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Expert Commentary

Long-Term Testosterone Replacement in HIV-Infected Men: A Call for Reexamination

Drs. Gabriel Chamie and Annie Luetkemeyer discuss the risk and benefits of testosterone replacement therapy and examine the long-term implications for HIV-infected patients receiving antiretroviral treatment.

Testosterone supplementation is widely used for persons with HIV infection. A recent chart review of the electronic medical record at the San Francisco General Hospital HIV clinic indicated that approximately 11% of 1,400 male patients were receiving androgen replacement. In the years when there was no effective treatment for HIV, testosterone was helpful for the treatment of wasting attributable to HIV. In 2011, however, when the great majority of patients with HIV can expect to have improved health and life expectancy through effective treatment with ART, even in the presence of drug-resistant HIV, it is time to reexamine the risks and benefits of long-term testosterone supplementation for HIV-infected men.

For patients who are on indefinite testosterone therapy, HIV care providers should explain the indication for ongoing replacement and have a frank discussion with them about the risk and benefits.

Hypogonadism, defined as decreased testicular production of testosterone, occurs commonly with HIV infection and chronic illness. However, establishing an accurate laboratory confirmation of a true hypogonadal state can be challenging and, if not done appropriately, may lead to a mistaken diagnosis of hypogonadism and inappropriate testosterone replacement. Total testosterone should be measured in the morning, when testosterone levels are highest. A low total testosterone measurement warrants repeat testing for confirmation. Random non-morning testosterone measurements may not be accurate indicators of hypogonadism. Checking free testosterone by equilibrium dialysis may be the most accurate way to effectively measure testosterone levels (especially because sex hormone-binding globulin [SHBG] is elevated in patients with HIV infection); however, this test is expensive and limited in availability. A confirmed low testosterone result should be followed by testing of luteinizing hormone and follicle-stimulating hormone to establish primary (ie, testicular in origin) vs secondary (ie, owing to pituitary or hypothalamic dysfunction) hypogonadism, as secondary hypogonadism may require further evaluation.

Interpreting low testosterone levels in aging men is an additional challenge. It is known that testosterone levels decline with age, and there is no clear level that defines hypogonadism in older men.(1)

It also is important to note that testosterone commonly is lowered in the setting of reversible illness and with the use of certain medications, such as methadone and risperidone, which may raise prolactin and lower testosterone. It is unclear whether androgen replacement is indicated in these settings, and it is recommended that testosterone levels be reevaluated after illness has resolved for a more accurate assessment of the presence of hypogonadism.

When to Treat Hypogonadism

Current indications for short-term testosterone replacement therapy in men are appropriate laboratory confirmation of low testosterone in addition to 1 or more of the following: a) multiple symptoms of androgen deficiency; b) low libido or erectile dysfunction; c) chronic glucocorticoid treatment; and d) HIV infection with weight loss.(2) Current HIV primary care guidelines recommend evaluating testosterone levels only if patients have signs or symptoms of deficiency,(3) because low testosterone in the absence of symptoms is not an indication for replacement.

The appropriate duration of treatment depends on the indication for testosterone replacement; however, in the majority of situations, therapy should not be indefinite. Current Endocrine Society guidelines state that, "Overall, short-term (3- to 6-month) testosterone use in HIV-infected men with low testosterone levels and weight loss can lead to small gains in body weight and LBM [lean body mass] with minimal change in quality of life and mood. This inference is weakened by inconsistent results across trials."(2) Unfortunately, no data are available to guide decision making in terms of when to reevaluate the need for testosterone therapy or how it should be discontinued. That leads to individuals being started on testosterone for appropriate indications but then remaining on replacement therapy indefinitely, resulting in years of costly treatment that may be unnecessary and possibly harmful.

Some guidelines indicate that testosterone may be beneficial for eugonadal HIV-infected men with AIDS wasting.(2) However, the increase in muscle mass with androgen replacement has been demonstrated to be the same as that achieved with progressive resistance training.(4) Therefore, use of testosterone in eugonadal men with AIDS wasting generally is not warranted, particularly in the current era of highly effective treatment of HIV itself, which is the optimal treatment for wasting.

Concerns about Long-Term Androgen Replacement

We cannot forget the important lessons learned from the use of hormone replacement therapy (HRT) for women. In the early years after its introduction, HRT seemed to be a perfectly sensible treatment. Because menopause leads to a decrease in estrogen levels and is associated with an increase in heart disease, dyslipidemia, osteoporosis, and symptoms of estrogen deficiency, the solution seemed obvious--treat estrogen deficiency to restore women's health. HRT was adopted on a large scale for many years without supporting evidence and with the enthusiastic buy-in of providers and patients for the simple reason that estrogen made women feel better and should be beneficially correcting a deficiency. However, randomized controlled trials led to a rude awakening that long-term HRT, in particular with both progesterone and estrogen, is associated with increased rates of heart disease, thromboembolic disease, and breast cancer,(5, 6, 7) and HRT is now largely restricted to short-term use for menopausal symptoms.

The use of HRT may mirror what has occurred with androgen replacement for HIV-infected men. Similar to the situation in the early days of estrogen replacement therapy, data on long-term testosterone replacement are lacking and providers are operating under the assumption that fixing a laboratory deficiency should improve health in addition to making men feel better. However, a warning flag was raised by a recent study of HIV-uninfected older men with limited mobility and low to low-normal testosterone levels (100-350 mg/dL).(8) In this study, testosterone replacement led to increases in strength but also to higher rates of cardiovascular events, and the trial was discontinued prematurely owing to safety concerns. In addition to possible adverse cardiovascular effects, testosterone replacement is known to contribute to erythrocytosis, reduced spermatogenesis, growth in subclinical and metastatic prostate cancer, and other effects that may detrimentally impact health when given long-term. The fact is that we simply do not know the risks of long-term testosterone replacement and may be exposing patients to increased risks of heart disease, prostate cancer, and other unknown adverse effects. To compound matters, HIV-infected men may be at higher risk of complications from androgen replacement, given the increasingly recognized elevated risks of cardiovascular disease, liver disease, and non-AIDS-defining cancers associated with HIV infection.

Conclusions

We clearly need more rigorous data on long-term outcomes to clarify the risks and benefits of testosterone replacement in HIV-infected hypogonadal men, as well as data to guide how best to safely discontinue long-term testosterone treatment. Testosterone testing itself is fraught with problems; laboratory evaluation for testosterone deficiency often is performed incorrectly by providers and, particularly with older men, there is no clear indication of what constitutes a "normal" testosterone level. There certainly may be a role for short-term testosterone replacement in symptomatic HIV-infected men with confirmed low testosterone. However, what initially is intended to be short-term androgen replacement frequently becomes lifelong therapy. The practice of indefinite testosterone replacement must be reexamined, particularly once patients are doing well on ART, with evidence of immune reconstitution and a return to healthy body mass index. For patients who are on indefinite testosterone therapy, HIV care providers should explain the indication for ongoing replacement and have a frank discussion with them about the risk and benefits.

References

  1. Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab. 2002 Feb;87(2):589-98. PMID: 11836290.
  2. Bhasin S, Cunningham GR, Hayes FJ, et al; Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010 Jun;95(6):2536-59. PMID: 20525905.
  3. Aberg JA, Kaplan JE, Libman H, et al; HIV Medicine Association of the Infectious Diseases Society of America. Primary care guidelines for the management of persons infected with human immunodeficiency virus: 2009 update by the HIV medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2009 Sep 1;49(5):651-81. PMID: 19640227.
  4. 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 Sep 5;133(5):348-55. PMID: 10979879.
  5. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998 Aug 19;280(7):605-13. PMID: 9718051.
  6. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-33. PMID: 12117397.
  7. Nelson HD, Humphrey LL, Nygren P, et al. Postmenopausal hormone replacement therapy: scientific review. JAMA. 2002 Aug 21;288(7):872-81. PMID: 12186605.
  8. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010 Jul 8;363(2):109-22. PMID: 20592293.