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Oxandrolone Enhances Hepatic Ketogenesis in Adult Men Gloria Lena Vega, Phd,*Y Jacob J

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Oxandrolone Enhances Hepatic Ketogenesis in Adult Men Gloria Lena Vega, Phd,*Y Jacob J J Investig Med: first published as 10.2310/JIM.0b013e318189153d on 5 January 2016. Downloaded from Journal of Investigative Medicine 56(7):920–924, 2008 Ó 2008 by The American Federation for Medical Research | ORIGINAL ARTICLE | Oxandrolone Enhances Hepatic Ketogenesis in Adult Men Gloria Lena Vega, PhD,*y Jacob J. Clarenbach, MD,* Fredrick Dunn, MD,y and Scott M. Grundy, MD, PhD*y | ABSTRACT | INTRODUCTION Background: Immediate administration of oxandrolone Anabolic steroids stimulate expression of hepatic lipase markedly increases hepatic lipase activity and reduces (HL).1,2 Hepatic lipase possesses both phospholipase levels of plasma high-density lipoprotein. and triglyceride-lipase activities. An increase in HL Rationale for the study: We postulated that oxandro- activity is accompanied by a reduction in plasma high- lone should increase hepatic lipase and that the non- density lipoprotein cholesterol (HDL-C) levels; this esterified fatty acids generated would enhance hepatic increase further appears to enhance the lipolysis of tri- ketogenesis during an extended fat tolerance test. glyceride-rich lipoproteins (TGRLP) and to promote Main Results: Eighteen men participated in the study uptake of remnant lipoproteins into the liver.2Y4 Because using short-term administration of oxandrolone (10 mg/d) of the effects of anabolic steroids on HL, we posed the over a week. Subjects had evaluation of hepatic keto- question of whether an increased lipolysis of TGRLP at genesis at baseline and after 7 days of administration the surface of liver cells might increase the influx of of oxandrolone. Ketogenesis was assessed by mea- fatty acids into the liver. As a first step to examine this suring plasma levels of 3-hydroxybutyrate during a fat possibility, we further asked whether anabolic steroids tolerance test. Oxandrolone increased fasting levels of might promote hepatic ketogenesis, which could be 3-hydroxybutyrate by 70%, and increased the area under secondary to increased influx of fatty acids into the liver the curve during an FFT by 53% above pretreatment and enhanced fatty acid oxidation. Because a precise levels without affecting the areas under the curve for non- quantification of fatty acid oxidation in humans is not pos- esterified fatty acids, glycerol, or triglycerides. Fasting sible, we measured plasma levels of 3-hydroxybutyrate 3-hydroxybutyrate levels correlated with nonesterified as a surrogate indicator. Previous studies have shown fatty acids and with triglycerides; however, there were that plasma 3-hydroxybutyrate correlates with rates of no significant correlations with any other parameter. ketogenesis, which in turn correlates with rates of fatty Conclusions: This study shows that short-term adminis- acid oxidation.5Y8 If hepatic ketogenesis during anabolic http://jim.bmj.com/ tration of oxandrolone results in marked increases in steroid administration is not increased, then an increased hepatic ketogenesis. This finding is consistent with an influx of fatty acids into the liver is unlikely. increased influx of fatty acids into the liver secondary to lipoprotein lipolysis by increased hepatic lipase. How- | ever, the possibility cannot be ruled out that oxandrolone METHODS acts directly in the liver to stimulate fatty acid oxidation. Eighteen adult men were recruited into the study at the on September 23, 2021 by guest. Protected copyright. Therefore, the observation of increased ketogenesis will Veterans Affairs Medical Center in Dallas. Their charac- require further studies to determine the molecular basis teristics are shown in Table 1. Nine subjects had meta- of the response. bolic syndrome as previously defined.9 Basal plasma Key Words: steroids, 3-hydroxybutyrate, nonesterified triglycerides ranged from 51 mg/dL to 340 mg/dL, fatty acids, hepatic lipase low-density lipoprotein cholesterol level ranged from 80 mg/dL to 182 mg/dL and HDL-C from 19 mg/dL to 74 mg/dL. None were taking lipid-lowering drugs, and From the *Center for Human Nutrition of the University of Texas none had history of cardiovascular disease, endocrine Southwestern Medical Center at Dallas, and the yVeterans Affairs Medical Center, Dallas, TX. disorders, liver dysfunction, or contraindications for par- The study was supported partially by the Veterans Affairs Medical ticipating in the study. The trial had a sequential design Center Merit Award, Moss Heart Foundation and Center for Human of baseline evaluation followed by oral administration of Nutrition. oxandrolone (10 mg/d) for 7 days with a repeat of the Reprints: Gloria Lena Vega, PhD, and Scott M. Grundy, MD, PhD, baseline tests. The protocol was approved by the Institu- Center for Human Nutrition, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9052. E-mail: Gloria.Vega@ tional Review Board for Investigation in Humans and all utsouthwestern.edu and [email protected]. subjects gave informed written consent. 920 Journal of Investigative Medicine Copyright @ 2008 American Federation for Medical Research. Unauthorized reproduction of this article is prohibited. J Investig Med: first published as 10.2310/JIM.0b013e318189153d on 5 January 2016. Downloaded from Hepatic Ketogenesis in Adult Men TABLE 1. Clinical Characteristics of Subjects cholesterol, and study of ketogenesis during an extended Mean T SEM Median fat tolerance test (FTT). For the latter, after an overnight Age (yr) 58.6 T 1.8 59.5 fast, subjects ingested a heavy whipping cream drink Body mass index (kg/m2) 29.8 T 1.2 30.5 containing 75 g of fat (100% of calories from fat with Waist circumference (cm) 101.2 T 2.9 99.8 70% long-chain saturates). After cream ingestion, they Systolic blood pressure (mm Hg) 136.5 T 2.5 135.0 were allowed to drink water and sugar-free tea during T Diastolic blood pressure (mm Hg) 79.6 1.9 82.0 the succeeding 10 hours. Arterialized blood samples Total cholesterol (mg/dL) 202 T 7.8 199 Non-HDL cholesterol (mg/dL) 163 T 8.9 166 were obtained in sodium-ethylenediaminetetraacetic Total apolipoprotein B (mg/dL) 125 T 7.0 132 acid (2 mg/mL) before (t = 0) and every 2 hours until HDL, high-density lipoprotein. 8 hours after the meal. Subjects kept their hand in an iso- thermal box (T =70-C) to obtain arterialized blood sam- Subjects had a clinical evaluation for inclusion into ples. To avoid ongoing in vitro lipolysis by plasma the study, and after recruitment, they had anthropometry, lipoprotein lipase, blood samples were immediately measurement of fasting plasma lipids and lipoprotein placed on ice, centrifuged to separate plasma, which http://jim.bmj.com/ on September 23, 2021 by guest. Protected copyright. FIGURE 1. Effect of oxandrolone on plasma fasting levels and post-prandial levels of triglyceride (panels A and B, respectively), non-esterified fatty acids (panels C and D, respectively) and glycerol (panels E and F, respectively). The term baseline signifies the study before oxandrolone treatment and oxandrolone during treatment. There were no significant changes in either fasting or the post-prandial levels for any of the metabolites between baseline and on-treatment measurements. Numerical data shown in the figure represent means T standard error of the means. Volume 56, Issue 7 921 Copyright @ 2008 American Federation for Medical Research. Unauthorized reproduction of this article is prohibited. J Investig Med: first published as 10.2310/JIM.0b013e318189153d on 5 January 2016. Downloaded from Vega et al FIGURE 2. Effect of oxandrolone on fasting levels of 3-hydroxybutyrate (panel A) and during an extended fat tolerance test (panel B). Results are shown as box-and-whisker plots. Numerical data shown in the figure represent means T standard error of the means. The term baseline signifies the study before oxandrolone treatment and oxandrolone during treatment. Oxandrolone therapy significantly increased the fasting and post-prandial levels of 3-hydroxybutyrate by repeated ANOVA after Bonferroni-Dunn adjustments for multiplicity of testing (P G 0.0028 for panel A and P G 0.0086 for panel B). was frozen at j80-C. Analysis was carried out in less were increased by 70% (Fig. 2), and oxandrolone than 24 hours. In preliminary testing, we demonstrated raised the AUC for 3-hydroxybutyrate by 53% after that no significant lipolysis of triglycerides occurred oral fat loading. There was a consistent direction of before analysis under these conditions. The 3-hydroxy- change in 3-hydroxybutyrate on oxandrolone therapy in butyrate, nonesterified fatty acids (NEFA), triglycer- spite of considerable baseline variation in NEFA levels ides, and glycerol were measured from plasma spec- among individuals of the study. This resulted in a highly trophotometrically using enzymatic assays (Roche statistically significant increase in 3-hydroxybutyrate Diagnostics/Boehringer Mannheim Corp, Indianapolis levels on oxandrolone treatment (Fig. 2). IN). Levels of plasma total cholesterol, triglycerides, and HDL-C were measured using standardized enzy- | DISCUSSION matic assays as described previously.10 Levels of plasma apolipoprotein B were quantified as detailed In the current study, oxandrolone therapy was accompa- previously.11 nied by a striking increase in plasma 3-hydroxybutyrate T levels. This change almost certainly reflects an increase Data are summarized as mean SEM. The primary 5Y8 end point of the study was the change in the area under in hepatic ketogenesis and raises the question of mechanism. Several possibilities can be considered. the curve (AUC) of plasma 3-hydroxybutyrate during the http://jim.bmj.com/ extended FTT before and after 7 days of treatment with First, an increased hepatic ketogenesis could be sec- oxandrolone. The effects of oxandrolone on metabolites ondary to increased influx of fatty acids into the liver associated with an increased activity of HL. In fact, as of interest were analyzed by comparing the baseline to 1,2,12 treatment levels during fasting or the AUCs during the previously reported, we observed a marked decrease extended FTT. Analysis was carried out by repeated- in plasma levels of HDL-C associated with anabolic measures analyses of variance with Bonferroni-Dunn steroid administration.
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