169. Hypothalamic-Pituitary Pathophysiology Flashcards by Michael Peabody

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

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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

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Medical therapy for acromegaly

Cabergoline - dopamine agonist

Octreotide, lanreotide - somatostatin analogs

Pegvisomant - GH Receptor antagonist

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Resistance to ADH

defective V2 receptor signaling
congenital defect

Caused by:

drugs
hypercalciuria
hypokalemia
mutation of V2 receptor
Aquaporin 2 mutation

Nephrogenic Diabetes Insipidus

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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

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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

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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

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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

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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

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HA Visual field defects

Cranial nerve palsies

Hypopituitarism

Diabetes Insipidus

Temp dysregulation and dysregulation of food intake (rare)

Mass effects of sellar lesions

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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

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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

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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

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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

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Medical therapies for Cushing’s

Steroidogenesis blockers

Steroid receptor antagonist

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GH receptor antagonist used to treat acromegaly

Less activation –> less IGF-1 production

Pegvisomant

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Deficiency of vasopressin secretion or action

Polyuria - large volume of dilute urine

Polydipsia - increased thirst

Diabetes Insipidus

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Hypopituitarism

Disordered vasopressin regulation

Hyperprolactinemia

Other hypothalamic dysfunction if very large and bilateral

food intake
temperature dysregulation

Manifestations of hypothalamic disease

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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

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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

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Pituitary transcription factor mutation of __ GH, TSH, PRL deficiencies

Pit-1

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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

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Asymptomatic Symptomatic d/t mass effects

Primary therapy is surgery

Nonfunctional pituitary adenomas

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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

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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

169. Hypothalamic-Pituitary Pathophysiology Flashcards

(58 cards)