromocriptine
Manifestations:
- prepubertal
- postpubertal
Diagnosis:
- measure LH, FSH, estradiol, testosterone
Common:
- mass lesions
- reversible weight loss and increased exercise
- idiopathic
Treatment:
- Men: testosterone
- Women: birth control
- Women wanting to be pregnant: stimulate gonad w/ gonadotrophins
Gonadotrophin deficiency
Associated w/ failure of postpartum lactation
Usually associated with loss of other hormones
- Sheehan’s syndrome
- Lymphocytic hypophysitis
- ACTH loss
- other mass lesions of the sella
NO treatment
Hypoprolactinemia
Clinical characteristics:
- male >> female
- >40yo
Normal past history of gonadal function
- normal puberty and fertility
Enormous pituitary size causing mass effects
- visual field defects
- hypopituitarism
- hyperprolactinemia
- extrasellar extension on MRI
Can make isolated alpha and beta subunits or intact LH or intact FSH
Gonadotroph adenomas
HA Visual field defects
Cranial nerve palsies
Hypopituitarism
Diabetes Insipidus
Temp dysregulation and dysregulation of food intake (rare)
Mass effects of sellar lesions
Congenital malformations
- often related to transcription factor mutations
Hydrocephalus Tumors
- craniopharyngiomas
- pituitary adenomas
- dysgerminomas Trauma
- surgery
- irradiation
- external Infiltrative disease
- sarcoidosis
- Langerhans cell histiocytosis
Inflammation/infection
- encephalitis
- meningitis
Etiology of Hypothalamic Dysfunction
Manifestation:
secondary hypoadrenalism
- lose cortisol and adrenal androgens
- aldosterone relatively normal (from RAS)
- Na+ low from lack of cortisol
- K+ normal bc aldosterone is normal
Inability to respond to stress
- failure to treat –> death
Diagnosis:
- low cortisol and ACTH
- decreased response to hypoglycemia
- decrease cortisol response to injection Cotrosyn (synthetic ACTH) if chronic condition —> normal response if acute condition
ACTH deficiency
Inability to suppress GH levels during an oral glucose tolerance test
Elevated serum IGF-1 levels MRI to identify location, size of tumor
- 60% macroadenomas
Visual fields if tumor found to be abutting chiasm
Evaluate for hypopituitarism if macroadenoma
Diagnostic testing for acromegaly
Normally caused by a pituitary tumor
- also caused by a craniopharyngioma
- can also be idiopathic
Increased fat mass
Decreased muscle mass
Decreased energy, increased fatigue
Poor QOL
Adult GH deficiency
Medical therapies for Cushing’s
Steroidogenesis blockers
Steroid receptor antagonist
GH receptor antagonist used to treat acromegaly
Less activation –> less IGF-1 production
Pegvisomant
Deficiency of vasopressin secretion or action
Polyuria - large volume of dilute urine
Polydipsia - increased thirst
Diabetes Insipidus
Hypopituitarism
Disordered vasopressin regulation
Hyperprolactinemia
Other hypothalamic dysfunction if very large and bilateral
- food intake
- temperature dysregulation
Manifestations of hypothalamic disease
Mutation in Type 1A subunit of Protein Kinase A (PRKAR1A)
Pituitary adenoma in 10% (GH producing)
Spotty skin pigmentation
Myxomas
Schwannomas
Pigmented nodular adrenal cortical disease causing Cushing’s syndrome in 30%
Carney Complex
Mutations in HESX1, SOX2, SOX3, OTX2
Absent septum pellucidum
Agenesis of corpus callosum
Optic nerve dysplasia
Hypothalamic developemental dysfunction leads to hypopituitarism
Variable presentation
Septo-Optic Dysplasia
Pituitary transcription factor mutation of __ GH, TSH, PRL deficiencies
Pit-1
Infiltrative hypothalamic disease
- often presents in middle age
May be pulmonary interstitial disease
- get diffusing capacity measurement
Osteolytic lesions, especially in jaw
Treat w/ alkylating agents, focal irradiation, vinca alkaloids
Langerhans Cell Histiocytosis
Asymptomatic Symptomatic d/t mass effects
Primary therapy is surgery
Nonfunctional pituitary adenomas
Prolactinomas
- continued growth despite medical therapy and surgery GH, ACTH, and TSH secreting pituitary adenomas
- persistent hormone secretion despite surgery
- often used in conjunction with medical therapy
- primary therapy when surgery is contraindicated
Clinically nonfunctional adenomas
- tumor recurrence
Indications for radiotherapy
Inflammatory destruction of pituitary often with ACTH loss
Lymphocytic hypophysitis
Pituitary transcription factor mutation of __ GH, TSH, PRL, LH, FSH deficiencies
Prop-1
Germline mutations in gene for AIP
- tumor suppressor
- found in 1/3 of patients
- most commonly in those with GH and PRL producing tumors (pituitary tumors)
Often large tumors presenting in childhood
Familial Isolated Pituitary Adenoma (FIPA) Syndrome
In men:
- lack of libido, impotence, infertility, decreased hair growth, osteoporosis
In women:
- lack of libido, oligo/amenorrhea, infertility, osteoporosis
Postpubertal gonadotrophin deficiency
Due primarily to prior treatment with glucocorticoids which suppress the HPA axis for up to a year
With mass lesions, a late loss
Treatment:
- In the setting of hypopituitarism with multiple deficiencies, always replaces with hydrocortisone first
- no need for mineralocorticoid
ACTH deficiency
Usually caused by prolactin-secreting pituitary adenomas
Also caused by decrease dopamine getting to the normal lactotroph cells
- hypothalamic tumors or infiltrative disease
- meds: antipsychotics, verapamil, metoclopramide
Hyperprolactinemia
2 main transcription factors involved in hypothalamic development and pituitary cell differentiation
Prop-1 and Pit-1
Decreases the pulsatile release of GnRH from the hypothalamus leading to hypogonadism
Hyperprolactinemia
Usually functional and reversible
D/t stress/illness
Seen w/ weight loss
Seen in individuals with increased exercise habits
Acquired hypogonadotropic hypogonadism
Manifestation: secondary hypothyroidism
Diagnosis: low T3 and T4, low/normal TSH
Treatment: l-thyroxine - dose adjusted based solely on T4 levels and not TSH levels
TSH deficiency
Integration of signals in ___ causes increase in food intake
Damage to this area causes lack of appetite and weight loss
Lateral hypothalamus
Pituitary necrosis occurring w/in a few hours of delivery and generally associated with obstetric hemorrhage
- hypotension –> occlusive vasospasm –> ischemic necrosis of pituitary
Acute: w/in 30 days of delivery
- hypotension, tachycardia, failure to lactate
Chronic: months to years later
- varying degree of hypopituitarism
May have partial to complete DI, which must be looked for
Sheehan’s Syndrome
Mutations found in the alpha subunit of the Guanine nucleotide binding stimulatory regulatory protein (Gs) that couples the GHRH receptor to adenyl cyclase in pituitary GH-secreting adenomas in about 40% of patients w/ acromegaly
Mutations result in unregulated, high activity of adenyl cyclase and secretion of GH and cell proliferation
GSP mutation in acromegaly
Diagnostic test used to see if GH and ACTH response is adequate in individuals Inject insulin into a non-diabetic pt
Insulin-induced hypoglycemia
HTN, cardiomyopathy, valvular disease
Cerebrovascular events and HA
Hypogonadism
Arthritis
- GH stimulates cartilage growth
Colon polyps
Glucose intolerance/DM
Respiratory complications/sleep apnea
Acromegaly comorbidities
Primary deficiency of ADH
- destruction of posterior pituitary
- increased degradation by placenta
- gestational
Caused by:
- tumors
- trauma
- infections
- granulomatous diseases
- infundibulohypophysitis
- genetic
- idiopathic
Central Diabetes Insipidus
Can be isolated to CNS
- infiltrative hypothalamic disease CSF pleiocytosis, increased ACE levels
Treat w/ steroids
Sarcoidosis
Syndrome caused by hemorrhage into tumor
Symptoms and signs:
- HA
- Altered consciousness
- Visual symptoms
- Stiff neck
- Fever
- Nausea and vomiting
- Hypotension Hypopituitarism is common SIADH/DI rare
Pituitary apoplexy
Congenital hypogonadotrophic hypogonadism
D/t mutation in gene for protein that facilitates migration of GnRH and olfactory neurons from olfactory placode to anterior septal region of hypothalamus and olfactory bulbs
Associated w/ anosmia and late puberty
Kallmann’s Syndrome
Medical therapy for TSH-secreting tumors
Somatostatin analogs - octreotide and lanreotide
Starting dose
- 150-300 micrograms/day regardless of body weight
Evaluate every 1-2 month for clinical symptoms and measurement of IGF-1 levels
Increase dose to obtain IGF-1 levels in middle of normal range (age and sex-adjusted) while avoiding symptoms
Older individuals tend to need smaller doses
GH treatment
Cysts lined with squamous epithelium and contain serous or oily fluid
On MRI, nodular, lobular well-demarcated cystic mass, often w/ rim enhancement
Predominantly suprasellar with some intrasellar component
Cause varying degrees of hypopituitarism, hyperprolactinemia, and DI
- often causes HA, visual field defects, and may cause hydrocephalus
Craniopharyngioma
Caused by:
- diaphragmatic defect
- congenital
- benign intracranial hypertension
- congenital embryopathy
- txn factor mutations
- asymptomatic infarction in many adults
- autoimmune
Results in hypopituitarism, rare visual defects, CSF in sella turcica
Primary Empty Sella Syndrome
<8yo in girls, <10yo in boys
Central (hypothalamic) vs. Peripheral (gonad, adrenal)
More common in girls
- 1/3 have organic disease (esp. boys)
Mechanisms triggering early gonadotrophin secretion largely unknown
Rare:
- hamartoma or dysgerminoma secreting GnRH
Precocious Puberty
Feedback signals in ___ cause decrease in food intake
Damage to this area causes obesity
Ventromedial hypothalamus
Infiltrative hypothalamic disease
Often make hCG
- measure in CSF
Usually very radiosensitive
Dysgerminoma
Order of pituitary hormones lost after radiotherapy or with pituitary injuries
GH, then LH/FSH, ACTH, TSH
Common sequela of irradiation therapy
Hypopituitarism
Normally is asymptomatic if water intake is reduced proportionally
However, if water intake is maintained or increased
- hyponatremia
- water intoxication: HA, nausea, confusion, death
Excessive vasopressin secretion (SIADH)
Defective GH receptor
- AR disease
Unable to generate IGF-1
Treat w/ IGF-1 treatment
Laron’s Syndrome (GH Insensitivity Syndrome)
Mutation in menin gene causing pituitary tumor
- tumor suppressor
Occurs w/ parathyroid and pancreatic tumors (PPP)
MEN 1
Pituitary transcription factor mutation of __ Variable deficiencies
- GH, TSH, ACTH, FSH, LH, vasopressin
- in association w/ midline brain abnormalities and optic nerve hypoplasia
HESX1
Treatment of Central Diabetes Insipidus
Urine output decreases to normal in 1-2 days
Water retention and resultant fall in serum sodium is minimal
Desmopressin (DDAVP)
Used acutely in hospital to treat SIADH
- vasopressin blocker
Conivaptan
