Vet Times The website for the veterinary profession https://www.vettimes.co.uk Treatments for pituitary and adrenal-dependent Cushing s Author : KAREN CRAWFORD, REBECCA LITTLER Categories : Vets Date : October 6, 2014 KAREN CRAWFORD BVMS, MRCVS REBECCA LITTLER MA, VetMB, PhD, CertSAM, DSAM, MRCVS look at both forms of hyperadrenocorticism, and advise on the importance of determining which form is present before choosing the optimum treatment Summary Cushing s disease, or hyperadrenocorticism (HAC), is one of the most common endocrinopathies in companion animals and is defined as the combination of clinical signs that results from effects of hypercortisolism in the body. Typical clinical signs include polyphagia, polyuria, polydipsia, panting, pot-bellied appearance and dermatological changes. The disease is common in dogs and ferrets and is rarely, though increasingly, recognised in cats. Overproduction of adrenocorticotropic hormone by a small, benign pituitary microadenoma (pituitary-dependent hyperadrenocorticism) is the most common cause of HAC. Less commonly, the condition occurs due to the presence of an adrenal tumour (adrenal-dependent HAC, or ADH). It can be useful to differentiate between the two causes when attempting to select the most appropriate treatment modality. Treatment may be medical or surgical. The treatment method chosen for a dog with HAC depends on several factors, including availability, efficacy, potential side effects, cause and severity of disease, concurrent diseases and the preferences of the client and clinician. Cost of treatment and follow-up evaluation should also be taken into account. 1 / 7
Key words hyperadrenocorticism, hypercortisolism, Cushing s, trilostane HYPERADRENOCORTICISM (HAC), also known as Cushing s syndrome, is one of the most common endocrinopathies in companion animals and results from a chronic excess of glucocorticoids. Two spontaneous forms of the disease exist, and the disease may also be iatrogenically induced by administration of exogenous steroids. Overproduction of adrenocorticotropic hormone (ACTH) by a small, benign pituitary microadenoma (pituitary-dependent hyperadrenocorticism or PDH) is the most common cause of HAC. Larger pituitary tumours (pituitary macroadenoma) also occur and can be associated with neurological signs. Less commonly, the condition results from overproduction of cortisol by an adrenal tumour (adrenaldependent HAC or ADH). It can be useful to differentiate between the two causes to give clients a clearer idea of prognosis and likely course of the disease, but also to help select the most appropriate treatment. The treatment method chosen for a dog with HAC depends on several factors, including availability, efficacy, presence of malignancy, potential side effects, cause and severity of disease, concurrent diseases and the preferences of the client and clinician. Cost of treatment and follow-up evaluation should also be taken into account. PDH medical management Trilostane (Vetoryl; Dechra), a synthetic steroid analogue that competitively inhibits steroid synthesis by blocking 3-beta-hydroxysteroid dehydrogenase, is the current licensed treatment for HAC in the UK. Use of trilostane for treatment of canine PDH was first reported in 1998 and several studies have since confirmed its clinical efficacy (Bell et al, 2006; Neiger et al, 2002; Vaughan et al, 2008). Trilostane is available in 10mg, 30mg, 60mg and 120mg capsules. Since it was licensed a number of studies have investigated the safety and efficacy of reducing the initial dose rate. As a result of published literature, which suggests lower starting doses are efficacious and may reduce the risk of side effects, the manufacturer s recommended starting dose has changed to 2mg/kg once daily (previously 3mg/kg to 6mg/kg once daily). Administration of the medication with food is recommended to enhance absorption. Monitoring is carried out based on clinical response and by performing an ACTH stimulation test 2 / 7
four to six hours after trilostane administration. Post-ACTH cortisol concentrations of 70nmol/l to 250nmol/l have been suggested to equate to good disease control (Neiger et al, 2002; Vaughan et al, 2008); however, in the authors experience a post-acth cortisol concentration of 40nmol/l to 150nmol/l tends to produce a better effect. The manufacturers recommend monitoring after 10 days, four weeks, 12 weeks, and thereafter every three months, following initial diagnosis and after each dose adjustment. As aldosterone synthesis is also affected (although to a lesser degree than cortisol) by blockade of 3-betahydroxysteroid dehydrogenase, monitoring of serum biochemistry, including electrolytes, is advised. Most owners will notice a reduction in signs such as polyuria/polydipsia in the first 10 days, although other clinical signs, such as skin changes, can take several months to resolve. In the majority of cases, the authors have found it sensible not to increase the trilostane dose at the first recheck, as increasing dosage at this early stage can often lead to development of trilostane overdose. More than half of dogs treated with trilostane will subsequently require some adjustment from their initial starting dose though, with some needing higher or more frequent dosages. The duration of cortisol suppression achieved appears to vary substantially; however, in most dogs cortisol concentrations remained suppressed for less than 13 hours. Even so, good control of the disease can be achieved in a large number of dogs with once daily dosing. Some dogs that do not show satisfactory clinical improvement despite adequate cortisol concentration at peak effect will benefit from twice-daily administration of trilostane. The total daily dose when administering the medication twice daily is generally lower than that required with once daily dosing. Trilostane is well tolerated by most dogs, although minor side effects such as mild lethargy and reduced appetite are sometimes reported transiently. More severe adverse effects, including anorexia, depression, vomiting and diarrhoea, can occur and trilostane has been associated with the development of hypoadrenocorticism. In animals showing such signs, trilostane should be stopped and an ACTH stimulation test performed together with monitoring of haematology, biochemistry and electrolytes. Animals showing signs of an adrenal crisis may require fluid therapy and steroid replacement (glucocorticoids with or without mineralocorticoids), as well as symptomatic treatment with antiemetics and gastroprotectants. Most cases will make a rapid recovery and, once recovery of the adrenal axis has been documented, trilostane can be restarted, although the dose should be reduced by 25 per cent to 50 per cent. Less commonly, reports have documented adrenal necrosis (Chapman et al, 2004) and such animals may require steroid supplementation for life. The most serious complication reported is sudden death (Neiger et al, 2002), and this has occurred in a small number of cases without signs of hypoadrenocorticism; the role of trilostane role in these deaths has not been documented. 3 / 7
As HAC is commonly diagnosed in older dogs, concurrent disease processes are often present and these may affect the response to treatment. In particular, diabetes mellitus often occurs concurrently with HAC and HAC is known to lead to insulin resistance. In the majority of cases, controlling HAC will not result in complete resolution of diabetes; however, reducing cortisol levels may increase responsiveness to insulin. Many authors have recommended prospectively reducing insulin dose when starting therapy for HAC, although one study (McLauchlan et al, 2010) showed instigating trilostane treatment was not consistently associated with a reduction in insulin requirement. It is, therefore, possible that reductions in insulin dose at the start of trilostane therapy will not be required in all cases. No specific guidelines exist and the authors advise careful monitoring. Trilostane use is contraindicated in patients with hepatic or renal insufficiency and these cases can pose particular problems. In addition, some patients exhibit severe and/or consistent side effects meaning they are unable to tolerate trilostane therapy. For dogs that do not tolerate trilostane therapy, use of off-licence mitotane, also known as o,p -DDD (Lysodren), which was the treatment of choice prior to the advent of trilostane, may be considered. This drug is an adrenocorticolytic with a direct cytotoxic effect on the adrenal cortex, resulting in selective, progressive necrosis and atrophy. Treatment involves an induction and a maintenance phase and must be monitored closely as side effects are relatively common. Disadvantages of mitotane therapy include its lack of licence, potential for development of irreversible adrenocortical insufficiency, potential drug intolerance, and relatively high frequency of relapse during treatment. Readers are referred to the reference list for suitable treatment protocols. Efficacy of other treatments with either central or peripheral action for treatment of PDH have been investigated (Rijnberk et al, 1988; Peterson and Drucker, 1978; Stolp et al, 1984; Feldman et al, 1998). Ketoconazole, an oral anti-fungal medication, has been shown to inhibit synthesis of glucocorticoids and androgens (Feldman et al, 1998). It effectively lowers circulating cortisol concentrations, but has minimal effect on mineralocorticoids. Ketoconazole has been associated with hepatotoxicity, and for that reason should probably not be considered a suitable alternative therapy for HAC dogs with hepatic insufficiency. Although ketoconazole can control HAC in some dogs, about half of them will fail to respond adequately to treatment (Lien and Huang, 2008) and given the expense, the need for twice-daily dosing and life-long administration, and the lack of efficacy in some cases its use cannot be routinely recommended. Selegiline (L-deprenyl) has also been proposed as an alternative therapy for dogs with HAC. It is thought to work through enhancing dopamine concentration, and thereby down-regulating ACTH secretion. This is probably only effective in dogs where the pituitary tumour arises within the pars intermedia, where ACTH is dependent on dopamine. Most studies have shown little endocrinologic effect, but some clinical improvement (Bruyette et al, 1997; Reusch et al, 1999) and the authors have seen clinical improvement when using this drug for treatment of HAC dogs with renal insufficiency. 4 / 7
PDH surgical management Transsphenoidal pituitary surgery is the treatment of choice in people with PDH and hypophysectomy has been described in dogs with PDH (Hanson et al, 2005; Meij et al, 2002). This approach is unlikely to be suitable in all cases and only specialist surgeons with suitable facilities should perform such surgery. Until recently, only one institution in Europe regularly performed this procedure; however, one case has recently been reported at the RVC, making it the first centre in the UK to successfully perform this surgery. PDH managing neurological signs Neurological signs may be noted at any stage during treatment and typically reflect expansion of a pituitary tumour. Commonly seen clinical signs include central blindness, loss of appetite and altered mental alertness. Severity of neurological deficits is a significant prognostic indicator and patients with large intracranial tumours are at increased risk of intracranial haemorrhage or sudden expansion of the tumour following treatment. Advanced imaging (CT or MRI) is required for diagnosis. Radiation therapy can be effective in many cases, although typically the neurological signs improve more rapidly than the endocrinologic signs (Goossens et al, 1998; de Fornel et al, 2007). Radiotherapy does not always result in adequate control of HAC, particularly if the tumour is very large, and medical therapy is often still warranted following radiation treatment. ADH medical management Patients with ADH can potentially be medically managed as for PDH, and medical stabilisation is recommended before considering surgery. In addition, for dogs with inoperable tumours or evidence of metastasis at the time of diagnosis, medical treatment may be appropriate. Mitotane can be used as an adrenocorticolytic in an attempt to control or destroy the adrenal tumour; however, the licensed product, trilostane, has been shown to result in a comparable median survival time (Helm et al, 2011; Arenas et al, 2014) and case reports have described good efficacy in controlling clinical signs of HAC in dogs with ADH. Trilostane is not cytotoxic and therefore will have no effect on growth of the tumour or metastases, but it can be considered a safe and acceptable palliative treatment and, in the authors experience, is generally suitable for medical stabilisation in cases of ADH prior to surgery. Trilostane may be preferable to mitotane for stabilisation prior to surgery as it is less likely to render the tumour more friable. ADH surgical management The ideal treatment for dogs with HAC secondary to a functional adrenocortical tumour is surgical 5 / 7
removal of the tumour. This strategy is not without risk, but has the potential for an excellent, and curative, outcome (Kyles et al, 2003; Massari et al, 2011). Preoperative medical stabilisation is generally recommended and probably improves survival. It is important to investigate the extent of local or metastatic spread and to determine the degree of vascular involvement prior to surgery, and advanced imaging is essential for this. Adrenalectomy is technically challenging and a skilled surgeon, together with careful anaesthetic management, is required. Secretion of cortisol from the tumour results in atrophy of the zona fasciculata and zona reticularis. In some dogs the aldosterone producing cells of the zona glomerulosa also atrophy. This means glucocorticoid substitution intraoperatively and postoperatively is required and mineralocorticoid treatment may also be necessary. Where bilateral adrenal tumours are present and bilateral adrenalectomy is required, life-long mineralocorticoid and glucocorticoid replacement is needed. Please note some of the medications mentioned in this article are not licensed. References Arenas C, Melian C and Perez-Alenza M D (2014). Long-term survival of dogs with adrenaldependent hyperadrenocorticism: a comparison between mitotane and twice daily trilostane treatment, J Vet Intern Med 28(2): 473-480. Bell R, Neiger R, McGrotty Y et al (2006). Study of the effects of once daily doses of trilostane on cortisol concentrations and responsiveness to adrenocorticotropic hormone in hyperadrenocorticoid dogs, Vet Rec 159(9): 277-281. Bruyette D S, Ruehl W W, Entriken T et al (1997). Management of canine pituitarydependent hyperadrenocorticism with l-deprenyl (Anipryl), Vet Clin North Am Small Anim Pract 27(2): 273-286. Chapman P S, Kelly D F, Archer J et al (2004). Adrenal necrosis in a dog receiving trilostane for the treatment of hyperadrenocorticism, J Sm Anim Pract 45(6): 307-310. de Fornel P, Delisle F, Devauchelle P et al (2007). Effects of radiotherapy on pituitary corticotroph macrotumours in dogs: a retrospective study of 12 cases, Can Vet J 48(5): 481-486. Feldman E C, Bruyette D S, Nelson R W and Farver T B (1998). Plasma cortisol response to ketoconazole administration in dogs with hyperadrenocorticism, J Am Vet Med Assoc 197(1): 71-78. Goossens M M, Feldman E C, Theon A P et al (1998). Efficacy of cobalt 60 radiotherapy in dogs with pituitary-dependent hyperadrenocorticism, J Am Vet Med Assoc 212(3): 374-376. Hanson J M, van t Hoofd M M, Voourhout G, Kooistra H S and Meij B P (2005). Efficacy of transsphenoidal hypophysectomy in treatment of dogs with pituitary-dependent hyperadrenocorticism, J Vet Intern Med 19(5): 687-694. Helm J R, McLauchlan G, Boden L, Frowde P E, Collings A J, Tebb A J, Elwood C M, Herrtage M E, Parkin T D and Ramsey I (2011). A comparison of factors that influence 6 / 7
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