Professor Ian Holdaway Endocrinologist

Auckland District Health Board

A land of milk and giants – hormone-

secreting pituitary tumours

I M Holdaway, Endocrinologist, Auckland

Acromegaly

Prolactinomas

Cushing’s disease

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

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)

Who should you suspect as

acromegalic?

A. Spot diagnosis on appearance

Who should you suspect as

acromegalic?

B. In those with obstructive sleep apnoea

Who should you suspect as

acromegalic?

C. In those with features of carpal tunnel

syndrome

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

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?

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

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

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]

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

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

)

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

Not cured

Cured

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)

Troublesome symptoms of acromegaly –

prevalence before and after curing the disorder

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

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

Has there been any success with

screening for acromegaly in

General Practice?

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

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

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

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

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)

Depot octreotide

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

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

Shrinkage of GH-secreting macroadenoma

with LAR octreotide therapy

Baseline 6 months 12 months

(Mercado et al 2007)

The land of milk…..

Prolactinomas of the pituitary

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

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)

Physical signs relevant to hyperprolactinaemia:

1.Galactorrhea

2. Montgomery tubercule hypertrophy

3. Any signs of hypogonadism?

(reduced testicular volumes etc)

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

microadenoma

Pituitary MRI scan

showing a

microprolactinoma

Pituitary macroprolactinoma

causing visual field defects

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)

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”

cabergoline

Cabergoline is also very effective at shrinking

prolactinomas

Effect of treatment with cabergoline on tumour volume

in previously untreated patients with prolactinomas

Colao et al, 2000

Dramatic shrinkage of the pituitary

The land of milk, giants, and centrally

obese patients with striae and facial

plethora……

Pituitary –based Cushing’s

syndrome

(“Cushing’s disease”)

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

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

Cushinoid fat distribution and body habitus

Testing for

thinning of the

skin

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

Effect of

treatment of

Cushing’s

disease on

complications of

the disorder

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)

Pituitary Cushing’s disease

Survival of patients

with Cushing’s

syndrome is

decreased compared

with the matched

general population

SMR cured = 2.3

SMR not cured = 5.7