Author Name: Victoria Purves; BSc (Hons) Bioveterinary Science
PPID is the most commonly diagnosed equine endocrine disorder in the United Kingdom, which is caused by degeneration of neurons leading to a decrease in dopamine production. Pergolide and cyproheptadine are frequently used in the treatment of this disease. Research found a significant decrease in plasma ACTH concentration after treatment with pergolide whereas no such decrease was seen when treating using cyproheptadine. Three separate studies used a retrospective design to examine data records held on PPID treatment. These studies had a limited sample size meaning some results were not statistically analysed. A further study chose to examine over 2000 cases and found 54.8% had a decrease in ACTH concentration when treated with pergolide. Because of the larger sample size these results had greater external validity and were more representative of the population. Dosage was not standardised between studies, as dosing is generally based on clinical experience. However a double dose (approximately 1mg/kg bwt) of cyproheptadine was more likely to show an improvement in ACTH concentration. Research measured response to treatment via various methods; using owners’ perception of improvement in clinical signs is suggested to be more subjective than measuring hormone levels. Measuring ACTH concentration was chosen over the dexamethosone suppression test in many cases because of anecdotal evidence that dexamethosone increases the risk of laminitis. When results from ACTH concentration were examined, the effect of seasonality and variability of a single ACTH sample were not considered, however by combining ACTH concentration with improvement in clinical signs results this showed an increased reliability as response to treatment was not measured on a single result.
Pituitary pars intermedia dysfunction (PPID), also known as equine Cushing’s disease, is the most commonly diagnosed equine endocrine pathology in the UK (22%); most frequently affecting elderly horses 15 years and older (McGowan, Pinchbeck and McGowan, 2013; Miller et al, 2008). Horses with PPID have hyperplasia of pars intermedia of the pituitary gland with single or multiple adenomas present (McFarlane, 2011). PPID is a neurodegenerative disease, where dopaminergic neurons undergo oxidative damage which causes a decrease in the quantity of dopamine production. This decrease affects the negative feedback of the pars intermedia which triggers overproduction of proopiomelanocortin (POMC) peptides such as adrenocorticotropic hormone (ACTH), α- melanocyte stimulating hormone and β-endorphins (see figure 1) (Sojka-Kritchevsky and Johnson, 2014; McGowan, Pinchbeck and McGowan, 2013; Gehring et al, 2010). This imbalance produces an endocrine effect leading to clinical signs. Clinical signs include hirsutism which is a pathognomic sign, hyperhydrosis, chronic laminitis, polyuria, polydipsia, muscle wasting and supraorbital fat (Durham et al, 2014; Rohrbach et al, 2012; Perkins et al, 2002).
Figure 1: The POMC processing pathway (McFarlane, 2011).
Pergolide mesylate and cyproheptadine are commonly used in the treatment of PPID and multiple studies have examined the efficacy of these treatments, however pergolide is the only licensed treatment for PPID in the UK (Rendle et al, 2013a; Donaldson et al, 2002). With the increasing prevalence of PPID and between 24-82% of cases also suffering from recurrent or chronic laminitis which decreases the welfare of these individuals, more information on the medication choices and horses’ response to treatment is required (Grenager, 2010; Donaldson et al, 2002). The aim of this paper is to critically analyse research on cyproheptadine and pergolide in the treatment of PPID.
2.0. Current Research
2.1. Diagnostic Techniques
Measurement of the efficacy of PPID treatment can be performed using a range of diagnostic tools, there is no ‘gold standard’ for diagnosis (ante-mortem) therefore no specific test is relied upon (McFarlane, 2011). Hirsutism is often used as an indicator of PPID due to being pathognomonic. Laboratory methods most commonly relied upon for diagnosis are plasma ACTH concentration and the dexamethosone suppression test (DST) (Grenager, 2010). Elevated plasma ACTH levels (greater than reference range of 9-35pg/ml) are indicative of PPID. The DST requires a blood test pre and post administration of dexamethosone, 20hrs post administration a serum cortisol of greater than 1µg/dL is suggestive of PPID (McFarlane, 2011; Grenager, 2010).
2.2. Comparison of efficacy of pergolide and cyproheptadine
Research has compared the treatment of PPID with pergolide and cyproheptadine (Rohrbach et al, 2012; Donaldson et al, 2002; Perkins et al, 2002; Schott et al, 2001). Donaldson et al (2002) found a strong significant decrease (P= less than 0.001) in ACTH levels after treatment with pergolide and 85% of owners that treated PPID with pergolide saw an improvement in clinical signs. Schott et al (2001) also found a significant decrease in ACTH concentration. Rohrbach et al (2012) however, found when examining response to treatment after 2 months only 40% of owners found pergolide effective. Literature suggests that pergolide is a more effective treatment as it is a dopamine D² receptor agonist that stimulates dopamine receptors. This leads to a decrease in POMC peptide production, thus directly decreasing ACTH production and therefore plasma ACTH concentration (see figure 1) (Gehlen, May and Bradaric, 2014; McFarlane, 2011; Grenager, 2010).
Both Schott et al (2001) and Donaldson et al (2002) concurred that there was no significant decrease in ACTH concentration after treatment with cyproheptadine. Less than 30% of owners noted an improvement in clinical signs (Rohrbach et al, 2012; Donaldson et al, 2002). On the other hand Perkins et al (2002) found a significant decrease in ACTH levels from baseline to first recheck (P= 0.03), where there was a 62% decrease for cyproheptadine treatment and only a 60% decrease for pergolide. On closer analysis only 27% of cyproheptadine treated individuals returned to reference range (below 35pg/ml) compared to 40% of pergolide treated horses. Cyproheptadine is a non-selective serotonin antagonist, that competes for serotonin receptor sites and prevents serotonin from regulating ACTH although the exact effect of serotonin on the pars intermedia is unknown (Grenager, 2010; Divers, 2008).
2.2.1. Study Design and Sample Size
Donaldson et al (2002), Perkins et al (2002) and Rohrbach et al (2012) used a retrospective design, this format could be beneficial as a large quantity of data can be collected and various outcomes analysed (Collis and Hussey, 2009; Hess, 2004). To induce PPID or leave certain animals untreated would be unethical especially in the presence of laminitis, as the horse would continue to suffer (Mann, 2003). Therefore these studies chose to examine data records. Nevertheless the cases chosen are subject to selection bias as the researcher chooses the cases to be examined, Rohrbach et al (2012) states that the sample was chosen by convenience, Donaldson et al (2002) analysed cases from a particular veterinary hospital therefore results have a decreased external validity because of this bias (Collis and Hussey, 2009; Hess, 2004). Considerations must also be made that the data collected originally may be inaccurate, or missing details as there was no emphasis on collection of precise data, this is because the intention of the records were for purposes other than research (Hoffman, 2007; Mann, 2003).
The studies by Donaldson et al (2002), Perkins et al (2002) and Rohrbach et al (2012) used various inclusion criteria to identify individuals suitable for analysis of treatment type. 34, 42 and 27 horses respectively were used in these studies. The small sample size in Perkins et al (2002) study meant that no statistical analysis was performed to identify if a significant decrease in ACTH levels (to less than 35pg/ml) was found. A decrease would indicate a return to reference range for this hormone and effectiveness of pergolide (McFarlane, 2011). Also as only 10 horses were treated with pergolide no analysis could be executed on the relationship between ACTH levels and improvement in clinical signs. Therefore conclusions, that the improvement in hirsutism was because of treatment with pergolide, could only be suggested and were not fully supported by statistical analysis. Consequently Rendle et al (2013a) noted evidence for treatment was limited to research using only small sample sizes and therefore examined treatment of 2122 cases of PPID. Results showed 54.8% of horses had a minimum of a 75% decrease in ACTH concentration or a return in ACTH to reference range when treated with pergolide. The larger quantity of cases meant that these results were more representative of the population, reduced bias and increased external validity of the data collected, so findings were more accurate (Collis and Hussey, 2009; Oakshott, 2009).
2.2.2. Drug Dosage
Rohrbach et al (2012) research gave no details of the dosage of each PPID treatment administered or the source of the drug, meaning there was no form of standardisation between the treatment given. Dosage varies between Donaldson et al (2002) and Perkins et al (2002) (as shown in table 1) meaning there can be no direct comparison. In Perkins et al (2002) 27/32 horses received a double dose of cyproheptadine, in contrast to Donaldson et al (2002) who gave a more standardised treatment, with all horses receiving the set dose of cyproheptadine. Results showed a 62% decrease in ACTH concentration in Perkins et al (2002) whereas Donaldson et al (2002) found no significant decrease. Quantities administered and formulation can affect the response rate seen between animals (Rohrbach et al, 2012) indicating that an increased dose of cyproheptadine has an effect on clinical response.
Table 1: Comparison of dosages administered in research by Perkins et al (2002) and Donaldson et al (2002).
|Pergolide (every 24hrs)||Cyproheptadine (every 24hrs)|
|Perkins et al (2002)||‘full dose’=1.7µg/kg bwt||‘full dose’= 0.5mg/kg bwt|
|Donaldson et al (2002)||Median dose = 3.0µg/kg bwt||0.25mg/kg bwt|
No such conclusion could be drawn about pergolide as dose ranged from 1.7-5.5µg/kg bwt (Donaldson et al, 2002). Rendle et al (2013b) states that dosing is based on clinical experience, which therefore could indicate why the large variation in dosage was seen. Anecdotal evidence suggests when treating with pergolide 1mg per horse should be used then if there is no improvement after 6 weeks gradually increasing the dose until a change is seen (McFarlane, 2011; Grenager, 2010). More recent research by Rendle et al (2013a) indicates that when a dose of less than 0.5µg/kg bwt was used it was less probable to see a decrease in ACTH levels.
2.2.3. Measuring Improvement in PPID Cases
Improvement of PPID was evaluated using different methods, Rohrbach et al (2012) chose to analyse response after treatment using owners’ perception of improvement of clinical signs of PPID. This method means data can be collated quickly and owners are more likely to notice small changes in clinical signs (Oakshott, 2009). Pongratz, Grauber and Eser (2010) also measured improvement using clinical signs, 79% of owners were satisfied with pergolide treatment, compared to only 40% in Rohrbachs’ et al (2012) research. Variation in results may be because of recall bias or owners exaggerating an improvement to a particular clinical sign. Therefore measuring changes in hormone levels can give a more objective response (Durham et al, 2014; Mann, 2003). Perkins et al (2002) also studied treatment effect on clinical signs, but chose to use a veterinary perspective as the results are likely to be less subjective. Donaldson et al (2002) noted both veterinary examination of improvement in clinical signs and owners’ opinion of the effect of treatment; increased data collected leads to increased accuracy of results.
Schott et al (2001) diagnosed PPID with DST or plasma ACTH concentration, compared to both Perkins et al (2002) and Donaldson et al (2002) who only examined ACTH levels. The use of ACTH concentration is advantageous over DST because DST is more invasive as it requires two blood samples; whereas ACTH only requires one (McFarlane, 2011). The administration of dexamethosone has anecdotal association with an increased risk of laminitis, which is frequently seen in horses with PPID (Rohrbach et al, 2012; Donaldson et al, 2002). Nonetheless more recently research has shown that a seasonal increase in ACTH concentration occurs in both clinically healthy horses and those with PPID (Beech et al, 2009). Higher ACTH concentration was seen in September and December where concentrations greater than 80-100pg/ml were suggestive of PPID (Lee, Zylstra and Haritou, 2010; Donaldson et al, 2005). Perkins et al (2002) and Donaldson et al (2002) both testified an ACTH concentration greater than 35pg/ml was indicative of PPID and gave no details of the months when measurements were taken. Therefore due to the effect of seasonality and variability in single ACTH samples healthy animals may have been diagnosed with PPID and evaluation of treatments may be inaccurate (Lee, Zylstra and Haritou, 2010; Beech et al, 2009). So by combining findings of ACTH concentrations with examination of clinical signs there is an increase in the reliability as improvement is not measured on one result alone (Divers, 2008).
Perkins et al (2002) gave no details on length of time between ‘rechecks’ in the 12 month investigation period, meaning it is difficult to compare to other studies. This information would also be beneficial to identify the average duration time for treatments to show a decrease in ACTH concentration. Donaldson et al’s (2002) average treatment time was 2 months for pergolide and 2.5 months for cyproheptadine. Analysis showed a negative correlation (r= -0.726) between ACTH concentration and duration of treatment with pergolide, as shown in figure 2. This is supported by Rendle et al (2013b) who found duration of treatment was positively associated with response to treatment (p=0.039). A short study duration was a disadvantage as it could not be identified if correlation continued. Durham et al (2014) postulates that in cases which have had no initial response to treatment, 3-4 years later improvement has been seen in some instances.
Figure 2: A graph to show the relationship between duration of treatment and ACTH concentration (Donaldson et al, 2002).
Literature suggests that pergolide is the most effective treatment of PPID as multiple studies have shown improvement in clinical signs and a decrease in plasma ACTH concentration. This is because pergolide directly stimulates dopamine receptors decreasing POMC production. In comparison, treatment with cyproheptadine is inconclusive, research showed a decrease in ACTH concentration in some studies but not in others. Nevertheless the variability of single ACTH measurements must also be taken into consideration. By using larger sample sizes and reducing the selection bias when choosing sample populations this increases the external validity of data collected. Further research would be beneficial to provide information on standardisation of dosing as quantities varied greatly between studies. Also a longer study duration would be advantageous to identify if the initial decrease in ACTH concentration was maintained and indicate if those animals that did not initially respond to treatment may do so after a longer period.
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