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Andy Durham Andy Durham Andy Durham Andy Durham BSc.BVSc.CertEP.DEIM.DipECEIM.MRCVS
� the pars intermedia is normally under tonic
inhibition by dopaminergic neurones from
the hypothalamus (paraventricular nuclei)
� in PPID there is decreased inhibitory
dopaminergic input to the pars intermedia
� the consequence of loss of inhibition is:
� hypersecretion
� hypertrophy
� hyperplasia
� adenoma
• Subclinical
• Excessive hair growth
• Susceptibility to laminitis
• Polydipsia/polyuria
• Lethargy
• Excessive sweating
• Susceptibility to infections
• Fat redistribution
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� do not expect all PPID cases to be hairy and
drinking a lot
� often the first (and only) signs are laminitis
=
Pars distalis
Adrenal
ACTHcortisol
----DEXDEXDEXDEX
<27 <27 <27 <27 nmolnmolnmolnmol/L/L/L/L
Pars distalis Dysfunctional pars intermedia
Adrenal
ACTH ACTHcortisol
----DEXDEXDEXDEX
<27 <27 <27 <27 nmolnmolnmolnmol/L/L/L/L
>27 >27 >27 >27 nmolnmolnmolnmol/L/L/L/L
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0
1
2
3
4
5
6
7
8
0 4 8 12 16 20
cort
iso
l µµ µµg
/dL
time hours
normal response
19h : < 1µg/dL
< 27 nmol/L
27 nmol/L, 1 µµµµg/dL
PPID
normal
40 µg/kg DEX
PPID (n) Normal (n) Cut-off Sensitivity Specificity Accuracy
42 18 27 nmol/L 100% 100% 100% Dybdal et al 1994
17 25 27 nmol/L 65% 76% 71% Frank et al 2006
3 6 27 nmol/L 66% 100% 89% Beech et al 2007
Sensitivity = % PPID cases that test positiveSpecificity = % normal horses that test negativeAccuracy = % correct test results
1. Collect into EDTA tube
2. Chill sample within 3 hours of collection
3. Centrifuge as soon as possible
4. Keep chilled during shipping to laboratory
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PPID (n) Normal (n) Cut-off Sensitivity Specificity Accuracy Ref
24 7 55 pg/mL 100% 100% 100% Van der Kolk et al 1995
6 10 35 pg/mL 67% 100% 88% Beech et al 2007
25 23 35 pg/mL 71% 96% 83% Beech et al 2011
84%84%84%84% 97%97%97%97% 90%90%90%90%
Sensitivity = % PPID cases that test positive
Specificity = % normal horses that test negative
Accuracy = % correct test results
1. Stress/pain
2. Stability
3. Seasonality
4. Safety
• no significant effect unless quite
severe
• ACTH stable for at least 3 hours, then
must be chilled
• seasonal reference intervals available
for ACTH (highest sensitivity Aug-Oct)
• concerns with use of dexamethasone
but not a major issue
• when appropriate reference intervals are used, the autumn is the best time to test for PPID
• greater sensitivity and specificity than tests run during rest of year
• a “bio-stimulation” test !
• also detects “controlled PPID” cases that might lose control in the autumn
• ODST?
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Compare samples before and after 1 mg TRH iv
� Cortisol response
100
125
150
175
200
225
250
0 15 30
Co
rtis
ol
nm
ol/
l
time (mins)
PPID
(n=7)
normal
(n=16)
McFarlane et al (2005)
0
250
500
750
1000
1250
1500
1750
0 10 20 30 40 50 60
AC
TH
pg
/m
LA
CT
H p
g/m
LA
CT
H p
g/m
LA
CT
H p
g/m
L
Time postTime postTime postTime post----TRH (TRH (TRH (TRH (minsminsminsmins))))
Data from: McFarlane et al 2005,
Beech et al 2007,2011
○○○○ mean normal
1 mg TRH iv
0
250
500
750
1000
1250
1500
1750
0 10 20 30 40 50 60
AC
TH
pg
/m
LA
CT
H p
g/m
LA
CT
H p
g/m
LA
CT
H p
g/m
L
Time postTime postTime postTime post----TRH (TRH (TRH (TRH (minsminsminsmins))))
Data from: McFarlane et al 2005,
Beech et al 2007,2011
xxxx mean PPID
○○○○ mean normal
100 pg/mL35 pg/mL
1 mg TRH iv
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PPID(n)
Normal (n)
Time post-TRH
Cut-off Sensitivity Specificity Accuracy Ref
6 10 10 mins 100 pg/mL 100% 100% 100%Beech et al
2007
6 10 30 mins 35 pg/mL 100% 89% 94%Beech et al
2007
25 23 30 mins 35 pg/mL 95% 91% 94%Beech et al
2011
Sensitivity = % PPID cases that test positive
Specificity = % normal horses that test negative
Accuracy = % correct test results
• Cortisol?
• PPID ≠ hyperadrenocorticism
• ACTH in PPID cases is not very
bioactive
• Plasma cortisol in PPID cases is
the same as normal horses
Insulin Resistance
HyperinsulinaemiaHyperglycaemia
(glucose intolerance)
impaired glucose
uptake
stimulates
pancreatic secretion
receptor
downregulation?
compensatory
pancreatic secretion,
decreased insulin clearance
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HyperinsulinHyperinsulinHyperinsulinHyperinsulin
----aemiaaemiaaemiaaemia
Native Native Native Native
BreedBreedBreedBreed
Regional Regional Regional Regional
ObesityObesityObesityObesity
Lack of Lack of Lack of Lack of
exerciseexerciseexerciseexercise
LAMINITISLAMINITISLAMINITISLAMINITIS
PPIDPPIDPPIDPPID
PasturePasturePasturePasture
Equine Metabolic Equine Metabolic Equine Metabolic Equine Metabolic SyndromeSyndromeSyndromeSyndrome
• PPID cases with insulin > 188 mU/L less likely to survive ((McGowan et al 2004)
• Insulin concentration correlated with grade of laminitis (Walsh et al 2009)
• Change in insulin correlated with change in laminitis grade (Walsh et al 2009)
LaminitisLaminitisLaminitisLaminitis
Hyperinsulin-aemia
PPIDPPIDPPIDPPID
42 PPID cases with laminitis - in feed glucose test
high insulin response
28 (67%)
normal insulin response
14 (33%)
Data from Liphook Equine Hospital Laboratory
++++ ����
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Dose of pergolide?� Orth et al 1982 10.0 µg/kg sid
� Peters 1995 0.85 µg/kg bid
� Watson et al 1998 1.8-2.8 µg/kg sid
� Donaldson et al 2002 1.7-5.5 µg/kg sid
� Sgorbini et al 2004 6.0-8.0 µg/kg sid
� Schott et al 2001 2.0 µg/kg sid
Improvement in test results after pergolide?
ODST ACTH� Peters 1995 7/9
� Watson et al 1998 6/6
� Donaldson et al 2002 14/20
� Perkins et al 2002 3/5
� Sgorbini et al 2004 2/2
� Schott et al 2001 7/20
36% 648 cases648 cases648 cases648 cases
Median interval 46 days
Median ACTH pre tx 113 pg/mL
Median ACTH post tx 41 pg/mL
Mean % reduction -62%
Wilcoxon P<0.0001
• Follow-up at 4-6 weeks: ACTH decreased in 91.8% cases
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� 2122 horses treated with Pergolide
◦ Jan 2007 to Dec 2012
◦ Follow-up > 4 weeks after starting pergolide
Back to ref
Range
28%
>75% improvement
27%
< 75% improvement
45%
Taylor et al. (unpublished)
� Durham et al (2009)
� 35yo gelding with PPID and
hyperglycaemia
� glucose normalised within 12 h
� Rendle et al. (unpublished)
� 6 horses with PPID (4 μg/kg) SID
� Response in hours
� Plateau after 10d
0
20
40
60
80
100
120
140
1 3 5 7 9 11 13 15 17
AC
TH
pg
/ml
Days
0 hours
2 hours
12 hours
2.5
5.0
7.5
10.0
12.5
15.0
17.5
-72 -48 -24 0 24 48 72 96
pla
sma
glu
cose
(m
mo
l/L)
Time (hours)
Glucose
Pergolide
timeCases responding
average range
1 week 63% 46-78%
2 weeks 80% 73-88%
4 weeks 91% 85-97%
• the majority of cases that respond to pergolide will do so
within the first week of treatment
• only 1/33 cases (3%) was known to have definitely not
responded by 4 weeks
• recommend that ACTH is rechecked 4 weeks after starting
pergolide treatment and dosage adjusted if response is
disappointing
Durham (unpublished)
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• 23 PPID cases
o started pergolide Nov ‘08 – Jan ’09
o initial dose 2 µg/kg
o 3 month check - dose increased to 4 µg/kg if no response
o 6 month check
• 8 cases were non-responders at 3 and 6 months but carried on
treatment at 4 µg/kg
o 2 years later - 5 had responded
o 3 years later - 6 had responded
Hal Schott, Michigan, ACVIM forum 2012
• When horses respond to pergolide they generally do so
fairly quickly – between a day and 4 weeks
• Occasionally may take much longer (years!)
• May reflect a balance of importance between:
• rapid pharmacologic interference with pituitary
secretion
• slower inhibition of growth and proliferation of an
enlarged pars intermedia
• inappetance is the only prominent adverse effect
• occurs mainly at initiation of treatment or following a
dose increase
• usually resolves within a few days of discontinuing
therapy
• restarting treatment at a lower dose with a gradual
increase is often tolerated
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• a minority of PPID cases do not respond well to even
high doses of pergolide
• alternatives:
• cyproheptadine 0.25 mg/kd q 12h
• trilostane 1 mg/kg q 24h
• if horse remains hyperinsulinaemic despite good
response in ACTH?
• pergolide + metformin 30 mg/kg q 12h
1. begin with 0.002 mg/kg pergolide q 24h
2. recheck monthly and adjust dosage as required
3. maximum dose = 0.010 mg/kg (or budget)
4. non-responders at maximum dose:
1. carry on with affordable dosage as might eventually respond
2. try adding cyproheptadine 0.25 mg/kg q 12hrs
5. when stable and controlled, try to decrease dose and
retest?
6. consider dose adjustments between August and October
• Clinical
• PPID has a spectrum of disease and pathology
• not all cases show “typical” clinical signs
• laminitis is a prominent problem
• Diagnostics
• basal ACTH is the preferred 1st line test
• consider TRH stimulation for borderline or unexpected results
• don’t forget insulin!
• Treatment
• pergolide is drug of choice
• may require dose customisation
• monitoring ACTH useful indicator of response