Apply AndroGel to upper arm, shoulder, or abdomen, but not the scrotum. Apply Testim only to upper arm or shoulder.
Apply Fortesta to the front and inner thigh.
Easier to use and better tolerated than testosterone patches. Can transfer to others via intimate contact.
Delayed Puberty
In some boys, puberty fails to occur at the usual age (i.e., before age 15 years). Most often, this failure reflects a familial pattern of delayed puberty and does not indicate pathology. Puberty can be expected to occur spontaneously, but later than usual. Hence, although androgen therapy can be employed, treatment is not an absolute necessity. However, the psychological pressures of delayed sexual maturation are sometimes greater than a boy can tolerate. In these cases, a limited course of androgen therapy is indicated. Both fluoxymesterone [Androxy] and methyltestosterone [Android, Methitest, Testred] are approved for this purpose.
If delayed puberty is the result of true hypogonadism, long-term replacement therapy is indicated (see later section “Androgen Preparations for Male Hypogonadism”).
Replacement Therapy in Menopausal Women
Testosterone replacement therapy can alleviate some menopausal symptoms, especially fatigue, reduced libido, and reduced genital sensitivity. Testosterone is not approved for replacement in women in the United States, although it is approved in the United Kingdom.
Treatment of Transsexualism
Testosterone is used as masculinizing therapy for patients who are born with a female body but self-identify as male. Anticipated effects are increased hair growth over the face and body, a deepening of the voice, breast tissue atrophy, and cessation of menses. An increase in muscle tissue relative to adipose tissue also occurs. Therapy is highly individualized by specialists in transgender health.
Cachexia
Cachexia is a wasting of the body associated with severe illnesses such as AIDS, severe trauma, and chronic systemic infections. Testosterone levels often decline in these patients, putting them at risk for wasting and loss of muscle mass. Testosterone therapy decreases this risk. Oxandrolone [Oxandrin] is FDA approved for this purpose. Oxandrolone is an anabolic steroid that is a synthetic derivative of testosterone.
Black Box Warning: Oxandrolone [Oxandrin]
Oxandrolone can cause peliosis hepatitis, a condition in which blood-filled cysts form in the liver leading to liver failure or intraabdominal hemorrhage. It can also contribute to the development of highly vascular liver tumors.
An increased risk for atherosclerosis can occur secondary to marked elevations in LDL and decreases in HDL.
Anemias
Androgens are sometimes used in men and women to treat anemias that have been refractory to other therapy. Anemias most likely to respond include aplastic anemia, anemia associated with renal failure, Fanconi anemia, and anemia caused by cancer chemotherapy. Androgens help relieve anemia by promoting synthesis of erythropoietin, the renal hormone that stimulates production of red blood cells and, possibly, white blood cells and platelets. With the emergence of other therapies such as erythropoietin stimulating agents, however, androgens have fallen out of failure for off-label treatment of anemia.
Adverse Effects
PATIENT-CENTERED CARE ACROSS THE LIFESPAN
Androgens
| Life Stage | Considerations or Concerns |
| Children | Androgens can cause virilization in children. They can also accelerate epiphyseal closure, thereby decreasing adult height. |
| Pregnant women | Androgens are Pregnancy Risk Category X: the ability to cause fetal harm outweighs any possible therapeutic benefit. Potential fetal changes include vaginal malformation, clitoral enlargement, and formation of a structure resembling the male scrotum. Virilization is most likely when androgens are taken during the first trimester. Women who become pregnant while using androgens should be informed about the possible effect on the fetus. |
| Breastfeeding women | Testosterone is excreted in breast milk. Breastfeeding is contraindicated. |
| Older adults | Older patients are at an increased risk for thromboembolic conditions such as myocardial infarction or stroke. Beers Criteria identify testosterone and methyltestosterone as potentially inappropriate for patients 65 years and older. |
Virilization in Women, Girls, and Boys
Virilization is the most common complication of androgen therapy. When taken in high doses by women, androgens can cause acne, deepening of the voice, proliferation of facial and body hair, male-pattern baldness, increased libido, clitoral enlargement, and menstrual irregularities. Clitoral growth, hair loss, and lowering of the voice may be irreversible. Masculinization can also occur in children. Boys may experience growth of pubic hair, penile enlargement, increased frequency of erections, and even priapism (persistent erection). In girls, growth of pubic hair and clitoral enlargement may occur. To prevent irreversible masculinization, androgens must be discontinued when virilizing effects first appear.
Premature Epiphyseal Closure
When given to children, androgens can accelerate epiphyseal closure, thereby decreasing adult height. To evaluate androgen effects on the epiphyses, radiographic examination of the hand and wrist should be performed every 6 months.
Hepatotoxicity
Androgens can cause cholestatic hepatitis and other disorders of the liver. Clinical jaundice may occur but is rare. Patients receiving androgens should undergo periodic tests of liver function. If jaundice develops, it will reverse after discontinuation of androgen use. Androgens may also be carcinogenic: hepatocellular carcinoma has developed in some patients after prolonged use of these drugs.
It must be emphasized that not all androgens are hepatotoxic: liver damage is associated primarily with the 17-alpha-alkylated androgens. These androgens all share a structural feature in common: an alkyl group substituted on carbon 17 of the steroid nucleus. Because of their capacity to cause liver damage, the 17-alpha-alkylated compounds should not be used long term. In contrast to the 17-alpha-alkylated androgens, testosterone and the testosterone esters (testosterone cypionate, testosterone enanthate) are not associated with liver disease.
Effects on Cholesterol Levels
Androgens can lower plasma levels of high-density lipoprotein (HDL) cholesterol (“good cholesterol”) and elevate plasma levels of low-density lipoprotein (LDL) cholesterol (“bad cholesterol”). These actions may increase the risk for atherosclerosis and related cardiovascular events.
Prostate Cancer
Androgens do not cause prostate cancer, but they can promote the growth of this cancer after it occurs. Accordingly, androgens are contraindicated for men with diagnosed prostate cancer. Men without diagnosed prostate cancer should be monitored for emergence of covert cancer.
Edema
Edema can result from androgen-induced retention of salt and water. This complication is a concern for patients with heart failure and for those with a predisposition to developing edema from other causes. Treatment consists of discontinuing the androgen and giving a diuretic, if needed.
Abuse Potential
As discussed later, androgens are frequently misused (abused) to enhance athletic performance. Because of their abuse potential, nearly all androgens are regulated as Schedule III controlled substances.
Risk for Thromboembolic Events
There have been post-marketing reports of thromboembolic events, including stroke, myocardial infarction, deep vein thrombosis, and pulmonary embolism. These events are believed to be the result of testosterone’s erythropoietic effects. While long-term clinical trials are not available and randomized control trials have been inconclusive, the concern was sufficient to prompt the U.S. Food and Drug Administration (FDA) to issue a Testosterone Product Safety Alert in 2014 to address this potential life-threatening concern. (See http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm384225.htm)
Androgen Preparations for Male Hypogonadism
Treatment options for androgen replacement therapy have expanded in recent years. In the past, intramuscular (IM) therapy with a long-acting testosterone ester was the major treatment mode. Today, we have six attractive alternatives: a nasal gel, transdermal patch, transdermal gel, topical solution, buccal tablet, and implantable subcutaneous pellets. All of these formulations are regulated as Schedule III controlled substances.
Oral Androgens
Only two androgens are approved for oral therapy of male hypogonadism. Both drugs—fluoxymesterone and methyltestosterone—are 17-alpha-alkylated androgens and therefore pose a risk for hepatotoxicity. Accordingly, they should not be used long term and hence are not first-line agents.
Transdermal Testosterone
Testosterone is available in three transdermal formulations: patch, gel, and liquid. With all three formulations, testosterone is absorbed through the skin and then slowly absorbed into the blood.
Patches
Testosterone patches [Androderm] are indicated for male hypogonadism. Two strengths are available, delivering 2 mg or 4 mg of testosterone in 24 hours. Patches are applied once daily to the upper arm, thigh, back, or abdomen. The principal adverse effect is rash at the site of application.
Gels
Black Box Warning: Testosterone Gel and Topical Solution
Secondary exposure to testosterone gel on uncovered skin and to testosterone gel on unwashed clothing has resulted in virilization in children.
Testosterone is available in four gel formulations, sold as AndroGel, Testim, Fortesta, and Vogelxo. AndroGel contains 1% or 1.62% testosterone; Testim contains 1% testosterone; and Fortesta contains 2% testosterone. Vogelxo is available in both unit-dose tubes and multidose metered pumps. Each unit-dose tube provides 50 mg testosterone. Each actuation of the pump provides 12.5 mg testosterone. All four gels are applied once daily to treat male hypogonadism. After the gel is applied, testosterone is absorbed rapidly into the skin and then slowly into the blood over the next 24 hours. Compared with transdermal patches, the gels have three advantages: they (1) cause less local irritation, (2) can’t fall off, and (3) produce more consistent testosterone levels.
The principal disadvantage of the gels is that testosterone can be transferred to others by skin-to-skin contact. This is possible because only 10% of an applied dose is absorbed; the other 90% remains on the skin after the gel dries. In one study, blood levels of testosterone were doubled in female partners of gel users after 15 minutes of intimate contact that occurred 2 to 12 hours after the gel had been applied. Testosterone transfer is a concern because the drug can cause virilization of female partners and can also cause fetal harm. In children, contact transfer can cause genital enlargement, premature development of pubic hair, advanced bone age, increased libido, and aggressive behavior. In most cases, these effects regress after testosterone exposure stops. To reduce the risk for unintended gel transfer, the following guidelines should be followed:
• Gel users should wash their hands with soap and warm water after every application.
• Gel users should cover the application site with clothing once the gel has dried.
• Gel users should wash the application site before skin-to-skin contact with another person.
• Women and children should avoid skin-to-skin contact with application sites on gel users.
• Women and children who make accidental contact with a gel application site should wash contaminated skin immediately.
AndroGel is supplied in a metered-dose pump that delivers 12.25 mg per actuation (1% ) or 20.25 mg per actuation (1.62%) and in unit-dose foil packets containing 20.25 mg of testosterone (of which 2.5 mg becomes absorbed) and 40.5 mg of testosterone (of which 5 mg becomes absorbed). The gel is applied once daily (preferably in the morning) to clean, dry skin of the shoulders, upper arms, or abdomen—but not the genitalia. Instruct patients to squeeze the entire contents of the packet into the palms and then immediately apply the gel to the skin and rub it in. To prevent the transfer of testosterone to others, patients should wash their hands and, after the gel has dried, keep the treated area covered with clothing. Because testosterone can be washed off, patients should wait 5 to 6 hours before showering or swimming. To ensure safe and effective dosing, blood levels of testosterone should be measured 14 days after initiating therapy and periodically thereafter.
Testim is available in 5-g tubes that contain 50 mg of testosterone, of which 10% (5 mg) gets absorbed. It is applied once daily to skin of the shoulders or upper arms, but not to the abdomen or scrotum. As with AndroGel, patients should wash their hands immediately and keep the treated area covered. They should also avoid showering for at least 2 hours. Testosterone levels should be checked after 14 days and periodically thereafter.
Fortesta is supplied in a metered-dose pump that delivers 10 mg of testosterone per actuation. All doses are applied to the front or inner thigh. As with AndroGel, patients should wash their hands immediately and keep the treated area covered. Also, they should avoid swimming or showering for at least 2 hours. Fortesta is a flammable, alcohol-based formulation, and hence patients should avoid flames or smoking until the gel has dried. Testosterone levels should be checked after days 14 and 35 and periodically thereafter.
Vogelxo in the tube formulation is applied in the same manner as Testim. Vogelxo in the metered-dose pump is applied just as Fortesta is applied. For both, the same advice and precautions apply.
Topical Solution
Testosterone topical solution for underarm application [Axiron] is much like the testosterone gels. The principal difference is the application site: Axiron liquid is formulated specifically for application to the axilla, whereas Testim is applied to the shoulder or upper arm, and AndroGel is applied to the shoulder, upper arm, or abdomen. After application, testosterone is absorbed rapidly into the skin and then slowly into the blood. Steady-state levels are reached in 14 days. After application stops, blood levels take 7 to 10 days to decline to baseline.
Axiron is supplied as an alcohol-based solution in a metered-dose pump that delivers 30 mg of testosterone per actuation. Dosing is done by pumping the liquid onto an applicator (supplied with the pump) and then applying the liquid to clean, dry, intact skin of the underarm—and not to anyplace else. Patients should not swim or bathe for 2 hours after application. If an underarm deodorant or antiperspirant is used, it should be applied before applying testosterone (to avoid contaminating the deodorant or antiperspirant dispenser). Because of its alcohol content, Axiron liquid is flammable. Accordingly, users should stay away from flames until the solution has dried.
Axiron is applied to each axilla at the same time every morning. After 14 days or longer, blood levels of testosterone are measured, and dosage is adjusted up or down as indicated.
Like the testosterone gels, testosterone topical solution can be transferred to others through skin-to-skin contact, posing a risk to women and children. Accordingly, the same guidelines noted previously should be followed. That is, Axiron users should wash their hands after every application, cover the application site with clothing after the solution has dried, and wash the application site before anticipated skin-to-skin contact with another person. Women and children should avoid contact with skin where Axiron was applied and should wash contaminated skin if accidental contact with an application site occurs.
Nasal Gel
Testosterone nasal gel [Natesto] is the newest formulation approved for testosterone administration. It comes in a metered-dose pump that sprays 5.5 mg of testosterone each time the pump is actuated.
Because the drug is administered nasally, patients with nasal disorders or abnormalities (e.g., chronic sinusitis, a severely deviated nasal septum) should not take this drug. There has not been adequate testing for interactions with other nasally administered drugs. Currently, only adrenergic agonists (e.g., oxymetazoline nasal spray) are approved for administration with Natesto.
The route of administration can cause localized reactions. These include rhinorrhea, epistaxis, and nasopharyngitis; however, these tend to be modest effects.
Administration instructions are supplied with the drug; however, it is important that the provider be aware of these in order to answer patient questions.
1. The pump should be primed before use and excess gel removed.
2. The patient should blow the nose before administration.
3. The pump is inserted into the nostril with the tip aimed toward the lateral nostril wall.
4. The pump is depressed slowly until it stops.
5. As the tip is withdrawn, it should be wiped against the lateral nostril wall to ensure that any remaining gel is distributed to the nostril.
6. After administration in both nostrils, the nose should be lightly massaged below the nasal bridge.
7. The patient should avoiding blowing or sniffing for at least 1 hour after administration.
Implantable Testosterone Pellets
Testosterone pellets [Testopel] are long-acting formulations indicated for male hypogonadism and delayed puberty. The pellets are implanted subdermally in the hip area or abdominal wall lateral to the umbilicus. Each pellet contains 75 mg of testosterone. The usual dosage is 150 to 450 mg (2–6 pellets) every 3 to 6 months. About one third of the dose is absorbed the first month, one fourth the second month, and one sixth the third month. For patients switching from IM testosterone propionate or IM testosterone enanthate, the recommended dosage is 2 pellets for each 25 mg of IM testosterone used weekly. For example, a patient receiving 75 mg of IM testosterone enanthate each week would switch to 6 pellets every 3 to 4 months.
Testosterone Buccal Tablets
Testosterone buccal tablets [Striant], approved for male hypogonadism, produce steady blood levels of testosterone. Tablets are applied to the gum area just above the incisor tooth, and are designed to stay in place until removed. To ensure good adhesion, tablets should be held in place (with a finger over the lip) for 30 seconds. The recommended dosage is 1 tablet every 12 hours, alternating sides of the mouth with each dose. If a tablet falls out before 8 hours, it should be replaced with a new one for the remainder of the dosing interval. If a tablet falls out after 8 hours, it should be replaced with a new one, and the next scheduled dose should be skipped (i.e., the replacement tablet should remain in place for 16 hours or so). The tablets are not affected by eating, drinking, chewing gum, or brushing teeth. Adverse effects, which are usually transient, include local irritation, bitter taste, and taste distortion. Treatment for up to 1 year has not caused serious gum changes. It has been hypothesized that transfer of testosterone from buccal routes may occur through saliva transfer during kissing.
Intramuscular Testosterone Esters
Two IM testosterone esters are available: testosterone cypionate [Depo-Testosterone] and testosterone enanthate [Delatestryl]. Both drugs are formulated in oil, and both are long acting. After IM injection, these drugs are slowly absorbed and then hydrolyzed to release free testosterone. Unfortunately, these preparations produce testosterone blood levels that vary widely: testosterone levels are higher than normal immediately after dosing and decline to lower than normal before the next dose. As a result, patients may experience significant variations in libido, energy, and mood.
Androgen (Anabolic Steroid) Abuse by Athletes
Many athletes take androgens (anabolic steroids) and androgen precursors to enhance athletic performance. The potential benefits of this practice, although substantial, are accompanied by significant risks. Drugs commonly used by athletes include nandrolone, stanozolol, and methenolone. All of these drugs are regulated as controlled substances, making their use without a prescription illegal.
Who takes steroids? Steroid use is especially prevalent among baseball players, football players, weight lifters, discus throwers, shot-putters, and bodybuilders. These drugs are also used by sprinters and athletes in endurance sports (e.g., cycling, Nordic skiing). Steroids are used by athletes of all ages. This includes professionals as well as athletes in college, high school, and junior high. Use is not limited to males: some females also take them, despite masculinizing effects.
What can anabolic steroids do for the athlete? Exogenous androgens can significantly increase muscle mass and strength in males and females of all ages when given in sufficiently large doses. After 10 weeks, one study showed that testosterone treatment produced a 7-pound increase in muscle mass in subjects who did not exercise and a 13-pound increase in subjects who exercised and took the drug. In contrast, exercise in the absence of exogenous testosterone produced only a 4-pound increase in muscle mass. Similar increases were shown in the subjects’ ability to bench-press weights. However, the potential for adverse effects of androgens is substantial. Salt and water retention can lead to hypertension. When administered in the high doses used by athletes, androgens suppress release of LH and FSH, resulting in testicular shrinkage, sterility, and gynecomastia. Acne is common. Reduction of HDL cholesterol and elevation of LDL cholesterol may theoretically accelerate development of atherosclerosis. Because most of the androgens that athletes take are 17-alpha-alkylated compounds, hepatotoxicity (cholestatic hepatitis, jaundice, hepatocellular carcinoma) is an ever-present risk. Most recently, androgens have been linked with kidney damage. In females, androgens can cause menstrual irregularities and virilization (growth of facial hair, deepening of the voice, decreased breast size, uterine atrophy, clitoral enlargement, and male-pattern baldness); baldness, growth of facial hair, and voice change may be irreversible. In boys and girls, androgens promote premature epiphyseal closure, reducing attainable adult height. In boys, androgens can induce premature puberty.
What about psychological effects? Androgens are reputed to cause depression, manic episodes, and aggressiveness. There have been very few controlled studies to measure psychological effects of androgens; however, in the controlled studies undertaken, dosages of androgens were less than those typically taken by athletes. Surveys of athletes who engage in anabolic steroid use indicate an association with risky behavior and aggression; however, it is possible that these were inherent traits of the surveyed athletes regardless of steroid use.
Long-term androgen use can lead to an abuse syndrome. Characteristics include preoccupation with androgen use and difficulty in stopping use. When androgens finally are discontinued, an abstinence syndrome can develop similar to that produced by withdrawal of alcohol, opioids, and cocaine.
Because of their abuse potential, anabolic steroids are classified as Schedule III substances under an amendment to the Controlled Substances Act. (Schedule III drugs are defined as those with a low to moderate potential for dependence.) For more information on drug abuse in sports, a good place to start is www.wada-ama.org, the website of the World Anti-Doping Agency. This organization is dedicated to promoting, coordinating, and monitoring the fight against use of anabolic steroids and other banned substances in sports. Other good resources include the United States Anti-Doping Agency (http://www.usada.org) and the National Center for Drug-Free Sport (http://www.drugfreesport.com/index.asp).
Prescribing and Monitoring Considerations
Preadministration Assessment
Therapeutic Goals
Males
Treatment of hypogonadism is the only FDA approved use of androgens.
Identifying High-Risk Patients
Androgens are contraindicated for pregnant women, for men who have prostate cancer or breast cancer, and for enhancing athletic performance.
Administration Considerations
Advise patients to take oral androgens with food if gastrointestinal (GI) upset occurs.
Transdermal Gel and Solution
Advise patients to wash their hands after applying the gel and to cover the site of application with clothing (to prevent transferring testosterone to others). Instruct patients not to shower or swim for several hours (to avoid washing the drug off). Warn users of the topical solution to avoid being near flames until the liquid has evaporated.
Buccal
Instruct patients to apply buccal tablets to the gum just above the upper incisor tooth and to apply pressure (using a finger on the lip) to ensure good adhesion.
Implantable Pellets
Pellets are implanted subdermally (under local anesthesia) in the hip region or in the abdominal wall lateral to the umbilicus.
Nasal
Instruct patients to blow the nose before using, apply to the lateral nostril wall of both nares, massage the nose after administration, and avoid sniffing or blowing for at least 1 hour after administration.
Ongoing Monitoring and Interventions
Minimizing Adverse Effects
Virilization
Virilization may occur in women, girls, and boys. Assess for deepening voice, chest and facial hair, acne and menstrual irregularities at each clinical encounter. Irreversible changes may be avoided if androgens are withdrawn early.
Premature Epiphyseal Closure
Accelerated bone maturation in children can decrease attainable adult height. Monitor effects on epiphyses with radiographs of the hand and wrist twice yearly.
Hepatotoxicity
The 17-alpha-alkylated androgens can cause cholestatic hepatitis, jaundice, and other liver disorders. Rarely, liver cancer develops. Monitor for signs and symptoms of liver dysfunction such as jaundice, fatigue, and malaise. Obtain periodic tests of liver function. Liver function normalizes after cessation of drug use. Avoid long-term use of 17-alpha-alkylated preparations.
Edema
Salt and water retention may result in edema. Assess for edema and weight gain at each clinical encounter. Treatment consists of androgen withdrawal and, if necessary, use of a diuretic.
Teratogenesis
Androgens can cause masculinization of the female fetus. Rule out pregnancy before androgen use. Ensure that female patients of child-bearing age are using adequate contraception and engaging in consistent use.
Prostate Cancer
Avoid androgens in men with diagnosed prostate cancer. In men without diagnosed prostate cancer, monitor for exacerbation of preexisting but covert prostate cancer.
Injury From Skin-to-Skin Transfer of Topical Testosterone
Topical testosterone—applied as a gel or topical solution—can transfer to others through skin-to-skin contact. It has been hypothesized that transfer of testosterone from buccal routes may occur through saliva transfer during kissing. Transfer of testosterone to women can cause masculinization, as well as fetal harm if the woman is pregnant. Transfer to children can cause genital enlargement (penis or clitoris), premature development of pubic hair, advanced bone age, increased libido, and aggressive behavior.
