Pituitary Gland Dysfunction Flashcards
Release of GH (somatotrope)
GHRH promoter
Somatostatin inhibitory
Actions of GH
GH leads to IGF-1 release and increased blood glucose leading to:
increased bone and cartilage mass/growth
increased protein synth/muscle synth
increased fat breakdown/TGA levels
Increased salt/H2O
gigantism
GIGANTISM-Growth hormone excess before puberty (before closure of the growth plates).
acromegaly
ACROMEGALY-GH excess after puberty (after completion of linear growth).
-acral/facial changes
-HA
-hyperhidrosis
-oligo/amenorrhea
OSA
-htn
dyslipidemia
parasthesias/carpal tunnel
impaired glucose tolerance/diabetes mellitus
Diagnosis of GH excess
Clinical Features of GH excess (old pictures are helpful), AND
Elevated IGF-1 level (age and gender matched)-best screening test. Integrated 24 h secretion. Long-half life.
Conversely, GH levels fluctuate widely over 24 hrs and normal values can overlap with GH-secreting tumors.
OGTT-GH test for equivocal cases, or post-op assessment of cure.
Pituitary MRI-macroadenomas are detected in greater than 80% of acromegaly.
Tx of acromegaly
Multidisciplinary: neurosurg, endocrinologist, neuropath, radiologist, radiation/onc
Tx:
surgery
med therapy (somatostatin analogs, GH receptor antag)
radiation therapy
Adult GH deficiency manifestations
Body Composition:
Increased Fat Deposition
Decreased Muscle Mass, Strength and Exercise Capacity
Bone Strength:
Increased Bone Loss and Fracture Risk
Metabolic and Cardiovascular Effects
Increased Cholesterol Levels
Increased Inflammatory and Prothrombotic Markers (C-reactive protein).
Psychological Well-Being:
Impaired Energy and Mood
Quality of Life
Growth hormone tx
- kids
- adults?: modest benefit
- no hard end points
Dx of AoGHD
Provocative testing for GH reserve:
limited reagents
-Gold standard: insulin induced hypoglycemia
Contraindications: Elderly, h/o seizure disorder, coronary artery disease or cerebrovascular disease.
GHRH-Arginine (second best test), although no longer available in U.S
Available tests: Arginine and glucagon stimulation tests
IGF-1 Level -Low (in the setting of multiple other pituitary hormone deficiencies). Must be age/gender-matched.
Hyperprolactinemia
Physiological
Pregnancy, suckling, sleep, stress
Pharmacological:
Estrogens (OCPs)
Antipsychotics, antidepressants (TCAs), anti-emetics (e.g., Reglan), opiates
Pathological
Pituitary Stalk Interruption
Hypothyroidism, chronic renal/liver failure, seizure
Prolactinoma
Most common functional pituitary adenoma
prolactinomas
F:M 10:1
Median age 34
Women: galactorrhea 30-80% menstrual irregularity infertility impairs GnRH pulse generator
Men: glactorrhea less than 30% visual field abnorm HA impotence EOM paralysis anterior pituitary malfunction
Prolactinoma Dx
Random PRL level
100-150 ng/dl with microadenomas
greater than 200-250 with macro
Pituitary MRI
Prolactin deficiency
Etiology: Severe pituitary (lactotrope) destruction from any cause (e.g., pituitary tumors, infiltrative diseases, infectious diseases, infarction, neurosurgery or radiation).
Clinical Presentation: Failed lactation in post-partum females, no known effect in males.
Diagnosis: low basal PRL level
Cortisol functions
“stress” hormone
Primary Functions:
Gluconeogenesis
Breakdown of Fat and Protein for Glucose Production
Control Inflammatory Reactions
Chronic cortisol excess
Changes in Carbohydrate, Protein and Fat Metabolism Peripheral Wasting of Fat/Muscle Central obesity, Moon facies, fat pads Osteoporosis Diabetes Hypertriglyceridemia
Changes in Sex Hormones
Amenorrhea/Infertility
Excess hair growth (women)
Impotence
Salt and Water Retention
HTN and Edema
Impaired Immunity
Neurocognitive Changes
ACTH dependent cortisol excess
- corticotrope adenoma (Cushing’s disease)
- Ectopic Cushing’s (ACTH/CRH tumors)
70-75% of endogenous hypercortisolism
ACTH independent cortisol excess
adrenal adenomas
adrenal carcinoma
nodular hyperplasia (micro or macro)
25-30%
Cushing’s predominance
female middle aged
Screening guidelines for cushing’s
pts with multiple and progressive “high discriminatory” features of Cushing’s
Plethoric/moon facies Wide (greater than 1 cm), violaceous striae (abdominal, axillary) Spontaneous Ecchymoses Proximal Muscle Weakness Early/Atypical Osteoporosis (atraumatic rib fx)
Cortisol rhythms
Episodic ACTH/cortisol secretions daily
Major ACTH/cortisol burst in the early morning (before awakening).
Cortisol Nadir 11-12 pm (assuming a normal sleep-wake cycle)
Cortisol binding
most bound to transcortin (cortisol binding globulin-CBG)
10-15% bound to albumin (less tightly)
5% free
Screening Tests for Cushing’s
Disrupted Circadian Rhythm:
Midnight Salivary or Serum Cortisol
Increased Filtered Cortisol Load :
24 hr Urine Free Cortisol
Attenuated Negative Feedback: Low Dose (1 mg) Dexamethasone Suppression test (11-12 p.m.)
Pseudo-Cushing’s Disease
overactivation of the HPA axis, without tumorous cortisol hypersecretion:
Severe Depression/Anxiety/OCD
Severe Obesity
?Obstructive Sleep Apnea
Alcoholism
Poorly-controlled DM/hypoglycemia
Physical Stress (acute illness, surgery, pain)
Cushing’s Disease Work-up
ACTH Level:
-plasma ACTH levels are usually high-normal to mildly elevated in Cushing’s
Imaging: pituitary MRI
Inferior petrosal sinus sampling: for a negative/equivocal MRI
Central Adrenal Insufficiency (AI)
Etiologies of Secondary/Tertiary AI
Suppression of the HPA axis:
S/p tumor resection for Cushing’s Syndrome (pituitary, ectopic or adrenal)
Supraphysiologic exogenous glucocorticoid use (most common) greater than 5-7.5 mg prednisone (or equivalent glucocorticoid dose) for >1 month
Drugs: Opioids and megace
Hypothalamus/Pituitary Diseases and/or their treatments.
Other-Isolated ACTH deficiency (very rare)
Clinical Presentation of secondary/tertiary AI
Fatigue
Anorexia, nausea/vomiting and weight loss
Generalized malaise/aches
Scant Axillary/Pubic hair (DHEA-S dependent in females)
Hyponatremia and Hypoglycemia
Central AI testin
Basal testing:
random am cortisol level, less than 3 ug/dl is AI, greater than 18 excludes AI
Stimulation tests:
insulin induced hypoglycemia (gold standard)
Cosyntropin (synthetic ACTH) stim test valid for assessing HPA axis only if prolonged loss of pituitary signaling and resulting adrenal atrophy
Hypogonadism Differential dx
high FSH/LH: Hypergonadotropic Congenital Anorchia Klinefelter's syndrome Testicular injury Autoimmune testicular dz glycoprotein tumor (rare)
Low FSH/LH
Hypogonadotropic hypogonadism
Hypothalamic/pituitary diseases: macoedemas, prolactinomas, XRT
Isolated GnRH deficiency
Hemochromatosis
Functional deficiency:
critical illness, OSA, starvation, Meds-opiates, glucocorticoids
Features of hypogonadism in females
novulatory cycles oligo/amenorrhea, infertility Vagina dryness, dyspareunia Hot Flashes Decreased libido Breast atrophy Reduced bone mineral density
Features of hypogonadism in males
Reduced libido
Erectile dysfunction
Oligospermia or azoospermia
Infertility
Decreased muscle mass, testicular atrophy and decreased BMD
Hot flashes with acute and severe onset of hypogonadism
LH/FSH (gonadotropin) excess
- majority of FSH/LH tumors are clinically silent
- rare presentations: ovarian hyperstim syndrome (F) or macro-orchidism (males)
Middle aged pts (m greater than f) with macroadenomas and related mass effects (HA, vision loss, CN palsies, and or pit hormone def)
Gonadotropinoma dx
Blood tests: usually low FSH/LH, T/E2
Pituitary MRI
Immunohistochemical analyses
(+FSH, LH, or ASU staining) of the resected tumor
Thyrotropin (TSH) elevatin
Etiologies:
secondary
Thyrotropin secreting pituitary tumor very rare (less than 1% of pit tumors)
thryoid hormone resistance
Central hyperthyroidism
Clinical Presentation
Thyrotropinoma (TSHoma)-similar clinical presentation to primary hyperthyroidism (e.g., goitre, tremor, weight loss, heat intolerance, hair loss, diarrhea, irregular menses) but also with associated mass effects (e.g., headaches, vision loss, loss of pituitary gland function) from macroadenoma.
Diagnosis
Elevated Free T4 and a non-suppressed TSH
Pituitary MRI (greater than 80% macroadenomas)
Central TSH deficiency
Etiologies
Pituitary/Hypothalamic Diseases and/or their treatments
Critical Illness/Starvation-Euthyroid Sick Syndrome
Congenital defects (TSH-beta mutations, PROP1, POUF1 mutations). Pediatric onset
Drug induced-supraphysiologic steroids, dopamine, rexinoids.
Clinical presentation: similar to primary hypothyroidism (e.g., fatigue, weight gain, cold intolerance, constipation, hair loss, irregular menses). Possible mass effects
Diagnosis: Low Free T4 levels in the setting of a low or normal TSH
Hypopituitarism
Definition: Deficiency of 1 or more pituitary hormones. Panhypopituitarism=loss of all pituitary hormones
Etiologies:
Congenital-Genetic Diseases (transcription factor mutations)
Acquired-Pituitary Lesions and/or their treatments (75%)
Macroadenomas/Pituitary Surgery/Radiation Therapy
Infiltrative/Infectious/Granulomatous diseases
Traumatic Brain Injury/Subarchnoid Hemorrhage
Apoplexy
Apoplexy
Definition: Clinical syndrome of headache, vision changes, ophthalmoplegia and altered mental status caused by the sudden hemorrhage or infarction of the pituitary gland.
Occurs in ~10-15% of pituitary adenomas; sub-clinical disease is more common
Diagnosis: Pituitary MRI or CT
Treatment
Emergent surgery is indicated for evidence of severe vision loss, rapid clinical deterioration, or mental status changes.
Stress dose steroids for adrenal insufficiency.
Pituitary hormone deficiency
predictable loss of anterior pituitary hormones
ADH deficiency common with metastatic tumors (breast, lung, or GI) or craniopharyngiomas, but not pituitary adenomas
Presentation and dx of hypopituitarism
-depends on severity
-similar presentation to target gland hormone def w/ exceptions:
Primary adrenal insufficiency also presents with hyperkalemia from mineralcorticoid deficiency and hyperpigmentation from ACTH excess.
Dx: basal and dynamic testing
Management of hypopituitarism
Treatment of Anterior Pit. Hormone Deficiencies (End Organ Hormone Replacement):
Thyroid – Multiple L-thyroxine formulations available.
Adrenal – Physiologic hydrocortisone or prednisone
Medic Alert Bracelet, Sick day rules for glucocorticoid replacement
No mineralcorticoid replacement needed
Gonadal –
Various formulations-oral/transdermal E2, transdermal/IM Testosterone
Gonadotropin or pulsatile GnRH therapy
Growth Hormone
Various Formulations of subcutaneous shots (not orally active).
Prolactin – SQ formulation, research purposes only.
Posterior pituitary gland clinical syndromes
-assoc with disorders of AVP (arginine vasopressing) = ADH antidiuretic hormone
Release controlled primarily by high osmolar states via hypothalamic osmoreceptors
ADH release also controlled by hypovolemia (baroreceptors)
Mech of ADH action
V1: vascular vasoconstriction, platelet aggregation
V2: antidiuretic effects in kidney
adenylate cyclase activation leads to movement of aquaporin water channels to the cell membrane leads to water reabs
SIADH
Definition: A syndrome of inappropriate AVP release/action in the absence of physiologic osmotic or hypovolemic stimulus.
Hallmark is the excretion of inappropriately concentrated urine in the setting of hypo-osmolality and hyponatremia.
SIADH is one of the most frequent causes of hyponatremia, and occurs in an estimated:
15-22% of hospitalized patients
5-7% of ambulatory patients
SIADH Etiologies
Major Categories:
Malignant Disease- Carcinoma, Lymphoma, Sarcomas
Pulmonary Disorders-Infections, Asthma, Cystic Fibrosis, Positive Pressure Ventilation
CNS Disorders-Infection, Tumors, Trauma, Bleeds
Drugs-Stimulate/Potentiate AVP release/actions
Narcotics, Nicotine, Anti-psychotics, Carbamazepine, Vincristine
Miscellaneous-Nausea, Stress and Pain
SIADH Clinical presentation
- depends on severity/rapidity of devel
- Manifests with neurological symptoms from osmotic fluid shifts and brain edema
Plasma Na 130-135: asx 125-130: anorexia, n/v, HA, irritable 115-125: altered sensorium, gait disturbance less than 115: seizure, coma, death
SIADH Dx
Hyponatrema (Na less than 135 mmol/L) and hypotonic plasma osmolaltiy (less than 275 mOsm/kg)
Inapp urine conc (urine osm greater than 100) with normal renal func
euvolemic status
exclude other potential causes of euvolemic hypo-osmolality
Hypothyroidism
Hypocortisolism
SIADH Tx
Identify and Reverse Underlying Disorder (when possible)
Treatment depends on the severity of hyponatremia, the rate of development and the patient’s symptomatology
Mild-to-Moderate Hyponatremia (Na+ ~120-134 mmol/L) Water Restriction (500-1000L/24hrs) V2 Receptor Antagonists (\$\$$) Salt tablets, Lasix, Urea (Europe)
Severe:
usually Na less than 120 mmol/L
Hypertonic (3%) Saline-if patient is symptomatic (delirium/seizure/coma)
Reducing risk of hyponatremia complications
Limit Correction of Chronic Hyponatremia:
less than 12 mmol in the first 24 hrs.
Slower correction with other risk factors associated with osmotic demyelination syndrome
Hypokalemia, alcoholism, poor nutritional status
NO LIMITATIONS with acute onset hyponatremia
(eg less than 48 hr onset, marathon runners)
Diabetes insipidus
Definition-DI is a syndrome of hypotonic polyuria as a result of either:
Inadequate ADH secretion
Inadequate renal response to ADH
Hallmark-Voluminous (Urine output greater than 40ml/kg/d) dilute urine
Main Causes:
Central Diabetes Insipidus
Nephrogenic Diabetes Insipidus
Pregnancy-increased ADH metabolism from placental vasopressinase, but is generally not clinically relevant
Primary Polydipsia
Clinical Significance: Can lead to severe dehydration if thirst mechanisms are impaired, or if the patient has limited access to water.
DI Etiologies
nephrogenic vs neurogenic
Nephrogenic DI
Congenital: X-linked recessive AVP V2 receptor gene mutation; autosomal recessive aquaporin-2 water channel gene mutation
Drugs: demeclocycline, lithium, amphotericin B
Electrolyte abnormalities: hypokalemia and hypercalcemia
Infiltrative kidney diseases: sarcoidosis and amyloidosis
Vascular disease: sickle cell anemia
Neurogenic DI
Neoplasms: craniopharyngioma, metastatic pituitary disease (e.g., colon, breast, lung)
Idiopathic:+AVP Ab
Congenital defects: autosomal dominant AVP neurophysin gene mutation
Inflammatory/Infectious/granuloma pituitary diseases: lymphocytic hypophysitis, histiocytosis, sarcoidosis
Trauma/Vascular event: neurosurgery, TBI/deceleration injury
Post op/trauma related DI
Classic Triphasic response:
Primary phase– DI-polyuric phase due to axonal shock/decreased AVP release (days 1-5)
Secondary phase – SIADH from degenerating neurons/excessive AVP release (days 6-11)
Tertiary phase-Permanent DI after depleted ADH stores and if greater than 80% AVP neuronal cell death
Permanent DI-uncommon complication with an experienced neurosurgeon
Isolated Second (SIADH) Phase-More Common (~25%)
Outpatient DI Dx
Confirm polyuria with 24 hr urine volume collection (normalized to creatinine)
Exclude hyperglycemia (osmotic diuresis), renal insufficiency and electrolyte disturbances (K+/Ca 2+)
Assess Urine and Plasma Osmolalities
Consider Water Deprivation Test
Pituitary Imaging (for suspected neurogenic DI)
Water Deprivation Test
Fluid restriction to stimulate ADH release
Measure Uosm , Posm Serum Na+ and Urine output
Urine concentration Response to dDAVP
+/- ADH Level after mild dehydration
Central DI Tx
Anti-Diuretic Hormone Replacements
First Line-dDAVP (nasal, oral or parenteral routes of administration)
Longer half-life than ADH
No Vasopressor Effect
Second-Line-ADH (IV, SQ or IM routes of administration).
Goals:
Resolution of Polyuria/Polydipsia
Minimal disruption of sleep/daily routine
Normal Serum Sodium
