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Use of the chasteberry preparation Corticosal® for the treatment of pituitary pars intermedia dysfunction in horses

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The objective of this study was to describe the efficacy of PPID treatment with the combined supplement corticosal® containing chasteberry. Thirty-eight horses and ponies with PPID were devided into three groups and received either the chasteberry preparation (group Tl) or pergolide in addition to the chasteberry preparation (group T2) for six months or pergolide in addition to a placebo for the first three months and pergolide in addition to the chasteberry preparation for the following three months (group T3). Clinical and laboratory examinations were performed at three times points. Within group Tl, a significant difference in clinical parameters between the first and second examination (p = 0.0042) as well as between the second and third examinations (p = 0.0001) was observed. The clinical signs improved significantly based on the clinical overall score. On the basis of the collected data, beneficial effects of the chasteberry preparation corticosal® on clinical parameters for PPID were determined.
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Pferdeheilkunde 29 721
Pferdeheilkunde 29 (2013) 6 (November/Dezember) 721-728
Use of the chasteberry preparation Corticosal®
for the treatment of pituitary pars intermedia dysfunction
in horses
Zrinjka Bradaric1, Anna May2and Heidrun Gehlen1
Clinic for Horses, Free University of Berlin1and Equine Clinic, Ludwig-Maximilian-University of Munich2, Germany
Summary
The objective of this study was to describe the efficacy of PPID treatment with the combined supplement corticosal®containing chasteberry.
Thirty-eight horses and ponies with PPID were devided into three groups and received either the chasteberry preparation (group T1) or per-
golide in addition to the chasteberry preparation (group T2) for six months or pergolide in addition to a placebo for the first three months
and pergolide in addition to the chasteberry preparation for the following three months (group T3). Clinical and laboratory examinations
were performed at three times points. Within group T1, a significant difference in clinical parameters between the first and second exami-
nation (p = 0.0042) as well as between the second and third examinations (p= 0.0001) was observed. The clinical signs improved signi-
ficantly based on the clinical overall score. On the basis of the collected data, beneficial effects of the chasteberry preparation corticosal®
on clinical parameters for PPID were determined.
Keywords: Cushing’s syndrom / horses / pituitary / epidemiology / Vitex agnus-castus / PPID
Der Einsatz des Mönchspfeffer-Präparats Corticosal®zur Behandlung des Equinen Cushing Syndroms (PPID)
Ziel dieser Studie war die Überprüfung der Wirksamkeit des mönchspfefferhaltigen Kombinationspräparats Corticosal®zur Behandlung des
Equinen Cushing Syndroms (PPID). 38 an PPID erkrankte Pferde und Ponys wurden in drei Versuchsgruppen eingeteilt und erhielten über
einen Zeitraum von sechs Monaten entweder das Kombinationspräparat (Gruppe T1) oder Pergolid zusammen mit dem Kombinationsprä-
parat (Gruppe T2) oder die ersten drei Monate Pergolid und ein Placebo und die weiteren drei Monate Pergolid und das Kombinations-
präparat (Gruppe T3). An drei Untersuchungszeitpunkten wurden die klinische Symptomatik und verschiedene Blutparameter anhand eines
festgelegten Score Systems ermittelt. In Gruppe T1 konnten sowohl zwischen den ersten und zweiten Untersuchungszeitpunkten
(p = 0,0042) als auch zwischen den zweiten und dritten Untersuchungszeitpunkten (p = 0,001) signifikante Unterschiede der klinischen
Parameter festgestellt werden. Die klinischen Symptome verbesserten sich signifikant gemessen am klinischen Gesamtscore. Anhand der
erhobenen Daten konnte ein positiver Effekt des mönchspfefferhaltigen Präparates Corticosal®auf die klinische Symptomatik von den am
Cushing Syndrom erkrankten Pferden festgestellt werden.
Schlüsselwörter: Cushing Syndrom / Pferde / Hypophyse / Epidemiologie / Vitex agnus-castus / PPID
Z. Bradaric et al.
Introduction
Pituitary Pars Intermedia Dysfunction (PPID) is a progressive
neurodegenerative disease found in aged horses and ponies
(
McFarlane
2011). Even though the cause of PPID remains
unclear, oxidative stress damaging neurons is suggested as
initial event (
Donaldson
et al. 2005). Neuronal impairment
leads to loss of dopaminergic inhibition of the pituitary pars
intermedia, resulting in melanocytic proliferation and increa-
sed production of pro-opiomelanocortin (POMC) and POMC
derivatives like adrenocorticotropic hormone (ACTH), mela-
nocyte stimulating hormone and beta-endorphin (
Donaldson
et al. 2005,
Goudreau
et al. 1992). The most commonly
used treatment is pergolide-mesilate, an ergot-alkaloid deri-
vative, which acts as D2-receptor agonist on the pituitary
gland and decreases POMC production. The efficacy of per-
golide has been proven in different studies that take the
improvement of clinical symptoms and laboratory parameters
into account (
Coursen
et al. 2001,
Beech
et al. 2002,
Divers
et al. 2002,
Corazza
et al. 2004).
It is hypothesized that Vitex agnus-castus (chasteberry) – a
medicinal plant with dopaminergic action shows effective-
ness in the treatment of PPID by increasing dopaminergic acti-
vity in the equine pituitary. Chasteberry is a phytotherapeutic
traditionally recommended for hyperprolactinemia and pre-
menstrual syndrome in women (
Schellenberg
2001). Meier et
al. (
Berger
et al. 2000) identified diterpenes as the active sub-
stances in Vitex agnus-castus (VAC) extracts that bind to D2
and D3 pituitary receptors. The VAC extract therefore is a com-
bined D2/D3 dopamine receptor agonist. In a study perfor-
med on rats, the binding of the VAC extracts to D2 receptors
resulted in decreased prolactin secretion (
Gorkow
et al.
1994). As PPID in horses is also a D2 receptor-mediated dise-
ase, chasteberry has been evaluated as a single therapeutic.
However, compared to pergolide treatment, no improvement
of ACTH concentrations, the dexamethasone suppression test
or clinical symptoms was shown (
Beech
et al. 2002).
In Germany, a combined feed additive containing chasteberry
(Corticosal®) was specially developed for horses with PPID.
The aim of this study was to evaluate the efficacy of this spe-
cial Vitex agnus-castus preparation in the treatment of PPID
based on clinical signs and plasma ACTH, insulin and gluco-
se concentrations before, during and after administration.
Materials and Methods
Horses
Thirty-eight horses and ponies with PPID were included in this
study. The inclusion criteria were an ACTH plasma concentra-
tion >50 pg/ml and a clinical score above five. All horses
were privately owned and lived under different housing con-
ditions. In the course of the study, neither the stable environ-
ment nor the feeding regimen changed.
Group assignment
Groups were defined according to their pre-treatment. Untre-
ated horses and ponies were assigned to group T1. This was
the largest group (25 horses) and it was established to deter-
mine the efficacy of the chasteberry preparation in untreated
animals. Thirteen horses which had received pre-treatment
with pergolide were randomly divided into control groups T2
(6 horses) or T3 (7 horses). For pre-treated horses, the inclu-
sion criteria were pergolide treatment for at least three
months and no dosage changes throughout the six- month
duration of the study. For animal welfare reasons, there was
no group without any treatment.
Study period
The study period was six months, between January and
August 2011. The parameters for each horse had to be docu-
Use of the chasteberry preparation corticosal®for the treatment of pituitary pars intermedia dysfunction in horses
Pferdeheilkunde 29
722
mented for at least six months. A second examination was
performed three months after the initial examination and a
final examination took place after six months.
Treatment group definition
During the study period, the horses in group T1 received the
chasteberry preparation1only, whereas the horses in group
T2 received the chasteberry preparation and pergolide2. Hor-
ses in group T3 received pergolide for six months with the
addition of a placebo for the first three months and then swit-
ched to pergolide in addition to the chasteberry preparation
for the following three months (Table 1). Neither the owners
nor the investigator knew whether the animals received the
placebo or the active treatment. The chasteberry formulation
was administered according to the manufacturer’s instruc-
tions (0.05 g/kg PO/q24h) mixed with feed. Besides chaste-
berry, it contains phytotherapeutics like ginseng and articho-
ke, special nutrients and antioxidants. The pergolide dosage
was adjusted by the veterinarian in the field and ranged from
2 to 3g/kg PO/q24h.
Clinical examination
The same investigator performed a standardized clinical exa-
mination for PPID at different times using a composite scoring
system (Table 2) to assess clinical parameters. To avoid addi-
tional stress for the animals all examinations were performed
at the stables the horses were housed. At each examination
time, the following parameters were investigated: hypertri-
chosis, hyperhidrosis (excessive sweating), swayed back, pen-
dulant abdomen, skeletal muscle atrophy, behavior and
abnormal fat distribution. The symptoms were rated using a
score from 0 (non-existent) to 3 (severe). Furthermore, polyu-
ria and polydipsia, reported by the owners, were evaluated
Table 2 Scoring system of the typical clinical parameters of PPID (score grade 0-3)
/ Score-System der typischen klinischen Symptome von PPID
Score
0
1
2
3
hirsutism
none
hair coat long, at least visible in parts
of the body, eg. legs and lower jaw
hair coat generalized long, partly
curly
hair coat generalized
long, curly
hyperhidrosis
none
occasional localized sweating or
extensive sweating after exercise
occasional to frequent sweating
on at least two parts of the body
generalized severe
hyperhidrosis
sway back
none
minor
moderate
severe
pendulous abdomen
none
minor
moderate
severe
muscle atrophy
none
in one region of the body
in two regions of the body
generalized
behaviour
alert,
unremarkable
mildly depressed
lethargic
apathic
abnormal fat distribution
none
one body part (eg. neck, supraorbitally
or croup)
two body parts
at least three body
parts
polydypsia
no
yes
polyuria
no
yes
Table 1 Group assignment (T1-T3) and different treatment regimen /
Gruppeneinteilung (T1-T3) und unterschiedliche Behandlungsmethoden
Horses
Treatment
n=25
Chasteberry preparation (six months)
n=6
Pergolide + Chasteberry preparation (six months)
n=7
Pergolide +1.) Placebo (1st three months) 2.) Chasteberry preparation (2 nd three months)
and rated (a score of 0 if non-existent and of 1 if existent).
The evaluation of polyuria and polydipsia was performed by
the animal owner and therefore a subjective assessment
based on the state of the litter and water intake in case of
housings where watering was performed manually in drinking
troughs. Standardization of measuring polyuria and polydip-
sia was not possible due to the different housing and
management of the horses. At each examination time, an
overall score for clinical presentation was established for
each patient.
Blood examinations
At each examination time, blood samples were collected from
the horses to evaluate the efficacy of treatment. Among other
parameters, plasma ACTH as well as insulin and glucose
levels were determined after a fasting period of 12 hours. For
evaluating plasma ACTH, 4 ml venous blood was sampled
into EDTA vacutainers (Vacuette®K3, Greiner, Germany).
Samples were centrifuged immediately at 3000rpm for
15minutes to obtain EDTA plasma, which was filled into a
labelled Eppendorf vacutainer and immediately refrigerated
at +4° to +8°C until shipment on the same day. All samples
were sent to the laboratory in a cooled container and analy-
zed the following day. ACTH levels were measured using che-
miluminescence immunoassay (CLIA; Immulite 2000 XPi3,
Laboklin, Germany). A validated chemiluminescence immu-
noassay was used for determining insulin levels (Centaur XP,
Testkit IRI4, Laboklin, Germany). For evaluation of insulin,
4ml venous blood was sampled into a serum separator tube
(Vacuette®Z, Greiner, Germany) and for the evaluation of
glucose, 2 ml venous blood was sampled into a tube contai-
ning potassium oxalate and sodium fluoride (Vacuette®FX,
Greiner, Germany). All samples were sent to the laboratory
(Laboklin, Germany) and analysed by validated assays.
Statistical analysis
Analyses were carried out using the statistical software Easy-
Stat 4.4. Parameters were indicated as arithmetic mean, stan-
dard deviation and median. Correlations were made using
the same program. Statistical analysis of ACTH values bet-
ween the groups was performed by the non-parametric Kru-
skal-Wallis test and by the Wilcoxon test and by means of the
statistical software SAS®9.25. Comparison of values within
the groups was performed using univariate analysis and Stu-
dent’s t-test. Clinical scores were also analyzed with the Kru-
skal-Wallis and Wilcoxon tests. Differences were considered
statistically significant at p < 0.05. Inclusion criteria for stati-
stical analysis were at least values of two different examina-
tions per patient.
Results
Study population
The study group comprised 17 ponies, 16 warmbloods, four
thoroughbreds and one draft horse. The median age was 24
years (range, 16–38 years), 61 % of the animals were 16 to
25 years old, 66 % of the horses were kept in stables and
Z. Bradaric et al.
Pferdeheilkunde 29 723
34% on pasture. There were 22 mares (57.9 %) and 16 gel-
dings (42.1 %).
Twelve horses did not finish the full study period, eight of them
dropping out before the second examination and four before
the third. Nine of the drop-outs belonged to group T1, two to
group T2 and one to group T3. The reasons for the loss of
these twelve animals were euthanasia in eight cases (colic (2),
heart failure (2), tendon rupture, fracture, laminitis and sep-
sis) and at the request of owners (start of pergolide treatment
(2), stop of pergolide treatment and no reason given).
Clinical symptoms
Within group T1, a significant difference concerning the clini-
cal score between the first and second examinations
(p=0.0042) as well as between the second and third exami-
nations (p = 0.0001) was observed. At the third examination
time, there was no difference in clinical score between the
groups (Fig 1).
Improvement of clinical symptoms was evident to the exami-
ner at the different examination times. Especially remarkable
changes were the normalization of hair coat (Figs. 2a, b) and
behavioral changes. Owners described their horses and
ponies as more lively and alert; these behavioral changes
were also observed by the veterinarian during the examina-
tions. Hypertrichosis improved in all groups. At the beginning
of the study, all horses showed a minimum score of one or
two. The mean score for T1 and T2 was 2.4 and for T3 1.8.
There was no statistical significant difference between groups
at any time. When the third examination was performed, a
significant statistical difference was observed from that of the
first examination within each group (Fig. 3). The mean score
for T1 was 0.7, for T2 0.3 and for T3 0.8. Hyperhidrosis was
determined in 47.4 % of horses at the first examination but
was not correlated with hypertrichosis. Polydipsia and polyu-
ria were present in 33 % of the horses at the first examination
Fig. 1 Clinical overall score at first (day 1), second (after three
months) and third (after six months) examination in the different tre-
atment groups T1-T3. The difference between the first and third exa-
mination in group T1 and T2 tends to be significant (p =0.0719).
Klinischer Gesamt-Score im Rahmen der ersten (Startzeitpunkt), zwei-
ten (nach drei Monaten) und dritten (nach sechs Monaten) Untersu-
chung in den verschiedenen Behandlungsgruppen T1-T3. Der Unter-
schied zwischen der ersten und dritten Untersuchung in den Gruppen
T1 und T2 ist tendenziell signifikant (p =0.0719).
and improved to 13%. In group T1, they decreased to 7%, in
group T2 to 25% and in group T3 to 20%.
Plasma ACTH
In treatment groups T1 and T2, ACTH levels decreased slight-
ly between the first and second examinations, but increased
to above initial levels at the third examination (Fig. 4). In
Use of the chasteberry preparation corticosal®for the treatment of pituitary pars intermedia dysfunction in horses
Pferdeheilkunde 29
724
group T3, ACTH values increased slightly at the second exa-
mination and showed a slight decrease towards the third exa-
mination. The difference between treatment groups T1 and
T3 at the third examination was statistically significant
(p=0.0407). The increase within treatment group T1 was
statistically significant (p=0.0054), while the increase within
group T2 was shown not to be statistically significant
(p=0.0625).
Glucose and insulin metabolism
At each of the three examination time points, fasting levels of
insulin and glucose were measured. Based upon the referen-
ce range of the laboratory, seven horses (18.4 %) showed
hyperglycemia and three horses (7.9 %) hyperinsulinemia,
while five animals (13.2 %) had hyperglycemia combined with
hyperinsulinemia.
To sum up, 15 of 38 horses (39.5 %) suffering from PPID had
an altered glucose and insulin metabolism. Forty percent of
Fig. 3 Scores (0–3) for hypertrichosis in the different groups
(T1–T3), at first, second and third examination (p<0.05=statistical-
ly significant), T1 p =0.04, T2 p =0.001, T3 p =0.007
Auswertungen (0–3) zur Hypertrichose in den einzelnen Behand-
lungsgruppen (T1–T3) bei der ersten, zweiten und dritten Untersu-
chung (p<0.05 = statistisch verbessert), T1 p = 0.04, T2 p= 0.001,
T3 p = 0.007.
Figs. 2a and b 23-year-old Haflinger mare of group 1, at initial
examination in January 2011 (a) and at 3rd examination in July
2011 (b), showing a distinct improvement in clinical signs.
Eine 23-jährige Haflingerstute aus der Gruppe T1 zeigt eine deutliche
Verbesserung der klinischen Symptome bei der ersten Untersuchung im
Januar 2011 (a) und bei der dritten Untersuchung im Juli 2011 (b).
Fig. 5 Logarithmic delineation of insulin values at first, second
and third examination in the different groups T1–T3. * p<0.05.
Logarithmische Beschreibung der Insulinwerte der ersten, zweiten
und dritten Untersuchung in den unterschiedlichen Untersuchungs-
gruppen T1–T3. * p<0.05
Fig. 4 Endogenous ACTH levels in the course of the study, mea-
sured at the first, second and third examination in the different
groups T1–T3. The difference between T1 and T3 at the 3rd exami-
nation was determined to be statistically significant (p=0.0407).
ACTH-Werte im Verlauf der Studie, gemessen zum ersten, zweiten
und dritten Untersuchungszeitpunkt in den Behandlungsgruppen
T1T3. Der zwischen T1 und T3 im Rahmen der dritten Untersu-
chung ermittelte Unterschied war statistisch signifikant (p =0.0407).
a
b
Use of the chasteberry preparation corticosal®for the treatment of pituitary pars intermedia dysfunction in horses
Pferdeheilkunde 29
726
these horses were treated with pergolide. In the course of the
study, no improvement in glucose and insulin metabolism was
observed. Regarding insulin values, a significant difference
between T1 and T3 as well as between T2 and T3 was evident
at the second examination time. Insulin values in treatment
group T3 were considerably higher compared to the other
treatment groups (Fig. 5). Glucose levels showed no differen-
ce between the different treatment groups at any time during
the study period. ACTH levels did not correlate with insulin
and glucose values. Insulin and glucose levels showed a wide
variance in horses with similar ACTH values.
Laminitis
Twenty-four horses (63.2%) of the study group had had lam-
initis before. At the beginning of the study no horse or pony
showed laminitis. In the course of the study, two ponies deve-
loped acute laminitis following the second examination. One
horse belonged to group T1 and one horse to group T2. Both
ponies had been out on pasture before development of acute
laminitis and showed increased insulin and glucose levels at
the second examination.
Discussion
Regarding the study population, the ratio of warmbloods to
ponies was quite balanced. According to other studies, there
was no breed predilection for PPID (
McFarlane
2011,
McGo-
wan
2008,
McGowan
2008). The average age was 24 years.
An average age of 20 years was described in a study by
Breu-
kink
et al. (1995). PPID can also be recognized in younger
horses, as previous studies have shown (
Baumgartner
et al.
1990,
Brüns
2001,
Sommer
2003). There was no relations-
hip between age or breed and the treatment received. The
proportion of mares (58%) was higher than that of male hor-
ses (42%) but no statistically significant sex difference was
determined. Other studies did not show any sex predilection
for developing PPID either (
Breukink
et al. 1993,
Couëtil
et
al. 1996,
Schott
2002).
This study had no control group without any treatment for ani-
mal welfare reasons, as PPID is a severe disease leading to
an impaired quality of life for the affected horses. The disease
takes a progressive course and improvement of symptoms
cannot be expected without therapy (
McFarlane
2011,
Breu-
kink
et al. 1995,
Schott
2002).
Concerning clinical signs, a significant improvement was
observed within treatment group T1. These horses, which had
not received any treatment before, responded well to the cha-
steberry preparation. At the third examination after six
months, almost no difference was observed between group
T1 and the control groups T2 and T3 which had been treated
with pergolide. Based on the overall clinical score it can be
concluded that clinical symptoms improved significantly
based on the overall clinical scores. Treatment with the cha-
steberry preparation resulted in a significant clinical improve-
ment in the previously untreated animals. Compared to
group T1, the influence of the chasteberry preparation on
horses receiving constant pergolide medication was much
lower. This can be explained by the proven efficacy of pergo-
lide treatment in PPID horses (
Beech
et al. 2002,
Divers
2008), indicating that the dosage was appropriate for them.
Between the first and second examinations, all three groups
showed a distinct reduction in the overall clinical score, a fact
partly based upon the seasonal shedding of the hair coat.
However, owners reported delayed or no shedding of hair
coat in the years before. Even horses which had received per-
golide before showed a great improvement in hypertrichosis
when they were fed the chasteberry preparation compared to
previous years. To conclude, the chasteberry preparation see-
med to have a great influence on the parmeter hypertrichosis
and shedding of the hair coat. Furthermore, behavioral chan-
ges were observed. The patients became more alert throug-
hout the study and owners reported positive mental develop-
ment. This was not only based on subjective statements by the
owners but was also noticed by the investigator.
Acute laminitis occurred once in group T1 and once in group
T2. Both horses had already experienced laminitic episodes
before and acute laminitis occurred shortly after the second
examination, after they had been taken out to pasture. This
shows the inability of the chasteberry preparation to prevent
laminitis either alone or in combination with pergolide treat-
ment in patients with a preexistent condition when they have
access to pasture.
To date, only one study has evaluated the potency of a chaste-
berry preparation in horses with PPID. Beech et al. (
Beech
et al.
2002) observed no positive effect of Vitex agnus-castus on cli-
nical symptoms, some horses even showed deterioration of
PPID symptoms. The study used Vitex agnus-castus extract
without further information regarding its concentration or other
ingredients. On the other hand, the chasteberry preparation
used in this study is specially developed for horses with PPID
and contains not only chasteberry but other useful phytothera-
peutics and nutrients. The chasteberry showed dopamine-ago-
nistic properties and in combination with the other ingredients
it could be responsible for improving the other parameters like
shedding of hair coat or improvement of behavior.
ACTH plasma levels decreased between the first and second
examination in treatment groups T1 and T2, but they increa-
sed in group T3. These variations might be explained by the
influence of the chasteberry preparation, although the diffe-
rences were not statistically significant.
Between the second and third examinations, plasma ACTH
levels increased markedly in treatment groups T1 and T2.
This increase was statistically significant within group T1 bet-
ween the first and third examination. Furthermore, the diffe-
rence between treatment group T1 and T3 at the third exami-
nation was statistically significant. Although clinical symptoms
improved, the ACTH levels increased in group T1 and in
group T2. This is contrary to a study of Donaldson et al.
(2002), in which ACTH values normalized in 60% of the hor-
ses under pergolide.
As the increase occurred in the pergolide-treated group as
well, other factors must also be present to influence ACTH
values. If the ACTH increase was only due to the inefficacy of
the chasteberry preparation, no increase would be measura-
ble in the pergolide-treated group. Different studies showed a
Z. Bradaric et al.
Pferdeheilkunde 29 727
seasonal influence on ACTH levels. Plasma ACTH levels are
higher in early fall (August to October) due to a reduction of
daylight and decline in winter, reaching their lowest levels in
January (
Beech
et al. 2009,
Copas
et al. 2012,
Elliott
2010).
In a recent study performed by
Funk
et al. (2011), a stronger
reaction of ACTH levels after TRH stimulation in July than in
February was seen.
In the present study, the characteristic clinical symptoms and
ACTH values did not correlate. While clinical symptoms
improved with therapy, ACTH values increased. Until now,
determination of ACTH values has been regarded as the
parameter of choice to evaluate efficacy of treatment and to
change the dosage if needed.
As clinical symptoms improved considerably during the cour-
se of the study, adjustment of dosage was not necessary.
However, the question arises whether monitoring of ACTH
values is essential for adjustment of dosage or whether chan-
ges in dosage should be rather be based upon development
of clinical symptoms.
On initial examination 39.5% of horses and ponies showed
alterations in their insulin and glucose metabolism. In the lite-
rature up to 60 % of the patients suffering from PPID show
elevated serum insulin concentrations (
McFarlane
2011).
40% of the horses in the current study with alterations in insu-
lin and glucose metabolism were treated with pergolide. The
results suggest that pergolide treatment does not necessarily
lead to the regulation of insulin and glucose metabolism.
In the course of the study, the ratio of horses with altered glu-
cose and insulin metabolism did not improve. A possible cau-
se could be variations in access to pasture. In January and
February, at the initial examination horses were not taken out
on pasture and, apart from concentrated feed, no other sour-
ce of starch was available. During the pasture season, the
ratio of horses showing insulin resistance increased.
Other authors have also described a relation between grass
intake and altered equine metabolism (
McGowan
2008,
Kronfeld
2006,
Adair
et al. 2008). The placebo group sho-
wed significantly higher insulin levels at the second examina-
tion time than the groups receiving the chasteberry prepara-
tion. It can be concluded that the chasteberry preparation
seemed to have an influence on insulin levels.
Limitations of data collection
The limitation in performing this study was the failure rate wit-
hin the study population mostly due to reasons other than
PPID. Because of the failure rate, the groups were reduced
and only 26 horses could be analyzed at the final examina-
tion. Groups T2 and T3 became quite small for statistical
analysis and the results must be observed critically. A study
analyzing long-term effects of pergolide therapy showed a
low survival time of 7.9 months in horses with PPID (
Graubner
et al. 2010). Patients included in these kinds of studies are
generally old and in advanced stages of PPID.
For a better understanding of the increase of plasma ACTH
under the chasteberry preparation and pergolide in August,
horses should have been examined at the beginning of the
year again when lower ACTH levels are generally expected
due to seasonal variations in pituitary activity.
Conclusion
Based on the results of this study, the chasteberry prepara-
tion represents a treatment option for horses with PPID.
Especially in cases in which horses do not tolerate pergolide
treatment or owners decide against pergolide medication,
the chasteberry preparation may serve as an alternative. To
determine the long-term effect on clinical signs and labora-
tory parameters, further studies need to be performed. Con-
tinuing studies on the chasteberry preparation in combina-
tion with individually optimized stabling conditions and fee-
ding regimens should be carried out in order to determine
the effect on the disease state. These potential studies would
be useful in determining disease progression under the
influence of the chasteberry preparation. Furthermore,
results could be compared with those of horses treated with
pergolide. To sum up, the collected data provides evidence
of the positive effects that this special chasteberry prepara-
tion has on the clinical symptoms of horses and ponies suf-
fering from PPID. Quality of life was improved in the study
population.
Conflict of interest statement
None of the authors has any financial or personal relation-
ships that could inappropriately influence or bias the content
of the paper.
Manufacturer’s addresses
1.Corticosal®, Navalis Nutraceuticals GmbH, Filderstadt,
Germany
2Prascend®, Boehringer Ingelheim, Ingelheim, Germany
3Immulite 2000XPi, Siemens, Eschborn, Germany
4CentaurXP, Testkit IRI, Siemens, Eschborn, Germany
5SAS®9.2, SAS Institute Inc., Cary, USA
Abbreviations
ACTH Adrenocorticotropic hormone
PPID Pituitary Pars Intermedia Dysfunction
ml Milliliters
pg/ml Picogram per milliliter
POMC Proopiomelanocortin
VAC Vitex agnus-castus
References
Adair S., Frank N
. and
Geor R
. (2008) Guide to insulin resistance &
laminitis for equine practitioners. LLOYD Inc. 2008
Baumgartner W., Capen C. C.
and
Heinrichs M
. (1990) Immunocy-
tochemical Demonstration of Proopiomelanocortin-derived Pepti-
des in Pituitary Adenomas of the Pars Intermedia in Horses. Vet
Pathol. 27, 419-425
Funk R. A., Stewart A. J., Wooldridge A. A., Kwessi E., Kemppainen R.
J., Behrend E. N., Zhong Q. and Johnson A. K.
(2011) Seasonal
changes in plasma adrenocorticotropic hormone and a-melanocy-
te-stimulating hormone in response to thyrotropin-releasing hormo-
ne in normal, aged horses. J. Vet. Intern. Med. 25, 579-585
Goudreau J., Lindley S
. and
Lookingland K
. (1992) Evidence that
hypothalamic periventricular dopamine neurons innervate the inter-
mediate lobe of the rat pituitary. Neuroendocrinol. 56, 100-105
Gorkow C., Jarry H., Leonhardt S
. and
Wuttke W
. (1994) In vitro
prolactin but not LH and FSH release is inhibited by compounds in
extracts of Agnus castus: direct evidence for a dopaminergic prin-
ciple by the dopamine receptor assay. Exp. Clin. Endocrinol. 102,
448-454
Graubner C., Pongratz M. C
. and
Wehrli-Eser M
. (2010) Equine
Cushing’s syndrome: Long-term effect of pergolide therapy. Pfer-
deheilkunde 26, 598-603
Kronfeld D
. (2006) Insulin resistance predicted by specific proxies. J.
Equine Vet. Sc. 26, 281-284
McFarlane D
. (2011) Equine pituitary pars intermedia dysfunction.
Vet. Clin. North Am. Equine Pract. 27, 93-113
McGowan C
. (2008) The role of insulin in endocrinopathic laminitis.
J. Equine Vet. Sc. 28, 603-607
McGowan T.
(2008) Aged horse health, management and welfare.
[PhD Thesis] Queensland, Australia: The University of Queens-
land, 2008.
Schellenberg R
. (2001) Treatment for the premenstrual syndrome
with agnus castus fruit extract: prospective, randomised, placebo
controlled study. Brit. Med. J. 322,134-137
Sommer K.
(2003) Das Equine Cushing Syndrom: Entwicklung eines
ACTH-Bioassays für die Ermittlung des biologisch-immunreaktiven
Verhältnisses von endogenem ACTH in equinen Blutproben [PhD
dissertation]. Hannover, Germany: School of Veterinary Medicine
Hannover, 2003.
Schott H. C
. (2002) Pituitary pars intermedia dysfunction: Equine
cushing’s disease. Vet. Clin. North Am. Equine Pract. 18, 237-
270
Prof. Dr. Heidrun Gehlen
Equine Clinic
Free University of Berlin
Oertzenweg 19b
14163 Berlin
Germany
heidrun.gehlen@fu-berlin.de
728 Pferdeheilkunde 29
Use of the chasteberry preparation corticosal®for the treatment of pituitary pars intermedia dysfunction in horses
Beech J., Boston R. C., Lindborg S.
and
McFarlane D
. (2009) Evalu-
ation of plasma ACTH, alpha-melanocyte-stimulating hormone,
and insulin concentrations during various photoperiods in clinical-
ly normal horses and ponies and those with pituitary pars interme-
dia dysfunction. J. Am. Vet. Med. Assoc. 235, 715-722
Beech J., Donaldson M. T., LaMonte B. H., Morresey P.
and
Smith G
.
(2002) Treatment with pergolide or cyproheptadine of pituitary
pars intermedia dysfunction (equine Cushing’s disease). J. Vet.
Intern. Med. 16, 742-746
Beech J., Donaldson M
. and
Lindborg S
. (2002) Comparison of Vitex
agnus castus extract and pergolide in the treatment of equine cus-
hing syndrome. AAEP Proceedings 48, 175-177
Berger D., Hoberg E., Meier B., Schaffner W
. and
Sticher O
. (2000)
Pharmacological activities of Vitex agnus-castus extracts in vitro.
Phytomedicine 7, 373-381
Breukink H. J., van Garderen E., Kalsbeek H. C
.,
van der Kolk J. H
.
and
Wensing T
. (1993) Equine pituitary neoplasia: a clinical
report of 21 cases (1990-1992). Vet. Rec. 133, 594-597
Breukink H. J., Kalsbeek H. C., van der Kolk J. H
. and
Wensing T
.
(1995) Laboratory diagnosis of equine pituitary pars intermedia
adenoma. Domest Anim Endocrinol. 12, 35-39
Brüns C
. (2001) Diagnose und Therapieverlauf des equinen Cushing-
Syndroms – Rolle des endogenen ACTH. PhD dissertation. Hanno-
ver, Germany: School of Veterinary Medicine Hannover, 2001.
Copas V.
and
Durham A
. (2012) Circannual variation in plasma
ACTH concentrations in normal horses and ponies and those with
pituitary pars intermedia dysfunction. Equine Vet J. 44, 440-443
Corazza M., Maccheroni M., Panzani D
. and
Sgorbini M
. (2004)
Equine cushing-like syndrome: diagnosis and therapy in two
cases. Vet. Res. Commun. 28 Suppl 1, 377-380
Couëtil L., Knoll J.
and
Paradis M. R
. (1996) Plasma adrenocortico-
tropin concentration in healthy horses and in horses with clinical
signs of hyperadrenocorticism. J. Vet. Intern. Med. 10, 1-6
Coursen C. L., Eberhart S. W. and Schott H. C.
(2001) The Michigan
cushing’ s project. AAEP Proceedings 47, 22-24
Divers T.
(2008) Pergolide and Cyproheptadine: Which medication
to choose for treatment of equine cushing’s disease? J. Equine Vet.
Sc. 28, 370-371
Divers T. J., Erb H. N., Lamb S., Nydam D. V., Perkins G. A
. and
Schanbacher B
. (2002) Plasma adrenocorticotropin (ACTH) con-
centrations and clinical response in horses treated for equine Cus-
hing’s disease with cyproheptadine or pergolide. Equine Vet. J. 34,
679-685
Donaldson M., Dybdal N
. and
McFarlane D
. (2005) Nitration and
increased alpha-synuclein expression associated with dopaminer-
gic neurodegeneration in equine pituitary pars intermedia dysfunc-
tion. Neuroendocrinol. 17, 73-80
Elliott S. B.
(2010) Effects of pituitary pars intermedia dysfunction
(PPID), season and pasture diet on blood adrenocorticotropic hor-
mone and metabolite concentrations in horses [Master thesis].
Knoxville, Tennessee: University of Tennessee, 2010
... Horses can also present with hyper-and hypo-dopaminergic conditions, including stereotypic behaviours (SB; [37,55]) and pituitary pars intermedia dysfunction (PPID; [40]), respectively. Interestingly, there is also an observation that horses with PPID present with significant alterations in temperament, including an increase in depression, lethargy and apathetic manifestations with disease progression [4]. However, this temperament alteration has not yet been linked with the reduction of DA which occurs within these animals. ...
... Therefore, our finding that a decrease in SBR is correlated with higher 'Docility' could provide an important early indicator for those at risk of PPID development. This is of significance given that depression, lethargy and an apathetic outlook are observed following PPID diagnoses [4], and could therefore link towards a more 'docile' temperament. Thus, should the horse demonstrate an uncharacteristic alteration in temperament by increasing in 'Docility', this may signify that there are alterations with regards to DA physiology that could indicate the development of PPID. ...
Article
A relationship between dopamine and temperament has previously been described in human cases of dopaminergic dysfunction. Adjustment in temperament prior to disease manifestation can enable the early identification of individuals at risk of such conditions, and scope exists to extend this application of temperament alterations to cases of dopaminergic dysfunction in horses. A multivariate and mixed-methods approach utilising a questionnaire along with two inferred measurements of dopamine activity (Spontaneous Blink Rate [SBR] and Behavioral Initiation Rate [BIR]) were recorded from direct observation of animals (n=99) to identify the potential relationship between dopamine and temperament in horses. Principal components analysis (PCA) of 36 temperament variables revealed nine Principal Components, including 'Anxiety' and 'Docility', which accounted for 72.4% of the total variance. Component scores were calculated and correlated with SBR and BIR utilising Spearman Rank Correlation Coefficient analysis. The component 'Anxiety' was found to have a significant positive relationship with SBR, whereas 'Docility' was observed to have a significant negative relationship with SBR. These results indicate a relationship between dopamine and temperament within the horse that is certainly worthy of further study. Potential mechanisms involving neural dopaminergic and GABAergic systems are presented, in addition to how such alterations could be utilised to probe for equine dopamine dysfunction pending future research.
... One systematic review 17 and 13 additional publications [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] were identified that provided data on the frequency of clinical signs within veterinary-diagnosed PPID cases, which were considered in combination with the outcomes from the panel Delphi consultation to categorise clinical signs by the index of clinical suspicion (Table 5). A summary of the key recommendations is presented in Table 6 and Figure 5. i.e., are PPID negative but test positive) and false negative (FN; ...
Article
Full-text available
Background Pituitary pars intermedia dysfunction (PPID) is a prevalent, age‐related chronic disorder in equids. Diagnosis of PPID can be challenging because of its broad spectrum of clinical presentations and disparate published diagnostic criteria, and there are limited available treatment options. Objectives To develop evidence‐based primary care guidelines for the diagnosis and treatment of equine PPID based on the available literature. Study design Evidence‐based clinical guideline using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework. Methods Research questions were proposed by a panel of veterinarians and developed into PICO or another structured format. VetSRev and Veterinary Evidence were searched for evidence summaries, and systematic searches of the NCBI PubMed and CAB Direct databases were conducted using keyword searches in July 2022 and updated in January 2023. The evidence was evaluated using the GRADE framework. Results and recommendations The research questions were categorised into four areas: (A) Case selection for diagnostic testing, pre‐test probability and diagnostic test accuracy, (B) interpretation of test results, (C) pharmacological treatments and other treatment/management options and (D) monitoring treated cases. Relevant veterinary publications were identified and assessed using the GRADE criteria. The results were developed into recommendations: (A) Case selection for diagnostic testing and diagnostic test accuracy: (i) The prevalence of PPID in equids aged ≥15 years is between 21% and 27%; (ii) hypertrichosis or delayed/incomplete hair coat shedding provides a high index of clinical suspicion for PPID; (iii) the combination of clinical signs and age informs the index of clinical suspicion prior to diagnostic testing; (iv) estimated pre‐test probability of PPID should be considered in interpretation of diagnostic test results; (v) pre‐test probability of PPID is low in equids aged <10 years; (vi) both pre‐test probability of disease and season of testing have strong influence on the ability to diagnose PPID using basal adrenocorticotropic hormone (ACTH) or ACTH after thyrotropin‐releasing hormone (TRH) stimulation. The overall diagnostic accuracy of basal ACTH concentrations for diagnosing PPID ranged between 88% and 92% in the autumn and 70% and 86% in the non‐autumn, depending on the pre‐test probability. Based on a single study, the overall diagnostic accuracy of ACTH concentrations in response to TRH after 30 minutes for diagnosing PPID ranged between 92% and 98% in the autumn and 90% and 94% in the non‐autumn, depending on the pre‐test probability. Thus, it should be remembered that the risk of a false positive result increases in situations where there is a low pre‐test probability, which could mean that treatment is initiated for PPID without checking for a more likely alternative diagnosis. This could compromise horse welfare due to the commencement of lifelong therapy and/or failing to identify and treat an alternative potentially life‐threatening condition. (B) Interpretation of diagnostic tests: (i) There is a significant effect of breed on plasma ACTH concentration, particularly in the autumn with markedly higher ACTH concentrations in some but not all ‘thrifty’ breeds; (ii) basal and/or post‐TRH ACTH concentrations may also be affected by latitude/location, diet/feeding, coat colour, critical illness and trailer transport; (iii) mild pain is unlikely to have a large effect on basal ACTH, but caution may be required for more severe pain; (iv) determining diagnostic thresholds that allow for all possible contributory factors is not practical; therefore, the use of equivocal ranges is supported; (v) dynamic insulin testing and TRH stimulation testing may be combined, but TRH stimulation testing should not immediately follow an oral sugar test; (vi) equids with PPID and hyperinsulinaemia appear to be at higher risk of laminitis, but ACTH is not an independent predictor of laminitis risk. (C) Pharmacologic treatments and other treatment/management options: (i) Pergolide improves most clinical signs associated with PPID in the majority of affected animals; (ii) Pergolide treatment lowers basal ACTH concentrations and improves the ACTH response to TRH in many animals, but measures of insulin dysregulation (ID) are not altered in most cases; (iii) chasteberry has no effect on ACTH concentrations and there is no benefit to adding chasteberry to pergolide therapy; (iv) combination of cyproheptadine with pergolide is not superior to pergolide alone; (v) there is no evidence that pergolide has adverse cardiac effects in horses; (vi) Pergolide does not affect insulin sensitivity. (D) Monitoring pergolide‐treated cases: (i) Hormone assays provide a crude indication of pituitary control in response to pergolide therapy, however it is unknown whether monitoring of ACTH concentrations and titrating of pergolide doses accordingly is associated with improved endocrinological or clinical outcome; (ii) it is unknown whether monitoring the ACTH response to TRH or clinical signs is associated with an improved outcome; (iii) there is very weak evidence to suggest that increasing pergolide dose in autumn months may be beneficial; (iv) there is little advantage in waiting for more than a month to perform follow‐up endocrine testing following initiation of pergolide therapy; there may be merit in performing repeat tests sooner; (v) timing of sampling in relation to pergolide dosing does not confound measurement of ACTH concentration; (vi) there is no evidence that making changes after interpretation of ACTH concentrations measured at certain times of the year is associated with improved outcomes; (vii) evidence is very limited, however, compliance with PPID treatment appears to be poor and it is unclear whether this influences clinical outcome; (viii) evidence is very limited, but horses with clinical signs of PPID are likely to shed more nematode eggs than horses without clinical signs of PPID; it is unclear whether this results in an increased risk of parasitic disease or whether there is a need for more frequent assessment of faecal worm egg counts. Main limitations Limited relevant publications in the veterinary scientific literature. Conclusions These findings should be used to inform decision‐making in equine primary care practice.
Article
Full-text available
Clinical improvement and reversal of abnormal endocrine tests is better with pergolide treatment than with cyproheptadine treatment. In addition to being more problematic in terms of sample handling under field conditions, our data suggest that measurement of plasma adrenocortico-tropin (ACTH) concentration alone may not be a reliable endocrine test for diagnosis of equine Cushing's disease. Authors' addresses: Department of Large Animal Clinical Sciences, D-202 Veterinary Medical Center, Michigan State University, East Lansing, MI 48824-1314 (Schott, Eber-hart, Nachreiner, Refsal, Ewart, and Marteniuk) and American Veterinary Medical Association, 1931 North Meacham Road, Suite 100, Schaumburg, IL 60173-4360 (Coursen). © 2001 AAEP.
Article
Pergolide is the drug of choice for treatment of equine Cushing's syndrome (ECS). There are only few detailed studies describing the longterm effects of pergolide treatment in ECS patients. The goal of this study was to evaluate the long-term effects of a pergolide therapy in ECS patients in Switzerland by means of owners' survey using a questionnaire. Thirty-eight horses diagnosed with ECS between 1999 and 2009 at the Vetsuisse Faculties Zurich and Bern, respectively, and treated for at least 1 month with pergolide (Permax®, Lilly SA, Genf) were included in the study. Diagnosis of ECS was based on history and clinical signs; in 37 horses it was confirmed with a dexamethasone suppression test (DST) and/or measurement of plasma ACTH concentration. The clinical signs before treatment were characterised and the effect of therapy was determined by interrogating the horse owners using a questionnaire. Statistical analysis of the data was performed using a McNemar's test. The examined horses were 22 (13-36) years old (mean (min-max)]. The population contained 22 warmblood horses, 11 cobs und 5 ponies, including 14 mares, 23 geldings und 1 stallion. Clinical signs were hirsutism (33/9) [(number of offected horses before treatment; number after treatment)], hyperhidrosis (24/7), poor performance (21/3), lethargy (22/3), polyuria/polydipsia (15/5), muscle wasting (19/11), weight loss (13/4), laminitis (15/3), ataxia (11/3), skin infections (10/4), bronchitis (4/2) and conjunctivitis (6/2). The dosage of pergolide was 1-2 μg/kg p.o. SID and the duration of treatment was 13.8 (1-38) months. According to the owners, horses responded to treatment within 2 to 4 weeks after initiation of therapy. Thirty-four of the 38 owners (79%) were satisfied with the treatment. Adverse effects were rarely observed (n=11) and if so, they were transient and mild (anorexia, lethargy, diarrhoea). At the time of the study, 10 horses had died or were euthanized (recurrent laminitis, colic, bone fracture, loss of use). The length of survival of these horses after start of treatment was 7.9 (1-22) months. The results indicate an improvement of the clinical signs after pergolide therapy in most of the patients when judged by the owners. At the dosage used here, adverse effects are rare and mostly clinically irrelevant. In conclusion, the administration of pergolide in ECS patients can be supported on the basis of the results in this study.
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Medical records of 27 horses (including 13 ponies) treated with pergolide or cyproheptadine for pituitary pars intermedia dysfunction were reviewed to determine the effect of treatment on plasma ACTH, insulin, and glucose concentrations and clinical signs. Prior to treatment, the most common clinical signs were laminitis, hirsutism, and abnormal body fat distribution. The median pergolide dose was 3.0 μLg/kg PO q24h (range, 1.7–5.5 ±g/kg). All horses treated with cyproheptadine were given 0.25 mg/kg PO q24h. After pergolide treatment, ACTH concentrations (n = 20; median = 30.4 pg/ml; range, 4.2–173) were significantly lower (P < .01) than those in horses treated with cyproheptadine (n = 7; median = 141.0 pg/ml; range, 10–1,230). Among horses treated with pergolide, there was a correlation between ACTH concentration after treatment and the duration of treatment (P < .001) and pergolide dose (P= .04). Significantly (P= .02) more owners of horses treated with pergolide (85%, 17/20) reported an improvement in clinical signs compared to owners of horses treated with cyproheptadine (28%, 2/7).
Article
Pituitary pars intermedia dysfunction (PPID) is a common endocrinopathy, frequently diagnosed via plasma adrenocorticotropic hormone (ACTH) concentrations. Seasonal variation in plasma ACTH concentrations has been described in normal horses prompting caution in diagnosing PPID at certain times of the year. The aims of this study were to determine appropriate reference intervals for equine plasma ACTH throughout the year; and to examine the circannual variation of plasma ACTH concentrations in PPID cases. Plasma ACTH can be used as a test for PPID throughout the year with the use of appropriate reference intervals. Data for reference interval calculations were obtained from samples collected from inpatients of Liphook Equine Hospital (non-PPID group, n=156). Data from PPID cases (n=941) were obtained from samples submitted to the Liphook Equine Hospital Laboratory from horses with a clinical suspicion of PPID found to have plasma ACTH concentrations greater than our upper reference interval for that time of year. Upper limits for reference interval of plasma ACTH were 29 pg/ml between November and July and 47 pg/ml between August and October. Circannual variation in plasma ACTH occurred in both non-PPID and PPID horses with the highest ACTH concentrations found between August and October in both groups (P<0.0001). The greatest difference between the 2 populations also occurred between August and October. Plasma ACTH can be used for the diagnosis and monitoring of PPID throughout the year with the use of appropriate reference intervals. These findings demonstrate an increase in pituitary gland secretory activity during the late summer and autumn in both normal and PPID cases.
Article
Results of diagnostic tests for equine pituitary pars intermedia dysfunction (PPID), including endogenous ACTH concentration and the overnight dexamethasone suppression test (DST), are affected by season. New and potentially more sensitive diagnostic tests for equine PPID, such as thyrotropin-releasing hormone (TRH)-stimulated ACTH response, have been developed, but have had limited evaluation of seasonality. Our purpose was to evaluate seasonal changes in plasma ACTH and alpha-melanocyte-stimulating hormone (α-MSH) responses to TRH administration. Nine, healthy, aged horses with normal DST results. Synthetic TRH (1 mg) was administered IV. Plasma ACTH and α-MSH concentrations were measured at 0, 5, 10, 15, 20, 25, 30, 45, 60, and 180 minutes. Testing was performed in February, July, August, September, October, and November. Mean TRH-stimulated ACTH and α-MSH concentrations were compared across months and time by repeated measures analysis of variance. Significance was set at the P < .05 level. Concentrations of ACTH and α-MSH significantly increased after TRH administration. Endogenous and TRH-stimulated ACTH and α-MSH concentrations were significantly different across months with higher concentrations in the summer and fall compared with February. Plasma ACTH and α-MSH responses to TRH administration experience seasonal variation, with TRH-stimulated ACTH and α-MSH concentrations increasing from summer through fall. These results support previous evidence of a seasonal influence on the equine pituitary-adrenal axis. More research is warranted with a larger number of horses to determine if seasonal reference ranges for TRH stimulation testing need to be defined.