This condition is more commonly referred to as Equine Cushing’s, but strictly speaking this is not an accurate term. Cushing’s syndrome in people describes a clinical condition that occurs in response to persistent high levels of cortisol (hypercortisolism), irrespective of the cause. Horses with PPID do not generally have persistent high levels of cortisol. Consequently, most vets will refer to the equine condition as PPID.
It is estimated that around 20-25% of equids over 15 years of age have dysfunction of their pituitary gland.
Anatomy and physiology
The normal pituitary gland is divided into 3 main regions: the pars distalis, the pars nervosa; and the pars intermedia. The pars distalis, also known as the anterior pituitary, secretes growth hormone (GH), prolactin, thyroid stimulating hormone (TSH), and the reproductive hormones luteinizing hormone (LH) and follicle stimulating hormone (FSH). The pars distalis also secretes some adrenocorticotrophic hormone (ACTH). The pars nervosa secretes oxytocin and antidiuretic hormone (ADH). The pars intermedia secretes the precursor polypeptide pro-opiomelanocortin (POMC) which is cleaved into multiple peptides, including ACTH, alpha melanocyte stimulating hormone (alpha MSH), beta endorphins, and corticotropin like intermediate lobe peptide (CLIP).
Secretion of POMC from the pars intermedia is tightly regulated by input from the hypothalamus. This is mostly under the control of dopamine. Dopamine acts on the D2 receptors of the melanotropes to inhibit cell proliferation and transcription of POMC. A deficiency of dopamine ‘releases’ the pars intermedia allowing it to hypertrophy and secrete excessive amounts of POMC and related hormones. It is believed that the dopaminergic fibres from the hypothalamus undergo age-related oxidative damage leading to decreased dopamine at the level of the pars intermedia of the pituitary gland.
Most of the ACTH produced from the abnormal pituitary is biologically inactive. Therefore, despite high ACTH concentrations there is minimal adrenal gland stimulation and typically no hypercortisolaemia. Again, the term Equine Cushing’s Disease is inappropriate.
What are the signs of PPID?
Hypertrichosis is a condition of abnormal, typically excessive hair growth anywhere on the body. This was previously referred to as hirsutism, but that term more correctly describes body hair on parts of the body where hair is normally absent. Hypertrichosis is present in around 70% of horses with confirmed PPID. There is an increased number of follicles in the anagen or growth phase of hair production. The initial signs commonly include failure to shed a normal winter coat. The hair becomes long, thick, wavy, and is often matted. The precise mechanism responsible for hypertrichosis is unknown – ACTH can stimulate hair growth; alpha-MSH may also play a role.
Muscle loss becomes apparent, particularly the epaxial (top-line) and abdominal muscles. The change in abdominal muscle mass can lead to a ‘pot-bellied’ appearance. The precise mechanism is not known but may involve a reduction in the synthesis of protein and increased protein breakdown (proteolysis). The overall loss of muscle can lead to poor muscular tone and weakness. There is often a redistribution of fat to the supraorbital region, the crest and the tail head.
Weight loss is common, particularly in older animals with PPID. Again, the precise cause is not known but high levels of alpha MSH appear to reduce appetite producing a net calorie deficit.
Hyperhidrosis (increased sweating) is often generalized and may be related in part to the presence of hypertrichosis in horses in warmer climates. It can also occur in clipped PPID horses in cooler climates. As with many of the signs of PPID precise mechanisms have not been determined. In some horses with gross enlargement of the pituitary gland there may be compression of the thermoregulatory region of the hypothalamus. This can lead to intermittent periods of increased body temperature (pyrexia) in some animals.
Increased consumption of water and increased urination (polydipsia and polyuria) is present in around 30% of cases. Fluid losses from hyperhidrosis may contribute to these signs.
Affected animals are more prone to opportunistic infections due to dysfunction of the immune system. It is believed that impaired function of neutrophils may contribute to this increased susceptibility to infection. Tooth root infections leading to bacterial sinusitis appear to be more common in PPID affected animals.
Laminitis can be seen in some PPID-affected animals. This clinical sign is more common in ponies with PPID than horses. It appears that laminitis is more closely linked to concurrent equine metabolic syndrome (EMS) and hyperinsulinemia, rather than PPID alone. It is possible that PPID could exacerbate insulin dysregulation through unknown mechanisms. Certainly in animals with confirmed EMS concurrent PPID can severely complicate treatment. Consequently, PPID status should be investigated in any aged horse with poorly controlled EMS, irrespective of whether overt clinical signs associated with PPID are present or not. Although uncommon, suspensory ligament degeneration is described in older animals with PPID.
Neurologic signs can be seen in animals with advanced PPID. Signs can include somnolence, circling, and seizure. It is thought that these animals may suffer from the consequences of massive enlargement of the pituitary gland and resultant compression of other structures in the cranium.
How to diagnose PPID
The test of choice is a baseline endogenous plasma ACTH concentration. The time of the day does not influence the result. However ACTH can be elevated with severe pain (not mild or moderate), stress, transport, sedation and some medications (e.g., clenbuterol). This test has an overall sensitivity of 68% and a specificity of 86% when interpreted in consideration of the time of the year. Values for ACTH concentration in normal horses and ponies vary from month to month, and are dependent on daylight length. The values are highest around the autumn equinox and lowest between the winter and spring equinox. In Perth (approximately 32 degrees south of the equator) the values are highest in March. Townsville is closer to the equator (20 degrees south) and normal values are slightly higher with less seasonal variation than Perth, although values also peak in March.
Unless there are specific co-existing circumstances (laminitis, hyperinsulinemia, see above) testing should not be performed in horses with no clinical signs.
If signs are relatively mild and/or the horse is younger (10-15 years of age) it may be prudent to perform a thyrotropin releasing hormone (TRH) stimulation test. This can also be used when there is a high index of suspicion of clinical disease but baseline testing is within the normal range. TRH causes the pituitary gland to release more POMC, and post-TRH ACTH concentrations are substantially higher level in horses with PPID. A baseline blood sample is taken, then 1 mg TRH is injected intravenously, and a second blood sample exactly 10 minutes later. The test should not be performed within 12 hours of a concentrate meal, but hay access is fine. Chewing, licking, yawning, flehmen and coughing have been reported immediately after TRH but these are transient and mild. Normal values pre- and post-TRH in a small number of Perth horses is shown below.
In general terms a post-TRH ACTH concentration of less than 110 pg/mL is normal, between 110 and 500 pg/mL equivocal, and greater than 500 pg/mL definitive. If TRH is not available it would be wise to retest between February and April.
It is possible to perform a combined TRH stimulation test and an oral sugar test on the same visit. The following figure is from Manfredi et al. 2023.
Management
Based on the pathophysiology of PPID the obvious approach to management centres on replacing dopamine. There are two registered dopamine agonists for use in horses in Australia: 1) pergolide tablets (1mg tablets Prascend, Boehringer Ingelheim); and 2) pergolide liquid (1mg/5mL, Ranvet). Both are administered by mouth once daily. There is an unregistered long acting dopamine agonist that is given by intramuscular injection (cabergoline 5 mg/mL, BOVA Aus). This product is given at a dose rate 0.002 – 0.010 mg/kg and is often administered weekly. The primary basis for cabergoline use is owner compliance, as many people struggle to medicate daily.
Treatment is lifelong, although some have restricted dopamine use to 6 months of the year, eg January to June in Australia, in early and/or mild cases.
Some success has been reported using a serotonin antagonist, cyproheptadine. This is used in conjunction with pergolide in animals that are resistant to therapy with pergolide alone at maximal doses. Cyproheptadine is not recommended as monotherapy for PPID. It is often used initially at a dose of 0.25 mg/kg PO once daily, potentially increasing over several weeks to 0.6 -1.2 mg/kg PO once daily.
Pergolide treatment: It is common to start horses with a single 1 mg tablet once daily. The dose is titrated using increments of 0.5 to 1.0 mg based on improvement in signs and a reduction in plasma ACTH concentration. It is not recommended to exceed 3 mg daily. Improvements are generally not seen until treatment has been used for several months. Rechecking clinical progress and diagnostic testing is recommended at 6-12 month intervals – this allows the dose to be adjusted as necessary. Increasing the dosage is likely in most animals, due to disease progression and possible drug tolerance. Side effects are relatively uncommon but some animals can experience feed refusal and lethargy shortly after starting the medication. Anorexia can be a problem in animals concurrently treated for insulin dysregulation/hyperinsulinemia with SGLT inhibitors. If anorexia occurs then reduce the dose by half before slowly increasing again once appetite is normal. To avoid signs some have recommended starting horses on 0.25 mg daily, and then increasing every 3 days until 1 mg is reached. Similar side-effects are observed after cabergoline – recommend starting cabergoline at 0.002 mg/kg to reduce the incidence of side-effects.
The clinical response is more important than the magnitude of the reduction in ACTH concentration. Most affected horses (>70%) do not achieve normal ACTH concentrations on therapy. Positive clinical responses include improved haircoat, improvement in bodyweight, reversal of muscle atrophy. These typically don’t occur until a minimum of 2 months after treatment, with some animals not showing improvement until 3-4 years after being on the therapy. Options for owners where pergolide does not improve signs or lower ACTH levels at higher doses (e.g., 3 mg daily) include the addition of cyproheptadine or switching to cabergoline.
In general terms pergolide won’t extend the lifespan of PPID affected horses but will hopefully improve the quality of life.
Don’t chase the numbers, look at the horse!
It is also important to look closely at diet, particularly in animals with concurrent equine metabolic syndrome (EMS). Likewise, attention to dental care, parasite control, and farriery are all critical. Many of these animals are body clipped once or twice yearly.