professor ian holdaway - gp cme 159 holdaway - the world of... · prolactin, so long-acting...
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Professor Ian Holdaway Endocrinologist
Auckland District Health Board
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A land of milk and giants – hormone-
secreting pituitary tumours
I M Holdaway, Endocrinologist, Auckland
Acromegaly
Prolactinomas
Cushing’s disease
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Acromegaly
The quandary of a rare condition
(prevalence ~ 60-80 per million) which, however, carries serious sequelae if not treated:
- high burden of complications
- major reduction in life expectancy
Once diagnosed, effective treatment is available
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What should a GP know about
acromegaly?
• Who to suspect
• How to diagnose it
• Effective treatment is available
(Treatment details and options would not be
considered as core knowledge for family
physicians)
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Who should you suspect as
acromegalic?
A. Spot diagnosis on appearance
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Who should you suspect as
acromegalic?
B. In those with obstructive sleep apnoea
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Who should you suspect as
acromegalic?
C. In those with features of carpal tunnel
syndrome
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Who should you suspect as
acromegalic?
D. The challenge – to keep the condition in
mind when seeing those with diabetes,
hypertension, cardiac disease or arthritis
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Questions to ask a patient if you
suspect acromegaly
• Does the family think your appearance has
changed? (photos helpful)
• Has your shoe size gone up?
• Have you needed to expand or re-size your
finger rings?
• Are you excessively sleepy in the day? (Epworth
questionnaire)
• Do you sweat excessively?
• Do you have numbness/tingling in the hands?
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Why is early diagnosis important?
• Mortality in acromegaly is at least doubled compared with the general population, with 10 or more years of life lost
• Successful treatment reduces mortality to expected levels
• Successful treatment reduces the complications of the disorder
• Delay in diagnosis is an independent risk factor increasing mortality
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Mortality in acromegaly from the20 major published series
Ale
xander
(198
0)
Ext
abe
(199
3)
Ben
gtsso
n (198
8)
Abosc
h (199
8)
Hold
away
(200
4)
Bat
es (1
993)
Shim
atsu
(199
8)
Bea
uregar
d (200
3)
Wright (
1970
)
Ben
gtsso
n (199
9)
Sher
lock
(200
9)
Orm
e (1
998)
Trepp (2
005)
Bie
rmas
z (2
004)
Nab
arro
(198
7)
Ayu
k (2
004)
Swea
ringen
(199
9)
Arita
(200
3)
Kau
ppinen
(200
5)
Aro
sio (2
012)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5O
bserv
ed
-to
-exp
ecte
d m
ort
ali
ty
NZ patients
observed
expected
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0
0.2
0.4
0.6
0.8
1
0 5 10 15 20 25 30
Time (years)
Pro
ba
bilit
y
Acromegaly (with 95%
confidence limits)
Normal population
Survival of patients with acromegaly following
treatment (Holdaway et al, 2003) [n=208, 72 deaths]
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Cure of acromegaly restores
survival to normal
0
0.2
0.4
0.6
0.8
1
0 5 10 15 20 25 30
Time (Years)
Pro
po
rtio
n S
urv
ivin
g
normal GH & IGF-I
Disorder still
active
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Change in age of death of acromegalic individuals in
Auckland over time
20
30
40
50
60
70
80
90
Number of values
Minimum
25% Percentile
Median
75% Percentile
Maximum
Mean
Std. Deviation
Std. Error
Lower 95% CI of mean
Upper 95% CI of mean
Sum
<1/1/2000
68
33.99
52.56
62.70
70.35
86.22
61.57
12.97
1.573
58.43
64.71
4187
>1/1/2000
37
39.56
65.62
74.40
80.45
90.87
71.99
12.02
1.976
67.98
76.00
2664
Table Analyzed
Column A
vs
Column B
Unpaired t test
P value
P value summary
Are means signif. different? (P < 0.05)
One- or two-tailed P value?
t, df
How big is the difference?
Mean ± SEM of column A
Mean ± SEM of column B
Difference between means
95% confidence interval
R squared
F test to compare variances
F,DFn, Dfd
P value
P value summary
Are variances significantly different?
Data 2
<1/1/2000
vs
>1/1/2000
0.0001
***
Yes
Two-tailed
t=4.033 df=103
61.57 ± 1.573 N=68
71.99 ± 1.976 N=37
-10.42 ± 2.584
-15.55 to -5.290
0.1364
1.165, 67, 36
0.6277
ns
No
P<0.0001
Died after1/1/2000
Died before1/1/2000
Ag
e a
t d
eath
(yrs
)
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What about the complications of acromegaly –
do they diminish with treatment?
0
10
20
30
40
Acromegaly cured
Acromegalynot cured
New Zealand acromegalics with clinical joint disorders
* p <0.01
% w
ith
jo
int
pro
ble
ms
Prevalence of diabetes in acromegaly(Auckland patients)
0 2 4 6 8 10 12 14 16 18 20
Cured acromegaly
Active acromegaly
NZ population
Acromegaly
Percentage
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Not cured
Cured
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Cardiac disease in acromegaly
The Auckland experience
1. Cardiac disease at diagnosis = 19%
2. Post-treatment cure, cardiac disease = 7%
3. Post-treatment not cured, cardiac disease = 20%
(p<0.05)
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Troublesome symptoms of acromegaly –
prevalence before and after curing the disorder
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How can you confirm a diagnosis of
acromegaly?
• Measure the serum IGF-I level – an
elevated level usually indicates growth
hormone excess (cost ~ $25)
• Growth hormone itself is not a good
indicator since it is released in a pulsatile
manner, and single measurements are
difficult to interpret
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Pituitary
Liver Bone
Muscle, fat
etc IGF-I
Growth
hormone
Why is IGF-I a good marker of acromegaly?
Because IGF-I is the down-stream mediator of growth
hormone action
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Has there been any success with
screening for acromegaly in
General Practice?
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Results of screening 17,000 patients from 9
General Practices in Brazil over 6 months in 2010,
using a simple 2-question questionnaire
Rosario & Calsolari, 2012
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Screening for acromegaly in 2270 diabetic
patients in a hospital outpatient setting using
serum insulin-like growth factor-I
2270 patients
62 raised serum IGF-I
56 confirmed on second
sample
3 confirmed acromegaly
Rosario 2011
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Early detection of acromegaly
• Efforts to screen for the condition to date
are probably not cost effective
• Thus, being alert to the possible diagnosis
remains the key – in NZ most referrals
have been from General Practice
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What about treatment?
Until about 20yrs ago surgery and radiotherapy were
the only means of treatment, but only cured ~50% of
patients
The reason? Trans-sphenoidal surgery
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Recent developments
• The advent of effective medical (non-surgical)
treatment has meant that the great majority of
acromegalics can now be brought into the “cure”
range of growth hormone and IGF-I
Surgery
Cure (~ 50%)
Not cured
Medical therapy
( ~ 80-90%
overall cure)
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Depot octreotide
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Growth
hormone
Growth
hormone
Somatostatin
receptor
Action of
somatostatin
analogues such
as octreotide
pituitary
60-70% of
acromegalics
achieve safe
levels of GH
with octreotide
therapy
GH-secreting
cell
somatostatin
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Meta-analysis by Freda et al, 2005, n= 612 17 surgical series 1987-2011
Remission of acromegaly with initial surgery
or with LAR octreotide treatment
0
10
20
30
40
50
60
Per
cen
t re
mis
sio
n
wit
h t
reatm
en
t
Surgery LAR octreotide
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Shrinkage of GH-secreting macroadenoma
with LAR octreotide therapy
Baseline 6 months 12 months
(Mercado et al 2007)
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The land of milk…..
Prolactinomas of the pituitary
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When should you think of a
potential prolactin problem?
• Irregular periods or ammenorrhea
• Infertility (men or women)
• Galactorrhea
• Breast discomfort
• Men with low serum testosterone
• Reduced libido
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But, not all prolactin excess is
pathological….. Physiologic hyperprolactinaemia:
• Venepuncture stress (1.5-2x upper limit of normal)
• Other stress (up to 2x uln)
• Pregnancy (up to 4x uln or higher)
• Lactation ( “ “ “ “ )
• Macroprolactinaemia (innocent, usually detected by laboratory)
Medications:
• Oestrogen –containing OCPs
• Occaisonally progestins (depot provera)
• Dopamine antagonists (e.g. risperidone etc)
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Physical signs relevant to hyperprolactinaemia:
1.Galactorrhea
2. Montgomery tubercule hypertrophy
3. Any signs of hypogonadism?
(reduced testicular volumes etc)
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Important pathological causes of an
elevated serum prolactin
• Pituitary microprolactinoma (levels usually
1000-8000 mIU/L)
• Pituitary macroprolactinoma (levels high,
usually 10,000 – 100,000 mIU/L)
Tricky prolactin levels: • Venepuncture stress (if suspected can sample via iv line at rest)
• Don’t forget medication effects
• Rare issues (hypothyroidism, renal impairment, fits etc)
• Pituitary stalk pressure from a non-functioning adenoma or similar
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microadenoma
Pituitary MRI scan
showing a
microprolactinoma
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Pituitary macroprolactinoma
causing visual field defects
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Pituitary stalk pressure
Occurs when the pituitary stalk is distorted or compressed by a large
non-functioning pituitary adenoma.
The usual inhibitory control of prolactin secretion by dopamine coming
down the pituitary portal vessels is interrupted → raised prolactin
(about 600-3000mIU/L i.e.similar to a microprolactinoma)
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Treatment of prolactin excess
• Dopamine is the physiologic inhibitor of
prolactin, so long-acting dopamine
analogues give prolonged suppression of
prolactin production
- bromocryptine
- cabergoline
• Prolactin excess has been facetiously
termed “cabergoline deficiency”
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cabergoline
Cabergoline is also very effective at shrinking
prolactinomas
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Effect of treatment with cabergoline on tumour volume
in previously untreated patients with prolactinomas
Colao et al, 2000
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Dramatic shrinkage of the pituitary
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The land of milk, giants, and centrally
obese patients with striae and facial
plethora……
Pituitary –based Cushing’s
syndrome
(“Cushing’s disease”)
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When should you suspect
Cushing’s syndrome?
• Patient appearance
• Diabetics, hypertensives, osteoporotics
with “extra” (cushingoid) features
• Simple obesity unlikely to be due to
Cushing’s syndrome
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Clinical clues for Cushings:
• Central fat distribution with slim limbs
• Skin changes (acne, skin thinning,
bruising, active striae, hirsuitism)
• Facial plethora
• Lymphoedema
• Proximal myopathy
• Above features in those with hypertension/
diabetes/ hypokalaemia/ osteoporosis
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Cushinoid fat distribution and body habitus
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Testing for
thinning of the
skin
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How can you screen for Cushing's
syndrome?
• Best test = overnight dexamethasone
suppression test (1mg dexamethasone taken at 11pm followed by a blood
cortisol at the local laboratory 9am the next morning)
Normal = plasma cortisol <50nmol/l
“Grey zone” = 50-135nmol/l
• Next option = 24hr urine cortisol (<380nmol/24hr)
• Or spot bedtime urine cortisol <12nmol/mmol creatinine
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Effect of
treatment of
Cushing’s
disease on
complications of
the disorder
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Further testing and treatment
• Can be difficult to distinguish between pituitary-based Cushing’s syndrome (Cushing’s disease) and ectopic ACTH syndrome
• Usual cause of Cushing's disease is a small ACTH-secreting pituitary adenoma, can be difficult to see on scan
• Treatment is by pituitary surgery. Bilateral adrenalectomy less favoured but is curative. Some medical options also available in difficult cases (ketoconazole, metyrapone etc)
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Pituitary Cushing’s disease
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Survival of patients
with Cushing’s
syndrome is
decreased compared
with the matched
general population
SMR cured = 2.3
SMR not cured = 5.7
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