Testosterone Replacement for Hypogonadism ...

Testosterone Replacement

Testosterone Replacement for Hypogonadism: Clinical Findings and Best Practices Ulrich R. Hengge, MD

Hypogonadism is highly prevalent in HIV-infected patients and has been associated with the late stages of AIDS and with AIDS wasting. There are a number of studies exploring treatment options. Testosterone replacement, with the exception of the transscrotal delivery patch, has been observed to have a beneficial effect on lean body mass and body weight in hypogonadal and eugonadal men with the AIDS wasting syndrome. Resistance exercise training also has had favorable effects on body weight and muscle cell mass. In hypogonadal men with AIDS treated with testosterone replacement therapy, researchers noted a positive effect on depression scores. Key words: HIV/AIDS • Hypogonadism • HIV wasting • Testosterone replacement therapy • Oxymetholone

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pproximately 30% of all HIV-positive men, and approximately 50% of men with AIDS,1 are hypogonadal. In several studies, hypogonadal status has been shown to correlate with a late stage of the disease, low lymphocyte count, weight loss, and reduced muscle mass.2-5 The free level of testosterone in serum is a good marker for measuring the efficacy of antiretroviral therapy and for determining the status of hypogonadism. There have been several trials on the subject of testosterone replacement and wasting. An early trial by Grinspoon and colleagues1 assessed testosterone replacement in a 6month, randomized, placebo-controlled study in 51 men with AIDS wasting. The patients were randomly assigned to receive either testosterone enanthate, 300 mg, or placebo every 3 weeks. In the testosterone group, there were statistically significant increases of approximately 2 kg in fat-free mass (P = .036), lean body mass (P = .041), and muscle mass

(P = .004), whereas in the placebo group all 3 of these measurements were reduced. Overall body weight did not differ significantly between the 2 groups. A study by Bhasin and colleagues6 evaluated intramuscular testosterone replacement and resistance exercise in hypogonadal men to test the hypothesis that exercise could enhance the effects of testosterone therapy. The study was performed as a 16-week, double-blind trial of 61 persons randomized to 1 of the following 4 groups: placebo injections every 3 weeks and no exercise; testosterone enanthate, 100 mg per week, and no exercise; placebo and exercise; or a combination of testosterone enanthate, 100 mg per week, and exercise. Body weight increased in the group receiving testosterone therapy alone and in the group receiving exercise therapy alone. An important finding was that there was no increase in weight or lean body mass in the group combining testosterone and exercise but

Dr Hengge is professor of medicine at Heinrich Heine University Medical School, Düsseldorf, Germany. SUPPLEMENT The AIDS Reader S15

Changes in muscle mass (mm2 )


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Figure 1. Change in muscle mass by volume in eugonadal HIV wasting patients undergoing progressive exercise 3 times per week compared with those receiving oxymetholone, 200 mg/wk, via intramuscular injection. (Data from Grinspoon S et al. J Clin Endocrinol Metab. 2000.3)

only in the groups with testosterone or exercise alone. All treatment groups increased their maximum voluntary muscle strength compared with the placebo group, and thigh muscle volume was increased in both the testosterone and the progressive resistance exercise groups. There was also an increase in hemoglobin levels in the group receiving testosterone supplements. A study by Grinspoon and colleagues7 analyzed intramuscular testosterone and/or exercise in eugonadal men with AIDS wasting. This was the first study on testosterone replacement in AIDS wasting patients to address eugonadal men. The study was structured as a 12week, controlled trial, with 54 participants who were randomized to receive either a 200-mg/week testosterone injection or placebo and/or progressive resistance exercise. Supervised progressive exercise 3 times a week achieved roughly the same outcome as the intramuscular testosterone injection alone (Figure 1).7 Both treatment arms achieved statistically significant improvements in muscle mass compared with placeS16 The AIDS Reader SUPPLEMENT

bo. This demonstrated that if a patient is willing and able to exercise on a regular basis, the effect achieved can be the same as that achieved with testosterone therapy. Although they are associated with significant improvements in weight and muscle mass, intramuscular testosterone injections are also painful and not well tolerated by patients. An alternative delivery method, the testosterone transscrotal delivery patch, was assessed in a 12-week, randomized, double-blind trial including 133 men with AIDS, all older than 18 years, in the preHAART era.8 No effect on either weight or lean body mass was observed with the transscrotal delivery method. Transscrotal testosterone replacement did not adversely affect any of the immunologic parameters that were assessed, but the investigators reported that the hormone was not maintained at adequate levels over the course of the day. Because transscrotal testosterone therapy did not adequately increase testosterone levels and improve wasting in the study patients, the

authors concluded that the scrotal patch cannot be recommended in HIV-positive patients for testosterone replacement. AIDS Wasting Syndrome

AIDS wasting syndrome remains an important clinical issue. It is present in one form or another in 80% of the AIDS patients in the United States and Europe.9-11 In Germany, a study by Schmitt-Rau and colleagues12 showed that about 61% of physicians used androgen replacement as a first-line treatment for this condition. The definition of AIDS wasting initially used in the CDC guidelines was an involuntary weight loss of either 10% in the previous 12 months or 7.5% in the previous 6 months. However, pioneering work by Polsky and colleagues13 has shown that the time until death as a result of AIDS can be predicted by the loss of body cell mass. Based on this, the authors put forward a definition of AIDS wasting as a 5% loss of body cell mass in the previous 6 months. According to this definition, a body cell mass of less than 35% of body weight can be considered to constitute AIDS wasting in men; for women, the criterion is a body cell mass of less than 23%. The major causes of AIDS wasting syndrome are reduced nutritional intake, malabsorption, infection, and HIV enteropathy, which is illdefined. Altered metabolism and patient medications are additional causes. Treatment Strategies for AIDS Wasting

The treatment strategies that have been pursued in recent years have been appetite stimulants, such as megestrol acetate or dronabinol; optimization of nutritional status through dietary supplements; and cytokine inhibitors, such as thalidomide or pentoxifylline.

Truly anabolic proteins, such as the human growth hormone or insulin-like growth factors, have also been used in a number of trials. All of these trials were performed before the advent of HAART. There was significant weight gain reported in all of these studies, but most were open-label studies with uncontrolled initial observations. Nonetheless, the studies confirmed that anabolic steroids have an impact on weight gain, with some studies showing effects on body composition and lean body mass.14,15 Oxymetholone for the Treatment of HIV Wasting

One agent that has been investigated for the treatment of HIV wasting is oxymetholone, because it has a ratio of anabolic to androgenic effect that is approximately 7 times greater than that of methyltestosterone.16,17 Because of this anabolic predominance and lack of androgenic effects, the drug is safe to administer to women with severe wasting.17,18 Oxymetholone was studied in a randomized, double-blind, placebo-controlled, phase 3 trial in eugonadal women and men.19 The objectives were to evaluate the safety and efficacy of oxymetholone for AIDS wasting, to document weight gain, to analyze oxymetholone’s side-effect profile, and to measure its effects on body composition. One hundred twelve patients were screened, and 92 patients were randomized to receive oxymetholone, 50 mg 3 times daily; oxymetholone, 50 mg 2 times daily; or placebo for the double-blind treatment period in the first 16 weeks. The placebo group was subdivided into 2 groups: some patients were assigned to 2 tablets of placebo and some to 3 tablets of placebo. The double-blind phase was followed by an open-label treatment phase of 50 mg twice a day from week 17 to week 32 as a SUPPLEMENT The AIDS Reader S17


crossover for patients initially assigned to the placebo group. A substantial number of patients were lost to follow-up. The age of the subjects fell in the range between 38 and 42 for all 3 study groups. The groups were predominantly white; the mean weight was 60 kg for the placebo group, 66.2 kg in the 3-times-aday group, and 65.2 kg in the twicea-day group. There was no statistically significant difference in weight between the groups, but body cell mass and lean body mass, as a result of the randomization bias, were significantly lower in the group receiving placebo. This disparity may have been attributable to the greater percentage of women in the placebo group. The 3-times-a-day oxymetholone group showed a rapid increase in body weight within the first 8 weeks and then reached a plateau phase during which body weight stayed essentially the same. The same progression occurred in the twice-a-day oxymetholone group. The placebo group maintained an essentially stable weight until week 16, when therapy was switched to 50 mg oxymetholone twice a day provided that the patient gave consent. The mean change in body weight over the course of the 16-week period was 3.5 ± 0.5 kg for the twicedaily group, 3.0 ± 0.7 kg for the 3times-daily group, and 1.0 ± 0.7 kg for the placebo group (P < .05). One would generally expect the weight gain to be higher in the 3-times-daily group; however, the oxymetholone 3-times-daily group had a greater number of treatment interruptions, which may be the cause of the lower gain in body weight in this group. Over the first 16 weeks of treatment, the twice-daily group experienced a statistically significant (P < .0001) increase in body cell mass of 3.8 ± 0.4 kg, as opposed to 0.5 ± 0.8 kg in the placebo group. There was S18 The AIDS Reader SUPPLEMENT

also a statistically significant increase in lean body mass in both of the groups receiving oxymetholone; in the twice-daily group, the increase was 2.9 kg, and in the 3-times-daily group, the increase was 1.8 kg. There was a significant increase of 1.0 kg/m2 in body mass index in both of the oxymetholone groups. Body fat did not change over the course of the study. In the 3-times-daily arm, the incidence of adverse effects was 14%; these effects were primarily related to the liver, as would be expected during use of anabolic steroids. Adverse effects included diarrhea, enlarged clitoris, hepatitis C reactivation, and increased liver enzyme levels. Severe hepatomegaly and jaundice, which were fully reversible at cessation of the drug, developed in 1 person in the twice-daily group. The individual grade 3 and 4 changes in both liver enzyme levels are shown in Figure 2.19 In the 3times-daily group, there was an early onset of liver toxicity, whereas in the twice-daily group there was minimal liver toxicity until week 16 of treatment, when the toxicity reached the same percentage as that in the 3-times-daily group. In the open-label phase, 75 persons agreed to continue on to the twice-daily regimen. Body weight was maintained in persons who initially received oxymetholone, while those previously taking placebo experienced a gain in body weight and lean body mass. Liver toxicity levels remained relatively constant. As was expected, many patients in the twicedaily group showed suppression of testosterone to a degree that was statistically significant; this effect was not observed in the placebo group. Luteinizing hormone and folliclestimulating hormone were also suppressed by oxymetholone to a degree that was statistically significant. Because of this feedback loop, clini-

Oxymetholone 50 mg tid

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Figure 2. Percentage of patients receiving oxymetholone, 50 mg tid, oxymetholone, 50 mg bid, or placebo in whom grade 3 or 4 liver toxicity developed at 4, 8, 12, and 16 weeks following the start of treatment. (Adapted with permission from Hengge UR et al. AIDS. 2003.19)

cians must taper the dosages when stopping treatment with oxymetholone, as opposed to ending treatment abruptly, so that endogenous testosterone production can start again. This phase 3 trial demonstrated the anabolic effects of oxymetholone in eugonadal patients with AIDSassociated wasting. The twice-daily regimen appeared to be as effective as 3-times-daily dosing but was associated with fewer liver toxicity events. The results of the 16-week, open-label continuation phase indicated that anabolic gains were maintained. Overall, these data indicate that it would be desirable to begin with a twice-daily regimen and then taper the oxymetholone treatment to maintain the desired changes in lean body mass and total body mass. Bone Density and Testosterone Replacement

Fairfield and colleagues20 examined bone density in 54 eugonadal men with AIDS wasting. These persons were randomized to receive either testosterone or placebo and/or progressive resistance training. After 12 weeks, the increase in bone density

was statistically significant (P = .02) in patients receiving treatment; the increase was 2.5%. However, in the group receiving placebo, bone density declined by 1.5%. These findings suggest that bone density can be significantly improved by a short-term course of testosterone injections. Quality of Life

Quality of life is an increasingly important issue in patients with HIV infection, given the large number of drugs and their side effects, which can interfere with daily living. Grinspoon and colleagues3 assessed the level of depression in 51 men with hypogonadism and wasting, who were randomized to either testosterone enanthate, 300 mg, or placebo injected intramuscularly every 3 weeks. The patients were matched by age and weight with eugonadal AIDS wasting patients, who served as the baseline. The depression score index used was the Beck Depression Inventory, which is a standardized instrument assessing anxiety, sadness, and lack of interest in daily life. The normal range for this score contains values of less than 10. SUPPLEMENT The AIDS Reader S19


The hypogonadal patients had a statistically significantly (P = .02) higher mean depression score than baseline, with an average score of 15.5. The eugonadal patients had a normal depression score. After data were controlled for weight, viral load, CD4 cell count, and antidepressant use, the investigators were able to show a highly significant relationship between improvement in the Beck Depression Inventory score and an increase in testosterone levels (P < .01 for free testosterone, P < .001 for total testosterone) (Figure 3).3 To study the effects of testosterone replacement on depression in hypogonadal HIV patients, Rabkin and colleagues21 conducted a 6week, double-blind trial, followed by a 12-week observation period. The 70 HIV patients in this study had hypogonadism that was clinically similar to that associated with erectile dysfunction, with substantial loss of sexual desire in conjunction with other associated symptoms. The patients were randomized to receive either intramuscular testosterone therapy or placebo. A number

of different outcome measures were used in the study, including libido, mood, energy, and sexual function. The main summary result was that after the 6-week treatment period, 74% of the persons randomized to testosterone therapy reported much improved or very much improved libido, versus 19% of those who were receiving the placebo (P < .001). When this measurement was repeated at week 12, which was the maintenance period after follow-up, the improvement in libido remained statistically significant. Energy level improvement was also statistically significant (P < .01). As a desirable side effect, muscle mass increased in the testosterone group by 1.6 kg. Summary

Testosterone replacement, with the exception of the transscrotal delivery patch, has been observed in several studies to have a consistent beneficial effect on lean body mass and body weight in hypogonadal men.1,3,6,8,22 Testosterone replacement and resistance exercise training had a favorable impact on muscle cell

0

Changes in Beck score

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Figure 3. Mean changes in scores measured by Beck Depression Inventory in hypogonadal men receiving testosterone enanthate, 300 mg every 3 weeks, versus those receiving placebo. (Data from Grinspoon S et al. J Clin Endocrinol Metab. 2000.3) S20 The AIDS Reader SUPPLEMENT

mass increase.19 In hypogonadal men with AIDS treated with testosterone replacement therapy, researchers have noted a positive effect on mood and depression scores as well.21 Testosterone replacement may also be useful as short-term adjunctive therapy in eugonadal HIVinfected men, under appropriate monitoring, when improvement in bone density or reduction of depression is desirable. In persons with AIDS wasting, there should be careful evaluation of the potential causes of hypogonadism, as well as consistent measurement of the free testosterone level before treatment attempts. □ References 1. Grinspoon S, Corcoran C, Askari H, et al. Effects of

androgen administration in men with the AIDS wasting syndrome: a randomized, double-blind, placebocontrolled trial. Ann Intern Med. 1998;129:18-26. 2. Dobs AS. Androgen therapy in AIDS wasting. Baillieres Clin Endocrinol Metab. 1998;12:379-390. 3. Grinspoon S, Corcoran C, Stanley T, et al. Effects of hypogonadism and testosterone administration on depression indices in HIV-infected men. J Clin Endocrinol Metab. 2000;85:60-65. 4. Willey S, Roulet V, Reeves JD, et al. Human Leydig cells are productively infected by some HIV-2 and SIV strains but not by HIV-1. AIDS. 2003;17:183-188. 5. Habasque C, Aubry F, Jegou B, Samson M. Study of the HIV-1 receptors CD4, CXCR4, CCR5 and CCR3 in the human and rat testis. Mol Hum Reprod. 2002;8:419-425. 6. Bhasin S, Storer TW, Javanbakht M, et al. Testosterone replacement and resistance exercise in HIVinfected men with weight loss and low testosterone levels. JAMA. 2000;283:763-770. 7. Grinspoon S, Corcoran C, Parlman K, et al. Effects of testosterone and progressive resistance training in eugonadal men with AIDS wasting: a randomized, controlled trial. Ann Intern Med. 2000;133:348-355. 8. Dobs AS, Cofrancesco J, Nolten WE, et al. The use of a transscrotal testosterone delivery system in the treatment of patients with weight loss related to

human immunodeficiency virus infection. Am J Med. 1999;107:126-132. 9. Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med. 1998;338:970-976. 10. Wanke CA, Silva M, Knox TA, et al. Weight loss and wasting remain common complications in individuals infected with human immunodeficiency virus in the era of highly active antiretroviral therapy. Clin Infect Dis. 2000;31:803-805. 11. Balslev U, Monforte AD, Stergiou G, et al. Influence of age on rates of new AIDS-defining diseases and survival in 6546 AIDS patients. Scand J Infect Dis. 1997;29:337-343. 12. Schmitt-Rau K, Kehlenbeck P, Bichler J, et al. HIVassociated metabolic disorders and ways of their management: results of a survey in Germany. In: Program and abstracts of the 4th International Conference on Nutrition and HIV Infection and the 2nd European Workshop on Lipodystrophy; April 19-21, 2001; Cannes, France. Abstract P-42. 13. Polsky B, Kotler D, Steinhart C. HIV-associated wasting in the HAART era: guidelines for assessment, diagnosis, and treatment. AIDS Patient Care STDs. 2001;15:411-423. 14. Forbes GB. The effect of anabolic steroids on lean body mass: the dose response curve. Metabolism. 1985;34:571-573. 15. Forbes GB, Porta CR, Herr BE, Griggs RC. Sequence of changes in body composition induced by testosterone and reversal of changes after drug is stopped. JAMA. 1992;267:397-399. 16. Pavlatos AM, Fultz O, Monberg MJ, Vootkur A. Review of oxymetholone: a 17alpha-alkylated anabolic-androgenic steroid. Clin Ther. 2001;23:789-801; discussion 771. 17. Camerino B, Sala G. Anabolic steroids. Fortschr Arzneimittelforsch. 1960;2:71-134. 18. Hengge UR, Baumann M, Maleba R, et al. Oxymetholone promotes weight gain in patients with advanced human immunodeficiency virus (HIV-1) infection. Br J Nutr. 1996;75:129-138. 19. Hengge UR, Stocks K, Wiehler H, et al. Doubleblind, randomized, placebo-controlled phase III trial of oxymetholone for the treatment of HIV wasting. AIDS. 2003;17:699-710. 20. Fairfield WP, Finkelstein JS, Klibanski A, Grinspoon SK. Osteopenia in eugonadal men with acquired immune deficiency syndrome wasting syndrome. J Clin Endocrinol Metab. 2001;86:2020-2026. 21. Rabkin JG, Wagner GJ, Rabkin R. A double-blind, placebo-controlled trial of testosterone therapy for HIV-positive men with hypogonadal symptoms. Arch Gen Psychiatry. 2000;57:141-147; discussion 155156. 22. Coodley GO, Coodley MK. A trial of testosterone therapy for HIV-associated weight loss. AIDS. 1997; 11:1347-1352.

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