With the prevalent use of opioids in the treatment of acute and chronic pain, the effect on the hypothalamus is often overlooked. Fatigue, low libido and decline in mental function are frequently associated with chronic opioid use. Any man on opioid therapy, especially methadone (Dolophine, Methadose, Westadone), who complains of chronic fatigue should have his total testosterone level checked.

Long-term replacement of testosterone can induce a general improvement of the male chronic pain patient’s quality of life, an important clinical aspect of pain management. The administration of testosterone in chronic pain patients with low testosterone improved their pain-rating indexes. The Aging Males’ Symptoms Scale was used in the referenced study along with a sexual dimension index. Both scales showed significant improvement over time.

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The female hormone estrogen can be synthesized from testosterone in many tissues throughout the body. Testosterone is converted to two active metabolites, 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT), which mediate some actions of testosterone in target tissues. Most of the circulating E2 is derived from peripheral aromatization of testosterone in adipose tissue, and DHT is derived by 5α-reduction of testosterone.23

Estradiol is a metabolite of testosterone that causes many of the side effects of testosterone replacement therapy. As the testosterone is replaced, estradiol levels will also increase. Rising estradiol levels can increase such side effects as gynecomastia, enlarged prostate, elevated hematocrit count, and increased moodiness. Estradiol levels should be followed along with total testosterone and free testosterone in any patient receiving testosterone replacement therapy.

Testosterone replacement therapy

Morbidity and mortality are higher in men with below- normal serum testosterone. The goal of testosterone replacement therapy is to relieve the symptoms of low testosterone and restore testosterone levels to the mid-to-normal range.

Testosterone therapy can be administered through injection, cream, or patch. The half-life of injectable testosterone is approximately eight days. A testosterone injection every seven to 10 days is recommended for a stable therapeutic level. The absorption rate of testosterone cream is unpredictable, and the cream can be transferred to others who come in contact with the applicant. The testosterone patch can get wet and may come off. There is currently no oral testosterone replacement therapy available in the United States.

Testosterone undecanoate, which is absorbed predominantly through the lymphatic system, is widely used outside the United States and has the best safety data. However, this form of testosterone is unlikely to raise levels above the mid-range.5

Testosterone replacement therapy is not without its risks (Table 2). Users may be at risk for prostate cancer, worsening symptoms of benign prostatic hypertrophy, liver toxicity and tumor, worsening symptoms of sleep apnea and congestive heart failure, gynecomastia, infertility and skin diseases. Because exogenous testosterone will suppress the hypothalamic–pituitary–thyroid axis, testosterone replacement therapy is not appropriate for men who wish to father a child.5 The severity of these risks depends on the man’s age, life circumstances and other medical conditions.24

Table 2. Potential risks of testosterone replacement therapy

Stimulate growth of prostate cancer and breast cancer
Worsen symptoms of benign prostatic hypertrophy
Cause liver toxicity and liver tumor
Cause gynecomastia
Cause erythrocytosis
Cause testicular atrophy and infertility
Cause skin diseases
Cause or exacerbate sleep apnea

Contraindications to testosterone replacement therapy include metastatic prostate cancer, breast cancer, undiagnosed prostate nodule or induration, unexplained prostate-specific antigen (PSA) elevation, erythrocytosis, severe benign prostatic hyperplasia symptoms, unstable severe congestive heart failure and untreated obstructive sleep apnea (Table 3).5

Table 3. Contraindications to testosterone ­replacement therapy

Cause liver toxicity and liver tumor>
Metastatic prostate cancer
Breast cancer
Undiagnosed prostate nodule or induration
Unexplaned elevation of prostate-specific antigen (>3 ng/mL)
Erythrocytosis (hematocrit >50%)
Severe benign prostatic hyperplasia (International Prostate Symptom Score >19)
Unstable sever congestive heart failure (class III or IV)
Untreated obstructive sleep apnea

Testosterone monitoring

Serum testosterone levels vary significantly as a result of circadian and circannual rhythms, episodic secretion, and measurement variations. Concentrations may be affected by illness and certain medications. Total testosterone concentrations are also influenced by alterations in SHBG concentrations.24

On initial evaluation for testosterone replacement therapy, obtain a complete blood count (CBC) and total chemistry panel and measure levels of thyroid-stimulating hormone (TSH), LH, FSH, total testosterone, free testosterone, PSA, prolactin and estradiol. If the testosterone level is <150 ng/dL on two morning visits, obtain an MRI to rule out pituitary adenoma or disease. After the fourth injection, evaluate the total testosterone, free testosterone, and estradiol levels and adjust the testosterone dose accordingly.

The goal of testosterone replacement therapy is total testosterone between 400 ng/dL and 600 ng/dL and a free testosterone between 15 ng/dl and 20 ng/dl. At these normal levels, symptoms of hypogonadism resolve.

A digital rectal examination should be performed and PSA should be tested prior to initiating testosterone replacement therapy; a follow-up PSA test should be performed every three months. If the PSA value is increasing over time, refer the patient to urology for evaluation. All abnormal PSA results on the first visit should be referred for evaluation, and testosterone replacement therapy should not be started until cleared by a urologist.

Men with hypothyroidism will almost always have low testosterone, but not all patients with low testosterone will have hypothyroidism. If the patient has low testosterone on screening, a TSH should be performed to rule out hypothyroidism.

LH and FSH are used to rule out disease of the hypothalamus-pituitary axis. A prolactin level should also be obtained if disease of the pituitary gland is suspected.

During testosterone replacement therapy, a CBC (specifically a hematocrit) as well as total testosterone, free testosterone, LH, FSH, estradiol, and PSA levels should be obtained every 90 days. Testosterone replacement therapy can thicken the blood. If the hematocrit is >50%, testosterone therapy should be stopped or the dose reduced.

Side effects of testosterone replacement therapy

If gynecomastia, nipple tenderness, enlarged prostate, increased hematocrit, fluid retention, and/or increased moodiness occur in a patient with increased estradiol levels, prescribe anastrozole (Arimidex) 1 mg, one half to one tablet every morning of testosterone injection. If estradiol levels continue to rise and symptoms are present, the dose can be increased to one tablet three times a week. Antibiotic soap should clear up any acne that occurs as a result of treatment.


Testosterone replacement therapy is associated with significant improvement in the physical and mental function of men diagnosed with low testosterone. The natural decline in testosterone with age is the most prevalent cause of this condition. The main complaints of men with low testosterone are fatigue, decreased muscle mass, erectile dysfunction, waning libido and weight gain. A known association exists among the triad of low testosterone, metabolic syndrome and erectile dysfunction.

Testosterone replacement to normal levels also has positive effects on depression and bone density. Chronic opioid use can lower total testosterone, but replacement has a positive effect on overall pain levels.

Mental function and cognition is also improved with testosterone replacement in those who have low testosterone. A normal testosterone level most likely provides cardiovascular protection. The major contraindication for androgen supplementation is the presence of a prostatic carcinoma.5

Response to testosterone replacement therapy must be assessed regularly. If no symptom improvement is noted, treatment should be discontinued and the patient investigated for other possible causes of the clinical presentation. 

Steven W. Salyer, PA-C, is a practicing emergency-medicine physician assistant in San Antonio, Tex.

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All electronic documents accessed May 7, 2013.