Clinical Toxicology

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Multivitamins and phospholipids complex protects the hepatic cells from androgenic-anabolic-steroids-induced toxicity

Thomas A. Pagonis a; George N. Koukoulis a; Christos S. Hadjichristodoulou b; Paraskevi N. Toli b; Nikiforos V. Angelopoulos c a Department of Endocrinology, Thessaly University Medical School, Larissa, Greece b Department of Hygiene and Epidemiology, Thessaly University Medical School, Larissa, Greece c Department of Psychiatry, University Hospital, Thessaly University Medical School, Larissa, Greece First Published on: 30 August 2007 To cite this Article: Pagonis, Thomas A., Koukoulis, George N., Hadjichristodoulou, Christos S., Toli, Paraskevi N. and Angelopoulos, Nikiforos V. (2007) 'Multivitamins and phospholipids complex protects the hepatic cells from androgenic-anabolic-steroids-induced toxicity', Clinical Toxicology, 46:1, 57 — 66 To link to this article: DOI: 10.1080/15563650701590910 URL: http://dx.doi.org/10.1080/15563650701590910

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Clinical Toxicology (2008) 46, 57–66 Copyright © Informa Healthcare USA, Inc. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.1080/15563650701590910

ARTICLE LCLT

Multivitamins and phospholipids complex protects the hepatic cells from androgenic-anabolic-steroids-induced toxicity THOMAS A. PAGONIS, M.D. PH.D.1, GEORGE N. KOUKOULIS, M.D. PH.D.1, CHRISTOS S. HADJICHRISTODOULOU, M.D. PH.D.2, PARASKEVI N. TOLI, M.SC.2, and NIKIFOROS V. ANGELOPOULOS, M.D. PH.D.3 Hepatoprotective effect of multivitamins and phospholipids complex

1

Department of Endocrinology, Thessaly University Medical School, Larissa, Greece Department of Hygiene and Epidemiology, Thessaly University Medical School, Larissa, Greece 3 Department of Psychiatry, University Hospital, Thessaly University Medical School, Larissa, Greece 2

Introduction. Androgenic-anabolic-steroids (AAS)-induced hepatotoxicity typically occurs with C-17 alkylated oral agents abused by exercising individuals at clinically recommended doses. Injectable compounds appear to have the same risk for hepatotoxicity, but are applied in doses three to six times higher than clinically recommended. AAS users occasionally try to avoid the well-known hepatotoxic effects associated with the abuse of a multitude of AAS agents, by using the pharmaceutical agent compound N a phospholipid/vitamin preparation. Primary Objective. The investigation of the actual hepatoprotective effect of compound N against AAS-induced toxicity. Methodology. This was an observational cohort study of 320 athletes; 160 were AAS users and the other 160 were not abusing any substances. Of the 160 users, 44 were using AAS and compound N (group A), and 116 were using solely AAS (group B). The 160 athletes abstaining from substances abuse acted as controls (group C). All athletes were tested for alterations in serum levels of hepatic enzymes. Enzyme levels before the study’s onset and after the end of the 8-week AAS regimes were compared among the three groups, in order to delineate the hepatoprotective effect of compound N. Results. Prior to our research all groups showed normal values in all enzymes except creatine kinase (CK). After the 8-week period, CK levels were slightly lower in group A, but without variation in Groups B and C; γGlutamyl Transferase (γGT) levels remained normal. Groups A and C had no elevations in any of the enzymes, except CK, while in group B all enzymes’ values were elevated above the normal range. The only factor differentiating AAS users in group A from those in group B was the use of compound N, thus the results being suggestive of the compound’s detoxification effect. The severity of AAS abuse was positively associated with the degree of changes (Δ values) in all measured enzymes except γGT and CK. Conclusions. Previous suggestions that serum hepatic enzyme elevations in exercising AAS abusers are connected to muscle fiber damage rather than the abuse itself, are contradicted by our results. Since all AAS abusing athletes were prone to exhibit elevations in enzymes’ values, the mean values of group A were to be similar to those observed in group B, exceeding normal values. The group hepatic enzyme values of group B were significantly higher than the group C (control). Notably, group A did not have any statistically significant difference in the hepatic enzyme values compared to group C. The effect of exercise on these enzymes’ elevations was ruled out by the comparability of training regimens and AAS toxicity was correlated to the severity of AAS abuse. Keywords Anabolic steroids toxicity; Steroid-induced liver damage; Hepatoprotection

Introduction Anabolic androgenic steroids (AAS) are synthetically manufactured chemical compounds (1,2) derived from the manipulation of three natural steroid hormones: testosterone, nandrolone, and dihydrotestosterone. This is preformed in an effort to diminish the androgenic effects while retaining or optimising the anabolic effects of the parental molecules (3–5). Synthetic AAS can be abused by injection, ingestion or transdermal administration. Irrespectively of the root of

Received 8 September 2005; accepted 28 April 2006. Address correspondence to Thomas A. Pagonis, M.D., Panagouli 12, 41222, Larissa, Greece. E-mail: [email protected]

administration they are associated with hepatotoxic effects (6), due to structural modifications (7) (e.g., alkylation, methylation, etc.). Hepatotoxicity is more prevalent in oral AAS (8) and directly connected with the C-17 alpha alkylation that makes them notably resistant to liver catabolism (9). Non-alkylated oral compounds use a 17-beta carboxylic acid ester, 1-methylation, or a 17-beta enol linkage in order to decrease liver catabolism (10). Injectable AAS compounds have esters attached to the 17-beta hydroxyl group in an effort to increase half-life and activity. Exercising individuals are commonly using AAS agents (11) in a continuous effort to increase their muscle mass (12), strength, and performance (13,14). They do this by consistently practicing polypharmacy (15): self-administering a combination of various oral and/or injectable compounds,


58 typically in supraphysiological doses (16). The AAS toxicity is easily monitored by the combined compound toxicity (17), which is expressed and easily monitored by the elevation of hepatic enzymes in serum (18). There have been numerous case reports of hepatic damage secondary to AAS use (19–25) indicated by elevated serum hepatic enzymes, which return to normal once the AAS are discontinued (26). This is one of the reasons forcing athletes to abuse AAS on an intermittent rather than continuous basis (27). AAS-induced hepatotoxicity is relatively common and typically occurs with C-17 alkylated agents, while non-alkylated agents are less likely to produce liver damage. As oral AAS formulations are commonly C-17 alkylated agents, they are typically administered by users at doses close to those therapeutically recommended (28) in order to minimize adverse hepatic effects. Injectable formulations of C-17 alkylated agents appear to have comparable hepatotoxic hazard, but are applied in doses three to six-fold higher than those therapeutically recommended (29,30). To avoid AAS-induced hepatotoxicity (31,32) athletes are using various herbal preparations that seem to exert some hepatoprotective effects (33). Recently, an approved pharmaceutical compound (hereafter called compound N) was approved for treatment of liver steatosis (34) and other hepatic dysfunction (35–37). Although compound N is widely used by athletes, its hepatoprotective effect on AASinduced hepatic damage has not been studied. The aim of this study that was to evaluate the effects of compound N on the elevation in serum enzyme markers of hepatic injury in nonprofessional athletes abusing AAS.

Material and Methods Participants We constructed general-information-collection questionnaires that were used to categorize exercising individuals and identify users. 6,500 questionnaires were issued in health clubs, gymnasiums, and athletic/sport’s centers. 5,074 questionnaires (78.06%) were filled and collected: 1,983 (39.08%) belonged to recreational athletes, 2,163 (42.63%) to amateurs, and 928 (18.29%) to body builders. Data provided were categorized and elaborated. Seventy-nine percent of the body builders, 62% of the amateurs, and 43% of the recreational athletes were identified as AAS users. All individuals received an identification number and by use of a random number generator we recruited the necessary volume of participants for the three study groups in our cohort in numbers sufficient to give the study the necessary weight. Three hundred and twenty healthy amateur and recreational athletes were recruited in the study. One hundred and sixty of them were AAS abusers self-administering regimens they had obtained by themselves. From these 160 users, 44 abused AAS with the addition of compound N (group A), and

T.A. Pagonis et al. the remaining 116 abused AAS only (group B). Athletes participating in this study as members of groups A and B were all habitual abusers of AAS that had frequently used different AAS compounds in the past; however, they had not used AAS for at least five weeks before the beginning of the study. One hundred and sixty athletes not taking AAS or compound N were recruited as controls (group C). These 160 controls were matched for age, gender, and athletic categorization. Athletes taking any other medication were excluded from the study. Demographical characteristics for the total of 320 athletes participating in the research, included: date of birth, gender and athletic categorization. Participants’ age ranged from a minimum value of 20 years to a maximum of 45, with a mean value of 26.7 years and a standard deviation of 5.07. 116 of the participants (36.3%) were females and 204 (63.7%) were males. One hundred and sixty (50%) of the athletes in the study were body builders, 108 (22.8%) amateurs, and 52 (27.2%) were recreational athletes. Individual demographical characteristics for each of the three studied groups (A, B, and C) did not show any statistically significant difference between them. Composition of compound N Compound N comes in the commercial form of a soft gelatine capsule containing 300 mg of natural, essential polyunsaturated phospholipids [polyene phosphatidylcholine] (diglyceride esters of choline–phosphoric acid and unsaturated fatty acids, predominantly linoleic acid in 70% concentration), 6 mg of thiamine mononitrate (vitamin B1), 6 mg of riboflavin (vitamin B2), 6 mg of pyridoxine hydrochloride (vitamin B6), 6 μg of cyanocobalamin (vitamin B12), 30 mg of nicotinamide, 6 mg of DL-alpha-tocopherol acetate (vitamin E), 0.11% m/m sodium ethylparaben (preservative), and 0.057% m/m sodium propylparaben (preservative). The most commonly used dosage was what was clinically recommended: two capsules three times daily with meals. Abuse pattern AAS users were following regimes that they had obtained themselves. Substances and doses of AAS declared by athletes of groups A and B are presented in Table 1, along with the percentage of athletes using each agent and the therapeutically applied dose (dose used in medicine) for each agent. Subjects in groups A and B were self-administering a combination of at least two oral and two injectable AAS in regimens lasting eight weeks. The maximum number of different AAS used in a single regimen was three orals and three injectables. There were no statistically significant differences concerning use patterns, regimens, AAS agents, therapeutic indexes (TI=androgenic activity/anabolic activity), and applied doses between medium and heavy abusers of groups A and B (group B also included light abusers). In addition to AAS, group A athletes were also receiving compound N (two capsules, three times a day) with meals.

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Hepatoprotective effect of multivitamins and phospholipids complex Table 1. Types and doses of AAS (oral or injectable) used by athletes, along with percentage of users for each steroid Substance Oral agents (mg per day) Fluoxymesterone Methyltestosterone Oxandrolone Oxymetholone Stanozolol Ethylestrenol Methandrostenolone Methenolone acetate Testosterone undecanoate Quinbolone Methylandrostenediol Norethandrolone 4–Chlorodehydromet hyltestosterone Mesterolone Injectable agents (mg per week) Nandrolone decanoate Nandrolone phenylpropionate Nandrolone cypionate Nandrolone hexylophenylpropionate Nandrolone undecanoate Nandrolone laurate Nandrolone cyclohexylpropionate Testosterone enanthate Testosterone cypionate Testosterone propionate Testosterone cyclohexylpropionate Testosterone phenylpropionate Dromostanolone propionate Methenolone enanthate Methylandrostenediol Trenbolone hexahydrobenzylcarbonate Oxabolone cypionate

Range of abused dose

Clinical dose* 10–40 10–25 10–20 50 5–15 10–20 5–10 25–50 40–160 20–40 5–15 10–20 10–20 25–75 50–100 25–50 50–100 50 80,5 50–100 50 100 100 50–125 148–296 25–50 100 100 50–100 76–152 25–50

Mean abused dose

% of users

20 to 40 50 to 90 20 to 30 50 to 150 25 to 75 30 to 50 30 to 100 80 to 170 320 to 450 80 to 120 30 to 50 40 to 60 50 to 150 25 to 100

37.5 76.5 26.0 125.5 70.0 45.5 89.5 155.0 442.5 115.5 45.0 55.5 135.0 75.0

23 31 65 71 85 16 92 17 9 22 77 20 5 19

200 to 600 200 to 400 200 to 600 200 to 600 241.5 to 644 400 to 600 100 to 400 250 to 1000 200 to 600 300 to 600 592 to 888 300 to 500 200 to 400 200 to 400 200 to 500 228 to 456 300 to 600

525 345 475 425 483 425 325 750 425 525 740 400 350 325 375 342 525

76 54 34 12 41 5 6 79 69 95 23 11 6 21 22 31 4

*Recommended by the manufacturing companies and patent holders. For comparison purposes, the dose recommended in clinical practice is also shown.

AAS are used by athletes in a regime referred to as cycle (38) which typically consists of an exotic combination of multiple oral and/or injectable formulations of different agents (39), used in supra physiological doses for the span of numerous weeks (varying from 4 to 12) (40,41). This modern type of usage is mainly based on anecdotal information and is supported by a strong belief that a combination of some of the most potent AAS with some milder ones, for a sufficient period of time, will effectively produce dramatic results in muscle mass, strength and overall physique improvement (42). Within a cycle, doses of each of the individual AAS used are varying from a minimum to a maximum value. The initial modest doses are quickly followed by an escalation in the administered milligrams of each AAS agent, which is usually reaching a climax (maximum dose) two weeks before the cycle’s end. This maximum dose is then maintained for the rest of the cycle’s duration. Frequent dosage administration

and shortening of available AAS injection sites due to the post-administration muscle soreness (43) forces users to invest the biggest portion of their cycle budget in numerous different potent anabolic oral compounds and some strong injectable ones. The biggest challenge for us was the stratification of users into groups of similar severity according to the parameters of the abuse patterns observed in each case.

Abuse stratification system (AbuStraS) To achieve our purpose we decided to divide users into groups according to the severity of the abuse. For the abuse severity assessment we used AbuStraS (44), a novel system of categorization of AAS abusers (created by the researchers) that takes into consideration the following abuse parameters: the number (n) of compounds used, the type of AAS (ty), the


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T.A. Pagonis et al.

used dosages (D), the Therapeutic Index (androgenic activity/ anabolic activity=TI) of the agents, the number of cycles used in the past (C), and finally the duration of time (dT) that each cycle lasted (Table 2). The severity in each parameter is arbitrarily scored from the lighter to the heavier with 1, 2, and 3 points (Table 1). The total score (sum) a user receives by addition of the points in each parameter, is used to categorize their AAS abuse. According to AbuStraS, the smallest total score a user belonging to the lighter levels of all subscales can acquire is between six and 12 points, a user belonging to the middle levels of all subscales is from 12 to 18 points, and a user belonging to the higher levels of all subscales is above 18 points. Therefore, an athlete with less than 12 points is characterised as light abuser, with 12–18 points as medium abuser, and with more than 18 points as heavy abuser. According to AbuStraS, 14 athletes of group A were characterized as

Table 2. Characteristics of the abuse stratification system (AbuStraS) used for categorization of AAS users Parameters

Points

1. Number (n) of compounds used a. Less than three (n < 3) b. 3 up to 5 (3 ≤ n ≤ 5) c. More than 5 (n > 5) 2. Type of AAS (ty) a. Transdermal b. Per os c. Injectable 3. Used dosage (D) a. Less than the therapeutically used dosage (D < Α) b. Equal to the therapeutically used dosage (D = Α) c. Greater than the therapeutically used dosage (D > Α) 4. Therapeutic Index (TI) of the compounds used a. ΤΙ varying from 1:13 up to 1:8 b. ΤΙ varying from 1:7 up to 1:3 c. ΤΙ varying from 1:2 up to 1:1 5. Number of cycles used in the past (C) a. No previous use (C=0) b. 1 to 3 cycles in the past (1 ≤ C ≤3) c. More than 3 cycles in the past (C > 3) 6. The duration of time (dT) that each cycle lasts a. equal to or less than 2 weeks (dT ≤ 2) b. 3 to less than 6 weeks (3 ≤ dT < 6) c. 6 to less than 8 weeks (6 ≤ dT < 8) d. Equal to or more than 8 weeks (dT ≥ 8) Categorization Light abuse Medium abuse Heavy abuse

1 2 3 1 2 3 1 2 3

1 2 3 1 2 3 1 2 3 4

Total score < 12 12 ≤ Total score ≤ 18 Total score > 18

Athletes with less than 12 points are characterized as light abusers, those with 12–18 points as medium abusers, and those with more than 18 points as heavy abusers.

medium abusers and the other 30 as heavy abusers. No light abuser was enrolled in group A. In group B, 28 athletes were characterized as light abusers, 45 as medium abusers, and 43 as heavy abusers.

Study design All participants received personalized dietary regimes (45,46) on the basis of their body mass index (BMI), composed of 55% carbohydrates, 35% proteins, and 10% fatty acids (47). The regimen also included specific instructions to avoid use of several dietary factors and supplements that could interfere with our study, e.g., alcohol, caffeine, creatine, hormone precursors, androstenedione, and DHEA among others. All participants followed a matching weight training exercise program five times per week, with resistance training adapted to each athlete’s potential (use of common percentage of individuals maximum power (48), ensuring common training intensity), using identical exercises, repetitions, sets, and training frequencies, training two major muscle groups plus abdominals and lower back, in every training session, in conjunction with a 20 minute cardiovascular exercise regimen (comprised of low intensity treadmill jogging). All participants were healthy individuals that were not receiving any additional medications and gave their written consent for participation in the research. The research lasted six months because individuals belonging to groups A and B were not in cycle periods simultaneously. Each athlete was monitored solely for the time equivalent of a single cycle they put themselves into. Validity and homogeneity of all groups was safeguarded by random doping control tests (testing of urine samples by means of gas chromatography/mass spectrometry) (49) on all three groups, according to the International Olympic Committee’s Protocol and guidelines (50) (e.g., following all their practices trying to avoid substitution of urine or other fraud), testing for metabolites of all banned substances included on the IOC list. Each athlete was categorized by receiving an individual identification number. All numbers were incorporated into a random number generator program (RNG version 3.0 for Windows, ALT-Pro Inc., Thessaloniki, Greece). Thirty-eight random doping control tests were performed during the fourth week of the study in athletes identified by the numbers produced by the generator. Nineteen doping control tests were performed in group A, 14 in group B, and five in group C. All urinalysis tests for uncontrolled substances validated the group placement of tested athletes. Serum aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), gamma-glutamyltranspeptidase (γGT), and creatine kinase (CK) levels were measured at baseline and thereafter every 10 days, up to the final measurement (for athletes in groups A and B this final

61


Hepatoprotective effect of multivitamins and phospholipids complex measurement coincided with the end of their individual AAS regimes). Athletes used as controls (group C) were similarly tested. In total, each athlete was subjected to seven blood testing sessions; the final at the end of the eighth week (week nine). Serum levels of all enzymes were measured using a Cobas Mira Plus Chemistry Analyzer (Roche 1992, © 2005, Roche Instrument Center - Rotkreuz, Switzerland).

are presented as mean ± standard deviation. Mann-Whitney/ Wilcoxon two-sample non-parametric test (KruskalWallis test for two groups) was used to compare not normally distributed data. Differences between groups were considered significant at a P value < 0.05. All reported P values are two-sided. SPSS version 9.0 for Windows (SPSS, Inc., Chicago, Illinois, USA) was used for all statistical analyses.

Ethical issues The Institutional Review Board of the Medical Faculty of the University of Thessaly approved the research protocol. All participants were provided with a specialized information manual stressing the adverse and dangerous side effects of AAS abuse. Athletes who were not discouraged by our intervention gave a written informed consent prior to their inclusion in the research. Observed athletes were following AAS regimes that they had obtained by themselves and all AAS used were also self-obtained.

Statistical methods AAS-induced hepatotoxicity was evaluated during the study period by comparing serum enzymes levels. Values

Results As shown in Table 1, abusers were using various per os and injectable AAS in daily or weekly doses significantly higher than the clinically recommended. Hepatic enzymes levels at baseline were comparable between groups and within normal range except CK (Table 3). CK levels were higher than the upper normal range as it was expected due to the fact that all participants were exercising individuals. At the end of the study the enzymes increased significantly in all groups (Table 3). However this increase in controls (group C) and abusers taking compound N (group A) did not exceed the upper normal range. On the contrary, this increase was significantly higher than the upper normal range in the abusers of group B who did not take compound N (Table 4).

Table 3. Mean (± SD) levels of serum enzymes in all studied groups over the study period Group SGOT A (n=44) B (n=116) C (n=160) SGPT A (n=44) B (n=116) C (n=160) LDH A (n=44) B (n=116) C (n=160) ΓGT A (n=44) B (n=116) C (n=160) CK A (n=44) B (n=116) C (n=160) ALP A (n=44) B (n=116) C (n=160)

Baseline

1st test (10th day)

2nd test (20th day)

3rd test (30th day)

4th test (40th day)

5th test (50th day)

17.64 ± 7.2 16.85 ± 6.7 16.88 ± 7.1

21 ± 5.3 55 ± 7 16 ± 5

22 ± 6.1 78.5 ± 12.5 15.5 ± 4.7

21.5 ± 7 80.5 ± 16.2 17 ± 8.2

23.5 ± 8.5 82 ± 18.1 16.5 ± 7.5

24 ± 6.6 81.5 ± 27.9 17 ± 9.3

22.68 ± 8.2 91.95 ± 31.16 19.11 ± 7.2

0,0029 0,0000 0,0073

19.36 ± 9 18.27 ± 7.6 17.82 ± 7.3

19.5 ± 9 61 ± 7.6 16 ± 7.3

20 ± 9 75.5 ± 7.6 15.5 ± 7.3

21.5 ± 9 83 ± 7.6 16.5 ± 7.3

23.5 ± 9 85.5 ± 7.6 17.5 ± 7.3

25 ± 9 89 ± 7.6 17 ± 7.3

26.00 ± 10.5 99.36 ± 29.8 20.74 ± 7

0,0030 0,0000 0,0000

178.5 ± 34.4 290.5 ± 31.9 157 ± 32.1

181 ± 34.4 295 ± 31.9 156.5 ± 32.1

183.55 ± 33.9 307.56 ± 37.7 169.19 ± 31.2

0,0413 0,0000 0,0062

22.5 ± 6.0 24 ± 6.8 18 ± 7.3

24 ± 6.0 28.5 ± 6.8 17 ± 7.3

23 ± 6.0 30 ± 6.8 18.5 ± 7.3

23.89 ± 5.4 29.59 ± 7.1 21.66 ± 7.2

0,0079 0,0000 0,0000

Final test

P value

168.36 ± 34.4 159.97 ± 31.9 161.19 ± 32.1

166 ± 34.4 219 ± 31.9 155 ± 32.1

173.5 ± 34.4 281 ± 31.9 152 ± 32.1

20.45 ± 6.0 16.64 ± 6.8 17.73 ± 7.3

20 ± 6.0 16 ± 6.8 17 ± 7.3

21± 6.0 18.5 ± 6.8 16.5 ± 7.3

353.73 ± 32.6 344.72 ± 31.1 345.70 ± 32.6

353 ± 32.6 465.5 ± 31.1 340.5 ± 32.6

350 ± 32.6 582 ± 31.1 341 ± 32.6

348.5 ± 32.6 669 ± 31.1 341.5 ± 32.6

344 ± 32.6 680.5 ± 31.1 342 ± 32.6

341.5 ± 32.6 684.5 ± 31.1 340.5 ± 32.6

330.66 ± 28.5 695.46 ± 31.7 349.64 ± 32.8

0,0014 0,0000 0,1042

40.45 ± 25.5 37.52 ± 20.5 50.40 ± 25.0

42.5 ± 25.5 134 ± 20.5 46.5 ± 25.0

58.5 ± 25.5 151.5 ± 20.5 47 ± 25.0

62 ± 25.5 166 ± 20.5 50.5 ± 25.0

64 ± 25.5 171 ± 20.5 51 ± 25.0

63.5 ± 25.5 174.5 ± 20.5 49 ± 25.0

61.66 ± 25.7 172.46 ± 24.4 59.40 ± 26.1

0,0000 0,0000 0,0004

176 ± 34.4 286 ± 31.9 154 ± 32.1

The statistical significance between values at zero and the ninth week is indicated by P value.

T.A. Pagonis et al.

Table 4. Mean (± SD) serum enzymes levels before and after light, medium, and heavy AAS abuse in group B Stratification of group B according to abuse pattern Group B (n=116) Enzyme levels and P values SGOT (U/L) P value SGPT (U/L) P value ALP (U/L) P value γGT (U/L) P value CK (U/L) P value LDH (U/L) P value

Light abuse (n=28) Before

Medium abuse (n=45)

After

14.7 ± 7.1

Before

56.3 ± 7.8

17.3 ± 51.3

0,000 66.5 ± 10.9

23.2 ± 2

55.7 ± 22.2

25.4 ± 7.8

16 ± 7.3

0,000 338.6 ± 24.4 151.4 ± 26.7

After

17.8 ± 5.8

91.8 ± 12.6 0,000 0,000

203 ± 27.3 30.4 ± 7.2

341.5 ± 32.5

274.7 ± 27.2

160.7 ± 32.4

0,000

133.6 ± 19.3 0,000

18.1 ± 6.1 27.8 ± 6.9 17.7 ± 6

0,000 688.4 ± 28.6

0,000

80.2 ± 56.3

18.8 ± 7.2

149.1 ± 11.1

0,000

16 ± 7.2

Before

0,000

17.6 ± 8.9 0,000

After

Heavy abuse (n=43)

0,000

209 ± 37.1 31.5 ± 5.5

0,000 707 ± 31.9

0,000

142.3 ± 23.1 0,000

313 ± 31.9

352 ± 32.6 164.8 ± 34

0,000

710.1 ± 36.1 0,000

328.7 ± 33.9

0,000

* p