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.
Only a tiny amount of ACTH is released from the pars intermedia in normal horses. ACTH release from the PI is reduced or stopped by dopamine from the hypothalamus. In horses with PPID, the dopamine-producing neurons in the hypothalamus become damaged, less dopamine is produced, with the result that more hormones - ACTH, beta-endorphin, alpha-MSH, CLIP - are produced, and these cause the clinical signs of PPID. Treatment with pergolide/Prascend "replaces" the dopamine that has been lost, and reduces hormone production from the PI.
"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.
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.
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.
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
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).
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
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.