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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