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
Pain, e.g. from laminitis
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.
Also freezing the blood sample before it has been separated by centrifuge can cause falsely high ACTH concentrations (Andy Durham - Liphook Equine Hospital).
A horse MUST be showing or have a history of clinical signs for a diagnosis of PPID. For clinical signs see: PPID, Pituitary Pars Intermedia Dysfunction, Video comparing PPID symptoms and normal aging and Is it PPID or is it EMS? However, unless the person assessing the horse is very experienced with PPID, early signs of PPID can be missed, and sometimes clinical signs are only seen with hindsight, once the horse starts treatment and starts to improve.
Note that a long haircoat is highly suggestive of PPID in an older horse but it is not an absolute diagnosis – e.g. malnutrition can cause haircoat changes and false positive blood results. Concurrent disease can also affect clinical signs and blood results.
Some cases where ACTH results may have been affected by stress, sedation, dental work and twitching
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.
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.
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 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:
"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
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
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).
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
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
Yes, any breed of horse or pony can get PPID, and there is no gender predilection.
Risk increases with age, and clinical signs are most frequently first seen in horses in their mid-teens.
However data collected from over 3100 horses tested for PPID during Boehringer Ingelheim's Talk about Laminitis campaign in spring 2012 have suggested that PPID could be common in laminitic horses as young as 10 years old - Veterinary Record 2012;171:239
Horses as young as 7 (Heinrichs et al 1990, Orth et al 1982) have been diagnosed with PPID.
Donaldson et al. 2004 gives the age range of horses suspected of having PPID as 3 to 28 years, with median age 15.5 (however some of these could have been falsely diagnosed in the autumn as seasonal reference ranges for ACTH were not used).
There may be differences between horses and ponies. At the 2011 BEVA Congress Andy Durham suggested that PPID may be a cause of IR in horses. Ponies develop PPID at a younger age than horses, suggesting that IR and hyperinsulinaemia may predispose ponies to PPID. In 744 cases of PPID studied, insulin was higher in younger PPID ponies than in older PPID ponies, suggesting that they were IR at the onset of PPID, but that weight loss which is frequently a symptom of PPID improved their insulin sensitivity.
Nicholas Frank suggests that PPID should be considered in any horse older than 15, but that ponies with EMS can develop PPID at a younger age (> 10) - ponies that become obese at a young age and then develop Equine Metabolic Syndrome have an increased risk of developing PPID when they reach their teens - EMS appears to predispose a pony to PPID.
It should be remembered that testing for PPID has improved significantly in recent years and that it has only recently been recognised that the majority (c. 90%) of laminitis cases have an endocrine cause.
We've recently heard several reports of horses with PPID showing aggressive and/or excitable behaviour.
One horse was reported as changing from being a gentle giant to kicking out (particularly when having his belly groomed or rugs changed), biting, squealing, being sensitive to touch and difficult to catch, with his owner being unable to pick up his feet or groom him some days. The horse had recently started on Prascend but the unusual behaviour preceded treatment and had been going on for several months. Some days he seemed fine but lethargic, others horrible. He was also difficult to keep weight on and had had several weeks treatment for possible gastric ulcers with Gastroguard - scoping post treatment found no evidence of gastric ulcers, he wasn't scoped before treatment started so it isn't known whether he did actually have ulcers.
Another owner reported a similar experience with her pony gelding. Before starting Prascend he wouldn't tolerate being brushed and would lift a leg in warning if his owner for example looked at his sheath area (which was swollen). Prascend was started and he became aggressive towards other horses so had to be kept separate, he was unpredictable and although he appeared to enjoy being ridden, he would sometimes stop and refuse to go forwards without a battle. After several months of treatment with Prascend he's back to his normal self, and his owner concluded that his hormone levels had to settle down and adjust.
A cob gelding in his 20s was diagnosed with PPID and started treatment with Prascend just over a year ago. He became aggressive after starting treatment, kicking out when being handled and biting, becoming very sensitive to being touched, nervous and difficult to catch. He has arthritis in front and hind legs.
We do rarely hear reports of hyper-excitability, nervousness and behaviour changes with both PPID and pergolide/Prascend, but it seems to be far more normal for horses with PPID to be lethargic and docile. What may happen is as the Prascend takes effect, the anti-inflammatory, pain relieving and sedating hormones (e.g. alpha-MSH, beta-endorphin) produced in excess are reduced, and any existing pain is likely to be more obvious - this is often seen if horses have arthritis.
In the Ask the vet live: Equine Cushing’s Disease (PPID) in September 2012 with Nicholas Frank and Marian Little, an owner asked:
Q. Can treatment with pergolide make horses more irritable/unpleasant?
And received the answer:
Owners of PPID horses often say “the lights are on but no one’s home” – over time PPID tends to
make horses more lethargic & docile.
Often when treated with pergolide horses become much more energetic and perhaps bolshy – likely
restoring the normal function of the pituitary that the horse lost some time ago – horses with
advanced PPID are often very gentle with sweet personalities, and sometimes owners prefer their
PPID horse to the one they find after treatment!
Also when some of the excess “feel-good” hormones are removed with treatment, some horses start
to feel age-related aches & pains that were masked with PPID – need to rule these out.
We know that horses can have large variations in hormone levels just a few days (or hours) apart, perhaps that might help explain daily variations in temperament.
Aggressive or unusual behaviour could be a pain reaction, and may not necessarily be linked to the PPID or treatment, and your vet should always be consulted.
The FDA New Animal Drug Application for Prascend Sept 2011 lists " Behaviour change – 5% - included kicking, aggression, agitation, nervous behaviour and increased activity. One horse required a temporary reduction in dose due to energetic behaviour" when horses with PPID were started on 1 mg Prascend.
If you believe that aggressive behaviour is related to Prascend, you should report it:
Please report adverse reactions to Prascend
But be certain that the changes seen started after treatment with Prascend was introduced.
Ensure that the horse's diet is providing all essential nutrients in the correct balance - Diet.
One research paper suggested that supplementing magnesium above NRC levels may help to reduce reaction time in horses:
Dodd JA, Doran G, Harris P, Noble GK
41 Magnesium aspartate supplementation and reaction speed response in horses
May 2015 Volume 35, Issue 5, Pages 401–402