Diseases of the Pituitary GlandDiseases of the Pituitary Gland

Benjamin Glaser, M.D.Endocrinology and Metabolism Service

Hadassah-Hebrew University Medical Center

Pituitary DiseasePituitary 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 SectionHuman Pituitary in Sagittal Section

Pituitary

Optic Chiasm

AnteriorCommissure

Hypothalamus

Third Ventricle

Pineal Body

MamillaryBody

MedianEminence

Anterior ClinoidsPosterior Clinoids

Carotids

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.

Normal Pituitary: Gross anatomyNormal Pituitary: Gross anatomy

StalkAnterior

Posterior

Embryogenesis of the Human PituitaryEmbryogenesis of the Human Pituitary

Hypothalamic releasing hormones

, ADH

Normal Pituitary: Coronal MRINormal Pituitary: Coronal MRI

Optic Chiasm

InfundibulumCavernousSinus

Pituitary

Sphenoid sinus

Third Ventricle

Normal Pituitary: Sagittal SectionNormal Pituitary: Sagittal Section

Optic Chiasm

Infundibulum

Pituitary

Sphenoid sinus

SupraSellar fossa

Human Pituitary in Coronal SectionHuman Pituitary in Coronal Section

Pituitary glandInternal carotid artery

IIIIVVI

V

Sphenoid Sinus

Cranial Nerves

Human Pituitary in Coronal SectionHuman Pituitary in Coronal Section

Diseases of the PituitaryDiseases 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 HormonesPituitary Gland Hormones

TSHThyroidGland

Adrenal Gland

ACTH

LHFSH

Testes/Ovaries

GH Prolactin

IGF-1

Vasopressin(Anti-diuretic Hormone)

Oxytocin

Vasopressin BiosynthesisVasopressin Biosynthesis

Transport and Maturation

SP AVP NP GP

Production

Gene expression Preprohormone

SP, signal peptide; AVP, arginine vasopressin; NP, neurophysin; GP, glycoprotein

Cell body in paraventriculaor Supraoptic nucleus

AVP

Mature Hormone

GlycosylationProteolysisAmidation

Storage and release in posterior pituitary

AVP NP GP

Packaging

Prohormone

Receptor-mediated effects of AVPReceptor-mediated effects of AVP

Receptor

Subtype Site of Action Activation Effects

V1a

- vascular smooth muscle cells- platelets- lymphocytes and monocytes- liver

vasoconstrictionplatelet aggregationcytokine releaseglycogenolysis

V1b - anterior pituitaryACTH and -endorphin release

V2- renal collecting duct principal cells

free water reabsorption

Lee et al., Am Heart J 146:9-18, 2003

AVP regulation of water reabsorption from renal tubular AVP regulation of water reabsorption from renal tubular cellscells

AVPAVPAVP VAVP V22

ReceptorReceptor

AQP3AQP3

AQP4AQP4

Basolateral Basolateral membranemembrane

Luminal Luminal membranemembrane

HH22OO

HH22OOAQP2AQP2

Exocytic Exocytic InsertionInsertion

Endocytic Endocytic RetrievalRetrieval

cAMPcAMP

ATPATP

PKAPKA

RecyclingRecyclingvesiclevesicle

AQP2AQP2GTPGTP(Gs)(Gs)

Co

llectin

g d

uct

Co

llectin

g d

uct

Va

sa r

ect

aV

asa

re

cta CollectingCollecting Duct CellDuct Cell

Thyroid hormoneGlucocorticoid Dependent

Renal Concentrating MechanismRenal Concentrating Mechanism

Cortex

Medulla

NaH2O

Dilute

400

800

1100

H2O

H2O

Concentrated

10+ Liters/day

ADH PresentNa

H2O

300

Modified from Schrier, Renal and Electrolyte Disorders,

Na

Renal Diluting MechanismRenal Diluting Mechanism

Cortex

Medulla

NaH2O

Dilute

400

500

600

H2O

Na

Dilute

10+ Liters/day

ADH AbsentNa

H2O

Modified from Schrier, Renal and Electrolyte Disorders,

AVP Stimulation and EffectsAVP Stimulation and Effects

hyperosmolalityhyperosmolalityhypovolemia hypovolemia angiotensin IIangiotensin II

vasoconstrictionvasoconstriction renal Hrenal H22O O

reabsorptionreabsorption

baroreceptors baroreceptors natriuretic natriuretic peptidespeptides

AVPAVP

––++

V1a ReceptorsV1a Receptors V2 Receptors V2 Receptors

PainPainNauseaNausea

++

Adapted from Orlandi, 2009

ADH SecretionADH Secretion

290 300 310280270

ADHPlasmaLevels

ADH levels increase Markedly as soon as The plasma osmolalityincreases about 285

Plasma Osmolality

GoldilocksGoldilocksApproach to EndocrinologyApproach to Endocrinology

GoldilocksGoldilocksApproach to EndocrinologyApproach to Endocrinology

Too Hot

Too Cold

Just right

Hyperfunction

Hypofunction

Normal Function

Syndrome of Inappropriate ADH

DiabetesInsipidus

Diabetes InsipidusDiabetes Insipidus

ADH Deficiency

Diabetes InsipidusDiabetes Insipidus((ADH Deficiency)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 InsipidusDiabetes 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 Differential Diagnosis of Nephrogenic Diabetes Insipidus (partial list):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 Differential Diagnosis of Central Diabetes InsipidusDiabetes 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 Diabetes Insipidus: Clinical EvaluationEvaluation

• 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 InsipidusCentral Diabetes InsipidusTreatmentTreatment

• 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 ADHSyndrome of Inappropriate ADH

Syndrome of Inappropriate ADH Syndrome of Inappropriate ADH (SIADH)(SIADH)

• Clinical findings:– Hyponatremia– Normokalemia – Euvolemia (mild volume expansion)

SIADH - Water and Sodium BalanceSIADH - 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

0.49

28.2

1.430.060.17

21

0.53 0.010.03

7.2

0.72 0.010

5

10

15

20

25

30

Na < 116 Na < 135 Na > 145 Na > 165

Prevalence (%)

Acute hospital careAmbulatory hospital careCommunity care

Hawkins. Clin Chim Acta 337:169-172, 2003

(data from 303,577 samples on 120,137 patients available for analysis)

Symptomatic hyponatremia: neurological manifestations

• headache

• irritability

• nausea/vomiting

• mental slowing

• confusion/delerium

• disorientation

• stupor/coma

• convulsions

• respiratory arrest

life-threatening, usually acute

symptomatic but less impaired; usually chronic

normal brain hyponatremic brain

Acute hyponatremia can cause death from cerebral edema and brain herniation

Neurological symptoms are correlated with the level of hyponatremia, but with considerable

individual variability across patients

Arieff et al., Medicine 55:121-129, 1976

Robertson et al. Robertson et al. Am J Med Am J Med 72:339-353, 198272:339-353, 1982

Plasma AVP levels are inappropriately elevated Plasma AVP levels are inappropriately elevated in most patients with SIADHin most patients with SIADH

0

7

1011

98

654321

230 240 250 260 270 280 290 300 310

Plasma Osmolality (mOsm/kg)

Pla

sma

Vas

op

ress

in (

pg

/mL

)

Normal Normal RangeRange

TumorsExtrathoracicMediastinalPulmonary

CNS DisordersAcute psychosisHemorrhageInflammatory and

demyelinating diseasesMass lesionsStrokeTrauma

DrugsCarbamazepine PhenothiazinesChlorpropamide Prostaglandin-synthesis Clofibrate inhibitorsCyclophosphamide SSRIs Desmopressin MAO inhibitorsNicotine Tricyclics Oxytocin VincristineOpiates

Pulmonary DisordersAcute respiratory failureInfectionsPositive-pressure ventilation

SIADH

Causes of SIADHCauses of SIADH

MiscellaneousHIV infectionIdiopathicPainPostoperative stateProlonged exerciseSenile atrophySevere nausea

Syndrome of Inappropriate ADH Syndrome of Inappropriate ADH (SIADH)(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 AxesAnterior Pituitary Gland Axes

TSHThyroidGland

Adrenal Gland

ACTH

LHFSH

Testes/Ovaries

GH Prolactin

IGF-1

Distribution of Endocrine Cells in Distribution of Endocrine Cells in PituitaryPituitary

Posterior Pituitary

LHFSH10%

ACTH20%

TSH5%

GH50%

PRL15%

LHFSH10%PRL

15%

GH50%

ThyrotropinReleasing Hormone

CorticotropinReleasingHormone

GrowthHormoneReleasingHormone

Somatostatin(Somatotropin

Release Inhibiting

Factor)

Dopamine

GonadotropinReleasingHormone

Stimulator of secretion

Inhibitor of secretion

Pituitary Control of Thyroid/AdrenalPituitary Control of Thyroid/Adrenal

Corticotropin Releasing Hormone

Adreno-Cortico Trophic Hormone

Thyroid Stimulating Hormone

ThyrotropinReleasingHormone

Pituitary Gonadal Axis

Loss of Pituitary FunctionLoss of Pituitary Function

Loss of Pituitary FunctionLoss 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: EtiologyLoss 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 TestsAnterior Pituitary Function Tests(Stimulation 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 Hormone Replacement Therapy in Panhypopituitary PatientPanhypopituitary Patient

• Adrenal Cortex:– Dexamethasone 0.25 - 0.75 mg/d– Prednisone 5-7.5 mg/d– Hydrocortisone 15-30 mg/d– Cortosone Acetate 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 -- TreatmentHypopituitarism -- 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)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 Diurnal Variation in Pulsatile Growth Hormone SecretionHormone Secretion

Regulation of GH SecretionRegulation of GH Secretion

SS

GRH

Acetylcholine

GH

IGF-1+

T3

Sleep

?Dopamine

GlucoseTRH

Arginine

InhibitionStimulation

Alpha adrenergicOpiatesGABA

Somatostatin

Growth HormoneReleasing Hormone

Insulin-like Growth Factor 1

Growth-Hormone: Growth-Hormone: Regulation of SecretionRegulation 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: Growth-Hormone: Regulation of SecretionRegulation 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 - StructureSomatostatin - Structure

COOHNH2Prepro-somatostatin

Pro-somatostatin

Somatostatin - 28

Somatostatin -14

COOH

COOH

COOH

116

28

14

Somatostatin -Cellular ActionSomatostatin -Cellular Action

ACGi

Phospholipase C

Tyrosine phosphatase

Somatostatin 14

Somatostatin 28

Ca++

K+

close

5 ReceptorSubtypes

12

34

5

ATP

cAMP

GH Receptor DimerizationGH Receptor Dimerization

Activation

Binding site 1Binding site 2

JAK Kinase

Signal Transduction andTranscription Activator

Insulin-Like Growth Factor 1Insulin-Like Growth Factor 1

• 70 Amino Acids, structurally similar to Pro-insulin

• GH stimulates secretion. • Blood levels decreased by starvation and liver

disease• Most GH-sensitive tissues produce IGF-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 ActionsGrowth Hormone Actions

• Growth promoting, Insulin-like– Increased:

• Protein synthesis• Amino acid

transport• Muscle mass• Bone and cartilage

growth• Cell proliferation

• Anti-Insulin– Lipolysis

– Ketogenesis

– Hyperglycemia

– Peripheral insulin resistance

Growth-Hormone Deficiency (1)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)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)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 TestsGH Stimulation Tests

InhibitionStimulation

SS

GRH

GH

IGF-1+

Dopamine

Acetylcholine

Sleep Arginine

Alpha adrenergic

(Clonidine)Stress (Exercise, ITT)

Growth-Hormone Deficiency (4)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 ExcessGrowth-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

GigantismGigantism

28 October 2013, Turkey

Duomo Di Milano

Growth-Hormone ExcessGrowth-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)Acromegaly (1)

• Prevalence: 40-50 / 106

• Incidence: 3-4 / 106

• Mean age of onset: 32 years

• Mean age at diagnosis: 42 years

• Prognosis: 2x increased mortality

Acromegaly - Signs and SymptomsAcromegaly - 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):Acromegaly (3):DiagnosisDiagnosis

• 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 SecretionRegulation of GH Secretion

SS

GRH

GH

IGF-1+

TRH

InhibitionStimulation

Glucose

Dopamine

Acromegaly Treatment OptionsAcromegaly Treatment Options

• Surgery

• Radiation

• Medical

Natural SomatostatinNatural 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 Synthetic Somatostatin Analogue OctreotideAnalogue Octreotide

• Clinical utility is enhanced due to:– Plasma half- life 1-2 hours– Drug action Variable 3-12h– Drug delivery IV or SC

• Specificity:– Partial selectivity

• (GH>glucagon>gastric acid>insulin)

• No rebound phenomenon upon cessation of treatment

Somatostatin AnalogsSomatostatin Analogs

Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys

Native Somatostatin-14S - S

dPhe-Cys-Phe-dTrp-Lys-Thr-Cys-Thr(ol)Octreotide: S - S

dPhe-Cys-Phe-dTrp-Lys-Thr-Cys-Thr(ol)Octreoscan: 111In-DTPA S - S

Lanreotide: dnal-Cys-Tyr-dTrp-Lys-Val-Cys-Thr

S - S

SomatostatinSomatostatinActions on the Gastro-intestinal TrackActions on the Gastro-intestinal Track

Lamberts et al NEJM, 1996

Adverse Side-Effects of Adverse Side-Effects of Somatostatin AnalogsSomatostatin Analogs

• Common side-effects– Pain at injection site– Abdominal pain and

cramps– Diarrhea, steatorrhea– Impaired glucose tolerance– Gallstone formation

Decrease side-effects by:Avoid fat intake for first 2 weeks after initiation of therapyShort acting preparations:

Warm injection to room temperature before administrationInject slowlyUse highest possible concentration of drugInject about 1 hour after meals

• Rare side-effects– Rash– Alopecia – Water intoxication– Hypoglycemia

Acromegaly: Novel Treatment Acromegaly: Novel Treatment Approaches Approaches

• Growth hormone antagonists– Growth hormone analog with one binding site

mutated

Dominant Negative GH AnalogDominant Negative GH Analog

Binding site 1 Binding site 2

Binding site 2 Mutated

No dimerizationNoactivationNo signal transduction

Acromegaly: Novel Treatment Acromegaly: Novel Treatment Approaches 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

ProlactinProlactin

ProlactinProlactin

• 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 ProlactinCellular 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 HyperprolactinemiaEffects 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 HyperprolactinemiaEffects 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 VariationProlactin - Diurnal Variation

SW

I+II

WAKE

REM

200

400

600

24 Hour Clock Time

08 14 20 02 08

Sleep

Pla

sma

Pro

lact

in (

pm

ol/

l)

Control of Prolactin SecretionControl of Prolactin Secretion

Lactotropes

Estrogen

Thyroid Hormone

Prolactin

+Hypothalamus

+

-

-

Breast milk synthesis

-

PRFs(TRH)Dopamine

(Other PIFs?)

Prolactin Effect on Prolactin Effect on Gonadotrophin SecretionGonadotrophin Secretion

GnRH

+

Inhibits

Hyperprolactinemia

Stimulates

LH

Gonadotrophs

Gonads

Hypothalamus

Pituitary

Dopamine

Differential Diagnosis of Differential Diagnosis of HyperprolactinemiaHyperprolactinemia

• 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 Differential Diagnosis of HyperprolactinemiaHyperprolactinemia

• 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 Differential Diagnosis of HyperprolactinemiaHyperprolactinemia

• 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 TreatmentProlactinoma: Results of Treatment

Response Recurrence

SurgeryMicroprolactinoma 60-80% 50%

Macroprolactinoma 10-30% ~100%

Radiotherapy Normalization of PRL after ~10 years

Medical TherapyMicroprolactinoma >90%Macroprolactinoma 50-80%

The EndThe EndThe EndoThe Endo

Schematic View of an ADH-Sensitive Collecting Schematic View of an ADH-Sensitive Collecting Tubule CellTubule Cell

ATP

cAMP

A

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.

kinase

B

C H2OH2O Cortisol and

Thyroid Hormone requiring

ADH receptor

Adenyl cyclase

cAMP

ATP

Control of ADH SecretionControl of ADH Secretion

Osmoreceptor(preoptic nucleusanterior hypothalamus)

Paraventricular nucl.Supraoptic nucl.

PosteriorPituitary

Nausea

Pain

Baroreceptrors Aorta Carotids Atria Thoracic veinsDepolarization

ADH+Neurophysin(1.5 hours)

Water

NaGlucose

Acromegaly: Treatment optionsAcromegaly: Treatment options

Transsphenoidal Surg. Radiotherapy Octreotide Bromocriptine

Micro 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% 50% no data 50% 10%

Disadvantages

Recurrence 5-10%* Late response inconv. & cost Low efficacy

Complications

Hypopit. 15% >50% None None

Other DI- 2-3% Neuro deficits Gallstones Nausea, hypotens.

* Actual long-term recurrence probably higher