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Management Recommendations > Testosterone Replacement

Ward 86 Management Recommendations

Testosterone Replacement Treatment for HIV-infected Men with Androgen Deficiency

updated July 2017

Contributors: Elizabeth Murphy, MD
Gabriel Chamie, MD

Prior to the mid-1990s when effective antiretroviral treatment (ART) regimens became widely available, 50% of men with symptomatic HIV disease had low serum testosterone levels,(1) and those androgen-deficient men with unintentional weight loss clearly benefited from testosterone replacement therapy (TRT) with reported increases in muscle mass and improved quality of life.(2) However, in the modern ART era, estimates of androgen deficiency prevalence among HIV-infected men are far lower, especially among those without wasting, and there is evidence that modern ART regimens actually improve testosterone levels.(3) In addition, recent data indicate that prolonged TRT is associated with serious health risks. Of particular note, a cohort study of 14,454 HIV-infected men published in 2015 reported that the rate of TRT initiation was 2.5 times higher in this cohort than in the overall U.S. male population and that rates of appropriate laboratory monitoring pre- and post-TRT initiation were low (see below).(4) Thus, we believe TRT should be considered only for men who have symptoms consistent with androgen deficiency and who have a morning, total serum testosterone level of <300 ng/dL.

(These recommendations are adapted from guidelines established by the Endocrine Society (5) along with expert opinions from Ward 86 and the San Francisco General Hospital Endocrine Clinic.)

  1. Symptomatic androgen deficiency:

    1. Signs and symptoms of androgen deficiency are not very specific and can be confounded by age, concomitant illnesses, the severity of androgen deficiency, and previous testosterone therapy.

    2. Findings likely to be seen in men with prolonged, severe androgen deficiency include decrease in libido and spontaneous erections, gynecomastia, loss of axillary and pubic hair, small testes, and low bone mineral density on dual-energy X-ray absorptiometry (DEXA) screening.

    3. Less specific signs and symptoms of clinically significant androgen deficiency include fatigue, depression, mild anemia, reduced muscle mass, and increased body fat.

  2. Measuring baseline testosterone level:

    1. To obtain an accurate serum testosterone value, a morning serum specimen should be collected, and a total serum testosterone should be requested (assays measuring free testosterone are too variable to be clinically useful).

    2. If the morning level is <300 ng/dL, confirm this value with a second morning serum testosterone level and request a simultaneous luteinizing hormone (LH) level.

    3. Testosterone levels should not be measured during any acute illness.

    4. Testosterone assays are not well calibrated among laboratories, so these recommendations are based on using an assay with a lower limit of the normal range of approximately 300 ng/dL.

    5. Of note, testosterone levels normally decline by 1-2% per year as men age. Conditions that lower serum sex-hormone binding globulin (SHBG) such as obesity, nephrotic syndrome, hypothyroidism, glucocorticoid therapy, diabetes, acromegaly, and the presence of anabolic steroids can lower total serum testosterone. However, treating the underlying condition typically corrects the low total testosterone level.

  3. Additional baseline testing before initiating TRT

    1. We recommend checking a luteinizing hormone (LH) level at the time of the second morning testosterone check because most cases of HIV-associated androgen deficiency are due to hypothalamic, hypogonadotrophic hypogonadism, in which LH levels will be inappropriately normal or low. However, inappropriately low LH levels also can be caused by a primary pituitary problem (eg, pituitary adenoma or other mass). If the LH is inappropriately normal or low when the total testosterone is <100 ng/dL, one should further assess anterior pituitary function with serum measurements of prolactin, TSH, and free T4 and strongly consider obtaining a pituitary MRI.

    2. If total serum testosterone is low and the LH is elevated (an appropriate pituitary response to the low testosterone levels), evaluate the patient for primary testicular failure.

  4. Initiation of testosterone therapy

    1. If the patient has two low total testosterone values with symptoms consistent with androgen deficiency, initiation of therapy can be considered.

    2. Prior to initiating testosterone therapy, check hematocrit. If the patient is >40 years old, also check PSA level.

    3. If PSA is >0.6 ng/mL, perform a rectal exam to check for a prostate mass.

    4. Contraindications to TRT:

      1. Metastatic prostate cancer or breast cancer
      2. Unevaluated prostate nodule or induration
      3. Prostate serum antigen (PSA) level >4 ng/mL (>3 ng/mL in high-risk groups)
      4. Hematocrit >50%
      5. Severe symptoms of prostatic hyperplasia
      6. Congestive heart failure that is not well controlled
      7. Untreated obstructive sleep apnea
    5. Any androgen supplement other than a testosterone formulation, eg, oxandrolone (Anavar) or nandrolone (Deca-Durabolin), is contradicted because of safety concerns (eg, renal failure due to focal segmental glomerulosclerosis, left ventricular dysfunction, mood changes, and hepatotoxicity).

  5. For patients who are already receiving TRT and who did not meet the above criteria prior to initiating TRT, we recommend:

    1. First, educate the patient about the newly appreciated serious health risks of continuing TRT.

    2. Suggest the patient take a TRT holiday for at least 2 months.

    3. At the end of this holiday, conduct the above evaluation to determine whether reinitiation of TRT is appropriate.

  6. Evaluating TRT during therapy

    1. The goal of TRT is to achieve a morning total testosterone level in the middle of the normal range (ie, 400-700 ng/dL). Testing should be done at a midpoint between IM testosterone injections, or 1 week after initiating testosterone gel, or 3-12 hours after application of a testosterone patch.

    2. After 3-6 months, another testosterone level and hematocrit should be checked, as well as a PSA if the initial PSA was >0.6 ng/mL. If, at this point, the patient's possible symptoms of androgen deficiency are not significantly better, TRT should be discontinued.

    3. If TRT is continued, check hematocrit yearly and decrease the testosterone dosage if hematocrit increases into the abnormally high range.

  7. Benefits and risks of TRT:

    1. Data supporting the benefit of TRT are weak. Most studies in young men with low testosterone levels have been open-label without a placebo group. In older men and those with chronic illness, few large clinical trials have demonstrated clinical efficacy. While increased muscle mass and decreased fatigue generally has been observed in these trials, the effects on erectile dysfunction have been inconsistent.

    2. On the other hand, TRT can increase the risks of erythrocytosis and cardiovascular events. Several recent studies have reported that TRT is associated with an increased risk of myocardial infarction and stroke, particularly among men with low total testosterone levels who have evidence of or are at high risk of cardiovascular disease (see Table below for details). This is of particular concern for HIV-infected patients because, even with virologic suppression on ART, HIV is an independent risk factor for cardiovascular disease. Of note, in March 2015, the FDA announced that manufacturers of testosterone drugs will be required to change drug warning labels to indicate that testosterone could increase the risk of heart attacks and strokes and should not be prescribed to treat symptoms brought on by age, such as declining sexual drive.

    3. There are insufficient data from randomized trials to assess TRT as a risk factor for prostate cancer. A large case-control study based on the National Prostate Cancer Registery of Sweden involving 38,000 prostate cancer patients and 200,000 age-matched controls found no association between TRT and overall prostate cancer risk.(6)
  8. For HIV-infected men, more rigorous screening for and safety monitoring of TRT is needed than has been the standard of practice to date. An observational study published in 2015 and conducted in 7 HIV clinics in the United States (4) reported that only 24% of 1,482 patients who initiated TRT had testosterone deficiency documented by serum testing prior to starting TRT. Only 61% had a serum testosterone measured during follow-up, only 34% of those over 40 years old had a baseline PSA screening test, and only 12% had a PSA measured during follow-up.(4)

Table. Data on Cardiovascular Risks of Testosterone Replacement Therapy (TRT)

  • Among a cohort of 8,709 men in the Veterans Administration health care system who had low serum testosterone and were undergoing coronary angiography for clinical indications, the use of TRT was associated with increased subsequent risk of a composite endpoint consisting of mortality, myocardial infarction, and ischemic stroke.*
  • In a placebo-controlled, randomized trial of testosterone gel administered to 209 community-dwelling men ≥65 years old, who had limitations in mobility and a total serum testosterone level of 100-350 ng/dL, 22% of subjects in the testosterone group, as compared with 5% in the placebo group, had serious cardiovascular-related adverse events (p < .001).**
  • A systematic review and metaanalysis was conducted of placebo-controlled, randomized trials of TRT lasting ≥12 weeks in duration. TRT was associated with an increased risk of serious cardiovascular-related events, particularly in those trials not funded by the pharmaceutical industry.***
  • In a double-blind, placebo-controlled trial, 170 men aged 65 or older with an average of 2 serum testosterone levels lower than 275 ng/dL and symptoms suggestive of hypogonadism were randomized to TRT or placebo. Coronary artery noncalcified plaque volume measured by CT angiography increased more in patients assigned TRT.****

* Vigen R, O'Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013 Nov 6;310(17):1829-36.

** 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.

*** Xu L, Freeman G, Cowling BJ, et al. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. 2013 Apr 18;11:108.

**** Budoff MJ, Ellenberg SS, Lewis CE, et al. Testosterone treatment and coronary artery plaque volume in older men with low testosterone. JAMA. 2017 Feb 21;317(7):708-16.

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References

  1. Dobs AS, Dempsey MA, Ladenson PW, et al. Endocrine disorders in men infected with human immunodeficiency virus. Am J Med. 1988 Mar;84(3 Pt 2):611-6.
  2. Grinspoon S, Corcoran C, Askari H, et al. Effects of androgen administration in men with the AIDS wasting syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1998 Jul 1;129(1):18-26.
  3. Dubé MP, Parker RA, Mulligan K, et al. Effects of potent antiretroviral therapy on free testosterone levels and fat-free mass in men in a prospective, randomized trial: A5005s, a substudy of AIDS Clinical Trials Group Study 384. Clin Infect Dis. 2007 Jul 1;45(1):120-6.
  4. Bhatia R, Murphy AB, Raper JL, et al; Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS). Testosterone replacement therapy among HIV-infected men in the CFAR Network of Integrated Clinical Systems. AIDS. 2015 Jan 2;29(1):77-81.
  5. 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.
  6. Loeb S, Folkvaljon Y, Damber JE, et al. Testosterone replacement therapy and risk of favorable and aggressive prostate cancer. J Clin Oncol. 2017 May 1;35(13):1430-6.