Hormonal Treatment for Integumentary Disease in Animals

Glucocorticoids have profound effects on nearly all cell types and organ systems, particularly immunologic and inflammatory activity. They may be used in either an anti-inflammatory or immunosuppressive capacity, depending on the dosage. Glucocorticoids are used for hypersensitivity dermatoses, contact dermatitis, immune-mediated diseases (eg, pemphigus, pemphigoid, or lupus erythematosus), and neoplasia (eg, mast cell tumor or lymphoma). Glucocorticoids may be classified according to their duration of effect and relative potency ( see Table: Glucocorticoids). They may be administered by mouth, intravenously, intramuscularly, or subcutaneously.

The anti-inflammatory dosage of prednisolone is 0.5–1 mg/kg, PO, every 24 hours in dogs (severe cases may require 2 mg/kg, PO, every 24 hours), 1–2 mg/kg, PO, every 24 hours in cats, and 0.8–2.2 mg/kg, PO, every 24 hours in horses. This dosage is administered for an induction period of 5–7 days and then reduced to the lowest possible maintenance dosage (ideally 0.25 mg/kg, PO, every 48–72 hours or lower in dogs and 0.4–1 mg/kg every 48–72 hours in horses). Maintenance doses must be administered ≥48 hours apart to minimize adrenal suppression and chronic adverse effects. The immunosuppressive dosage of prednisolone is 2.2 mg/kg, PO, every 24 hours in dogs (up to 6.6 mg/kg, PO, every 24 hours may be required in severe disease), 4.4 mg/kg, PO, every 24 hours in cats, and 2–4 mg/kg, PO, every 24 hours in horses. Dexamethasone may be used in horses at an anti-inflammatory induction dosage of 0.1 mg/kg, PO, every 24 hours and then reduced to 0.05 mg/kg every 48–72 hours as a maintenance and at 0.1–0.2 mg/kg, PO, every 24 hours as an immunosuppressive dosage before reducing to maintenance dosages.

The induction period is generally longer (10–20 days) than with anti-inflammatory dosing but is then gradually tapered in a stepwise fashion to an alternate-day dosing regimen once there is evidence of disease remission. Treatment should never be stopped abruptly because of the risk of inducing signs of hypoadrenocorticism. If relapse occurs during the tapering process, the dose is increased to at least one step above the point at which the relapse occurred and tapered again if possible. In many cases, treatment may be withdrawn entirely without relapse, whereas others require lifelong treatment.

Administration by mouth is preferred, because dosing can be more closely regulated and physiologic processes are disrupted less than with repositol forms. In some cases, difficulties with animal handling or owner adherence may require injectable treatment. This is normally satisfactory for acute, short-term disease that does not require repeated administration (eg, a single injection of methylprednisolone acetate alters adrenocortical function in dogs for up to 10 weeks).

Adverse effects include polyuria, polydipsia, polyphagia, weight gain, increased susceptibility to infection, gastrointestinal ulceration, pancreatitis, osteoporosis, hyperglycemia, steroid myopathy, and calcinosis cutis. The extent and severity of adverse effects are related to the dose, duration, and type of glucocorticoid used, along with individual patient sensitivity. The most commonly encountered infections are urinary tract infections, pyoderma, and pulmonary infections. Urinary tract infections may develop in many animals on long-term glucocorticoid treatment (68% in one study), and these animals may show no clinical signs of the infection. Bacteriologic culture of urine is recommended every 3–6 months for all animals on long-term treatment.

Progressive hepatocellular swelling due to glycogen accumulation may develop during glucocorticoid treatment. Alkaline phosphatase (ALP), ALT, and gamma-glutamyl transferase activities all show progressive increases. In dogs, the initial ALP activity increase is due to hepatic ALP but later is due to a cortisone isoenzyme.

Most injectable forms are labeled for intramuscular use; however, they are commonly administered subcutaneously. Local areas of alopecia, pigmentation, and epidermal and dermal atrophy may occur with subcutaneous injection.

Thyroid hormones are indicated as replacement treatment for primary, secondary, and tertiary hypothyroidism. Most cases of canine hypothyroidism are primary in nature and are due to autoimmune destruction of the thyroid gland. Drug-induced low thyroid hormone concentration or euthyroid sick syndrome are not indications for supplementation with thyroid hormones.

Synthetic levothyroxine (T₄) is the drug of choice for canine hypothyroidism. Most dogs respond clinically to a dosage of 0.02 mg/kg, PO, every 12 hours long-term. Insufficient serum concentrations after 4–6 weeks of treatment or lack of a clinical response after 12 weeks are indications to increase the dose. In rare cases for animals that cannot convert T₄ to T₃, synthetic liothyronine (T₃) may be used at a dosage of 4–6 mcg/kg, PO, every 8–12 hours long-term. It should not be used for routine treatment of hypothyroidism because it bypasses the normal cellular regulatory pathways and has a short half-life. Crude preparations from thyroid tissue and synthetic thyroid hormone combinations that mimic the T₄:T₃ ratio in humans should not be used in animals.

Clinical signs of thyrotoxicosis in cats and dogs are rare. They include polyuria, polydipsia, nervousness, aggressiveness, panting, diarrhea, tachycardia, pyrexia, and pruritus. Complications in dogs are usually related to concurrent cardiac or adrenal insufficiencies. In animals with a marginal cardiac reserve, T₄ medication should be initiated at one-fourth the recommended dose and gradually increased to full dose over a 1-month period.

Trilostane is a hormonally inactive, steroid competitive inhibitor of the adrenal enzyme 3-beta-hydroxysteroid dehydrogenase. It is used in treatment of pituitary-dependent hyperadrenocorticism. It inhibits the production of progesterone and 17-hydroxyprogestrone and their end products, including adrenal, gonadal, and placental hormones. However, inhibition of adrenal steroidogenesis occurs at lower doses than those required to inhibit steroid hormone synthesis in other organs. The recommended starting dosage for dogs is 2–10 mg/kg, PO, every 24 hours; however, this may be increased or decreased, based on periodic adrenocorticotropic hormone (ACTH) stimulation test results (performed 3–8 hours after trilostane administration). If the post-ACTH plasma cortisol concentration is < 20 nmol/L, trilostane administration should be stopped for 48–72 hours and the ACTH stimulation test repeated. If the post-ACTH plasma cortisol concentration is 20–200 nmol/L, the dosage should not be altered. If the post-ACTH plasma cortisol concentration is >200 nmol/L, the dosage should be increased.

Adverse effects include depression, ataxia, hypersalivation, vomiting, muscle tremors, and skin changes. Sudden death has been reported in a small number of cases. Iatrogenic hypoadrenocorticism can occur but is generally reversible. Because of its inhibition of placental hormones, trilostane is contraindicated in pregnant and nursing animals and in any animals intended for breeding. Serial biochemical, electrolyte, and hematologic analyses and ACTH stimulation tests should be performed to monitor hepatic and renal function before treatment and at 10 days, 4 weeks, 12 weeks, and every 3–6 months thereafter.

Mitotane is a chlorinated hydrocarbon with potent adrenocorticolytic effects, causing selective necrosis of the zona fasciculata and zona reticularis and partial or complete necrosis of the zona glomerulosa. It is used to treat pituitary-dependent hyperadrenocorticism. Before starting treatment, food intake (amount), time taken to eat, and 24-hour water intake should be recorded to determine a baseline. Once this has been established, a loading dosage is administered (25 mg/kg, PO, every 12 hours) until the animal becomes lethargic, water intake drops, appetite is reduced, or the animal has other gastrointestinal adverse effects (vomiting, diarrhea), or after 5 days of administration. An ACTH stimulation test should be performed to confirm whether adequate adrenal suppression has been achieved.

Most dogs respond to mitotane treatment at the initial loading dosage within 5–10 days, and the decision to change to maintenance treatment should be based on clinical signs (reduced appetite and water intake) and ACTH stimulation test results. Dogs with a post-ACTH plasma cortisol concentration < 25 nmol/L should receive no medication for 2 weeks and should then be treated with 25 mg/kg per week divided into 2 or 3 doses. Dogs with a post-ACTH plasma cortisol concentration of 25–125 nmol/L should receive 25 mg/kg per week in 2 or 3 doses, and dogs with a post-ACTH cortisol concentration >125 nmol/L should receive 50 mg/kg per week.

During maintenance treatment, an ACTH stimulation test should be performed after 1 month and then every 3–4 months. If the post-ACTH plasma cortisol concentration is < 25 nmol/L, the dose of mitotane should be reduced; if the concentration exceeds 125 nmol/L, the dose should be increased, usually by about 20%–25% weekly. Although most dogs are stable on maintenance treatment, their adrenal reserve may not be adequate to handle major stress (physiological or psychological). In these cases, mitotane administration should be discontinued and replaced with glucocorticoids (usually prednisone at 0.2 mg/kg, PO, every 24 hours, tapered) during this period.

Adverse effects are relatively common, particularly in cases of mitotane overdose. These include clinical signs of hypoadrenocorticism (eg, weakness, ataxia, depression, vomiting, diarrhea, and inappetence). Biochemical and hematologic analysis may be unremarkable despite systemic illness. Treatment includes lowering the dose or ceasing administration of mitotane and supplementing with glucocorticoids. Clinical improvement usually occurs within 1–6 hours. Iatrogenic hypoadrenocorticism is the most serious adverse effect and may develop at any time during maintenance treatment. Administration of mitotane should be stopped and appropriate supplementation with glucocorticoids and mineralocorticoids started. Other rare CNS adverse effects include ataxia, apparent blindness, circling, and head pressing.

The two most commonly used forms of progesterone are megestrol acetate and medroxyprogesterone acetate. Megestrol acetate has a quick onset of action and potent glucocorticoid and slight mineralocorticoid activity, and it may be administered by mouth. Medroxyprogesterone acetate is antiestrogenic and has important glucocorticoid activity. Neutered male and female cats with bilateral alopecia suspected to be caused by sex hormone imbalances may respond to treatment. The dosage of megestrol acetate is 2.5–5 mg/cat, PO, every 48 hours, decreasing to every 1–2 weeks for maintenance. Medroxyprogesterone acetate is administered at a dosage of 50–100 mg/cat, IM, and may be repeated in 3–6 months.

Progestogens should be avoided whenever possible because of adverse effects; severe, prolonged adrenocortical suppression occurs even with low doses. Diabetes mellitus has been reported in cats treated with megestrol acetate. Decreased spermatogenesis, pyometra, increased concentrations of growth hormone with acromegaly, mammary gland hyperplasia and tumors, and behavioral changes may occur.

Growth hormone (somatotropin) is a polypeptide produced by the anterior lobe of the pituitary gland (adenohypophysis) that acts either directly on target tissues or indirectly via insulin-like growth factors (somatomedins) produced by the liver. It is necessary for hair growth and for development of elastin fibers in the skin. It is used to treat growth hormone–responsive alopecia in dogs. Either bovine, porcine, or human growth hormone (0.1 U/kg, 3 times per week, for 4–6 weeks) is effective. Hair usually regrows in 2–3 months, and remission may last from 6 months to 3 years. Growth hormone is diabetogenic, and dogs can develop transient or permanent diabetes mellitus during treatment. Weekly monitoring of blood glucose concentration before and during treatment is recommended.

Several syndromes in dogs and cats have been attributed to imbalances of sex hormones; however, the etiopathogenesis of these disorders is generally poorly understood. Hypoestrogenism in spayed female dogs, hypoandrogenism in male dogs, and feline acquired symmetric alopecia may respond to sex-hormone treatment. Dosages for sex-hormone replacement treatment are empirical. Hypoestrogenism in spayed female dogs may be treated with diethylstilbestrol (0.02 mg/kg, PO, every 24 hours, for 3 weeks of every month, until hair regrows or for a maximum total dose of 1 mg/dog). After hair regrows, the maintenance dose should be administered 1–2 times per week. An alternative protocol is to treat every other day or twice weekly until the patient responds. Hair regrowth should be evident in 3–4 weeks, with a complete response within 4 months. Exogenous estrogen can cause bone marrow hypoplasia, so CBC and platelet count should be performed weekly during treatment. Other potential adverse effects include induction of estrus, hepatotoxicity, nymphomania, abortion, pyometra, or prostatic hyperplasia. Cats are highly sensitive to estrogens, and a total dose of 10 mg of diethylstilbestrol can be lethal.

Hypoandrogenism of male dogs may be treated with methyltestosterone (0.5–1 mg/kg up to a total maximal dose of 30 mg, PO, every 48 hours. Alternatively, testosterone propionate can be administered at dosages of 0.5–1 mg/kg, every 7 days, or at 2 mg/kg, IM, every 4–16 weeks. Complications include aggressive behavior, greasy coat, prostatic hypertrophy, and hepatotoxicity. Liver function should be evaluated before treatment and monthly during treatment.

Repositol testosterone (12 mg/cat, IM) may be administered once for treatment of feline acquired symmetric alopecia or may be combined with a low dose of diethylstilbestrol (0.625 mg/cat, IM) or with a low dose of estradiol (0.5 mg/cat, IM). Hepatobiliary disease has been reported in cats administered testosterone.

Melatonin is produced in the pineal gland and is involved in the control of photoperiod-dependent molting of some mammals. Secretion is inversely related to daylight length and is highest during the winter. Various canine hair growth disorders including recurrent flank alopecia, pattern baldness, and excessive trichilemmal keratinization have improved with melatonin supplementation. Recurrent flank alopecia may be treated with 36-mg subcutaneous implants. Oral melatonin is also available; an empirical dosage of 3–6 mg/dog, PO, every 6–8 hours, has been used successfully.

• Also see pet health content regarding drugs used to treat skin disorders.