Canine Alopecia Secondary to Human Topical Hormone Replacement Therapy in Six Dogs
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.
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, alopecia areata, pemphigus foliaceus, and epitheliotrophic T-cell lymphoma. Alopecia secondary to those diseases usually presents with a patchy or well-demarcated distribution, while noninflammatory dermatoses tend to result in a diffuse and often symmetrical appearance.1 Noninflammatory causes of alopecia may arise from 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).
Case Report
Household 1
A 19 mo old castrated male Boston terrier (case 1) presented with a 1 yr history of progressive alopecia. The dog had a historical diagnosis of juvenile-onset generalized demodicosis that resolved following appropriate therapy with ivermectina (500 μg/kg per os q 24 hr) and frequent bathing with a benzoyl peroxideb shampoo. Blood work performed prior to referral to the authors revealed a mild leukocytosis (17.10 × 109/L; reference range, 4.0–15.50 × 109/L) with a mature neutrophilia (12.48 × 109/L; reference range, 2.06–10.60 × 109/L) and monocytosis (1.03 × 109/L; reference range, 0.0–0.84 × 109/L), as well as a mild thrombocytosis (489 × 109/L; reference range, 170–400 × 109/L). The remainder of the complete blood count (CBC), serum biochemical profile, serum total thyroxine (T4), and serum free T4 values were within normal limits. Following an ineffective diet trial and continued progressive alopecia, the dog was referred to a dermatologist.
At the time of initial presentation, marked, noninflammatory alopecia of all ventral surfaces and moderate patchy alopecia of the lateral thorax, abdomen, and proximal extremities were appreciated. No other significant findings were noted on either physical examination or skin scrape samples. Based on clinical presentation and physical exam, a noninflammatory alopecia secondary to an underlying endocrinopathy or follicular dysplasia was suspected. Two 6 mm diameter punch biopsies were obtained from alopecic areas and submitted for histological evaluation. Histopathology results revealed minimal acanthosis, moderate basal melanosis, mild orthokeratotic hyperkeratosis and infundibular hyperkeratosis, kenogen follicles, small sebaceous glands, and a lack of inflammatory cells. Those results were suggestive of alopecia secondary to an underlying endocrine disturbance resulting in follicular arrest. Following review of the histopathology results, the referring veterinarian was contacted to verify a bilateral orchiectomy had been performed to rule out the possibility of cryptorchidism and a Sertoli cell tumor as the cause of the dog's clinical presentation. At that time, it was discovered the referring veterinarian had repeated a total T4 and submitted serum baseline testosterone levels that were reported to be within normal limits. An adrenocorticotropic hormone (ACTH) stimulation test was performed with synthetic corticotropinc (0.125mg IV), and pre- and 1 hr poststimulation serum samples were sent frozen overnight for analysisd. Results demonstrated elevated baseline and postACTH levels for androstenedione (pre, 0.09 nmol/L; reference range, 0.00–0.01 nmol/L; post, 0.17 nmol/L; reference range, 0.01–0.10 nmol/L), estradiol (pre, 760.26 pmol/L; reference range, 84.80–238.98 pmol/L; post, 641.69 pmol/L; reference range, 85.53–254.77 pmol/L), progesterone (pre, 7.54 nmol/L; reference range, 0.10–0.54 nmol/L; post, 21.34 nmol/L; reference range, 0.70–4.61 nmol/L), and 17-hydroxyprogesterone (pre, 5.95 nmol/L; reference range, 0.25–0.70 nmol/L; post, 21.18 nmol/L; reference range, 0.80–8.36 nmol/L). Baseline and postACTH stimulation serum levels for cortisol and aldosterone were within normal limits. During discussion of adrenal panel results with the owner, it was discovered that she was enrolled in a clinical trial for a THRT product involving application of estradiol and progesterone creamse to her medial forearms. Based on the new information from the owner and adrenal panel results, the cause of the dog's alopecia was determined to be hyperestrogenism secondary to exogenous estradiol exposure. At that time, the owner was advised to discuss alternative treatment options for herself with her physician. Complete resolution of the dog's alopecia was observed 3.5 mo following discontinuation of THRT by the owner.
Household 2
Household two contained three unrelated Chinese pugs: a 3 yr old spayed female (case 2), a 4.5 yr old castrated male (case 3), and a 5.5 yr old spayed female (case 4). All three dogs were presented with varying degrees of progressive alopecia ranging in duration from 2–6 mo, with cases 2 and 3 previously having been evaluated by several different veterinarians. Case 2 had a CBC, serum biochemical profile, and total T4 performed 2 mo prior to presentation, which were within normal limits. Case 3 also had a prior CBC and serum biochemical profile performed, which were within normal limits.
At the time of presentation to the authors, all three dogs displayed varying degrees of noninflammatory alopecia. Extent of the alopecia ranged from mild to complete along ventral surfaces and included mild to moderate patchy alopecia of the lateral thorax, abdomen, and proximal extremities with varying degrees of hyperpigmentation. Mild to moderate vulvar enlargement was noted with cases 2 and 4, and vaginal discharge was also noted in case 2. In case 3, mild preputial enlargement was appreciated, while significant nipple enlargement was observed with cases 2 and 3. No other significant findings were noted on physical exam, and skin scrape samples for mites were negative for all three dogs. Because multiple unrelated dogs from the same household presented with similar clinical symptoms, the owner was interviewed further regarding possible exposures all three dogs may have shared. The owner stated that 4 mo prior to development of clinical signs in case 2, she had begun using an estradiol-based form of THRTf that was applied to the medial aspect of her forearms daily. Interestingly, the owner noted that the two most severely affected dogs spent more time sitting on her lap than the less affected dog. The clinical presentation and history provided by the owner were suspicious for hyperestrogenism secondary to exogenous estradiol exposure. At that time, samples for dermatophyte test medium cultures were acquired from all three dogs that resulted in no observable growth. In addition, a CBC, serum biochemical analysis, and total T4 were performed, and all values were within normal limits for all three dogs. Multiple 6 mm punch biopsies were acquired from alopecic areas on cases 2 and 3 (the two more severely affected dogs) and submitted for histologic evaluation. Histopathology results were similar for the two dogs and demonstrated mild to moderate orthokeratotic hyperkeratosis and infundibular hyperkeratosis, mild basal melanosis, a predominance of kenogen hair follicles, and small sebaceous glands. Case 3 also had a slightly atrophic epidermis. Finally, serum samples were shipped frozen overnight (to the same laboratory used in case 1) for baseline estradiol, progesterone, and testosterone levels. Estradiol levels were elevated in all three dogs (case 2, 1292.19 pmol/L; reference range, 113.07–256.60 pmol/L; case 3, 402.34 pmol/L; reference range, 84.8–238.98 pmol/L; case 4, 290.01 pmol/L; reference range, 113.07–256.60 pmol/L), and progesterone levels were elevated in two dogs (case 2, 4.01 nmol/L; reference range, 0.03–1.56 nmol/L; case 3, 2.32 nmol/L; reference range, 0.03–0.54 nmol/L). All three dogs' baseline testosterone levels were within normal limits.
Baseline hormone levels and biopsy results confirmed the suspicion of hyperestrogenism secondary to accidental THRT exposure in the three dogs. After interpretation of diagnostic results, the owner was advised to contact her physician regarding possible alternative treatment options. Following discontinuation of THRT by the owner, all three dogs had complete resolution of their alopecia and symptoms of feminization within 4 mo.
Household 3
The third household consisted of two unrelated dogs: a 7 yr old castrated male basenji (case 5) adopted 1.5 years prior to presentation and an 11 yr old spayed female basenji (case 6) with a historical diagnosis of Fanconi syndrome. The two dogs were presented for progressive alopecia of 1 and 2.5 yr duration, respectively. Both cases had blood work and dermatophyte test medium cultures performed prior to presentation. In both cases, culture yielded no growth and both dogs had a total T4 level within normal limits. Regarding case 5, a CBC, serum biochemical analysis, and low-dose dexamethasone suppression test were all within normal limits. The CBC of case 6 was unremarkable, and only mild alterations consistent with the dog's history of Na bicarbonate supplementation and prior diagnosis of Fanconi syndrome were observed. This pre-existing condition was being managed by a veterinary internal medicine specialist at the time of presentation.
At the time of presentation to the authors, marked alopecia with hyperpigmentation along the ventral surfaces, lateral thorax, abdomen, and proximal extremities were observed in both cases (Figure 1). The presence of significant nipple enlargement with comedone formation in the surrounding skin was observed in both cases. Moderate vulvar enlargement was appreciated in case 6, while no other significant findings were noted with the rest of the general physical exam. Skin scrape samples for parasites were negative in both cases.
Citation: Journal of the American Animal Hospital Association 51, 2; 10.5326/JAAHA-MS-6247
Based on clinical presentation and physical exam findings, noninflammatory alopecia secondary to THRT exposure was suspected. Further questioning of the owner revealed an estradiol form of THRT use for the past 3 yr (the same product used by the owner in household 2). One 6 mm punch biopsy sample from alopecic areas on both dogs was acquired and submitted for histological evaluation. Serum samples were acquired from both dogs and shipped frozen overnight to the same laboratory used in the previously described cases for baseline estradiol, progesterone, and testosterone levels. Histopathology results were almost identical in both cases, demonstrating mild epidermal atrophy, mild to moderate orthokeratotic hyperkeratosis and infundibular hyperkeratosis, moderate basal melanosis, presence of kenogen follicles, and small sebaceous glands. In case 6, mild excessive trichilemmal keratinization was also appreciated. Baseline estradiol levels were elevated in both dogs (case 5, 577.08 pmol/L; reference range, 84.80–238.98 pmol/L; case 6, 526.05 pmol/L; reference range, 113.07–256.60 pmol/L), and progesterone levels were elevated in case 5 (2.77 nmol/L; 0.03–0.54 nmol/L). Testosterone levels were within normal limits in both cases.
The clinical presentation, biopsy results, and serum hormone levels were consistent with hyperestrogenism secondary to THRT exposure, and the owner was advised to consult with her endocrinologist for an alternative treatment option. Following discontinuation of THRT by the owner, complete resolution of alopecia and symptoms of feminization were noted in cases 5 and 6 by 4.5 and 5.5 mo, respectively (Figure 2).
Citation: Journal of the American Animal Hospital Association 51, 2; 10.5326/JAAHA-MS-6247
Discussion
Alopecia secondary to hyperestrogenism is well recognized in the dog and has been seen with ovarian cysts, granulosa cell tumors, Sertoli cell tumors, and diethylstilbestrol administration for urethral sphincter incompetence in spayed female dogs.2,3 In this report, six unrelated dogs from three households were presented for progressive alopecia subsequently diagnosed as hyperestrogenism secondary to accidental exposure to their owners' THRT. Although that phenomenon has been recognized by veterinarians, to the authors' knowledge, this is the first report to describe the clinical findings and outcomes in a case series of dogs presenting with alopecia secondary to THRT exposure.4 To date, the only peer-reviewed article regarding THRT exposure in the dog has been a case report of a 4 mo old bichon frise that was presented for reproductive abnormalities.5
The alopecic pattern characterized in dogs with hyperestrogenism is bilaterally symmetrical hair loss beginning in the perineal and inguinal region that continues to progress and involve the abdomen, thorax, flanks and proximal extremities.2,3 Variations of this pattern were observed in all cases presented in this report. The severity of alopecia observed in the cases was proportional to duration of THRT exposure experienced by the individual dogs. Various degrees of hyperpigmentation were also observed in the affected alopecic areas, consistent with previously described reports of hyperestrogenism.2,3 Owners first noted signs of alopecia in their dogs between 4 and 6 mo after beginning THRT.
Feminization and sexual disturbances are also common features of dogs diagnosed with hyperestrogenism regardless of the inciting cause. Clinical signs previously described in dogs with hyperestrogenism have been irregular or persistent estrous cycles, vulvar and nipple enlargement, gynecomastia, vaginal discharge, attraction of other dogs, pendulous prepuce, and linear preputial dermatosis.2,3 In the one previously published case report, persistent hemorrhagic vaginal discharge was the initial presenting complaint.5 Five of the six dogs in this report were noted to have physical examination findings suggestive of feminization at the time of presentation, which included nipple, vulvar, or preputial enlargement. Clinical signs of feminization were only noticed in case 6 by the owner, who expressed concern of vulvar enlargement at the time of initial presentation.
Routine histopathology sampling and processing with hematoxylin and eosin staining were performed on skin biopsy samples obtained from five of the six cases. Those samples demonstrated four similar histologic features: mild to moderate basal melanosis, orthokeratotic hyperkeratosis and infundibular hyperkeratosis, predominance of kenogen follicles, and small to mildly atrophic sebaceous glands. Other findings observed on histopathology were mild epidermal acanthosis or epidermal atrophy and excessive trichilemmal keratinization in one case. Although those findings 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 present with similar histological findings on biopsy are primarily hypothyroidism, hypercortisolism, and alopecia X.6,7 Those conditions are clinically differentiated from one another based on breed, the constellation of clinical signs, abnormalities detected via routine blood work and urinalysis, thyroid function testing, and pituitary adrenal axis evaluation.
Bone marrow suppression has been observed in the dog secondary to both endogenous and exogenous hyperestrogenism.8,9 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 cases. The only changes observed on CBC occurred in case 1, in which a mild leukocytosis most consistent with a stress leukogram was noted. Although an initial leukocytosis may be seen prior to leukopenia as the earliest change with hyperestrogenism, this is unlikely with case 1 given the chronicity of THRT exposure prior to CBC acquisition and the concurrent presence of a thrombocytosis. However, given that the mechanism of estrogen-induced myelotoxicity is not fully understood and is likely an idiosyncratic reaction, this potential complication should be considered in all cases of estrogen exposure.8,9 Unlike hypercortisolism or hypothyroidism, hyperestrogenism is not associated with observed changes in serum biochemical analysis and provides another point of distinction between conditions that result in canine alopecia.2 The only abnormalities observed on serum biochemical analysis noted herein occurred with case 6, which were consistent with the dog's historical diagnosis and treatment for Fanconi syndrome. Finally, a total T4 was acquired just prior to or at the time of presentation in all cases and measured well within normal limits for each dog, 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 support a diagnosis and not be used as a definitive test. Diagnosis of hyperestrogenism, regardless of the cause, should be based on patient history, clinical signs, a lack of diagnostic test results 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 concentration ranging from 0.06 to 1.7% and are provided in various formulations. Regarding households two and three, the product containing the highest concentration was used by each of the owners. Following identification of the estrogen source, all owners were asked to consult with their physicians about possible alternative therapeutic options. Following discontinuation of THRT by all three owners, all dogs had complete resolution of their clinical signs by 5.5 mo (range, 3–5.5 mo). The time required for clinical resolution of alopecia in those cases was consistent with expected time frames for hair regrowth in short-coated dogs that have no other underlying abnormalities.11
Conclusion
The cases presented herein were diagnosed with alopecia secondary 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 hyperestrogenism-induced 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.
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).
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.
Contributor Notes
