for Health Care Providers
Androgen Deficiency
Note: Some medications mentioned in this chapter may not be available on the VHA National Formulary. Consult VA pharmacists for alternatives.
Key Points
- Androgen deficiency is relatively common among HIV-infected individuals, although its prevalence has decreased as ART use has increased.
- Symptoms of HIV-associated androgen deficiency can include loss of muscle mass, fatigue, depression, decreased libido, difficulty concentrating, and reduced functional status.
- Testosterone replacement can alleviate these symptoms to varying degrees.
- Men with low-normal serum testosterone but symptoms of androgen deficiency may benefit from replacement therapy.
- Most HIV-infected men with androgen deficiency will have the hypogonadotropic variant rather than testicular failure; measuring follicle-stimulating hormone (FSH) and luteinizing hormone (LH) can help distinguish the two types.
- The use of testosterone replacement in women with HIV-associated wasting remains under study.
Background
Veterans with HIV*
Male androgen deficiency: 2%
Androgen deficiency is defined as subnormal testosterone production with associated symptoms. Hypogonadism is a more general term that refers to deficient sex hormone production; in men, it refers to defective testosterone production, whereas in women, it refers to defective estrogen production.
This chapter will address testosterone deficiency in HIV-infected adults; for information on female hypogonadism, see Women's Health.
Mechanisms may be primary (testicular) or secondary (hypothalamic/pituitary).
- Primary (hypergonadotropic) androgen deficiency: low testosterone (free, bioavailable, or total) + elevated FSH and/or LH.
- Secondary (hypogonadotropic) androgen deficiency: low testosterone (free, bioavailable, or total) + low or inappropriately normal FSH and/or LH.
Most HIV-infected men (up to 75%) with decreased testosterone levels have secondary (ie, pituitary) androgen deficiency.
Up to 50% of men with AIDS-related wasting had abnormally low testosterone levels in studies done before the availability of effective ART. Many HIV-infected women also have subnormal androgen levels (note that normal testosterone levels in women are approximately one tenth those in men).
Prevalence of androgen deficiency has declined with the use of ART, but remains substantial: Up to 20% of men on ART with less-than-ideal body weight have abnormally low free testosterone.
Manifestations in men include reduced muscle mass, decreased strength, fatigue, depression, difficulty concentrating, decreased libido, oligospermia, reduced functional status, and bone loss.
Manifestations in women are less studied, but include fatigue, decreased libido, and wasting.
Treatment of hypogonadal HIV-infected men with testosterone can lead to increased muscle mass and quality of life, and improvements in depression. In women, treatment has shown increase in weight and social functioning.
Possible causes of androgen deficiency in HIV-infected men include:
- HIV infection (mechanism unclear)
- Cirrhosis
- Medications/drugs (eg, opiates, glucocorticoids, ketoconazole, anabolic steroids, megestrol, or testosterone)
- Tumors, infection, or infiltration of the hypothalamus or pituitary gland
- In addition to endocrine abnormalities, symptoms may include headaches, seizures, visual disturbances (temporal field cuts, diplopia)
- Prolactinoma
- Metastatic disease
- Granulomatous disease
- Abscess
- Radiation therapy, chemotherapy
- Trauma
- Malnutrition
Evaluation
| Symptoms | Note: Onset can be subtle and symptoms may be attributed to other causes ("getting older," primary depressive disorder, anxiety, chronic illness) |
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| Physical examination | To include assessment of muscle mass, secondary sexual characteristics. Check for: |
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| Laboratory evaluation | Laboratory measurements to evaluate androgen deficiency are imperfect. Total testosterone reflects all circulating testosterone components: free (unbound) testosterone + testosterone bound (loosely) to albumin and (tightly) to sex hormone-binding globulin (SHBG). Only free testosterone and albumin-bound testosterone are bioavailable. SHBG can increase with old age, liver disease, and androgen deficiency itself, thus increasing the total testosterone measured while potentially decreasing the amount of unbound (active) testosterone. However, total testosterone is a reasonable initial screening test. It should be checked in the morning, and if low it should be repeated to confirm testosterone deficiency. Determination of free testosterone by equilibrium dialysis is considered the gold standard, but is not available in many laboratories. |
| Initial evaluation: | |
Serum testosterone: morning blood sample for total testosterone
FSH, LH to distinguish primary from secondary androgen deficiency. | |
| Other tests: | |
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Management
Evaluate and treat potential reversible causes of androgen deficiency (see above). (Note that in persons with advanced HIV disease, effective ART may reverse androgen deficiency.)
Testosterone is the preferred treatment Ffor men with documented androgen deficiency (signs and symptoms with abnormal total testosterone, usually <200-320 ng/dL, or free testosterone, usually <6.5 ng/dL), testosterone is the preferred treatment.
Some authorities recommend testosterone replacement therapy in men with symptoms of androgen deficiency (see Symptoms, above), but low-normal testosterone levels.
Typical recommended dosages for men (note that testosterone is classified as a Schedule III drug by the U.S. Drug Enforcement Agency):
- IM testosterone (cypionate or enanthate):
- 100 mg IM every 7 days
- 200 mg IM every 14 days
- 300 mg IM every 21 days
- Longer dosing intervals with higher dosages are more convenient, but risk higher peak levels and greater fluctuations in testosterone level.
- Transdermal (patch) testosterone: 1 patch (5 mg) applied daily.
- Testosterone gel: 5 mg applied daily to trunk and shoulders. Patient should be instructed to wash hands thoroughly after application to avoid transfer of gel to others. (Note: Testosterone gel can be transferred to persons in contact with the treated patient and has been associated with virilization in children and women. Patients should be counseled about the potential effect of testosterone gel in close contacts and to use gel in areas less likely to contact others.)
- Transscrotal testosterone: 6 mg patch applied daily.
For women with HIV-associated wasting and subnormal serum testosterone, twice weekly transdermal testosterone (5 mg twice weekly) for 6 months has been studied as a treatment. This treatment resulted in an increase in muscle mass with no significant side effects. There are no firm guidelines for testosterone use in women.
Testosterone is absolutely contraindicated in men with prostate cancer or patients with a history of breast cancer; it should be used with extreme caution in men with benign prostatic hypertrophy, and only after urologic consultation. Urologic consultation is recommended prior to testosterone treatment in those with prostate-specific antigen (PSA) of >4 ng/mL, or >3 ng/mL in patients with higher risk of prostate cancer (eg, African Americans or patients with a first-degree relative with prostate cancer).
Testosterone therapy usually is well tolerated. Potential adverse effects of testosterone therapy include:
- Testicular atrophy
- Hirsutism
- Gynecomastia
- Prostatic enlargement and unmasking of occult prostate cancer
- Acne
- Mood swings (especially with high doses of IM testosterone)
- Polycythemia (more common with IM testosterone)
- Elevations in ALT, AST
- Dyslipidemia
- Skin irritation at patch site
- Sleep apnea (rare)
- Myocardial infarction (controversial)
- In women, testosterone may also cause virilization; start with low doses and monitor closely for adverse effects
Follow up 2-3 months after starting replacement:
- Measure serum testosterone response to check for efficacy of dosage:
- IM testosterone: measure serum testosterone at midpoint between doses
- Patch: measure 3-12 hours after application
- Gel: timing not critical, as blood levels are constant
- Assess for side effects and check hepatic transaminases and hemoglobin/hematocrit; discontinue testosterone if hematocrit >54%.
- In case of adverse effects, discontinue or lower the dosage of testosterone.
- With the IM formulation, may consider switching to a transdermal formulation, which gives more even dosing and avoids high peak testosterone levels. May also consider switching from high-dose/less-frequent administration to lower-dose/more-frequent administration.
- Testosterone therapy may unmask cryptic prostate cancer. Examine the prostate every 6-12 months, looking for prostatic enlargement; check serum prostate-specific antigen (PSA) in older men.
- If significant enlargement on therapy develops, masses or nodules are detected, or PSA becomes abnormally elevated, discontinue testosterone and refer to Urology for evaluation.
Discontinuation of testosterone replacement:
- There currently are no evidence-based guidelines for discontinuation of testosterone replacement. If the underlying cause of hypogonadism has been addressed (such as effective treatment of HIV), it is reasonable to consider discontinuation of testosterone therapy with monitoring for recurrence of symptoms.
Note: Other anabolic steroids such as oxandrolone, an orally available alkylated androgen, are not recommended in place of testosterone, as they do not have the same effects in the body and may convey higher risk of adverse effects, such as hepatic toxicities (peliosis hepatis, hepatoma, cholestatic jaundice) and lipid derangements. Nandrolone, a parenteral androgen with more anabolic properties than testosterone, is no longer available in the United States.
When to Refer
| Endocrinology |
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| Urology |
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References
- American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients-2002 update
. Endocr Pract. 2002 Nov-Dec;8(6):440-56. - Corcoran C, Grinspoon S. Treatments for wasting in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1999 Jun 3;340(22):1740-50.
- 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.
- Grinspoon S. Androgen deficiency and HIV infection. Clin Infect Dis. 2005 Dec 15;41(12):1804-5.
- Klein RS, Lo Y, Santoro N, et al. Androgen levels in older men who have or who are at risk of acquiring HIV infection. Clin Infect Dis. 2005 Dec 15;41(12):1794-803.
- Miller K, Corcoran C, Armstrong C, et al. Transdermal testosterone administration in women with acquired immunodeficiency syndrome wasting: A pilot study. J Clin Endocrinol Metab. 1998 Aug;83(8):2717-25.
- Mylonakis E, Koutkia P, Grinspoon S. Diagnosis and treatment of androgen deficiency in human immunodeficiency virus-infected men and women. Clin Infect Dis. 2001 Sep 15;33(6):857-64.
- Rietschel P, Corcoran C, Stanley T, et al. Prevalence of hypogonadism among men with weight loss related to human immunodeficiency virus infection who were receiving highly active antiretroviral therapy. Clin Infect Dis. 2000 Nov;31(5):1240-4.
- Rosner W, Auchus RJ, Azziz R, et al. Position statement: Utility, limitations, and pitfalls in measuring testosterone: An Endocrine Society position statement. J Clin Endocrinol Metab. 2007 Feb;92(2):405-13.
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