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Hormonal Therapy for Integumentary Disease

By Michael Shipstone, BVSc, FACVSc, DACVD, Queensland Veterinary Specialists

Glucocorticoids:

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 selected. Glucocorticoids are used for hypersensitivity dermatoses, contact dermatitis, immune-mediated diseases (eg, pemphigus, pemphigoid, lupus erythematosus), and neoplasia (eg, mast cell tumor, lymphoma). Glucocorticoids may be classified according to their duration of effect and relative potency (see Table: Glucocorticoids). They may be administered PO, IV, IM, or SC.

Glucocorticoids

Drug

Relative Potency

Duration of Effect

Hydrocortisone (cortisol)

1

<12 hr

Prednisolone

4

12–36 hr

Prednisone

4

12–36 hr

Methylprednisolone

5

12–36 hr

Triamcinolone

5

12–36 hr

Flumethasone

15–30

36–48 hr

Betamethasone

25

>48 hr

Dexamethasone

30

>48 hr

The anti-inflammatory dosage of prednisolone is 0.5–1 mg/kg/day in dogs (severe cases may require 2 mg/kg/day) and 1–2 mg/kg/day in cats. This dosage is given for an induction period of 5–7 days and then reduced to the lowest possible maintenance dosage (ideally 0.25 mg/kg, every 48–72 hr or lower in dogs). Maintenance doses must be given ≥48 hr apart to minimize adrenal suppression and chronic adverse effects. The immunosuppressive dosage of prednisolone is 2.2 mg/kg/day in dogs (up to 6.6 mg/kg/day may be required in severe disease) and 4.4 mg/kg/day in cats.

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 In many cases, therapy may be withdrawn entirely without relapse, whereas others require lifelong treatment.

Administration PO 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 therapy. 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 wk).

Adverse effects include polyuria, polydipsia, polyphagia, weight gain, increased susceptibility to infection, GI 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 animal sensitivity. The most commonly encountered infections are urinary tract infections, pyoderma, and pulmonary infections. Urinary tract infections may develop in many animals on longterm glucocorticoid therapy (68% in one study), and these animals may show no clinical signs of the infection. Urine should be cultured for bacterial growth every 3–6 mo in all animals on longterm therapy.

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

Most injectable forms are labeled for IM use; however, they are commonly given SC. Local areas of alopecia, pigmentation, and epidermal and dermal atrophy may be seen with SC injection.

Thyroid Hormone:

Thyroid hormones are indicated as replacement therapy 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 hormone levels 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, bid. Insufficient serum levels after 4–6 wk of treatment or lack of a clinical response after 12 wk are indications to increase the dose. Synthetic liothyronine (T3) may be used for those rare animals that cannot convert T4 to T3. It should not be used for routine treatment of hypothyroidism, because it bypasses the normal cellular regulatory pathways and has a short half-life. Dosage is 4–6 mcg/kg, PO, bid-tid. Crude preparations from thyroid tissue and synthetic thyroid hormone combinations that mimic the T4:T3 ratio in people should not be used in animals.

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 dosage and gradually increased to full dosage over a 1-mo period.

Trilostane:

Trilostane is a hormonally inactive, steroid competitive inhibitor of the adrenal enzyme 3β-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, the 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/day, PO, but this may be increased or decreased, based on periodic adrenocorticotropic hormone (ACTH) stimulation test results (performed 3–8 hr after trilostane administration). If the post-ACTH plasma cortisol concentration is <20 nmol/L, trilostane administration should be stopped for 48–72 hr 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 wk, 12 wk, and every 3–6 mo thereafter.

Mitotane (o,p′DDD):

o,p′DDD 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 therapy, food intake (amount), time taken to eat, and the 24-hr water intake should be recorded to determine a baseline. Once this has been established, a loading dose is administered daily (25 mg/kg, bid) until the animal becomes lethargic, water intake drops, appetite is reduced, or the animal has other GI adverse effects (vomiting, diarrhea) or after 5 days of administration. An ACTH stimulation test should be performed to confirm whether adequate suppression of the adrenals has been achieved.

Most dogs respond to o,p′DDD therapy at the initial loading dose within 5–10 days, and the decision to change to maintenance therapy 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 wk and should then be treated with 25 mg/kg/wk divided into 2 or 3 doses. Dogs with a post-ACTH plasma cortisol concentration of 25–125 nmol/L should receive 25 mg/kg/wk in 2 or 3 doses, and dogs with a post-ACTH cortisol concentration >125 nmol/L should receive 50 mg/kg/wk.

During maintenance therapy, an ACTH stimulation test should be performed after 1 mo and then every 3–4 mo. If the post-ACTH plasma cortisol concentration is <25 nmol/L, the dose of o,p′DDD 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 therapy, their adrenal reserve may not be adequate to handle major stress (physiologic or psychologic). In these cases, o,p′DDD administration should be discontinued and replaced with glucocorticoids (0.2 mg/kg/day, PO, tapered) during this period.

Adverse effects are relatively common, particularly in cases of o,p′DDD overdose. These include 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 o,p′DDD and supplementing with glucocorticoids. Clinical improvement is usually seen within 1–6 hr. Iatrogenic hypoadrenocorticism is the most serious adverse effect and may develop at any time during maintenance treatment. Administration of o,p′DDD should be stopped and appropriate supplementation with glucocorticoids and mineralocorticoids started. Other rare CNS adverse effects include ataxia, apparent blindness, circling, and head pressing.

Progesterones:

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 given PO. Medroxyprogesterone acetate is antiestrogenic and has significant 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 hr, decreasing to every 1–2 wk for maintenance. Medroxyprogesterone acetate is given at a dosage of 50–100 mg/cat, IM, and may be repeated in 3–6 mo.

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

Growth Hormone:

Growth hormone (somatotropin) is a polypeptide produced by the anterior pituitary that acts either directly on target tissues or indirectly through insulin-like growth factors (somatomedins) produced by the liver (also see The Pituitary Gland). 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 IU/kg, 3 times/wk for 4–6 wk) is effective. Hair usually regrows in 2–3 mo, and remission may last from 6 mo to 3 yr. Growth hormone is diabetogenic, and dogs can develop transient or permanent diabetes mellitus during therapy. Weekly monitoring of blood glucose before and during therapy is recommended.

Sex Hormones:

Several syndromes in dogs and cats have been attributed to imbalances of sex hormones; however, the etiopathogenesis of these disorders is generally poorly documented. Hypoestrogenism in spayed female dogs, hypoandrogenism in male dogs, and feline acquired symmetric alopecia may respond to sex-hormone therapy. Dosages for sex-hormone replacement therapy are empirical. Hypoestrogenism in spayed female dogs may be treated with diethylstilbestrol (0.02 mg/kg/day for 3 wk of every month until hair regrows or for a maximum total dose of 1 mg/dog). After hair regrows, the maintenance dosage should be given 1–2 times/wk. An alternative protocol is to treat every other day or twice weekly until a response is seen. Hair regrowth should be evident in 3–4 wk, with a complete response within 4 mo. Exogenous estrogen can cause bone marrow hypoplasia, so a CBC and platelet count should be performed weekly during therapy. 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, PO, up to a total maximal dose of 30 mg every 48 hr. Alternatively, testosterone proprionate can be given IM once weekly at dosages of 0.5–1 mg/kg, or every 4–16 wk at 2 mg/kg. Complications include aggressive behavior, greasy hair coat, prostatic hypertrophy, and hepatotoxicity. Liver function should be evaluated before treatment and monthly during therapy.

Repositol testosterone, 12 mg/cat, IM, may be given 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 given testosterone.

Melatonin:

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 tricholemmal keratinization have improved with melatonin supplementation. Recurrent flank alopecia may be treated with 36-mg SC implants. Oral melatonin is also available; an empirical dosage of 3–6 mg/dog, tid-qid, has been used successfully.

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