Pituitary pars intermedia dysfunction

What it is

Pituitary pars intermedia dysfunction (PPID, formerly called "equine Cushing's disease") is an age-related neurodegenerative disease. Dopaminergic neurons of the hypothalamus send their axons to the pars intermedia of the pituitary and restrain its activity with dopamine. When those neurons degenerate, through oxidative stress according to the most accepted hypothesis, the brake is lost: the cells of the pars intermedia multiply (hyperplasia and, over time, adenoma) and overproduce peptides derived from pro-opiomelanocortin (POMC), such as α-MSH, β-endorphin, CLIP and ACTH.

The signs are not explained by excess cortisol alone, which is often not consistently raised; the whole set of POMC peptides, compression of the hypothalamus by the adenoma and the insulin dysregulation that accompanies many cases, and which is mainly responsible for laminitis, all play a part.

Who it affects

Older horses, ponies and donkeys: it is rare under 10 years of age and its frequency rises with age. It is estimated to affect about one in five equids aged 15 years or more. Age is the only consistently demonstrated risk factor; data on breed and sex are conflicting.

Anatomy involved

The pituitary is not represented in the model; the brain and the organs where the consequences are seen are highlighted instead.

• Brain: the pituitary gland hangs from the floor of the diencephalon, below the hypothalamus, attached to it by the infundibular stalk and lodged in the hypophyseal fossa of the basisphenoid. It has an adenohypophysis, with the pars distalis and pars intermedia, and a neurohypophysis. The dopaminergic neurons that control the pars intermedia lie in the periventricular nuclei of the hypothalamus. A large adenoma can compress the hypothalamus, which is linked to disturbed thermoregulation and sweating, and rarely the optic chiasm.
• Skin: the most characteristic sign is hypertrichosis: a long, often curly coat that does not shed in spring or sheds late and incompletely. There is also excessive or reduced sweating and a greater tendency to skin infections.
• Hooves: laminitis, due to the associated insulin dysregulation, is the most serious complication. Hoof abscesses are also common.
• Epaxial muscles: muscle atrophy is seen first along the topline (longissimus and the other epaxial muscles), which makes the spine prominent and changes saddle fit; there may also be abnormal fat distribution, especially above the eyes and at the tailhead.

Clinical signs

• Hypertrichosis or delayed shedding.
• Laminitis, sometimes as the first sign.
• Loss of muscle along the topline and over the rump, with a pendulous abdomen.
• Lethargy, reduced performance.
• Polyuria and polydipsia, abnormal sweating.
• Recurrent infections (sinusitis, periodontal disease, hoof abscesses), slow wound healing, higher faecal parasite egg counts and infertility.

Diagnosis

• It is based on the combination of age, clinical signs and endocrine tests: the pre-test probability decides how the result is interpreted, and in a young horse without signs a positive result is probably false.
• Basal plasma ACTH: the most widely used test. ACTH rises physiologically in autumn, so seasonal reference intervals are used. Breed, latitude, feeding, transport and severe illness also influence it.
• TRH stimulation test: ACTH is measured before and 10 or 30 minutes after injecting TRH; it detects earlier cases, but has fewer reference data outside autumn.
• It is worth also measuring insulin (basal or after an oral sugar test), because insulin dysregulation is what predicts the risk of laminitis.

Treatment and prevention

• Pergolide: a dopamine agonist that replaces the lost brake; it is given orally once a day for life. It improves most signs in most horses and lowers ACTH, but does not usually correct insulin dysregulation. It can cause transient loss of appetite at the start. The dose is adjusted to the clinical response and ACTH.
• Management: clipping horses with hypertrichosis, hoof and dental care, parasite control guided by faecal egg counts, and an adapted diet: low in sugars and starch if there is insulin dysregulation, and with enough protein and energy if the horse is losing weight.
• In the EU, pergolide authorised for horses cannot be used in animals intended for human consumption: the treated horse must be declared in its passport as excluded from the food chain. In other countries national regulations and their withdrawal periods apply.

Key studies

• BEVA primary care guidelines (Menzies-Gow et al., 2024), developed with the GRADE method. Prevalence in equids aged 15 years or more is between 21 and 27%, and hypertrichosis or delayed shedding gives a high clinical suspicion. Diagnostic accuracy of basal ACTH was 88–92% in autumn and 70–86% outside autumn, depending on pre-test probability; that of ACTH after TRH was 92–98% and 90–94%, although based on a single study. Pergolide improves most signs but does not alter insulin dysregulation in most cases, and chasteberry provides no benefit. The guideline itself acknowledges that the available evidence is limited.
• Ireland and McGowan (2018), systematic review of 29 publications, almost all case series or cross-sectional studies. The most robust prevalence estimates were 21.2% in equids aged 15 years or more and 2.9% in the general equine population. The most frequent signs were hypertrichosis, laminitis and epaxial muscle atrophy. Only age was confirmed as a risk factor.
• Meyer et al. (2022), systematic review and meta-analysis of 11 diagnostic accuracy studies of basal ACTH: sensitivity 0.72 (95% CI 0.62–0.82) and specificity 0.88 (0.79–0.93); with the usual cut-off of 35 pg/mL, 0.66 and 0.87. The authors conclude that ACTH can confirm the disease in horses with high clinical suspicion, but should not be used to screen horses without signs. The included studies had a substantial risk of bias.
• Tatum et al. (2020), systematic review of 28 publications on the efficacy of pergolide. Most reported overall clinical improvement in more than 75% of cases; ACTH fell in 44–74% of horses and normalised in 28–74%. Most were case series or field trials without a control group, so a meta-analysis was not possible.
• Horn et al. (2019), retrospective study of 274 equids with PPID from 8 centres in Australia. Laminitis was diagnosed in 89.9% and insulin dysregulation in 76.5% of the horses in which they were investigated. Being a pony, having better body condition and receiving pergolide were associated with longer survival. Testing was not uniform across centres.