Prolactin Om

8/12/2019 Prolactin Om

1/49

Prolactinoma & Hyperprolactinaemia

Julian Davis

Dept of Endocrinology

Manchester Royal Infirmary


2/49

Prolactinoma and hyperprolactinaemia

Prolactin biology Presentation

Epidemiology

Pathogenesis

Investigation

Treatment Pregnancy


3/49

Hypothalamic-pituitary hormone axes

Hypothal Pituitary Target organ hormone

CRH ACTH cortisol

TRH TSH thyroxine

GnRH LH T, E2

GnRH FSH inhibin

GHRH GH IGF-1

DA Prolactin


4/49

Human prolactin: milestones

1971 - hPRL immunoassay developed

- prolactinomas identified

- CB154 (bromocriptine) suppresses PRL

1981 - hPRL cDNA cloned

- homology with GH noted

1988 - PRL-R cloned: cytokine receptor structure

1996 - PRL-R knockout mice characterised- fertility phenotype: blastocyst maturation, implantation, lactation

- maternal behaviour phenotype

- adipose depots


5/49

Regulation of prolactin

Hypothalamic regulation

Dopamine

TRH

VIP

somatostatin

Paracrine regulation

EGF

FGF2

galanin

NGF, BK...

Peripheral hormones

oestrogen

Overall:

stress

circadian time: high at night

breast-feeding


6/49

Causes of hyperprolactinaemiaDrugs Dopamine antagonists phenothiazines, metoclopramide, domperidone, sulpiride

SSRIs: fluoxetine etc.

Monoamine oxidase inhibitors

Tricyclic antidepressants

Fenfluramine

Methyldopa

Verapamil

Miscellaneous Hypothyroidism

Polycystic ovary syndrome

Acromegaly

Chronic renal failure

CirrhosisChest wall lesions

Hypothal-pituitary disease Prolactinoma

Pit. stalk disconnection: trauma; pituitary adenoma; empty sella

craniopharyngioma, meningioma, glioma, dysgerminomaIdiopathic


7/49

Prolactinoma and hyperprolactinaemia

Microadenoma

Macroadenoma

PRL supp resses LH and

FSH puls at i l i ty

Women

amenorrhoea

galactorrhoea

loss of libido

Men

hypogonadism

loss of libido mass effects


8/49

Prolactinoma and hyperprolactinaemiaNon-tumoral (idiopathic)

hyperprolactinaemiaProlactinoma

lactotroph


9/49

How common? Population estimates

Tumours Incidence Prevalence

cases/million/year cases/million popul.

Prolactinoma 6-10 60-100 say 1/10,000NF tumour 7-9 70-90

GH tumour 4-6 40-60

Cushings 2-3 20-30

RN Clayton, Stoke series, 1988-98

Hyperprolactinaemia

40 of 10550 = 0.4%- 6 pituitary disease say 6/10,000- 10 macroprolactin- 7 pregnant- 13 drug-induced

K. Miyai et al, 1986


10/49

How common? Autopsy and scan dataAutopsy (meta-analysis by Molitch, 1997)

Variable rates: 1-27%, average 11%

males=females

3 / 1403 are macroadenomas

46% stained for prolactin

Scanning:

CT: >3mm adenomas in 4-20% (Molitch, 97)

MR: 10 / 100 if 2 reviewers agreed, 25-48 / 100 if one only

(Hall, 94), i.e. highly observer-dependent


11/49

Macroprolactinaemia

monomeric: 23kD

PRL monomer

Prolactin on gel chromatographs

Macroprolactin found in 25% of

hyperprolactinaemic patients -

?significance

Macroprolactin isoforms precipitate

with PEG-

screening test for asymptomatic patients

with high prolactin

big: 45-50kD

big-big (PRL-Antibody): >100kD


12/49

Pathogenesis: theories

Genetic alteration

In single cell

Hormonal

dysregulation

Polyclonal tumour

arises by hyperplasia

of multiple precursor cells

Monoclonal tumour

expansion

from single cell


13/49

Pathogenesis: dysregulation?

Hormonal

dysregulation . high dose oestrogen: PRLomatransgenic GHRH excess: GHoma

Polyclonal tumour

arises by hyperplasia

of multiple precursor cells. tumours recur after complete excision

background hyperplasia on histology


14/49

Pathogenesis: intrinsic genetic defect?

Genetic alterationin single cell

Gsp mutation

MEN-1 mutation

Monoclonal tumour

expansion

from single cell

Clonality studies


15/49

Combined model of pathogenesis

Occasional

mutations ariseHormonal

environment favours

cell proliferation:

?oestrogens

?dopamine?corticosteroids

?growth factors

Selective growth

of clones carrying gene

mutations that favourcell growth/survival


16/49

Investigation

History, medication Exclude pregnancy

Consider PCOS Repeat PRL sample (unstressed)

consider pituitary disease


17/49

Investigation serum PRL

Normal range: many labs quote 10,000 suggests macroprolactinoma


18/49

Investigation Thyroid status: T4, TSH

Ovarian status: oestradiol/testosterone, LH, FSH

?Adrenal status: 0900 cortisol (synacthen test)

?Consider acromegaly: GH, IGF-1

Visual fields: confrontation, formal testing

Imaging


19/49

Investigation: visual field testing


20/49

Investigation: pituitary imaging

CT scan: axial coronalLateral skull X-ray


21/49

Pituitary imaging: MR scans are best


22/49

Prolactinoma therapy

Drug therapy

Surgery

Radiotherapy


23/49

Indications for treatment

Hypogonadism

oestrogen deficiency - BMD, symptoms

androgen deficiency

anovulatory infertility

loss of libido

Galactorrhoea

Pituitary mass

headache

vision


24/49

Treatment

Dopamine agonists

bromocriptine

cabergoline

quinagolide Oestrogen replacement

Nothing

Surgery

Radiotherapy


25/49

Dopamine agonists

Bromocriptine

introduced 1971

reduces prolactin in 85-90%

restores gonadal function in 80-90% (women)

significant tumour shrinkage in 80% mostly in first 3 months, but effect continues

useful shrinkage in 24-48h

side-effects 12% cannot tolerate

nausea

postural hypotension

abdo pain mood change


26/49

Dopamine agonists induce ovulation


27/49

Bromocriptine: prolactinoma shrinkage


28/49

Bromocriptine: PRL suppression, tumour

shrinkage

55y female

PRL 656,000mU/L

BCR treatment only


29/49

Prolactinoma shrinkage by MR:

macro and microprolactinomas,sensitive or resistant to cabergoline

macro - sens macro - res

micro - sens

micro - res

Colao 2004


30/49

Newer dopamine agonists

Cabergoline

given 1-2 weekly: 0.5-4 mg/week

normalises prolactin in up to 85%

Quinagolide given daily 75-150ug

similar efficacy to Cab and BCR

Side-effectsless common than BCR

nausea

postural hypotension

abdo pain mood change, depression


31/49

Oestrogen replacement

If main problem for women is oestrogen deficiency:

if no significant adenoma bulk

if no significant galactorrhoea

if serial MR scan monitoring available

then oestrogen replacement alone may be reasonable

2 small, short-term studiesCorenblum & Donovan, Fertil Steril, 1993

Testa et al, Contraception, 1998


32/49

Nothing

If no disturbance from hyperprolactinaemia:

if no significant adenoma bulk

if no significant galactorrhoea

if normal ovarian function maintained

if serial MR scan monitoring available

then no treatment may be reasonable


33/49

Natural history

Long-term follow-up

156 untreated patients followed over 8y (Molitch, 1999)

tumour expansion in 6%

PRL levels stable or fell in 75%

i.e. prolactinomas may be very indolent, may remit, may not

need treatment

Cessation of dopamine agonists


34/49

Cessation of dopamine agonists

DAs cessation recurrent hyperprolactinaemia

tumour re-expansion

But early retrospective studies in microprolactinoma:

About 20% of women remained well off DAs

- near normal PRL levels- regular menses

- no galactorrhoea

?worth a trial off treatment after 2-5 yrs

Might long-term DAs may be cytocidal to lactotrophic cells?

Cessation of dopamine agonists:


35/49

Cessation of dopamine agonists:

prospective study -Colao et al, (2003) NEJM, 349:2023

200 patients 25 non-tumoral

105 microprolactinoma

70 macroprolactinoma-stable on cabergoline, PRL suppressed to normal (25g/L; 550mU/L)-small tumour residue, or no residue

Cabergoline withdrawn after 2-5y: recurrence rates

Non-tumoral hyperprolactinaemia 24%

Microprolactinoma 30%

Macroprolactinoma 36%

possibility of permanent remission, even for macroadenomas

chances better if scan showed no tumour residue

caution for longer term follow-up, but worth trial withdrawal


36/49

Transsphenoidal pituitary surgery

Potential for long-term cure and

avoidance of DA side-effects

Outcomes poor even in specialist

hands - 50-75% long-term endocrineremission for microadenomas

Radiotherapy


37/49

Radiotherapy

Prevents tumour regrowth

Slow onset of effect

50% patients still

hyperprolactinaemic at 10yrs

Gradual hypopituitarism

P l ti i i


38/49

Prolactinoma size in pregnancy

Pituitary size increases by 36%:pregnancy cells = mitotic lactotrophs

post-partum lactotrophs regress, but only partlyNormal

pregnancy

Prolactinoma

Prolactin levels in pregnancy


39/49

Prolactin levels in pregnancy

4000mU/L

Non-pregnant


40/49

Microprolactinoma enlargement

Non-pregnant

32 weeks pregnant(headache, VFs N.)


41/49

Macroprolactinoma enlargement

Non-pregnant Pregnant


42/49

Risks of prolactinoma enlargement

Microadenoma: 1-5% 1%

Macroadenoma: 15-35% 23%

Molitch, J Reprod Med 1999


43/49

MICROprolactinoma

Gemzell & Wang (1979, Fertil Steril)

91 pregnancies:

1 case: headache & VF defect at 12 weeks

3 cases: headache - no treatment

Molitch meta-analysis (1985, NEJM)

16 series, 246 women

4 (1.6%) headache/VF defect 11 (4.5%) asymptomatic enlargement


44/49

MACROprolactinoma

Gemzell & Wang (1979, Fertil Steril)

56 pregnancies:

19 cases (= 34%): headache,VF defect:

Rx: nothing (12), surgery (5), bromocriptine (1), steroids (1)

Molitch meta-analysis (1985, NEJM)

16 series, 45 women

7 (15%) headache/VF defect 4 (8%) asymptomatic enlargement


45/49

Case: prolactinoma & pregnancy

28y woman, 6mm microadenoma

Prolactin 1800-2500mU/L

Treated bromocriptine:

Prolactin normalised menses regular

conceives

Plan?


46/49

Prolactinoma & pregnancy Bromocriptine stopped

VFs normal

Prolactin rises:

12 weeks 3866 18 weeks 5227

28 weeks 8878

34 weeks 12908

Plan?


47/49

Prolactinoma and pregnancy 30y woman

22mm macroprolactinoma, abutting optic chiasm

Presented with headache and slight VF loss

On cabergoline:

prolactin now normal

awaiting follow-up MR scan

Now pregnant

Advice?


48/49

Issues Continue or stop cabergoline?

teratogenicity: no excess so far

lactation: will be prevented

risk of symptomatic enlargement off drug ~25-35%?

Prior surgery? reduces enlargement risk to 3%


49/49

Prolactinoma: summary

Common endocrine problem

Diagnostic pitfalls

Pathogenesis not clear

Long-term medical therapy Possible eventual remission

Issues of pregnancy management

Prolactin Om

Documents

Transcript of Prolactin Om