Ellen N. Behrend

Glucocorticoid Therapy: Pharmacology, Indications, and Complications

Glucocorticoids are one of the most commonly prescribed classes of medication in veterinary medicine, with numerous applications ranging from physiologic replacement therapy to immunosuppression. Due to the presence of glucocorticoid receptors in almost all cells, both the desired and undesired effects of glucocorticoid therapy are manifold. This article discusses the physiologic alterations possible with glucocorticoid therapy, glucocorticoid pharmacology, nonendocrine indications, and different therapeutic strategies. The adverse reactions potentially associated with glucocorticoid therapy also are examined.

Diagnosis of Spontaneous Canine Hyperadrenocorticism: 2012 ACVIM Consensus Statement (Small Animal)

This report offers a consensus opinion on the diagnosis of spontaneous canine hyperadrenocorticism. The possibility that a patient has hyperadrenocorticism is based on the history and physical examination. Endocrine tests should be performed only when clinical signs consistent with HAC are present. None of the biochemical screening or differentiating tests for hyperadrenocorticism are perfect. Imaging can also play a role. Awareness of hyperadrenocorticism has heightened over time. Thus, case presentation is more subtle. Due to the changes in manifestations as well as test technology the Panel believes that references ranges should be reestablished. The role of cortisol precursors and sex hormones in causing a syndrome of occult hyperadrenocorticism remains unclear.

Diagnosis of Canine Hyperadrenocorticism

Canine hyperadrenocorticism is one of the most common endocrinopathies in dogs. Diagnosis remains difficult in some cases due to factors such as the presence of non-adrenal illness and limitations in the tests. Differentiation between the pituitary and adrenal forms is important for providing accurate prognostic information and delineating treatment options and protocols. This article reviews the tests available for diagnosis (screening) and differentiation and evaluates their advantages and disadvantages. Recommendations for testing are made.

Pituitary-adrenal function in dogs with acute critical illness

OBJECTIVE To evaluate pituitary-adrenal function in critically ill dogs with sepsis, severe trauma, and gastric dilatation-volvulus (GDV). DESIGN Cohort study. ANIMALS 31 ill dogs admitted to an intensive care unit (ICU) at Washington State University or the University of Pennsylvania; all dogs had acute critical illness for < 48 hours prior to admission. PROCEDURES Baseline and ACTH-stimulated serum cortisol concentrations and baseline plasma ACTH concentrations were assayed for each dog within 24 hours after admission to the ICU. The change in cortisol concentrations (Delta-cortisol) was calculated for each dog. Morbidity and mortality data were recorded for each patient. RESULTS Overall, 17 of 31 (55%) acutely critically ill dogs had at least 1 biochemical abnormality suggestive of adrenal gland or pituitary gland insufficiency. Only 1 (3%) dog had an exaggerated response to ACTH stimulation. Dogs with Delta-cortisol < or = 83 nmol/L were 5.7 times as likely to be receiving vasopressors as were dogs with Delta-cortisol > 83 nmol/L. No differences were detected among dogs with sepsis, severe trauma, or GDV with respect to mean baseline and ACTH-stimulated serum cortisol concentrations, Delta-cortisol, and baseline plasma ACTH concentrations. CONCLUSIONS AND CLINICAL RELEVANCE Biochemical abnormalities of the hypothalamic-pituitary-adrenal axis indicative of adrenal gland or pituitary gland insufficiency were common in critically ill dogs, whereas exaggerated responses to ACTH administration were uncommon. Acutely ill dogs with Delta-cortisol < or = 83 nmol/L may be more likely to require vasopressors as part of the treatment plan.

Regulation of Dexras1 Expression by Endogenous Steroids

Dexras1, a newly identified member of the Ras superfamily of proteins, was discovered in AtT-20 corticotrope cells because its expression was induced in response to glucocorticoids (dexamethasone; Dex). As yet, the function of Dexras1 is unknown, but its rapid induction in response to glucocorticoids suggests the possibility that it may be involved in negative feedback regulation of corticotropin secretion. To better understand the control of Dexras1 expression, possible effects of other steroid hormones on its expression were studied in both AtT-20 cells and in mouse pituitaries. AtT-20 cells were treated with each of 6 steroids [aldosterone, corticosterone (Cort), Dex, β-estradiol (E2), progesterone and testosterone] for 2 h. Dexras1 expression was assessed using both reverse transcription polymerase chain reaction (RT-PCR) and Northern analysis. Expression of the gene was only induced in response to glucocorticoid treatment (Dex or Cort). The 6 steroids were also injected into mice, pituitaries were harvested and total RNA was obtained for RT-PCR analysis. Surprisingly, treatment with E2, not only injection of glucocorticoids, induced Dexras1 expression in mouse pituitary. Other steroids were without effect. The results suggest that in AtT-20 corticotropes, Dexras1 expression is only induced by glucocorticoid-type steroids. In pituitary glands of mice, the gene’s expression is also responsive to E2. We conclude that either Dexras1 expression in corticotropes from normal mice is regulated differently from that in AtT-20 cells, or that Dexras1 is also expressed in other pituitary cells than corticotropes.

Seasonal Changes in Plasma Adrenocorticotropic Hormone and α‐Melanocyte‐Stimulating Hormone in Response to Thyrotropin‐Releasing Hormone in Normal, Aged Horses

BACKGROUND Results of diagnostic tests for equine pituitary pars intermedia dysfunction (PPID), including endogenous ACTH concentration and the overnight dexamethasone suppression test (DST), are affected by season. New and potentially more sensitive diagnostic tests for equine PPID, such as thyrotropin-releasing hormone (TRH)-stimulated ACTH response, have been developed, but have had limited evaluation of seasonality. OBJECTIVE Our purpose was to evaluate seasonal changes in plasma ACTH and alpha-melanocyte-stimulating hormone (α-MSH) responses to TRH administration. ANIMALS Nine, healthy, aged horses with normal DST results. METHODS Synthetic TRH (1 mg) was administered IV. Plasma ACTH and α-MSH concentrations were measured at 0, 5, 10, 15, 20, 25, 30, 45, 60, and 180 minutes. Testing was performed in February, July, August, September, October, and November. Mean TRH-stimulated ACTH and α-MSH concentrations were compared across months and time by repeated measures analysis of variance. Significance was set at the P < .05 level. RESULTS Concentrations of ACTH and α-MSH significantly increased after TRH administration. Endogenous and TRH-stimulated ACTH and α-MSH concentrations were significantly different across months with higher concentrations in the summer and fall compared with February. CONCLUSIONS AND CLINICAL IMPORTANCE Plasma ACTH and α-MSH responses to TRH administration experience seasonal variation, with TRH-stimulated ACTH and α-MSH concentrations increasing from summer through fall. These results support previous evidence of a seasonal influence on the equine pituitary-adrenal axis. More research is warranted with a larger number of horses to determine if seasonal reference ranges for TRH stimulation testing need to be defined.

Seasonal variation in results of diagnostic tests for pituitary pars intermedia dysfunction in older, clinically normal geldings

OBJECTIVE To determine whether seasonal variations exist in endogenous plasma ACTH, plasma α-melanocyte-stimulating hormone (α-MSH), serum cortisol, and serum insulin concentrations and in the results of a dexamethasone suppression test for older, clinically normal geldings in Alabama. DESIGN Cohort study. ANIMALS 15 healthy mixed-breed geldings (median age, 14 years). PROCEDURES Sample collection was repeated monthly for 12 months. Dexamethasone (0.04 mg/kg [0.02 mg/lb], IM) was administered and cortisol concentrations were determined at 15 and 19 hours. Radioimmunoassays were used to measure ACTH, α-MSH, cortisol, and insulin concentrations at each testing time. Hormone concentrations were compared between months via repeated-measures ANOVA and correlated with age within each month. RESULTS A significant time effect was found between months for α-MSH and insulin concentrations. Endogenous cortisol and ACTH concentrations remained within existing reference ranges. Significant correlations were detected between age and ACTH concentration for several fall and winter months and between age and insulin concentration for September. CONCLUSIONS AND CLINICAL RELEVANCE Older horses have higher ACTH concentrations in several fall and winter months and higher insulin concentrations in September than do younger horses. Seasonally specific reference ranges are required for α-MSH and insulin concentrations, with significantly higher concentrations detected in the fall. Practitioners should be advised to submit samples only to local laboratories that can provide such reference ranges for their local geographic region.

Diagnosis of Canine Hypothyroidism

The most common sample received by our endocrine testing laboratory is submitted for the diagnosis of hypothyroidism in a dog. The current tests most frequently employed in our laboratory for thyroid evaluation in dogs are total T4, free T4 by dialysis, and canine TSH measurement. Each test has strengths and weaknesses and suffers from the possibility of both false positive and false negative results. This article provides a working description of each test and an approach to interpretation of results. Other tests that are less commonly used are also discussed. Examples of interpretation of test results in individual hypothyroidsuspect dogs are presented for illustration.

Use of Compounded Adrenocorticotropic Hormone (ACTH) for Adrenal Function Testing in Dogs

Serum cortisol concentrations were measured in five healthy dogs in response to five adrenocorticotropic hormone (ACTH) preparations. Cortisol concentrations were similar at time 0 (pre-ACTH) and at 30 and 60 minutes after injection of all forms of ACTH. However, at 90 and 120 minutes post-ACTH, serum cortisol concentrations were significantly lower following injection of two compounded forms of ACTH. The data showed that injection of four compounded forms of ACTH caused elevations in serum cortisol concentrations of a similar magnitude as cosyntropin in samples collected 60 minutes after administration; but concentrations at later times varied, depending on the type of ACTH used.

Efficacy of selective mineralocorticoid and glucocorticoid agonists in canine septic shock

Objective:Corticosteroid regimens that stimulate both mineralocorticoid and glucocorticoid pathways consistently reverse vasopressor-dependent hypotension in septic shock but have variable effects on survival. The objective of this study was to determine whether exogenous mineralocorticoid and glucocorticoid treatments have distinct effects and whether the timing of administration alters their effects in septic shock. Design, Setting, Subjects, and Interventions:Desoxycorticosterone, a selective mineralocorticoid agonist; dexamethasone, a selective glucocorticoid agonist; and placebo were administered either several days before (prophylactic) or immediately after (therapeutic) infectious challenge and continued for 96 hrs in 74 canines with staphylococcal pneumonia. Measurements and Main Results:Effects of desoxycorticosterone and dexamethasone were different and opposite depending on timing of administration for survival (p = .05); fluid requirements (p = .05); central venous pressures (p ⩽ .007); indicators of hemoconcentration (i.e., sodium [p = .0004], albumin [p = .05], and platelet counts [p = .02]); interleukin-6 levels (p = .04); and cardiac dysfunction (p = .05). Prophylactic desoxycorticosterone treatment significantly improved survival, shock, and all the other outcomes stated, but therapeutic desoxycorticosterone did not. Conversely, prophylactic dexamethasone was much less effective for improving these outcomes compared with therapeutic dexamethasone with the exception of shock reversal. Prophylactic dexamethasone given before sepsis induction also significantly reduced serum aldosterone and cortisol levels and increased body temperature and lactate levels compared with therapeutic dexamethasone (p ⩽ .05), consistent with adrenal suppression. Conclusions:In septic shock, mineralocorticoids are only beneficial if given prophylactically, whereas glucocorticoids are most beneficial when given close to the onset of infection. Prophylactic mineralocorticoids should be further investigated in patients at high risk to develop sepsis, whereas glucocorticoids should only be administered therapeutically to prevent adrenal suppression and worse outcomes.