Pituitary pars intermedia dysfunction (PPID) is a slowly progressive neurodegenerative disease of the older horse. Diagnosis of PPID is based on the signalment, clinical signs and further diagnostic test results. There is no ideal further diagnostic test for equine PPID; however, plasma basal adrenocorticotropic hormone (ACTH) concentrations and the ACTH response to thyrotropin releasing hormone (TRH) are currently thought to be the most appropriate tests available. Management of the disease includes use of the dopamine agonist pergolide to replace the lost dopaminergic inhibition of the pars intermedia, and management changes to help improve insulin sensitivity if necessary. There have been several recent publications relevant to the diagnosis and treatment of PPID that will be summarised here.
Systematic review of the use of basal ACTH concentrations to diagnose PPID
A systematic review and meta-analysis of previously published studies focusing on the diagnostic accuracy of basal ACTH concentrations for the diagnosis of PPID was undertaken (Meyer, 2020). The results from 10 studies were included in meta-analysis; the overall sensitivity was 68 percent and the specificity was 86 percent, supporting the current recommendation that basal ACTH concentrations should be used as an initial diagnostic test and that further diagnostic tests should be performed in cases that test negative.
ACTH: Should we use diagnostic cut-offs or reference intervals to diagnose PPID?
ACTH is the most conveniently measured hormone originating from the pars intermedia and its concentration has a good correlation with clinical signs. Therefore, detection of an increased plasma concentration of baseline ACTH is the most common method used to identify PPID cases or confirm a clinical suspicion of PPID (McFarlane et al., 2005; Horn et al., 2019).
The definition of an increased plasma baseline ACTH concentration is controversial as ACTH increases with stress, exercise, season, diet, disease status and age (Alexander et al., 1988, 1991; Alexander and Irvine, 1998; Copas and Durham, 2011; Jacob et al., 2017; Stewart et al., 2019). To remove some of the effects of these variables and improve the detection of subclinical PPID cases, the provocative TRH stimulation test has been developed and is extensively used both clinically and in research (Frank et al., 2006; Beech et al., 2007; Horn and Bertin, 2019). However, as with measurement of plasma baseline ACTH concentration, there is similar variability with season, age, stress and diet with the TRH stimulation test (Funk et al., 2011; Diez de Castro et al., 2014).
Several studies have determined guidelines for interpretation of plasma basal or post‐TRH‐stimulation ACTH concentrations to diagnose PPID; however, differences between studies, from methodologies pertaining to the sampled population, to the processing of the samples and the statistical analyses, have led to determination of either plasma ACTH reference intervals (RIs) or plasma ACTH diagnostic cut-off values (DCOVs). The reference interval is the range of a value that is deemed normal for a physiologic measurement in healthy individuals and encompasses 95 percent of values of a reference population, whereas a diagnostic cut-off value is a limit used for binary classification, mainly between normal versus pathological. The use of DCOVs or RIs results in differences in the definition of an increased plasma ACTH concentration. The clinical consequences of the current variations in the definition of an increased plasma ACTH concentration include the risk of missing PPID cases and exposing horses to the risk of complications associated with PPID, or on the other end of the spectrum, the risk of medicating healthy horses, limiting their athletic careers as a result of the use of controlled medications.
In the UK, seasonally adjusted reference intervals are primarily used to interpret basal ACTH and post-TRH-stimulation ACTH concentrations to diagnose PPID and monitor response to treatment. A recently published study sought to compare the test characteristics of baseline and post-TRH-stimulation plasma ACTH concentrations in horses (72 control and 34 cases) using diagnostic cut-off values and reference intervals and to determine the clinical consequences of using each method (Horn et al., 2020). Horses underwent monthly TRH stimulation tests and DCOVs and RIs were determined monthly. Baseline ACTH concentrations were accurate to diagnose PPID (0.91 ± 0.06) with DCOVs increasing the test sensitivity from 61 percent to 87 percent, and RIs increasing test specificity from 85 percent to 98 percent (Horn et al., 2020). Thyrotropin‐releasing hormone stimulation improved test accuracy from 91 percent to 97 percent. The authors of this paper concluded that the use of DCOVs would be recommended to improve the detection of early cases of PPID where missing a diagnosis of PPID might have detrimental effects, while the use of RIs would be recommended to ensure no horse is treated unnecessarily, for example due to the controlled nature of the substance in athletic horses or when the owner has limited finances. In addition, they suggested that these results emphasised the necessity of a clinical context and a diagnostic goal when performing these tests that should be discussed between the veterinarian and the owner.
Clinically and temporally specific diagnostic thresholds for plasma ACTH in the horse
A retrospective study using a large laboratory database of equine plasma ACTH concentrations was undertaken to derive temporally specific diagnostic thresholds for equine plasma ACTH concentration to be used alongside clinical judgement in each individual week of the year and appropriate for the degree of clinical suspicion in any given case (Durham et al., 2020). Thus, similar to the study described above, this study focused on the concept of the diagnostic threshold varying according to the degree of clinical suspicion of the disease and according to whether it was more important to be confident that the result is truly positive (high test sensitivity) or truly negative (high test specificity).
Combined testing to simultaneously diagnose PPID and insulin dysregulation
A subset of animals with PPID have insulin dysregulation (ID) and this is associated with an increased risk of laminitis and a poorer prognosis. Thus, it is important to determine insulin sensitivity in animals with PPID. The TRH stimulation test and the two-step insulin sensitivity test are commonly used methods to diagnose, respectively, PPID and ID. A recent study investigated the diagnostic value of combining the TRH stimulation test and the two-step insulin sensitivity test to diagnose PPID and ID simultaneously (Horn and Bertin, 2019). The effect of combined testing on plasma ACTH and blood glucose concentrations, or the percentage decrease in blood glucose concentration, was not significantly different from the effect obtained with independent testing. Thus, combining the tests appears to be a useful diagnostic tool for equine practitioners in the field.
Use of sedation in association with the TRH stimulation test
Stress or excitement is a concern when performing endocrine tests on fractious horses. Sedation may be a solution; however, perturbation of test results may preclude useful information. A study in nine healthy horses revealed that basal ACTH concentrations were not affected by detomidine (0.01mg/kg) alone (DET) or in combination with butorphanol (0.01mg/kg; DET/BUT), indicating that sedation with these compounds may be achieved when needing to measure basal plasma ACTH (Oberhaus et al., 2021). However, treatment with DET and DET/BUT did alter the prolactin, TSH, MSH and ACTH responses to TRH; therefore, the use of these drugs may not be advisable when assessing endocrine responses to TRH stimulation.
Can endocrine dysfunction be reliably tested in aged horses that are experiencing pain?
Fifteen horses with treated low to moderate pain intensities were used to determine whether different intensities and types of treated pain influenced basal ACTH and the ACTH response to TRH such that it would lead to a false positive result in the diagnosis of PPID (Gehlen et al., 2020). There was no significant difference in the basal or stimulated ACTH concentration in horses with pain and controls, between different pain intensities or between disease groups (eg colic, laminitis, orthopaedic problems). Thus, measuring the basal ACTH concentration and performing the TRH stimulation test for the diagnosis of PPID seem to be possible in horses with low to moderate pain.
Does pergolide restore pars intermedia dopamine concentrations?
PPID is characterised by loss of the dopaminergic neurones in the equine pituitary pars intermedia, and dopamine concentrations are markedly reduced in pars intermedia (PI) tissue of PPID-affected animals. Treatment with pergolide was associated with a restoration of PI tissue dopamine concentrations to values not significantly different from those in age-matched animals without PPID (Fortin et al., 2020).
Does pergolide improve immune function?
Systemic immune function is altered in PPID horses and it is likely that this results in an increased risk of opportunistic infection. Despite reducing circulating ACTH concentrations, pergolide treatment does not appear to influence immune function in PPID animals (Miller et al., 2021).
Efficacy of pergolide for the management of PPID
A systematic review of the published literature was undertaken to evaluate the evidence regarding whether pergolide treatment results in improvement in clinical signs and/or ACTH concentrations compared to no treatment or other unlicensed treatments (Tatum et al., 2020). Twenty-eight publications were included in the review; most were descriptive case series, cohort studies or non-randomised, uncontrolled field trials. Despite marked variation in study populations, case selection, diagnostic protocols, pergolide dose, follow-up period and outcome measures, in most of the included studies pergolide was reported to provide overall clinical improvement in more than 75 percent of cases. However, reported improvements in individual clinical signs varied widely and determining the efficacy of pergolide for treating specific clinical signs with any degree of certainty was not possible. A reduction in plasma ACTH concentrations was reported in 44 to 74 percent of cases, while normalisation to within reported reference intervals occurred in 28 to 74 percent of cases. In general, reduction in plasma ACTH concentrations was much more varied than overall improvement in clinical signs and the two did not always correspond. The authors concluded that the available evidence demonstrates improvement in clinical and endocrine parameters in response to pergolide treatment.
Factors associated with survival, laminitis and insulin dysregulation in horses with PPID
A retrospective study of 274 equids with PPID from eight institutions across Australia was undertaken to investigate factors associated with survival, laminitis and insulin dysregulation (Horn et al., 2019). Being a pony, having an adequate body condition score and pergolide administration were associated with survival. Laminitis was diagnosed in 89.9 percent of cases and ID was present in 76.5 percent of cases in which they were investigated. The authors concluded that ID should be investigated in all equids diagnosed with PPID and maintenance of an adequate body condition and administration of pergolide are fundamental in PPID management.
What are the most important unanswered questions?
Finally, a recent study sought to engage with veterinarians and horse owners to identify evidence gaps (“uncertainties”) and prioritise them into a list of the 10 most important PPID research questions (Box 1; Tatum et al., 2021). Most questions are centred around treatment, with questions focusing on additional management strategies, effective medical treatments other than pergolide, dosing of pergolide throughout the year, and safety and efficacy of pergolide treatment. Several studies have reported that pergolide is effective at improving clinical signs and ACTH concentrations, and this was generally the viewpoint of participating veterinary surgeons at the beginning of the investigation. However, discussions with owners throughout the process highlighted that this is not always the case for individual animals. The process highlighted the need for a more robust evidence base for pergolide as a treatment and the need to investigate concurrent and alternative options.