ATC Class:G03BA03
VA Class:HS100
REMS: FDA approved a REMS for testosterone to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of testosterone and consists of the following: medication guide or elements to assure safe use and implementation system. See the FDA REMS page ([Web]). |
Testosterone, the principal endogenous androgen, is a naturally occurring androgenic anabolic steroid hormone.
Testosterone is used for replacement or substitution of diminished or absent endogenous testicular hormone caused by certain medical conditions.133, 175
Diagnosis of hypogonadism must be confirmed by laboratory testing prior to initiation of testosterone therapy.133, 175 (See Dosage and Administration.)
The safety and efficacy of testosterone replacement therapy in men with low testosterone concentrations related to aging have not been established.133, 175 (See Late-onset Hypogonadism under Uses: Uses in Males.)
In males, testosterone is used for the management of congenital or acquired primary hypogonadism such as that resulting from orchiectomy or from testicular failure caused by cryptorchidism, bilateral torsion, orchitis, or vanishing testis syndrome. Testosterone also is used in males for the management of congenital or acquired hypogonadotropic hypogonadism such as that resulting from idiopathic gonadotropin or gonadotropin-releasing hormone (luteinizing hormone releasing hormone) deficiency or from pituitary-hypothalamic injury caused by tumors, trauma, or radiation. If any of these conditions occur before puberty, androgen replacement therapy will be necessary during adolescence for the development of secondary sexual characteristics and prolonged therapy will be required to maintain these characteristics. Prolonged androgen therapy also is required to maintain sexual characteristics in other males who develop testosterone deficiency after puberty.
Hypogonadism in males may manifest with signs and symptoms of testosterone deficiency and/or infertility, with manifestations depending principally on the age of the patient at the time of development.123 Hypogonadism seldom is recognized before the age of puberty unless it is associated with growth retardation or other anatomic and/or endocrine abnormalities.123 When hypogonadism develops before puberty onset, manifestations include small testes, phallus, and prostate; minimal pubic and axillary hair; disproportionately long arms and legs (secondary to delayed epiphyseal closure); reduced male musculature; gynecomastia; and a persistently high-pitched voice.123 Postpubertal loss of testicular function results in slowly evolving subtle clinical manifestations, which may be difficult to appreciate in aging men because they often are attributed to growing old.123, 130, 131 Growth of body hair usually slows, while the voice and size of the phallus and prostate remain unchanged.123 Patients with postpubertal hypogonadism may manifest a progressive decrease in muscle mass, libido loss, impotence, oligospermia or azoospermia, and/or occasionally menopause-type hot flushes (with acute onset of hypogonadism).123, 130, 131 Hypogonadism also is associated with a risk of osteoporosis and resultant fractures.122, 123, 130, 131 Many cases of postpubertal hypogonadism are initially detected during fertility evaluations.123
Hypogonadism Associated with HIV Infection
Hypogonadism occurs commonly in human immunodeficiency virus (HIV)-infected men, particularly as their disease progresses to acquired immunodeficiency syndrome (AIDS).123, 124, 125, 126, 128, 129, 141 Hypogonadism has been reported in up to 50% of HIV-infected men, being most likely in those with AIDS; however, the incidence may now be lower as a result of highly active antiretroviral therapy (HAART) and resultant improved overall health in HIV-infected patients.128, 129 Such patients generally exhibit low serum testosterone concentrations and usually low (indicating hypothalamic-pituitary involvement) or occasionally high (indicating testicular involvement) gonadotropin concentrations.123, 141 In addition to typical manifestations of hypogonadism (e.g., impaired sexual mood and functioning, loss of body hair, gynecomastia, bone loss, impaired sense of well-being), hypogonadal HIV-infected men may exhibit a disproportionate loss of lean body mass and muscle wasting.124, 125, 126 128, 129, 132, 141 The etiology of hypotestosteronism in HIV-infected men likely is multifactorial and may show interindividual variation and may include primary testicular problems, changes in the hypothalamic-pituitary-gonadal axis, and/or changes caused by chronic illness, poor nutrition, or medications; approximately 25% of hypogonadism cases in HIV-infected men are primary.124, 125, 126, 128 Testosterone replacement therapy is considered the androgen of choice for the treatment of androgen deficiency (e.g., hypogonadism) and AIDS wasting in HIV-infected men.126
The safety and efficacy of testosterone replacement therapy for men with late-onset hypogonadism (i.e., low testosterone concentrations related to aging) have not been established.133, 175 Although endogenous testosterone concentrations decline with aging and manifestations of hypogonadism such as decreased libido, impotence, decreased body hair growth, decreased muscle mass, increased risk of cardiovascular disease, and decreased bone mass and resultant osteoporosis may occur,123, 130, 131, 175 it is unclear whether these symptoms are related to such decreased concentrations or to normal aging; therefore, the need to replace testosterone in aging men is unclear.175
There currently is a paucity of information from well-designed studies on the use of testosterone in middle-aged or older men who do not meet the clinical diagnostic criteria for established hypogonadism but who may have testosterone levels in the low range for young adults and/or who show one or more manifestations common to both aging and hypogonadism.156 In addition, studies that have been conducted generally have been of short duration, involved small numbers of patients, and often lacked adequate controls.156 Therefore, assessments of risks and benefits have been limited to date, and uncertainties remain about the value of testosterone therapy in older men without a clinical diagnosis of hypogonadism.156 In most studies to date, it appears that older men were given testosterone dosages that increased testosterone levels to the normal physiologic range for young adult males.156 Because of the potential risks of testosterone therapy and the availability of other safe and effective intervention options for some of the diseases and conditions it is intended to prevent or treat (e.g., bisphosphonates for osteoporosis), testosterone should be considered a therapeutic rather than a preventative measure in aging men.156 Although endogenous testosterone levels clearly decline with aging, it currently is unclear whether such decreased levels affect health outcomes in older men.156 Much remains unknown about how physiologic pathways are affected by changes in endogenous testosterone concentrations or by the administration of exogenous testosterone in aging men.156
Current limited evidence suggests that testosterone therapy in aging men may produce beneficial effects on body composition, strength, bone density, frailty, cognitive function, mood, sexual function, and quality of life.156, 184 However, additional evidence from well-designed studies is needed to further elucidate the role of testosterone therapy in men with low testosterone concentrations related to aging.176
Testosterone Replacement Therapy for Hypogonadism
Men with symptomatic hypogonadism and clearly low testosterone concentrations (free or total, considering SHBG) are potential candidates for testosterone replacement therapy; however, the potential prostatic risk must be considered.123, 130, 131 Serum total (bound and free) testosterone concentrations less than 300 ng/dL generally are considered indicative of hypogonadism in men,123, 130 and the biochemical goal of hormone replacement therapy with testosterone generally is to increase serum total testosterone concentrations to within the normal physiologic range of 300-1200 ng/mL.123 The principal goals of testosterone replacement are to restore sexual function, libido, well-being, and behavior; to stimulate and maintain virilization (e.g., secondary sex characteristics such as muscle mass, body hair, phallus growth); to optimize bone density and prevent osteoporosis; to possibly normalize somatotropin (growth hormone) concentrations in geriatric men; to potentially improve cardiovascular risk; and to restore fertility in cases of hypogonadotropic hypogonadism.123 In HIV-infected men, additional goals include improvement in mood (e.g., depression), energy level (fatigue), quality of life, and lean body mass (wasting syndrome);124, 125, 126, 128, 132 however, clinical response to testosterone therapy in HIV-infected men is not necessarily correlated to baseline serum testosterone concentrations, and eugonadal HIV-infected men may benefit from such therapy.129, 132
When the diagnosis is well established, testosterone may be used to stimulate puberty in carefully selected males with delayed puberty. These males usually have a family history of delayed puberty that is not caused by a pathologic disorder. Brief treatment with conservative doses of an androgen may occasionally be justified in these males if they do not respond to psychologic support. Because androgens may adversely affect bone maturation in these prepubertal males, this potential risk should be fully discussed with the patient and his parents prior to initiation of androgen therapy. (See Cautions: Pediatric Precautions.) If androgen therapy is initiated in these prepubertal males, radiographs of the hand and wrist should be obtained at 6-month intervals to determine the effect of therapy on the epiphyseal centers. Testosterone is designated an orphan drug by the FDA for use in this condition.
Corticosteroid-induced Hypogonadism and Osteoporosis
Patients receiving long-term corticosteroid therapy may develop hypogonadism secondary to inhibition of secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary as well as secondary to direct effects on the testes and ovaries, and such hypogonadism may be associated with bone loss.122 Therefore, all patients receiving prolonged corticosteroid therapy should be assessed for possible hypogonadism, which should be corrected if present.122 Unlike experience with hormone replacement therapy (HRT, combined estrogen and progestin therapy) in postmenopausal women receiving chronic prednisone therapy, there currently is only limited information on the effect of androgen (e.g., testosterone) replacement therapy in men with hypogonadism secondary to long-term corticosteroid therapy.122 In a small study in men with corticosteroid-treated asthma and low serum testosterone concentrations, lumbar spine bone mass density (BMD) was increased nearly 4% after 12 months of monthly testosterone injections; lean body mass also was increased and fat mass was reduced.122 Therefore, men who develop low serum testosterone concentrations while receiving long-term corticosteroid therapy should be offered testosterone replacement therapy in an attempt to treat hypogonadism and possibly reduce the risk of corticosteroid-induced osteoporosis† when contraindications to androgen therapy are not present.122 Some experts (e.g., the American College of Rheumatology) recommend that such men with serum testosterone concentrations below the physiologic range (i.e., less than 300 ng/mL) receive replacement therapy.122 The goal of testosterone replacement therapy in men receiving long-term corticosteroid therapy is to provide serum testosterone concentrations within the therapeutic range.122 It is important that the possibility of prostate cancer be ruled out in any man being considered for such replacement therapy.122 For additional information on the management of corticosteroid-induced osteoporosis, see Cautions: Musculoskeletal Effects in the Corticosteroids General Statement 68:04.
Although testosterone replacement therapy may restore sexual function in hypogonadal men (see Uses in Males: Hypogonadism, in Uses), 123, 159, 160 the American Urological Association (AUA) states that the drug is not indicated for the treatment of erectile dysfunction in men with normal serum testosterone concentrations†.158 Outcome measures in studies to date are inadequate to evaluate testosterone's efficacy in eugonadal men.158 In men with borderline testosterone concentrations, a clinical trial of replacement therapy may be warranted in the management of erectile dysfunction;159 however, the risks of hormone replacement must be weighed carefully.159
Inoperable Carcinoma of the Breast
In females, testosterone has been used for the palliative treatment of androgen-responsive, advanced, inoperable, metastatic (skeletal) carcinoma of the breast in women who are 1-5 years postmenopausal. Primary goals of therapy in these women include ablation of the ovaries. Other methods of counteracting estrogen activity include adrenalectomy, hypophysectomy, and/or antiestrogen therapy (e.g., tamoxifen). Androgen therapy also has been used in premenopausal women with carcinoma of the breast who have benefited from oophorectomy and are considered to have a hormone-responsive tumor. The decision to use androgen therapy in women with carcinoma of the breast should be made by an oncologist with expertise in the treatment of this carcinoma.
Postpartum Breast Pain and Engorgement
Testosterone formerly was used for the prevention of postpartum breast pain and engorgement†; however, the drug does not appear to prevent or suppress lactation. Testosterone esters also have been used in combination with estrogens for the prevention of postpartum breast pain and engorgement; however, the FDA has withdrawn approval of estrogen-containing drugs for this indication. Data from controlled studies indicate that the incidence of substantial painful engorgement is low in untreated women, and the condition usually responds to analgesic or other supportive therapy.
In females, testosterone esters also are used in combination with estrogens for the management of moderate to severe vasomotor symptoms† associated with menopause in patients who do not respond adequately to estrogens alone. While estrogen/androgen combinations were found to be effective for the management of vasomotor symptoms associated with menopause under a determination made by the FDA in 1976, formal administrative proceedings were initiated by the FDA in April 2003 to examine the effectiveness of estrogen/androgen combinations for this indication.154, 155 FDA is undertaking this action because the agency does not believe there is substantial evidence available to establish the contribution of androgens to the effectiveness of estrogen/androgen combinations for the management of vasomotor symptoms in menopausal women who do not respond to estrogens alone.154, 155 The FDA will allow continued marketing of combination estrogen/androgen products while the matter is under study.155
Because of their anabolic and androgenic effects on performance (ergogenic potential) and physique, androgens have been misused and abused by athletes, bodybuilders, weight lifters, and others, including high school- and college-aged individuals engaged in sports.100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 114, 115, 116, 120, 194 The drugs also have been misused and abused for cosmetic purposes by noncompetitors attempting to achieve bodies with lean muscle mass.114 Although historically the drugs have been regarded as ineffective for anabolic and androgenic uses in athletes, limited evidence suggests that androgens may increase skeletal muscle mass and strength when used in conjunction with proper (e.g., high-protein, high calorie) diet and training but that their use is not associated with increased power or capacity for aerobic work.114, 115, 116, 120 There continues to be a lack of evidence of long-term beneficial effects, and the drugs have been associated with substantial adverse health effects and toxicity.114, 115, 116, 118, 194 When used to improve athletic performance and physique, dosages employed often substantially (e.g., 10- to 1000-fold) exceed usual therapeutic dosages of the drugs.100, 101, 104, 105, 107, 108, 109, 112, 114, 135 In addition, several androgens often are taken concomitantly (“stacking”) for extended periods.100, 101, 103, 104, 105, 107, 108, 110, 114, 115 The extent of misuse and abuse of androgens has not been fully determined,101, 103, 114 but nonmedical use is believed to be widespread.114, 118 Estimates for the rate of misuse and abuse by weight lifters and body builders have ranged up to 50-80%.110, 114 However, in terms of actual numbers, it has been suggested that most misuse and abuse of androgens are by individuals who never compete in sports.114, 118 Evidence from one study indicates that about 7% of male high school seniors use or have used the drugs.103, 104, 114 Although the likelihood of use was increased in males intending to participate in school-sponsored sports (particularly football and wrestling),103, 104, 108, 114 35% of users had no intention of participating in school-sponsored sports.103 About 40% of these high school students admitted initiating use of the drugs at 15 years of age or younger.103, 104 In studies of college students, androgen use among athletes ranged up to about 20%.104
Following review of data from published literature and case reports in October 2016, the FDA concluded that misuse and abuse of androgens are associated with serious adverse effects.194 Serious adverse effects including increased aggression, hostility, and antisocial behavior (“roid rage”);100, 101, 102, 104, 107, 108, 109, 116, 135 psychotic manifestations and affective disorders (e.g., manic episode, depression, paranoia, psychosis, delusions, hallucinations);102, 104, 105, 106, 107, 108, 112, 114, 135 changes in libido;101, 102, 107, 109, 116 cardiovascular events (e.g., cardiac arrest, myocardial infarction [MI], hypertrophic cardiomyopathy, congestive heart failure [CHF], cerebrovascular accident);100, 101, 102, 104, 107, 108, 111, 112, 114, 116, 119, 135 and hepatotoxicity (e.g., abnormal liver function test results, liver tumors [hepatic adenomas, hepatocellular carcinoma], peliosis hepatis, jaundice)100, 101, 102, 104, 107, 108, 109, 110, 112, 114, 116, 135 have been reported in individuals who misuse and abuse androgens.135 Other potential adverse effects of androgens in adolescents or younger children include premature bone maturation and epiphyseal closure100, 101, 102, 103, 104, 108, 110, 114, 116, 135 with resultant irreversible short stature,100, 101, 104, 114, 116, 135 precocious puberty,135 possible increased risk of ruptured tendons and ligaments and of tendinitis,104, 112 and acne.100, 101, 102, 104, 105, 107, 108, 112, 116 Other potential adverse effects of androgens in males include transient ischemic attacks,135 convulsions,193 hypomania,135 irritability,135 dyslipidemias,135 gynecomastia,100, 101, 104, 105, 108, 110, 112, 114, 116, 193 hair loss,105, 110, 114, 116 testicular atrophy and sperm abnormalities (oligospermia, decreased motility, abnormal morphology, azoospermia),100, 101, 102, 103, 104, 105, 107, 110, 112, 114, 116, 135, 193 impotence,100 subfertility,135 infertility,135 and prostatic enlargement100, 104, 114 with resultant difficulty in urinating.105, 114 Other potential adverse effects in females include clitoral enlargement (which may be irreversible),100, 101, 102, 104, 107, 112, 114, 116, 135, 193 menstrual irregularities,101, 102, 104, 107, 108, 112, 114, 116, 135, 193 hirsutism,100, 101, 102, 104, 107, 108, 112, 135 androgenetic alopecia,100, 101, 107, 108, 112, 114, 135 deepened voice,100, 101, 102, 104, 105, 107, 108, 112, 114, 135 breast atrophy,100, 101, 102, 104, 107, 108, 112, 135 and virilization.135 Manifestations of withdrawal (e.g., depressed mood, major depression, fatigue, cravings, restlessness, irritability, anorexia, insomnia, decreased libido, hypogonadotropic hypogonadism) may occur if androgens, such as testosterone, are discontinued abruptly or the dosage is substantially reduced in patients who are physically dependent or receiving supratherapeutic doses of the drug; withdrawal symptoms may persist for weeks or months.135
Serum testosterone concentrations should be evaluated in patients who may be misusing or abusing androgens (e.g., patients experiencing serious adverse cardiovascular or psychiatric effects); however, serum testosterone concentrations may be below or within the normal range in patients abusing synthetic derivatives of testosterone.133, 135, 136, 157, 161, 162, 186, 187, 188, 189, 190, 192, 194 Because of the potential for serious adverse effects associated with misuse and abuse of androgens, preventive measures have been initiated, including educational programs,100, 101, 102, 103, 108, 109, 114, 120 interdiction of black market supplies,100, 101, 104, 114 drug screening of athletes with associated penalties for use,101, 104, 107, 108, 110, 112, 114 and other control measures.100, 101, 104, 107, 109, 113, 114 The prescription, dispensing, distribution, and use of most androgens currently are restricted as controlled substances.104, 108, 113, 115, 164, 165 In addition, medical and sports experts, including the American College of Sports Medicine, American Medical Association, American Academy of Pediatrics, American College Health Association, National Strength and Conditioning Association, National Collegiate Athletic Association, National Football League, US Olympic Committee, and the International Olympic Committee, consider the use of androgens to enhance athletic performance or physique inappropriate and unacceptable because of known adverse effects, lack of data regarding long-term gains in size and strength, and potential long-term adverse sequelae and because their use by athletes is contrary to the rules and ethical principles of athletic competition.101, 102, 107, 114, 115, 116
Diagnosis of hypogonadism must be confirmed by laboratory testing prior to initiation of testosterone therapy.133, 175 To confirm this diagnosis, serum testosterone concentrations should be measured in the morning on at least 2 separate days and must be consistently below the normal range.133, 175 Serum testosterone concentrations may be low later in the day in men with or without hypogonadism; therefore, measuring testosterone concentrations later in the day should be avoided.175
Testosterone is administered by IM injection; percutaneously by topical application of a transdermal system, solution, or gel to the skin; intranasally; subcutaneously as a biodegradable implant; and intrabuccally (transmucosally) as a buccal tablet.117, 133, 135, 136, 157, 161, 162, 186, 187, 188, 189, 190
Testosterone cypionate (Depo®-testosterone), testosterone enanthate (Delatestryl®), and testosterone undecanoate (Aveed®) are administered by deep IM injection into the gluteal muscle; the usual precautions for IM administration should be followed.117, 162, 189
Because of the risk of serious pulmonary oil microembolism reactions and anaphylaxis following IM administration of testosterone undecanoate, patients should be observed for 30 minutes in a healthcare setting following each IM injection of the drug.189
Restricted Distribution Program
Because of the potential for serious pulmonary oil microembolism reactions and anaphylaxis in patients receiving IM testosterone undecanoate (Aveed®) (see Cautions: Sensitivity Reactions and also Other Adverse Effects), testosterone undecanoate must be obtained through a restricted distribution program, the Aveed® Risk Evaluation and Mitigation Strategy (REMS) Program, designed to minimize the risk of pulmonary oil microembolism reactions and anaphylaxis.189 Clinicians and institutions that prescribe and/or dispense testosterone undecanoate must enroll in and comply with all requirements of the Aveed® REMS Program.189 Institutions are required to have appropriate equipment for the treatment of serious pulmonary oil microembolism and anaphylactic reactions for immediate use in patients receiving the drug.189 For additional information or to enroll in the Aveed® REMS program, clinicians may contact 855-755-0494 or visit www.AveedREMS.com.189
Testosterone pellets are administered as a biodegradable implant subcutaneously into the hip or other fatty area by a clinician; the usual precautions for subcutaneous implantation should be followed.136, 191
Patients receiving transdermal testosterone therapy (Androderm®) should be carefully instructed in the proper use and disposal of the transdermal system.133 To obtain optimum results, patients should be given a copy of the patient instructions provided by the manufacturer.133 To expose the adhesive surface of the system, the protective liner should be peeled and discarded prior to administration.133
The transdermal system should then be applied topically to a clean, dry area of skin on the back, abdomen, upper arm, or thigh by firmly pressing the system with the adhesive side touching the skin; the system should not be applied to the scrotum.133 The system should be applied immediately after removal from its protective pouch and removal of the protective liner.133 The system should be pressed firmly in place, ensuring good contact, particularly around the edges.133 The application site should not be oily, damaged, or irritated.133 Application of transdermal systems over bony prominences or on a part of the body that may be subject to prolonged pressure during sleep or sitting (e.g., the deltoid region of the upper arm, the greater trochanter of the femur, the ischial tuberosity) should be avoided, because burn-like blisters may occur.133 If the transdermal system becomes loose, the system should be smoothed down by firmly rubbing around the edges.133 If the system should inadvertently come off before noon following application the previous evening, a new system may be applied until the next scheduled application that evening.133 If the transdermal system comes off later in the day, the system should not be replaced until the next scheduled application that evening.133 If a system comes off, it should not be reapplied with tape.133
To minimize and/or prevent potential skin irritation, each testosterone transdermal system should be applied at a different site, with an interval of at least 1 week allowed between applications to a particular site.133 Mild skin irritation may be ameliorated by application of over-the-counter topical hydrocortisone cream after system removal; alternatively, a small amount of triamcinolone acetonide cream 0.1% may be applied to the skin under the drug reservoir to minimize irritation (ointment formulations should not be used because they may reduce testosterone absorption).133, 143
Testosterone transdermal systems are applied once daily;133 to produce serum testosterone concentrations that mimic endogenous profiles, the system should be applied at night (e.g., 10 p.m.).133 The system should be left in place for approximately 24 hours; after this period, the system should be removed and discarded and a new system applied.133
The transdermal system does not need to be removed during sexual intercourse nor while showering or bathing; however, patients should avoid swimming, showering, or washing the administration site for at least 3 hours following application.133
Patients receiving testosterone topical gel (AndroGel®, Fortesta®, Testim®, Vogelxo®) or solution (Axiron®) should be instructed on use of the gel or solution and given a copy of the patient instructions provided by the manufacturer.135, 157, 186, 187, 190, 192
AndroGel® is commercially available as unit-dose packets or as a metered-dose pump.135, 190 AndroGel® should be applied topically once daily, preferably in the morning, to clean, dry, intact skin only; testosterone topical gel 1% (AndroGel® 1%) should be applied on the shoulders, upper arms, and/or abdomen and testosterone topical gel 1.62% (AndroGel® 1.62%) should be applied only on the shoulders and upper arms.135, 190 The gel should not be applied to other parts of the body (e.g., genitals, chest, axillae, knees, back).135, 190 To apply a dose from the unit-dose packet, the entire contents of the packet should be squeezed into the palm of the hand and immediately applied to the application site; alternatively, a portion of the contents should be squeezed into the palm of the hand and applied to the application site and the procedure repeated until the entire contents of the packet has been applied.135, 190 Alternatively, the gel can be applied directly to the application site.190 Patients using the metered-dose pump should be instructed to prime the pump prior to initial use by depressing the pump 3 times; this gel should be discarded by rinsing down the sink or placing in household trash in a manner that avoids accidental exposure or ingestion by household members or pets.190 To apply a dose from the metered-dose pump, the gel may be collected in the palm of the hand by pressing the pump firmly and fully; the gel is applied to the application site.190 Patients should immediately wash their hands with soap and water following application of the gel.135, 190 Before dressing, the patient should allow the application site to dry; after the gel has dried, the application site should be covered with clothing (e.g., a shirt) to prevent transfer of testosterone to another individual.135, 190 Following application of AndroGel® 1 or 1.62%, patients should avoid swimming, showering, or washing the application site for at least 5 or 2 hours, respectively.135, 190
Testim® is commercially available as unit-dose tubes.157 Testim® should be applied topically once daily, preferably in the morning, to clean, dry, intact skin only on the shoulders and/or upper arms; the gel should not be applied to the abdomen or genitals.157 Upon opening the tube, the entire contents should be squeezed into the palm of the hand and immediately applied to the application site.157 Patients should immediately wash their hands with soap and water following application of the gel.157 Before dressing, the patient should allow the application site to dry; after the gel has dried, the application site should be covered with clothing (e.g., a shirt) to prevent transfer of testosterone to another individual.157 Patients should avoid swimming, showering, or washing the administration site for at least 2 hours following application.157
Vogelxo® is commercially available as unit-dose tubes or packets and as a metered-dose pump.187 Vogelxo® should be applied topically once daily to clean, dry, intact skin only on the shoulders and/or upper arms; the gel should not be applied to the abdomen or genitals.187 To apply a dose from the unit-dose tube or packet, the entire contents of the tube or packet should be squeezed into the palm of the hand and immediately applied to the application site.187 Patients using the metered-dose pump should be instructed to prime the pump prior to initial use by pressing the pump 3 times; this gel should be discarded by rinsing down the sink to avoid accidental exposure or ingestion by others.187 To apply a dose from the metered-dose pump, the gel may be collected in the palm of the hand by pressing the pump firmly and fully; the gel is applied to the application site.187 Patients should immediately wash their hands with soap and water following application of the gel.187 Before dressing, the patient should allow the application site to dry; after the gel has dried, the application site should be covered with clothing (e.g., a shirt) to prevent transfer of testosterone to another individual.187 Patients should avoid swimming, showering, or washing the application site for at least 2 hours following administration.187
Fortesta® is commercially available as a metered-dose pump.192 Fortesta® should be applied topically once daily, in the morning, to clean, dry, intact skin only on the front and inner thighs; the gel should not be applied to the genitals or other parts of the body.192 Patients should be instructed to prime the pump prior to initial use by pressing the pump 8 times; this gel should be discarded by rinsing down the sink or placing in household trash in a manner that avoids accidental exposure or ingestion by others.192 To apply a dose from the metered-dose pump, the gel should be applied directly to the application site; the area of the thigh adjacent to the scrotum should be avoided.192 Patients should use one finger to gently and evenly rub the gel into the application site.192 Patients should immediately wash their hands with soap and water following application of the gel.192 Before dressing, the patient should allow the application site to dry; after the gel has dried, the application site should be covered with clothing (e.g., pants, shorts) to prevent transfer of testosterone to another individual.192 Patients should avoid swimming, showering, or washing the application site for at least 2 hours following administration.192
Axiron® is commercially available as a metered-dose pump.186 Axiron® should be applied topically once daily to clean, dry, intact skin only on the axilla; the solution should not be applied to the genitals or other parts of the body (i.e., abdomen, shoulders, upper arms).186 Patients should be instructed to prime the pump prior to initial use by pressing the pump 3 times; this solution should be discarded by rinsing down a basin, sink, or toilet.186 To dispense a dose from the metered-dose pump, the solution should be dispensed into the applicator cup.186 To apply a dose from the applicator cup, the applicator cup should be held upright and placed onto the application site and then wiped steadily up and down.186 If the solution drips or runs, excess solution should be collected using the applicator cup; the solution should not be rubbed in with fingers or hands.186 Application sites should be allowed to dry completely prior to another application.186 Deodorants and antiperspirants should not affect the efficacy of Axiron®; however, application of a deodorant or antiperspirant (stick or roll-on) should occur prior to application of Axiron® to avoid contamination of the deodorant or antiperspirant product.186 Patients should immediately wash their hands with soap and water following application of the solution.186 Before dressing, the patient should allow the application site to dry; after the solution has dried, the application site should be covered with clothing (e.g., shirt) to prevent transfer of testosterone to another individual.186 Patients should avoid swimming, showering, or washing the application site for at least 2 hours following administration.186
Prior to any situation in which skin-to-skin contact with other individuals at the site of testosterone gel or solution application is anticipated, patients should wash the application site(s) thoroughly with soap and water to remove any testosterone residue.135, 157, 170, 171, 186, 187, 190, 192 If unwashed or unclothed skin at the site of testosterone gel or solution application comes in contact with the skin of another individual, the general area of contact should be washed with soap and water as soon as possible.135, 157, 170, 171, 186, 187, 190, 192 Studies show that residual testosterone is removed from the skin surface by washing with soap and water.170, 171 Signs of virilization in children (e.g., changes in genital size, libido, or development of pubic hair) and women (e.g., changes in body hair distribution, substantial increases in acne) and the possibility of secondary exposure to topical testosterone products (AndroGel®, Axiron®, Fortesta®, Testim®, Vogelxo®) should be brought to the attention of a clinician.135, 157, 170, 171, 186, 187, 190, 192 (See Cautions: Precautions and Contraindications.)
Patients receiving testosterone extended-release buccal (transmucosal) tablets (Striant®) should be instructed on use of the buccal system and given a copy of the patient instructions provided by the manufacturer.161 Testosterone extended-release buccal (transmucosal) tablets are applied to the gum region twice daily, morning and evening (approximately 12 hours apart).161 Upon opening the packet, the rounded-side surface of the buccal tablet should be placed against the gum and held in place with a finger over the lip and against the buccal tablet for 30 seconds.161 The buccal tablet should be placed just above the incisor tooth; the application site should be alternated between the left and right upper incisors.161 The buccal tablet is designed to stay in place until removed.161 Care should be taken not to dislodge the buccal tablet; placement of the tablet should be verified after tooth brushing, use of mouthwash, and eating or drinking liquids.161 The buccal tablet should not be chewed or swallowed.161 If the buccal tablet fails to properly adhere to the gum or falls off, the buccal tablet should be removed and a new tablet applied.161 If the buccal tablet must be replaced within 8 hours after application, the new tablet can remain in place until the next regularly scheduled dose (i.e., the application schedule employed should be continued).161 If the tablet must be replaced more than 8 hours after application, the replacement tablet can remain in place for the remainder of the current dosing interval as well as the next full dosing interval.161 To remove the buccal tablet, the tablet should be slid downward from the gum toward the tooth.161
Testosterone nasal gel (Natesto®) is administered intranasally using a metered-dose nasal pump.188 Patients should be instructed carefully in the use of the nasal pump.188 To obtain optimum results, patients also should be given a copy of the patient instructions provided by the manufacturer.188 Testosterone nasal gel should be administered intranasally 3 times daily; the nasal gel should not be applied to other parts of the body.188 Patients should be instructed to prime the pump prior to initial use by depressing the pump 10 times; this gel should be discarded by rinsing down a sink with warm water.188 Prior to administration of testosterone nasal gel, patients should clear their nasal passages.188 Patients should place their right index finger on the pump of the actuator and slowly insert the actuator into the left nostril until the finger reaches the base of the nose.188 To ensure adequate application of the gel, the tip of the actuator should be in contact with the lateral wall of the nostril.188 To dispense a dose from the metered-dose pump, the pump should be slowly pressed until it stops and the tip of the actuator should be wiped along the inside of the lateral nostril wall upon removal from the nose.188 This procedure is then repeated using the patient's left index finger for administration to the right nostril.188 Patients should lightly massage the application site by pressing on the nostrils just below the nasal bridge.188 Patients should avoid blowing their nose or sniffing for 1 hour following application.188 If testosterone nasal gel gets on the hands, patients should wash their hands with soap and warm water.188
Dosage of testosterone is variable and should be individualized according to the condition being treated; the severity of symptoms; the patient's age, gender, and history of prior androgenic therapy; and the specific testosterone preparation being used.
Various dosage regimens have been used to induce pubertal changes in hypogonadal males. Some clinicians recommend that lower dosages be used initially, followed by gradual increases in dosage as puberty progresses; subsequently, the dosage may be decreased to maintenance levels. Other clinicians state that higher dosages are required initially to induce pubertal changes and lower dosages can then be used for maintenance therapy after puberty. The chronologic and skeletal ages of the patient must be considered when determining the initial dosage and subsequent dosage adjustment.
For replacement of endogenous testicular hormone in androgen-deficient males, the usual IM dosage of testosterone cypionate or testosterone enanthate is 50-400 mg every 2-4 weeks.117, 162 The recommended initial dosage of testosterone undecanoate is 750 mg every 4 weeks for the first 2 doses, then 750 mg every 10 weeks thereafter.189 In general, testosterone therapy is initiated with full therapeutic doses; subsequent dosage adjustment should be made according to the patient's tolerance and therapeutic response.
Alternatively, some clinicians state that complete androgen replacement in hypogonadal men generally can be achieved with 50-100 mg of testosterone cypionate or testosterone enanthate administered IM every 7-10 days.123 This regimen generally will achieve relatively physiologic testosterone concentrations throughout the time interval between doses.123 Longer time intervals between IM doses are more convenient but are associated with greater fluctuations in testosterone concentrations.123 Higher dosages produce longer-term effects but higher peak concentrations and wider swings between peak and nadir testosterone concentrations and resultant symptom fluctuation in many patients.123 If less frequent injection is desired, 100-150 mg IM every 2 weeks may be considered.123 While 300 mg IM every 3 weeks also may be considered for convenience, such dosing is associated with wider testosterone fluctuations and generally is inadequate to ensure a consistent clinical response.123 For men who develop pronounced symptoms in the week prior to the next dose with such prolonged dosing intervals, a smaller dose at a shorter dosing interval should be tried; in general, serum total testosterone concentrations should exceed 250-300 ng/dL just before the next dose.123
If full androgen replacement is not required, lower testosterone dosages are used.123 For example, in adult males with prepubertal onset of hypogonadism who are going through puberty for the first time with IM testosterone replacement, testosterone therapy may be initiated at 50 mg every 3-4 weeks, gradually increasing the dose in subsequent months as tolerated up to full replacement within 1 year.123
Attainment of full virilization in men with hypogonadism may require up to 3-4 years of IM testosterone replacement.123 Patients generally should be monitored at 4-6 months to assess clinical progress, review compliance, and determine whether any complications or psychologic adjustment problems are present.123
For delayed puberty, the usual IM dosage of testosterone enanthate is 50-200 mg every 2-4 weeks for a limited period of time (e.g., 4-6 months).162
Inoperable Carcinoma of the Breast
For the palliative treatment of advanced, inoperable, metastatic carcinoma of the breast in women, the usual IM dosage of testosterone enanthate is 200-400 mg every 2-4 weeks.162
For replacement of endogenous testicular hormone in androgen-deficient males, the usual dosage of testosterone pellets is 150-450 mg implanted subcutaneously every 3-6 months.136 Dosage adjustment should be made according to the patient's tolerance and therapeutic response.136
For delayed puberty, the dosage of testosterone pellets is generally less than the dosage used for male hypogonadism and for a limited period of time (e.g., 4-6 months).136
Transdermal testosterone (Androderm®) is commercially available as a system delivering 2 mg/24 hours or 4 mg/24 hours.133 Dosage should be adjusted according to determinations of serum testosterone concentrations.133
When Androderm® is used for the treatment of male hypogonadism, the usual initial transdermal dosage is 4 mg once daily administered nightly as one system delivering 4 mg/24 hours.133 Dosage should be adjusted according to morning serum testosterone concentrations approximately 2 weeks following initiation of therapy.133 Depending on requirements, dosage can be increased to 6 mg once daily administered nightly as one system delivering 4 mg/24 hours plus one delivering 2 mg/24 hours or can be decreased to 2 mg once daily administered nightly as one system delivering 2 mg/24 hours.133
Patients currently maintained on a transdermal dosage of 2.5 mg once daily may be switched to one system delivering 2 mg/24 hours at the next scheduled dose.133 Patients currently maintained on a transdermal dosage of 5 mg once daily may be switched to one system delivering 4 mg/24 hours at the next scheduled dose.133 Patients currently maintained on a transdermal dosage of 7.5 mg once daily may be switched to 6 mg once daily with one system delivering 4 mg/24 hours plus one delivering 2 mg/24 hours.133
Approximately 2 weeks after switching therapy, the early morning serum testosterone concentrations should be measured in patients following system application the previous evening to ensure proper dosing.133
Topical testosterone is commercially available as a 1% gel in unit-dose packets containing a 25-mg dose of testosterone (2.5 g of gel) (AndroGel®)135 or a 50-mg dose of testosterone (5 g of gel) (AndroGel®, Vogelxo®);135, 187 as a 1.62% gel in unit-dose packets (AndroGel®) containing a 20.25- or 40.5-mg dose of testosterone (1.25 or 2.5 g of gel, respectively);190 as a nonaerosol metered-dose pump (AndroGel® [each actuation of the pump delivers 1.25 g of gel containing 20.25 mg of testosterone after priming],190 Fortesta® [each actuation of the pump delivers 0.5 g of gel containing 10 mg of testosterone after priming],192 Vogelxo® [each actuation of the pump delivers 1.25 g of gel containing 12.5 mg of testosterone after priming]);187 or in unit-dose tubes (Testim®, Vogelxo®) containing a 50-mg dose (5 g of gel).157, 187
For the treatment of male hypogonadism, the usual initial dosage of testosterone gel 1% (AndroGel® 1%, Testim®, Vogelxo®) is the entire contents of a packet or tube containing 50 mg of testosterone, the entire contents of 2 packets containing 25 mg of testosterone, or 4 actuations of the pump (5 g of gel) applied topically once daily, preferably in the morning; this dose delivers about 5 mg of testosterone systemically.135, 157, 187 The usual initial dosage of testosterone gel 1.62% (AndroGel® 1.62%) is the entire contents of a packet containing 40.5 mg of testosterone or 2 actuations of the pump (2.5 g of gel) applied topically once daily in the morning.190 The usual initial dosage of Fortesta® is 40 mg of testosterone or 4 actuations of the pump (2 g of gel) applied topically once daily in the morning.192 Dosage should be adjusted according to serum testosterone concentrations obtained at regular intervals following initiation of AndroGel® 1% therapy,135 approximately 14 days after initiating daily application of Testim® or Vogelxo®,157, 187 approximately 14 and 28 days after initiating daily application or dosage adjustment of AndroGel 1.62%,190 and approximately 14 and 35 days after initiating daily application or dosage adjustment of Fortesta®.192
If serum testosterone concentrations are below the normal range in a patient receiving AndroGel® 1%, the dosage can be increased initially to 75 mg of testosterone (7.5 g of gel) and, if necessary, subsequently to 100 mg of testosterone (10 g of gel).135 If serum testosterone concentrations exceed the normal range in a patient receiving AndroGel® 1% therapy, the daily dosage may be decreased.135 AndroGel® 1% should be discontinued if the serum testosterone concentrations consistently exceed the normal range at a daily dosage of 50 mg of testosterone (5 g of gel).135
If serum testosterone concentrations are below the normal range in a patient receiving Testim® or Vogelxo®, the dosage can be increased to 100 mg of testosterone (10 g of gel, 8 actuations of the pump).157, 187
If serum testosterone concentrations exceed 750 ng/dL in a patient receiving AndroGel® 1.62%, the dosage should be decreased to 20.25 mg of testosterone (1.25 g of gel, 1 actuation of the pump).190 If serum testosterone concentrations are below 350 ng/dL in a patient receiving AndroGel® 1.62%, the dosage should be increased initially to 60.75 mg of testosterone (3.75 g of gel, 3 actuations of the pump) and, if necessary, subsequently to 81 mg of testosterone (5 g of gel, 4 actuations of the pump).190
In patients receiving Fortesta®, the dosage should be decreased by 20 mg of testosterone (2 actuations of the pump) if serum testosterone concentrations reach or exceed 2500 ng/dL or by 10 mg of testosterone (1 actuation of the pump) if serum testosterone concentrations are 1250 ng/dL or greater, but less than 2500 ng/dL; however, if a 10-mg dosage of testosterone requires further reduction, Fortesta® should be discontinued.192 If serum testosterone concentrations are below 500 ng/dL in a patient receiving Fortesta®, the dosage of testosterone can be adjusted in 10-mg increments (1 actuation of the pump); however, the daily dosage should not exceed 70 mg of testosterone (7 actuations of the pump).192
Topical testosterone is commercially available as a solution in a metered-dose pump (Axiron®; each actuation of the pump delivers 1.5 mL of solution containing 30 mg of testosterone after priming).186 For the treatment of male hypogonadism, the recommended initial dosage of testosterone solution is 60 mg (2 actuations of the pump) applied topically once daily.186 Dosage should be adjusted according to serum testosterone concentrations obtained following initiation of therapy and at least 14 days after initiating daily application or dosage adjustment of testosterone solution.186 If serum testosterone concentrations exceed 1050 ng/dL in a patient receiving testosterone topical solution, the dosage should be decreased from 60 mg (2 actuations of the pump) to 30 mg (1 actuation of the pump); however, if a 30-mg dosage of testosterone requires further reduction, testosterone topical solution should be discontinued.186 If serum testosterone concentrations are below 300 ng/dL in a patient receiving testosterone topical solution, the dosage of testosterone can be adjusted in 30-mg increments (1 actuation of the pump); however, the daily dosage should not exceed 120 mg of testosterone (4 actuations of the pump).186
When testosterone buccal (transmucosal) tablets (Striant®) are used for the treatment of male hypogonadism, the usual dosage is 30 mg (one extended-release tablet) twice daily, morning and evening (about 12 hours apart).161 Serum testosterone concentrations should be obtained just prior to the morning dose 4-12 weeks after initiation of therapy with testosterone buccal tablets.161 If total serum testosterone concentrations are consistently outside of the normal range, testosterone buccal tablets should be discontinued.161
Intranasal testosterone is commercially available as a gel in a metered-dose nasal pump (Natesto®; each actuation of the pump delivers 0.122 g of gel containing 5.5 mg of testosterone after priming).188 For the treatment of male hypogonadism, the recommended initial dosage of testosterone nasal gel is 1 actuation of the pump per nostril for a total dosage of 11 mg 3 times daily.188 Dosage should be adjusted according to serum testosterone concentrations obtained at least 1 month after initiating therapy and periodically thereafter.188 If serum testosterone concentrations consistently exceed 1050 ng/dL, testosterone nasal gel should be discontinued.188 If serum testosterone concentrations are consistently below 300 ng/dL, testosterone nasal gel should be discontinued and alternative therapy considered.188 If severe rhinitis occurs, testosterone nasal gel should be temporarily interrupted until resolution of symptoms; however, if severe rhinitis persists, testosterone nasal gel should be discontinued and alternative therapy considered.188
Dosage in Renal and Hepatic Impairment
The manufacturers of testosterone enanthate injection, testosterone undecanoate injection, and testosterone transdermal system, topical gel, topical solution, nasal gel, and buccal tablets state that clinical studies involving patients with renal or hepatic impairment have not been conducted.133, 135, 157, 161, 186, 187, 188, 189, 190, 192 Therefore, there are no special population dosage recommendations at this time.135, 157, 190
Adverse effects associated with testosterone are similar to those of other synthetic or natural androgens and include acne, flushing of the skin, gynecomastia, increased or decreased libido, habituation, and edema. In addition, gynecomastia frequently develops and occasionally persists in patients being treated for hypogonadism.
Long-term clinical safety studies have not been conducted to date to determine the cardiovascular effects of testosterone replacement therapy in men.133 Epidemiologic data and results from randomized, controlled clinical trials have been inconclusive for determining the risk of serious adverse cardiovascular events (i.e., nonfatal myocardial infarction [MI], nonfatal stroke, death) with testosterone use compared with nonuse.133
In 2 observational studies, the risk of serious adverse cardiovascular events was increased in patients receiving testosterone replacement therapy compared with those not receiving such therapy;175, 177, 178 however, 2 other observational studies found a mortality benefit with use of testosterone replacement therapy and one observational study was inconclusive.175, 179, 180, 181 In addition, findings from 2 meta-analyses of data from published, randomized, controlled clinical trials show conflicting results.175, 182, 183 Because the current evidence regarding the cardiovascular risk associated with testosterone replacement therapy is weak because of the limited scope, quality, design, and size of the clinical trials, the FDA has requested additional evidence from well-designed studies to further elucidate the cardiovascular risk associated with testosterone use.175, 176
Following review of the data from several observational studies and meta-analyses in March 2015, the FDA concluded that use of testosterone is associated with a possible increased risk of serious adverse cardiovascular events.175 Clinicians should inform patients of this potential increased risk when deciding whether to use or continue to use testosterone replacement therapy.133 Although the FDA Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management Advisory Committee (DSaRM) concluded that there was insufficient evidence to suggest that the potential cardiovascular risk was confined to a certain subset of patients, some experts state that testosterone replacement therapy should be used with caution in patients at high risk for cardiovascular disease, such as older men or those with diabetes mellitus or obesity.176
IM administration of anabolic steroids has been associated with urticaria and inflammation at the injection site, postinjection induration, and furunculosis.
Pellet extrusion at or near the implantation site, generally during the first month following subcutaneous implantation of testosterone pellets (Testopel®), has been reported in postmarketing surveillance; infection also may occur at the implantation site.136 Infection and/or extrusion at the implantation site may be manifested with induration, inflammation, fibrosis, bleeding, contusions, wound drainage, pain, and pruritus.136
The most common adverse effect associated with transdermal testosterone is local irritation at the site of application.133, 134, 137, 138, 139, 140, 143 In clinical studies with Androderm® transdermal systems, most patients developed mild to moderate erythema at the site of application at some time during therapy; 37% of patients receiving this preparation experienced pruritus at the application site, 12% experienced burn-like blisters (manifesting with bullae, epidermal necrosis, or ulceration) on the skin immediately under the system, and 6, 3, and 3% developed vesicles, burning, and induration, respectively, at the application site.133, 137, 139 In patients who developed burn-like blisters, most such lesions were associated with application of the system over bony prominences or on body parts that may have been subject to prolonged pressure during sleep or sitting (e.g., over the deltoid region of the upper arm, the greater trochanter of the femur, or the ischial tuberosity), and such administration should be avoided; the more severe lesions healed over several weeks with occasional scarring, and such lesions should be treated as burns.133, 137, 139 Application site reactions occurring in less than 3% of patients receiving Androderm® include bullae, mechanical irritation, and contamination.133
In one comparative study, the incidence of application site reactions was substantially less with Testoderm® TTS (no longer commercially available in the US) than with Androderm®,138 possibly because of the lower amount of delivered alcohol (a permeation-enhancer excipient in the transdermal systems) per unit area of skin with Testoderm® TTS.138 The possibility exists that excipients other than alcohol also may play a role in application site reactions.138 Mild skin irritation may be ameliorated with topical application of over-the-counter hydrocortisone cream; alternatively, application of triamcinolone acetonide 0.1% cream under the central drug reservoir of the transdermal system may decrease the incidence and severity of application site reactions.133, 143
Application site reactions were reported in 5, 3, or 4% of patients who received 50, 75, or 100 mg, respectively, of testosterone gel 1% (as AndroGel® 1%) topically for up to 6 months in a clinical trial, but none of these patients required treatment or discontinued the drug because of these reactions.135 Application site reactions were reported in 2.14% of patients who received testosterone gel 1.62% (as AndroGel® 1.62%), but none of these patients discontinued the drug because of these reactions.190 In a long-term (up to 3 years) follow-up study, application site reactions were reported in 5.6% of patients.166 Application site reactions were reported in 2 or 4% of patients receiving 50- or 100-mg doses, respectively, of another testosterone gel formulation (Testim®, Vogelxo®) compared with placebo (3%).157, 187 Application site reactions were reported in 16.1% of patients receiving another testosterone gel formulation (Fortesta®).192 AndroGel® 1% appears to have minimal potential for inducing phototoxic reactions.135 Other application site reactions reported with AndroGel® 1% during postmarketing surveillance include pruritus, dry skin, erythema, rash, discolored hair, and paresthesia.135 The possibility that testosterone transfer to another individual (including women and children) could occur when skin-to-skin contact is made with the application site should be considered.135, 157, 190 (See Cautions: Precautions and Contraindications.) In vitro studies have shown that 96% of residual testosterone is removed from the skin by washing with soap and water.190
In clinical studies with a testosterone topical solution (Axiron®), irritation (5-7% of patients) or erythema (7-8% of patients) developed at the application site following 120 or 180 days of therapy, respectively.186
The most common adverse effects associated with testosterone nasal gel are nasal discomfort, nasal scabbing, rhinorrhea, epistaxis, nasopharyngitis, bronchitis, upper respiratory tract infection, and sinusitis.188 In a clinical study with Natesto® nasal gel, most patients developed mild to moderate adverse effects; however, long-term effects of testosterone nasal gel are unknown because of limited data.188
Gum or mouth irritation, bitter taste, and gum pain or tenderness have been reported in 9.2, 4.1, and 3.1%, respectively, of patients receiving testosterone buccal tablets (Striant®) in one controlled study.161 Gum edema or taste perversion occurred in 2% of patients receiving the drug in this study.161 Most gum-related adverse effects were transient; gum irritation generally resolved in 1-8 days and tenderness resolved in 1-14 days.161
Oligospermia and decreased ejaculatory volume may occur in males receiving excessive dosage or prolonged administration of testosterone. Priapism or excessive sexual stimulation in males, especially geriatric patients, may also occur. If priapism or excessive sexual stimulation develops during testosterone therapy, the drug should be discontinued temporarily, since these are signs of excessive dosa if therapy with testosterone is reinstituted, a lower dosage should be used. Male pattern of baldness may also occur.
Amenorrhea and other menstrual irregularities and inhibition of gonadotropin secretion occur commonly in females.
Gynecomastia can occur in males receiving testosterone replacement therapy as a result of aromatization of testosterone to estradiol and changes in sex hormone binding globulin (SHBG).123 Surgery can be considered for such patients.123
Testosterone, especially its active metabolite dihydrotestosterone (DHT), stimulates growth of the prostate and seminal vesicles.123 In hypogonadal men receiving testosterone replacement, such growth did not exceed the volumes expected in normal men.123 Testosterone therapy was associated with an overall mean increase in serum prostate-specific antigen (PSA) concentrations of 0.11-0.14, 0.13, 0.1-0.2, or 0.5 ng/mL in studies evaluating the effect of topical testosterone gel (AndroGel®), topical testosterone solution (Axiron®), testosterone nasal gel (Natesto®), or testosterone undecanoate injection (Aveed®), respectively, on serum PSA concentrations in men with hypogonadism. 135, 163, 186, 188, 189, 190 In one study, PSA was reduced in 21%, unchanged in 22%, and increased in 57% of patients receiving testosterone replacement therapy for 1 year.163 Increased serum PSA concentrations also were observed in 18% of hypogonadal men receiving AndroGel® 1% for up to 42 months; most of these increases occurred within the first year of therapy.166 No clear relationship between testosterone replacement therapy and prostate cancer has been established to date, although anecdotal reports have been published; additional long-term studies are needed to clarify the potential risk.123 (See Cautions: Mutagenicity and Carcinogenicity.)
Other adverse genitourinary effects of testosterone include epididymitis and bladder irritability. Impaired urination, prostatic enlargement, prostate cancer, testicular atrophy, oligospermia, priapism, gynecomastia, and mastodynia have been reported during postmarketing experience with topical testosterone gel (AndroGel® 1%).135
Endocrine and Metabolic Effects
Virilization, including deepening of the voice, hirsutism, and clitoral enlargement, occur commonly in females; these changes may not be reversible following discontinuance of the drug.
Secondary exposure to testosterone resulting in virilization of children has been reported with use of topical testosterone gel during postmarketing surveillance.167, 168, 169, 170, 171, 172, 173 (See Cautions: Precautions and Contraindications.) The FDA has fully reviewed 8 reports of secondary exposure to testosterone from testosterone gel products in children 9 months to 5 years of age.167, 169 Additional cases in children have been reported and currently are under FDA review.167 Signs and symptoms have included enlargement of the penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age.167, 169, 170, 171, 172 In most cases, these signs and symptoms resolved with removal of the testosterone exposure.169, 170, 171, 172 However, in a few cases, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronologic age.169, 170, 171 In some of these children, invasive diagnostic procedures were performed as a result of the delay in recognizing the underlying cause of the signs and symptoms.169 Direct contact of the child with application sites on the skin of men using testosterone gel was reported in most of the cases.170, 172, 173 The possibility of secondary exposure from contact with items such as shirts and bed linens of men receiving testosterone gel also may be considered.170, 172, 173
Because of the aromatization of testosterone to estradiol, lipid abnormalities usually do not develop secondary to testosterone replacement, and the ratio of HDL to total cholesterol generally remains constant.123 However, the possibility that lipid abnormalities may develop should be considered.123 (See Cautions: Precautions and Contraindications.) Anabolic steroids that do not undergo aromatization increase LDL-cholesterol and lower HDL-cholesterol, which could increase cardiovascular risk.123
Hypercalcemia resulting from osteolysis, especially in immobile patients and those with metastatic carcinoma of the breast, has been reported in patients receiving testosterone. (See Cautions: Precautions and Contraindications.) The drug should be discontinued if hypercalcemia occurs in patients with cancer, since this may indicate progression of metastases to the bone. Retention of water, sodium, chloride, potassium, and inorganic phosphates has also occurred in patients receiving the drug. If edema is present before or develops during therapy, administration of diuretics may be required.
Sleep apnea has occurred occasionally in men receiving testosterone replacement.123, 144 Although the mechanism of testosterone-induced apnea remains to be elucidated, a relationship between sex hormones and sleep apnea has been suggested since untreated males are more likely than females to develop this disorder and disordered breathing during sleep is more common among healthy males than among premenopausal women.144 In addition, loud snoring is more common in untreated men than in women, and physiologic mechanisms for snoring and obstructive sleep apnea are similar.144 Therefore, it has been postulated that abnormal relaxation of pharyngeal muscles seen in both snoring and obstructive sleep apnea is affected by circulating concentrations of hormones, including testosterone.144 If manifestations of sleep apnea occur or worsen in testosterone-treated patients, sleep studies should be performed and testosterone replacement dosage should be decreased or the drug discontinued if sleep apnea is confirmed.123, 144 In addition, patients receiving testosterone replacement should be advised to report any sleep-associated changes such as snoring, daytime somnolence, and emotional disturbances.144
Sleeplessness, headache, anxiety, mental depression, and generalized paresthesia also have occurred in patients receiving testosterone. Headache, dizziness, sleep apnea, insomnia, depression, emotional lability, nervousness, hostility, amnesia, and anxiety have been reported during postmarketing experience with topical testosterone (AndroGel® 1%).135
Hypersensitivity reactions, including skin manifestations and anaphylactoid reactions, have occurred rarely with testosterone.189 Allergic contact dermatitis has been reported with topical administration (e.g., as transdermal systems) of testosterone.133, 137, 142 (See Cautions: Local Effects.)
Supraphysiologic concentrations of testosterone can stimulate erythropoiesis.123 Increased hemoglobin and hematocrit and possibly adverse effects secondary to hyperviscosity may result.135, 123, 166 In addition, leukopenia, polycythemia, and suppression of clotting factors II, V, VII, and X also have occurred in patients receiving testosterone.
Cholestatic hepatitis, peliosis hepatis, hepatic neoplasms, jaundice and abnormal liver function test results have occurred in patients receiving androgens, principally 17-α-alkylandrogens such as fluoxymesterone or methyltestosterone. (See Cautions in Methyltestosterone 68:08.) Multiple hepatic adenomas have been reported with long-term use of testosterone enanthate injection.133 Abnormal liver function tests (e.g., ALT, AST, gamma-glutamyltranspeptidase [GGTP], bilirubin) also have been reported during postmarketing surveillance with topical testosterone (AndroGel® 1%).135
Other adverse effects associated with testosterone therapy include nausea, chills, and excitation. Nausea, asthenia, edema, malaise, dyspnea, acne, alopecia, sweating, weight gain, hypertension, and vasodilation (hot flushes) have been reported during postmarketing experience with topical testosterone (AndroGel® 1%).135
Serious pulmonary oil microembolism reactions, including cough, urge to cough, dyspnea, hyperhidrosis, throat tightness, angina, dizziness, and syncope, have occurred rarely with IM testosterone undecanoate.189 In clinical trials, pulmonary oil microembolism reactions have occurred during or immediately following IM administration of 750 mg or 1 g of testosterone undecanoate; these reactions have been reported following administration of the third and tenth injection of the drug.189 Although these reactions generally lasted a few minutes and resolved following initiation of supportive measures, some reactions persisted for several hours and required emergency care and/or hospitalization.189 (See Dosage and Administration: Administration.)
Precautions and Contraindications
Testosterone shares the toxic potentials of other androgens, and the usual precautions of androgen therapy should be observed. When testosterone esters are used in combination with estrogens, the usual precautions associated with estrogen therapy should also be observed. (See Cautions in Conjugated Estrogens 68:16.04.) Clinicians prescribing estrogens should be aware of the risks associated with use of these drugs and the manufacturers' labeling should be consulted for further discussion of these risks and associated precautions.
Patients receiving testosterone replacement therapy should be monitored periodically for response and tolerance.123 Some clinicians recommend that patients be monitored every 3-4 months during the first year of testosterone replacement, and periodically thereafter.123 Patients with benign prostatic hyperplasia (BPH) receiving androgen therapy are at increased risk for worsening of signs and symptoms of BPH.135 Patients treated with androgens also may be at increased risk for development of BPH and/or prostate cancer.135, 157 (See Cautions: Mutagenicity and Carcinogenicity.) The manufacturers of testosterone transdermal system, nasal gel, and topical solution state that evaluation of patients for prostate cancer is appropriate prior to initiation of therapy, 3-6 months after initiation of therapy, and then in accordance with current standards of care.133, 186, 188 The manufacturers of testosterone topical gel, testosterone buccal tablets, and testosterone undecanoate injection state that evaluation of patients for prostate cancer is appropriate prior to initiating and during androgen therapy.161, 187, 189, 190, 192 Some clinicians recommend that rectal prostate examination be performed routinely along with assessment of prostate-related symptoms every 6-12 months.123 Additionally, determination of PSA should be performed annually in older men.123
Increases in hematocrit may occur during testosterone therapy as a manifestation of increased red blood cell (RBC) mass, and may require dosage reduction or discontinuance of testosterone.135 Increased RBC mass also may increase the risk for a thromboembolic event.135 Annual determination of hematocrit is recommended by some clinicians during testosterone replacement therapy because of the hormone's erythropoietic potential.123 Determination of hematocrit should occur prior to initiation of therapy, and is appropriate 3-6 months after initiation of therapy, and then annually thereafter.133, 135, 157, 161, 186, 187, 188, 189, 190, 192 Patients receiving high dosages of testosterone should have periodic hemoglobin and hematocrit determinations, since polycythemia may occur. Some clinicians state that hyperviscosity states are relative contraindications to testosterone therapy.123
Changes in serum lipid profiles may require dosage adjustment or discontinuance of testosterone therapy.135 Some clinicians recommend that patients receiving testosterone replacement have a lipid profile performed at baseline, 6-12 months after initiation of therapy, and then annually thereafter.123 Androgen therapy should be used with caution in cancer patients at risk of hypercalcemia (and associated hypercalciuria).135 Regular monitoring of serum calcium concentrations is recommended in these patients.135
Cardiovascular events, including MI or stroke, have been reported during postmarketing experience with testosterone preparations.133 Testosterone should be used with caution in patients at high risk for cardiovascular disease (e.g., older men, those with diabetes mellitus or obesity).176 Patients should be advised to immediately report symptoms suggestive of MI or stroke (e.g., chest pain, shortness of breath, unilateral weakness, difficulty talking) to their clinician.175
Venous thromboembolic events, including deep-vein thrombosis (DVT) and pulmonary embolism (PE), have been reported during postmarketing experience with testosterone preparations.133, 185 Patients reporting symptoms of pain, edema, warmth, and erythema in a lower extremity or presenting with acute shortness of breath should be evaluated for possible DVT or PE, respectively.133 If venous thromboembolism is suspected, testosterone therapy should be discontinued and appropriate evaluation and management should be initiated.133
Testosterone should be used with caution in patients with cardiac, renal, and/or hepatic dysfunction since edema may occur as a result of sodium and water retention.135, 166 Edema, with or without congestive heart failure, may be a serious complication in patients with preexisting cardiac, renal, and/or hepatic disease.135, 157 If edema occurs during testosterone therapy and it is considered a serious complication, the drug should be discontinued; diuretic therapy may also be necessary.157 Testosterone cypionate (Depo®-testosterone) is contraindicated in patients with serious cardiac, hepatic, or renal disease.117
Females should be carefully monitored for signs of virilization (e.g., deepening of the voice, hirsutism, clitoromegaly, menstrual irregularities) during testosterone therapy. The drug should generally be discontinued when mild virilization is evident, since some adverse androgenic effects (e.g., voice changes) may not subside following discontinuance of the drug. The woman and physician may decide that some virilization is acceptable during treatment for carcinoma of the breast.
Males should be carefully monitored for the development of priapism or excessive sexual stimulation since these are signs of excessive dosage. Males, especially geriatric patients, may become overly stimulated. Stimulation to the point of increasing the nervous, mental, and physical activities beyond the patient's cardiovascular capacity should be avoided when testosterone is used to treat decreased testosterone concentrations related to aging. Geriatric males may be at increased risk of developing prostatic hypertrophy and carcinoma during androgen therapy.
Adult or adolescent males should be advised to report too frequent or persistent penile erections to their physician. Females should be advised to report hoarseness, acne, menstrual changes, or the growth of facial hair to their physician. All patients should be advised to report nausea, vomiting, changes in skin color, or ankle swelling to their physician.
Treatment of hypogonadal men with testosterone products may potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung diseases.135, 157 Some clinicians also state that a history of sleep apnea is a relative contraindication to testosterone therapy.123 (See Cautions: Systemic Effects.)
Testosterone topical gels and topical solution contain a flammable vehicle (alcohol), and should not be exposed to an open flame or ignited materials (e.g., a lighted cigarette).135, 157, 186, 187, 190, 192 The topical gel or topical solution is no longer flammable once the gel or solution has dried.135, 157, 186, 187, 190, 192
Virilization in children and women can occur following secondary exposure to testosterone in topical testosterone preparations, including gels or solution.135, 157, 170, 171, 172, 173, 186, 187, 190, 192 Cases of secondary exposure resulting in virilization of children have been reported during postmarketing surveillance of topical testosterone preparations.170, 171, 172, 173, 186 (See Cautions: Endocrine and Metabolic Effects.) Signs and symptoms of virilization in children have included enlargement of the penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age.170, 171, 172 In most cases, these signs and symptoms regressed with removal of the testosterone exposure.170, 172 However, in a few cases, enlarged genitalia did not fully return to age-appropriate normal size, and bone age remained modestly greater than chronologic age.170
The risk of testosterone transfer in some of these reported cases was increased by lack of adherence to precautions for the appropriate use of the topical testosterone preparations.170, 186 Men using topical testosterone gel or solution should strictly adhere to the recommended instructions for use and appropriate precautions from the manufacturers to minimize the potential for secondary exposure to testosterone in other individuals.170, 171, 186 (See Dosage and Administration: Administration.) Children and women should avoid contact with application sites on the skin of men using topical testosterone products.170, 171, 186
Inappropriate changes in genital size or development of pubic hair or libido in children, changes in body hair distribution, substantial increase in acne, or other signs of virilization in adult women, and the possibility of secondary exposure to testosterone topical gel should be brought to the attention of a clinician.170, 171 Testosterone topical gel should be promptly discontinued at least until the cause of virilization in such children and women has been identified.170, 171
Testosterone transdermal system (Androderm®) should be removed before undergoing magnetic resonance imaging (MRI), since the transdermal system contains aluminum and may cause skin burns at the application site.133
Serious pulmonary oil microembolism reactions and anaphylaxis have been reported following IM administration of testosterone undecanoate.189 Patients should be monitored for 30 minutes following each dose of IM testosterone undecanoate.189
Adverse nasal reactions have been reported with testosterone nasal gel.188 Because of limited data in patients with a history of nasal disorders (e.g., nasal or sinus surgery, nasal fracture within the previous 6 months, nasal fracture resulting in a deviated anterior nasal septum), mucosal inflammatory disorders (e.g., Sjogren's syndrome), and/or sinus disease, testosterone nasal gel is not recommended in such patients.188 Patients should be advised to report nasal symptoms to their clinician to determine if further evaluation by an ear, nose, and throat (ENT) specialist or discontinuance of testosterone nasal gel is necessary.188
Testosterone topical gel, topical solution, nasal gel, transdermal system, and buccal tablets and testosterone undecanoate injection (Aveed®) are not indicated for use in women, have not been evaluated in women, and should not be used in women.133, 135, 157, 161, 186, 187, 188, 189, 190, 192
Testosterone is contraindicated in males with carcinoma of the breast or known or suspected carcinoma of the prostate.157 Testosterone also is contraindicated in women who are or may become pregnant or who are breastfeeding.157 (See Cautions: Pregnancy, Fertility, and Lactation.) Testosterone cypionate injection, testosterone enanthate injection, and testosterone undecanoate injection are contraindicated in patients with known hypersensitivity to the drug or any ingredient in the respective formulation.117, 162, 189 Because of the potential risk of serious adverse health effects, testosterone should not be used for enhancement of athletic performance or physique.101, 102, 107, 114, 116, 117 (See Uses: Misuse, Abuse, and Dependence.) Patients should be informed of the serious adverse effects associated with misuse and abuse of androgens.135
Androgens should be used with extreme caution in children and only by specialists who are aware of the adverse effects of these drugs on bone maturation. Testosterone should be used cautiously to stimulate puberty, and only in carefully selected males with delayed puberty. (See Uses: Uses in Males.) In children, testosterone may accelerate bone maturation without producing compensatory gain in linear growth. This adverse effect may result in compromised adult stature. The younger the child, the greater the risk of testosterone compromising final mature stature. If testosterone is administered to prepubertal children (e.g., to stimulate puberty in males), the drug should be used with extreme caution, and radiographic examination of the hand and wrist should be performed every 6 months to determine the rate of bone maturation and to assess the effect of treatment on the epiphyseal centers. If testosterone is to be used to stimulate puberty in a male with delayed puberty, the potential risk of therapy should be fully discussed with the patient and his parents prior to initiation of the drug.
Safety and efficacy of testosterone topical gel, topical solution, nasal gel, transdermal system, and buccal tablets and testosterone undecanoate injection (Aveed®) in pediatric patients younger than 18 years of age have not been established.133, 135, 157, 161, 186, 187, 188, 189, 190, 192 Safety and efficacy of testosterone cypionate injection (Depo®-testosterone) in pediatric patients younger than 12 years of age have not been established.117 Secondary exposure to testosterone in children can occur with the use of topical testosterone preparations, including gels or solution, in other individuals.135, 157, 170, 171, 186, 187, 190, 192 (See Cautions: Precautions and Contraindications.)
Clinical studies evaluating testosterone enanthate injection (Delatestryl®), testosterone undecanoate injection (Aveed®), and testosterone topical gel (AndroGel®, Fortesta®), topical solution, nasal gel, and transdermal system have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric patients respond differently than younger adults.133, 135, 162, 186, 188, 189, 192 There also are insufficient long-term safety data with testosterone enanthate injection, testosterone undecanoate injection, and testosterone topical gel (AndroGel®, Fortesta®, Testim®, Vogelxo®). topical solution, nasal gel, and transdermal system to determine the potential risks of cardiovascular disease, prostate cancer, and prostatic hyperplasia in geriatric adults.133, 135, 157, 162, 186, 187, 188, 189, 192 The manufacturer of testosterone buccal tablets (Striant®) states that no substantial differences in safety and efficacy were observed in clinical studies in patients 65 years of age or older relative to younger adults.161 Differences in pharmacokinetics were observed between geriatric and younger adults in studies with Striant®, but it is not known whether these differences are clinically important.161
Mutagenicity and Carcinogenicity
Hepatocellular carcinoma has reportedly occurred in patients receiving long-term therapy with high dosages of androgens. Regression of the tumor does not always occur following discontinuance of androgen therapy. Geriatric patients may be at increased risk of developing prostatic hypertrophy and carcinoma during androgen therapy, although the manufacturers state that conclusive evidence to support this risk is lacking. Testosterone replacement is contraindicated in men with known or suspected prostate cancer or male breast cancer since the drug can stimulate tumor growth in androgen-dependent neoplasms.123, 133, 134, 135, 136 The prostate and breasts should be examined carefully prior to initiating testosterone therapy in men and at follow-up visits.123, 126 Baseline and follow-up determinations of PSA also should be performed in older men (e.g., older than 50 years of age) at increased risk for prostate cancer.123, 126
Following implantation of testosterone in mice, cervical-uterine tumors developed which occasionally metastasized. There is some evidence to suggest that injection of testosterone into some strains of female mice increases their susceptibility to hepatomas. Testosterone has also been shown to increase the number of tumors and decrease the degree of differentiation of chemically induced tumors in rats. It is not known whether androgens, including testosterone, are mutagenic.
Pregnancy, Fertility, and Lactation
Testosterone may cause fetal harm when administered to pregnant women due to the potential for virilization of a female fetus.135, 157 Androgenic effects including clitoral hypertrophy, labial fusion of the external genital fold to form a scrotal-like structure, abnormal vaginal development, and persistence of a urogenital sinus have occurred in the female offspring of women who were given androgens during pregnancy. The degree of masculinization is related to the amount of drug given to the woman and the age of the fetus; masculinization is most likely to occur in a female fetus when exposure to androgens occurs during the first trimester. Since the risks clearly outweigh the possible benefits in women who are or may become pregnant, testosterone is contraindicated in such women.135, 157 Women who become pregnant while receiving the drug should be informed of the potential hazard to the fetus.
Pregnant women or those who may become pregnant should be aware of the possibility that testosterone could be transferred from patients treated with topical preparations of the drug such as their sexual partners or other individuals in close physical contact.135, 157 (See Cautions: Precautions and Contraindications.) Testosterone transdermal system (Androderm®) has an occlusive backing that prevents the partner from coming in contact with active ingredient in the system.133 Transdermal systems that inadvertently are transferred to a sexual partner should be removed immediately and the contacted skin washed.134 Pregnant women should avoid skin contact with testosterone topical gel application sites in men.135, 157 (See Cautions: Precautions and Contraindications.) If unwashed or unclothed skin to which testosterone topical gel has been applied comes in direct contact with the skin of a pregnant woman, the general area of contact by the woman should be washed with soap and water immediately.135, 157 In vitro studies show that residual testosterone is removed by such washing.166
Although the effect of testosterone on fertility in humans has not been conclusively determined, the drug produces oligospermia and decreased ejaculatory volume in males. With high dosages of androgen therapy, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone possibly leading to adverse effects on semen parameters including sperm count.135 Priapism and excessive sexual stimulation also have occurred in males receiving the drug. (See Cautions: Precautions and Contraindications.) Increased or decreased libido also has been reported.
It is not known whether testosterone is distributed into milk. The manufacturers of testosterone enanthate injection (Delatestryl®) and testosterone pellets (Testopel®) state that because of the potential for serious adverse reactions to androgens in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.136, 162 The manufacturer of testosterone cypionate injection (Depo®-testosterone) states that use in nursing women is not recommended.117 Testosterone topical gel, topical solution, nasal gel, transdermal system, and buccal tablets and testosterone undecanoate injection (Aveed®) are not indicated for use in women.133, 135, 157, 161, 186, 187, 188, 189, 190, 192 Testosterone topical gel, topical solution, nasal gel, and buccal tablets and testosterone undecanoate injection also are contraindicated in nursing women because of the potential for serious adverse reactions in nursing infants.135, 157, 161, 186, 187, 188, 189, 190, 192 Exposure of a female nursing infant to androgens may result in varying degrees of virilization.135 Testosterone and other androgens also may adversely affect lactation.135
Testosterone may potentiate the action of oral anticoagulants, causing bleeding in some patients. When testosterone therapy is initiated in patients receiving oral anticoagulants, dosage reduction of the anticoagulant may be required to prevent an excessive hypoprothrombinemic response. In patients receiving concomitant therapy with testosterone and anticoagulants, more frequent monitoring of INR and prothrombin time is recommended, especially during initiation or discontinuance of therapy.135
Increased serum oxyphenbutazone concentrations have reportedly occurred in patients receiving androgens concurrently with oxyphenbutazone.157
Changes in insulin sensitivity or glycemic control may occur in patients receiving androgen therapy.135 The metabolic effects of androgens may decrease blood glucose concentrations and insulin requirements in patients with diabetes.135, 157
Concomitant administration of testosterone with ACTH or corticosteroids may result in increased fluid retention and edema formation.135, 157 Therefore, testosterone should be administered with caution in patients with cardiac, renal, and/or hepatic disease.135, 157 Patients should be monitored for fluid retention and edema formation.133
Administration of IM testosterone cypionate resulted in increased clearance of propranolol in one study.157, 174 It is not known whether there is a potential for this interaction with topically administered testosterone gel.157
Topical administration of 0.1% triamcinolone cream prior to application of a testosterone transdermal system did not alter absorption of testosterone; however, pretreatment with topical administration of triamcinolone ointment substantially reduced absorption of testosterone.133
Administration of intranasal oxymetazoline, a sympathomimetic nasal decongestant, prior to administration of testosterone nasal gel (Natesto®) did not alter absorption of testosterone.188 Concomitant administration of testosterone nasal gel with other drugs administered intranasally has not been studied.188 The manufacturer does not recommend concomitant use with such drugs.188
Protein bound iodine (PBI) concentrations may be decreased in some patients during testosterone therapy; however, this does not appear to be clinically important. Androgens may decrease thyroxine-binding globulin concentrations, resulting in decreased total serum thyroxine (T4) concentrations and increased resin uptake of triiodothyronine (T3) and T4. Free thyroid hormone concentrations remain unchanged, and there is no clinical evidence of thyroid dysfunction.135
Testosterone may cause a decrease in creatinine and creatine excretion and increase the excretion of 17-ketosteroids.
Electrolyte changes (e.g., nitrogen, calcium, potassium, phosphorus, sodium), changes in serum lipids (e.g., hyperlipidemia, elevated triglycerides, decreased high-density lipoprotein [HDL]-cholesterol), impaired glucose tolerance, and fluctuating testosterone concentrations have been reported during postmarketing surveillance with a topical testosterone gel (AndroGel®).135
Testosterone is the principal endogenous androgen. Endogenous androgens are essential hormones that are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics, including the growth and maturation of the prostate, seminal vesicles, penis, and scrotum; development of male hair distribution, such as beard, pubic, chest, and axillary hair; laryngeal enlargement and thickening of the vocal cords; and alterations in body musculature and fat distribution.
Testosterone, like other androgenic anabolic hormones, also produces retention of nitrogen, potassium, sodium, and phosphorus; increases protein anabolism; and decreases amino acid catabolism and urinary calcium concentrations. Nitrogen balance is improved only when there is sufficient intake of calories and protein.
Androgens are responsible for the growth spurt that occurs during adolescence and for the eventual termination of linear growth that results from fusion of the epiphyseal growth centers. Although endogenous androgens accelerate linear growth rates in children, the drugs may cause a disproportionate advancement in bone maturation, and long-term administration of the drugs in prepubertal children may result in fusion of the epiphyseal growth centers and premature termination of the growth process.
Exogenous administration of androgens inhibits the release of endogenous testosterone via feedback inhibition of pituitary luteinizing hormone (LH). Following administration of large doses of exogenous androgens, spermatogenesis may also be suppressed as a result of feedback inhibition of pituitary follicle-stimulating hormone (FSH).
Androgens reportedly stimulate the production of erythrocytes, apparently by enhancing the production of erythropoietic-stimulating factor.
Endogenous serum testosterone concentrations vary from hour to hour, and periodic declines below the normal range can occur occasionally in otherwise healthy men.123 Serum concentrations of the hormone exhibit diurnal variation, with highest concentrations of circulating testosterone occurring in the early morning hours.123 For a reliable testosterone determination, use of 3 pooled morning serum testosterone samples can minimize errors attributable to variation in concentrations of the hormone.123 Testosterone circulates principally in bound form, mainly to sex hormone binding globulin (SHBG; testosterone-estradiol binding globulin, TEBG) and albumin.123 Testosterone is tightly bound to SHBG and is not biologically active, whereas the fraction associated with albumin is only weakly bound and can dissociate to unbound, active hormone.123 Only about 2% of endogenous testosterone circulates unbound while 30-40% circulates bound to SHBG and the rest is bound to albumin and other proteins.123, 135
For information on the pharmacokinetics of endogenous testosterone, see Pharmacology.
Following oral administration of testosterone, only small amounts of the drug reach systemic circulation unchanged. The low bioavailability of orally administered testosterone results from metabolism of the drug in the GI mucosa during absorption and on first pass through the liver. The synthetic androgens (i.e., fluoxymesterone, methyltestosterone) are less extensively metabolized following oral administration.
Esterification of testosterone generally results in less polar compounds. The enanthate ester of testosterone is absorbed slowly from the lipid tissue phase at the IM injection site, achieving peak serum concentrations about 72 hours after IM injection; thus, this preparation has a prolonged duration of action (i.e., up to 2-4 weeks) following IM administration. Because IM injection of testosterone esters causes local irritation, the rate of absorption may be erratic.
Testosterone is absorbed systemically through the skin following topical application as a gel,135, 157, 187, 190, 192 solution,186 or transdermal system.123, 133, 134, 137, 145, 146, 147, 148, 149, 150, 151, 152 Following topical application of a hydroalcoholic gel formulation of testosterone (AndroGel®, Testim®, Vogelxo®) to the skin, the gel quickly dries on the skin surface, which serves as a reservoir for sustained release of the hormone into systemic circulation.135, 157, 187 Approximately 10% of a testosterone dose applied topically to the skin as a 1% gel is absorbed percutaneously into systemic circulation.135, 157, 187
The manufacturer of AndroGel® states that increases in serum testosterone concentrations were apparent within 30 minutes of topical application of a 100-mg testosterone dose of the 1% gel, with physiologic concentrations being achieved in most patients within 4 hours (pretreatment concentrations were not described); percutaneous absorption continues for the entire 24-hour dosing interval.135 Serum testosterone concentrations approximate steady-state levels by the end of the initial 24 hours and are at steady state by the second or third day of dosing of the 1% gel.135 With daily topical application of the 1% gel (AndroGel®), serum testosterone concentrations 30, 90, and 180 days after initiating treatment generally are maintained in the eugonadal range.135 Administration of 10 or 5 g of the 1% gel (AndroGel®) daily results in average daily serum testosterone concentrations of 792 or 566 ng/dL, respectively, at day 30.135 Following discontinuance of such topical therapy, serum testosterone concentrations remain within the normal range for 24-48 hours but return to pretreatment levels by the fifth day after the last application.135 The manufacturer states that mean concentrations of the active metabolite dihydrotestosterone (DHT) were within or about 7% above the normal range 180 days after initiating daily topical application of 50 or 100 mg, respectively, of testosterone as the gel.135 Increases in DHT concentrations appeared to parallel those of testosterone, and the mean steady-state ratio of DHT to testosterone was maintained in the normal range during the 180-day treatment period.135
Following administration of testosterone gel (Testim®), physiologic concentrations of testosterone are achieved within 24 hours; percutaneous absorption continues for the entire 24-hour dosing interval.157 Administration of 10 or 5 g of Testim® daily results in average daily serum testosterone concentrations of 612 or 365 ng/dL, respectively, at day 30.157 DHT concentrations increase in parallel with testosterone concentrations; DHT concentrations have remained within the normal range during a 90-day treatment period.157
Following topical application of testosterone solution (Axiron®) to the skin, ethanol and isopropyl alcohol evaporate leaving testosterone on the skin surface, which serves as a reservoir for sustained release of the hormone into systemic circulation.186 Following topical application of testosterone solution daily, serum testosterone concentrations reach steady-state levels by approximately 14 days.186 Following discontinuance of such topical therapy, serum testosterone concentrations return to pretreatment levels by 7-10 days after the last application.186 DHT concentrations increase in parallel with testosterone concentrations; mean steady-state ratios of testosterone to DHT have remained within the normal range during a 120-day treatment period.186
Following topical application of transdermal systems of testosterone, the hormone is absorbed percutaneously into systemic circulation.123, 133, 134, 137, 145, 146, 147, 148, 149, 150, 151, 152 Although interindividual variation in percutaneous testosterone absorption occurs, serum testosterone concentrations achieved with recommended dosages of transdermal systems of the drug generally reach the normal range during the first day of dosing and are maintained during continuous dosing without accumulation.133 Average daily serum testosterone concentrations in patients receiving Androderm® reportedly are 498 ng/dL at steady state.133 Mean ratios of testosterone to DHT are within the normal range.147
With topical application of a transdermal preparation, the extent of percutaneous testosterone absorption varies according to the site of application,123, 147 possibly secondary to regional differences in skin permeability, cutaneous blood flow, and/or degree of adhesion between the transdermal system and skin.147 In one study in which transdermal systems were applied to the abdomen, back, chest, shin, thigh, or upper arm, serum hormone profiles were qualitatively similar with each site, but steady-state serum concentrations showed significant differences, decreasing in order with the back, thigh, upper arm, abdomen, chest, and shin.133, 147 Application of Androderm® transdermal systems to the abdomen, back, thighs, or upper arms results in achievement of similar serum testosterone concentration profiles, and these sites are recommended as optimal for rotation of application sites during chronic therapy.133, 147 Daily nighttime (at approximately 10 p.m.) application of Androderm® transdermal system results in a serum testosterone concentration profile that mimics the endogenous diurnal pattern in healthy young men.133 In one study, showering 3 hours after application of Androderm® decreased peak plasma concentrations of testosterone by 0.4% compared with not showering 3 hours after application of the transdermal system.133 In addition, showering 3 hours after transdermal system application did not substantially alter the systemic exposure of testosterone.133
Following intranasal administration of testosterone nasal gel (Natesto®), peak plasma concentrations occur approximately 40 minutes after administration.188 Average daily serum testosterone concentration in patients receiving 11 mg of the nasal gel 3 times daily is 421 ng/dL.188 DHT concentrations increase in parallel with testosterone concentrations; mean steady-state ratios of testosterone to DHT have remained within the normal range during a 90-day treatment period.188
Following buccal (transmucosal) administration of testosterone (Striant®), the drug is absorbed transmucosally from the buccal mucosa; testosterone that is absorbed systemically via the oral mucosa bypasses first-pass metabolism.161 Following administration of testosterone buccal tablets every 12 hours, steady-state concentrations of testosterone are achieved after the second dose.161 Testosterone concentrations decrease to concentrations below the normal range about 2-4 hours after removal of the buccal tablet.161 Average daily serum testosterone concentrations in patients receiving the buccal tablet are 520-550 ng/dL at steady state.161 Increases in DHT concentrations appear to parallel those of testosterone, and mean steady-state ratios of testosterone to DHT are within the normal range.161
Following IM administration of testosterone undecanoate (Aveed®), the drug is slowly absorbed from the lipid phase and hydrolyzed to testosterone.189 Following IM administration of testosterone undecanoate 750 mg, peak plasma concentrations of testosterone occur after a median of 7 days and steady-state concentrations are achieved after the third injection (14 weeks).189 Increases in DHT concentrations appear to parallel those of testosterone, and mean ratios of testosterone to DHT are within the normal range.189
Circulating testosterone is chiefly bound in the serum to sex steroid binding globulin (sex hormone binding globulin, SHBG; testosterone-estradiol-binding globulin, TEBG) and albumin.134, 135 Because testosterone easily dissociates from albumin, the albumin-bound drug is presumed to be pharmacologically active.133, 134, 135 The SHBG-bound portion is not considered to be pharmacologically active.133, 134, 135
In serum, testosterone is bound with high affinity to SHBG and with low affinity to albumin.133 The amount of SHBG in serum and the total testosterone concentration determine the distribution of pharmacologically active and non-active forms of the androgen.133, 134, 135 SHBG-binding capacity is high in prepubertal children, declines during puberty and adulthood, and increases again during the later decades of life.134, 135 Approximately 30-40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free), and the rest is bound to albumin and other proteins.123, 134, 135
The plasma half-life of testosterone reportedly ranges from 10-100 minutes. The plasma half-life of testosterone cypionate after IM injection is approximately 8 days.117 Following removal of an Androderm® transdermal system, plasma testosterone concentrations decline with an apparent half-life of approximately 70 minutes and hypogonadal concentrations are reached within 24 hours.133
Testosterone is metabolized principally in the liver to various 17-ketosteroids via 2 different pathways. The major active metabolites of testosterone are estradiol and DHT. In many tissues, the activity of testosterone appears to depend on reduction to DHT, which binds to SHBG with greater affinity than does testosterone. Testosterone and its metabolites are excreted in urine and feces. Approximately 90% of an IM dose of testosterone is excreted in urine as glucuronic and sulfuric acid conjugates of the drug and its metabolites; approximately 6% of a dose is excreted in feces, principally as unconjugated drug.
Testosterone is a naturally occurring androgenic anabolic steroid hormone. The drug may be obtained from animal testes but is usually prepared synthetically from cholesterol. Dehydroepiandrosterone is an intermediate in the synthesis of the drug that can be treated by chemical or microbiologic processes to form testosterone. Testosterone is commercially available as the base, and as the cypionate, enanthate, and propionate esters.
Testosterone occurs as white or slightly creamy white, odorless crystals or as a crystalline powder and is practically insoluble in water, freely soluble in dehydrated alcohol, and soluble in vegetable oils. Testosterone cypionate occurs as a white or creamy white, crystalline powder that is odorless or has a slight odor and is insoluble in water, freely soluble in alcohol, and soluble in vegetable oils. Testosterone enanthate occurs as a white or creamy white, crystalline powder that is odorless or has a faint odor characteristic of heptanoic acid and is insoluble in water and soluble in vegetable oils. Testosterone undecanoate occurs as a white to off-white, crystalline powder.189
Testosterone cypionate injection is a sterile solution of the drug in a suitable vegetable oil (e.g., cottonseed oil), which may also contain benzyl alcohol as a preservative.117
Testosterone enanthate injection is a sterile solution of the drug in a suitable vegetable oil (e.g., sesame oil), which may also contain chlorobutanol as a preservative.162
Testosterone undecanoate injection is a sterile solution of the drug in a suitable vegetable oil (e.g., castor oil).189
Transdermal testosterone (Androderm®) is commercially available as a system that consists of an outer layer of metallized polyester, ethylene-methacrylic acid copolymer (Surlyn®), and ethylene vinyl acetate; a drug reservoir of testosterone, alcohol, glycerin, glycerol monooleate, methyl laurate, and purified water, gelled with an acrylic acid copolymer; a permeable polyethylene microporous membrane; and a peripheral layer of acrylic adhesive surrounding the central, active drug delivery area of the system.133 The central delivery surface of the system is sealed with a peelable laminate disk composed of a 5-layer laminate containing polyester, polyesterurethane adhesive, aluminum foil, polyesterurethane adhesive, and polyethylene; the disk is attached to and removed with the release liner, a silicone-coated polyester film that should be removed prior to application.133
Testosterone topical gel is a clear to translucent, colorless, hydroalcoholic gel containing testosterone.135, 157, 187, 190, 192 AndroGel® also contains alcohol, purified water, sodium hydroxide, carbomer 980, and isopropyl myristate;135, 190 Testim® also contains alcohol 74%, purified water, pentadecactone, carbopol, acrylates, propylene glycol, glycerin, polyethylene glycol, and tromethamine;157 Fortesta® also contains alcohol, purified water, propylene glycol, 2-propanol, oleic acid, carbomer 1382, triethanolamine, and butylated hydroxytoluene;192 Vogelxo® also contains alcohol, oleyl alcohol, purified water, glycerin, carbomer copolymer Type B, carbomer homopolymer Type C, diisopropyl adipate, methyl laurate, polyethylene glycol, propylene glycol, and tromethamine.187 Each g of testosterone gel 1% contains 10 mg of testosterone.135, 157, 187 Each g of testosterone gel 1.62% contains 16.2 mg of testosterone.190 Each g of testosterone gel 2% contains 20 mg of testosterone.192
Testosterone topical solution is a clear to colorless solution containing testosterone.186 Axiron® also contains alcohol, isopropyl alcohol, octisalate, and povidone.186 Each mL of testosterone solution contains 20 mg of testosterone.186
Testosterone nasal gel is a slightly yellow gel containing testosterone.188 Natesto® also contains castor oil, oleoyl polyoxylglycerides, and colloidal silicon dioxide.188 Each g of testosterone nasal gel contains approximately 45 mg of testosterone.188
Testosterone buccal (transmucosal) preparations (Striant®) contain the drug in a system that provides controlled and extended release of testosterone as the buccal system gradually hydrates.161 In addition to testosterone, the system also contains lactose (anhydrous and monohydrate), carbomer 934P, hypromellose, magnesium stearate, polycarbophil, colloidal silicon dioxide, starch, and talc.161
Testosterone enanthate injection (Delatestryl®) should be stored at room temperature.162 A precipitate may form if the injection is stored at a low temperature; however, this will dissolve after warming and rolling the syringe or vial containing the drug between the palms of the hands. Testosterone undecanoate injection (Aveed®) should be stored at 25°C, but may be exposed to temperatures of 15-30°C.189 Testosterone cypionate injection (Depo®-testosterone) should be stored at 20-25°C.117
Testosterone pellets (Testopel®) should be stored at 25°C, but may be exposed to temperatures of 15-30°C.136
Testosterone topical gels (AndroGel®, Fortesta,® Testim®, Vogelxo®) should be stored at 20-25°C, but may be exposed to temperatures of 15-30°C.135, 157, 187, 190, 192 Testosterone topical solution (Axiron®) should be stored at 25°C, but may be exposed to temperatures of 15-30°C.186 Testosterone transdermal system (Androderm®) should be stored at 20-25°C and protected from excessive heat.133 Testosterone nasal gel (Natesto®) should be stored at 20-25°C, but may be exposed to temperatures of 15-30°C.188 Testosterone buccal (transmucosal) tablets (Striant®) should be stored at 20-25°C and should be protected from heat and moisture.161
Testosterone transdermal systems, topical gels, topical solutions, nasal gels, and buccal tablets should be disposed of in household trash in a manner that prevents accidental application or ingestion by children or pets.133, 135, 157, 161, 186, 188
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Distribution of testosterone undecanoate injection (Aveed®) is restricted.189 (See REMS and also see Restricted Distribution Program under Administration: IM Injection, in Dosage and Administration.)
Most preparations containing testosterone or its salts, esters, or ethers are subject to control under the Federal Controlled Substances Act of 1970, as amended by the Anabolic Steroids Control Act of 1990 and 2004, as schedule III (C-III) drugs.113, 164 (See Uses: Misuse and Abuse.) However, manufacturers of certain preparations containing androgenic anabolic steroid hormones (principally combinations that also include estrogens) have applied for and obtained for their products(s) an exemption from the record-keeping and other regulatory requirements of the Federal Controlled Substances Act.121, 165 Under provisions of the Act, specific products can be exempted from such control by the Attorney General, in consultation with the Secretary of Health and Human Services, if the product is determined not to possess any significant potential for abuse because of concentration, preparation, combination, and/or delivery system. Because regulatory requirements for a given preparation containing an androgenic anabolic steroid may be subject to change based on these provisions, the manufacturer should be contacted when specific clarification about a preparation's status is required.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Buccal (Transmucosal) | Tablets, extended-release | 30 mg | Striant® (C-III) | |
Nasal | Gel | 5.5 mg | Natesto® (C-III) | |
Parenteral | Implant, pellets for subcutaneous use | 75 mg | Testopel® (C-III) | |
Topical | Gel | 1% (12.5 and 50 mg)* | Testosterone Gel (C-III) | |
Vogelxo® (C-III) | ||||
1% (25 and 50 mg)* | AndroGel® (C-III) | |||
Testosterone Gel (C-III) | ||||
1% (50 mg)* | Testim® (C-III) | Endo | ||
Testosterone Gel (C-III) | ||||
1.62% (20.25 and 40.5 mg)* | AndroGel® (C-III) | AbbVie | ||
2% (10 mg)* | Fortesta® (C-III) | Endo | ||
Solution | 30 mg/1.5 mL* | Axiron® (C-III) | ||
Testosterone Topical Solution (C-III) | ||||
Transdermal System | 2 mg/24 hours (9.7 mg/32 cm2) | Androderm® (C-III) | ||
4 mg/24 hours (19.5 mg/39 cm2) | Androderm® (C-III) | Allergan |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection (in oil) | 200 mg/mL* | Depo®-Testosterone (C-III) | |
Testosterone Cypionate Injection (C-III) |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection (in oil) | 200 mg/mL* | Delatestryl® (C-III) | Endo |
Testosterone Enanthate Injection (C-III) |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection (in oil) | 250 mg/mL | Aveed® (C-III) | Endo |
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