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Androgen Deficiency and HIV

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%

*Veterans in the VA HIV Clinical Case Registry in care in 2007 who had an ICD-9 code corresponding to this condition

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

SymptomsNote: Onset can be subtle and symptoms may be attributed to other causes ("getting older," primary depressive disorder, anxiety, chronic illness)
  • Loss of libido
  • Weight loss, especially of lean muscle mass
  • Erectile dysfunction
  • Oligospermia/decreased ejaculate volume
  • Depressive symptoms, poor concentration
  • Fatigue
  • Infertility
Physical examinationTo include assessment of muscle mass, secondary sexual characteristics. Check for:
  • Visual fields (to evaluate for pituitary lesion impairing optic nerve)
  • Small or soft testes (size smaller than approximately 4.5-6.5 cm long x 2.8-3.3 cm wide; suggests atrophy)
  • Testicular masses(roll each testicle between thumb and 1st two fingers, feeling for fixed or firm masses, which may not be tender)
  • Gynecomastia; suggests primary androgen deficiency if FSH or LH is elevated
Laboratory evaluationLaboratory 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

  • Average serum testosterone levels decrease with age, and there is no absolute cutoff dividing normal from subnormal serum testosterone. One approach defines normal as >2.5 standard deviations below the mean serum total testosterone of healthy young males (approximately 319 ng/dL, per the American Association of Clinical Endocrinologists [AACE]).
  • If total testosterone level is below or near normal, most authorities recommend rechecking total testosterone and measuring free testosterone (by equilibrium dialysis, if feasible, or by free testosterone concentration) or bioavailable testosterone. The analog method of measuring free testosterone is not recommended.

FSH, LH to distinguish primary from secondary androgen deficiency.

Other tests:
  • Other pituitary hormone levels (prolactin, growth hormone, TSH), if hypopituitarism (hormone levels low) or pituitary adenoma (hormone levels high) is suspected.
  • Sperm count and motility, if fertility is an issue.
  • Consider MRI if workup suggests hypothalamic or pituitary mass or other abnormality (eg, abnormal pituitary hormone levels, visual field lesions, or neurologic signs).
  • Testicular ultrasound if testicular masses are detected on examination.

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
  • Lack of symptomatic improvement
  • Diagnostic uncertainty, especially if secondary androgen deficiency remains in the differential diagnosis
  • Evidence of hypothalamic or pituitary mass
Urology
  • Testicular masses
  • Prostatic enlargement, masses, or nodules, or elevated PSA

References