1. Kate Lissett
South Devon Healthcare

2. Topics to cover
 Masses – presentation, testing management
 Prolactinomas
 Hypothalamic syndromes
The purpose is this session is not to information giving
but to discuss and debate clinically important issues,
and to reinforce your knowledge/learning in this area.

3. 66-year-old man has CT on the general medical take when
presenting with symptoms of stroke.
Suggestive of pituitary adenoma (in addition to confirming
diagnosis of stroke) and 1.8 cm pituitary adenoma is
confirmed on MRI.
 What basic tests will you do; be specific.
 What are the pitfalls of the testing strategy you have
chosen (false negative rates, etc.)
 What factors would affect decision making around
intervention.
 What follow-up strategy would you follow - use literature
to justify this.

4. What tests
 Prolactin – and at what level are you confident this is
not a prolactinoma
 Classical teaching 2000 – 5000 “grey area”
 Prolactin “virtually never” > 2000 in NFPA (3 exceptions
in 226 patients) Karavitaki N et al.
 Some form of testing of the HPA axis
 Testosterone, LH, FSH
 TSH and T4
 IGF1 ?

5. Testing of HPA axis
 9 am cortisol
 <100 nmol/l diagnostic adrenal insufficiency in absence
of exogenous steroids (watch for Dex in premed)
 > 400 nmol/l normal if not ill
 No normative data in unwell patients, multiple
confounders - level of CBG, impact of illness per se,
have low treatment threshold and retest when well.
 What about exogenous estrogen...

6. Provocative testing of HPA axis in
pituitary disease (1)
 ITT contraindicated in our patient and in IHD (do an
ECG), epilepsy (caution in post radiotherapy patients)
 SST
 Unreliable in acute pituitary insufficiency (within 4
weeks of insult)
 Approx 1 in 20 false normal in pituitary disease
 Normative values with immunoassays are lower than
those with flurometric assays and vary according to
assay used
 5% cut off for normal individuals 510 - 626 nmol/l
dependant on assay (Clark P et al. Clin end (1998)

7. Provocative testing of HPA axis in
pituitary disease (2)
 Glucagon stimulation test – unreliable, false normal
result (Agha A et al (2004) JCEM
 Overnight metyrapone test
 Metyrapone at midnight, measure levels of 11
deoxycortisol at 0800,
 Normal > 200 nmol/l (Cegla et al,(2013) Clin end. 78,
738 -742)
 New test, limited by availability of 11 DOC assay, but
interesting

10.  75 year old
 Diagnosis psychogenic polydypsia because recurrent
admissions with hyponatraemia
 SST under COTE, peak 850 nmol/l
 Seen by endocrine team – LH, FSH low, E2 low,
 MRI pit macroadenoma, ITT peak 250 nmol/l

11. What to do
 Use what ever tests you can do safely, plus evidence of
other pituitary hormone deficits clinical acumen.....
 Low threshold to treat in ill patient

12. How will you diagnose and treat
TSH deficiency
“T4 should be placed in middle to upper part of normal
range”
 Often ignored
 Over treats up to 50% of hypopit population
 Commence T4 in patients with ft4 <12pmol/l and
consider treatment in patients with T4 <14 pmol/l
(Koulouri O et al, Clin End (2011)

13. What about diagnosis and
treatment of GHD
 How to make diagnosis?
 GHRH arginine probably most useful in this case –
remember to use a weight based cut off
 Is it safe?
 Probably – number of studies in non irradiated patients
with GHD and pituitary adenomas (studies included
surgically treated patients including those with residual
tumour) showed no increase in risk of recurrence or
increase in tumour size.

14. Factors affecting decisions around
intervention
 Risk of increase in size over 4 years
 44% for macros, 67% of whom developed new visual field
defects (Karavitaki N, et al).
 Micro risk 19%

15. What is the natural history of nonoperated
nonfunctioning pituitary adenomas?
Clinical Endocrinology
Volume 67, Issue 6, pages 938-943, 11 JUL 2007 DOI: 10.1111/j.1365-2265.2007.02990.x
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2265.2007.02990.x/full#f3

16. What is the natural history of nonoperated
nonfunctioning pituitary adenomas?
Clinical Endocrinology
Volume 67, Issue 6, pages 938-943, 11 JUL 2007 DOI: 10.1111/j.1365-2265.2007.02990.x
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2265.2007.02990.x/full#f2

17. Factors affecting decisions around
intervention
 Life expectancy
 Potential risks of treatment
 Op per se (mortality in most series 0.6 -1.6%)
 Risk of pit hormone deficiencies - dependant on size
tumour, surgical experience
 Remember hyopit associated with RR death 1.20 - 2.17

18. If you adopt conservative strategy,
how will you follow up
 Endocrine society guideline
 FU imaging: 6 months in first instance for macro and 1
year for micro
 Imaging at 1 yearly intervals following this for 3 years for
macro and 1-2 yearly for micros
 “Gradually less frequent follow up after that”
 “Share uncertainty with patient”

19.  A 46 year old woman attends clinic. She has been
under follow up for a presumed microprolactinoma (3
mm lesion seen on mri) for 15 years, treated with
dopamine agonists.

20.  What potential pitfalls are there in the diagnosis of
prolactinoma

21. Figure 4 Schematic illustrating potential sources of interference in immunometric
assays for prolactin
Smith TP et al. (2007) Technology Insight: measuring prolactin in clinical samples
Nat Clin Pract Endocrinol Metab 3: 279–289 doi:10.1038/ncpendmet0447

23.  When would you stop treatment, how would you
monitor, and how long will YOU follow up for (when
you are a consultant with a pending list!)
 If prolactin increases post withdrawal of therapy, what
then......

24.  In the longer term, dopamine agonist therapy is
associated with complete regression of both micro and
macroadenomas in around 20% of men and women.
 Meta-analysis of 19 studies, persisting
normoprolactinaemia is more likely if patients have
been treated for idiopathic hyperprolactinaemia, if
treatment duration is of more than 2 years, or if
cabergoline has been used.
Dekkers OM et al. Recurrence of hyperprolactinemia afterwithdrawal of
dopamine agonists:systematic review and meta-analysis. JC EM 2010; 95:
43–51.

25.  Monitoring of prolactin levels should continue for 2–3
years post withdrawal of dopamine agonist.
 If therapy needs to be reinstituted, then further
attempts at withdrawing medication can be made in
another 2 years if prolactin levels have been well
suppressed after the second trial of dopamine agonist
treatment.

26.  What if this was a macroprolactinoma?

27.  What strategy would you employ regarding
surveillance re SE of dopamine agonists and why?

28.  Immediate SE of nasal stuffiness, postural
hypotension and nausea in about 10% of patients on
bromocriptine and in 1–5% of cabergoline treated
patients.
 Symptoms usually settle with time, can help to take at
night and with food.
 Postmarketing surveillance cases of aggression and
psychotic disorder have been reported in patients
taking cabergoline, caution in patients with a
significant history of psychosis or mood disorder.

29. Risk of heart valve abnormalities.
 Biologically plausible; cabergoline and pergolide in
particular stimulate the cardiac valve 5HT2B receptor
implicated in dexfenfluramine-related valve fibrosis.
 Bromocriptine and quinagolide have weaker affinity
for receptor.

30.  Recent meta-analysis of nine observational studies
 639 prolactinoma patients treated with cabergoline
 Largely reassuring.
 The nine studies vary in size, choice of controls,
grading of echo findings, and number and blinding of
the echocardiographers who assessed echo results.

31.  Small Italian study of 50 patients showed an increased
prevalence of asymptomatic TR (54% in prolactinoma
patients compared with 0% in staff controls and 18%
in untreated prolactinoma patients)
 Confounders included more hypertension in the study
group and an concerns re number of
echocardiographers reporting the echos.
 In the remaining eight studies comprising 589
cabergoline-treated prolactinoma patients, there was
no association between cabergoline therapy and
significant valvulopathy.

32. What is the best advice to current or potential
patients on dopamine agonists?
 Prudent to inform patients of the small possible risk of




valvular lesions, perform a cardiovascular examination
prior to starting therapy.
Monitor clinically
?? Serial (1–2 yearly) echo in higher dose and/or longterm therapy with dopamine agonists.
Regular consideration to a trial of therapy withdrawal
Keeping dopamine agonist dosage to a minimum.

33.  In 2007, 2 major studies published supporting an
increased risk of valvulopathy in Parkinsons treated with
D2 agonists.
 155 Italian patients with Parkinson’s disease, clinically
important regurgitation was found in 28.6% of
cabergoline-treated patients, 0% of patients treated with
other dopamine agonists and in 5.6% of controls.
 Cumulative dose related
 The cumulative total dose of cabergoline used in
Parkinson’s disease ranged from 2500–6700 mg compared
with 200–500 mg to treat patients with prolactinoma.

34.  UK general practice database study
 Rate of cardiac valve regurgitation with cabergoline
4.9 but not with other dopamine agonists
 The adjusted incidence-rate ratios were particularly
concerning for doses of more than 3 mg per day of
cabergoline as well as dose duration longer than 6
months (i.e. total cumulative dose >540 mg

35.  Are there any other issues that it may be appropriate
to consider for this patient?