Pituitary Pars Intermedia Dysfunction or PPID is a common dopaminergic neurodegenerative disease of older horses and ponies.  Clinical signs include laminitis (often occurring in the autumn), muscle wasting, regional fat deposits, lethargy, hirsutism (a long, often curly coat that may not shed) and infections e.g. sinusitis.

The pituitary gland is suspended from the hypothalamus at the base of the brain, near the optic nerve.  Together, the hypothalamus and pituitary gland affect many functions of the body, including metabolism, immune response and inflammation, body temperature, hunger and thirst, reproduction and growth, cardiovascular function, stress response - fight or flight.

The pituitary gland consists of 3 major hormone-releasing lobes: the pars distalis, pars intermedia and pars nervosa.  In the healthy horse:
The pars distalis mostly releases ACTH (affects metabolism, stress - stimulates cortisol), some beta-endorphin (affects pain, behaviour, immune system, vascular tone), Growth Hormone, Follicle Stimulating Hormone, Luteinizing Hormone, Thyroid Stimulating Hormone and prolactin.
The pars nervosa releases Arginine Vasopressin (anti-diuretic hormone) (affects water balance and cardiovascular function) and oxytocin (affects reproduction and growth).
The pars intermedia mostly releases alpha-MSH (affects coat and skin, metabolism, obesity, is anti-inflammatory and reduces fever), beta-endorphin and CLIP (similar to ACTH, may stimulate insulin).
In the PPID horse the pars intermedia also releases ACTH.

In a healthy horse, dopamine producing neurons from the hypothalamus release dopamine into the pars intermedia.  The dopamine acts as a brake and stops hormone production.
With PPID the neurons are slowly lost (PPID is a neurodegenerative disease - it gets progressively worse) and the reduction in dopamine (there can be up to 9 times less dopamine in the pars intermedia of a horse with PPID than a healthy horse of the same age) causes:
the production of POMC peptide hormones (alpha-MSH, beta-endorphin, CLIP and ACTH) to increase - hormone levels may be more than 100 times greater than in a normal horse;
pars intermedia cells to divide (hyperplasia) and enlarge (hypertrophy), causing the pituitary gland to increase in size (may be > 6 times larger than in a normal horse), and often leading to large or multiple small adenoma (tumour) formation.  The expansion of the pars intermedia can cause the other pituitary lobes to become compressed.  

For more information, see the Prascend Mode of Action video below: 

Q.  Does a high ACTH result mean my horse has PPID?

A.  Not necessarily, no.  ACTH comes from the pituitary gland.  The pituitary gland in the horse is divided into 3 main hormone releasing sections.  Both the pars distalis (PD) and the pars intermedia (PI) produce ACTH, although in healthy horses, hardly any ACTH is produced by the pars intermedia.  

ACTH is released from the pars distalis in response to any form of stress, and is reduced or stopped by high levels of ACTH or cortisol in the blood - this is known as feedback.

​When blood is tested for ACTH levels, it is not possible to tell whether the ACTH came from the PD (normal stress response) or the PI (PPID).  Therefore if a horse is stressed when the blood is taken, it could be ACTH from the PD, i.e. a normal stress response, that causes ACTH to be above levels considered normal, or it could be ACTH from the PI indicating PPID, or it could be a bit of both.

"Stress" can be due to 
Illness
Pain, e.g. from laminitis
Excitement
Exercise
Travelling
Use of a twitch
Veterinary procedures, e.g. dental work
Fear of vet/needles

Some medicines increase ACTH, e.g clenbuterol (Ventipulmin).  

​Some sedation drugs may affect ACTH, insulin or glucose.

Some cases where ACTH results may have been affected by stress, sedation, dental work and twitching

Pony 1 
Initial ACTH 335 pg/ml in September - PPID diagnosed.
0.5 mg Prascend prescribed, 6 weeks later ACTH was 51 pg/ml.
Prascend increased to 0.75 mg.  
Clinical signs of PPID improved and at next blood test (January) there were no obvious signs of PPID.
January ACTH was tested again after the pony had had his teeth floated by the vet, had become stressed and been twitched, and the twitch was kept in place during the blood collection.  ACTH was 300 pg/ml.
A week later when the pony was calm and not twitched, ACTH was tested again and was 29 pg/ml.

Pony 2
Initial ACTH 128 pg/ml in October - PPID diagnosed.
1 mg Prascend prescribed, 1 month later ACTH was 147 pg/ml.
Prascend was increased to 1.5 mg, ACTH was retested in February and was 62 pg/ml.
The pony was needle-phobic and became very stressed during the blood collections despite being given sedation.

Pony 3
Initial ACTH 75 pg/ml in December - PPID diagnosed.
1 mg Prascend prescribed and the pony showed considerable improvement, becoming livelier, PU/PD decreasing.
February ACTH was retested and the pony was twitched, the owner was baffled, given the improvement in clinical signs, when ACTH was 86 pg/ml, and the vet wanted to double the Prascend dose.

Widget
Widget was diagnosed with PPID in April from clinical signs (laminitis, not shedding coat, lethargy) and was prescribed 0.5 mg Prascend.
8 weeks later (June?) after being given Dormosedan gel and injected sedation, his ACTH was 300 pg/ml.  His Prascend was increased to 1 mg.
3 months later (September?) again after oral and injected sedation, his ACTH was 900 pg/ml and his vet suggested that he be put to sleep.
Widget is still doing well.  He no longer has ACTH tested as he finds it too stressful, instead his Prascend dose is based on his clinical signs.

There are reasons why ACTH might not decrease once treatment is started.  For example, ACTH concentrations increase during the seasonal rise (July - November), and it is released in a pulsatile manner.  Differences of up to 50% have been seen between samples taken just a few minutes apart, and in research by Rendle et al 2014 one PPID horse had ACTH results ranging from around 250 to over 1000 pg/ml in 27 tests taken over a 3 week period, whereas another horse that had ACTH levels around 300 pg/ml had very similar results for all 27 tests - the differences between the horses were put down to individual variation.  However, in the above cases clinical signs had improved with treatment, and the owners were suprised by higher than expected ACTH results when their horses were stressed, sedated or twitched.

Further information and references:

Gehlen H, Jaburg N, Merle R, Winter J
Can Endocrine Dysfunction Be Reliably Tested in Aged Horses That Are Experiencing Pain?
Animals 14 August 2020 10 1426; doi:10.3390/ani10081426

 "Isolation distress and mild to moderate illness and pain do not appear to affect plasma ACTH. General anaesthesia, strenuous exercise, sedation, severe illness and severe pain may all increase plasma ACTH."  From Dealing with Equine PPID in Equine Practice   

Vet J. 2010 Apr;184(1):100-4 (PubMed)
Plasma levels of heat shock protein 72 (HSP72) and beta-endorphin as indicators of stress, pain and prognosis in horses with colic
Niinistö KE, Korolainen RV, Raekallio MR, Mykkänen AK, Koho NM, Ruohoniemi MO, Leppäluoto J, Pösö AR.
"Plasma beta-endorphin was related with severity of colic and survival, as well as with plasma cortisol, ACTH and lactate concentrations, heart rate, PCV and pain score." 

Vet Clin Equine 27 (2011) 
Hypothalamic-Pituitary Gland Axis Function and Dysfunction in Horses
Hurcombe SDA
Endotoxaemia, sepsis, critical illness, acute abdominal pain, colic and proinflammatory cytokines may increase ACTH.

Peeters M1, Sulon J, Beckers JF, Ledoux D, Vandenheede M
Comparison between blood serum and salivary cortisol concentrations in horses using an adrenocorticotropic hormone challenge
Equine Vet J. 2011 Jul;43(4):487-93. doi: 10.1111/j.2042-3306.2010.00294.x. Epub 2010 Sep 29
"Cortisol concentrations during venous catheter placement increased, but did not differ significantly from baseline, in both serum and saliva. This means that catheter placement should not involve as high a stress to horses as transport (Fazio et al. 2008; Schmidt et al. 2010b) or competition (Cayado et al. 2006)."
However, note that these horses were "accustomed to handling and sampling sessions" - a horse that shows a strong fear reaction to a vet/needle might have a different stress response.

Vet Clin Equine 27 (2011) 35-47 
Endocrine Dysregulation in Critically Ill Foals and Horses 
Toribio RE 
Endotoxaemia in mares induces AVP, oxytocin and ACTH release (Alexander et al. 1996).  Cortisol concentrations were elevated in acutely laminitic horses (Clarke et al. 1982).

Fazio E, Medica P, Aronica V, Grasso L, Ferlazzo A.
Circulating beta-endorphin, adrenocorticotrophic hormone and cortisol levels of stallions before and after short road transport: stress effect of different distances. 
Acta Vet Scand. 2008;50(1):6. Published 2008 Mar 3. doi:10.1186/1751-0147-50-6

Diez de Castro E, Lopez I, Cortes B, Pineda C, Garfia B, Aguilera-Tejero E
Influence of feeding status, time of the day and season on baseline ACTH and the response to TRH-stimulation test in healthy horses
Domestic Animal Endocrinology published online 07 March 2014

Ventipulmin (Clenbuterol)​

J Physiol Pharmacol. 2001 Dec;52(4 Pt 2):795-809
Involvement of constitutive (COX-1) and inducible cyclooxygenase (COX-2) in the adrenergic-induced ACTH and corticosterone secretion
Bugajski J, Głód R, Gadek-Michalska A, Bugajski AJ
"The secretion of ACTH and corticosterone was elicited by i.c.v. administration of adrenergic agonists.... clenbuterol (10 µg), a selective 2-adrenergic agonist."  10 ug clenbuterol adminstered icv to rats caused ACTH to increase from 100 pg/ml in controls to 1100 pg/ml in treated rats, and corticosterone to increase from 8 ug/dl in controls to 42 ug/dl in treated rats. 

Using a twitch may cause high ACTH concentrations - using a twitch on donkeys resulted in a significant increase in mean plasma ACTH concentration in Hendrike Vreeman's PhD thesis The Twitch in Donkeys.

The precise cause of PPID is still unknown, but ​It's likely there are several factors that cause the neurodegeneration that leads to PPID, including oxidative stress, metabolic factors e.g. EMS, toxins, chronic stress, and there may be a genetic predisposition.

Research suggests that localised oxidative stress may contribute to dopaminergic neuron damage and death. However in 2005 Dianne McFarlane found that "there was no evidence of systemic accumulation of oxidative stress markers or deficiencies in antioxidant capacity in horses with PPID, suggesting that these are unlikely to be major predisposing factors in the development of PPID" (Systemic and pituitary pars intermedia antioxidant capacity associated with pars intermedia oxidative stress and dysfunction in horses). 

In her 2011 paper on Equine PPID, Dr McFarlane states that pituitary antioxidant capacity has not been shown to be impaired in horses with PPID, but that the impairment of the activity of pituitary manganese superoxide dismutase found in older horses may contribute to the risk of PPID developing with age.

She goes on to say that excellent nutrition is important for horses with PPID, and that in theory, feeds high in antioxidants could slow the neurodegenerative process associated with PPID, but that there is currently no evidence for this. Early treatment with pergolide to replace the missing dopamine and reduce excess hormone production and the clinical signs of PPID is advised. Interestingly, research by Gille et al. (2002) found that "pergolide protects dopaminergic neurons under conditions of elevated oxidative stress"; similarly research by Uberti et al. in the same year suggested that "pergolide ... may interfere with the early phases of the oxidative stress-induced neurotoxic process". Dr McFarlane theorises that any antioxidant and neuroprotective properties of pergolide could be beneficial in slowing the progression of PPID.

In her presentation Is it PPID or is it EMS – Diagnosing Equine Endocrine Disease, Dianne McFarlane suggests that horses with EMS may be at greater risk of developing PPID as they get older – horses with EMS should be monitored and tested for PPID.

In conclusion, optimal management and treatment with pergolide is recommended for horses with PPID, but it appears that further research is needed before we can say for sure exactly what might cause or slow the progression of this common equine neurodegenerative disease.

Possible causes of PPID are discussed at the 2011 Equine Endocrinology Summit:
Pathophysiology of Pituitary Pars Intermedia Dysfunction in 2011 Dianne McFarlane, DVM, PhD, Dipl. ACVIM

See also Vet Clin North Am Equine Pract. 2011 Apr;27(1):93-113 (part of paper available online)
Equine pituitary pars intermedia dysfunction
McFarlane D

Research and Articles

Fortin JS, Hetak AA, Duggan KE, Burglass CM, Penticoff HB, Schott II HC 
Equine pituitary pars intermedia dysfunction: a spontaneous model of synucleinopathy
Scientific Reports August 2021 11, 16036. https://doi.org/10.1038/s41598-021-95396-7.  Open Access.​

See also:
Parkinson's Disease & PPID/Causes of PPID