Veterinary Dermatology 2004, 15, 285 293

Blackwell Publishing, Ltd.

Treatment of canine Alopecia X with trilostane

ROSARIO CERUNDOLO*,, DAVID H. LLOYD*, ANGELO PERSECHINO,
HELEN EVANS and ANDRIA CAUVIN
*Department of Veterinary Clinical Sciences, Royal Veterinary College, University of London, Hawkshead
Campus, North Mymms, Herts, UK
Department of Veterinary Clinical Sciences, Faculty of Veterinary Medicine, Naples, Italy
Cambridge Specialist Laboratory Services, Cambridge, UK
Attimore Veterinary Group, Welwyn Garden City, UK
(Received 6 October 2003; accepted 18 March 2004)

Abstract Sixteen Pomeranians and eight miniature poodles presenting with clinical signs of alopecia X, elevated
blood concentrations of 17-hydroxyprogesterone post stimulation with adrenocorticotropic hormone and
increased urinary cortisol /creatinine ratios were treated with trilostane, a competitive inhibitor of 3-hydroxysteroid dehydrogenase. Trilostane was given once or twice daily at a mean dose of 10.85 mg kg1 day1. Adrenal
function was evaluated with a follow-up of 28 months in the Pomeranians and 33 months in the miniature
poodles. Treatment with trilostane led to complete hair re-growth in 85% of the Pomeranians and in all of the
miniature poodles within 4 to 8 weeks. No adverse events attributed to treatment with trilostane were recognized. The hair re-growth might have been the result of a down-regulation of adrenal steroids and/or of the noncompetitive inhibition of the oestrogen receptors at the hair follicle level.
Keywords: alopecia, dog, hair, skin, trilostane.

IN TRO D U C T ION
Alopecia X is a form of canine adult-onset alopecia
that was formerly known variously as congenital adrenal
hyperplasia, pseudoCushings syndrome, castrationresponsive dermatosis and adult-onset hyposomatotropism, but the diversity in names is merely descriptive
and based upon the differences in endocrine findings
and/or clinical responses to various therapeutic modalities.1,2 It is known to affect Nordic breeds such as the
Alaskan malamute, chow chow, keeshond, Pomeranian,
samoyed and Siberian husky, and also other breeds
including the miniature poodle.36 Clinically it manifests as progressive, symmetrical, truncal, nonpruritic
hair loss with variable hyperpigmentation occurring in
both males and females between 1 and 5 years of age.
Affected dogs are clinically healthy and routine haematology and biochemistry show normal results. Various
endocrine abnormalities have been suspected and
treatment with growth hormone, sex hormones, mitotane or neutering has given inconsistent results.
Trilostane is reported to be a competitive inhibitor
of the conversion of pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone and androstenediol by
blocking the enzyme 3-hydroxysteroid dehydrogenase
(3-HSD).7 It has been used since the 1970s for the
treatment of Cushings syndrome in humans,8 breast
cancer9 and termination of pregnancy in women,10 and

Correspondence: R. Cerundolo, Department of Clinical Studies, School

of Veterinary Medicine, University of Pennsylvania, 3900 Delancey Street,
Philadelphia PA 19104, USA. E-mail: cerundol@vet.upenn.edu
2004 European Society of Veterinary Dermatology

experimentally in sheep.11 It has been reported to be

effective in equine Cushings syndrome12 and for the
treatment of canine hyperadrenocorticism.1315
Alopecia X has been postulated to be an endocrine
disorder characterized by an increased blood concentration of 17-hydroxyprogesterone (17-OHP) due to
abnormal activity of the 21-hydroxylase enzyme.16 Our
studies have also shown that alopecic dogs have a slight
increase of cortisol production.6 We hypothesized that
trilostane could promote hair re-growth in affected
dogs, by modulating adrenal steroidogenesis, downregulating the levels of 17-OHP and cortisol, through
the inhibition of the 3-HSD enzyme (Fig. 1).
Our aim was to study the responses of affected animals
to treatment with trilostane. The study was focused on
pedigree Pomeranians and miniature poodles so as to
generate data within a well-defined group of dogs.

M AT E R IA L S A N D M E T H O D S
Animals
Adult Pomeranians or miniature poodles fulfilling defined
inclusion criteria (Table 1) for the diagnosis of Alopecia
X were recruited from owners responding to an epidemiological survey carried out in the UK and from the
patients referred to the Dermatology Service at the Royal
Veterinary College Queen Mother Hospital for Animals
or the University of Veterinary Medicine in Naples.6
Details of the diagnostic procedures have been previously described.6 Briefly, all dogs were submitted to
routine physical and dermatological examination, and
dermatological diagnostic procedures to rule out
285

286

R Cerundolo et al.

Mineralocorticoids

Glucocorticoids

Trilostane
block

Dehydroepiandrosterone sulphate

Cholesterol
SCC

Sex hormones

17.20 L

17-OH

Pregnenolone

17-Hydroxypregnenolone

3-HSD
17-OH

17.20 L

17-Hydroxyprogesterone

Androstenedione
5-red

21-OH
11-HS

21-OH

Androstenediol

3-HSD

3-HSD

Progesterone

17-HSD

Dehydroepiandrosterone

3-HSD
17-HSD
17-HSD

Androstanedione

Testosterone
5-red

Dihydrotestosterone (DHT)

11-Deoxycorticosterone
3-HSD
11-OH

Corticosterone
18-OH

11-OH

21-OH

Cortisol

18-Hydroxycorticosterone 11-HSD
18-HSD

Aldosterone

3-HSD

11-Deoxycortisol 21-Deoxycortisol

Cortisone

Androsterone

17-HSD 3-Androstanediol

Epiandrosterone

3-Androstanediol

-gluc

-gluc

3-Androstanediol gluc.

Androsterone gluc.
Aromatase

Aromatase

Estrone

17-HSD

Table 1. Proposed inclusion criteria for Alopecia X

1
2
3

4
5
6
7
8
9
10

Predisposed breed
Age of onset: between 2 and 6 years
Clinical pattern of alopecia: truncal progressive hair loss and /
or woolly coat quality, with or without cutaneous
hyperpigmentation
Absence of systemic clinical signs
Normal haematological and biochemical findings
Normal thyroid function
Abnormal steroidogenesis: increased concentration of 17OHP* pre and/or post-ACTH stimulation
Increase in cortisol /creatinine ratio in most of the urine samples
collected over a 10-day period
Mild or moderate suppression of cortisol /creatinine ratio by
the (blood or oral) low dose dexamethasone suppression test
Histological findings of trichilemmal keratinization of the hair
follicles

*17-OHP, 17-hydroxyprogesterone; ACTH, adrenocorticotrophic

hormone.

bacterial or fungal infections, parasitic infestations

and causes of alopecia other than endocrine disease.
Routine haematology, blood biochemistry, and urine
analysis was carried out on affected dogs to assess
health status. All the results were within the respective
reference ranges. At the initial consultation hormonal
tests were carried out. These included evaluation of
thyroid (serum thyroxine and thyroid stimulating hormone [TSH], or TSH stimulation test) and adrenal
function (plasma endogenous adrenocorticotrophic
hormone [ACTH], serum cortisol and 17-OHP, preand post-ACTH, cortisol/creatinine ratios measured
daily for 10 days and also by the oral low dose dexamethasone suppression test), and measurement of serum
sex hormone concentrations (oestradiol, progesterone
and testosterone). Affected dogs showed normal thyroid function; the adrenal function tests showed elevated concentrations of blood 17-OHP pre and/or post
stimulation with ACTH and elevated urinary concentrations of cortisol/creatinine (C/C) ratio on 1 or
more (but never all) of the test days. The oral low dose
dexamethasone suppression test was normal or
showed marginal suppression of the pituitary-adrenal
axis. However, physical signs, and haematological and

Oestradiol

Figure 1. Outline of the biosynthetic pathways

of steroidogenesis for the three zones of the
adrenal cortex. From left to right: in red the
zona glomerulosa; in brown the zona
fasciculata; in blue the zona reticularis, and
in green steroidogenesis in peripheral tissues
(modified from Cerundolo et al.).31
SCC: Side-chain-cleavage cytochrome P450 ;
17-OH: 17-hydroxylase P450; 17.20 L:
17.20-Lyase P450; 3-HSD: 3-Hydroxysteroid
dehydrogenase/5- 4-isomerase; 21-OH:
21-Hydroxylase P450; 11-OH: 11Hydroxylase P450; 18-OH: 18-Hydroxylase;
18-HSD: 18-Hydroxysteroid dehydrogenase;
17-HSD: 17-Hydroxysteroid
dehydrogenase; 5-red: 5-reductase (types I
and II); 3-HSD: 3- or 3-Hydroxysteroid
dehydrogenase; -gluc: -glucoronidase;
Aromatase: Aromatase P450.

blood biochemical changes consistent with classical

hyperadrenocorticism were not identified in any of the
dogs. Biopsy samples from all affected dogs were
collected for histological examination and showed
changes consistent with Alopecia X.17

Treatment
Daily oral treatment with trilostane (Modrenal 60 mg
capsules) was initiated according to body weight (Table 2)
and to the following guidelines: < 2.5 kg: 20 mg dog1;
2.55.0 kg: 30 mg dog1; > 5 kg and < 10 kg: 60 mg dog1.
Owners were asked to administer the drug at lunchtime
(12 noon3 p.m.), either during or after a meal. No
dogs over 10 kg were entered into the study.

Re-examination
Dogs were re-examined after 10 days and 4 weeks of
treatment, and also after 12 weeks and 1 year in some
cases. At each re-examination, usually carried out
between 8 a.m.12 p.m., routine haematological, biochemical and urine analysis were carried out to assess
health status; an ACTH stimulation test was also
performed collecting blood prior to and 1 h after intravenous administration of 0.125 mg dog1 of tetracosactrin acetate (Synacthen; Ciba, Horsham, West Sussex,
UK) for cortisol and 17-OHP determination to evaluate
the degree of adrenal suppression (Table 3). Serum samples
were sent to an external laboratory (CSLS, Cambridge)
for standard radioimmunoassay. Lower limits of sensitivity for the hormonal assays were: cortisol 20 nmol L1,
17-OHP 1.0 nmol L1. The interassay variation for
each assay was: cortisol, 37%, 17-OHP, 311%. These
hormones were determined using human kits that had
been validated for the dog.
Progress was subsequently reviewed approximately
every 6 months. If no response to treatment was
observed after 2 months, the dose of trilostane was
doubled, with administration once or twice a day.

Statistical analysis
Comparison of dose rates between Pomeranians and
miniature poodles, and between male and female

2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 285 293

Trilostane in Alopecia X

287

Table 2. Signalment and maximum daily trilostane dosage of Pomeranians and miniature poodles
Case
Pomeranians
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Mean
(range)

Sex

Coat
colour

Age
(years)*

Age at
onset

Weight
(kg)

Trilostane
(mg)

FN
FN
FN
FN
FN
FN
FN
F
M
M
M
M
M
M
M
M

Sable
black
Sable
Sable
Sable
Sable
Sable
Sable
Sable
Sable
Sable
Sable
Sable
Sable
Sable
Sable

3
4
6
6
7
8
9
8
8
5
2
4
6
6
6
6
5.88
(29)

2 1 /2
3
4
6
4 1 /2
4
8
7
7
4
1 1 /2
3 1 /2
4
4
4
4

2.0
1.7
1.8
2.1
3.0
3.5
2.3
4.7
2.0
3.4
1.7
2.5
1.6
3.0
4.0
2.5
2.61
(1.6 4.7)

30
40
40
20
40
30
20
30
20
20
20
30
20
40
30
20

15.00
23.53
22.22
9.52
13.33
8.57
8.70
6.38
10.00
5.88
11.76
12.00
12.50
13.33
7.50
8.00
11.76
(5.8823.53)

Chocolate
Chocolate
White
White
White
Black
White
White

11
6
5
6
7
7
8
9
6.89
(511)

8
4
4
5
4
5
7
8

4.5
9.2
4.5
5
4.9
7
2
5.7
5.35
(2.09.2)

30
60
30
60
30
60
30
60

6.67
6.52
6.67
12.00
6.12
8.57
15.00
10.53
9.01
(6.1215.00)

Miniature poodles
A
F
B
FN
C
M
D
M
E
MN
F
M
G
M
H
M
Mean
(range)
Overall
(range)

6.50
(211)

3.53
(1.69.2)

(mg kg1)

10.85
(5.8823.53)

F, female; FN, neutered female; M, male; MN, neutered male.

*Age at the time of the consultation; age of onset of the hair loss according to the owners; dogs not responding; dose administered in two
parts, morning and evening.

Pomeranians, was carried out using the MannWhitney

U-test. Comparison of pre- and post-ACTH stimulation
levels of 17-OHP in Pomeranians before and during
therapy with trilostane was carried out using Kruskal
Wallis one-way , with the Dunn adjustment for
multiple comparisons. The Unistat Statistical Package
(version 4.53) was used.

RESU LTS
Animals
A total of 16 Pomeranians (seven neutered females,
one female and eight males) and eight miniature
poodles (one female, one neutered female and six
males) with alopecia X were studied. At the time of the
first consultation ages ranged from 2 to 9 years in
Pomeranians and from 5 to 11 years in miniature
poodles, although the age of onset of hair loss was
earlier in life. Weight ranged from 1.6 to 4.7 kilos in
Pomeranians and 2.09.2 kilos in miniature poodles
(Table 2). Affected dogs showed various degrees of truncal
alopecia (Figs 2a, 3a and 4a).

Clinical findings
Treatment with trilostane resulted in complete hair regrowth in 14 of 16 (85%) Pomeranians and in all miniature poodles (Figs 2b, 3b and 4b). No re-growth was
observed in two Pomeranians after 6 months of therapy. In most Pomeranians and miniature poodles hair
re-growth occurred within 4 to 8 weeks. In two Pomeranians (cases 2 and 3) it occurred after 6 and 4 months,
respectively. In Pomeranians, the hair coat quality was
initially woolly and normal primary and secondary
hair appeared later on. In white miniature poodles the
hair re-growth was a light brown colour, especially over
the limbs, but subsequently this grew white.

Dose

The mean dose rate (mg kg1 day1) causing hair regrowth was 11.76 (range 5.8823.53) in Pomeranians
and 9.01 (range 6.1215.00) in miniature poodles.
However, there was no significant difference between
doses in the two breeds (P = 0.22, 2-tail probability;
Fig. 5). Amongst Pomeranians, there was no difference
in effective dose rates between males and neutered
females (P = 0.49, 2-tail probability). Numbers of

2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 285293

288

Cortisol
day 10

17-OHP
day 10

Cortisol
4 weeks

17-OHP
4 weeks

Cortisol
12 weeks

17-OHP
12 weeks

Cortisol
1 year

17-OHP
1 year

Case

Pre

Post

Pre

Post

Pre

Post

Pre

Post

Pre

Post

Pre

Post

Pre

Post

Pre

Post

Follow-up
(months)

1
2
3
4
5
6*
7
8
9
10
11
12
13
14
15
16

89
174
120
< 20
70

231
< 20
63
52
50
265
77
89
97
88

140
186
318
< 20
239

308
< 20
110
63
< 20
448
77
400
150
109

> 60
44
18.7
> 50
4.9

11.4
28
44
26
30
35
15.8
23
19
35

> 60
> 60
50
> 50
23

20
30
59
35
> 60
> 50
16.7
46
48
53

150
147
85
< 20
51

135
< 20
ND
ND
ND
209
65
88
92
74

551
145
305
52
240

144
< 20
ND
ND
ND
366
157
208
147
181

15.8
25
13.7
55
8.1

17.5
11.1
ND
ND
ND
21
13
18.2
21
25

> 60
58
26
> 60
21

20
11.1
ND
ND
ND
39
15.5
29
28
36

135
187
123
< 20
87

143
ND
86
49
34
201
68
78
ND
72

325
189
267
45
193

179
ND
173
87
46
353
142
192
ND
153

12
23
11
42
6.0

15
ND
23
18
8.9
16
7
14
ND
19

45
47
21
56
13

18
ND
31
23
12
31
15
19
ND
27

ND
ND

ND
ND

ND
< 20
ND
ND
ND
ND

ND
151
ND

ND
ND

ND
ND

ND
< 20
ND
ND
ND
ND

ND
228
ND

ND
ND

ND
ND

ND
8.1
ND
ND
ND
ND

ND
20
ND

ND
ND

ND
ND

ND
9.8
ND
ND
ND
ND

ND
37
ND

RG 18
RG 23
RG 6
RG 12
NG
NG
RG 11
RG 16
RG 7
RG 7
RG 9
RG 17
RG 12
RG 23
RG 28
RG 8

A
B
C
D
E
F
G
H

129
95
< 20
63
127
117
< 20
337

345
156
< 20
94
102
168
< 20
439

19.1
18
12
15
18.5
22
13.1
35

> 50
33
16
17
27
29
14.6
75

ND
68
74
< 20
ND
75
< 20
277

ND
97
100
< 20
ND
218
< 20
263

ND
22
14
10.7
ND
13.2
ND
21

ND
37
17
11.9
ND
23
ND
23

115
71
120
ND
87
89
< 20
196

198
99
151
ND
112
185
45
211

12
19
ND
ND
8.0
11
7
27

23
31
ND
ND
12.5
17
16
30

ND
ND
104
< 20
ND
ND
ND
168

ND
ND
200
< 20
ND
ND
ND
203

ND
ND
2.9
4.7
ND
ND
ND
8.1

ND
ND
13.8
7.0
ND
ND
ND
9.8

RG 12
RG 12
RG 33
RG 32
RG 14
RG 7
RG 27
RG 27

Abnormal values are in bold. ND, not done. *As it was too stressful for the dog have hormonal testing the owner refused to do them; RG, full re-growth; NG, no re-growth; (follow-up period in months); dead.
Reference ranges: cortisol pre-ACTH: < 250 nmol L1; cortisol post-ACTH stimulation: less than 600 nmol L1; 17-OHP pre-ACTH: < 3.0 nmol L1; 17-OHP post-ACTH stimulation: < 4.0 nmol L1;
17-OHP (post-ACTH) borderline: 4.0 6.0 nmol L1.

R Cerundolo et al.

2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 285 293

Table 3. Cortisol and 17-OHP concentration in Pomeranians and miniature poodles pre- and post-ACTH stimulation carried out on day 10 and after 4 and 12 weeks, in some case also after 1 year from the beginning
of the therapy with trilostane

Trilostane in Alopecia X

289

Figure 2. (a) Pomeranian with sable coat showing diffuse alopecia

and hyperpigmentation. (b) After 6 months treatment with
trilostane.
Figure 3. (a) Pomeranian with black coat showing patchy truncal
alopecia. (b) After 12 months treatment with trilostane.

female miniature poodles were insufficient for comparison. No correlation was apparent between age and the
effective dose of trilostane (Fig. 6).

Follow-up
Treated dogs have been followed up over a period of
8 to 33 months (Table 3). Follow-up was either by the
authors (RC, AC) or through their referring veterinarians.
Owners were also routinely called by telephone by RC.
Hair re-growth occurred within 4 to 8 weeks in all
but two dogs (cases 2 and 3), in which it was apparent
only after 6 and 4 months, respectively, of therapy. In
these cases the coat started to grow back when the dose
was increased from 20 mg q24 h to 20 mg q12 h, suggesting that the initial dose was too low. In case 14, hair
re-growth was evident but slow and doubling the dose
after 2 months resulted in profuse hair re-growth.
When full hair re-growth was achieved, trilostane
administration was reduced in some cases. A maintenance dose of 20 mg thrice weekly has been instituted
in two Pomeranians (cases 2 and 4) without any recurrence of hair loss. In case 15, the once daily dose was
reduced to 20 mg every other day but there was thinning of the coat. Trilostane was then increased to
30 mg q24 h until full hair re-growth was achieved and
then to 30 mg thrice weekly; full hair re-growth was
maintained. In four miniature poodles (cases C, D, G

and H), complete hair re-growth was present after

6 months of therapy and trilostane was then given
twice a week. No episodes of hair loss have occurred
since the reduced dose frequency was started (8 to
18 months follow-up). In two cases, C and G, trilostane
was initially given twice a week for a further 6 months
and was then withdrawn. No episodes of hair loss have
occurred since then (7 months follow-up). In white
miniature poodles hair re-growth from the alopecic
areas was initially brown in colour but then resumed
the normal white colour (Fig. 7). During these
7 months they were clipped for aesthetic reasons and
the coat has continued to grow.
Two of the Pomeranians, belonging to the same
owner, were treated for a period of 6 months at dose
rates of 13.33 and 8.57 mg kg1 day1, respectively,
without hair re-growth. The owner was unwilling to
allow higher doses to be tried. No adverse events
attributable to treatment were noted in any dogs.

Laboratory tests
Routine haematological, blood biochemical (including
electrolytes) and urine analysis carried out during
trilostane treatment showed normal results (data not
shown). However, the ACTH stimulation test showed that

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290

R Cerundolo et al.

Figure 6. Relationship of age and dose rates with hair growth

amongst the Pomeranians ( blue) and miniature poodles (red).

Figure 7. Miniature poodle showing initially brown colouration of

the coat but later the normal white colour was restored.

Figure 4. (a) Miniature poodle with white coat showing truncal

alopecia. (b) After 6 months treatment with trilostane.

tion showed suppressed adrenal function as values

were always far below the reference range (Table 3).

Death
Two of the Pomeranians (case 3 and 13) died during the
study. Heart murmurs were diagnosed in these dogs by
the local veterinarian. Trilostane had been continued
in these dogs for 6 and 12 months, respectively, without
any abnormal clinical or laboratory findings.

D ISC U S S IO N

Figure 5. Distribution of dose rates resulting in hair growth

amongst the Pomeranians (blue column) and miniature poodles
(red column).

the concentrations of 17-OHP in both the Pomeranians

and the miniature poodles after 10 days and 4 weeks of
trilostane were even higher than before starting the
therapy (Pre-ACTH, P = 0.0000; post-ACTH, P = 0.0015).
Cortisol concentrations pre- and post-ACTH stimula-

The pathogenesis of Alopecia X has been the subject of

considerable debate, and response to treatment has
often been used to support the different theories that
have been put forward.
Neutering has been the surgical treatment of choice
in male dogs with partial or complete hair re-growth
occurring within 34 months.18 Only one of the miniature
poodles we examined had been castrated 4 years before
the examination but the hair loss had started subsequently.
Various drugs such as testosterone, mitotane, ketoconazole, prednisone, growth hormone, melatonin and
dL-alfa-tocopheryl nicotinate plus l-cysteine have also
been used with inconsistent results.1,35,1926

2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 285 293

Trilostane in Alopecia X
Schmeitzel et al. suggested that Alopecia X is similar
to human congenital adrenal hyperplasia (CAH),27
which is caused by abnormal adrenal steroidogenesis
due to partial activity of the 21-hydroxylase enzyme
present during cortisol formation. However, this has
been refuted by a recent genetic study showing that no
mutation of the 21-hydroxylase gene is present in
affected Pomeranians.28
We have recently confirmed that abnormal steroidogenesis is present in affected dogs as they have not only
an increased serum 17-OHP concentration but also
mildly increased cortisol production and excretion,
resembling natural pituitary-dependent hyperadrenocorticism. We have postulated that this is a breedassociated mild form, or a variant of pituitary-dependent
hyperadrenocorticism.6
As trilostane is a competitive inhibitor of the 3HSD enzyme that converts 17-hydroxypregnenolone
to 17-OHP and then cortisol, we hypothesized that it
might be useful in affected dogs by modulating steroidogenesis in the cortisol pathway. This study has
shown that trilostane is a valid and safe choice for the
treatment of Alopecia X. Its effect seems to be dose
responsive, with dogs responding at daily doses from
less than 6 to over 23 mg kg1. Individual response or
sensitivity to trilostane might also be possible. These
figures are not precise in terms of real effects owing to
slight variations in the capsule content. The content
was normally divided into two or three parts by the
owners. Reformulation of the capsule content by a
local pharmacist or the manufacturer would allow
more precise dosing. Side effects associated with adrenal function suppression were not observed in treated
dogs and routine biochemical investigations did not
show any electrolyte abnormalities.
Further studies are required to titrate the dose
requirements more accurately. It is clear that there is
scope for varying the dosage used once a good clinical
response is achieved. This will be of great benefit in
reducing the cost of maintenance therapy. It is possible
that trilostane works in reversing hair loss by initiating
new hair growth and it may not be necessary for continued growth of anagen hairs; therefore, pulse therapy
may be effective. Further work is required to establish
this. The continuing hair growth in the two miniature
poodles that were withdrawn from therapy is unexplained. A more prolonged observation in such cases is
required. The two Pomeranians that were treated for a
period of 6 months and did not have hair re-growth
may have needed an increased dose. As the owner did
not want to continue the treatment, the reason for the
lack of efficacy in those two cases remains unknown.
The initial brown colouration, which occurred in white
miniature poodles, may have been caused by accumulation of melanin in the hair follicle bulbs as they
resumed the normal white colour.
In humans suffering 3-HSD deficiency, a saltwasting syndrome can occur, as well as acne, growth
acceleration, premature hair growth and hirsutism,
clitoromegaly and menstrual disorders in females, and

291

a varying degree of hypogonadism in males. Trilostane,

by reducing 3-HSD activity, may have stimulated hair
re-growth and subsequently CAH.27 The hair regrowth seen in treated dogs might be either the result of
corrected abnormal steroidogenesis or of iatrogenic
3-HSD deficiency with subsequent CAH inducing
hirsutism. Further studies are required in affected dogs
to evaluate the effects of trilostane.
As trilostane is an enzymatic inhibitor of 3-HSD,
we would expect to see decreased concentrations of
blood 17-OHP pre- and/or post-ACTH stimulation
but this did not occur in our dogs; on the contrary
concentrations increased. Although further studies are
needed, we hypothesize that trilostane may work in dogs
in a different way from that reported in other species.
Assuming that steroidogenesis is similar in mammals,
it is also possible that the enzymatic block of 3-HSD
leads to elevated formation of 17-hydroxypregnenolone,
which may interfere with the radioimmunoassay
of 17-OHP because there is a 3.2% cross-reactivity
when using the commercially available endocrine kit.
Despite this unexpected increase in 17-OHP concentration, therapy was continued as there were signs
of hair re-growth. Urinary C/C ratios were not measured during therapy as blood cortisol concentration
pre- and post-ACTH was far below the normal range
and we therefore expected normal to low excretion
of cortisol.
A previous study indicates that trilostane does
not react with any of the sex steroid receptors29
although a possible peripheral activity on oestrogen
receptors has recently been reported.30 It is questionable whether the hair re-growth achieved in our
patients is related to a peripheral activity of trilostane
(e.g. by blocking the oestrogen receptors in the hair
follicle) but further studies are necessary to look at the
hormonal receptor distribution in dogs with Alopecia
X and the effect of trilostane on the sex hormone and
corticosteroid receptors at the level of the hair follicles
in dogs.
Two Pomeranians (cases 3 and 13) died during the
follow-up period, but there is nothing to suggest that
these deaths were related to trilostane therapy as
both dogs had been examined just before their death
and routine blood tests had not shown any abnormal
findings. Both dogs had heart murmurs but the referring veterinarians felt that the dogs did not require
cardiac therapy. It is possible that trilostane might
have contributed to alteration of cardiac function
and it is advisable that cardiologists closely monitor
dogs with cardiac problems undergoing trilostane
therapy.
Alopecia X is probably only an aesthetic problem as
some of the affected dogs had been suffering from alopecia for as long as 2 years without developing any
other systemic clinical signs. The hair loss is a cause of
concern for most owners, especially in show dogs, and
treatment is demanded by the owners. The authors
believe that after making a correct diagnosis, therapy
with trilostane can be recommended.

2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 285293

292

R Cerundolo et al.

ACKN OWLEDGE ME NT S
The authors are grateful to the referring veterinarians
for assisting with examination and for testing many of
the cases. They would also like to thank the British
Kennel Club for initial support of the study and the
members of the British Pomeranian Clubs for active
collaboration; Ciba for providing the Synacthen used
in the study; and Stegram Pharmaceuticals for providing
financial support and the trilostane. The urinary hormonal
analyses were carried out at Prof. A. Rijnberks laboratory
by Dr M. M. A. R. Vaessen at the School of Veterinary
Medicine, University of Utrecht, the Netherlands.

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management of equine Cushings disease. Journal of Veterinary Internal Medicine 2001; 15: 322.
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14. Ruckstuhl NS, Nett CS, Reusch CE. Results of clinical

examinations, laboratory tests, and ultrasonography in
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17. Cerundolo R, Lloyd DH, Rest JR. Histopathology features of a canine syndrome characterised by alopecia and
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20. Lothrop CD. Pathophysiology of canine growth hormoneresponsive alopecia. Compendium on Continuing Education for the Practising Veterinarian 1988; 10: 13469.
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Trilostane in Alopecia X

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Rsum Seize Pomeranians et huit Caniche nain prsentant des signes cliniques compatibles avec une alopcie
X, des concentrations sanguines leves de 17-hydroxyprogesterone aprs stimulation par lACTH et une augmentation du RCCU ont t traits avec le trilostane, un inhibiteur comptitif de la 3 b-hydroxysteroid dehydrogenase. Le trilostane a t administr en une ou deux prises quotidiennes, la dose moyenne de 10.85 mg/kg/
jour. La fonction surrnalienne a t suivie pendant 28 mois pour les Pomeranians et 33 mois pour les Caniche.
Le traitement avec le trilostane a permis une repousse complte chez 85% des Pomeranians et chez tous les Caniche, en 4 8 semaines. Aucun effet secondaire na t not. La repousse pilaire pourrait tre lie une diminution
de la scrtion des strodes dorigine surrnalienne, et/ou une inhibition des rcepteurs aux oestrognes des
follicules pileux.
Resumen Diecisis perros Pomerania y ocho Caniche Miniatura presentando sntomas clnicos de alopecia X,
concentraciones sanguneas elevadas de 17-hidroxiprogesterona tras estimulacin con hormona adrenocorticotrpica y un ndice de cortisol/creatinina urinario elevado, fueron tratados con trilostano, un inhibidor competitivo de la dehidrogenasa 3 -hidroxisteroide. Se administr trilostano una o dos veces al da a una dosis media
de 10.85 mg / kg / da. La funcin adrenal fue evaluada con un seguimiento de 28 meses en los Pomerania y 33
meses en los Caniche Miniatura. El tratamiento con trilostano llev a un recrecimiento total del pelo en el 85%
de los Pomerania y en todos los Caniche Miniatura entre cuatro y ocho semanas. No se detectaron efectos adversos atribuibles al tratamiento con trilostano. El recrecimiento del pelo puede que fuera consecuencia de una regulacin a la baja de los esteroides adrenales y/o de una inhibicin no-competitiva de los receptores de estrgenos
a nivel del folculo.
Zusammenfassung Sechzehn Pomeranians und acht Zwergpudel mit klinischen Anzeichen von Alopecia X,
erhhter Blutkonzentration von 17-Hydroxyprogesteron nach Stimulation mit ACTH und erhhtem Cortisol/
Creatinin-Quotienten im Urin wurden mit Trilostan, einem kompetetiven Hemmer von 3--hydroxysteroidDehydrogenase behandelt. Trilostan wurde einmal oder zweimal tglich in einer durchschnittlichen Dosierung
von 10,85 mg/kg tglich gegeben. Die Nebennierenfunktion wurde mit einem follow up von 28 Monaten bei den
Pomeranians und 33 Monaten bei den Zwergpudeln berprft. Die Behandlung mit Trilostan fhrte bei 85% der
Pomeranians und bei allen Zwergpudeln innerhalb von vier bis acht Wochen zu einem vollstndigen Nachwachsen der Haare. Es wurden keine auf die Behandlung mit Trilostan zurckzufhrende Nebenwirkungen festgestellt. Das Nachwachsen der Haare kann auf eine Verminderung der adrenalen Steroide und/oder auf eine nicht
kompetetive Hemmung der strogen-Rezeptoren auf Ebene der Haarfollikel zurckzufhren sein.

2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 285293