CASE REPORTS

Canine Alopecia Secondary to Human Topical Hormone Replacement Therapy in Six Dogs Darren J. Berger, DVM, DACVD, Thomas P. Lewis, DVM, DACVD, Anthea E. Schick, DVM, DACVD, Rose I. Miller, DVM, DACVD, Diana G. Loeffler, MS, DVM, DACVP

ABSTRACT Alopecia is a common presenting complaint in veterinary medicine and is known to occur secondary to numerous primary conditions. In this report, six unrelated dogs from three households were subsequently determined to have developed alopecia as a result of accidental transdermal exposure to their owners’ topical hormone replacement therapy (THRT). All cases presented with alopecia ranging in duration from 2 mo to 2.5 yr. All dogs demonstrated alopecia affecting the ventral neck, thoracic and abdominal surfaces, proximal lateral extremities, and lateral trunk. At the time of initial presentation, five of six dogs were also noted to have physical exam findings suggestive of feminization. In all cases, serum total thyroxine was within normal reference range. Affected skin was biopsied in five dogs, and all samples demonstrated four similar histological characteristics: basal melanosis, epidermal and infundibular follicular hyperkeratosis, kenogen hair follicles, and small sebaceous glands. All dogs had elevated baseline estradiol levels, and four dogs had concurrent elevations of baseline progesterone. Average time to onset of clinical signs in those dogs was 5.5 mo after the owners started THRT. Following discontinuation of THRT by the owners, all dogs had complete resolution of their clinical signs by 5.5 mo. (J Am Anim Hosp Assoc 2015; 51:136–142. DOI 10.5326/JAAHA-MS-6247)

Introduction Presentation of canine patients with a primary complaint of alopecia is common amongst owners seeking veterinary medical care from both primary care practitioners and veterinary dermatologists. Alopecic conditions that occur in the dog are commonly classified as either inflammatory or noninflammatory in origin. Inflammatory dermatoses that result in alopecia are most commonly associated with demodicosis, pyoderma, and dermatophytosis, but also include such diseases as sebaceous adenitis,

one of two conditions: those that result from abnormal hair growth (e.g., congenital alopecia, color dilution alopecia, and black hair follicular dysplasia) or those causing hair cycle arrest (e.g., endocrine disturbances, alopecia X, recurrent flank alopecia, pattern baldness, and breed-specific alopecias).2 This report describes the clinical findings and outcomes in six unrelated dogs from three households presented with progressive alopecia that was subsequently determined to be the result of accidental transdermal exposure to their owners’ topical hormone replacement therapy (THRT).

alopecia areata, pemphigus foliaceus, and epitheliotrophic T-cell lymphoma. Alopecia secondary to those diseases usually presents

Case Report

with a patchy or well-demarcated distribution, while noninflam-

Household 1

matory dermatoses tend to result in a diffuse and often symmetrical

A 19 mo old castrated male Boston terrier (case 1) presented with a

appearance.1 Noninflammatory causes of alopecia may arise from

1 yr history of progressive alopecia. The dog had a historical

From the Iowa State University College of Veterinary Medicine, Ames, IA (D.B.); Dermatology for Animals (T.L., A.S., R.M.); and DVM

ACTH, adrenocorticotropic hormone; CBC, complete blood cell count; T4, thyroxine; THRT, topical hormone replacement therapy

Pathology Associates (D.L.). Correspondence: [email protected] (D.B.)

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Canine Alopecia Following Human THRT Exposure

diagnosis of juvenile-onset generalized demodicosis that resolved

cortisol and aldosterone were within normal limits. During

following appropriate therapy with ivermectina (500 lg/kg per os q

discussion of adrenal panel results with the owner, it was

b

24 hr) and frequent bathing with a benzoyl peroxide shampoo.

discovered that she was enrolled in a clinical trial for a THRT

Blood work performed prior to referral to the authors revealed a

product involving application of estradiol and progesterone

9

9

mild leukocytosis (17.10 3 10 /L; reference range, 4.0–15.50 3 10 / 9

L) with a mature neutrophilia (12.48 3 10 /L; reference range, 9

9

creamse to her medial forearms. Based on the new information from the owner and adrenal panel results, the cause of the dog’s

2.06–10.60 3 10 /L) and monocytosis (1.03 3 10 /L; reference

alopecia was determined to be hyperestrogenism secondary to

range, 0.0–0.84 3 109/L), as well as a mild thrombocytosis (489 3

exogenous estradiol exposure. At that time, the owner was advised

9

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10 /L; reference range, 170–400 3 10 /L). The remainder of the

to discuss alternative treatment options for herself with her

complete blood count (CBC), serum biochemical profile, serum

physician. Complete resolution of the dog’s alopecia was observed

total thyroxine (T4), and serum free T4 values were within normal

3.5 mo following discontinuation of THRT by the owner.

limits. Following an ineffective diet trial and continued progressive alopecia, the dog was referred to a dermatologist.

Household 2

At the time of initial presentation, marked, noninflammatory

Household two contained three unrelated Chinese pugs: a 3 yr old

alopecia of all ventral surfaces and moderate patchy alopecia of the

spayed female (case 2), a 4.5 yr old castrated male (case 3), and a

lateral thorax, abdomen, and proximal extremities were appreci-

5.5 yr old spayed female (case 4). All three dogs were presented

ated. No other significant findings were noted on either physical

with varying degrees of progressive alopecia ranging in duration

examination or skin scrape samples. Based on clinical presentation

from 2–6 mo, with cases 2 and 3 previously having been evaluated

and physical exam, a noninflammatory alopecia secondary to an

by several different veterinarians. Case 2 had a CBC, serum

underlying endocrinopathy or follicular dysplasia was suspected.

biochemical profile, and total T4 performed 2 mo prior to

Two 6 mm diameter punch biopsies were obtained from alopecic

presentation, which were within normal limits. Case 3 also had a

areas and submitted for histological evaluation. Histopathology

prior CBC and serum biochemical profile performed, which were

results revealed minimal acanthosis, moderate basal melanosis,

within normal limits.

mild orthokeratotic hyperkeratosis and infundibular hyperkerato-

At the time of presentation to the authors, all three dogs

sis, kenogen follicles, small sebaceous glands, and a lack of

displayed varying degrees of noninflammatory alopecia. Extent of

inflammatory cells. Those results were suggestive of alopecia

the alopecia ranged from mild to complete along ventral surfaces

secondary to an underlying endocrine disturbance resulting in

and included mild to moderate patchy alopecia of the lateral

follicular arrest. Following review of the histopathology results, the

thorax, abdomen, and proximal extremities with varying degrees of

referring veterinarian was contacted to verify a bilateral orchiec-

hyperpigmentation. Mild to moderate vulvar enlargement was

tomy had been performed to rule out the possibility of

noted with cases 2 and 4, and vaginal discharge was also noted in

cryptorchidism and a Sertoli cell tumor as the cause of the dog’s

case 2. In case 3, mild preputial enlargement was appreciated, while

clinical presentation. At that time, it was discovered the referring

significant nipple enlargement was observed with cases 2 and 3. No

veterinarian had repeated a total T4 and submitted serum baseline

other significant findings were noted on physical exam, and skin

testosterone levels that were reported to be within normal limits.

scrape samples for mites were negative for all three dogs. Because

An adrenocorticotropic hormone (ACTH) stimulation test was

multiple unrelated dogs from the same household presented with

c

performed with synthetic corticotropin (0.125mg IV), and pre-

similar clinical symptoms, the owner was interviewed further

and 1 hr poststimulation serum samples were sent frozen overnight

regarding possible exposures all three dogs may have shared. The

d

for analysis . Results demonstrated elevated baseline and post-

owner stated that 4 mo prior to development of clinical signs in

ACTH levels for androstenedione (pre, 0.09 nmol/L; reference

case 2, she had begun using an estradiol-based form of THRTf that

range, 0.00–0.01 nmol/L; post, 0.17 nmol/L; reference range, 0.01–

was applied to the medial aspect of her forearms daily.

0.10 nmol/L), estradiol (pre, 760.26 pmol/L; reference range,

Interestingly, the owner noted that the two most severely affected

84.80–238.98 pmol/L; post, 641.69 pmol/L; reference range, 85.53–

dogs spent more time sitting on her lap than the less affected dog.

254.77 pmol/L), progesterone (pre, 7.54 nmol/L; reference range,

The clinical presentation and history provided by the owner were

0.10–0.54 nmol/L; post, 21.34 nmol/L; reference range, 0.70–4.61

suspicious for hyperestrogenism secondary to exogenous estradiol

nmol/L), and 17-hydroxyprogesterone (pre, 5.95 nmol/L; reference

exposure. At that time, samples for dermatophyte test medium

range, 0.25–0.70 nmol/L; post, 21.18 nmol/L; reference range, 0.80–

cultures were acquired from all three dogs that resulted in no

8.36 nmol/L). Baseline and postACTH stimulation serum levels for

observable growth. In addition, a CBC, serum biochemical analysis,

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and total T4 were performed, and all values were within normal

(Figure 1). The presence of significant nipple enlargement with

limits for all three dogs. Multiple 6 mm punch biopsies were

comedone formation in the surrounding skin was observed in both

acquired from alopecic areas on cases 2 and 3 (the two more

cases. Moderate vulvar enlargement was appreciated in case 6,

severely affected dogs) and submitted for histologic evaluation.

while no other significant findings were noted with the rest of the

Histopathology results were similar for the two dogs and

general physical exam. Skin scrape samples for parasites were

demonstrated mild to moderate orthokeratotic hyperkeratosis

negative in both cases.

and infundibular hyperkeratosis, mild basal melanosis, a predom-

Based on clinical presentation and physical exam findings,

inance of kenogen hair follicles, and small sebaceous glands. Case 3

noninflammatory alopecia secondary to THRT exposure was

also had a slightly atrophic epidermis. Finally, serum samples were

suspected. Further questioning of the owner revealed an estradiol

shipped frozen overnight (to the same laboratory used in case 1)

form of THRT use for the past 3 yr (the same product used by the

for baseline estradiol, progesterone, and testosterone levels.

owner in household 2). One 6 mm punch biopsy sample from

Estradiol levels were elevated in all three dogs (case 2, 1292.19

alopecic areas on both dogs was acquired and submitted for

pmol/L; reference range, 113.07–256.60 pmol/L; case 3, 402.34

histological evaluation. Serum samples were acquired from both

pmol/L; reference range, 84.8–238.98 pmol/L; case 4, 290.01 pmol/

dogs and shipped frozen overnight to the same laboratory used in

L; reference range, 113.07–256.60 pmol/L), and progesterone levels

the previously described cases for baseline estradiol, progesterone,

were elevated in two dogs (case 2, 4.01 nmol/L; reference range,

and testosterone levels. Histopathology results were almost

0.03–1.56 nmol/L; case 3, 2.32 nmol/L; reference range, 0.03–0.54

identical in both cases, demonstrating mild epidermal atrophy,

nmol/L). All three dogs’ baseline testosterone levels were within

mild to moderate orthokeratotic hyperkeratosis and infundibular

normal limits.

hyperkeratosis, moderate basal melanosis, presence of kenogen

Baseline hormone levels and biopsy results confirmed the

follicles, and small sebaceous glands. In case 6, mild excessive

suspicion of hyperestrogenism secondary to accidental THRT

trichilemmal keratinization was also appreciated. Baseline estradiol

exposure in the three dogs. After interpretation of diagnostic

levels were elevated in both dogs (case 5, 577.08 pmol/L; reference

results, the owner was advised to contact her physician regarding

range, 84.80–238.98 pmol/L; case 6, 526.05 pmol/L; reference

possible alternative treatment options. Following discontinuation

range, 113.07–256.60 pmol/L), and progesterone levels were

of THRT by the owner, all three dogs had complete resolution of

elevated in case 5 (2.77 nmol/L; 0.03–0.54 nmol/L). Testosterone

their alopecia and symptoms of feminization within 4 mo.

levels were within normal limits in both cases.

Household 3

levels were consistent with hyperestrogenism secondary to THRT

The third household consisted of two unrelated dogs: a 7 yr old

exposure, and the owner was advised to consult with her

castrated male basenji (case 5) adopted 1.5 years prior to

endocrinologist for an alternative treatment option. Following

presentation and an 11 yr old spayed female basenji (case 6) with

discontinuation of THRT by the owner, complete resolution of

a historical diagnosis of Fanconi syndrome. The two dogs were

alopecia and symptoms of feminization were noted in cases 5 and 6

presented for progressive alopecia of 1 and 2.5 yr duration,

by 4.5 and 5.5 mo, respectively (Figure 2).

The clinical presentation, biopsy results, and serum hormone

respectively. Both cases had blood work and dermatophyte test medium cultures performed prior to presentation. In both cases,

Discussion

culture yielded no growth and both dogs had a total T4 level within

Alopecia secondary to hyperestrogenism is well recognized in the

normal limits. Regarding case 5, a CBC, serum biochemical

dog and has been seen with ovarian cysts, granulosa cell tumors,

analysis, and low-dose dexamethasone suppression test were all

Sertoli cell tumors, and diethylstilbestrol administration for

within normal limits. The CBC of case 6 was unremarkable, and

urethral sphincter incompetence in spayed female dogs.2,3 In this

only mild alterations consistent with the dog’s history of Na

report, six unrelated dogs from three households were presented

bicarbonate supplementation and prior diagnosis of Fanconi

for progressive alopecia subsequently diagnosed as hyperestrogen-

syndrome were observed. This pre-existing condition was being

ism secondary to accidental exposure to their owners’ THRT.

managed by a veterinary internal medicine specialist at the time of

Although that phenomenon has been recognized by veterinarians,

presentation.

to the authors’ knowledge, this is the first report to describe the

At the time of presentation to the authors, marked alopecia with

clinical findings and outcomes in a case series of dogs presenting

hyperpigmentation along the ventral surfaces, lateral thorax,

with alopecia secondary to THRT exposure.4 To date, the only

abdomen, and proximal extremities were observed in both cases

peer-reviewed article regarding THRT exposure in the dog has been

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FIGURE 1

Photograph of a 7 yr old castrated male basenji (case 5) and an 11 yr old spayed female basenji (case 6) showing the extent and

pattern of alopecia at the time of initial presentation secondary to exposure to their owner’s estradiol-based topical hormone replacement therapy (THRT).

a case report of a 4 mo old bichon frise that was presented for reproductive abnormalities.

5

hyperestrogenism have been irregular or persistent estrous cycles, vulvar and nipple enlargement, gynecomastia, vaginal discharge,

The alopecic pattern characterized in dogs with hyperestro-

attraction of other dogs, pendulous prepuce, and linear preputial

genism is bilaterally symmetrical hair loss beginning in the perineal

dermatosis.2,3 In the one previously published case report,

and inguinal region that continues to progress and involve the

persistent hemorrhagic vaginal discharge was the initial presenting

Variations of

complaint.5 Five of the six dogs in this report were noted to have

this pattern were observed in all cases presented in this report. The

physical examination findings suggestive of feminization at the

severity of alopecia observed in the cases was proportional to

time of presentation, which included nipple, vulvar, or preputial

duration of THRT exposure experienced by the individual dogs.

enlargement. Clinical signs of feminization were only noticed in

Various degrees of hyperpigmentation were also observed in the

case 6 by the owner, who expressed concern of vulvar enlargement

affected alopecic areas, consistent with previously described reports

at the time of initial presentation.

abdomen, thorax, flanks and proximal extremities.

of hyperestrogenism.

2,3

2,3

Owners first noted signs of alopecia in their

dogs between 4 and 6 mo after beginning THRT.

Routine histopathology sampling and processing with hematoxylin and eosin staining were performed on skin biopsy samples

Feminization and sexual disturbances are also common

obtained from five of the six cases. Those samples demonstrated

features of dogs diagnosed with hyperestrogenism regardless of

four similar histologic features: mild to moderate basal melanosis,

the inciting cause. Clinical signs previously described in dogs with

orthokeratotic hyperkeratosis and infundibular hyperkeratosis,

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FIGURE 2

Photograph of cases 5 and 6 showing complete resolution of alopecia at the follow-up examination 5.5 mo after the owner

discontinued her use of THRT.

predominance of kenogen follicles, and small to mildly atrophic

routine blood work and urinalysis, thyroid function testing, and

sebaceous glands. Other findings observed on histopathology were

pituitary adrenal axis evaluation.

mild epidermal acanthosis or epidermal atrophy and excessive

Bone marrow suppression has been observed in the dog

trichilemmal keratinization in one case. Although those findings

secondary to both endogenous and exogenous hyperestrogenism.8,9

were consistent with hyperestrogenism, they are not pathognomonic for the condition and are observed with several syndromes that result in follicular arrest.6,7 Alopecic conditions that can

Abnormalities seen on CBC secondary to excessive estrogen exposure include nonregenerative anemia, leukopenia, and thrombocytopenia. None of those changes were documented in the dogs presented in this report despite THRT exposure for .1 yr in three

present with similar histological findings on biopsy are primarily

cases. The only changes observed on CBC occurred in case 1, in

hypothyroidism, hypercortisolism, and alopecia X.6,7 Those

which a mild leukocytosis most consistent with a stress leukogram

conditions are clinically differentiated from one another based on

was noted. Although an initial leukocytosis may be seen prior to

breed, the constellation of clinical signs, abnormalities detected via

leukopenia as the earliest change with hyperestrogenism, this is

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unlikely with case 1 given the chronicity of THRT exposure prior to

concentration ranging from 0.06 to 1.7% and are provided in

CBC acquisition and the concurrent presence of a thrombocytosis.

various formulations. Regarding households two and three, the

However, given that the mechanism of estrogen-induced myelo-

product containing the highest concentration was used by each of

toxicity is not fully understood and is likely an idiosyncratic

the owners. Following identification of the estrogen source, all

reaction, this potential complication should be considered in all

owners were asked to consult with their physicians about possible

cases of estrogen exposure.8,9 Unlike hypercortisolism or hypothy-

alternative therapeutic options. Following discontinuation of

roidism, hyperestrogenism is not associated with observed changes

THRT by all three owners, all dogs had complete resolution of

in serum biochemical analysis and provides another point of

their clinical signs by 5.5 mo (range, 3–5.5 mo). The time required

distinction between conditions that result in canine alopecia.2 The

for clinical resolution of alopecia in those cases was consistent with

only abnormalities observed on serum biochemical analysis noted

expected time frames for hair regrowth in short-coated dogs that

herein occurred with case 6, which were consistent with the dog’s

have no other underlying abnormalities.11

historical diagnosis and treatment for Fanconi syndrome. Finally, a total T4 was acquired just prior to or at the time of presentation in

Conclusion

all cases and measured well within normal limits for each dog,

The cases presented herein were diagnosed with alopecia secondary

making a diagnosis of hypothyroidism unlikely. Baseline estradiol levels were acquired in all dogs and were above normal limits in all six cases. Simultaneous elevations of baseline progesterone values were recorded in four cases. Although elevated blood levels of estradiol are supportive of a diagnosis of hyperestrogenism, they are not consistently demonstrated in all cases of hyperestrogenism.2 A recent study investigating the variance of estradiol concentrations in normal dogs demonstrated a wide range in recorded values both within and between dogs. In that study, single significantly elevated samples were observed while a mean estradiol concentration from the group also exceeded the current upper reference range for the test.10 With the dogs described in this report, it is important to note that although two of the cases (cases 1 and 2) had baseline estradiol values recorded greater than three times the upper reference limit, the other four cases had values not significantly different from those observed by Frank et al. (2010). Given those recent findings and the limited data presented in this report, it would be advisable that in cases of suspected THRT exposure, baseline hormone levels be used to

to exogenous hyperestrogenism as a result of accidental exposure to their owners’ THRT. Those cases are unique in that no prior published cases of alopecia in dogs secondary to human THRT exposure have been described. Clinical signs, feminization, and histopathology are similar to previous reports of hyperestrogenisminduced alopecia in dogs. Following discontinuation of exposure, complete resolution of clinical signs was observed within 5.5 mo. Those observations indicate THRT exposure in dogs should be considered in cases of canine alopecia due to follicular arrest once more common causes have been excluded. The authors would like to thank Kimberly Coyner and Christopher Byers for their critical review and assistance with the manuscript. FOOTNOTES a b c d

support a diagnosis and not be used as a definitive test. Diagnosis of hyperestrogenism, regardless of the cause, should be based on

e

patient history, clinical signs, a lack of diagnostic test results

f

Ivomec; Merial Limited, Duluth, GA Pyoben; Virbac Animal Health, Nice, France Cortrosyn; Amphastar Pharmaceuticals, Rancho Cucamonga, CA Canine adrenal panel; University of Tennessee’s Veterinary Medical Center, Knoxville, TN Wiley Protocol; Wiley Chemists, Santa Fe, NM Evamist; Ther-Rx Corporation, St. Louis, MO

compatible with the more common causes of canine alopecia, and baseline serum sex hormone levels. All dogs in this report were diagnosed with hyperestrogenism due to exogenous exposure as the cause of their alopecia. The source of estrogen exposure in all cases was determined to be the owner’s transdermal THRT. All owners noted they were applying either an estradiol or estradiol combination product to their medial forearms and that the site of application was in frequent contact with their dogs. Currently, several commercial preparations containing estradiol are available and marketed in the United States for THRT in women. Those products vary in estradiol

REFERENCES 1. Frank LA. Non-inflammatory alopecia. In: Proceedings from the North American Veterinary Dermatology Forum; April 6–10, 2005; Sarasota, FL. p.13–16. 2. Mecklenburg L, Linek M, Tobin DJ. Hair loss disorders in domestic animals. 1st ed. Ames (IA): Wiley-Blackwell; 2009:93–175. 3. Sex hormones and the skin. In: Miller WH, Griffin CE, Campbell KL, eds. Muller and Kirk’s small animal dermatology. 7th ed. St. Louis (MO): Elsevier Mosby; 2013:531–40. 4. Lau, E. Scrutiny of secondary topical hormone exposure deepens. Veterinary Information Network. Available at: http://www.vin.com. Accessed May 21, 2013.

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5. Schwarze RA, Threlfall WR. Theriogenology question of the month. J Am Vet Med Assoc 2008;233(2):235–7. 6. Mu¨ntener 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– 21. 7. Atrophic diseases of the adnexa. In:Gross TL, Ihrke PJ, Walder EJ, et al., eds. Skin diseases of the dog and cat. Clinical and histopathologic diagnosis. 2nd ed. Oxford (UK): Blackwell Science; 2005:480–517.

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8. Weiss DJ. Drug-associated blood cell dyscrasias. Compend Contin Educ Vet 2012;34(6):E2 9. Sontas HB, Dokuzeylu B, Turna O, et al. Estrogen-induced myelotoxicity in dogs: a review. Can Vet J 2009;50:1054–8. 10. Frank LA, Mullins R, Rohrbach BW. Variability of estradiol concentration in normal dogs. Vet Dermatol 2010;21:490–3. 11. Diaz SF, Torres SM, Dunstan RW, et al. An analysis of canine hair regrowth after clipping for a surgical procedure. Vet Dermatol 2004;15: 25–30.