The Use of Trilostane for the Treatment of Alopecia X in Alaskan Malamutes
Three Alaskan malamutes with hair loss and slightly elevated blood concentrations of 17-hydroxyprogesterone after stimulation with adrenocorticotropic hormone (ACTH) were treated with trilostane. Trilostane, an inhibitor of 3 β-hydroxysteroid dehydrogenase, was given twice daily at a dose of 3.0 to 3.6 mg/kg per day orally for 4 to 6 months. Routine ACTH stimulation tests were performed over 8 months to evaluate the degree of adrenal function suppression. Treatment with trilostane led to complete hair regrowth in all three dogs within 6 months. No adverse effects associated with trilostane were recognized.
Introduction
A poorly understood type of hair loss affects Alaskan malamutes and is commonly called “coat funk” by malamute breeders. The condition is well recognized by breeders, and the American Alaskan Malamute Club (AMC) has sponsored research into this condition for several years. Informal results of this research are summarized on the AMC website.1 Male dogs are said to be more frequently affected.1 Affected dogs are presented with a progressive, nonpruritic hair loss generally starting between 2 and 7 years of age.1 Initially, the disorder is characterized by permanent loss of the guard hairs, giving affected dogs a “woolly lamb” appearance. The first affected areas are the neck, tail, and the pressure points such as the haunches. Subsequently, hair loss progresses to involve the whole body, but the head and limbs are spared. Affected dogs are healthy, and routine hormonal blood tests are normal.1 Various endocrine abnormalities or hair follicular disorders have been suspected, and affected dogs have been treated empirically with thyroxine, sex hormones, or castration. Results have been inconsistent, and hair regrowth has been temporary.1
The condition is considered by breeders to be similar to the syndrome called alopecia X, which affects other Nordic breeds.1 Alopecia X is associated with mild pituitary-dependent hyperadrenocorticism, and it has been successfully treated with trilostane in Pomeranians and miniature poodles.2,3 Successful trilostane therapy in these breeds prompted this evaluation of trilostane’s efficacy in three Alaskan malamutes with apparent alopecia X. Trilostane is an inhibitor of 3 β-hydroxysteroid dehydrogenase.4 It has been used since the 1970s for the treatment of Cushing’s syndrome in humans, for breast cancer and termination of pregnancy in women, and for experimental abortion in sheep.5–8 Trilostane has been reported to be effective in equine and canine hyperadrenocorticism and has recently been licensed for use in dogs with hyperadrenocorticism in the United Kingdom.9–11
The purpose of this study was to report the successful treatment with trilostane in three Alaskan malamutes suffering from “coat funk.”
Case Reports
Case No. 1
A 50-kg, 9-year-old, intact male Alaskan malamute was presented with generalized nonpruritic alopecia of 5 years’ duration. Initially, a progressive loss of truncal primary hair and the development of a woolly coat occurred. These changes progressed to alopecia affecting the neck, trunk, and abdomen, with progressive cutaneous hyperpigmentation. The head and the limbs were spared. Several episodes of superficial pyoderma responded to treatment with antibiotics. Previous therapy also included thyroxinea (10 μg/kg per os [PO] q 12 hours for 6 months) and then melatoninb (3 mg PO q 12 hours for 3 months), with no regrowth of hair. The dog was fed a commercially balanced diet and was otherwise in good health. On presentation, generalized alopecia was noted as described previously, and there was also dorsal scaling with comedones, a few pustules, and epidermal collarettes indicative of a superficial pyoderma. Sparse hair was present on the tail, with focal areas of alopecia on the dorsal aspect and at the tip. No systemic signs of internal disease or other dermatological lesions were present.
Differential diagnoses included hypothyroidism, hyperadrenocorticism, sex hormone imbalance (e.g., Sertoli’s cell tumor), alopecia X, demodicosis, and dermatophytosis. Routine dermatological investigations (e.g., skin scrapings, trichogram, and fungal culture) were negative for parasites and fungi. On a trichogram, most of the hairs were in the telogen stage. Routine hematological, biochemical, and urinalysis values were within normal ranges. Hormonal assays were performed to evaluate thyroid and adrenal function [Table 1]. Blood was collected before and 1 hour after intravenous (IV) administration of 0.25 mg of tetracosactin acetate,c and the results were within normal range [Table 1].
Ultrasonography of the testicles and the adrenal glands showed they were of normal size and shape. Although the testicles were clinically and ultrasonographically normal, castration was performed to rule out the possibility of an occult estrogen-secreting tumor (e.g., Sertoli’s cell tumor) and because such cases have anecdotally responded to castration.12 Histological examination of the testicles failed to reveal any abnormalities. Systemic antibiotic therapy with cephalexind (25 mg/kg PO q 12 hours) for 4 weeks and benzoyl peroxide shampooe to be used once weekly were instituted, and the superficial pyoderma resolved.
One year later, the dog remained healthy except for the alopecia, which had slightly progressed [Figure 1]. Routine hematological and biochemical tests and urinalysis were again within normal limits. Various hormonal assays were performed [Table 1]. An ACTH stimulation test showed normal cortisol concentrations on both pre- and postACTH assays but an increased concentration of 17-hydroxyprogesterone (OHP) postACTH. A low-dose dexamethasonef (0.01 mg/kg IV) suppression test was also performed, with cortisols measured before and at 4 and 8 hours. The results showed normal cortisol suppression at 4 hours with borderline suppression at 8 hours [Table 1]. Ultrasonography of the adrenal glands was repeated and found to be normal. Skin biopsy specimens from alopecic areas revealed follicular atrophy and hair follicles in telogen stage with trichilemmal keratinization [Figures 2A, 2B].
Because of a lack of response to previous therapies and because the clinical presentation and endocrine and histological findings were consistent with alopecia X, treatment with trilostaneg (3.6 mg/kg PO q 12 hours) was initiated.3 Two months later, slight hair regrowth was apparent, and hair growth was marked by 6 months [Figures 3A, 3B]. Follow-up reexaminations were performed 2 weeks, 4 weeks, 3 months, and 6 months after starting therapy to evaluate the safety, efficacy, and degree of adrenal suppression caused by the trilostane. At each examination, routine hematological, biochemical, and electrolytes assays were performed. All results were normal. An ACTH stimulation test was also performed at each examination, and the cortisol assays were within the normal range, confirming that suppression of adrenal function was not excessive with the dose of trilostane used [Table 2]. No adverse effects were reported by the owner. After 6 months of daily therapy, trilostane was reduced to twice weekly. One year after starting the therapy, the hair coat was considered good, and trilostane was completely withdrawn. No alopecia has developed during the 18 months of follow-up.
Case No. 2
A 40-kg, 4-year-old, intact male Alaskan malamute was presented for a lack of hair regrowth following loss of his winter coat and progressive alopecia over a 2-month period. Dermatological examination revealed a sparse, dull, and woolly coat. Marked hair loss was evident on the trunk, thighs, and base of the tail [Figure 4]. The skin in the affected areas was hyperpigmented.
Routine dermatological (e.g., skin scrapings, trichogram, and fungal culture), hematological, biochemical, and urinary tests were all normal. Results of thyroid function tests and sex hormone assays were normal. PostACTH stimulation tests showed increased concentrations of 17-OHP, and the 8-hour cortisol assay of the low-dose dexamethasonef suppression test was at the upper limits of normal [Table 1]. On ultrasonography, both testicles and the adrenal glands were normal in size and shape. Skin biopsy specimens were collected from the alopecic areas and were similar to case no. 1. Trilostane therapy was started at 3 mg/kg PO q 12 hours. Follow-up examinations and blood testing were performed similar to case no. 1 and were normal [Table 2]. Full hair regrowth occurred within 4 months. No side effects were noted from the trilostane. After 4 months of daily therapy, trilostane was reduced to twice weekly. Eight months after starting the therapy, the hair coat was considered good, and trilostane was completely withdrawn. No alopecia has developed during the 12 months of follow-up.
Case No. 3
A 40-kg, 4-year-old, intact male Alaskan malamute was presented with progressive hair loss of 2 months’ duration, which affected the neck, trunk, and tail. General physical examination revealed no abnormalities, but the dermatological examination showed a generalized, sparse, woolly coat with marked alopecia and hyperpigmentation of the tail. Routine dermatological (e.g., skin scrapings, trichogram, and fungal culture) investigations were negative for ectoparasites and fungi. Results of hematological and biochemical tests were within normal limits. Results of endocrine tests and histopathology of skin biopsies were similar to case nos. 1 and 2 [Table 1]. Therapy with trilostane (3 mg/kg PO q 12 hours) was started, and follow-up examinations were performed as done for case nos. 1 and 2 [Table 2]. Full hair regrowth was evident within 4 months of therapy. No adverse effects were reported by the owner. After 4 months of daily therapy, trilostane was reduced to twice weekly. Six months after starting the therapy, the hair coat was considered good, and trilostane was completely withdrawn. No alopecia has developed during the 16 months of follow-up.
Pedigree Analysis
Five-generation pedigrees were available for the three dogs. For all three dogs, one common male ancestor was present. This ancestor was the sire of case no. 1 and also his maternal grandfather. The common ancestor was also present twice in the sire’s line and once in the dam’s line of case no. 2. The common ancestor was present twice in the sire’s line of case no. 3.
Control Group
An ACTH stimulation test was also performed in three clinically normal Alaskan malamutes (with the owners’ consent), using the same protocol as in the affected dogs. All measured hormones were normal. The concentrations of 17-OHP in the postACTH assay in the affected dogs (before treatment) were significantly different from the clinically normal dogs (P=0.0495, two-tail probability; Mann-Whitney U test).h
Discussion
The three cases detailed in this report fit the description of the “coat funk” described by Alaskan malamute breeders and also matched the criteria for alopecia X.3 The clinical presentation of generalized, symmetrical alopecia was compatible with an endocrine disorder. Tests on these three dogs indicated normal thyroid function and showed that pre- and postACTH cortisol levels were in the normal range. Results of a low-dose dexamethasone suppression test did not reveal hyperadrenocorticism in any of the dogs. Other tests, such as urinary cortisol/creatinine ratios collected over a 10-day period, might have detected a periodic increase of cortisol excretion (as found in Pomeranians with abnormal pituitary-adrenal axis function), but they were not performed in the cases reported here.2 Because no other clinical signs or hematological and biochemical abnormalities were present, hyperadrenocorticism was considered unlikely in all three dogs.
PostACTH concentrations of 17-OHP were increased in all three cases, in contrast to a recent report by Frank et al.13 However, in the report by Frank et al., the dermatological/endocrinological status of the dogs was unclear, thus making comparison difficult with the dogs reported here. Differences between both sets of tests may also have arisen from the use of a different laboratory for the 17-OHP assay techniques.14 Comparisons with 17-OHP concentrations in clinically healthy Alaskan malamutes showed that the affected dogs in this report had increased concentrations that were statistically significant. The measurement of 17-OHP has been utilized as an indicator of adrenal and gonadal steroidogenesis; however, the reference ranges of normal Alaskan malamutes, of dogs with abnormal steroidogenesis, and of dogs with hyperadrenocorticism require further evaluation.15–19 Furthermore, the correlation between elevations in 17-OHP concentrations and alopecia needs to be explained. It is possible that other hormones involved in steroidogenesis and/or their effect at the level of the hair follicle may play an important role in inducing hair loss in predisposed dogs.
Although this report describes only three cases and does not allow confident assessment of heritability, there is an indication from the pedigrees of the three dogs that a familial predisposition may be present. A common ancestor was found in all three pedigrees, and it appeared in both the sire’s and the dam’s line of two of the reported cases. Anecdotal reports from Alaskan malamute breeders suggest that this condition may easily spread throughout the breeding population, because females might be asymptomatic carriers, and affected males generally do not exhibit clinical signs until they are mature.1 Thus, dogs may have been used for breeding several times before the disease becomes apparent. Blood tests, such as the measurement of the 17-OHP before and after ACTH administration, or genetic mapping of affected dogs, might be useful to screen for carriers of the condition and to eliminate them from breeding programs; however, further studies are necessary to validate such a screening program.
The histological findings of these dogs resembled the hair follicle abnormalities found in other dog breeds with adult-onset alopecia or alopecia X, and suggested that similar factors (e.g., endocrine) may have affected the hair follicle function, leading to progressive hair loss.
This alopecia of malamutes appears to be only an aesthetic problem. One of the affected dogs (case no. 1) suffered from alopecia for some time without developing any other clinical signs. The woolly coat and hair loss are major causes of concern for breeders and owners. Many anecdotal reports exist of treatment for affected dogs with various surgical or medical modalities. Neutering has been the treatment of choice in the past, and hair regrowth has been achieved in some cases, but it may last for only a few years.1 Whether alopecia occurs in neutered dogs early in life is unclear. Drugs such as mitotane have also been used with variable results; however, there is a risk of adverse effects with mitotane. Growth hormone therapy has also been suggested, but the risk of adverse effects is high and the response to therapy uncertain.12 Melatonin has been proposed as a safe alternative to other drugs in dogs with alopecia X.20 Melatonin may modulate steroidogenesis of sex hormones, especially at high doses, but its efficacy in the treatment of affected malamutes has not been studied.21
Results of the study reported here suggest that trilostane is a valid and safe choice for the treatment of this type of hair loss in Alaskan malamutes. Side effects associated with adrenal function suppression were not observed in these dogs, and routine biochemical tests did not show any abnormalities. The effect of trilostane might be related to the modulation of steroidogenesis both at the adrenal level and/or at the skin/hair follicle by down-regulating steroid production or up-regulating ACTH production with subsequent hair regrowth.22,23 Further studies are required to evaluate the exact mechanism of action and adverse effects of long-term use.
The dose of trilostane used in this study was lower than that used in Pomeranians and miniature poodles, and it may have accounted for the slower response in hair regrowth in these cases (when compared to the other two breeds).3 The cost of trilostane is an issue in the long-term treatment of such large-breed dogs. In affected Pomeranians, administering the drug two or three times weekly has enabled hair growth and coat quality to be maintained in some dogs, and these lower frequencies may also prove efficacious in the malamute.3 It might be possible to vary the dosage once a good clinical response is achieved, which would be an advantage in reducing the cost of the maintenance therapy. It is possible that trilostane works in reversing hair loss by initiating new hair growth, and the drug may not be needed continuously for growth of anagen hairs; therefore, pulse therapy may also be effective.
Conclusion
The type of hair loss reported in this paper is a well-recognized syndrome among breeders and owners of Alaskan malamutes. Its pathogenesis is not well understood, but the dogs in this report had mildly elevated blood concentrations of 17-OHP following administration of ACTH. Trilostane was effective and apparently safe for treating this condition in three affected malamutes.
Eutirox; Bracco, Milano, Italy
Melatonina, generic; Italy
Synacthen; Novartis, Origgio, Italy
Ceporex; Glaxo Wellcome, Verona, Italy
Fatroxid; Fatro, Ozzano Emilia, Italy
Decadron fosfato; Merck Sharp & Dohme, Milano, Italy
Modrenal; Stegram, Billingshurst, England
Unistat Statistical Package, version 4.53; Unistat Ltd. London, England
Acknowledgments
The authors are grateful to Stegram Pharmaceuticals for supplying trilostane; to Helen Evans of the Cambridge Specialist Laboratory Service, Cambridge, United Kingdom, for performing the hormonal measurements; and to Kristian Pederson, DVM, for performing the ACTH stimulation tests in normal Alaskan malamutes. The authors have no financial interest in the manufacture of trilostane.
Citation: Journal of the American Animal Hospital Association 41, 5; 10.5326/0410336
![Figures 2A, 2B—. (A) Histopathology of affected skin of the dog in Figure 1, showing follicular atrophy and hyperkeratosis with hair follicles in telogen stage and trichilemmal keratinization (hematoxylin and eosin [H&E] stain, bar=400 μm); (B) Higher magnification of a hair follicle with trichilemmal keratinization (H&E stain, bar=50 μm).](/view/journals/aaha/41/5/p339fig2a.jpeg)
![Figures 2A, 2B—. (A) Histopathology of affected skin of the dog in Figure 1, showing follicular atrophy and hyperkeratosis with hair follicles in telogen stage and trichilemmal keratinization (hematoxylin and eosin [H&E] stain, bar=400 μm); (B) Higher magnification of a hair follicle with trichilemmal keratinization (H&E stain, bar=50 μm).](/view/journals/aaha/41/5/full-p339fig2a.jpeg)
![Figures 2A, 2B—. (A) Histopathology of affected skin of the dog in Figure 1, showing follicular atrophy and hyperkeratosis with hair follicles in telogen stage and trichilemmal keratinization (hematoxylin and eosin [H&E] stain, bar=400 μm); (B) Higher magnification of a hair follicle with trichilemmal keratinization (H&E stain, bar=50 μm).](/view/journals/aaha/41/5/inline-p339fig2a.jpeg)
![Figures 2A, 2B—. (A) Histopathology of affected skin of the dog in Figure 1, showing follicular atrophy and hyperkeratosis with hair follicles in telogen stage and trichilemmal keratinization (hematoxylin and eosin [H&E] stain, bar=400 μm); (B) Higher magnification of a hair follicle with trichilemmal keratinization (H&E stain, bar=50 μm).](/view/journals/aaha/41/5/p339fig2b.jpeg)
![Figures 2A, 2B—. (A) Histopathology of affected skin of the dog in Figure 1, showing follicular atrophy and hyperkeratosis with hair follicles in telogen stage and trichilemmal keratinization (hematoxylin and eosin [H&E] stain, bar=400 μm); (B) Higher magnification of a hair follicle with trichilemmal keratinization (H&E stain, bar=50 μm).](/view/journals/aaha/41/5/full-p339fig2b.jpeg)
![Figures 2A, 2B—. (A) Histopathology of affected skin of the dog in Figure 1, showing follicular atrophy and hyperkeratosis with hair follicles in telogen stage and trichilemmal keratinization (hematoxylin and eosin [H&E] stain, bar=400 μm); (B) Higher magnification of a hair follicle with trichilemmal keratinization (H&E stain, bar=50 μm).](/view/journals/aaha/41/5/inline-p339fig2b.jpeg)
Citation: Journal of the American Animal Hospital Association 41, 5; 10.5326/0410336
Citation: Journal of the American Animal Hospital Association 41, 5; 10.5326/0410336
Citation: Journal of the American Animal Hospital Association 41, 5; 10.5326/0410336
Photograph of case no. 1, 1 year after castration, illustrating diffuse truncal hair loss and cutaneous hyperpigmentation.
(A) Histopathology of affected skin of the dog in Figure 1, showing follicular atrophy and hyperkeratosis with hair follicles in telogen stage and trichilemmal keratinization (hematoxylin and eosin [H&E] stain, bar=400 μm); (B) Higher magnification of a hair follicle with trichilemmal keratinization (H&E stain, bar=50 μm).
Case no. 1 at 2 months (A) and 6 months (B) after starting therapy with trilostane, illustrating sparse (A) and complete (B) hair regrowth.
Alopecia of the base of the tail in case no. 2. Note the hyperpigmentation of the skin in the affected area.
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