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Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
Pituitary disease
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Pituitary disease

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  • If patients have circulating serum macroprolactin (preformed complexes of IgG and prolactin), with most immunoassays the sandwich formation occurs and the macroprolactin complex is therefore detected; however, because macroprolactin is bioinactive, the result is clinically misleading and constitutes a false-positive result. (B) The hook effect is caused by grossly elevated serum prolactin levels simultaneously saturating both the capture and detection antibodies, preventing immunoassay sandwich formation and quantitative detection of prolactin. (C) If the patient has endogenous serum heterophilic antibodies that recognize the reagent animal immunoglobulin molecules in the immunoassay, these can bridge the capture and detection antibodies in the absence of prolactin and lead to a false-positive result. Abbreviation: PRL, prolactin.
  • Transcript

    • 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
    • 8.  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
    • 9. 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
    • 10. 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)
    • 11. 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.
    • 12. 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%
    • 13. 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
    • 14. 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
    • 15. 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
    • 16. 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”
    • 17.  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.
    • 18.  What potential pitfalls are there in the diagnosis of prolactinoma
    • 19. 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
    • 20.  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......
    • 21.  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.
    • 22.  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.
    • 23.  What if this was a macroprolactinoma?
    • 24.  What strategy would you employ regarding surveillance re SE of dopamine agonists and why?
    • 25.  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.
    • 26. 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.
    • 27.  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.
    • 28.  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.
    • 29. 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.
    • 30.  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.
    • 31.  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
    • 32.  Are there any other issues that it may be appropriate to consider for this patient?

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