A Small-Scale Clinical Trial to Determine the Safety ...

Humans, Clinical

HMR/2011-03-0066/16.6.2011/Macmillan

Authors

W. A. Bauman1,2,3,4, C. M. Cirnigliaro1, M. F. La Fountaine1,2,3, A. M. Jensen1, J. M. Wecht1,2,4, S. C. Kirshblum5,6, A. M. Spungen1,2,3,4

Affiliations

Affiliation addresses are listed at the end of the article

Key words ▶ lean tissue mass ● ▶ tetraplegia ● ▶ paraplegia ● ▶ hypogonadism ● ▶ androgen replacement ● therapy

Abstract ▼

received 10.03.2011 accepted 25.05.2011 Bibliography DOI http://dx.doi.org/ 10.1055/s-0031-1280797 Published online: 2011 Horm Metab Res © Georg Thieme Verlag KG Stuttgart · NewYork ISSN 0018-5043 Correspondence W. A. Bauman, MD Center of Excellence for the Medical Consequences of Spinal Cord Injury James J. Peters VA Medical Center 130 West Kingsbridge Road Bronx NY 10468 USA Tel.: +1/718/584 9000 Ext: 5420 Fax: +1/718/741 4675 [email protected]

Men with spinal cord injury are at an increased risk for secondary medical conditions, including metabolic disorders, accelerated musculoskeletal atrophy, and, for some, hypogonadism, a deficiency, which may further adversely affect metabolism and body composition. A prospective, open label, controlled drug intervention trial was performed to determine whether 12 months of testosterone replacement therapy increases lean tissue mass and resting energy expenditure in hypogonadal males with spinal cord injury. Healthy eugonadal (n = 11) and hypogonadal (n = 11) outpatients with chronic spinal cord injury were enrolled. Hypogonadal subjects received transdermal testosterone (5 or 10 mg) daily for 12 months. Measurements of body composition and resting energy expenditure were obtained at baseline and 12 months.

Introduction ▼ Lean tissue mass (LTM) is appreciated to be dramatically reduced below the level of lesion after acute spinal cord injury (SCI), but accelerated loss above the level of lesion has also been reported in those with chronic SCI [1]. This muscle wasting results in decreased energy expenditure and may ultimately lead to increased adiposity and associated deleterious metabolic consequences [2, 3]. A continued premature loss of LTM in persons with SCI would be anticipated to hamper functional independence and social integration [4], which would adversely affect quality of life and may be associated with increased cost of care [5, 6]. In individuals with chronic SCI, restoration of a favorable body composition may be impeded by the reduced ability to engage in normal levels of physical activity [7]. In men with SCI, serum total testosterone (T) levels are inversely related to

The testosterone replacement therapy group increased lean tissue mass for total body (49.6 ± 7.6 vs. 53.1 ± 6.9 kg; p < 0.0005), trunk (24.1 ± 4.1 vs. 25.8 ± 3.8 kg; p < 0.005), leg (14.5 ± 2.7 vs. 15.8 ± 2.6 kg; p = 0.005), and arm (7.6 ± 2.3 vs. 8.0 ± 2.2 kg; p < 0.005) from baseline to month 12. After testosterone replacement therapy, resting energy expenditure (1328 ± 262 vs. 1440 ± 262 kcal/d; p < 0.01) and percent predicted basal energy expenditure (73 ± 9 vs. 79 ± 10 %; p < 0.05) were significantly increased. In conclusion, testosterone replacement therapy significantly improved lean tissue mass and energy expenditure in hypogonadal men with spinal cord injury, findings that would be expected to influence the practice of clinical care, if confirmed. Larger, randomized, controlled clinical trials should be performed to confirm and extend our preliminary findings.

duration of injury (DOI) [8, 9] and previous reports documented a greater incidence of low T levels compared to matched control subjects [10]. The development of a hypogonadal state in some men with SCI may further aggravate the adverse changes in body composition, and possibly contribute to the associated metabolic disorders and a progressive loss of function [11–13]. Testosterone replacement therapy (TRT) may offer a logical, efficacious, and cost-effective intervention to, in part, counteract these untoward body composition, metabolic, and functional sequelae of hypogonadism in those with chronic SCI. Although TRT in able-bodied individuals is generally reported to improve body composition, with both increased LTM and decreased fat tissue mass (FTM), there is controversy concerning the efficacy of TRT to improve functional outcomes [14]. In hypogonadal men with chronic SCI, only

Bauman WA et al. Testosterone Replacement i Men with SCI … Horm Metab Res

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A Small-Scale Clinical Trial to Determine the Safety and Efficacy of Testosterone Replacement Therapy in Hypogonadal Men with Spinal Cord Injury

one limited prospective study has been performed with the administration of oxandrolone, a synthetic analogue of testosterone, in which favorable improvements in LTM were found, but these adaptations were associated with undesired changes in the serum lipid profile and increased liver enzymes [15, 16]. Whether TRT administration is safe and efficacious at increasing LTM, as well as a multiplicity of other potentially favorable outcomes, has yet to be addressed in men with SCI. This study was performed to determine the effects of 12-months of TRT on soft tissue body composition in hypogonadal men with chronic SCI. Changes in resting energy expenditure (REE) and safety outcomes were described and characterized (e. g., lipoprotein profile, hepatic panel, and prostate health) in those receiving TRT.

Subjects and Methods ▼ Subjects 22 healthy, chronic (> 1 year), nonambulatory men with SCI, American Spinal Injury Association (ASIA) Impairment Scale (AIS) of sensorimotor impairment (AIS A, B, or C), between the ages of 18 and 65 were recruited for participation from the Spinal Cord Injury Service of the James J. Peters Veterans Affairs Medical Center (JJPVAMC), Bronx, NY and the Kessler Institute for Rehabilitation (KIR), West Orange, NJ. Participants were excluded from the study if they had a diagnosed history of prostate cancer or current elevated prostate specific antigen (PSA ≥ 4.0 μg/l), elevated hematocrit (Hct) ≥ 55 %, abnormal liver function tests (≥ 2.5 times the upper limit of normal), abnormal digital rectal examination (DRE) revealing prostatic enlargement or possible malignancy, heart and/or vascular disease, acute or chronic illness of any etiology, cancer, significant psychological and/or sleep disorders. The study was approved by the Institutional Review Boards of the JJPVAMC and KIR. Written informed consent was obtained from each subject prior to study participation.

Procedures A prospective, controlled, drug intervention trial to assess the effects of 12-month TRT on body composition and REE in a cohort of hypogonadal men with SCI was performed. Of the 22 individuals enrolled, 11 subjects were designated hypogonadal (treatment group) and 11 subjects, eugonadal (control group), as determined by serum total T concentrations. For the purposes of this study, hypogonadism was defined as a serum total T concentration < 11.3 nmol/l, and eugonadal, ≥ 11.4 nmol/l. All participants had blood drawn for total T on 3 separate occasions between 8:00 and 10:00 AM and the average was used to determine group assignment. All participants were instructed to maintain their usual dietary and physical activity/exercise schedule over the course of the study. 7 participants in each group continued participation in weekly aerobic and/or resistance exercise sessions. After a baseline testing period, TRT was begun in the treatment group by application of a 5 mg T patch daily (Androderm, Watson Pharma Inc., Corona, CA, USA). If serum T levels were not within normal physiologic range after 2 months of TRT, the dose was increased to 10 mg (i. e., 2 patches) daily for the remainder of treatment. After 2 months, 5 of the 11 subjects in the treatment group required this titration. Subjects were instructed to place the patch on a clean, dry and shaved (if necessary) area of the


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skin on the thighs or abdomen in the morning (~ 09:00 h). The requirement for and scheduling of personal assistant care in 3 of the 11 participants resulted in patch placement during the evening (~ 21:00 h). To prevent skin irritation, T patch application sites were rotated among various sites located on the quadriceps and abdomen, with a 10-day interval between repeated uses of the same placement location. Subjects were instructed on the use of a topical corticosteroid (e. g., triamcinolone) cream at the application site if skin irritation developed. Patch compliance was monitored and determined by inventory of the number of returned patches each month. The average rate of compliance was excellent (97 ± 3.3 %) for the entire treatment period. Subjects in the control group received no intervention. Comprehensive physical examination and laboratory work were completed at baseline, 2, 6, and 12 months after initiating TRT in the treatment group and at baseline and 12 months in the control group. The physical examination for subjects in the treatment group included a DRE that was performed by an internist who was not affiliated with the study at each facility. Body composition and indirect calorimetry were completed on all subjects at baseline and 12 months.

Laboratory analysis Analyses for serum T and serum PSA were performed by Quest Diagnostics, Inc. (Teterboro, NJ, USA) using the ADVIA Centaur XP Immunoassay Chemiluminescent System according to the manufacturer′s specifications (Bayer Healthcare Diagnostics, Bohemia, NY, USA). Hemoglobin (Hb) and Hct % were obtained from the complete blood count with an ACT 10 Hematology Blood Analyzer (Beckman Coultur, Brea, CA, USA). Lipid profile [total cholesterol (TC), triglycerides (TG), and high density lipoproteins (HDL) with LDL levels estimated using the Friedewald equation [17], and liver function tests (LFTs) [aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltransferase (GGT), alkaline phosphatase (AP), and albumin] were determined in the General Chemistry Laboratory of the Veterans Affairs Medical Center using an ADVIA 1 650 automatic chemistry analyzer, following procedures recommended by the manufacturer (Bayer Diagnostics, Newbury, UK).

Body composition measurements For baseline and 12-month, body composition was measured in the morning after an overnight fast with subjects wearing a minimum amount of clothing that was appropriate for the procedure. A total body scan was performed in accordance with manufacturer guidelines using fan beam dual energy X-ray absorptiometry (DXA; GE LUNAR Prodigy Advance, software version 11.4 and 12.2, Madison, WI). Total body scans were performed and the energy level used for each total body scan was based on subject thickness (e. g., thin, standard, or thick). To analyze the results of each total body scan, proprietary software algorithms were used to segment the body into trunk, pelvis, and upper and lower extremities using the standard regions of interest. As part of the daily quality assurance during the study, a lumbar spine phantom (reference value 30 % fat) was scanned > 200 times with the CV % determined to be 0.9 %. In accordance with International Society for Clinical Densitometry guidelines [18], total body scans were repeated on 30 SCI subjects by the “on-and-off-the-table” method (i. e., subjects were repositioned between scans) and our precision error was equal to 1.2 % for LTM and 2.2 % for FTM.


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REE, oxygen consumption (VO2), and carbon dioxide (VCO2) production were obtained by indirect calorimetry. A metabolic cart (V-Max Encore 229, CareFusion, Yorba Linda, CA, USA) was used to quantify exhaled air from subjects for fractions of mixed expired O2 and CO2. Subjects arrived at the laboratory for testing between the hours of 8:00 and 10:00 AM, following a 12-h fast, with a minimum of 24 h free from any type of exercise. Subjects were transferred to a comfortable bed and instructed to lie still in a quiet, softly lit room for 20 min prior to testing. Data were collected under steady state conditions defined as ± 5 % change in respiratory quotient and ± 10 % change in VO2 and VE for a minimum of 5 min, consecutively. Predicted basal energy expenditure (pBEE) was determined by the Harris-Benedict equation [19], and the percent of predicted energy expenditure (% pEE) was calculated as follows: % pEE = REE/pBEE × 100. VO2 and VCO2 were continuously measured, averaged every 20 s, and converted to REE using the abbreviated Weir equation [20]. The REE was normalized to total body LTM, and the respiratory exchange ratio (RER) was calculated.

Statistical analysis Values are expressed as group mean ± SD. Unpaired t-tests were performed to identify group (treatment vs. control) differences for demographic (age, height, weight, BMI, DOI, screening serum T), laboratory (T, albumin, PSA, GGT, AST, ALT, AP, TC, HDL-C, LDL-C, TG, Hb, HCT), body composition (weight, LTM [for total, trunk, leg, and arm], FTM [for total, trunk, leg, and arm], total body % fat) and energy expenditure (VO2, RER, REE, REE/kg, pBEE) variables. Separate 2 factor (group: treatment, control) analysis of variance (ANOVA) with repeated measures on visit (baseline, month 12) were performed to identify changes in body composition and energy expenditure across time. Separate single factor repeated measures ANOVAs were performed to identify statistical changes in laboratory values across 4 visits (baseline, month 2, month 6, and month 12) in the treatment group and 2 visits (baseline and month 12) in the control group. To further characterize significant main and interaction effects, post-hoc paired t-tests were performed within group. One sample t-tests were performed on the percent change from baseline to month 12 [(month 12– baseline)/baseline*100] for comparison to the null hypothesis. An a priori level of significance was set at p ≤ 0.05. Statistical analyses were completed using Statview 5.0 (SAS Institute, Inc.).

Results ▼ Demographic data for subjects in the treatment and control ▶ Table 1). Subjects in the treatment groups are provided (● (hypogonadal) group were taller (p < 0.05) and older (p < 0.05) than those in the control (eugonadal) group. The groups were well matched for weight, BMI, and DOI. No significant differences were noted for the body composition or energy expenditure variables at baseline between the treatment and control ▶ Table 2). groups (●

Measures of body composition There were no significant group or visit main effects for compartmental FTM (e. g., total body, trunk, leg, or arm). However, a trend was noted toward a significant interaction effect for total body % fat (p = 0.0545); no change was observed in the control

▶ Table 2). There group and the treatment group declined 2.3 % (● were no group main effects found for compartmental LTM (e. g., total body, trunk, leg, or arm); however, significant main effects for visit were noted for trunk LTM (p = 0.0036) and arm LTM (p = 0.0009). In addition, significant interaction effects were observed for total body (p = 0.0059), trunk (p = 0.0097), and leg (p = 0.0047) LTM, with a trend toward significance in arm LTM (p = 0.0803). Within group pairwise comparisons of the change from baseline to month 12 for total body (p < 0.0005), trunk (p < 0.005), arm (p < 0.005) and leg (p = 0.005) LTM were significant in the treatment group, but not in the control group ▶ Table 2). One sample t-tests on the percent change from (● baseline to month 12 for total body (p = 0.001), trunk (p < 0.01), leg (p < 0.01) and arm (p < 0.01) LTM were significant in the treatment group compared to the null, but not in the control group ▶ Fig. 1). (●

Energy expenditure There were no significant group main effects for the energy expenditure variables [e. g., VO2/kg, RER, REE, REE/kg, pBEE and ▶ Table 2). A significant main effect for visit was % pEE] (● observed for REE (p = 0.0077) and a trend toward significance in VO2/kg (p = 0.0713), pBEE (p = 0.0809) and % pEE (p = 0.0619). A trend toward a significant interaction effect was present for REE (p = 0.051) and % pEE (p = 0.0701). Post-hoc analyses revealed that the month 12 observations for REE and % pEE were not statistically different between the treatment and control groups. However, within group pairwise comparisons of the changes from baseline to month 12 for REE (p < 0.05) and % pEE (p < 0.01) ▶ Table 2). were significant (●

Laboratory values and adverse effects There were no abnormal DRE findings noted in the treatment ▶ Table 3). At baseline, there were no statistical differgroup (● ences in mean laboratory values between the treatment and control groups, except for AP (p < 0.05) and AST (p < 0.05), which were greater in the treatment group than the control group, but the average values remained within normal limits. As expected by design, serum T levels at baseline in the hypogonadal group were statistically lower than in the control group (p < 0.0001). During TRT and at month 12, the lipoprotein profile, hepatic panel, and PSA values remained within the normal range ▶ Table 3). (● In the treatment group, there were minor adverse events that were categorized as possibly or probably related to TRT. 2 of the Table 1 Characteristics of the Study Groups

n Screening TT (ng/dl) Age (years) Height (m) Weight (kg) BMI (kg/m2) DOI (years) Paraplegia/Tetraplegia (n) Motor complete (n) Motor incomplete (n)

Control Group

Treatment Group

(TT ≥ 11.4 nmol/l)

(TT < 11.3 nmol/l)

11 516 ± 137 35 ± 9 1.74 ± 0.04 79.6 ± 9.2 26 ± 3 12 ± 9 6/5 9 2

11 257 ± 95* 43 ± 6† 1.79 ± 0.07† 82.9 ± 12.6 25 ± 3 13 ± 10 9/2 8 3

SD: standard deviation; TT: total testosterone; BMI: body mass index; DOI: duration of injury. Data are presented as mean ± SD. *p < 0.0001 for treatment vs. control; †

p < 0.05 for treatment vs. control



Energy expenditure

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Table 2 Soft tissue body composition and energy expenditure measurements

Weight (kg) LTM (kg) Total body Trunk Leg Arm FTM (kg) Total body Trunk Leg Arm Total Body % Fat VO2/kg (ml/min) RER REE (kcal/d) REE/kg (kcal/kg/d) pBEE (kcal/d) % pEE

Baseline

Month 12

Visit

Interaction

Treatment Control

82.1 ± 12.8 79.6 ± 9.2

85.3 ± 14.5 79.7 ± 10.1

Group –

–

– –

Treatment Control Treatment Control Treatment Control Treatment Control

49.6 ± 7.6 51.9 ± 8.1 24.1 ± 4.1 24.6 ± 3.3 14.5 ± 2.7 14.2 ± 3.5 7.6 ± 2.3 8.2 ± 1.4

53.1 ± 6.9* 50.5 ± 6.3 25.8 ± 3.8† 24.7 ± 3.2 15.8 ± 2.6† 13.9 ± 3.2 8.0 ± 2.2† 8.3 ± 1.5

– – – – – – – –

– – 0.0036 – 0.1067 – 0.0009 –

0.0059 – 0.0097 – 0.0047 – 0.0803 –

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control

29.5 ± 8.4 24.8 ± 8.8 16.5 ± 4.9 13.5 ± 4.6 9.3 ± 3.0 7.9 ± 3.1 2.5 ± 0.9 2.6 ± 1.5 35.8 ± 7.0 31.5 ± 9.4 2.26 ± 0.26 2.34 ± 0.25 0.89 ± 0.09 0.91 ± 0.11 1328 ± 262 1319 ± 112 26.8 ± 3.9 28.9 ± 12.0 1808 ± 188 1747 ± 143 73 ± 9 76 ± 7

29.8 ± 10.6 26.3 ± 9.0 16.5 ± 6.4 14.9 ± 5.4 9.2 ± 3.2 7.9 ± 2.9 2.4 ± 1.1 2.6 ± 1.4 33.5 ± 7.6 31.8 ± 9.2 2.40 ± 0.31 2.41 ± 0.36 0.90 ± 0.13 0.90 ± 0.10 1440 ± 262§ 1339 ± 128 27.0 ± 2.8 26.8 ± 3.6 1833 ± 214 1774 ± 178 79 ± 10‡ 76 ± 8

– – – – – – – – – – – – – – – – – – – – – –

– – – – – – – – 0.1709 – 0.0713 – – – 0.0077 – – – 0.0809 – 0.0619 –

– – – – – – – – 0.0545 – – – – – 0.051 – – – – – 0.0701 –

SD: standard deviation; kg: kilograms; LTM: lean tissue mass; FTM: fat tissue mass; RER: respiratory exchange ratio; REE: measured resting energy expenditure; REE/kg: measured REE per kilogram of lean tissue mass; pBEE: predicted basal energy expenditure; % pEE: percent predicted energy expenditure. Data are expressed as group mean ± SD. p-Value represents significant main effects. Change from baseline in treatment group: *p < 0.0005; †p < 0.005; ‡p < 0.01; and § p < 0.05

11 subjects developed minor skin irritations that resolved with the use of corticosteroid cream, and one subject developed acne that resolved with treatment. An additional 4 subjects developed mild lower extremity edema that was continually monitored and clinically managed by the use of compression stockings. In one subject at 12 months, the Hb and Hct rose to 1.81 g/l and 54.7 %, respectively, and decreased toward the normal range 6 months after discontinuing TRT. In a second subject, an approximate two-fold increase in ALT and GGT were noted at month 12, with values returning to within normal limits at the 6-month follow-up. No other elevations of LFTs were observed. There were no reports of mood fluctuations, depression, or other feelings of anxiety during the course of TRT.

Discussion ▼ This is the first treatment-controlled trial in hypogonadal men with SCI to demonstrate that 12 months of TRT improved LTM and energy expenditure after restoring serum total T to physiological levels. With diligent clinical monitoring and detailed instructions for T use, these salutary body composition changes Bauman WA et al. Testosterone Replacement i Men with SCI … Horm Metab Res

were achieved in a safe manner, and any untoward events were rapidly reversed by discontinuation of TRT or, in the case of patch-associated skin irritation, application of a topical corticosteroid. In previous reports in persons with SCI, in which oxandrolone was used as the androgenic agent, LTM adaptations were marginal and there were observed abnormal changes in the serum lipid profile and LFTs [14, 15]. The authors concluded that the adverse effects of oxandrolone treatment outweighed the modest improvements in body composition. Contrary to these findings, in our study the relatively low incidence and severity of adverse effects of TRT resulted in improvements of 7–10 % in LTM (depending on the respective compartment) and 9 % in REE. TRT has been shown to have inconsistent efficacy, with some reports demonstrating a positive effect on body composition [21, 24] and function [25], whereas other reports have shown minimal improvement in body composition [22, 26], and no clinically significant improvement in functional performance [22, 24, 27]. Persons with SCI are appreciated to be a model of accelerated sarcopenia, both above and below the level of SCI, making the reversal of this condition clinically relevant for functional and metabolic concerns [28, 29]. Although not addressed in our study herein, 12 months of TRT improved LTM and may have


p-Value

been associated with beneficial effects on physical function and general metabolism. Muscle atrophy in persons with SCI results in adverse metabolic changes and a lower REE [3,11]. Our findings revealed trends

Fig. 1 Percent change for total body, trunk, leg, and arm lean tissue mass (LTM); the darker boxes represent the treatment group and the lighter boxes, the control group. The percent change for total body (*p = 0.001), trunk (†p < 0.01), leg (†p < 0.01), and arm (†p < 0.01) LTM was significant in the treatment group compared to the null, but not in the control group.

toward a significant increase in REE and % pEE after TRT that confirm the observed improvements in skeletal muscle [4]. As expected, and similar to previous reports [3], in our study REE adjusted for LTM (REE/kg) was not significantly different between the groups. Increased EE, and an associated increase in LTM, has also been reported during administration of androgen therapy and progressive resistance exercise in patients with human immunodeficiency virus [30]. Compared to similar trials in the general population, our trial was relatively small. The reader should appreciate the logistical difficulty to perform a 12 month study in persons with SCI because of frequent issues related to general health, transportation constraints (e. g., not having a driver′s license/automobile, accessible public transportation, or the costly private transit), and, as in the able-bodied population, compliance with medication and followup visits. Although there was statistical and clinical changes associated with TRT, the translation and/or relevance of these findings with regard to functional gain was not addressed. As such, future randomized, controlled clinical trials should be performed to confirm our findings, as well as extend them to possible functional improvement in activities of daily living. The expected body composition changes of TRT include concomitant and opposite changes in lean and fat tissue mass. Although a demonstrated improvement to LTM with TRT was found, the expected reduction in FTM was not observed. We speculate that the absence of a measureable effect on FTM may be related to the extreme immobility of lower extremity muscle paralysis and primary wheelchair mobility. It is conceivable that a loss of FTM after TRT in

Table 3 Laboratory values and digital rectal examinations Laboratory

Normal range

Group

Baseline

Month 2

Month 6

Month 12

Total testosterone (nmol/l)

11.4–27.8

Albumin (g/l)

0.3–0.55

PSA (μg/l)

0–4.0

Treatment Control Treatment Control Treatment Control

8.7 ± 3.3* 18.4 ± 3.7 0.41 ± 0.04 0.40 ± 0.03 0.9 ± 0.7 1.3 ± 1.0

11.9 ± 8.7 – 0.41 ± 0.03 – 1.0 ± 0.5 –

15.0 ± 9.5 – 0.41 ± 0.03 – 1.3 ± 0.8 –

17.4 ± 6.9 19.2 ± 6.8 0.41 ± 0.02 0.42 ± 0.03 1.1 ± 0.8 1.3 ± 0.6

Hepatic panel GGT (U/l)

0–51

AST (U/l)

0–41

ALT (U/l)

30–50

AP (U/l)

30–115

Treatment Control Treatment Control Treatment Control Treatment Control

40 ± 38 17 ± 7 29 ± 8† 22 ± 6 28 ± 12 19 ± 11 88 ± 21† 66 ± 19

27 ± 15 – 26 ± 7 – 31 ± 15 – 88 ± 21 –

26 ± 11 – 26 ± 5 – 26 ± 6 – 89 ± 22 –

39 ± 41 18 ± 8 26 ± 6 25 ± 10 28 ± 13 22 ± 9 86 ± 30 62 ± 14

Lipid panel TC (mmol/l)

2.95–6.22

HDL-C (mmol/l)

> 0.9

LDL-C (mmol/l)

0–3.4

TG (mmol/l)

0.25–1.80

Hb (g/l)

1.32–1.71

HCT (%)

38.5–50

Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment Control Treatment

4.38 ± 0.66 4.31 ± 0.78 1.0 ± 0.2 0.9 ± 0.2 2.7 ± 0.5 2.8 ± 0.8 1.36 ± 0.74 1.44 ± 0.68 1.35 ± 0.14 1.42 ± 0.06 39.8 ± 4.4 40.1 ± 1.4 0

4.50 ± 0.63 – 1.1 ± 0.2 – 2.8 ± 0.5 – 1.46 ± 0.57 – 1.41 ± 0.15 – 42.0 ± 4.0 – 0

4.65 ± 0.89 – 1.0 ± 0.4 – 3.0 ± 0.8 – 1.20 ± 0.38 – 1.42 ± 0.15 – 41.9 ± 4.2 – 0

4.41 ± 0.57 4.36 ± 0.95 1.1 ± 0.2 1.0 ± 0.2 2.7 ± 0.5 2.6 ± 0.7 1.40 ± 0.62 1.56 ± 0.78 1.43 ± 0.15 1.39 ± 0.10 42.5 ± 4.7 40.2 ± 1.6 0

Abnormal DRE

PSA: prostate specific antigen; GGT: gamma glutamyltransferase; AST: aspartate aminotransferase; ALT: alanine aminotransferase; AP: alkaline phosphataase; TC: total cholesterol; HDL: high density lipoprotein; LDL: low density lipoprotein; Hb: hemoglobin; Hct: hematocrit; DRE: digital rectal exam. Data are presented as mean ± SD. *p < 0.0001 for treatment vs. control; †p < 0.05 for treatment vs. control



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those with SCI may not occur without an exercise and/or dietary modification intervention performed in parallel with TRT. In conclusion, TRT in hypogonadal men with SCI had a salutary and significant impact on body composition and energy expenditure, which did not appear to adversely affect prostate health or metabolic parameters. These changes may have a beneficial effect on physical function and general health in the SCI population. Larger prospective randomized-controlled trials in hypogonadal individuals with SCI who are administered TRT in the future will be required to better define the changes in body composition and to measure change in functional performance, metabolic parameters, emotional factors, independence, and social integration.

Acknowledgements ▼ The authors wish to thank the James J Peters VA Medical Center, Bronx, NY, the Department of Veterans Affairs Rehabilitation Research & Development Service, and the Kessler Institute for Rehabilitation, West Orange, NJ for their support. This work was funded by a Rehabilitation Research & Development (RR & D) National Center of Excellence for the Medical Consequences of Spinal Cord Injury (#B2648C & B4162C). This work has the Clinical Trial Registration Number: NCT00266864. Affiliations VA RR & D National Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, Bronx, NY, USA 2 Medical Service, James J. Peters VA Medical Center, Bronx, NY, USA 3 Department of Medicine, The Mount Sinai School of Medicine, New York, NY, USA 4 Department of Rehabilitation Medicine, The Mount Sinai School of Medicine, New York, NY, USA 5 Kessler Institute for Rehabilitation, West Orange, NJ, USA 6 Department of Physical Medicine and Rehabilitation, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA 1

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