RE: [ATAC-DrugDev] NATAP: Anabolic Steroids Increase Heart Attack Risk/Liver Tox: The Grunfeld study, A Waste of time and money.

[Guest guest]

To the HIV community and the press.

This report states nothing new, as several previous studies have documented the potential for this synthetic anabolic steroid (Oxandrin) to cause negative effects on liver metabolism and blood lipids. For Dr. Grunfeld to call for more studies to confirm this is like asking to waste money that could be spent more wisely in other areas where we really do need enlightenment.

The report on the study is sadly deficient. It does not state the entire truth, tilting its stated conclusion to make all steroids look bad. This is quite incorrect. This study did not look at "all" anabolic steroids, but looked at one steroid, one that is known to cause these problems, especially at the higher doses employed in this study. To state a general conclusion when only one item is investigated is the height of bad reporting. We should be wary of it in our media. It is a disservice to the less knowledgeable reader and the HIV+ person who may need anabolic steroids used therapeutically.

The article should have said "A synthetic 17-alpha alkylated (17-aa) anabolic steroid (Oxandrin) negatively effected liver metabolism and blood lipids with higher doses causing more problems."

The text should have had the clearly stated caveat "Testosterone, an oil-based beta-esterified injectable steroids has been proven to not have these negative effects."(1,2,3)

This is a gross example of irresponsible, inaccurate fear-based journalism that is used to sell newspapers and play up the fear of steroids that is rampant in the political system in the United States.

All 17-aa alkylated steroids, which are typically the ones that are made into tablets, are modified versions of testosterone that are verified to cause liver burden because they are not easily metabolized in the liver's first pass, the way the injectable (oil-based) beta-esterified steroids are. 17-aa steroids also upset blood lipids, and invert the HDL/LDL ratio in a way that predicts cardiovascular disease.

These molecules are not naturally found in the body, they are synthetic analogs of the natural hormone testosterone.

Testosterone therapy has been shown to improve blood lipids in males with type ll diabetes and be have therapeutic value for a number of other diseases, including rheumatoid arthritis (4) and HIV.(5-21) Furthermore, testosterone and other anabolic steroids have been shown to improve measures of immune competence that are critical in HIV, including cell-mediated immune response.(22,23,24)

Please strongly consider the money this study wasted and the negative impact this biased report it will have on the valuable therapeutic use of testosterone and other anabolic steroids in the treatment of HIV and other diseases.

Mooney

www.medibolics.com

www.michaelmooney.net

www.powerusa.org

References

1. Marquardt G.H., Logan C. E., Tomhave W.G., Dowben R.M., “Failure of non-17-alkylated steroids to produce abnormal liver function tests”. J.Clin Endo. 24:1334-36 1964

2. , et al, “Contrasting effects of testosterone and stanozolol on serum lipoprotein levels.” JAMA 1989, Feb 24; 261(8): 1165-1168.

3. Bhasin S et al, “The effects of supraphysionogic doses of testosterone on muscle size and strength in normal men.” NEJM July 4 1996, 333.1 : 1-7

4. Cutolo M et al, “Sex hormones, HLA, and rheumatoid arthritis” Clin Exp Rheumatol 1991 Nov-Dec:9 (6) : 641-6

Mendenhall

5. Berger JR, Pall L, Winfield D,”Effect of anabolic steroids on HIV-related wasting myopathy”, Southern Medical Journal 1993;86,8(Aug):865-866

6. Hengge UR et al, “Oxymetholone promotes weight gain in patients with advanced human immunodeficiency virus (HIV-1) infection.” Brit J Nutri (1996) 75 : 129-138

7. Gold J et al, “Safety and efficacy of nandrolone decanoate for treatment of wasting in patients with HIV infection.” AIDS (1996) 10 :745-752

8. Wagner G, Rabkin J, Illness stage, concurrent medications, and other correlates of low testosterone in men with HIV illness. JAIDSHR, 8(2):204-7 1995 Feb 1

9. Laudat A et al., Changes in systemic gonadal and adrenal steroids in asymptomatic human immunodeficiency virus-infected men: relationship

with the CD4 cell counts. Eur J Endocrinol, 133(4):418-24 1995 Oct

10. Rabkin J. et al., Testosterone Replacement Therapy: a recent innovation in the treatment of AIDS. Sidahora, ():51-2 1995 Winter

11. Klauke S et al., Hypogonadism in male patients with AIDS. Int Conf AIDS, 6(2):209 (abstract no. F.B.525) 1990 Jun 20-23

12. Holzman D, Testosterone wasting and AIDS (news) Mol Med Today, 2(3):93 1996 Mar 13. Engelson ES et al., Effects of testosterone upon body composition (letter) JAIDSHR,

14. Rabkin JG; Rabkin R; Wagner G Testosterone replacement therapy in HIV illness. Gen Hosp Psychiatry, 17(1):37-42 1995 Jan

15. Rabkin J, et al., Sexual dysfunction in homosexual HIV+ men: associations with immune function, endocrine, neurologic, and psychiatric factors. Int Conf AIDS, 9(1):417 (abstract no. PO-B16-1689) 1993 Jun 6-11

16. Rabkin J. et al., Testosterone Replacement Therapy: a recent innovation in the treatment of AIDS. Sidahora, ():51-2 1995 Winter

17. Wagner GJ; Rabkin JG; Rabkin R, A comparative analysis of standard and alternative antidepressants in the treatment of human immunodeficiency virus patients. Compr Psychiatry, 37(6):402-8 1996 Nov-Dec

18. Christeff N et al., Relationship between sex steroid hormone levels and CD4 lymphocytes in HIV infected men. Exp Clin Endocrinol Diabetes, 104(2):130-6 1996

19. Grunfeld C, State of the art in wasting: an interview with Carl Grunfeld, PhD. (interview by Jeff Getty) BETA, ():34-7 1995 Jun

20. Bucher et al., A prospective study on the safety and effect of nandrolone decanoate in HIV-positive patients. Int Conf AIDS (1996) 11(1):26. Abstract no.Mo.B.423.

21. Ehrichs L. “Testosterone may prevent AIDS wasting.” Family Practice Oct. 10, 1994, p.36 Quote: Dr. Caroline Becker, endocrinologist w/large multi-function practice in Mt. Kisco, NY “Even with individuals with pre-existing liver disease, I would have no compunction in giving them injectable testosterone.”

22. Mendenhall CL, Grossman CJ, Roselle GA, Hertelendy A, Ghosn SJ, Lamping K, K, “Anabolic steriod effects on immune function: differences between analogues.” J Steroid Biochemistry & Molecular Biology 1990, v. 37, N. 1:71-76

23. Calabrese, L.H, Kleiner, S.M., Barna, B.P., Skibrinski, CI,, “The effect of anabolic steroids and strength training on the human immune system”. sex steroids”. Endocr. Rev. 5(1984):435-55

24. Grossman, C.J., “Interactions between the gonadal steroids and the immune system”. Science 227 (4684): 257-61 18 Jan. 1985

From: ATAC-DrugDev [mailto:ATAC-DrugDev ] On Behalf Of JuLev@...Sent: Wednesday, March 01, 2006 6:20 AMTo: ATAC-Discuss ; ATAC-DrugDev Subject: [ATAC-DrugDev] NATAP: Anabolic Steroids Increase Heart Attack Risk/Liver Tox

Anabolic Steroid Use Increases Heart Attack Risk And Causes Liver Damage Toxic effects seen after only 12 weeks - could harm athletes who take steroids for performanceSAN FRANCISCO, CA -- February 20, 2006 -- Anabolic steroid use causes decreased levels of HDL or "good" cholesterol, increased levels of LDL or "bad" cholesterol, and serious liver toxicity within 12 weeks, according to a study that measured the effects of anabolic steroids on men with HIV wasting disease.The results have implications for athletes who take anabolic steroids to enhance performance, says principal investigator Carl Grunfeld, MD, PhD, chief of the metabolism and endocrine sections at the San Francisco VA Medical Center.The study is published in the March 2006 issue of the Journal of Acquired Immune Deficiency Syndromes. It is available online in the "Publish Ahead of Print" section of the journal.The researchers found that as expected, anabolic steroids lead to gains in both lean body mass and fat in men with HIV wasting."This is good news for people with devastating wasting illnesses, who suffer from the effects of loss of muscle mass and whose most immediate risk is that they will die of their disease," observes Grunfeld. "But for people who aren't this sick and who take anabolic steroids, there may be serious problems if these complications occur." Grunfeld, who is also a professor of medicine at the University of California, San Francisco, observes that "the biggest use of these steroids today is among body builders and athletes, who take these drugs to build muscle, but who could wind up with significantly damaged hearts and livers."The randomized, double-blind trial among 262 HIV-positive men was the largest study of its type on men with HIV-associated weight loss, according to the study authors.For the first 12 weeks of the trial, the men were randomly assigned to receive daily doses of either 20 mg, 40 mg, or 80 mg of the anabolic steroid oxandrolone or a placebo. They were allowed to receive open-label oxandrolone for the second 12-week period.Grunfeld says the adverse effects of the steroids were clear-cut within the first 12 weeks. "HDL plummets. LDL goes up. This predisposes people to an increased risk of heart attack. Furthermore, we found grade III and grade IV liver toxicity in some men, which means a very significant risk of serious liver damage." The men's testosterone levels were also depressed. These effects were not seen in men taking placebo, according to Grunfeld.The researchers observed that in men with the most wasting, the 20 milligram dose was more effective than higher doses in promoting weight gain. Subjects who weighed more and were healthier -- and were therefore more like athletes who use the drugs, observes Grunfeld -- required higher doses to gain weight. This is significant, he says, because it demonstrates in healthy people, "you need a higher dose to get a benefit -- and the higher the dose, the more the toxicity."Based on observed changes in HDL and LDL, Grunfeld estimates that heart attack risk would be increased 58% among men taking 20 milligrams of oxandrolone per day, two-fold with a 40 mg daily dose, and three-fold with 80 mg. "Add smoking or hypertension, and the risk becomes really serious," he says.The ability to promote gains in both muscle and fat makes these drugs unique among the medications used for HIV wasting disease, notes Grunfeld. He says that among patients with serious wasting illnesses, the benefits of immediate weight gain could still potentially outweigh the risks of longer-term heart and liver damage. For these patients, he says, it is important to have a store of fat as well as muscle mass, because "opportunistic infections burn up muscle if there's no fat there. The more fat you have, the less muscle you burn."Nonetheless, he notes, "We would still stop the drug among anyone who has grade III or grade IV liver toxicity."Grunfeld, who has no further plans to study steroids, says he would like to see the current study validated in two future studies by other investigators. The first would look exclusively at the 20 milligram dose in patients with significant wasting, because "it may work and have less toxicity." The second would investigate whether the same toxic effects occur in healthy individuals who take anabolic steroids.Co-authors of the paper were P. Kotler, MD, of St. Lukes Roosevelt Medical Center, New York; Dobs, MD, of s Hopkins School of Medicine, Baltimore; Marshal Glesby, MD, PhD, of the Community Research Initiative on AIDS, New York (at the time of the study); and Shalendar Bhasin, MD, of Drew University of Medicine and Science, Los Angeles (at the time of the study).The research was supported by a grant from Biotechnology General, Inc., now Savient Pharmaceuticals, Inc., makers of oxandrolone. In San Francisco, the grant was administered by the Northern California Institute for Research and Education.SOURCE: University of California - San FranciscoOxandrolone in the Treatment of HIV-Associated Weight Loss in Men A Randomized, Double-Blind, Placebo-Controlled StudyCarl Grunfeld, MD, PhD,* P. Kotler, MD,† Dobs, MD,‡ Marshall Glesby, MD,§ and Shalender Bhasin, MDk for the Oxandrolone Study GroupABSTRACTObjective: To evaluate the efficacy and safety of oxandrolone in promoting body weight and body cell mass (BCM) gain in HIV-associated weight loss.Methods: Randomized, double-blind, placebo-controlled trial. Two hundred sixty-two HIV-infected men with documented 10% to 20% weight loss or body mass index </= 20 kg/m2 were randomized to placebo or to 20, 40, or 80 mg of oxandrolone daily. After 12 weeks, subjects were allowed to receive open-label oxandrolone at a dose of 20 mg for another 12 weeks.Results: Body weight increased in all groups, including the group receiving placebo, during the double-blind phase (1.1 +/- 2.7, 1.8 +/- 3.9, 2.8 +/- 3.3, and 2.3 +/-2.9 kg in placebo and 20-, 40-, and 80-mg oxandrolone groups, respectively; all P <, 0.014 vs. baseline). BCM increased from baseline in all groups (0.45 +/- 1.7, 0.91 +/- 2.2, 1.5 +/- 2.5, and 1.8 +/- 1.8 kg in placebo and 20-, 40-, and 80-mg oxandrolone groups, respectively). At 12 weeks, only the gain in weight at the 40-mg dose of oxandrolone and the gain in BCM at the 40- and 80-mg doses of oxandrolone were greater than those in the placebo group,however. Oxandrolone treatment was associated with significant suppression of sex hormone-binding globulin, luteinizing hormone, follicle-stimulating hormone, and total and free testosterone levels. Treatment was generally well tolerated but accompanied by significant increases in transaminases and low-density lipoprotein as well as decreases in high-density lipoprotein.Conclusion: Oxandrolone administration is effective in promoting dose-dependent gains in body weight and BCM in HIV-infected men with weight loss.Testosterone supplementation increases fat-free mass and muscle strength in HIV-infected men with mild to moderate weight loss.30-37 Androgenic steroids promote positive nitrogen balance and weight gain (or amelioration of weight loss) in other catabolic illnesses, including acute alcoholic hepatitis, cancer, end-stagerenal disease, and burns.38-51 In studies of small numbers of patientswith HIV-associated wasting, orally administered androgens, such as oxandrolone and oxymetholone, and the parenterally administered androgen nandrolone decanoate have induced significant weight gain.43-51 Given the potential advantage of an orally administered anabolic therapy, such as oxandrolone, we undertook a double-blind, placebo-controlled, randomized trial of graded doses of oxandrolone in HIV-infected subjects with weight loss, testing its effects on weight gain, body composition, total work capacity, health-related QOL, and safety. METHODSSigned informed consent was obtained from each patient before entry under protocols approved by the institutional review board at each participating center. This was a randomized, placebo-controlled, parallel-group, double-blind, multisite clinical trial conducted at 25 sites between September 25, 1996 and July 20,1998.ParticipantsEligible subjects were HIV-infected men $18 years of age who had 10% to 20% unintentional weight loss from premorbid weight documented in medical records or a body mass index (BMI) </= 20 kg/m2, a Karnofsky Performance Scale score >60%, a life expectancy of >6 months, and the ability to consume a normal wellbalanced diet at entry as assessed by a dietitian. Therapy with antiretroviral medication was not required; however, subjects on antiretroviral therapy had to be on a stable regimen for more than 6 weeks at the time of entry.Exclusion criteria included any opportunistic infection within 60 days of enrollment; loss of >5% body weight in the previous 30 days; chronic fever >101 F with a frequency >/= 3 days per week for at least 2 weeks in the previous 30 days; aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase levels greater than 5 times the upper limit of normal and/or bilirubin level >2.0 mg/dL within 2 weeks; serum creatinine >2.0 mg/dL; known impaired digestive or absorptive function; chronic uncontrolled diarrhea (>3 liquid stools per day at least 4 days per week for >2 weeks); current treatment with anticoagulants or oral hypoglycemic agents; or treatment with appetite stimulants, weight-promoting agents, anabolic steroids, or testosterone inthe previous 4 weeks. This dose-ranging study did not include women, because it was not known whether doses of this magnitude would cause significant virilization in women.Treatment Assignment and RandomizationSubjects were assigned in concealed randomization (1:1:1:1) balanced at each center to placebo (4 tablets) or to 20 mg/d of oxandrolone (1 20-mg tablet of oxandrolone and 3 placebos), 40 mg/d (2 20-mg tablets of oxandrolone and2 placebos), or 80 mg/d of oxandrolone (4 20-mg oxandrolone tablets) provided by Savient Pharmaceuticals (East Brunswick, NJ [formerly Bio-Technology General, Corporation]). Investigators and patients were blinded to treatment assignment during the initial 12 weeks. After 12 weeks, all subjects whowished to continue were placed on 20 mg of oxandrolone in an open-label continuation.Subject AccountabilityTwo hundred sixty-two patients were randomized and included in the intent-to-treat analysis (placebo [n = 65], 20 mg of oxandrolone [n = 64], 40 mg of oxandrolone [n = 65], and 80 mg of oxandrolone [n = 68]). Of these, 195 subjectscompleted the double-blind phase and 193 completed the open-label phase. Of the 67 subjects who discontinued treatment during the double-blind phase, 12 were in the placebo group, 18 were in the 20-mg oxandrolone group, 18 were inthe 40-mg oxandrolone group, and 19 were in the 80-mg oxandrolone group. Reasons for discontinuations included adverse experience (20), death (6), intercurrent medical problem or disease-related complication (2), subject relocation or voluntary patient withdrawal (21), and noncompliance (18).SafetyNeither HIV RNA by RT-PCR nor CD4+ lymphocyte count was significantly affected by oxandrolone (Table 3). There were no significant changes in hemoglobin and white blood cell counts. However, there was a dose-dependentincrease in platelet count (P <0.017 for all doses of oxandrolone vs. placebo). There were small but significant increases in levels of creatinine and creatine kinase but not in blood urea nitrogen (BUN) in the oxandrolone groupscompared with the placebo group.Serum albumin, total protein, bilirubin, alkaline phosphatase, lactate dehydrogenase (LDH), and gamma-glutamyltransferase (GGT) levels were not significantly changed (see Table 3). However, there were dose-dependent increases in AST and ALT appearing by the first 4 to 8 weeks of therapy.The increase in AST was significant at the 80-mg dose compared with baseline, whereas the increase in ALT was significant at the 40-mg and 80-mg doses. Furthermore, there was a dose-related increase in the incidence of WHO grade III and IV liver toxicity for ALT and AST with increasing dose of oxandrolone (Table 4). For AST, WHO grade III and IV toxicity occurred in 2 of 61 subjects on placebo, 2 of 60 on 20 mg of oxandrolone, 6 of 61 on 40mg of oxandrolone, and 9 of 61 on 80 mg of oxandrolone. For ALT, WHO grade III and IV toxicity occurred in 1 of 61 subjects on placebo, 3 of 60 on 20 mg of oxandrolone, 7 of 61on 40 mg of oxandrolone, and 9 of 61 on 80 mg of oxandrolone (for trend, P = 0.0047). Three subjects receiving the 40-mg dose and 4 subjects receiving the 80-mg dosewere discontinued from the drug because of laboratory abnormalities.Glucose, triglyceride, and total cholesterol levels in patients receiving oxandrolone were not significantly different from those receiving placebo (see Table 3). There was a significant decrease in uric acid and plasma high-densitylipoprotein (HDL) cholesterol levels at all doses. Furthermore, there was a significant increase in low-density lipoprotein (LDL) cholesterol levels at the 40-mg and 80-mg doses.Six patents died during the placebo-controlled study (see Table 4), and 3 more died during the open-label phase or within 30 days of last receiving study medication during the placebo-controlled phase. Of the 9 subjects who died, 2 were on placebo, 3 were on 20 mg of oxandrolone, 2 were on 40 m of oxandrolone, and 2 were on 80 mg of oxandrolone. There were no significant differences between the treatment groups in the numbers of infections, serious adverse events (SAEs), or milder adverse events. Seven SAEs were reported in 6 subjects on placebo, 20 SAEs were reported in 13 subjects on 20 mg of oxandrolone, 24 SAEs were reported in 14 subjects on 40 mg of oxandrolone, and 20 SAEs were reported in 14 subjects on 80 mg of oxandrolone. One hundred eighty-one different types of infections and adverse events were reported.Overall dropout rates were similar among treatment groups (see Table 4). In some subjects, treatment discontinuation was prompted by more than 1 reason. There was a trend toward increased dropout because of an adverse experience or abnormal laboratory test results in the 40-mg and 80-mg oxandrolone groups attributable to treatment discontinuation for WHO grade III and IV elevations in AST and ALT. Gonadal-Pituitary FunctionBaseline total testosterone levels averaged close to the lower limits of normal (270 ng/dL; Table 5). At 12 weeks, serum LH and FSH concentrations decreased significantly from baseline in all oxandrolone-treated groups, consistent with an androgenic action. Serum SHBG concentrations also decreased with increasing doses of oxandrolone, which also suggests an androgenic effect of oxandrolone (SHBG was determined in a subset of patients, and total testosterone levelsin the subset were similar to those in the larger cohort; data not shown).Total and free testosterone concentrations measured by direct RIA did not show a dose-related change. We used celite chromatography to separate testosterone from oxandrolone before RIA and found that serum total testosterone concentrations were significantly decreased from baseline at all doses of oxandrolone but not with placebo treatment (see Table 5).Open-Label StudyAfter the double-blind placebo-controlled study, a subset of subjects opted to take 20 mg of oxandrolone in an openlabel study. All 4 groups receiving 20 mg of oxandrolone during this 12-week open-label phase continued to gain weight(Table 6). By the end of the open-label phase, there were no significant differences in weight gain among the groups. AST levels decreased; although AST levels remained above baseline, they were no longer significantly different from baseline (see Table 6).Extracts from Author DiscussionOxandrolone administration was generally well tolerated. Grade III and IV elevations of transaminases were observed in >5% of study participants, however, especially at the 80-mg dose. Careful monitoring of these parameters is therefore indicated after the initiation of oxandrolone therapy. Furthermore,LDL levels increased and HDL levels decreased.In spite of significant body weight gains and lean mass accretion, total work output during treadmill exercise did not significantly change during treatment. This is consistent with the growing body of data that androgenic steroids increasemuscle mass but do not affect measures of endurance, such as treadmill performance.62-64 Reports of randomized clinical trials published subsequent to the initiation of this study have reported significant gains in maximal voluntary strength with androgen supplementation of HIV-infected men with weightloss35; gains in muscle strength are generally proportional to increases in muscle mass.35Administration of oxandrolone has been associated with significant decreases in plasma HDL cholesterol levels and increases in LDL cholesterol levels.60,65,66 The administration of the 40- and 80-mg doses was associated with significantincreases in ALT and AST; these increases were transient and returned toward baseline in most subjects. Treatment discontinuations attributable to persistent and marked increases in transaminases were common and occurred in more than 5% of individuals. We found no increase in bilirubin or alkaline phosphatase.The decreases in HDL and increases in LDL represent a proatherogenic lipoprotein profile. Clinicians therefore need to weigh the risk-benefit ratio of this therapy. Wasting syndrome predicts a significant risk of complications and death,but even studies as large as this one are not large enough and have not been carried out long enough to determine whether reversal of that risk occurs with treatment of wasting and to determine the risk of cardiovascular disease. The risk of atherosclerosis predicted by this lipoprotein profile suggests that such therapy should be restricted to those with significant wasting or should be terminated when wasting has improved. Mean CD4 lymphocyte counts in this study were> 200 x 106/L, which is higher than in most earlier studies of HIV-associatedwasting (which often had mean values </= 50 x 106/L), indicating better health later in the epidemic. In that light, future studies should likely exclude those with obesity even in the presence of weight loss. In post hoc analysis, we found that the 20-mg dose was more effective in those with a BMI at entry of </= 22.5 kg/m2. The lower dose was accompanied by lesser increases in LDL and transaminases. Thus, a prospective study excluding obese patients couldestablish that a 20-mg dose is efficacious and associated with a lower frequency of adverse events.