Glucocorticoids suppress ACTH synthesis and secretion by the adenohypophysis. Extended exogenous glucocorticoid administration causes atrophy of the adrenocortical zonae fasciculata and reticularis. Weaning patients off glucocorticoid treatment in a step-wise fashion is recommended to allow recovery from adrenocortical suppression and restoration of appropriate responses to stressful situations.1 Although the effects of exogenous glucocorticoid treatment, regardless of route of administration, on cortisol secretion are known,2–5 similar evaluation of feedback effects of such treatment on circulating aldosterone concentration has not been performed, to our knowledge.
Adrenocorticotropic hormone has a role in the control of aldosterone synthesis and release from the zona glomerulosa of the adrenal gland. Daily ACTH administration to rats linearly increases the volume of the zona glomerulosa as a function of the number of days of treatment, and conversely, daily dexamethasone administration linearly decreases the volume.6 At a functional level, ACTH deficiency causes decreases in serum aldosterone concentration. In a study7 in dogs, the serum aldosterone concentration and concentrations of other adrenal steroid hormones were significantly decreased at 6 to 10 hours after hypophysectomy, compared with findings in dogs that underwent sham hypophysectomy. In that study,7 serum aldosterone and corticosterone concentrations decreased to 42% and 12% of prehypophysectomy values, respectively.
Thus, ACTH deficiency secondary to glucocorticoid administration could suppress serum aldosterone concentration, but to our knowledge, this has not been widely studied in dogs. In 2 studies,8,9 the acute effects of dexamethasone administration (0.1 mg/kg, IV) on serum aldosterone concentration in healthy dogs were evaluated; significant suppression of serum aldosterone concentration from pretreatment values was not evident at 2 hours after the dexamethasone injection but was evident at the 3- and 4-hour time points.8 A single study10 of chronic effects of glucocorticoid administration on plasma aldosterone concentration revealed significant suppression of basal aldosterone concentrations in dogs with iatrogenic hyperadrenocorticism. The extent to which glucocorticoid administration can suppress aldosterone secretion over time or the dose of glucocorticoid or duration of treatment required to cause that suppression is unknown.
Glucocorticoids are used to treat a wide variety of diseases. If treatment is discontinued abruptly, clinical signs of adrenocortical insufficiency can develop. Appropriate treatment for clinical signs of hormone deficiency that develop after rapid glucocorticoid withdrawal is believed to consist solely of glucocorticoid administration. However, such treatment may not adequately address problems such as hypotension that can be induced by aldosterone deficiency. In addition, patients are evaluated at times for spontaneous hypoadrenocorticism after discontinuation of glucocorticoid treatment via assessment of circulating electrolyte and cortisol concentrations. A supposition has been that if serum aldosterone concentration was affected, hypocortisolism was more likely a result of naturally occurring disease than an iatrogenic cause because glucocorticoid administration was assumed to not affect serum aldosterone concentration. This assumption, however, may not be valid.
The ACTH stimulation test evaluates adrenal gland function and is typically used clinically to assess glucocorticoid reserve. However, the test can also be used to evaluate aldosterone secretory capacity,9–12 and test results accurately reflect disease status in hypofunctional states. Serum aldosterone concentration is low in dogs with primary hypoadrenocorticism when hyponatremia and hyperkalemia are present.11 Furthermore, in some patients with electrolyte concentrations within the reference range despite ACTH stimulation results indicative of cortisol deficiency, serum aldosterone concentrations before and after ACTH stimulation were less than the lower reference limit. In those dogs, the disease state progressed to complete aldosterone deficiency, ultimately necessitating administration of mineralocorticoid supplements.11 Thus, measurement of serum aldosterone concentration after ACTH stimulation can reveal insufficiencies in mineralocorticoid secretion that are not detected by measurement of basal concentrations alone.
Therefore, the purpose of the study reported here was to evaluate the effects of oral administration of anti-inflammatory dosages of prednisone for 28 days on serum concentrations of aldosterone and cortisol (both before and after ACTH stimulation), sodium, chloride, potassium, and bicarbonate; anion gap; and osmolality in clinically normal dogs. Our hypothesis was that exogenous glucocorticoid administration would significantly decrease basal and ACTH-stimulated serum aldosterone concentrations and that hyponatremia, hypochloremia, or hyperkalemia (or combinations thereof) would develop.
Roxane Laboratories Inc, Columbus, Ohio.
Cortrosyn, Amphastar, Rancho Cucamonga, Calif.
Behrend EN, Martin L, Lee HP, et al. Dose response of aldosterone to ACTH stimulation in clinically healthy dogs (abstr). J Vet Intern Med 2007;21:597.
Coat-a-Count aldosterone assay, Diagnostic Products Corp, Los Angeles, Calif.
Coat-a-Count cortisol assay, Diagnostic Products Corp, Los Angeles, Calif.
SigmaStat for Windows, version 1.0, Jandel Scientific, SPSS Inc, Chicago, Ill.
Ganong WF. The adrenal medulla and adrenal cortex. In: Ganong WF, ed. Review of medical physiology. 22nd ed. New York: McGraw-Hill, 2005;357–381.
Moore GE, Hoenig M. Duration of pituitary and adrenocortical suppression after long-term administration of anti-inflammatory doses of prednisone in dogs. Am J Vet Res 1992;53:716–720.
Kemppainen RJ, Sartin JL, Peterson ME. Effects of single intravenously administered doses of dexamethasone on response to the adrenocorticotropic hormone stimulation test in dogs. Am J Vet Res 1989;50:1914–1917.
Roberts SM, Lavach JD, Macy DW, et al. Effect of ophthalmic prednisolone acetate on the canine adrenal gland and hepatic function. Am J Vet Res 1984;45:1711–1714.
Zenoble RD, Kemppainen RJ. Adrenocortical suppression by topically applied corticosteroids in healthy dogs. J Am Vet Med Assoc 1987;191:685–688.
Nussdorfer GG, Mazzocchi G, Robba C, et al. Effects of ACTH and dexamethasone on the zona glomerulosa of the rat adrenal cortex: an ultrastructural stereologic study. Acta Endocrinol (Copenh) 1977;85:608–614.
Farrell GL, Rauschkolb EW, Royce PC. Secretion of aldosterone by the adrenal of the dog: effects of hypophysectomy and ACTH. Am J Physiol 1955;182:269–272.
Javadi S, Kooistra HS, Mol JA, et al. Plasma aldosterone concentrations and plasma renin activity in healthy dogs and dogs with hyperadrenocorticism. Vet Rec 2003;153:521–525.
Willard MD, Refsal K, Thacker E. Evaluation of plasma aldosterone concentrations before and after ACTH administration in clinically normal dogs and in dogs with various diseases. Am J Vet Res 1987;48:1713–1718.
Golden DL, Lothrop CD. A retrospective study of aldosterone secretion in normal and adrenopathic dogs. J Vet Intern Med 1988;2:121–125.
Feldman EC, Nelson RW. Hypoadrenocorticism. In: Feldman EC, Nelson RW, eds. Canine and feline endocrinology and reproduction. 3rd ed. St Louis: Saunders, 2004;394–439.
Goy-Thollot I, Pechereau D, Keroack S, et al. Investigation of the role of aldosterone in hypertension associated with spontaneous pituitary-dependent hyperadrenocorticism in dogs. J Small Anim Pract 2002;43:489–492.
Kerl ME, Peterson ME, Wallace MS, et al. Evaluation of a low-dose synthetic adrenocorticotropic hormone stimulation test in clinically normal dogs and dogs with naturally developing hyperadrenocorticism. J Am Vet Med Assoc 1999;214:1497–1501.
Kemppainen RJ, Thompson FN, Lorenz MD. Use of a low dose synthetic ACTH challenge test in normal and prednisone-treated dogs. Res Vet Sci 1983;35:240–242.
Behrend EN, Weigand CM, Whitley EM, et al. Corticosterone-and aldosterone-secreting adrenocortical tumor in a dog. J Am Vet Med Assoc 2005;226:1662–1666.
Kintzer PP, Peterson ME. Mitotane (o,p′-DDD) treatment of 200 dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 1991;5:182–190.
de Morais HA. Disorders of chloride and water: hyperchloremia and hypochloremia. In: DiBartola SP, ed. Fluid therapy in small animal practice. 3rd ed. Philadelphia: WB Saunders Co, 2006;80–90.
Feldman EC, Nelson RW. Canine hyperadrenocorticism (Cushing's syndrome). In: Feldman EC, Nelson RW, eds. Canine and feline endocrinology and reproduction. 3rd ed. St Louis: Saunders, 2004;252–357.
Sandhu S, Silbiger SR, Lei J, et al. Effects of sex hormones on fluid and solute transport in Madin-Darby canine kidney cells. Kidney Int 1997;51:1535–1539.
Johnson JA, Davis JO, Baumber JS, et al. Effects of estrogens and progesterone on electrolyte balances in normal dogs. Am J Physiol 1970;219:1691–1697.
Hulter HN, Licht JH, Bonner EL Jr, et al. Effects of glucocorticoid steroids on renal and systemic acid-base metabolism. Am J Physiol 1980;239:F30–F43.
Waters CB, Adams LG, Scott-Moncrieff JC, et al. Effects of glucocorticoid therapy on urine protein-to-creatinine ratios and renal morphology in dogs. J Vet Intern Med 1997;11:172–177.
Moore GE, Mahaffey EA, Hoenig M. Hematologic and serum biochemical effects of long-term administration of anti-inflammatory doses of prednisone in dogs. Am J Vet Res 1992;53:1033–1037.