University of Minnesota Study Investigates Genetic Influence on PPID Treatment Response in Horses

A research team at the University of Minnesota is investigating the role genetics may play in how
horses respond to treatment for pituitary pars intermedia dysfunction (PPID), commonly known as equine Cushing’s disease. This condition, which affects up to 30% of older horses, can have serious consequences ranging from diminished performance to death.

 

PPID develops when neurons in the hypothalamus become damaged, resulting in the loss of control over the pituitary gland’s pars intermedia. While there is currently no cure, treatment focuses on slowing disease progression and managing clinical signs. The gold-standard medication for PPID is pergolide, a dopamine receptor agonist originally used to treat Parkinson’s disease in humans. Pergolide helps compensate for dopamine loss in hypothalamic neurons and is the most widely prescribed drug for PPID.

 

However, horses vary significantly in their response to pergolide. Treatment success rates are reported to range from 60–80%, but comparisons across studies are difficult due to differing definitions of “success.” Additionally, adverse effects are relatively common, with some studies reporting anorexia in up to 32% of treated horses. Other side effects may include colic, weight loss, and behavioural changes. These reactions often lead owners or veterinarians to reduce or discontinue treatment - causing symptoms to return or worsen and allowing the disease to progress.

 

It is well established in human medicine that genetic differences can influence how individuals respond to medications. Now, the same principle is being explored in horses.

 

The study, led by Dr. Molly McCue and Dr. Lauren Hughes from the UMN Equine Genetics and Genomics Laboratory, in collaboration with Dr. Dianne McFarlane from the University of Florida, aims to uncover genetic factors that affect pergolide response and adverse event susceptibility in horses with PPID.

 

“Our goal is to identify genetic variants that influence treatment outcomes,” explain the researchers. “If we find specific alleles that predict poor response or higher risk of side effects, this could lead to more personalised treatment—such as adjusted dosing strategies to improve safety and effectiveness.”

 

“As a veterinarian, I understand just how devastating PPID can be for horses and the owners that love them,” said Dr. Hughes in a UMN College of Veterinary Medicine news release. “I’m very excited about the potential of this research to improve how we diagnose, treat, and manage this important disease.”

 

The research team is actively seeking suitable horses to enrol in the study. They are looking for horses that meet the following criteria:

• Over the age of 15 at time of PPID diagnosis
• Diagnosis made by veterinarian and diagnosis included bloodwork
• Horse has/had clinical signs consistent with PPID (long shaggy haircoat, muscle atrophy, changes in mentation, or recurrent infections)
• Horse has been on pergolide therapy for a minimum of 6 months and has had recheck blood values (including ACTH, TRH stim, or dexamethasone suppression blood work)

 

If your horse meets the criteria, you are encouraged to participate. Your involvement is essential - this research would not be possible without the support of dedicated horse owners and their animals.

 

For more details, see:

 

https://vetmed.umn.edu/equine/research/equine-genetics-and-genomics-laboratory/projects/equine-pituitary-pars-intermedia-dysfunction-ppid/pergolide-study/pergolide-study-participation-requirements

 

https://www.youtube.com/watch?v=kZl2WvUBt1w

Investigating cabergoline for treating equine Cushing’s disease

 Cabergoline shows promise as a treatment option for equine Cushing’s disease, according to a recent report.

Cushing’s disease or Pituitary Pars Intermedia Dysfunction (PPID) is a common condition in older horses, resulting from increased activity in the intermediate lobe of the pituitary gland. This excessive activity has been attributed to nerve damage impairing its regulation, with dopamine acting as the crucial neurotransmitter. When dopamine levels are deficient, the pituitary gland becomes overactive, leading to the release of various hormones, such as adrenocorticotropic hormone (ACTH).

 

Clinical manifestations associated with PPID are well-documented and include hypertrichosis, laminitis, polyuria, polydipsia, lethargy, muscle wastage, and delayed wound healing.

 

Dopaminergic agonists, medications that mimic the action of dopamine, function by stimulating dopamine receptors in the pituitary gland. This stimulation results in the inhibition of the release of certain hormones, including ACTH, thereby mitigating clinical signs such as abnormal hair coat, muscle wasting, and laminitis.

 

Pergolide, a dopamine agonist, stands as the primary treatment for managing PPID and is approved for oral administration in equines. However, some horses may exhibit resistance to daily oral dosing. Cabergoline, another dopamine agonist like pergolide, currently is not licenced for use in horses.

 

A recent retrospective study conducted by Tania Sundra of Avon Ridge Equine Veterinary Services in Brigadoon, WA, Australia, along with colleagues, explored the efficacy of intramuscular extended-release cabergoline (ERC) injection in treating PPID. Despite being unlicensed, this treatment modality is increasingly utilized off-label in clinical practice for managing PPID. The study examined clinical records of privately-owned horses with PPID that had undergone intramuscular cabergoline treatment at Avon Ridge Equine Clinic.

 

The study examined the short-term (5–8 days) and longer-term (12 months) clinical and endocrinological responses to two doses of cabergoline: a low dose (0.005mg/kg) extended-release cabergoline (LDERC) and a high dose (0.01mg/kg) extended-release cabergoline (HDERC).

 

Results showed that although both doses of ERC led to a decrease in median ACTH concentration, the levels remained above the seasonal reference range in about half of the treated horses. However, similar responses had been noted in previous studies involving pergolide treatment for PPID.

 

Owners reported clinical improvement in 78.3% and 100% of horses treated with LDERC and HDERC, respectively. 

Common side effects of dopamine agonists, such as decreased appetite, lethargy, gastrointestinal upset, and behavioural changes, were observed. Notably, partial, self-limiting inappetence was reported in 30.0% of LDERC cases and 60% of HDERC cases, with seven horses exhibiting lethargy.

 

In cases of partial anorexia, owners noted that horses preferred long-stem forage (hay or grass) over cereal-based feeds. The clinical and endocrinological responses observed were consistent with previous reports of oral pergolide treatment.

 

The authors suggest that weekly injection of ERC may serve as an effective alternative to pergolide. The 0.005 mg/kg dose appeared to be as effective as the 0.01 mg/kg dose but with a lower risk of inappetence.

 

While cabergoline shows promise as a treatment option for PPID in horses, further research is necessary to fully establish its efficacy, safety profile, and optimal usage protocols.

 

 

For more details, see: 

 

Sundra T, Kelty E, Rossi G and Rendle D (2024) 

Retrospective assessment of the use of extended-release cabergoline in the management of equine pituitary pars intermedia dysfunction. 

Front. Vet. Sci. 11:1332337. 

https://doi.org/10.3389/fvets.2024.1332337

Help needed for study of effects of Cushing’s disease

A new study to explore the effects of Pituitary Pars Intermedia Dysfunction (PPID), commonly
known as Equine Cushing’s disease, in adult and older horses and ponies in the UK has been launched by the Royal Veterinary College (RVC), in partnership with CVS Group plc.

The primary objective of the study is to gain deeper insights into how the disease affects the quality of life of these animals. Ultimately, the findings aim to improve monitoring and decision-making, concerning the treatment of PPID in horses and ponies, benefiting their well-being around the world.

 

PPID is a common hormonal disorder that typically affects older equines. It is estimated to impact around 25% of horses and ponies aged 15 years and older. The disease manifests with various clinical signs such as laminitis, weight loss, and lethargy, that can significantly affect the animals' quality of life (QoL).

 

However, in the absence of validated equine QoL assessment tools, it is a challenge to make objective evaluations and informed decisions regarding the treatment and, in some cases, euthanasia for horses suffering from PPID. 

 

In a bid to enhance the support provided to animals, veterinarians, and owners, the RVC study aims to create a validated equine quality of life tool. This tool will serve as an objective assessment measure to understand the impact of PPID on the individual horse's quality of life. By having such a tool, veterinarians will be better equipped to make well-informed decisions concerning treatment and, if necessary, euthanasia options for horses and ponies diagnosed with PPID.

 

Heading this research is Aline Bouquet, a PhD Candidate and Research Assistant, with the support of Professor Nicola Menzies-Gow, Professor in Equine Medicine, and Professor Christine Nicol, Professor of Animal Welfare.

 

To achieve their goals, the RVC team is reaching out to horse and pony owners, requesting their participation in an online survey. The data collected from this survey will play a crucial role in the initial development of the quality-of-life tool, providing much-needed insights into the real-world experiences of animals affected by PPID. By participating in the survey, horse owners can actively contribute to improving the well-being and care of their beloved animals and those around the world facing the same condition.

 

Following the development of the validated equine quality of life tool, the RVC's research team plans to conduct a comprehensive study involving more than 100 horses recently diagnosed with PPID. This study will span over a two-year period, during which the impact of the disease and its treatment on the animals' quality of life will be closely observed.

 

Owners of the participating horses will be asked to complete a standardized online questionnaire every 3 months. This questionnaire will include the assessment of the animal's quality of life using the developed HRQoL (Health-Related Quality of Life) tool. Moreover, owners will be required to record details relating to the clinical signs associated with PPID and any other veterinary-related problems their horses may encounter during the study.

 

Owners of horses and ponies over ten years of age, both with and without PPID, are encouraged to participate in the study. The completion of the survey will take no more than 15 minutes, providing valuable data for evaluating the animal's quality of life, the presence and impact of PPID-related clinical signs, and any other associated veterinary issues.

 

By involving a substantial number of horses and closely monitoring them over a significant period, this study aims to shed light on how PPID affects equine quality of life and improve decision-making regarding treatment options and overall care for these animals.

 

Aline Bouquet, PhD Candidate and Research Assistant in the Assessment of Quality of Life in Equines with PPID, said: “Results from this project will better our understanding in how this disease and its treatment impact the quality of life of individual horses and ponies, which can hopefully then help vets and owners to assess and monitor the impact, guide management decision-making and thus improve the welfare of affected horses and ponies.”

 

Owners who wish to participate can sign up for the study at:

https://rvc.uk.com/PPID-survey-2023-stage1

 

More information about the study can be found at:

https://www.rvc.ac.uk/research/projects/objective-assessment-of-the-quality-of-life-of-equines-with-pituitary-pars-intermedia-dysfunction

Long-term treatment of PPID

Long-term use of pergolide to treat horses with pituitary pars intermedia dysfunction (PPID -or
Equine Cushing’s disease) produces clinical improvement in most cases, and improved endocrine test results in some, according to recent work.

Pergolide has become a popular treatment for PPID in horses.  Studies have found that it is generally effective in controlling the clinical signs of PPID and that it is well-tolerated by horses when used for up to a couple of years. However, research into its long-term use has been limited.  

 

A recent study, by Harold Schott and co-workers at Michigan State University, followed the outcome of longer-term treatment in PPID-affected equids from the time they first received pergolide for the rest of their lives. 

 

Dr Schott presented their findings at the 2022 American Association of Equine Practitioners (AAEP) Annual Convention held in San Antonio, Texas. 

Thirty privately owned equids (28 horses and 2 ponies) being treatmed with pergolide for PPID were enrolled in the study. Fifteen started on a dose of one pergolide tablet (1mg)  a day;  fifteen started on 2 tablets a day. The animals were treated for periods ranging up to twelve and a half years.

 

The research team monitored the response to treatment by contacting the owners every three months. They also examined the animals at various intervals until 12.5 years after treatment started.

 

Schott reported that, during the study period, five equids were euthanased for PPID- associated laminitis and 24 died or were euthanased for other age-related reasons. Survival time ranged from 0.6 to 12.5 years. The average (median) survival time was 3.3 years. One equid was still going strong at the end of the study.

 

Owners of 13 equids surviving after five and a half years reported continuing clinical improvement, such as healthier coat condition, better appetite and less frequent bouts of laminitis. At that stage, 75% of equids had normal endocrine test results.

 

Seven of the 15 equids that had started on the low dose of pergolide later had the dose increased to two tablets daily. 

 

Schott pointed out that, although some individuals eventually needed an increased dose, that was not always the case, and some continued to have a satisfactory response to a low dose of pergolide.

 

Generally, owners were satisfied with the response to long-term pergolide treatment. 

 

For more details, see:

 

Long-Term Response of Equids with Pituitary Pars Intermedia Dysfunction to Treatment with Pergolide 

Harold C. Schott II; Julie R. Strachota; Judith V. Marteniuk; and Kent R. Refsal.

Proceedings American Association of Equine Practitioners (2022) vol 68, p230

Funding available for PPID research

 Morris Animal Foundation is now accepting proposals for studies focused on all domesticated equid health topics, with a special interest in pituitary pars intermedia dysfunction (PPID also known as equine Cushing’s disease).

PPID is the most common endocrine disorder of older equids, affecting more than 20% of aged horses, ponies and donkeys. Applicants considering submitting a research proposal focused on this disease are directed to learn more about research questions of interest as identified during a PPID priority-setting partnership workshop.

 

Participants at the workshop reached a consensus on the top 10 questions of interest. These focused on long-term prognosis, diagnostic accuracy, efficacy of pergolide treatment, alternative treatment/management strategies and potential treatment options for poor responders to pergolide (see below.) 

 

A report* of the workshop is published in PLOS ONE. The quantity of questions generated indicates that there is still much to find out about the diagnosis, treatment and prognosis of PPID. 

 

All proposal topics should seek to advance the health and overall welfare of domesticated horses, ponies, mules, or donkeys. Applications are reviewed and rated based on impact and scientific rigor by the Foundation’s scientific advisory boards, made up of topic experts in the veterinary community.

 

Applications will be accepted until December 16, 2022. Interested researchers can find the proposal guidelines, proposal template, and other information at Morris Animal Foundation Apply for a Grant.

 

*For more details, see:

 

Equine pituitary pars intermedia dysfunction: Identifying research priorities for diagnosis, treatment and prognosis through a priority setting partnership. 

Tatum RC, McGowan CM, Dean RS, Ireland JL (2021) 

PLoS ONE 16(1): e0244784. 

https://doi.org/10.1371/journal.pone.0244784

Looking for adverse effects of pergolide

 

Pergolide is widely used in the treatment of PPID (Pituitary Pars Intermedia Dysfunction, or equine Cushing’s disease). The drug is also used in humans, where it has been associated with side effects, involving fibrotic lesions of the atrio-ventricular valves in the heart.

Heidrun Gehlen and colleagues in the Department of Veterinary Medicine, at the Free University of Berlin, conducted a study to see if pergolide causes similar problems in horses. 
 
Twenty-three horses of various breeds, aged between 19 and 30 years old, were included. All had been diagnosed previously with PPID, based on ACTH (adrenocorticotrophin hormone) concentration.
 
Twelve horses had been receiving pergolide for between 14 days and 6 years before the start of the study. These comprised the treatment group and continued to receive pergolide. Eleven other horses received no pergolide.
 
The researchers performed a complete echocardiographic exam on all horses, which showed that they were free of cardiovascular diseases, including the absence of valvular defects. 
 
Follow up examinations were performed on nine horses in the treatment group and five of the non-treatment group between 3 and 8 months later.
 
The researchers compared the findings in PPID horses being treated with pergolide with the untreated PPID horses.
 
They found that treatment with pergolide did not affect the ventricular function nor induce valvular disease. Measurements taken in the follow-up exam did not differ from those taken initially in both groups. None of the 12 pergolide-treated horses developed valvular regurgitation. 
 
The work is reported in the Journal of Veterinary Science. The authors conclude: “The main result of our small orientation study was that treatment with pergolide of a duration between 3 and 8 months in a horse population with confirmed PPID did not seem to affect the left ventricular function assessed by TDE and STE [tissue Doppler and two-dimensional speckle tracking echocardiography]. Furthermore, none of the horses developed valvular regurgitation in the observation period.”
 
They add that further studies are needed, with a larger population and longer follow-up period. 
 
For more details, see:
 
Preliminary study on the effects of pergolide on left ventricular function in the horses with pituitary pars intermedia dysfunction
Heidrun Gehlen,  Judith Fisch,  Roswitha Merle and Dagmar S. Trachsel
J Vet Sci. 2021 Sep;22(5):e64. 
https://doi.org/10.4142/jvs.2021.22.e64 

Chance to help Equine Cushing's research

 

Horse owners and carers can help research into the underlying causes of Pituitary Pars Intermedia Dysfunction (PPID) also known as Equine Cushing’s Disease, a condition common in older horses and ponies. Typical signs include a long curly hair coat and weight loss. The condition is associated with a range of problems the most serious of which is laminitis. 

Researchers at the University of Melbourne are conducting a survey of horse owners as part of a broader, major international project to improve the understanding and knowledge of the fundamental causes of the condition, in order to improve early diagnosis, treatment, husbandry and nutritional management.

 

The short online survey is designed to better understand how owners manage horses or ponies with PPID, and what the important factors are for them including: the ability to feed separately and cost of medications.

 

Lead researcher at the Melbourne Veterinary School, Dr Nicolas Galinelli said that it was important to gain a better understanding of current management practices when it comes to PPID. 

 

“We need to get a broader sense of what is working for horse owners so that we can improve health outcomes for these animals both in terms of the early recognition of PPID signs and in the way we determine the most appropriate treatment, management and nutrition.”

 

“PPID affects approximately 20 per cent of horses and is slightly more common in ponies. Sometimes it is treated with specific drugs that target the excessive production of hormones from the pituitary gland, whilst other owners may choose to only treat the clinical signs of the disease such as laminitis. Adapting the diet can also be helpful. We want to understand how owners make treatment decisions and which decisions are having the best outcomes,” Dr Galinelli said.

 

Veterinary pharmacology expert, Professor Simon Bailey added that the survey will ask owners about what factors are important for them in treating PPID, including the cost and side-effects of medications and the ability for horses to be fed separately. He said “We encourage owners to get in touch once our results have been finalised and published. We are keen to help share this information with the equine community and thank them for their support.” 

 

The research, supported by the Australian Research Council, is being undertaken by the Melbourne Veterinary School and Queensland University of Technology with industry partners including WALTHAM Petcare Science Institute (UK), Boehringer Ingelheim (Germany) and The Liphook Equine Hospital (UK).

 

The results from this anonymous survey will provide valuable information and contribute to improved targeted education of the horse owning public.

 

To complete the survey, go to:

 

https://melbourneuni.au1.qualtrics.com/jfe/form/SV_0GPNcsoVqyB6lo2

Online equine health talks

An online series of equine health seminars for Western Canada's horse community, is to be hosted by the Western College of Veterinary Medicine (WCVM)

Topics to be covered include Equine Asthma, foal care, cardiology, EMS and PPID and gastric ulcers. Talks take place on alternate Tuesday evenings starting February 23.

Although there is no charge, you need to register beforehand.

For more details, see:

https://wcvm.usask.ca/education/equine-seminars.php

Weight management key to laminitis control

Diet and management changes to thwart obesity are the best weapons in the battle to prevent laminitis according to veterinary experts at the 2019 British Equine Veterinary Association congress.

David Rendle, Equine Internal Medicine Specialist at Rainbow Equine Hospital explained that around 90% of laminitis cases have endocrinopathic laminitis, “which is the same as pasture associated laminitis.” This involves either equine metabolic syndrome (EMS) or pituitary pars intermedia dysfunction (PPID – Cushing’s disease). Although greater understanding of EMS and PPID has helped in preventing laminitis, there is still much that remains unknown.

Rendle pointed out that insulin dysregulation is often disregarded in the assessment of laminitis when PPID is suspected. He warned that if appropriate management changes are not implemented, the risk of laminitis may persist.

On the management of endocrinopathic laminitis he concluded that “central is clearly diet and management change, not pharmaceuticals.”

Andrew van Eps, from the University of Pennsylvania, reiterated that the key to prevention of endocrinopathic laminitis is early identification of horses at risk. “Management to reduce the laminitis risk in these cases can then include a combination of dietary control, pasture access management, weight loss and exercise which can dramatically reduce the risk of laminitis development or progression,” he said.

Nicky Jarvis, of Redwings Horse Sanctuary, explained the grave negative impact obesity has on horse health. “The horse isn’t just a little bit chunky it actually has ‘ill health’ because of that amount of fat,” she said.  

She went on to explain that if a horse has a body condition score of 5 out of 5, about 40% of its bodyweight is fat, equating to 240kg of fat for a 600kg horse. 

She explained her approach to weight loss, which aims at dropping 0.5 to 1% of the horse’s current bodyweight per week by feeding a daily ration (dry matter) equivalent to 1.5% of bodyweight. Appreciating that weight loss on the field can be difficult as intake can’t be quantified, she outlined practical management tactics such as strip grazing, grazing muzzles, track systems, shared grazing with sheep or pre-grazing with horses who are in healthy condition.

She emphasised the advantages of forage analysis to ensure hay is of a low water-soluble carbohydrate content (10 - 12%) and the benefits of soaking it.

For animals resistant to weight loss, despite a controlled diet, Jarvis

suggested the careful introduction of good quality barley straw as a partial forage alternative for horses with good teeth, at up to 40% of the ration.

She advised that, rather than resorting to crash diets, either in the summer, or once the horse has developed laminitis, it is better for the owners to appreciate that it is natural for horses to lose weight over winter. “And, if we can get them to keep those rugs off and persuade them not to go to their local shop and buy supplementary feeds and grains just because they feel cold, we wouldn’t have so many problems during the summer months.”

Should pergolide be given twice daily?

Pituitary Pars Intermedia Dysfunction (PPID or Cushings Disease) is one of the most common endocrine (hormonal) disorders of horses and ponies. Typically, older animals are affected. If left untreated, many cases develop laminitis.

Overactivity of the pars intermedia (middle lobe) of the pituitary gland results in increased adrenocorticotrophic hormone (ACTH) in the plasma. The baseline level of plasma ACTH is often used to diagnose PPID. This may not give a definitive result, and a dynamic “TRH stimulation test” may sometimes be used.

Pergolide is commonly used to treat horses and ponies with PPID. It is thought that PPID is due to degeneration of the nerves that inhibit activity of the pars intermedia of the pituitary. Pergolide may mimic or replace this lost inhibition and so reduce the ACTH production.

Pergolide is typically administered once daily in accordance with the product data sheet provided by the manufacturer.

Research carried out at Charles Sturt University, Wagga Wagga, New South Wales, Australia, and published recently in Domestic Animal Endocrinology, investigated the effect of oral pergolide in PPID-affected horses.

Six horses with PPID were included in the study. They received daily doses of pergolide (at 4µg/kg) once a day for the duration of the study, which lasted 18 days. Blood samples to monitor pergolide and ACTH were collected 0.5 hour before, and 2 and 12 hours after pergolide administration.

The research team found that oral pergolide had a rapid effect on plasma ACTH concentration, producing significant suppression of pars intermedia activity within hours. The plasma ACTH concentration reduced significantly within 12 hours of administration. Further reductions occurred up to 10 days after treatment started.

Fluctuations in the pergolide levels suggested that the drug was rapidly removed from the blood, with an elimination half-life of less than 12 hours. This could account for similar fluctuations in ACTH concentration.

The authors of the report suggest that to, reduce the fluctuation of ACTH levels, twice-daily dosing of pergolide may be more appropriate.

For more details, see:

Pharmacokinetics and pharmacodynamics of pergolide mesylate after oral administration in horses with pituitary pars intermedia dysfunction.

Rendle DI, Doran G, Ireland J, Edwards S.

Domest Anim Endocrinol. (2019) 68; p135-141.

https://dx.doi.org/ 10.1016/j.domaniend.2019.01.008