CorticosteroidsCorticosteroids are key regulators of whole-body homeostasis that provide an organism with the capacity to resist environmental corticosteroids effects on lab values and invasion of foreign substances. The effects of corticosteroids are widespread, including profound alterations in carbohydrate, protein, and lipid metabolism, and the modulation of electrolyte and water balance. Corticosteroids affect all of the major systems of the body, including the cardiovascular, musculoskeletal, nervous, and immune systems, and play critical roles in fetal development including the maturation of the fetal lung. Because so many systems are sensitive to corticosteroid levels, tight regulatory control is exerted on the system. The direct effects of corticosteroids are sometimes difficult to separate from their complex relationship with other hormones, in part due to the permissive action of low levels of corticosteroid on the effectiveness of other hormones, corticosteroids effects on lab values catecholamines steroid dosage by weight glucagon. Nevertheless, the effects of corticosteroids can be classified into two general categories:
Corticosteroids – Effect on lab values
Glucocorticoids are known to acutely increase blood pressure, suppress inflammation, and precipitate insulin resistance. However, the short-term effects of glucocorticoids on other cardiovascular risk factors remain incompletely characterized. Our objective was to determine the effects of a short course of dexamethasone on multiple cardiovascular biomarkers and to determine whether suppression of morning cortisol in response to low-dose dexamethasone is correlated with cardiovascular risk markers in healthy volunteers.
The study took place in a tertiary care hospital. Twenty-five healthy male volunteers, ages 19—39 yr, participated in the study. Subjects received either 3 mg dexamethasone twice daily or placebo for 5 d.
Subjects also underwent a low-dose 0. Parameters examined before and after the 5-d intervention included heart rate, blood pressure, weight, fasting lipid variables, homocysteine, renin, aldosterone, insulin resistance homeostasis model assessment , high-sensitivity C-reactive protein, B-type natriuretic peptide, flow-mediated and nitroglycerin-mediated brachial artery dilatation, and heart rate recovery after exercise.
All measurements were done in the morning hours in the fasting state. Dexamethasone increased systolic blood pressure, weight, B-type natriuretic peptide, and high-density-lipoprotein-cholesterol. Dexamethasone decreased resting heart rate, high-sensitivity C-reactive protein, and aldosterone and tended to attenuate nitroglycerin-mediated vasodilatation. There was no effect on flow-mediated vasodilatation, diastolic blood pressure, triglycerides, low-density-lipoprotein-cholesterol, nonesterified fatty acids, homocysteine, or heart rate recovery.
The response of circulating cortisol to low-dose dexamethasone had no significant correlation with any of the cardiovascular risk markers. Short-term glucocorticoids elicits both favorable and unfavorable effects on different cardiovascular risk factors.
Manipulation of specific glucocorticoid-responsive physiological pathways deserves further study. Glucocorticoid deficiency can result in hypotension, weight loss, hypoglycemia, and death, especially in the setting of stress 2. Conversely, exogenous or endogenous glucocorticoid excess can contribute to the development of hypertension, insulin resistance, hyperglycemia, weight gain, hyperhomocysteinemia, and atherosclerosis 3 — 6.
Although epidemiological studies and animal studies suggest accelerated atherosclerosis in the presence of long-term excessive exogenous glucocorticoid exposure 7 — 9 , the extent of inflammation confounds the relationship between glucocorticoid exposure and the atherosclerosis associated with inflammatory diseases In recent years, a growing body of literature suggests that altered endogenous glucocorticoid homeostasis may contribute to the metabolic syndrome and adverse cardiovascular outcomes 11 — 18 , whereas other studies have suggested salutary effects of glucocorticoids on the cardiovascular system Limited in vivo data are available to characterize the effects of glucocorticoids on specific cardiovascular risk factors, except for hypertension and glucose homeostasis, and, with long-term exposure, body fat redistribution.
Furthermore, central adiposity resulting from long-term glucocorticoid exposure, rather than glucocorticoids per se , may lead to many adverse cardiovascular effects, complicating the assessment of direct glucocorticoid effects on these risk factors 4.
Another issue that confounds the evaluation of glucocorticoid-specific regulation of cardiovascular risk factors is that most glucocorticoids used in clinical medicine, such as prednisone, hydrocortisone, and methylprednisolone, have substantial mineralocorticoid effects when used in pharmacological doses. As such, physiological studies using high doses of these agents are, in effect, examining the combined effects of glucocorticoids and mineralocorticoids 8 , 20 — Based on these limitations of existing literature, we sought to determine the specific short-term effects of glucocorticoids on cardiovascular biomarkers in healthy volunteers in whom active inflammatory diseases were absent.
We used dexamethasone because it has negligible mineralocorticoid effects 29 , 30 , and we chose a dose of dexamethasone that would be comparable to maximal stress-induced endogenous hydrocortisone production such as seen in sepsis , approximately to mg hydrocortisone equivalents daily 31 , We hypothesized that insulin resistance induced by dexamethasone would adversely affect endothelial function, lipid parameters particularly triglycerides and nonesterified fatty acids , B-type natriuretic peptide BNP , and heart rate recovery after exercise.
We also sought to determine whether dexamethasone would affect C-reactive protein CRP in healthy subjects with low baseline CRP values , given that glucocorticoids directly stimulate hepatic CRP production 33 while simultaneously suppressing inflammation. We were concerned with the direction of change in these parameters increase vs.
Based on preliminary work by others 14 , 34 , we also sought to relate these risk markers to the tone of the HPA axis, measured by low-dose dexamethasone suppression testing, to attempt to validate the hypothesis that subtly impaired suppression of endogenous cortisol is related to the metabolic syndrome.
We hypothesized that features of the metabolic syndrome, including high waist-to-hip ratio, high body mass index, blood pressure, the ratio of triglyceride to high-density lipoprotein HDL -cholesterol, insulin resistance, and endothelial dysfunction, would be negatively correlated with the magnitude of the decrease in circulating cortisol in response to low-dose dexamethasone.
We conducted a randomized, double-blind, placebo-controlled study in healthy young men. Subjects were treated with 3 mg dexamethasone twice daily for 5 d or with placebo.
Multiple physiological markers were assessed before and after the intervention. Additionally, we conducted a low-dose dexamethasone test before the pharmacological intervention; all subjects received 0. We recruited healthy nonsmoking men, ages 19—39 yr, by local advertisements; volunteers were given a stipend for participation.
Potential subjects were excluded if they had any of the following: Subjects underwent a full history and physical examination, including measurement of height, weight, and waist and hip circumferences. Subjects were advised to maintain their usual sleep-wake schedule, exercise, and dietary habits during the study and to report any changes in their health status or perceived adverse effects of study participation. A structured poststudy questionnaire allowed the subjects to report perceived effects of the study medication on health-related behaviors.
Subjects were advised not to take any prescription medications, over-the-counter medications, or alcohol during the protocol. All subjects provided written informed consent. Subjects were randomized by computer to receive dexamethasone or placebo. Investigators and subjects were unaware of treatment assignments.
At study completion, all subjects were asked to report whether they believed they received dexamethasone or placebo. Compliance was confirmed by measuring posttreatment cortisol levels expected to be undetectable in all subjects assigned to dexamethasone. Fasting h blood samples were obtained before and after the 5-d intervention. Serum triglycerides, total cholesterol, and direct low-density lipoprotein LDL -cholesterol were determined enzymatically Modular Analytics , and HDL-cholesterol was determined using the Friedewald formula.
Glucose was measured with an automated oxidation assay Modular Analytics. Plasma renin was measured as direct active renin by a monoclonal antibody-based two-site immunochemiluminometric assay on the automated Nichols Advantage System Nichols Diagnostics, San Juan Capistrano, CA. Blood pressure and heart rate were determined in triplicate in a rested sitting position using a single automated cuff DINAMAP ; the mean value of the three measurements of diastolic blood pressure, systolic blood pressure, and pulse rate were used in data analysis.
Heart rate was also determined while supine, after quietly resting for 15 min. Weight and height were determined manually using a single balance scale. Two-dimensional and Doppler flow images of the brachial artery were digitally stored in cine-loop DICOM format and transferred to a workstation for off-line analysis ProSolv Cardiovascular version 3.
A blinded investigator measured the brachial artery diameter before and after proximal arterial occlusion.
Transient arterial occlusion was accomplished using a blood pressure cuff placed 4 cm above the antecubital crease and inflated to mm Hg for 5 min and then rapidly deflated. Anatomic landmarks were used to maintain consistent positioning of the probe. Flow-mediated vasodilatation was defined as the percent increase in arterial diameter in response to this ischemic stressor. After a min supine resting period, non-endothelium-mediated vasodilatation was assessed in a similar fashion in response to a single 0.
Subjects underwent a standard Bruce treadmill protocol. To ensure that each subject exercised for the same amount of time and reached the same workload before and after the intervention, we did not exercise subjects to exhaustion. Subjects exercised for an identical duration of time during the postintervention assessment, regardless of heart rate.
Heart rate recovery was defined as the peak heart rate at the termination of exercise minus the heart rate 1 min into the recovery phase of the Bruce protocol This parameter is considered an index of parasympathetic reactivation after exertion We computed the change from baseline to post intervention in each measured variable; variables with highly skewed distributions were log-transformed before this calculation. We compared the placebo and dexamethasone groups on change from baseline using two-sample unequal variance t tests.
As a secondary analysis, we assessed whether the mean change from baseline within the dexamethasone group was equal to zero using one-sample t tests. We assessed the relationships among continuous variables using Pearson correlation coefficients. All tests were two-tailed and performed at a significance level of 0. Statistical analyses were performed using JMP 5.
Twenty-five subjects were enrolled in the protocol; 13 were randomized to receive dexamethasone and 12 to placebo. All subjects completed the protocol, and compliance was confirmed in all 13 dexamethasone-treated subjects via undetectable postintervention serum cortisol.
Brachial artery reactivity data were incomplete for two subjects, one in each group; one subject refused to take nitroglycerin during the postintervention assessment because of a headache during the baseline study, and technical difficulties affected the data for the other subject.
In the structured postintervention survey, three subjects in each group believed they had received the active drug; seven dexamethasone-treated subjects and four placebo-treated subjects believed they had received placebo. The remaining eight subjects were unsure. Nineteen of the subjects reported no change whatsoever in sleeping, eating, and exercise behaviors; the other six subjects reported minor changes in one or more of these behaviors. Dexamethasone-mediated changes in selected cardiovascular biomarkers.
The P values are for two-sided intergroup comparisons. Means are shown by the horizontal lines in the figure margins. The baseline values of the various measured parameters are shown in Table 1 ; the effects of the intervention are also presented in Table 1.
The metric-SI conversions are as follows: Although means and sd are presented for all parameters, log transformations were performed as appropriate before statistical testing. As shown in Table 1 , flow-mediated vasodilatation was similar in dexamethasone- and placebo-treated subjects, suggesting that short-term dexamethasone did not significantly impair endothelial function. We examined correlations between the absolute change in cortisol from baseline and the various cardiovascular biomarkers.
We also examined correlations between each biomarker and the percent decrement of cortisol from baseline. We found no significant correlations between the responsiveness of the HPA axis to low-dose dexamethasone and any of the metabolic-syndrome-associated parameters. Correlation coefficients between specific biomarkers and the absolute change in morning cortisol after 0. Also shown are the correlation coefficients between baseline cortisol levels and absolute postdexamethasone cortisol levels.
These changes occurred in the setting of a marked increase in insulin secretion but no significant change in circulating glucose levels. We did not find any evidence that short-term glucocorticoids adversely affect endothelial function. Before we address some key differences between our findings and those of other researchers, it is important to recognize that we used a drug dexamethasone with negligible mineralocorticoid activity 29 , 30 that suppresses endogenous cortisol which has substantial mineralocorticoid activity.
Therefore, it is conceivable that some of the effects we observed might have been mediated in part by decreased mineralocorticoid activity rather than glucocorticoid effects per se. In keeping with this, we did observe a significant reduction in aldosterone concentrations in the dexamethasone-treated subjects. Nevertheless, given the well-characterized adverse cardiovascular effects of mineralocorticoids 39 , we believe that the use of dexamethasone is a major strength of our study.
Indeed, other researchers who attempted to examine the effects of glucocorticoids on cardiovascular risk factors may have unknowingly generated findings that were mediated in part by mineralocorticoid effects of the drugs they chose such as hydrocortisone and prednisone 8 , 20 — Several of our findings deserve comment. Our intervention demonstrates that hyperinsulinemia per se , induced by a short course of glucocorticoids, does not invariably lead to the lipid changes typically associated with insulin resistance high triglycerides, raised nonesterified fatty acids, and low HDL.
Rather, glucocorticoids promote insulin secretion, which at the level of the liver is likely to limit the action of hepatic lipase, decreasing HDL catabolism Our lipid findings are consistent with one small, nonrandomized study of prednisone-treated patients with systemic inflammatory diseases 20 but differ from other nonrandomized reports that corticosteroid treatment raises triglycerides and LDL 21 , The placebo-controlled nature of our study, the short duration of treatment, and the use of healthy volunteers rather than patients with inflammatory diseases may explain the differences between our findings and those of other researchers.