Cushing’s Disease
Article by Caro Dach, an equine management student from Germany.
To find more such articles and join the network of equine students worldwide go to www.equineinvestigator.com

Have you ever noticed horses with extremely bulky and curly hairs, an abnormal fat distribution and a visible muscle reduction mainly in the back and in the hindquarters?

Mostly older horses show these signs which could be an indicator for the pituitary pars intermedia dysfunction (PPID) commonly known as Equine Cushing Disease.

In 1998, Fey et al. found that in the majority of cases, PPID is caused by dramatically increased hormone production in cells of the pars intermedia of the pituitary which mainly affects horses from 18 to 23 years in age. The increased hormone production leads to hyperplasia (proliferation of cells within an organ or tissue) which in turn can lead to adenoma formation (McGowan 2005). All equine breeds and types can be affected by PPID, but according to Schott (2006), a higher risk exists for ponies and Morgan horses. Also McGowan (2005) says that a higher risk is reported for ponies. However, no reliable research exists at present which would actually prove an increased risk for ponies and Morgan horses to be affected by PPID.

In 1999, Messner published some guidelines about how to diagnose PPID. Diagnosis should be based on clinical signs and dynamic endocrinological testing. The main clinical sign is hirsutism (extremely long hair coat which is not shed) among others like lethargy and decreased performance, dental abnormalities, deposition of fat (along the neck, over the tail head, above or behind the eyes (Pic.2)), infertility, loss of muscles in the back and in the hindquarters and chronic laminitis and infections (McGowan 2005; Schott 2006). According to Messner (1999), females are more affected by hirsutism; but again no research is done yet to back this thesis up.

In addition to apparent clinical signs, endocrinological tests are performed to identify PPID. Most common nowadays are DST (Dexamethasone Suppression Test) and TRH (Thyrotropin Releasing Hormone Stimulation Test). Messner (1999) describes the procedure of DST as follows: the test should begin between 4 p.m. and 6 p.m. A baseline sample is taken and afterwards 2 mg dexamethasone per 100 lb is given. 19 hours after the dexamethasone administration another sample is taken. Non-affected horses will have a cortisol level less than 1 µg/dl; affected horses will have a cortisol level higher than 1 µg/dl.

However, opinions about this test seem to vary. Schott (2006) points out that some equine veterinarians see DST as the “gold standard” to diagnose PPID. But according to Schott (2006), one main concern is that this test maybe worsens existing laminitis or can lead to it. But so far, long-time studies are still missing evaluating if a DST really enhances laminitis.

The TRH was especially used in the UK because it was suggested that TRH should be safer than DST regarding laminitis (McGowan 2005). For TRH, 1 mg Thyrotropin Releasing Hormone (0.5 mg TRH/pony) is administered and plasma cortisol levels are measured before and 15 to 60 minutes after giving TRH. The experience of McGowan (2005) shows that TRH is not highly reliable because interpretation of the measured percentage increase in cortisol concentrations is difficult. In support of this argument, Schott (2006) puts forward a similar opinion because again, interpretation of test results is difficult due to variation in baseline cortisol concentration.

To circumvent the problem of variation in baseline cortisol levels, the University of Tennessee developed a combination of both, DST and TRH (Schott 2006). The idea is to administer dexamethasone 3 hours before TRH to reduce cortisol concentration to similar baseline values in both, PPID affected horses and non-affected ones (Schott 2006). An actual report showed according to Schott (2006) that the combined test was more precisely (81 %) than the individual test elements (both, DST & TRH à 71 %). But on the other hand, Schott (2006) points out that the accuracy of all endocrinological tests was less than hirsutism alone (86 %). Therefore, space for improvement of endocrinological tests results is left in any case.

Nevertheless, concerned horse owners want the best medical treatment for their affected horses. As a result of improved health care offered even to older horses, the recognition of PPID increased in the last 10 years (Schott 2006).

Based on the Annual Meeting of the American Association of Equine Practitioners in 1995, the Michigan State University started a large project – the Michigan Cushing’s Project – in 1997 for duration of 2 years. They wanted to find out if there are any differences in clinical and endocrine responses in horses with PPID when treated with cyproheptadine or pergolide (2 most used drugs in the US at that time) or with nothing. Further, they were interested in how measurements of plasma cortisol levels or serum insulin concentration compare with DST or TRH test results and which tests are most suitable for monitoring response to treatment (Schott et al. 2001).

According to Schott et al. (2001), 147 horses were tested of PPID for the study by analyzing clinical signs and either, DST or TRH test results. Results showed that 77 horses were affected by it. The horses were between 12 and 34 years old and of all kind of breeds. Forty-eight percent were mares, 49 % geldings and 3 % stallions. Changes in clinical signs and endocrine test results were compared at the start and after 6 to 12 months with cyproheptadine, with pergolide and without treatment. Moreover, the accuracy of diagnostic tests (plasma cortisol or serum insulin concentration) was compared to the dynamic tests results (DST and TRH).

For 36 % of the 77 horses, non-supportive plasma cortisol levels were measured and for 29 % of the 77 horses, non-supportive serum insulin concentration was measured. Improvement in clinical signs was most appealing with pergolide, a few horses responded also on cyproheptadine and none showed improvement without treatment. Furthermore, more horses showed normal DST and TRH results after treatment with pergolide in comparison to treatment with cyproheptadine or without any treatment. Plasma cortisol and serum insulin concentration decreased to normal after 6 to 12 months after treatment with pergolide, whereas no significant changes were obtained with cyproheptadine or without treatment.

Corresponding to the ‘Michigan study’, pergolide offers the best results in treating PPID horses. Differences between the test results of cyproheptadine and no treatment at all were significantly low; therefore cyproheptadine does not seem to be beneficial for treating PPID horses. Measurements of plasma cortisol levels and serum insulin levels led to both, false positive and false negative results in comparison to DST and TRH tests. Thus, Schott et al. (2001) do not recommend using these tests to determine PPID in horses.

Having the benefits of pergolide in mind, its interesting that in 2002 Beech et al. conducted a study testing the effect of Vitex agnus castus Extract (chaste tree) in comparison to pergolide. In the past, Vitex agnus castus Extract (commercially available form of Vitex agnus castus) was used to treat female cycle disorders and some effect on PPID was somehow presupposed. However, Beech et al. (2002) found out that it had no beneficial effect on PPID, in contrast sometimes clinical signs even worsened and DST results remained abnormal in the tested horses. Except for one horse, pergolide improved the situation of every horse.

Hence, Beech et al. (2001) recommend further studies on pure Vitex agnus castus extracts on pituitary cells to demonstrate if hormone secretion is affected. Until then, they do not recommend it for treatment of PPID in horses. However, it has to be said that they conducted their research only with 14 horses which is in comparison to other studies a relatively low sample size.

Thus, pergolide is still the main drug to treat PPID in horses. Interestingly, a huge discussion is meanwhile going on in the US because pergolide is withdrawn from the US market for human use. Ryder (2007) reports for The Horse magazine that pergolide is used in humans to treat the Parkinson’s disease, but reportedly it could damage the human heart valves which led to the withdrawal of the pergolide products Permax (Valeant Pharmaceuticals) and two generic formulas (Par and Teva). Pergolide is not approved for veterinary use; therefore all PPID horses treated with pergolide are affected by the withdrawal. Right now, there is no legal way for wholesalers to bring pergolide into the country because compounding from bulk drug is forbidden by the FDA (Food and Drug Administration). To solve the problem, the FDA must allow the use of pergolide for veterinary use and the use of bulk drugs in veterinary compounding by giving an exception. At the moment, veterinarians guess that approximately 60.000 horses will be affected by the withdrawal. Finally, on May, 11 the FDA allowed bulk pergolide to be used in compounding pergolide for use in horses. Six weeks fighting for availability lay back, but were successful in the end.

Looking back on the studies done, pergolide is definitely the most successful drug for treating horses affected by PPID. But still, further research is needed to be able to improve endocrinological tests and to confirm assumptions like if a DST test really enhances laminitis in PPID horses and if ponies and Morgan horses are more affected by PPID than others, for instance.

This article was written by Caro Dach, an “Equine Management”- student from Germany.
To find more such articles and join the network of equine students worldwide go to www.equineinvestigator.com

References

Beech, J, Donaldson, MT & Lindborg, S 2002, ‘Comparison of Vitex agnus castus Extract and Pergolide in Treatment of Equine Cushing’s Syndrome’, AAEP (American Association of Equine Practitioners) Proceedings, Vol. 48, Retrieved from International Veterinary Information Service (www.ivis.org)

McGowan, CM 2005, ‘Diagnosis and treatment of equine cushings syndrome’, Clinical Review, Retrieved from The Veterinarian (www.theveterinarian.com.au), Issue Feb 2005

DIAVET 2005, ‘Das Equine Cushing Syndrom’, aktualisierte Ausgabe 7/2005, Retrieved from DIAVET Laboratorien (www.diavet.ch)

Fey, K, Jonigkeit, E, Moritz, A 1998, ’Equine Cushing syndrome (ECS). Case report, review of its diagnosis and therapy and substantial differences from Cushing syndrome in dogs’, Tierarztl Prax Ausg G Grosstiere Nutztiere, 1998 Feb;26 (1):41-7

Messer, NT 1999, ‘How to Diagnose Equine Pituitary Pars Intermedia Dysfuntion’, AAEP (American Association of Equine Practitioners) Proceedings, Vol. 45, Retrieved from International Veterinary Information Service (www.ivis.org)

Ryder, E 2007, ‘Equine Cushing’s Drug Pergolide to be Withdrawn for Human Use’, Retrieved from The Horse magazine (www.thehorse.com), Article # 9317, April 04 2007

Ryder, E 2007, ‘Pergolide: Veterinarians, Horse Owners Fighting for Availability’, Retrieved from The Horse magazine (www.thehorse.com), Article # 9405, April 17 2007

Ryder, E 2007, ‘Pergolide Availability: No FDA Announcement, Supplies Running Low’, Retrieved from The Horse magazine (www.thehorse.com), Article # 9526, May 04 2007

Ryder, E 2007, ‘Pergolide: FDA to Allow Compounding from Bulk’, Retrieved from The Horse magazine (www.thehorse.com), Article # 9573, May 11 2007

Schott et al. 2001, ’The Michigan Cushings’s Project’, AAEP (American Association of Equine Practitioners) Proceedings, Vol. 47, Retrieved from International Veterinary Information Service (www.ivis.org)

Schott, HC 2006, ‘Pituitary Pars Intermedia Dysfunction: Challenges of Diagnosis and Treatment’, AAEP (American Association of Equine Practitioners) Proceedings, Vol. 52, Retrieved from International Veterinary Information Service (www.ivis.org)