Testosterone replacement is reasonable for boys who have not entered puberty by age 14 years. It is also beneficial for most men with primary testicular failure (hypergonadotropic hypogonadism). Testosterone replacement or gonadal stimulation therapy is also warranted for men with severe hypogonadotropic hypogonadism of any etiology with serum testosterone levels less than 150 ng/mL (5.2 nmol/L). Testosterone therapy should also be considered for men with low or low-normal serum testosterone or free testosterone, along with elevated serum LH levels. For other men without elevated serum LH levels and an average of at least two morning serum total testosterone levels below 275 ng/dL (9.5 nmol/L, “physiologic hypogonadism”), a trial of testosterone therapy may be considered, particularly if they have at least three of the following six symptoms: erectile dysfunction, poor morning erection, low libido, depression, fatigue, and inability to perform vigorous activity. Testosterone replacement should be continued only if they clearly derive clinical benefit from therapy. Therapy can be adjusted with an aim to improve clinical symptoms while maintaining normal serum levels of testosterone or free testosterone. Men with physiologic low-normal serum testosterone levels above 325 ng/dL (11.3 nmol/L) are unlikely to benefit from testosterone therapy.
Testosterone replacement or stimulation therapy carries certain risks. Therefore, testosterone therapy should only be given to men who have a documented low serum total or free testosterone. Testosterone therapy should not be given to men with active breast cancer or prostate cancer. It is also prudent to monitor the hematocrit and lipid profile of men receiving testosterone, since therapy can cause erythrocytosis and hyperlipidemia. Testosterone therapy can also cause gynecomastia. Testosterone therapy is not given to men with untreated sleep apnea or heart failure.
Drug interactions can occur. Testosterone should be administered cautiously to men receiving coumadin, since the combination can increase the INR and risk of bleeding. Similarly, testosterone therapy can increase serum levels of cyclosporine, tacrolimus, and tolvaptan. Testosterone can predispose to hypoglycemia in diabetic men receiving insulin or oral hypoglycemic agents, so close monitoring of blood sugars is advisable during initiation of testosterone therapy.
Oral androgen therapy with methyltestosterone is not advisable due to the potential for causing liver tumors, peliosis hepatis, and cholestatic jaundice.
Men with severe osteoporosis may require treatment with bisphosphonates and vitamin D, in addition to testosterone replacement therapy. (See Osteoporosis.)
A. Therapies for Male Hypogonadism
Topical testosterone is usually applied once daily in the morning after showering. One or two fingers are used to apply the gel evenly to skin. Afterwards, the hands should be washed. Topical testosterone should not be applied to the breast or genitals. The gel should be allowed to air-dry (about 10 minutes) before dressing. Before close contact with women or children, a shirt must be worn or the areas of application washed with soap and water to prevent transfer of testosterone to them. The patient should avoid swimming, showering, or washing the application area for at least 2 hours following application.
Testosterone topical generic 1% gel is available in packets (12.5 mg/1.25 g, 25 mg/2.5 g, or 50 mg/5g) or tubes (50 mg/5 g). The recommended dose is 50–100 mg daily. Testosterone topical generic 2% gel is available in a gel pump (10 mg/0.5 g actuation). The recommended dose is 40–70 mg daily. Androgel 1% gel is available in 2.5-g packets (25 mg testosterone) and 5-g packets (50 mg testosterone) and in a pump that dispenses 12.5 mg testosterone per pump actuation: the recommended dose is 50–100 mg applied daily to the shoulders. Androgel 1.6% gel is available in a pump that dispenses 20.25 mg testosterone per pump actuation; the recommended dose is 40.5–81 mg daily. Testim 1% gel is available in 5-g tubes (50 mg testosterone); the recommended dose is 50–100 mg applied daily. Fortesta 2% gel is available in a pump that dispenses 10 mg testosterone per pump actuation; the recommended dose is 40–70 mg daily. Testogel is distributed in 5-g sachets (50 mg testosterone); this brand is not available in the United States. Testim, Fortesta, and Testogel may be applied to shoulders, upper arms, or abdomen. Axiron 2% solution is available in a pump that dispenses 30 mg per actuation; the recommended dose is 30–60 mg applied to each axilla daily. Vogelxo is a 1% testosterone gel that is available in packets or tubes (50 mg/5 g) or a gel pump (12.5 mg/1.25 g); it is applied to the shoulders in doses of 50–100 mg once daily.
The skin serves as a reservoir that slowly releases about 10% of the testosterone into the blood; serum testosterone levels reach a steady state in 1–3 days. The serum testosterone level should be determined about 14 days after starting therapy; if the level remains below normal or the clinical response is inadequate, the daily dose may be increased to 1.5 to 2 times the initial dose. Unfortunately, serum testosterone levels vary considerably during the day after topical testosterone gel application, such that a single serum testosterone level may not accurately reflect the average serum testosterone for that individual.
Testosterone transdermal systems (skin patches) are applied to nongenital skin. Androderm (2 or 4 mg/day) patches may be applied at bedtime in doses of 4–8 mg; it adheres tightly to the skin and may cause skin irritation.
The dose and injection intervals are adjusted according to the patient’s clinical response and serum testosterone levels drawn just before the next injection is due. A target serum testosterone level of 500 ng/dL (17.3 nmol/L) is suggested. Testosterone cypionate has been in use for decades; it is an intramuscular testosterone formulation that is available in solutions containing 200 mg/mL. Its main advantage is low cost. The usual dose is 200 mg every 2 weeks or 300 mg every 3 weeks. It is usually injected into the gluteus medius muscle in the upper lateral buttock, alternating sides. The injection technique must include sterile precautions and draw-back prior to injection to ensure against intravenous injection, which can result in pulmonary oil embolism.
Testosterone pellets (Testopel) are a very long-lasting depot testosterone formulation that is available as individual vials containing a single 75 mg implantable pellet in each vial. With sterile technique, the skin of the upper-outer buttock is anesthetized with lidocaine; using a trochar, the pellets are injected subcutaneously in doses of 150–450 mg every 3–6 months as an in-office procedure.
Testosterone undecanoate (Aveed, Nebido) is a long-lasting depot testosterone formulation. Its use is restricted to qualified health care facilities. It is usually injected into the gluteus medius muscle in the upper lateral buttock, alternating sides. Care must be taken to avoid intravascular injection by pulling back on the syringe plunger before injection; if any blood appears in the syringe, the needle is withdrawn and the syringe is discarded. Testosterone undecanoate (Aveed) is formulated as individual vials containing 750 mg/3 mL oily solution for intramuscular injection. The initial injection of 750 mg is followed by another 750 mg injection 4 weeks later and maintenance doses of 750 mg every 10 weeks. Testosterone undecanoate (Nebido) is formulated as individual vials containing 1000 mg/4 mL oily solution for intramuscular injection. The initial injection of 1000 mg is followed by another 1000 mg injection 6 weeks later and maintenance doses of 1000 mg every 12 weeks. A serum testosterone level is measured before the fourth dose; if the serum testosterone remains low, the dosing interval is shortened to every 10 weeks.
Caution: Testosterone undecanoate injections have caused serious pulmonary oil microembolism reactions that present with cough, dyspnea, tight throat, chest pain, and syncope. Anaphylaxis can also occur. Patients must be observed in the health care setting for 30 minutes after the injection in order to provide appropriate medical care for the complication.
Testosterone buccal tablets (Striant) are placed between the upper lip and gingivae. One or two 30-mg tablets are thus retained and changed every 12 hours. They should not be chewed or swallowed.
Intranasal gel testosterone (Natesto) is self-administered by a metered-dose nasal pump: one pump actuation (5.5 mg) into each nostril three times daily. The nasal pump needs to be primed by inverting it and pressing the pump 10 times before it is used the first time. It should not be used concurrently with intranasal sympathomimetic decongestants. Adverse effects include nasopharyngitis, sinusitis, bronchitis, epistaxis, nasal discomfort, and headache.
Oral testosterone supplementation is available as methyltestosterone 10-mg tablets. The usual dose is 10–50 mg daily, given either once daily or in divided doses. Oral methyltestosterone can produce acute hepatitis and chronic high-dose use can cause peliosis hepatis, cholestatic hepatitis, and hepatocellular carcinoma. Therefore, its use is not recommended, and it is no longer available in some countries.
Men with functional hypogonadotropic hypogonadism usually respond well to clomiphene citrate that is administered orally in doses that are titrated to achieve the desired clinical response with a serum testosterone level of about 500 ng/dL (17.3 nmol/L). Treatment with clomiphene is commenced with 25 mg on alternate days and increased to 50 mg on alternate days if necessary, with a maximum dose of 50 mg daily. Serum testosterone levels usually normalize while spermatogenesis usually improves.
Patients with hypogonadotropic hypogonadism may require therapy with gonadotropins, particularly to induce fertility. Men may receive hCG 1000 units subcutaneously three times weekly for 6 months; if the semen analysis shows inadequate sperm, FSH 75 units subcutaneously three times weekly is added. Many men prefer long-term therapy with hCG over testosterone therapy, but cost is an issue.
When hypogonadotropic hypogonadism is due to morbid obesity, significant weight loss will improve serum testosterone levels. The rise in serum testosterone is proportionate to the weight loss. Although diet-induced weight loss is beneficial, bariatric surgery has been much more effective and serum testosterone levels may normalize after dramatic weight loss.
B. Benefits of Testosterone Replacement Therapy
Testosterone therapy given for the indications listed under Treatment, above, usually benefits men with low serum testosterone and at least three manifestations of hypogonadism. Testosterone therapy can improve overall mood, sense of well-being, sexual desire, and erectile function. It also increases physical vigor and muscle strength. Testosterone replacement also improves exercise endurance and stair climbing ability. Long-term testosterone replacement causes significant weight loss and a reduction in waist circumference. After 2 years of testosterone replacement, muscle mass increases about 4.5%, while fat mass decreases by about 9.1%. Appropriate testosterone replacement therapy also appears to improve longevity.
C. Risks of Testosterone Replacement or Stimulation Therapy
Testosterone therapy does not appear to significantly increase the risk of prostate cancer or benign prostatic hypertrophy above that of normal men, as long as serum testosterone levels are maintained in the normal reference range on therapy. However, testosterone therapy is contraindicated in the presence of active prostate cancer. Hypogonadal men who have had a prostatectomy for low-grade prostate cancer, and who have remained in complete remission for several years, may have testosterone therapy given cautiously while monitoring serum PSA levels.
Erythrocytosis develops in some men who are treated with testosterone. Erythrocytosis is more common with intramuscular injections of testosterone enanthate than with transcutaneous testosterone. However, no increase in the incidence of thromboembolic events has been reported.
Testosterone therapy tends to aggravate sleep apnea in older men, likely through CNS effects. Surveillance for sleep apnea is recommended during testosterone therapy and a formal evaluation is recommended for all high-risk patients with snoring, obesity, partner’s report of apneic episodes, nocturnal awakening, unrefreshing sleep with daytime fatigue, or hypertension.
Men who are treated with testosterone frequently experience some increase in acne that is usually mild and tolerated; topical antiacne therapy or a reduction in testosterone replacement dosage may be required. Increases in intraocular pressure have occurred during testosterone therapy. During the initiation of testosterone replacement therapy, gynecomastia develops in some men, which usually is mild and tends to resolve spontaneously; switching from testosterone injections to testosterone transdermal gel may help this condition.
D. Risks of Performance-Enhancing Anabolic Steroids
Performance-enhancing agents, particularly androgenic anabolic steroids, are used by up to 2% of young athletes and by 20–65% of power sport athletes. They are often used as part of a “stacking” polypharmacy that may include nandrolone decanoate, dimethandrolone, testosterone propionate, or testosterone enanthate. These androgens are usually illegal, often contaminated by toxic substances (such as arsenic) and can produce toxic hepatitis, dependence, aggression, depression, dyslipidemias, gynecomastia, acne, male pattern baldness, hepatitis, thromboembolism, and cardiomyopathy. Arsenic contamination has been reported to cause multiorgan failure and death.