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Flashcards in Pituitary Gland Dysfunction Deck (56):
1

Release of GH (somatotrope)

GHRH promoter
Somatostatin inhibitory

2

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

3

gigantism

GIGANTISM-Growth hormone excess before puberty (before closure of the growth plates).

4

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

5

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.

6

Tx of acromegaly

Multidisciplinary: neurosurg, endocrinologist, neuropath, radiologist, radiation/onc

Tx:
surgery
med therapy (somatostatin analogs, GH receptor antag)
radiation therapy

7

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

8

Growth hormone tx

-kids
-adults?: modest benefit
-no hard end points

9

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.

10

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

11

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

12

Prolactinoma Dx

Random PRL level
100-150 ng/dl with microadenomas
greater than 200-250 with macro

Pituitary MRI

13

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

14

Cortisol functions

"stress" hormone

Primary Functions:
Gluconeogenesis
Breakdown of Fat and Protein for Glucose Production
Control Inflammatory Reactions

15

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

16

ACTH dependent cortisol excess

-corticotrope adenoma (Cushing's disease)
-Ectopic Cushing's (ACTH/CRH tumors)

70-75% of endogenous hypercortisolism

17

ACTH independent cortisol excess

adrenal adenomas
adrenal carcinoma
nodular hyperplasia (micro or macro)

25-30%

18

Cushing's predominance

female middle aged

19

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)

20

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)

21

Cortisol binding

most bound to transcortin (cortisol binding globulin-CBG)

10-15% bound to albumin (less tightly)

5% free

22

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.)

23

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)

24

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

25

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)

26

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

27

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

28

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

29

Features of hypogonadism in females

novulatory cycles
oligo/amenorrhea, infertility
Vagina dryness, dyspareunia
Hot Flashes
Decreased libido
Breast atrophy
Reduced bone mineral density

30

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

31

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)

32

Gonadotropinoma dx

Blood tests: usually low FSH/LH, T/E2
Pituitary MRI
Immunohistochemical analyses
(+FSH, LH, or ASU staining) of the resected tumor

33

Thyrotropin (TSH) elevatin

Etiologies:
secondary
Thyrotropin secreting pituitary tumor very rare (less than 1% of pit tumors)
thryoid hormone resistance

34

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)

35

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

36

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

37

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.

38

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

39

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

40

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.

41

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)

42

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

43

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

44

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

45

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

46

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

47

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)

48

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)

49

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.

50

DI Etiologies

nephrogenic vs neurogenic

51

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

52

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

53

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%)

54

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)

55

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

56

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