In the Name of God Prolactinoma - PowerPoint Presentation

Slide1

In the Name

of

God

Slide2

Prolactinoma

Diagnosis and Management

Navid Saadat, MD

Associate Professor of Endocrinology

Shahid Beheshti University of Medical Sciences

Slide3

Physiology

Prolactin(PRL)secreted by the lactotrophs

Delicate

balance between the prolactin-releasing (

TRH

and

VIP

) and inhibitory (

dopamine

) factors

Dopamine D

2

receptors (

D

2

R

) inhibit

PRL secretion

Cell proliferation

Slide4

Slide5

Hyperprolactinemia

PhysiologicalPharmacological

Pathological

Idiopathic

Slide6

Physiological

PregnancyLactationExercise

Sleep

Stress

Slide7

Pharmacological

AntipsychoticsTypical

Phenothiazines

Chlorpromazine

Butyrophenones

Haloperidol

Thioxanthenes

Thioridazine

Atypical

Risperidone

Tricyclic antidepressants

Clomipramine

Monoamine-oxidase inhibitors

Pargyline

Miscellaneous

Metoclopramide / Domperidone

Methyldopa

Verapamil

OCPs

Opiates and cocaine

Slide8

Pathological

Hypothalamic - Pituitary

stalk damage

Granulomas

Infiltrations

Irradiation

Trauma

Rathke’s

cyst

Pseudotumor

cerebri

Vascular abnormalities

Tumors

Craniopharyngioma

Germinoma

Hypothalamic metastases

Meningioma

Suprasellar pituitary

mass extension

Slide9

Pathological

PituitaryProlactinomaAcromegaly

Plurihormonal adenoma

Empty sella syndrome

Lymphocytic

hypophysitis

Surgery

Trauma

Slide10

Pathological

Systemic disordersHypothyroidismThyrotroph hyperplasia

Lactotroph

hyperplasia

PCOS

CKD

Cirrhosis

Miscellaneous

Physical or psychological stress

Chest wall lesions

Spinal cord

lesions

Epileptic seizures

Pseudocyesis

Ectopic (rare)

Slide11

Idiopathic

No specific

cause

Uncertain

etiology

Small

prolactinoma

may

be present that are too small to be detected

by MRI

Long-term follow-up

60%

=

PRL remains stable

30%

= PRL normalizes

10%

= PRL may rise

Slide12

PRL

concentrations in several causes of hyperprolactinemia

Macroprolactinoma

Microprolactinoma

Pregnancy

Stress

Drugs

Hypothalamic & other pituitary pathologies

Slide13

Prolactinoma

Slide14

Historical Background

Riddle et al. (1930

)

First

clinical

report

of a

syndrome

of amenorrhea

coupled with

galactorrhea

Friesen et al

. (

1972

)

First demonstrated

elevated

PRL levels in the serum of a patient with a

prolactinoma

Slide15

Classification

SizeMicroadenoma

< 10

mm in

diameter

Macroadenoma

≥ 10

mm in

diameter

Giant

> 40 mm

> 20 mm

of suprasellar extension

Extension

Supra-

, infra- and

parasellar

Invasion

Grossly

Radiologically

Microscopically

Slide16

Epidemiology

Prevalence of pituitary adenoma (PA)

Autopsy and

MRI

studies =

10-25%

Clinical =

1:1000

Annual incidence =

30 per 100,000

persons

Prolactinoma account

for

40-60

%

of all

PA

Sex

(female

to male

ratio)

10:1

< 50 years

1:1

> 50 years

Women

were

diagnosed

12

years

earlier than

menSizeMicroadenoma (80%)Almost exclusively in womenMacroprolactinoma (20%)Preferentially occurring in men95% is sporadic5% in a familial or genetic settingMultiple Endocrine Neoplasia (MEN-1)Familial Isolated PA (FIPA)Carney Complex (CNC)McCune-Albright Syndrome (MAS)

 

Slide17

Prolactinoma

Tumor size

usually

correlates

with

PRL

levels

PRL

>

200

ng/ml =

Strongly

indicative of prolactinoma

R/O drugs

Risperidone

,

Metoclopramide

and

Phenothiazines

PRL

> 500

ng/ml

=

Exclusively

observed in

prolactinoma

Exceptions

Macroprolactinemia

Hook effect

Cystic lesion

Less

well-differentiated

Slide18

Pathogenesis

Monoclonal in nature

Intrinsic

pituitary defect

Menin

pathway

A

ryl hydrocarbon receptor

I

nteracting

P

rotein

(

AIP)

gene mutation

NGF

pathway

VEGF

pathway

Bisphenol-A

?

Slide19

Clinical Manifestations

Signs and Symptoms Associated with Tumor Mass

Headaches

Blurred vision or decreased visual acuity

Visual

field abnormalities

Cranial nerve palsies

Hypopituitarism

Apoplexy

Seizures

Hydrocephalus

Signs and Symptoms Associated with Hyperprolactinemia

Amenorrhea

, oligomenorrhea, infertility

Galactorrhea

Decreased libido, impotence

Erectile dysfunction

, oligospermia

Osteopenia / osteoporosis

Hirsutism

Slide20

Diagnosis

Single measurement of PRL

without

excessive

venipuncture

stress

without

dynamic

testing

Assessing for

macroprolactin

Serial

dilution

(1:100) of serum samples

Hook effect

Distinguishing between

macroprolactinoma

and a large

nonfunctioning

adenoma

Excluding

Medications

Hypothyroidism

Renal failure

Pituitary and parasellar tumors

Slide21

Macroprolactinemia

Benign clinical conditionPrevalence =

10-40%

Aggregates

of glycosylated PRL

Complexing

of

PRL

with

PRL

antibodies

Distinguishable by

Gel filtration

chromatography

Gold

standard

method

Polyethylene glycol

(PEG

)

precipitation

Recovery

<

40

%

(rule

in macroprolactinemia)

Recovery

> 50%

(rule out

macroprolactinemia)

Slide22

Heterogeneity of PRL

Slide23

Paraclinical Evaluations

Pituitary function

Gonadotropins

Testosterone

FT

4

/FT

4

I

Cortisol

GH / IGF-1

BMD

Perimetry

Slide24

Imaging

CT scanCalcification

Bony

architecture

MRI

Soft tissue

Octreoscan

(

111

In-labeled octreotide)

PET

scan

(

18

F-labeled deoxyglucose)

Slide25

MRI Sagittal

View

of a

Prolactinoma

Slide26

Slide27

Treatment Modalities

MedicalDopamine

agonists

Bromocriptine

Cabergoline

Sex

steroid

replacement

Surgical

Transsphenoidal

(TSS)

Transcranial

Radiotherapy

Conventional

Stereotactic

Gamma Knife

Heavy particles

Proton beam

Slide28

Indications for Therapy

Mass effectsHeadachesVisual field defects

Cranial nerve palsy

Hypopituitarism

Hyperprolactinemia effects

Hypogonadism

Oligo/amenorrhea

Infertility

Decreased libido / Erectile dysfunction / Impotence

Low bone mass

Relative indications

Bothersome hirsutism

Bothersome galactorrhea

Slide29

Goals of Therapy

PRL normalizationSize

reduction

Visual

/

neurological

abnormalities correction

Gonadal

function restoration

Hypogonadism

Fertility

Pituitary

functions

preservation

Bone

loss prevention

Slide30

Pros and Cons of Medical Therapy

Benefits of long-term therapyAntimitotic

effect

Perivascular

fibrosis

Cell

necrosis

Apoptosis?

Drug-related aspects

Cost

Side

effects

Intolerance

Compliance

Surgery failure?

Slide31

Dopamine Agonists (DA)

First-line therapyEffective in

controlling

Clinical symptoms

PRL levels

Tumor volume

Cabergoline (DA

of

choice)

Long half-life

High

D

2

receptor affinity

Slow elimination

from pituitary

tissue

Dose response effect

Higher doses are more effective

PRL normalization (

median weekly dose of

1.0 mg

)

Microadenoma = 90

%

Macroadenoma = 80

%

Slide32

Dopamine AgonistsBromocriptine

(2.5 mg tablet)

Initial : 0.625-1.25

mg

qd hs

Maintenance :

2.5-10.0

mg

daily

qd / hs or bid

Cabergoline

(0.5 and 1.0 mg tablets)

Initial :

0.25-0.5 mg/wk hs

Maintenance

:

0.25-2.0 mg/wk/biwk

Occasional cases may require doses up

to 11-21 mg/wk (3mg/day

) for normalization of PRL

Slide33

Dose Adjustment Strategy

Dose escalationBromocriptine

increased by

1.25

-

2.5 mg

/d

Cabergoline

increased by

0.25

-

0.5

mg /wk

Rapid

dose escalation in

visual­ field

compromise

Doubling

of the dose

every

3-5 days

until

Limited

by side

effects

Reaching an optimal

dose

Slide34

Side Effects

CommonNausea / VomitingHeadache

Dizziness

Dry mouth

Dyspepsia

Nasal congestion

Infrequent

Fatigue

Anxiety

Depression

Alcohol intolerance

Rare

Psychosis

Cold sensitive vasospasm

Pleuro-pulmonary inflammatory fibrotic syndrome

Possible

Cardiac valve

abnormalities

Slide35

Treatment Monitoring

PRL &

Size

Once

a year for

3

years

Every

2

years

(stable patient)

Imaging

Perimetry

Echocardiography

Slide36

Remission Criteria

Specific

Normal

PRL level

No

visible

tumor

Acceptable

Decrease

in tumor

size

of at least

50%

from

baseline

Distance

of

at least

5 mm

between the tumor and the optic

chiasm

No

extrasellar

invasion

Hyperprolactinemia may spontaneously resolve

in

some

untreated

patients

Eumenorrheic

Postmenopausal

Slide37

Non-remission

CriteriaNon-normalized PRL

Increasing

tumor

size during

treatment

No

tumor shrinkage ≥ 50%

Tumors

>

5

mm

from

the optic

chiasm

Invasion

of cavernous sinus or

any other critical area

Slide38

Treatment Withdrawal

Major drawback Recurrence

1

st

year (

50%

)

2

nd

year (

30%

)

3

rd

year (

10%

)

Slide39

DAs Valvulopathy

Risk of valvular regurgitation

Mostly in Parkinson’ disease

3-6

mg

cabergoline

daily

10-20X

higher than

used

for

treatment

of

prolactinoma

Serotonin

(

5-HT

2B

) receptor has been implicated, due

to its

high concentration

in

Cardiac valves

Pulmonary arteries

Slide40

DAs Valvulopathy

Assessment of near 500 patients on

cabergoline

for more than

6 years

with cumulative dose of

300 mg

No

clinically significant valve

regurgitation

Cumulative

doses

Parkinson’s

disease

=

2600 -

6700

mg

Prolactinoma =

200 - 500 mg

Increased risk

Weekly

dose of

>

2 mg

If

valvulopathy found

Drug

holiday

Switch to

bromocriptine

Continue

cabergoline with annual echocardiography

Slide41

Patient Follow-up

PRL1 month after

therapy

Treatment intensification

MRI

Macroprolactinoma =

3 months

Microprolactinoma =

1

year

Perimetry

Macroprolactinoma

Comorbidities

Hypopituitarism

Bone loss

Spinal

BMD is decreased in both sexes by

25%

 

Slide42

Special

SituationsMacroprolactinoma

Giant Prolactinoma

Prolactinoma in males

Intolerant patients

Resistant

prolactinoma

Desire

for pregnancy

Prolactinoma and pregnancy

Prolactinoma and

breastfeeding

Psychosis associated with prolactinoma

Postmenopausal

women

Discordant response

Prolactinoma

in

MEN-1

Aggressive, invasive and malignant prolactinomas

Slide43

Macroprolactinoma

Tumor ≥ 10 mmMore common in

men

More

difficult

to manage

More

resistant

to treatment

More frequency of

Neurologic

symptoms

Pituitary dysfunctions

Risk of

apoplexy

Risk of symptomatic

enlargement

during pregnancy

Slide44

Macroprolactinoma

Cabergoline is drug of choice

Normalization

of PRL

Resolution of

Amenorrhea

Galactorrhea

Infertility

Sexual function

Shrinkage

of tumor

Resolution of

Visual field defects

Hypopituitarism

Dosage:

0.25-2.0

mg

/wk

(up to

11-21

mg

/wk)

Slide45

Macroprolactinoma

Shrinkage after

Treatment

with

Cabergoline

Before Treatment

After 1 Year Treatment

Slide46

Before Treatment

After Treatment

Visual-Field

Improvement

2 Months

Slide47

Giant Prolactinoma

Prevalence = 0.5-4.4%Definition

> 40 mm

> 20 mm

(suprasellar extension)

Very

high

PRL

>20,000 ng/ml

At

risk

for

Pituitary

apoplexy

Intratumoral

hematoma

Nonsurgical

CSF

rhinorrhea

Slide48

Cabergoline

(After

14

months

)

Slide49

Size=56 mm X 69 mm

PRL=122,260 ng/ml

PRL=25 ng/ml

Cabergoline

(After

40

months)

Slide50

Prolactinoma in

MalesGreater proportion of macroadenoma

More

invasiveness

Pharmacological

resistance

Symptoms and signs

Headaches

Loss of libido

Impotence

Visual field defects

Hypopituitarism

Exogenous

testosterone has the

potential to

Increase PRL by

aromatization

to estradiol

Render tumor

resistant

to DAs

Slide51

Intolerant

PatientsNo treatment

Low dose

at night

Gradual

dose

escalation

Intravaginal

administration (bromocriptine)

Cabergoline

instead of bromocriptine

HRT

Surgery

Radiotherapy

Slide52

Resistant Prolactinoma

Sensitivity of prolactinoma

to

DA is variable, ranging from

Highly sensitive

Responsive

Resistant

Partial

Complete (<1%)

Primary

Secondary

Early

Late

Mechanism(s

)

Reduced expression

of D

2

R isoforms

Short (D

2

S)

Long (D

2

L

)

NGF pathway disruption

Alterations

in intracellular signal

transduction

Gonadal steroid replacement

Transformation

to

carcinoma (rare)

Slide53

Resistant

ProlactinomaDrug resistance

differs from drug

intolerance

/

non-compliance

Prevalence

Microadenoma

=

10%

Macroadenoma

=

20%

Bromocriptine = 25%

Cabergoline =

10%

Definition

Biochemical

Failure

to achieve normoprolactinemia

Bromocriptine

=

15 mg/day

for at least

3 months

Cabergoline

=

2 (1.5-3.0) mg/wk

Infertility

Failure to restore fertilityMassFailure to achieve a 50% reduction in tumor sizeCharacteristicsMacroadenomaMenInvasiveKi67 and p53MEN-1

Slide54

Desire for Pregnancy

Normalization of PRL

No

evidence of pituitary

tumor

Ovulation induction

Clomiphene

Gonadotropins

Pulsatile GnRH

Prophylactic

TSS

/ Radiotherapy?

Risk of

hypopituitarism

Slide55

Prolactinoma

and PregnancyEstrogen-induced lactotroph

Hyperplasia

/

Hypertrophy

Pituitary volume

>

2X

PRL

X10

Risks to the mother

Adenoma

size

Risks to the fetus

Medical

therapy

Slide56

Prolactinoma and Pregnancy

All DAs cross

placenta

Drug

should be

discontinued

as

soon

as pregnancy has been confirmed

Bromocriptine is the preferred drug

Over

6000

pregnancies with

bromocriptine

Over

700

pregnancies with

cabergoline

Periodic

assessment of

PRL

is not useful

Periodic

perimetry

and or

MRI

are not

cost-effective

Visit

every 3 months

and asked about

Headaches

Changes in vision

MRI without contrast

Slide57

Imaging Study in Pregnancy

MRIs and perimetry are not indicated in the

absence

of

Headache

Visual field

changes

Indications for MRI

Neurologic

symp­toms or signs

Visual­ field

abnormalities

MRI study

Focusing

on the pituitary

Without

the use of

gadolinium

Slide58

Risks to the Mother

Increase in adenoma size

Headaches

Visual disturbances

Risk of

symptomatic

tumor

enlargement

Microadenoma

< 3%

Macroadenoma

Intrasellar

< 3%

Prior

therapy

<

3%

Without

therapy

> 30%

Slide59

Prior to conception

7 months gestation

Enlargement of Macroprolactinoma during Pregnancy

Slide60

Shrinkage

of macroadenoma by treatment with cabergoline in a

woman

Slide61

A:

Tumor is limited to sellar boundaries

during bromocriptine treatment

, before

pregnancy

B:

Tumor growth during the 4th month of pregnancy without bromocriptine use

Slide62

Potential Risks to the Fetus

No evidence of teratogenicity

in animal studies

No

evidence of

Miscarriages

Ectopic pregnancy

Trophoblastic disease

Multiple pregnancy

Congenital malformations

Both

cabergoline

and

bromocriptine

are considered to be

Class B

for use during pregnancy

Slide63

Potential Post-Natal Effects

Long-term follow-up children have shown no

ill

effects

Up to

9 years

for

bromocriptine

Up to

12 years

for

cabergoline

No

abnormalities were noted in the infants, except

One with an

undescended testicle

One with a

talipes deformity

Slide64

Prolactinoma and Breastfeeding

Breastfeeding does not increase the risk of prolactinoma

growth

Breastfeeding is an option for women with

Microprolactinoma

Stable macroadenoma

DA treatment should be

withheld

until

breastfeeding

is completed

Breastfeeding is

contraindicated

in women who have

neurologic symptoms

at the time of delivery

Slide65

Psychosis Associated

with ProlactinomaAntipsychotic dosage

reduction

Replacing with a

PRL-sparing

one

Clozapine

Quetiapine

Adding a dopamine antagonist

medication

Aripiprazole

Trial of DAs

Risk

of

psychiatric

decompensation

No

treatment in the

asymptomatic

patient

Gonadal steroid replacement

Hypogonadism

Low bone mass

Pituitary

surgery

Slide66

Postmenopausal Women

Symptoms of mass effect

and

larger

tumors

Treatment

Asymptomatic = None

Symptomatic, if

Macroadenoma

Mass

effect

Galactorrhea

HRT

Microadenoma =

Negligible

risk

Macroadenoma = Risk of

enlargement

Spontaneous

resolution

of hyperprolactine­mia

Slide67

Discordant

ResponseReduction in tumor size

without

normalization of PRL levels

Reduction

in

PRL

levels

without

reduction

in tumor size

Slide68

Discordant response

to bromocriptine

Slide69

Prolactinoma in

MEN-1CharacteristicsPrevalence =

20%

Larger

tumors

More

aggressive

behavior

Relatively

resistant

to

treatment

More

intensive

pharmacologic

therapy

Use

of

multiple

therapeutic modalities

Slide70

Aggressive/Invasive

and Malignant ProlactinomaOnly

0.2%

of all

pituitary tumors are

malignant

No

reliable pathological

markers

whereby the malignant potential of a prolactinoma can be

predicted

Pituitary carcinoma

probably

develops from preexisting

adenoma

in the

majority

of

cases

Very uncommonly, a prolactinoma is clearly malignant

ab

initio

Malignant

transformation

is usually a

late

event

2

months to 20 years

after the initial diagnosis

Occurs mostly in

MEN1

Heralded

byMultiple local recurrencesProgressive worsening of hyperprolactinemiaAn increasing degree of pharmacological resistanceManifested byIntracranial involvement (cortex, cerebellum, CP angle)Extracranial metastases (liver, lungs, bone, and lymph nodes)

Slide71

Treatment of Malignant Prolactinoma

SurgeryAids in the diagnosis

Local

control and

decompression

of vital

structures

Rarely

curative, because

these tumors are

Invasive

Infiltrating

Chemotherapy

Temozolomide

Long-lasting and significant response

PRL normalization

Tumor shrinkage

Reduction of CAB dosage

Pasireotide

Radiotherapy

Local

control

Radiosurgery

(

g

-knife)

Radiolabeled

somatostatin analogs

Slide72

Surgical Treatment

TSS, the procedure of choiceBenefitsSignificant

debulking

effect

Significant

reduction

of

weekly CAB dose by 50

%

Success rates

Microadenoma =

70 - 90

%

Macroadenoma =

30 - 50%

Recurrence rates

Microadenoma =

uncommon

Macroadenoma =

up to 80%

Pretreatment with bromocriptine (not cabergoline) may

compromised

surgery

outcome

due to

fibrosis

Complications

CSF rhinorrhea

Transient DI

Hypopituitarism

Slide73

Surgical Indications

ApoplexyUnstable and progressive neurological dysfunction

Intolerant

to DA therapy

Failure

of medical therapy

Resistant

prolactinoma

Cystic

or

hemorrhagic

prolactinoma

Tumor expansion

accompanied by neuro-ophthalmologic

deficits

during pregnancy that is

refractory

to reinstitution of DA therapy

CSF

leak

during administration of

DA

Planned pregnancy

following a previous pregnancy complicated by worrisome tumor enlargement

Personal choice

to avoid DA therapy during gestation (macroadenoma)

Psychiatric

condition for which DA are

contraindicated

Slide74

Goals of

Pituitary SurgeryRemoval of

tumor

as much as

possible

to

Avoidance

of

additional

neurologic

damage

Protect

healthy

pituitary

tissue

Factors

play a major role in fulfilling these

objectives

Experience

Instruments

Size

Location

Consistency

Vascularity

Slide75

Radiotherapy

Reserved forResistant

prolactinoma

Malignant

prolactinoma

Surgery

failure

Normalization

of

hyperprolactinemia in

1/3

of

patients

It may require up to

20 years

for the maximal effect

It may

never

restore PRL levels to normal

Local

control

of

tumor growth

Methods

Conventional

Stereotactic

radiosurgery

Gamma Knife

Brachytherapy (

32

P)Heavy particleProton beam

Slide76

Radiation-Related Adverse Effects

HypopituitarismCerebrovascular diseaseRadiation-induced

intracranial

tumors

Meningioma

Glioma

Cranial nerve injury

Optic neuropathy

Slide77

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