Download No Slide Title

Diseases of the Pituitary Gland
Benjamin Glaser, M.D.
Endocrinology and Metabolism Service
Hadassah-Hebrew University Medical Center
Pituitary Disease
• Goals of lectures:
– At the conclusion of the lectures and seminars (sadnaot) on
the pituitary gland, the student should be able to:
• Describe the gross anatomy of the pituitary gland, and discuss the
relevance of the gland's embryology and anatomy to the physiology
and pathology of the pituitary.
• Describe the normal control of secretion of vasopressin (ADH).
– Describe the normal control of secretion of anterior pituitary hormones.
• Discuss the symptoms, clinical signs, laboratory evaluation and
treatment of:
»
»
»
»
Diabetes insipidus
Acromegaly
Prolactinoma
Panhypopituitarism
Human Pituitary in Sagittal Section
Posterior Clinoids
Anterior Clinoids
Carotids
Third Ventricle
Pineal Body
Hypothalamus
Anterior
Commissure
Optic
Chiasm
Pituitary
Mamillary
Body
Median
Eminence
Normal Pituitary: Gross anatomy
Stalk
Anterior
Posterior
The normal gross appearance of the pituitary gland removed from the sella
turcica is shown here. The larger portion, the anterior pituitary
(adenohypophysis), is toward the top. The image at the left shows the superior
aspect of the pituitary with the stalk coming from the hypothalamus entering it.
The inferior aspect of the pituitary is shown at the right. The posterior pituitary
(neurohypophysis) is the smaller portion at the bottom.
Embryogenesis of the Human Pituitary
Hypothalamic
releasing
hormones
, ADH
Normal Pituitary: Coronal MRI
Third
Ventricle
Cavernous
Sinus
Optic Chiasm
Infundibulum
Pituitary
Sphenoid sinus
Normal Pituitary: Sagittal Section
Optic Chiasm
Supra
Sellar fossa
Infundibulum
Pituitary
Sphenoid sinus
Human Pituitary in Coronal Section
Pituitary gland
Internal carotid artery
III
IV
VI
Cranial Nerves
V
Sphenoid Sinus
Human Pituitary in Coronal Section
Diseases of the Pituitary
• Structural disorders
– Trauma - stalk section
– Surgery
– Tumor
• Functional
– Hormone Producing
• Non-functional
– May affect hormone
production
• Functional disorders
– Increased or decreased section
of hormones
• LH (Leutinizing Hormone)
• FSH (Follicle Stimulating
Hormone
• ACTH (Adrenocorticotrophic
Hormone)
• TSH (Thyroid Stimulation
Hormone)
• Growth Hormone
• Prolactin
Pituitary Gland Hormones
Thyroid
Gland
TSH
Vasopressin
(Anti-diuretic
Hormone)
ACTH
Adrenal Gland
LH
FSH
Testes/
Ovaries
Oxytocin
GH
IGF-1
Prolactin
Vasopressin Biosynthesis
Gene expression
Preprohormone
SP
AVP
NP
GP
Prohormone
Production
Cell body
in paraventricula
or Supraoptic
nucleus
AVP
Packaging
NP
GP
Glycosylation
Proteolysis
Amidation
AVP
Mature Hormone
Transport and Maturation
Storage and release
in posterior pituitary
SP, signal peptide; AVP, arginine vasopressin; NP, neurophysin; GP, glycoprotein
Receptor-mediated effects of AVP
Receptor
Subtype
Site of Action
Activation Effects
V1a
- vascular smooth muscle cells
- platelets
- lymphocytes and monocytes
- liver
vasoconstriction
platelet aggregation
cytokine release
glycogenolysis
V1b
- anterior pituitary
ACTH and endorphin release
- renal collecting duct
principal cells
free water
reabsorption
V2
Lee et al., Am Heart J 146:9-18, 2003
AVP
Collecting Duct Cell
AQP3
H2O
ATP
GTP
(Gs)
AVP V2
Receptor
AQP2
cAMP
Exocytic
Insertion
PKA
AQP2
AQP4
Basolateral
membrane
Recycling
vesicle
Thyroid hormone
Glucocorticoid
Dependent
Endocytic
Retrieval
Luminal
membrane
Collecting duct
Vasa recta
AVP regulation of water reabsorption from renal tubular
cells
H2O
Renal Concentrating Mechanism
Dilute
Cortex
10+ Liters/day
Na
H2O
300
400
Medulla
H2O
Na
H2O
800
ADH Present
H2O
1100
Modified from Schrier, Renal and Electrolyte Disorders,
Na
Concentrated
Renal Diluting Mechanism
Dilute
Cortex
10+ Liters/day
Na
H2O
400
Medulla
H2O
H2O
Na
500
ADH Absent
Na
600
Modified from Schrier, Renal and Electrolyte Disorders,
Dilute
AVP Stimulation and Effects
Pain
Nausea
+
hyperosmolality
hypovolemia
angiotensin II
baroreceptors
natriuretic
peptides
–
+
AVP
V1a Receptors
vasoconstriction
V2 Receptors
renal H2O
reabsorption
Adapted from Orlandi, 2009
ADH Secretion
ADH
Plasma
Levels
ADH levels increase
Markedly as soon as
The plasma osmolality
increases about 285
270
280
300
290
Plasma Osmolality
310
Goldilocks
Approach to Endocrinology
Goldilocks
Approach to Endocrinology
Syndrome of
Hyperfunction
Too
Hot
Inappropriate ADH
Diabetes
Hypofunction
Too Cold
Insipidus
Normal
JustFunction
right
Diabetes Insipidus
ADH Deficiency
Diabetes Insipidus
(ADH Deficiency)
• Symptoms:
– Polyuria (>2,000 cc/d)
• If pituitary, usually sudden onset
– Polydipsia
• If pituitary, usually ice cold water
• Signs
–
–
–
–
Dehydration
Hypernatremia
Normokalemia
Inappropriately dilute urine
Diabetes Insipidus
• Differential Diagnosis
– Osmotic diuresis (e.g. glucose)
– Excessive fluid intake
• Psychogenic
• Central
• Secondary
– Nephrogenic Diabetes Insipidus
– Central Diabetes Insipidus (ADH
deficiency)
Differential Diagnosis of Nephrogenic
Diabetes Insipidus (partial list):
• Genetic
• Chronic renal disease
–
–
–
–
Polycyctic disease
Pylonephritis
Ureteral obstruction
Advanced renal failure
• Electrolyte disorders
– Hypokalemia
– Hypercalcemia
• Drugs
– Alcohol
– Lithium
– Many others
• Miscellaneous
–
–
–
–
Multiple myeloma
Amyloidosis
Sjoger's disease
Sarcoidosis
Differential Diagnosis of Central
Diabetes Insipidus
• Pituitary tumor
–
–
–
–
–
Functioning (Prolactin, Growth Hormone etc)
Non-functioning
Craniopharyngioma
Dysgerminoma
Metastatic tumor (breast, lung)
• Trauma
– Surgery
– Head trauma
• Inflammation
– Infundibulo-hypophysitis
– Granulomatous disease (histiocytosis X, Sarcoid,
Tuberculosis)
• Genetic
Diabetes Insipidus: Clinical
Evaluation
• Water deprivation test:
– Complete fast
– Measure hourly urine and serum electrolytes,
orthostatic blood pressure and weight
– When plasma osmolarity ≥ 295 or urinary
osmolarity is stable, then give
• DDAVP 5mcg. s.c.
– Interpretation:
• Lack of ability to concentrate urine - DI
• Good response to DDAVP - Central DI
• No response to DDAVP – Nephrogenic DI
Central Diabetes Insipidus
Treatment
• Desmopressin (1-desamino-8-D-arginie vasopressin)
– Commercial names: DDAVP, Minerin
– Long-acting ADH analog
• Intra-nasal -- 10-40 mcg ever 8-12 hours
• Oral: 0.05 - 0.4 mg every 8-12 hours
• IV/SC: 1-2 mcg every 8-12 hours
– Monitor:
• Electrolytes -- SIADH
Syndrome of Inappropriate ADH
Syndrome of Inappropriate ADH
(SIADH)
• Clinical findings:
– Hyponatremia
– Normokalemia
– Euvolemia (mild volume expansion)
SIADH - Water and Sodium Balance
• Increased ADH activity
– Decreased free water clearance
– Increased total body water
• Hyponatremia
• Increased ECF volume
• Increased ECF volume
–
–
–
–
Increased GFR
Decrease proximal nephron Na+ reabsorption
Increased sodium loss
Minimizing increased ECF volume
• No edema
– Worsening hyponatremia
Prevalence of dysnatremias at initial
presentation to a health care provider
(data from 303,577 samples on 120,137 patients available for analysis)
30
Acute hospital care
Ambulatory hospital care
Community care
28.2
25
Prevalence (%)
21
20
15
10
7.2
5
0
1.43
0.49 0.17 0.03
Na < 116
Na < 135
0.53 0.72
Na > 145
0.06 0.01 0.01
Na > 165
Hawkins. Clin Chim Acta 337:169-172, 2003
Symptomatic hyponatremia:
neurological manifestations
•
•
•
•
•
•
•
•
•
headache
irritability
nausea/vomiting
mental slowing
confusion/delerium
disorientation
stupor/coma
convulsions
respiratory arrest
symptomatic but
less impaired;
usually chronic
life-threatening,
usually acute
Acute hyponatremia can cause death
from cerebral edema and brain herniation
normal brain
hyponatremic brain
Neurological symptoms are correlated with the
level of hyponatremia, but with considerable
individual variability across patients
Arieff et al., Medicine 55:121-129, 1976
Plasma Vasopressin (pg/mL)
Plasma AVP levels are inappropriately elevated
in most patients with SIADH
11
10
9
8
7
6
5
4
3
2
1
0
Normal
Range
230
240
250 260 270 280 290 300
Plasma Osmolality (mOsm/kg)
310
Robertson et al. Am J Med 72:339-353, 1982
Causes of SIADH
Pulmonary Disorders
Acute respiratory failure
Infections
Positive-pressure ventilation
Tumors
Extrathoracic
Mediastinal
Pulmonary
SIADH
Drugs
Carbamazepine
Phenothiazines
Chlorpropamide
Prostaglandin-synthesis
Clofibrate
inhibitors
Cyclophosphamide SSRIs
Desmopressin
MAO inhibitors
Nicotine
Tricyclics
Oxytocin
Vincristine
Opiates
CNS Disorders
Acute psychosis
Hemorrhage
Inflammatory and
demyelinating diseases
Mass lesions
Stroke
Trauma
Miscellaneous
HIV infection
Idiopathic
Pain
Postoperative state
Prolonged exercise
Senile atrophy
Severe nausea
Syndrome of Inappropriate ADH
(SIADH)
• Diagnosis:
– Hyponatremia
– Inappropriately elevated urine sodium
– No volume depletion or severe volume expansion
• Etiology:
–
–
–
–
–
Glucocorticoid deficiency
Hypothyroidism
Pulmonary lesions
CNS lesions
Drugs (Chlorpropamide)
• Treatment:
– Glucocorticoid/Thyroid hormone replacement (if
indicated)
– Water deprevation
– V2 receptor antagonists (in clinical trials)
Anterior Pituitary Gland Axes
Thyroid
Gland
TSH
ACTH
Adrenal Gland
LH
FSH
Testes/
Ovaries
GH
IGF-1
Prolactin
Distribution of Endocrine Cells in
Pituitary
Thyrotropin
Releasing
Hormone
Posterior Pituitary
Dopamine
PRL
15%
GH
50%
Stimulator of secretion
Inhibitor of secretion
LH
FSH
10%
Gonadotropin
Releasing
Hormone
LH
FSH
10%
PRL
15%
ACTH
20%
TSH
5%
GH
50%
Corticotropin
Releasing
Hormone
Growth
Hormone
Releasing
Hormone
Somatostatin
(Somatotropin
Release
Inhibiting
Factor)
Pituitary Control of Thyroid/Adrenal
Thyrotropin
Releasing
Hormone
Thyroid Stimulating
Hormone
Corticotropin Releasing Hormone
Adreno-Cortico Trophic Hormone
Pituitary Gonadal Axis
Loss of Pituitary Function
Loss of Pituitary Function
• Functional abnormalities
–
–
–
–
–
–
Gonadotrophins -- Gonadal Insufficiency
ACTH -- Adrenal Insufficiency
Thyroid -- Hypothyroidism
GH – Growth hormone deficiency
Prolactin -- No syndrome
Anti-diuretic hormone -- Diabetes Insipidus
• Structural abnormalities
– Visual field disturbance
– Cranial nerve dysfunction
– CNS leak
Loss of Pituitary Function: Etiology
• Congenital
• Pituitary tumors
– Functional
– Non-functional
• Non-pituitary tumors
– Craniopharyngioma
– Metastases
• Trauma
– Surgical
– Head trauma
• Inflammation
– Autoimmune
hypophysitis
– Granulomatous disease
• Histiocytosis X
• Sarcoid
• Tuberculosis
– Rathke’s pouch rupture
Anterior Pituitary Function Tests
(Stimulation tests)
•
•
•
•
Thyrotrophin Releasing Hormone (TRH)
Gonadotrophin Releasing Hormone (GnRH)
Metyropone stimulation test
GH-specific tests
– Clonidine, Arginine, Exercise, L-dopa
• Insulin-induced hypoglycemia (ITT, IST)
• Combined pituitary function test
– ITT + TRH + GnRH
Hormone Replacement Therapy in
Panhypopituitary Patient
• Adrenal Cortex:
–
–
–
–
Dexamethasone
Prednisone
Hydrocortisone
Cortosone Acetate
0.25 - 0.75 mg/d
5-7.5 mg/d
15-30 mg/d
25-37.5 mg/d
• Thyroid:
– Levothyroxin
100-200 mcg/d
• Maintain T4 level in upper normal range
• Gonadal Steroids:
– Estrogen/Progesterone or Testosterone
• Desmopressin
• Growth Hormone
Hypopituitarism -- Treatment
• Treatment:
– Hormonal Replacement
– Surgical
• Most tumors require surgery
– Radiation
•
•
•
•
Small effect
High probability of pituitary dysfunction
Low probability of secondary tumor
May have long-term subtle neurologic effects
– Medical
• Steroids for hypophysitis
• Specific treatment for granulomatous disease
• Rarely responsive to bromocriptine or octreotide
Growth Hormone
Growth Hormone (GH)
• Gene:
– Chromosome 17 q 22-24
– 191 amino-acids
• Protein
– Species specific
– Binds to 2 specific plasma proteins
• Low affinity, high capacity -- significance not known
• High affinity -- identical to extracellular domain of GH
receptor
– Absent in GH-receptor deficient states (Laron Dwarf)
– Decreased in GH excess
– Biologic significance
» Decreased clearance?
» Buffer effect?
• Receptor
– Highly species specific
Diurnal Variation in Pulsatile Growth
Hormone Secretion
Regulation of GH Secretion
Sleep
Arginine
Dopamine
?
Acetylcholine
Somatostatin
Glucose
TRH
Alpha adrenergic
Opiates
GABA
SS
GRH
GH
T3
Stimulation
Inhibition
Growth Hormone
Releasing Hormone
+
IGF-1
Insulin-like Growth Factor 1
Growth-Hormone:
Regulation of Secretion
• Growth Hormone Releasing Hormone
(GRH)
– 40 AA peptide, structurally similar to Glucagon
and Secretin
– Secreted in pulsitile manner
– Interacts with somatostatin to create normal
pulsitile GH secretion pattern
– Continuous stimulation with GRH results in
down-regulation of receptors, but pituitary still
responsive
– GRH-stimulated GH secretion can be inhibited
by Somatostatin
Growth-Hormone:
Regulation of Secretion
• Somatostatin
– 2 isoforms: 14 and 28 Amino Acids
synthesized from same pro-hormone molecule
– Pulsitile secretion with biologic half-life 1-3
minutes
– Suppresses both GH and TSH
– Produced in hypothalamus, brain, pancreatic
islets, GI tract
– At least 5 different receptor sub-types
– In hypothalamus acts as neuropeptide, secreted
by hypothalamic neurons and carried to
pituitary by portal system
Somatostatin - Structure
NH2
COOH
Prepro-somatostatin
116
COOH
Pro-somatostatin
COOH
Somatostatin - 28
28
Somatostatin -14
COOH
14
Somatostatin -Cellular Action
Ca++
close
K+
Somatostatin 14
Somatostatin 28
5 Receptor
Subtypes
1
3
Phospholipase C
2
4
Tyrosine phosphatase
5
a 
Gi
AC
ATP
cAMP
GH Receptor Dimerization
Binding site 1
Activation
Binding site 2
JAK Kinase
Signal Transduction and
Transcription Activator
Insulin-Like Growth Factor 1
• 70 Amino Acids, structurally similar to Proinsulin
• GH stimulates secretion.
• Blood levels decreased by starvation and liver
disease
• Most GH-sensitive tissues produce I GF-1 which
acts in a paracrine fashion.
• Circulating IGF-1 primarily of hepatic origin
• Circulating IGF-1 is bound to at least 6 different
IGF binding proteins.
– IGFBP-3 is regulated by GH
Growth Hormone Actions
• Anti-Insulin
–
–
–
–
Lipolysis
Ketogenesis
Hyperglycemia
Peripheral insulin
resistance
• Growth promoting,
Insulin-like
– Increased:
• Protein synthesis
• Amino acid
transport
• Muscle mass
• Bone and cartilage
growth
• Cell proliferation
Growth-Hormone Deficiency (1)
• Children
– Increased insulin sensitivity
• Hypoglycemia (mostly infants and small children)
– Decreased linear growth (Dwarfism)
– Decreased muscle mass, increased fat mass
• Adults
– Decreased muscle mass, increased fat mass
– Decreased sense of well being
Growth-Hormone Deficiency (2)
• Etiology:
– Children:
• Genetic:
–
–
–
–
Isolated GH deficiency
Growth hormone mutations
GH receptor deficiency (Laron Dwarf)
Multiple pituitary hormone deficiency (PIT-1, PROP-1)
• Tumor:
– Craniopharyngioma
– Dysgerminoma
– Adult:
• Trauma / Surgery / Radiation
• Tumor:
– Functioning or non-functioning pituitary
– Craniopharyngioma
– Metastatic (breast)
Growth-Hormone Deficiency (3)
• Diagnosis
– Stimulation tests:
•
•
•
•
•
Clonidine
L-dopa
Arginine
Exercise
Insulin-induced hypoglycemia
– Under most circumstances, at least 2 abnormal
tests required for definitive diagnosis
GH Stimulation Tests
Sleep
Arginine
Dopamine
Acetylcholine
Alpha adrenergic
(Clonidine)
Stress
(Exercise, ITT)
SS
GRH
GH
Stimulation
Inhibition
+
IGF-1
Growth-Hormone Deficiency (4)
• Treatment
– Human growth hormone replacement
• Human pituitary origin
– Expensive and insufficient supplies
– Creutzfeld-Jacob disease
• Recombinant DNA technology
– Plentiful
– Safe
– Expensive
– Use in GH-deficient adults standard in most
countries
– Use in elderly is controversial and not accepted
by most.
Growth-Hormone Excess
• Childhood
– Gigantism
• Adults
– Acromegaly
• Etiology
– 98%: GH-producing pituitary tumor
– 2%: Ectopic GHRH secretion
•
•
•
•
Small cell lung cancer
Bronchial or intestinal carcinoid tumors
Pancreatic islet cell tumor
Pheochromocytoma
Gigantism
28 October 2013, Turkey
Growth-Hormone Excess
• Childhood
– Gigantism
• Adults
– Acromegaly
• Etiology
– 98%: GH-producing pituitary tumor
– 2%: Ectopic GHRH secretion
•
•
•
•
Small cell lung cancer
Bronchial or intestinal carcinoid tumors
Pancreatic islet cell tumor
Pheochromocytoma
Acromegaly (1)
•
•
•
•
•
Prevalence:
Incidence:
Mean age of onset:
Mean age at diagnosis:
Prognosis:
40-50 / 106
3-4 / 106
32 years
42 years
2x increased mortality
Acromegaly - Signs and Symptoms
• GH Excess
– Enlargement of hands and
feet
– Thick skin
– Skin tags
– Sweating
– Sleep Apnea
– Carpal Tunnel Syndrome
– Glucose intolerance
– Osteoarthritis
– Colonic Polyps
• Tumor-related
– Headache
– Visual field defect
– Loss of pituitary
function
• Gonadotrophins
• TRH - hypothyroid
• ACTH - Addison’s
Acromegaly (3):
Diagnosis
• Abnormal net GH secretion over time:
– 24 hour GH profile (Night-time GH levels)
– Elevated IGF-1
– Elevated IGFBP-3
• Non-suppressible GH secretion
– Glucose suppression
• OGTT
• High-carbohydrate meal
Regulation of GH Secretion
Dopamine
Glucose
TRH
SS
GRH
GH
Stimulation
Inhibition
+
IGF-1
Acromegaly Treatment Options
• Surgery
• Radiation
• Medical
Natural Somatostatin
• Clinical utility is limited by:
– Plasma half- life
1-3 minutes
• Drug delivery:
– Intravenous only
– Specificity poor
• Cessation of treatment associated with
rebound phenomenon
Synthetic Somatostatin
Analogue Octreotide
• Clinical utility is enhanced due to:
– Plasma half- life 1-2 hours
– Drug action Variable 3-12h
– Drug deliveryIV or SC
• Specificity:
– Partial selectivity
• (GH>glucagon>gastric acid>insulin)
• No rebound phenomenon upon cessation of
treatment
Somatostatin Analogs
Native Somatostatin-14
S-S
Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys
S-S
Octreotide: dPhe-Cys-Phe-dTrp-Lys-Thr-Cys-Thr(ol)
111In-DTPA
S-S
Octreoscan: dPhe-Cys-Phe-dTrp-Lys-Thr-Cys-Thr(ol)
Lanreotide:
S-S
dnal-Cys-Tyr-dTrp-Lys-Val-Cys-Thr
Somatostatin
Actions on the Gastro-intestinal Track
Lamberts et al NEJM, 1996
Adverse Side-Effects of
Somatostatin Analogs
• Common side-effects
– Pain at injection site
– Abdominal pain and
cramps
– Diarrhea, steatorrhea
– Impaired glucose tolerance
– Gallstone formation
• Rare side-effects
–
–
–
–
Rash
Alopecia
Water intoxication
Hypoglycemia
Decrease side-effects by:
Avoid fat intake for first 2 weeks after initiation of therapy
Short acting preparations:
Warm injection to room temperature before administration
Inject slowly
Use highest possible concentration of drug
Inject about 1 hour after meals
Acromegaly: Novel Treatment
Approaches
• Growth hormone antagonists
– Growth hormone analog with one binding site
mutated
Dominant Negative GH Analog
Binding site 1
Binding site 2
Binding site 2 Mutated
No dimerization
Noactivation
No signal transduction
Acromegaly: Novel Treatment
Approaches
• Growth hormone antagonists
– Growth hormone analog with one binding site
mutated
– Dominant negative activity
– Disadvantages:
• GH levels not suppressed
• Difficult to monitor
• Effect on tumor unknown
– May actually stimulate tumor growth
Prolactin
Prolactin
• 198 Amino acid peptide structurally related
to Growth Hormone (GH)
• Lactotrophs which make up 40-50% of the
endocrine cells of the anterior pituitary
• During fetal development, prolactin cells
appear to differentiate from GH cells.
• Some cells maintain the ability to produce
both GH and Prolactin.
• Glycosylated and non-glycosylated forms
have different bioactivities.
Cellular Action of Prolactin
• Membrane bound receptor
• Action appears not to be cAMP
dependent
• Action may be mediated through
membrane phospholipase activity
resulting in protein kinase C activation
and calcium influx
Effects of Hyperprolactinemia
• Hypothalamus:
– Inhibition of GnRH production
• Mammary gland:
– Direct - stimulation of milk production and
secretion
– Indirect - decreased estrogen effect
• Ovaries:
– Direct - decreased responsiveness to
gonadotrophins
– Indirect - decreased gonadotrophin secretion at
level of hypothalamus/pituitary
Effects of Hyperprolactinemia
• Testes:
– Direct - decreased responsiveness to
gonadotrophins
– Indirect - decreased gonadotrophin secretion at
level of hypothalamus/pituitary
• Bones:
– Indirect - due to gonadal steroid deficiency
Prolactin - Diurnal Variation
SW
I+II
WAKE
Plasma Prolactin (pmol/l)
REM
600
400
200
Sleep
08
14
20
02
24 Hour Clock Time
08
Control of Prolactin Secretion
Hypothalamus
+
PRFs
(TRH)
Dopamine
(Other PIFs?)
-
+
Lactotropes
-
Estrogen
Thyroid Hormone
Prolactin
Breast milk synthesis
Prolactin Effect on
Gonadotrophin Secretion
Inhibits
Hypothalamus
GnRH
Dopamine
Stimulates
+
Pituitary
Hyperprolactinemia
Gonadotrophs
LH
Gonads
Differential Diagnosis of
Hyperprolactinemia
• Prolactin producing pituitary tumor
– Microprolactinoma (<1 cm)
– Macroprolactinoma (>1 cm)
– Mixed tumors (30% of GH producing tumors)
• Chronic renal failure
– Decreased clearance and suppressibility
• Thoracic sensory nerve stimulation
– Chest wall burns, incisions, trauma etc.
• Mental and physical stress
– May be mediated through ß-endorphin
suppression of dopamine secretion
Differential Diagnosis of
Hyperprolactinemia
• Medications
– Alpha-methyldopa, reserpine
– Phenothiazines, butyrophenones,
– benzamides (metoclopramide, sulpride)
Estrogens
– H2-receptor blockers (cimetidine)
– Opiates
• Hypothyroidism
• Decreased dopamine delivery to pituitary
– Pituitary, suprasellar and hypothalamic lesions
– Radiation damage to the hypothalamus
Differential Diagnosis of
Hyperprolactinemia
• Prolactin levels > 6,500 mIU/l is usually
indicative of macroprolactinoma.
• Stalk compression, medications, hypothyroidism
and stress usually result in prolactin levels < 1,500
and virtually always less than 5,000 mIU/l.
• Microprolactinomas, mass lesions compressing
the pituitary stalk frequently present with similar
prolactin levels.
Prolactinoma: Results of Treatment
Response
Recurrence
Surgery
Microprolactinoma
Macroprolactinoma
Radiotherapy
Medical Therapy
Microprolactinoma
Macroprolactinoma
60-80%
10-30%
Normalization of PRL after ~10 years
>90%
50-80%
50%
~100%
TheEndo
End
The
Schematic View of an ADH-Sensitive Collecting
Tubule Cell
Adenyl cyclase
ATP
ATP
kinase
cAMP
cAMP
ADH receptor
H2O
A
B
C
H2O
Cortisol and
Thyroid Hormone
requiring
ADH binds to the contraluminal surface, activating adenylyl cyclase and
generating cAMP. This causes cytoplasmic tubules containing water
channels, aquaporins (A), to fuse with the luminal membrane (B), allowing
free transport of water into the cell. C = particle aggregates in luminal
membrane.
Control of ADH Secretion
Osmoreceptor
(preoptic nucleus
anterior hypothalamus)
Water
Na
Glucose
Nausea
Pain
Paraventricular nucl.
Supraoptic nucl.
Depolarization
Posterior
Pituitary
ADH+
Neurophysin
(1.5 hours)
Baroreceptrors
Aorta
Carotids
Atria
Thoracic veins
Acromegaly: Treatment options
Transsphenoidal Surg. Radiotherapy
Micro
Octreotide
Bromocriptine
Macro
GH <5 mcg/l 80%
50-60%
77% (15 years)
65%
20%
GH <2 mcg/l 70%
40%
no data
40%
no data
Nl IGF-1
50%
no data
50%
10%
Late response
inconv. & cost Low efficacy
50%
Disadvantages
Recurrence 5-10%*
Complications
Hypopit.
15%
>50%
None
None
Other
DI- 2-3%
Neuro deficits
Gallstones
Nausea,
hypotens.
* Actual long-term recurrence probably higher