Association of Hyperestrogenemia and Bilateral Symmetric Flank Alopecia in a Neutered Female Boxer Dog

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1 Association of Hyperestrogenemia and Bilateral Symmetric Flank Alopecia in a Neutered Female Boxer Dog Arif KURTDEDE*, Ekrem Ç. ÇOLAKOĞLU*, Ali E. HAYDARDEDEOĞLU*, Hadi ALIHOSSEINI* *Department of Internal Medicine, Faculty of Veterinary Medicine, Ankara University, ANKARA /TURKEY Introduction An endocrinopathy associated with excessive or inadequate production of sex hormones or precursor sex hormones by gonads or adrenal glands are observed in middle-aged to older dogs (Paradis et al, 2002). As far as the skin is concerned, there appears to be little need for the sex hormones. Bilaterally symmetric alopecia of the neck, rump, perineum, flanks or trunk that become generalized (Muller & Kirk s, 2001). Neutered dogs and cats rarely lose hair in association with the neutering. However some of these endocrinopathy leading to alopecia ensue of bilateral adrenalectomy in neutered animal. Sex hormone imbalances e.g., estrogen excess associated with a Sertoli cell tumor, or progesterone treatments resulting hypoandrogenism condition, typically will induce coat changes (Paradis et al, 2002). Frequently sex hormone dermatosis often occurs in four types include; intact, neutered Male dogs and intact, neutered Female dogs. Alopecic skin with hyperpigmentation is common initiation clinical signs in these abnormalities. In addition to mentioned signs, according to excessive or inadequate secretion of sex hormone and sexuality of animal, other clinical signs differ. Secondary seborrhea, superficial pyoderma, concurrent gynecomastia, pendulous prepuce with testes abnormalities are seen in intact males. Easily epilated hairs seen commonly in sex hormone dermatosis in neutered male dogs. In neutered female dogs endocrinopathy thought to be associated with decreased sex hormone levels. This condition occurs with highest incidence at an early age (Medleau, 2001). In intact female dog excessive secretion of estrogen due to cystic ovaries or ovarian neoplasia in middle-age to older dogs rarely happen. In these cases generalized truncal alopecia with hyperpigmentation are seen (Muller & Kirk s, 2001). Case History A 5-year-old female neutered Boxer dog was presented with a history of symmetrical bilateral localized alopecia close to flank area to small animal clinic of Ankara University, Department of Internal Medicine (Fig 1,2,3).The affected areas were not pruritic but progressive hyperpigmentation was attracted. The clinical examination was normal besides, previous therapy with Ketoconazole shampoo had been led to fail. The Hematology and Serum biochemistry profile examinations have been showed in the tables 1& 2 and Hormone Analysis Test results have been shown in table 3. Table 1) Hematology Test Result Normal Range* WBC ^9/l LYM ^9/l MONO ^9/l GRA ^9/l LY % 53.0 % MONO % 3.1 % GR % 43.9 % RBC ^12/l HGB 15.8 g/dl HCT % MCV 76 fl MCH 24.5 pg MCHC 32.4 g/dl RDWc 13.6 % PLT ^9/l *Schalm's Veterinary Hematology,

2 Table 2) Serum Biochemistry Profile Test Result Normal Range* Glu (mg/dl) Urea (mg/dl) BUN (mg/dl) SCr (mg/dl) Total Protein (g/dl) Albumin (g/dl) Total Bilirubin (mg/dl) Direct Bilirubin (mg/dl) Cholesterol (mg/dl) Triglycerides (mg/dl) ALP (IU/L) ALT (IU/L) AST (IU/L) GGT (IU/L) Ca ++ (mg/dl) Na + (mmol/l) K + (meq/l) Cl - (mmol/l) *Fundamentals of Veterinary Clinical Pathology by Steven L. Stockham and Michael A. Scott (2008) Table 3) Hormone Analysis Tests Test T3 (Triiodothyronine) canine T4 (Thyroxine) FT3 (Free Triiodothyronine) canine FT4 (Free Thyroxine) E2 (Estradiol) Result ** ng/ ml g/ dl pm ol/l pm ol/l ng/ ml Reference Ranges* Differs to species dependent Differs to species dependent*** Cortisol (Morning) g/ dl *Arthur's Veterinary Reproduction and Obstetrics (2001) ** K Value for determination of Thyroid gland function: K value= (9 Free T4 ng/dl) (0.026 Cholesterol mg/dl) K value = [9 1.3] [ ] = = Hypothyroidism: Negative. (Laboratory profiles of small animal diseases, Charles Sodikoff 1995) *** Normal ranges of Estradiol in intact bitch are ng/ml. Neutered bitch has lower ranges (0-5 ng/ml). Interpretation of Laboratory Results and Treatment According to laboratory results hypothyroidism (K-value) and hyperadrenocortisism eliminated from check list. Hyperestrogenism was observed in neutered female dog in spite of neutering. Existence of any ectopic estorgen secreting source in was thought. In The Abdominal ultrasonographic examination did not obtained any clue including remnant mass in reproductive system and adrenal gland. The vaginal cytology test declared anestrus.the owner did not allow us to perform exploratory laparatomy for relieving remnant mass in the abdomen. To decrease of estrogen plasma concentration, administration of Methyl-Tesotoserone was decided. Methyl testosterone tablet 25mg (Afro tablet ) with 1mg/kg, every other day (maximum 30mg/dog) applied for 1 months (Plumb, 1999). Clinical Follow-up Alopecia and hyperpigmentation were improved during 13 th day of therapy as well to hairs regrowth caused to disappearing of alopecic area and any recurrent problem was not reported from owner during next 6 months. Reduction of cholesterol plasma level to normal ranges in order to methyl testosterone confirmed affecting of Testosterone on decrease of estrogen plasma level in our case (Abell et al, 1962). The serum biochemistry profile and estrogen plasma level was reexamined 4 th week in order to determining hepatic function and cholesterol levels (Table 4- a,b,c). The Figures of before and after treatment are shown in below. 2

3 Table 4) Laboratory Analysis Figures: Before treatment a) Hematology Test Result Normal Range WBC ^9/l LYM ^9/l MONO ^9/l GRA ^9/l LY % 10.6 % MONO % 7.6 % GR % 81.8 % RBC ^12/l HGB 13.9 g/dl HCT % MCV fl MCH 22.4 pg MCHC 30.3 g/dl RDWc 14.1 % PLT ^9/l *Schalm's Veterinary Hematology,2000. Fig. 1) Right flank Alopecia (Small Animal Clinic of Dep t of Internal Medicine Ankara University) b) Serum Biochemistry Profile (Hepatic enzymes reevaluation) Test Result Normal Range Total Protein (g/dl) Albumin (g/dl) Total Bilirubin (mg/dl) D. Bilirubin (mg/dl) Cholesterol (mg/dl) Triglycerides (mg/dl) ALP ALT (IU/L) AST (IU/L) GGT (IU/L) *Fundamentals of Veterinary Clinical Pathology by Steven L. Stockham and Michael A. Scott (2008) Fig. 2) Closer view - Right flank area Alopecia (Small Animal Clinic of Dep t of Internal Medicine Ankara University) c)estrogen Plasma Level Test Result NormalRange* Differs to species E2 (Estradiol) ng/ml dependent *Arthur's Veterinary Reproduction and Obstetrics (2001) Fig. 3) Closer view - Left flank Alopecia (Small Animal Clinic of Dep t of Internal Medicine Ankara University) 3

4 Figures After treatment Fig 4) View of Right alopecic area disappearing and regrowth of hair after 13 days treatment by methyl testosterone. (Small Animal Clinic of Dep t of Internal Medicine Ankara University) Fig 5) View of Left alopecic area disappearing and regrowth of hair after 13 days treatment by methyl testosterone. (Small Animal Clinic of Dep t of Internal Medicine Ankara University) Discussion The Bilaterally Flank symmetric alopecia with progressive hyperpigmentation in dogs in both sexes is observed more in endocrinopathy, sex hormone abnormalities, seasonal flank alopecia and alopecia X. Endocrine-related dermatosis observed more in middle-aged to older dogs. In cases with flank area alopecia thyroid and adrenal gland function should be examined initially. Other clinical findings of these endocrinopathy dermatosis should be evaluated for assessment of disease (Ferguson et al, 1994). On the other hand thyroid and adrenal function abnormality related dermatosis observe commonly in small and toy breeds (Zerbe et al, 2000). In our case thyroid and adrenal panel was examined and obtained normal results and absence of other clinical findings of thyroid or adrenal disturbances allowed us to eliminated them. Seasonal flank alopecia ( recurrent flank alopecia, cyclic flank alopecia) is one of flank symmetric alopecia causes in dog that occurs in northern hemisphere between November and March (Miller et al, 1993). This type of alopecia is seen companion with hair regrow that takes place spontaneously 3-8 months later (Paradis et al, 2000). Therapy is not currently available for seasonal flank alopecia; however, in one study Paradis (1995) reported that the next predicted episode of alopecia was prevented by melatonin supplementation in all nine dogs treated. There is no rationale for supplementation with thyroid, reproductive and growth hormones in seasonal flank alopecia (Curtis et al., 1996). Another reason for flank symmetric alopecia is Alopecia X. Alopecia X is defined as adrenal sex hormone imbalance, hyposomatotropism, growth hormone-responsive and Pseudo Cushing s disease that occurs in small breeds like Pomeranian, Samoyeds and miniature pinscher (Schmeitzel et al, 1993). The cause of this endocrinopathy is unclear but symptomatic therapy lead to disappear of alopecia. Dogs with alopecia X may respond to: Castration, Trilostane, Methyltestosterone, Mitotane, or Growth hormone (Neiger et al., 2002). Castration of the intact male dog with alopecia X may be the first treatment of choice. In our case history of ovariohysterectomy and absence of estrous cycles, moreover existence of high plasma estrogen levels focused us to presence of ectopic estrogen secreting source. Ovaries, uterus and adrenal gland are common estrogen secreting sources in female dogs. The abdominal ultrasonographic examination did not cleared any active mass over adrenal glands. On basis of owner unwilling to perform of exploratory laparatomy let us estimate nonovarian source of hyperestrogenism. Application of Methyl-Testosterone for reduction of plasma estrogen improved clinical signs and disappearing of alopecia. Testosterone- Responsive dermatosis is rare problem with 4

5 bilaterally symmetric alopecia of unknown cause in castrated male dogs (Hubert & Miller, 1990). Some authors state intact male dogs with testicular problems or tumor placed in this category because some affected animals show transient response to testosterone. According to literatures and small animal dermatology textbooks; no successful treatment of neutered females with nonovarian hyperestrogenism has been described (Schmeitzel et al 1993). Improvement of clinical signs in response of methyl-testosterone and reduction of estrogen plasma concentration in neutered bitch can be remarkable clinical trail in canine practice. Reference Abell LL., Mosbach EH., Kendall FE. (1962), Hypocholesteremic Effect of 17 - Methyltestosterone in Dogs, Circulation Research. 1962; 10:846.American Heart Association, Inc. Curtis CF (1995) Clinical features of canine idiopathic cyclical flank alopecia. Veterinary Dermatology Newsletter 17, Curtis CF, Evans H and Lloyd DH (1996) Investigation of the reproductive and growth hormone status of dogs affected by idiopathic recurrent flank alopecia. Journal of Small Animal Practice 37, Ebling FJG, Hale PA and Randall VA (1991) Hormones and hair growth. In: Physiology, Biochemistry, and Molecular Biology of the Skin, ed. LA Goldsmith, pp Oxford University Press, New York Endocrine and metabolic diseases, pp In Scott DW, Miller WH Jr, and Griffin CE Muller & Kirk s Small Animal Dermatology. Ed. 5.W.B. Saunders Philadelphia, PA. Ferguson DC Update on Diagnosis of Hypothyroidism. Vet Clin North Am Sm Anim Prect. 24: Heywood, R (R); Chesterman, H (H); Ball, S A (SA); Wadsworth, P F (PF); Toxicity of methyl testosterone in the beagle dog Jun; vol 7 (issue 3) : pp Hubert B, Olivry T: Dermtologie et hormones sexuelles chez les carnivores domestiques 1re partie: physiopathologie. Part Med Chir Anim Comp 25: 477, Medleau L, Hnilica KA,. (2001). Endocrine Diseases. In Small Animal Dermatology A Color Atlas and Therapeutic Guide. 2001, p W.B. Saunders Philadelphia, PA. Miller WH Jr: Sex hormone-related dermatoses in dogs. In: Kirk RW (ed): Current Veterinary Therapy X. W.B. Saunders Co., 1989, p 595. Miller MA and Dunstan RW (1993) Seasonal flank alopecia in Boxers and Airedale terriers: 24 cases ( ). Journal of the American Veterinary Medical Association 203, Neiger R, Ramsey I, O Connor J, Hurley KJ and Mooney CT (2002) Trilostane treatment of 78 dogs with pituitary-dependent hyperadrenocorticism. Veterinary Record 150, Paradis, M (1995) recurrent flank alopecia: treatment with melatonin. Proceedings of the American College of Veterinary Dermatology Annual Meeting, Santa Fe, 1995, p. 49 Paradis, M (2002) Gonadal sex hormone alopecias. British Veterinary Dermatology Study Group Proceedings, Autumn Meeting, Harlow, pp Paradis, M (1995) recurrent flank alopecia: treatment withmelatonin. Proceedings of the American College of Veterinary Dermatology Annual Meeting, Santa Fe, 1995, p. 49 Paradis M Melatonin Therapy for Alopecia. In Kirk s Current Veterinary Therapy, VIII, Small Animal Practice. W.B. Saunders, Philadelphia, PA. Paradis, M (2002) Gonadal sex hormone alopecias. British Veterinary Dermatology Study Group Proceedings, Autumn Meeting, Harlow, pp Paradis M and Cerundolo R (2003) An approach to symmetrical alopecia in the dog. In: BSAVA Manual of Small Animal Dermatology, 2nd edn, ed. AP Foster and CS Foil, pp BSAVA, Gloucester Plumb DC Veterinary Drugs Handbook. Ed. 3. Iowa State University Press, Ames, IA. Schmeitzel LP, Parker W: Growth hormone and sex hormone alopecia. In: Ihrke PJ. Et al (eds): advances in Veterinary Dermatology, Vol 2. Pergamon press, New York, 1993, p 451.) Schmeitzel LP and Parker W (1993) Growth hormone and sex hormone alopecia. In: Advances in Veterinary Dermatology, Volume 2, ed. PJ Ihrke, IS Mason and SD White, pp Zerbe CA Screening tests to Diagnosis Hyperadrenocortisism in Dogs and Cats. Compend Cont Edu Pract Vet. 22: