prolactin om
Post on 03-Jun-2018
224 Views
Preview:
TRANSCRIPT
-
8/12/2019 Prolactin Om
1/49
Prolactinoma & Hyperprolactinaemia
Julian Davis
Dept of Endocrinology
Manchester Royal Infirmary
-
8/12/2019 Prolactin Om
2/49
Prolactinoma and hyperprolactinaemia
Prolactin biology Presentation
Epidemiology
Pathogenesis
Investigation
Treatment Pregnancy
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
8/49
Prolactinoma and hyperprolactinaemiaNon-tumoral (idiopathic)
hyperprolactinaemiaProlactinoma
lactotroph
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
14/49
Pathogenesis: intrinsic genetic defect?
Genetic alterationin single cell
Gsp mutation
MEN-1 mutation
Monoclonal tumour
expansion
from single cell
Clonality studies
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
16/49
Investigation
History, medication Exclude pregnancy
Consider PCOS Repeat PRL sample (unstressed)
consider pituitary disease
-
8/12/2019 Prolactin Om
17/49
Investigation serum PRL
Normal range: many labs quote 10,000 suggests macroprolactinoma
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
19/49
Investigation: visual field testing
-
8/12/2019 Prolactin Om
20/49
Investigation: pituitary imaging
CT scan: axial coronalLateral skull X-ray
-
8/12/2019 Prolactin Om
21/49
Pituitary imaging: MR scans are best
-
8/12/2019 Prolactin Om
22/49
Prolactinoma therapy
Drug therapy
Surgery
Radiotherapy
-
8/12/2019 Prolactin Om
23/49
Indications for treatment
Hypogonadism
oestrogen deficiency - BMD, symptoms
androgen deficiency
anovulatory infertility
loss of libido
Galactorrhoea
Pituitary mass
headache
vision
-
8/12/2019 Prolactin Om
24/49
Treatment
Dopamine agonists
bromocriptine
cabergoline
quinagolide Oestrogen replacement
Nothing
Surgery
Radiotherapy
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
26/49
Dopamine agonists induce ovulation
-
8/12/2019 Prolactin Om
27/49
Bromocriptine: prolactinoma shrinkage
-
8/12/2019 Prolactin Om
28/49
Bromocriptine: PRL suppression, tumour
shrinkage
55y female
PRL 656,000mU/L
BCR treatment only
-
8/12/2019 Prolactin Om
29/49
Prolactinoma shrinkage by MR:
macro and microprolactinomas,sensitive or resistant to cabergoline
macro - sens macro - res
micro - sens
micro - res
Colao 2004
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
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:
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
37/49
Radiotherapy
Prevents tumour regrowth
Slow onset of effect
50% patients still
hyperprolactinaemic at 10yrs
Gradual hypopituitarism
P l ti i i
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
39/49
Prolactin levels in pregnancy
4000mU/L
Non-pregnant
-
8/12/2019 Prolactin Om
40/49
Microprolactinoma enlargement
Non-pregnant
32 weeks pregnant(headache, VFs N.)
-
8/12/2019 Prolactin Om
41/49
Macroprolactinoma enlargement
Non-pregnant Pregnant
-
8/12/2019 Prolactin Om
42/49
Risks of prolactinoma enlargement
Microadenoma: 1-5% 1%
Macroadenoma: 15-35% 23%
Molitch, J Reprod Med 1999
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
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
-
8/12/2019 Prolactin Om
45/49
Case: prolactinoma & pregnancy
28y woman, 6mm microadenoma
Prolactin 1800-2500mU/L
Treated bromocriptine:
Prolactin normalised menses regular
conceives
Plan?
-
8/12/2019 Prolactin Om
46/49
Prolactinoma & pregnancy Bromocriptine stopped
VFs normal
Prolactin rises:
12 weeks 3866 18 weeks 5227
28 weeks 8878
34 weeks 12908
Plan?
-
8/12/2019 Prolactin Om
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?
-
8/12/2019 Prolactin Om
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%
-
8/12/2019 Prolactin Om
49/49
Prolactinoma: summary
Common endocrine problem
Diagnostic pitfalls
Pathogenesis not clear
Long-term medical therapy Possible eventual remission
Issues of pregnancy management
top related