1. General Considerations

   1. The name alopecia X has been adopted because the nature of this condition is currently unknown. Alopecia X was previously referred as adult-onset growth hormone response alopecia, pseudo-cushing’s syndrome, castration responsive alopecia, biopsy-responsive alopecia, congenital adrenal hyperplasia-like syndrome, adrenal sex hormone imbalance and, more recently, hair cycle arrest. Hair cycle arrest is the histopathological hallmark of Alopecia X; thus, the name “hair cycle arrest” should be adopted.
   2. It is seen especially in young adult dogs at the age of 1 to 3 years but clinical signs can develop at 4 to 5 years of age.
   3. Females or males can be affected independent of neuter status.
   4. If alopecia develops in intact dogs, hair regrowth may occur after neutering but relapse after 1 to 2 years should be expected.
   5. There is predilection for Nordic breeds such as chow chow, Pomeranian, keeshound, spitz, Samoyed, Alaskan malamute and Siberian husky. However, it has also been reported in other breeds including miniature poodles. Pomeranians are over-represented.

2. Pathogenesis

   1. The cause of hair cycle arrest in these dogs is currently unknown. Genetic factors likely play a role since certain breeds are more often affected and it may occur in related dogs.
   2. Growth hormone was thought to play a role but this theory has fallen into disbelief.
   3. Some people believe that it is a form of pattern baldness similar to the disease in people where gain of function mutation of the gene that encodes the enzyme 5-alfa reductase has been identified. This enzyme converts testosterone to dihydrotestosterone (DHT). The accumulation of DHT in the scalp leads to follicular arrest and miniaturization of androgen-responsive hair follicles. A study looked at the mRNA expression of three 5-alfa reductase enzymes of normal skin of four intact females and three intact males. Samples were taken from skin sites frequently affected and less frequently affected with alopecia X. The authors found expression of two 5-alfa reductase isoforms (5-alfa R1 and 5-alfa R3). No significant differences were noted in expression levels of the isoforms between skin sites irrespective of gender. This study set the foundation for the investigation of mutation in this enzyme in dogs with alopecia X or hair follicle arrest.
   4. The disease has been postulated to be an endocrine disorder associated with an abnormality of the adrenal steroidogenesis due to partial deficiency of the 21-hydroxylase enzyme because many, but not all, affected dogs have an increase of adrenal intermediate hormones, especially 17-hydroxyprogesterone. However, recent studies have shown that the altered adrenal steroid hormones do not return to normal levels after response to therapy leading us to believe that abnormal adrenal steroidogenesis may not play a role in the pathogenesis of this disease. Moreover, in contrast to people with deficiency of the 21-hydroxylase enzyme (i.e. congenital adrenal hyperplasia), dogs with alopecia X do not develop signs of hyperandrogenism. Finally, no mutation in the canine 21-hydroxylase gene has been found in Pomeranians with alopecia X. These findings indicate that alterations in adrenal steroidogenesis do not play an important role in disease pathogenesis.
   5. A number of cases have also been associated with mildly elevated urine cortisol:creatinine ratio and some colleagues have considered alopecia X as a mild form of hyperadrenocorticism. However, affected dogs do not have any of the clinical signs (other than non-inflammatory alopecia) associated with hyperadrenocorticism. In addition, the ACTH stimulation test or low-dose dexamethasone suppression test are normal in affected dogs.
   6. One of the features of alopecia X is the trauma-induced hair growth indicating that local inhibition of anagen rather than systemic inhibition is related with disease pathogenesis. The most recent belief is an over-activity of hair follicles estrogen receptors. This theory is reasonable because the clinical signs of alopecia X are localized and estrogen and estrogen receptors are known to participate in anagen inhibition. Moreover, melatonin and trilostane, two drugs known to work for alopecia X, have shown to down regulate estrogen receptors in humans’ breast cancer cells in vitro. These findings support the theory that increased activity of estrogen receptors at the hair follicle level may play a role in this disease. However, the use of a specific estrogen receptor antagonist in dogs with alopecia X resulted in disappointing outcomes.

3. Clinical Signs

   1. The initial sign that may be overlooked is the development of a dry and dull hair coat and loss of guard hairs. Thereafter, alopecia of the neck, perineum, caudal dorsal back, tail, and caudal thighs develop. Eventually complete truncal alopecia occurs. Affected skin often becomes hyperpigmented to various extent.

1. 1. The pattern of alopecia resembles endocrinopathies such as hyperadrenocorticism and hypothyroidism and spares the head and distal legs. However, the caudal aspects of the thighs are often affected.

1. 3. Similar to other non-inflammatory alopecic disorders, this condition is NOT pruritic. Dogs are healthy other than having hair loss.
   4. Hyperpigmentation is often intense at the sites of alopecia but it is not always present.

1. 5. Hair will regrow in focal areas of trauma such as skin biopsy sites. This suggests that inflammation activates the growing phase of hair follicles. In other words, inflammation induces the resting phase of hair follicles (telogen or kenogen) to go to the growing phase (anagen).

4. Diagnosis

   1. Definitive diagnosis should be based on a characteristic history and clinical signs and laboratory test results that rule out other disorders associated with non-inflammatory alopecia such as, hypothyroidism, sex hormone imbalance in intact dogs, hyperadrenocorticism, follicular dysplasia, and flank alopecia.
   2. Perform multiple skin scrapings to rule out demodicosis.
   3. An ACTH stimulation test can be performed with the purpose of having the adrenal steroid hormones measured. If the 17-hydroxyprogesterone is elevated and hypothyroidism and hyperadrenocorticism have been ruled out, a presumptive diagnosis of alopecia X can be given. The test protocol is the same used for the diagnosis of hyperadrenocorticism; however, the samples have to be submitted to the Endocrinology Laboratory at the University of Tennessee for measurement of adrenal steroid hormones. This test is rarely performed by dermatologists because its diagnostic value is questionable.
   4. Urine cortisol/creatinine ratio has been increased in some cases and this finding can be supportive of alopecia X if other diseases (mainly hyperadrenocorticism) have been ruled out.
   5. Skin biopsy – The histopathologic findings are non-specific and compatible with endocrine skin disorders.

5. Treatment

   1. This is a disorder of aesthetic concerns and the option of no treatment should be discussed with the pet owner.
   2. Recommend neutering if the animal is intact. Hair should regrow in 3 to 4 months but relapses may occur after 1 to 2 years.
   3. If medical treatment is successful, it is important to advice owners that alopecia may recur after a few months to years despite continued therapy.
   4. A trial with melatonin can be performed using the empirical dosage of 3 mg every 8 hours for small breeds and 6-12 mg every 8 hours for large breeds. This drug should be tried for 3 to 4 months before the treatment efficacy can be evaluated.
   5. Other treatment options are:
      1. Trilostane – It is primarily used in the management of canine hyperadrenocorticism. However, it has been used successfully in the management of dogs with alopecia X. The dosages used in case reports were higher than the dosage currently recommended for the treatment of hyperadrenocorticism. The authors do not recommend using doses higher than 1.0 to 2.0 mg/kg twice daily to treat an aesthetic disease. Monitor dogs carefully for signs of Addison’s disease (i.e. lethargy, depression, vomiting, and diarrhea).
      2. Mitotane – It has also been used in the management of dogs with Alopecia X that have not responded to melatonin. The induction dosage is 15 to 25 mg/kg/day, which is lower than the induction dose recommended for the management of hyperadrenocorticism (50 mg/kg/day).  After 5 to 7 days, or earlier if signs of glucocorticoid deficiency develop, an ACTH stimulation test should be performed. Post-ACTH cortisol concentration has been reported to be around 12 µg/dl. After 5 to 7 days, start the maintenance at 15 to 25 mg/kg per week (divided into 2 to 3 days). Monitor carefully for signs of Addison’s disease when using this medication.
      3. Be sure to discuss with clients the potential side effects and cost of treating dogs with trilostane and mitotane. Benefits and cost have to be taken into consideration when treating a disease of aesthetic concerns.
      4. Deslorelin acetate (Suprelorin®) – It is a non-steroidal, peptide-based contraceptive implant containing a GnRH-agonist. It provides long-term suppression of pituitary gonadotrophin production and release. It has shown to induce hair regrowth within 2 to 4 months in intact male dogs with a success rate of about 75%. Spayed females did not respond in one study and neutered males have not been included in any of the published reports. In one study, no recurrence of alopecia occurred in two dogs (keeshond) after 14 months of a single deslorelin treatment. No adverse effects were noted in the reports. More studies need to be done to confirm these results but deslorelin can be considered a treatment option for Alopecia X, especially in intact male dogs.
      5. Microneedling is a technique used in people for many years for skin tightening and scar therapy. It involves administering to the skin multiple punctures with a drum-shaped instrument that has fine protruding needles. These needles generate tiny pinpoint perforations of the skin that close within a few minutes. Because of its regenerative properties, this intervention has shown to improve alopecia areata in people. A recent report (see reference below for more detail) showed 90% hair regrowth after 12 weeks of the intervention in two Pomeranian dogs with Alopecia X that had not responded to other treatment modalities. The dogs were anesthetized and microneedling (Dermaroller®) was applied to the alopecic areas diagonally, vertically and horizontally, four to five times in each direction until capillary bleeding was noted. They used two lengths of needles (1.5 mm and 2.5 mm) and found that the 2.5 mm was easier to apply and the hair regrew faster compared to the 1.5 mm. No recurrence was noted after 12 months of the procedure. No adverse effects were noted.
      6. Photobiomodulation with or without melatonin has been considered as treatment option for Alopecia X. Refer to the paper by Martins FA et al for details on the protocol proposed.

References

Albanese F, Malerba E, Abramo F et al. Deslorelin for the treatment of hair cycle arrest in intact male dogs. Vet Dermatol 2014; 25:519-288.

Cerundolo R, Lloyd D.H., Persechino A et al.  Treatment of canine Alopecia X with trilostane.  Vet Dermatol 2004; 15: 285-293.

Cerundolo R, Warren S. The use of deslorelin to promote hair regrowth in dogs with Alopecia X, in Proceedings. 26th Annual Congress of the ESVD-ECVD 2013; 184.

DeClementi C, Bailey K.L., Goldstein SC et al.  Suspected toxicosis after topical administration of minoxidil in 2 cats.  J Vet Emerg and Crit Care 2004; 14(4):287-292.

Frank L.A. Hnilica K.A., Oliver JW.  Adrenal steroid hormone concentrations in dogs with hair cycle arrest (Alopecia X) before and during treatment with melatonin and mitotane.  Vet Dermatol 2004; 15:278-284.

Layne EA and Richmond RV. Deslorelin implant treatment for hair cycle arrest (Alopecia X) in two intact male keeshonden. J Am Hosp Assoc 2018; 54. DOI 10.5326/JAAHA-MS-6646.

Lothrop, CD Jr.: Pathophysiology of growth hormone responsive dermatosis.  Compend. Cont. Ed.  1998; 1346-1352.

Martins FA, da Silva GA, de Oliveria APL, et al. Comparison between melatonin versus melatonin and photobiomodulation versus photobiomodulation in the treatment of Alopecia X in German Spitz dogs: Clinical, randomized, double-blinded, parallel, non-inferiority protocol. Plos One 2024; https://doi.org/10.1371/journal.pone.0304605.

Miller WH, Griffin GE, Campbell KL. Muller & Kirk’s Small Animal Dermatology. 7th ed. St. Louis: Elsevier Inc., 2013; 537-540.

Miller WH, Griffin GE, Campbell KL. Muller & Kirk’s Small Animal Dermatology. 7th ed. St. Louis: Elsevier Inc., 2013; 554-572.

Miller WH, Griffin GE, Campbell KL. Muller & Kirk’s Small Animal Dermatology. 7th ed. St. Louis: Elsevier Inc., 2013; 593-599.

Miller WH Jr, Scott DW. Follicular dysplasia of the Portuguese water dog. Vet Derm 1995; 6:67-74.

Muntener T, Schuepbach-Regula G, Frank L, et al. Canine noninflammatory alopecia: a comprehensive evaluation of common and distinguishing histological characteristics. Vet Dermatol  2012; 23: 206-e44. DOI: 10.1111/j.1365-3164.2012.01049.x

Schmeitzel LP & Lothrop CD Jr. Hormone abnormalities in Pomeranians with normal coat and those with growth hormone responsive dermatosis.  J Am Vet Med Assoc 1990; 15: 1333-1341.

Schmeitzel LP.  Sex hormone-related and growth hormone-related alopecias.  Vet. Clin. North. Am. (Small Anim Pract) 1990; 20: 1579-1601.

Stoll S. et al. Microneedling as a successful treatment for alopecia X in two Pomeranian siblings. Vet Dermatol 2015.

Welle M, Philippe U, Rüfenacht S, et al. MLPH genotype—melanin phenotype correlation in dilute dogs. J Hered 2009;100: S75–S79.