Possibly Everything You Might Wanto to Know about Testosterone I

Testosterone
by Medscape

Monograph - Testosterone, Testosterone cypionate, Testosterone enanthate, Testosterone propionate
Class: ANDROGENS(68:08)

Sections: Introduction | Uses | Dosage and Administration | Cautions | Drug Interactions | Laboratory test Interferences | Pharmacology | Pharmacokinetics | Chemistry and Stability | Preparations

Introduction

Testosterone, the principal endogenous androgen, is a naturally occurring androgenic anabolic steroid hormone.
Uses

Testosterone is used mainly for replacement or substitution of diminished or absent endogenous testicular hormone.

•Uses in Males

Hypogonadism

In males, testosterone is used for the management of congenital or acquired primary hypogonadism such as that resulting from orchidectomy 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.

Manifestations.

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. Hypogonadism seldom is recognized before the age of puberty unless it is associated with growth retardation or other anatomic and/or endocrine abnormalities. 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. 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. Growth of body hair usually slows, while the voice and size of the phallus and prostate remain unchanged. 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). Hypogonadism also is associated with a risk of osteoporosis and resultant fractures. Many cases of postpubertal hypogonadism are initially detected during fertility evaluations.

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). 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. Such patients generally exhibit low serum testosterone concentrations and usually low (indicating hypothalamic-pituitary involvement) or occasionally high (indicating testicular involvement) gonadotropin concentrations. 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. 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-pitutitary-gonadal axis, and/or changes caused by chronic illness, poor nutrition, or medications; approximately 25% of hypogonadism cases in HIV-infected men are primary. 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.

Male Climacteric.

The concept of male climacteric (andropause) remains controversial. However, growing evidence indicates that some aging men develop reduced testosterone production and associated 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. Measurements of free testosterone and/or sex hormone binding globulin (SHBG) concentrations usually are necessary to demonstrate the abnormality.

There currently is a paucity of information from well-designed study 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 manifestation common to both aging and hypogonadism. In addition, studies that have been conducted generally have been of short duration, involved small numbers of patients, and often lacked adequate controls. 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. 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. 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., biphosphonates for osteoporosis), testosterone should be considered a therapeutic rather than a preventative measure in aging men. Although endogenous testosterone levels clearly decline with aging, it currently is unclear whether such decreased levels affect health outcomes in older men. 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.

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. However, additional evidence from well-designed studies is needed to further elucidate the role of testosterone therapy in aging men. Well-designed studies also are needed to quantify the risks of testosterone therapy on symptomatic prostatic hyperplasia (BPH) and prostate cancer, which are of major concern. The Institute of Medicine (IOM) of the National Academies recognizes that clinical evidence to date suggests some benefit and possible risk of testosterone therapy in older men, but they state that additional placebo-controlled studies are needed to determine the nature and extent of therapeutic benefits in this age group.

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. Serum total (bound and free) testosterone concentrations less than 300 ng/dL generally are considered indicative of hypogonadism in men, 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. 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. 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); 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.

Delayed Puberty

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 US Food and Drug Administration (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. Therefore, all patients receiving prolonged corticosteroid therapy should be assessed for possible hypogonadism, which should be corrected if present. 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 conticosteroid therapy. 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. 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. 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. The goal of testosterone replacement therapy in men receiving long-term corticosteroid therapy is to provide serum testosterone concentrations within the therapeutic range. It is important that the possibility of prostate cancer be ruled out in any man being considered for such replacement therapy. For additional information on the management of corticosteroid-induced osteoporosis, see Cautions: Musculoskeletal Effects in the Corticosteroids General Statement 68:04.

•Uses in Females

Inopererable 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. Short-acting androgen preparations are preferred when these drugs are indicated for the treatment of carcinoma of the breast, particularly during the early stages of androgen therapy, since androgens occasionally appear to accelerate the disease. The use of a long-acting preparation may preclude attempts to arrest or reverse untoward effects of the drug on tumor progression, hypercalcemia, and/or sodium and water retention. 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 US Food and Drug Administration (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.

Menopause

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 US Food and Drug Administration (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. 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. The FDA will allow continued marketing of combination estrogen/androgen products while the matter is under study.

•Misuse and Abuse

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. The drugs also have been misused and abused for cosmetic purposes by noncompetitors attempting to achieve bodies with lean muscle mass. Although historically the drugs have been regarded as ineffective for anabolic and androgenic uses in athletes, recent 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. There continues to be a lack of evidence of long-term beneficial effects, and the drugs may be associated with substantial adverse health effects and toxicity. 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. In addition, several androgens often are taken concomitantly (‘‘stacking’’) for extended periods. The extent of misuse and abuse of androgens has not been fully determined, but nonmedical use is believed to be widespread. Estimates for the rate of misuse and abuse by weight lifters and body builders have ranged up to 50–80%. 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. Evidence from one study indicates that about 7% of male high school seniors use or have used the drugs. Although the likelihood of use was increased in males intending to participate in school-sponsored sports (particularly football and wrestling), 35% of users had no intention of participating in school-sponsored sports. About 40% of these high school students admitted initiating use of the drugs at 15 years of age or younger. In studies of college students, androgen use among athletes ranged up to about 20%.

Systematic studies to determine the risks of misuse and abuse of androgens have not been performed to date, but evidence from experience with legitimate medical use of the drugs and from case reports in athletes indicates that potential adverse effects in either gender include increased aggression and antisocial behavior (‘‘roid rage’’); psychotic manifestations and affective disorders (e.g., manic episode, depression); changes in libido; adverse alterations in lipoprotein profiles and increased risk of cardiovascular disease (e.g., coronary artery disease, stroke, atherosclerosis); hepatotoxicity (e.g., abnormal liver function test results, liver tumors [hepatic adenomas, hepatocellular carcinoma], peliosis hepatis, jaundice); premature bone maturation and epiphyseal closure with resultant irreversible short stature when initiated in adolescents or younger children; possible increased risk of ruptured tendons and ligaments and of tendonitis; and acne. Other potential adverse effects of androgens in males include gynecomastia, hair loss, testicular atrophy and sperm abnormalities (oligospermia, decreased motility, abnormal morphology, azoospermia), impotence, and prostatic enlargement with resultant difficulty in urinating. Other potential adverse effects in females include clitoral enlargement (which may be irreversible), menstrual irregularities, hirsutism, androgenetic alopecia, deepened voice, and breast atrophy.

Because of the potential for serious adverse effects associated with misuse and abuse of androgens, preventive measures have been initiated, including educational programs, interdiction of black market supplies, drug screening of athletes with associated penalties for use, and other control measures. The prescription, dispensing, distribution, and use of most androgens currently are restricted as controlled substances. 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.

Dosage and Administration

•Administration

Testosterone is administered by deep IM injection; implants (testosterone pellets) are administered by subcutaneous implantation; testosterone transdermal systems are administered percutaneously by topical application to the skin (Androderm®, Testoderm® TTS) or scrotum (Testoderm®, Testoderm® with Adhesive); and testosterone gel is applied topically to the skin.

IM Injection and Subcutaneous Implantation

Testosterone cypionate, testosterone enanthate, and testosterone propionate are administered by deep IM injection.
IM injection of testosterone and its esters should be made deep into the upper outer quadrant of the gluteus maximus.

If complications associated with subcutaneous testosterone implantation occur, the pellets should be removed; pellets occasionally may slough out, usually secondary to superficial implantation or lack of aseptic precautions.

Transdermal Administration

Patients receiving transdermal testosterone therapy should be carefully instructed in the proper use and disposal of the transdermal system. To obtain optimum results, patients should be given a copy of the patient instructions provided by the manufacturer. To expose the drug-containing film of Testoderm® or the adhesive surface of Testoderm® with Adhesive, Testoderm® TTS, or Androderm®, the protective liner should be peeled and discarded prior to administration.

For nonscrotal application, the transdermal system should then be applied topically to a clean, dry area of skin on the arm, back, or upper buttock for Testoderm® TTS or on the back, abdomen, upper arms, or thigh for Androderm® by firmly pressing the system with the adhesive side touching the skin; these systems should not be applied to the scrotum. If scrotal application is preferred, the transdermal system of Testoderm® or Testoderm® with Adhesive should then be applied topically to clean, dry, scrotal skin; these systems are intended for scrotal application only. The scrotum should be dry-shaved for optimum skin contact; chemical depilatories should not be used. The nonscrotal or scrotal system should be applied immediately after removal from its protective pouch and removal of the protective liner. The system should be pressed firmly in place with the palm of the hand for about 10 seconds, ensuring good contact, particularly around the edges. The application site should not be oily, damaged, or irritated. Application of Androderm® or Testoderm® TTS nonscrotal 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 since burn-like blisters may occur. If the system should inadvertently come off during the period of use, it may be reapplied or, if necessary, a new system may be applied; in either case, the application schedule employed should be continued.

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. The manufacturer of Androderm® states that mild skin irritation may be ameliorated with topical hydrocortisone cream 0.5 or 1% 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).

Testosterone transdermal systems are applied once daily; to produce serum testosterone concentrations that mimic endogenous profiles, the manufacturer states that Androderm® should be applied at night while the manufacture states that any of the Testoderm® preparations should be administered at about the same time each day preferably in the morning. Transdermal systems applied to the scrotum should be left in place for 22–24 hours and systems applied to other topical sites should be left in place for approximately 24 hours; after this period, the system should be removed and discarded and a new system applied.

The manufacturer of Androderm® states that the transdermal system does not need to be removed during sexual intercourse nor while showering or bathing. Androderm® and Testoderm® TTS have an occlusive backing that prevents sex partners from coming in contact with the active material in the system. Although transfer of the transdermal system itself from the patient’s body to that of their partner is unlikely, if such inadvertent transfer does occur, the transdermal system should be removed immediately and the contacted skin washed. Female partners of patients treated with the transdermal systems should contact a clinician if they notice changes in body hair distribution, significant increases in acne, or other manifestations of virilization.

Topical Administration

Testosterone topical gel should be applied topically once daily, preferably in the morning, to clean, dry, intact skin on the shoulders and upper arms and/or abdomen. The gel should not be applied to the scrotum. Upon opening the unit-dose packet or tube, the entire contents should be squeezed into the palm of the hand and immediately applied to the application site, which should then be allowed to dry for few minutes before dressing; after the gel has dried, the application site should be covered with clothing (e.g., a shirt) in order to prevent transfer to another individual. Hands should be washed with soap and water after application of the gel. It currently is not known how long showering or swimming should be delayed following application of testosterone gel. Pending further accumulation of data, the manufacturer of AndroGel® states that a reasonable approach to optimize testosterone absorption would be to wait at least 5–6 hours after application before showering or swimming. However, showering or swimming after the elapse of just 1 hour should have a minimal effect on the amount of testosterone gel absorbed if done very infrequently. The manufacturer of Testim® recommends that at least 2 hours should elapse between application of the gel and washing of the site.
If unwashed or unclothed skin at the site of testosterone gel 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.

•Dosage

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. Since regulation of dosage is much less flexible with testosterone implants (pellets) for subcutaneous implantation than with oral, transdermal, topical, or parenteral administration, the estimated amount of testosterone needed should be calculated with great caution.

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. In general, short-term administration (e.g., 4–6 months) of testosterone or testosterone esters and dosages in the lower end of the usual range for replacement are used for the treatment of delayed puberty in males.

IM Dosage

Male Hypogonadism.

For replacement of endogenous testicular hormone in androgen-deficient males, the usual IM dosage is 10–25 mg of testosterone or testosterone propionate 2 or 3 times weekly, 50–400 mg of testosterone cypionate every 2–4 weeks, or 50–400 mg of testosterone enanthate every 2–4 weeks. 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 75–150 mg of testosterone cypionate or enanthateadministered IM every 7–10 days. This regimen generally will achieve relatively physiologic testosterone concentrations throughout the time interval between doses. Longer time intervals between IM doses are more convenient but are associated with greater fluctuations in testosterone concentrations. 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. If less frequent injection is desired, 100–200 mg IM every 2 weeks may be considered. 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. 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.

If full androgen replacement is not required, lower testosterone dosages are used. For example, in adult males with prepubertal onset of hypogonadism who are going through puberty for the first time with testosterone replacement, testosteronecypionate or enanthate may be initiated at 50–100 mg every 3–4 weeks, gradually increasing the dose in subsequent months as tolerated up to full replacement within 1 year.

Attainment of full virilization in men with hypogonadism may require up to 3–4 years of IM testosterone replacement. 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.

For the management of postpubertal cryptorchidism in patients with evidence of hypogonadism, the usual IM dosage is 10–25 mg of testosterone or testosteronepropionate 2 or 3 times weekly.

Inoperable Carcinoma of the Breast

For the palliative treatment of advanced, inoperable, metastatic carcinoma of the breast in women, the use of short-acting androgen preparations rather than those with prolonged activity is preferred, especially during the early stages of treatment, since use of a long-acting preparation may preclude attempts to arrest or reverse untoward effects of the drug on tumor progression, hypercalcemia, and/or sodium and water retention. An IM dosage of 100 mg of testosterone or 50–100 mg of testosteronepropionate, has been given 3 times weekly. Alternatively, 200–400 mg of testosteronecypionate or testosterone enanthate has been given IM every 2–4 weeks.

Subcutaneous Implantation Dosage

For replacement of endogenous testicular hormone in androgen-deficient males (male hypogonadism), the usual dosage of testosterone implants (pellets) is 150–450 mg (two to six 75-mg pellets) implanted subcutaneously every 3–6 months.

For patients being transferred from IM testosterone propionate, the number of testosterone pellets to be implanted subcutaneously depends on the minimum daily requirement of testosterone propionate determined by a gradual reduction in the amount administered parenterally. The usual ratio is 150 mg (two 75-mg pellets) for each 25 mg of IM testosterone propionate required weekly. Thus, patients requiring 75 mg of IM testosterone propionate weekly will usually require 450 mg of testosterone (six 75-mg pellets) implanted subcutaneously. For patients requiring weekly IM injections of 50 mg, subcutaneous implantation of 300 mg (four 75-mg pellets) may be sufficient for approximately 3 months. Correspondingly lower subcutaneous implant dosages should be used in patients requiring lower IM dosages. Approximately one-third of an implanted dose is absorbed systemically during the first month, one-fourth during the second month, and one-sixth during the third month. Adequate effect usually persists for 3–4 months after subcutaneous implantation of the pellets, and occasionally for up to 6 months.

Transdermal Dosage

Transdermal testosterone is commercially available for nonscrotal topical application as a transdermal system delivering 2.5 mg/24 hours (Androderm®) or 5 mg/24 hours (Androderm®, Testoderm® TTS). Transdermal testosterone is commercially available for scrotal topical application as a transdermal system (Testoderm® with or without Adhesive) delivering 4 or 6 mg/24 hours. Dosage should be adjusted according to determinations of serum testosterone concentrations. Because of the variability in analytical values among diagnostic laboratories, all laboratory work for adjusting dosage and assessing the effects of transdermal testosterone should be done at the same laboratory so results can be compared. Patients who have not achieved desired results after 6–8 weeks of transdermal testosterone therapy should be considered for alternative forms of testosterone replacement therapy.
When Androderm® is used for nonscrotal application in the treatment of male hypogonadism, the usual initial transdermal dosage is 5 mg once daily administered nightly as one system delivering 5 mg/24 hours or as two systems delivering 2.5 mg/24 hours. Dosage should be adjusted according to morning serum testosterone concentrations. Depending on requirements, dosage can be increased to 7.5 mg once daily administered nightly as one system delivering 5 mg/24 hours plus one delivering 2.5 mg/24 hours or as three systems delivering 2.5 mg/24 hours or can be decreased to 2.5 mg once daily administered nighly as one system delivering 2.5 mg/24 hours.

When Testostoderm® TTS is used for nonscrotal application in the treatment of male hypogonadism, the usual initial transdermal dosage is 5 mg once daily administered at about the same time each day (preferably in the morning) as one system delivering 5 mg/24 hours. After 3–4 weeks of daily system application, dosage should be adjusted according to serum testosterone concentrations obtained 2–4 hours after application of a transdermal system. Dosage can be increased if necessary to 10 mg once daily administered as two systems delivering 5 mg/24 hours.

When Testostoderm® with or without Adhesive is used for scrotal application in the treatment of male hypogonadism, the usual initial transdermal dosage is 6 mg once daily administered at about the same time each day (preferably in the morning) as one system delivering 6 mg/24 hours. Alternatively when the scrotum cannot accommodate a 6-mg system, transdermal dosage can be initiated at 4 mg once daily administered as one system delivering 4 mg/24 hours. After 3–4 weeks of daily system application, dosage should be adjusted according to serum testosterone concentrations obtained 2–4 hours after application of a transdermal system.

Topical Gel Dosage

Topical testosterone is commercially available as a 1% gel in unit-dose packets (AndroGel®) containing a 25- or 50-mg dose (2.5 or 5 g of gel, respectively) or in unit-dose tubes (Testim®) containing a 50-mg dose (5 g of gel). For the treatment of male hypogonadism, the usual initial dosage of testosterone gel 1% is the entire contents of a packet containing 50 mg of testosterone (5 g of gel) applied topically once daily, preferably in the morning; this dose delivers about 5 mg of testosterone systemically. Dosage should be adjusted according to serum testosterone concentrations obtained approximately 14 days after initiating daily application of the gel. If serum testosterone concentrations are below the normal range or the clinical response is inadequate, 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).

Cautions

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.

•Local Effects

IM administration of anabolic steroids has been associated with urticaria and inflammation at the injection site, postinjection induration, and furunculosis.

The most common adverse effect associated with transdermal testosterone is local irritation at the site of application. In clinical studies with Androderm® transdermal systems, most patients developed mild-to-moderate erythema at the site of application at some time during therapy, which resolved spontaneously within 24–48 hours after removal of the system or was ameliorated with a topical corticosteroid or diphenhydramine; 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. In addition, 4% of patients receiving this preparation developed allergic contact dermatitis 3–8 weeks after initiation of therapy, which was characterized by pruritus, erythema, induration, and occasionally vesicles or bullae; these reactions recurred with each system application and required discontinuance of the preparation. 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. Application site reactions occurring in less than 1% of patients receiving Androderm® include bullae, mechanical irritation, and contamination.

In clinical studies with Testoderm® TTS, 12% of patients developed transient pruritus, 3% developed moderate-to-severe erythema, and 1% developed burning sensation at the application site; 1% of patients discontinued this preparation permanently because of application site reactions. There were no clinically important differences in the skin tolerability of geriatric patients 65 years of age and older vs younger patients. Contact sensitization occurred in 0.5% of patients receiving Testoderm® TTS for up to 6 weeks.

In one comparative study, the incidence of application site reactions was substantially less with Testoderm® TTS than with Androderm®, 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. Rechallenge with components of the Androderm® transdermal system showed ethanol sensitization in 4/5 patients who developed allergic contact dermatitis. The possibility exists that excipients other than alcohol also may play a role in application site reactions. In at least one patient, allergic contact dermatitis was attributed to testosterone. Mild skin irritation may be ameliorated with topical application of 0.5 or 1% 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.

Local reactions also are the most common adverse effects associated with scrotal application of tesosterone trandermal systems (Testoderm® with or without Adhesive), with most patients in clinical trials reporting scrotal pruritus, discomfort, or irritation at some time during therapy with these preparations. In patients who received the scrotal transdermal system without adhesive, all such reactions decreased with duration of use. In a study comparing nonscrotal application (back or upper outer arm) of transdermal systems of Androderm® and scrotal application of Testoderm® without Adhesive, allergic contact dermatitis and spontaneous flaring of prior application sites occurred in 12% of adult males receiving nonscrotal systems versus no confirmed cases in those receiving scrotal systems. Unlike nonscrotal transdermal systems which contain alcohol and/or other permeation enhancers, scrotal systems do not contain such permeation enhancers, and it has been suggested that the absence of these enhancers and/or other excipients may be responsible for the apparently improved local tolerability of scrotal formulations.

Application site reactions were reported in 3–5% of 154 patients who received testosterone gel (as AndroGel®) 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. In a long-term (up to 12 months) follow-up study, application site reactions were reported in 3.1–10% of patients. Application site reactions were reported in 2 or 4% of patients receiving 50- or 100-mg doses, respectively, of another testosterone gel formulation (Testim®) but less frequently than with placebo (8%). The possibility that testosterone transfer to another individual could occur when vigorous skin-to-skin contact is made with the application site should be considered; in vitro studies have shown that residual testosterone is removed from the skin by washing with soap and water.

Testosterone implants (pellets) occasionally may slough out of the implantation site. Such sloughing usually is the result of superficial implantation of the pellets or neglect to follow aseptic precautions.

•Genitourinary Effects

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 dosage; 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). Concomitant use of an aromatase inhibitor or surgery can be considered for such patients.

Testosterone, especially its active metabolite dihydrotestosterone (DHT), stimulates growth of the prostate and seminal vesicles. In hypogonadal men receiving testosterone replacement, such growth did not exceed the volumes expected in normal men. In a study of the effect of exogenous testosterone (administered transdermally or parenterally) on serum prostate-specific antigen (PSA) concentrations in men with hypogonadism, no correlation between testosterone therapy and PSA or prostate-specific membrane antigen was demonstrated. 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. (See Cautions: Mutagenicity and Carcinogenicity.)

Other adverse genitourinary effects of testosterone include epididymitis and bladder irritability.

•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.

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. However, the possibility that lipid abnormalities may develop should be considered. (See Cautions: Precautions and Contraindications.) Anabolic steroids that do not undergo aromatization increase LDL-cholesterol and lower HDL-cholesterol, which could increase cardiovascular risk.

Hypercalcemia resulting from osteolysis, especially in immobile patients and those with metastatic carcinoma of the breast, has been reported in patients receiving testosterone. 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.

•Nervous System Effects

Sleep apnea has occurred occasionally in men receiving testosterone replacement. 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. In addition, loud snoring is more common in untreated men than in women, and physiologic mechanisms for snoring and obstructive sleep apnea are similar. 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. 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. In addition, patients receiving testosterone replacement should be advised to report any sleep-associated changes such as snoring, daytime somnolence, and emotional disturbances.

Sleeplessness, headache, anxiety, mental depression, and generalized paresthesia also have occurred in patients receiving testosterone.

•Sensitivity Reactions

Hypersensitivity reactions, including skin manifestations and anaphylactoid reactions, have occurred rarely with testosterone. Allergic contact dermatitis has been reported with topical administration (e.g., as transdermal systems) of testosterone. (See Cautions: Local Effects.)

•Hematologic Effects

Supraphysiologic concentrations of testosterone can stimulate erythropoiesis. Increased hematocrit and possibly adverse effects secondary to hyperviscosity may result. In addition, leukopenia, polycythemia, and suppression of clotting factors II, V, VII, and X also have occurred in patients receiving testosterone.

•Hepatic Effects

Cholestatic hepatitis and jaundice and abnormal liver function test results have occurred in patients receiving androgens, principally 17-***945;-alkylandrogens such as fluoxymesterone or methyltestosterone. (See Cautions in Fluoxymesterone 68:08 and in Methyltestosterone 68:08.)

•Other Adverse Effects

Other adverse effects associated with testosterone therapy include nausea, chills and excitation.

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•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.

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. However, the possibility that lipid abnormalities may develop should be considered. (See Cautions: Precautions and Contraindications.) Anabolic steroids that do not undergo aromatization increase LDL-cholesterol and lower HDL-cholesterol, which could increase cardiovascular risk.

Hypercalcemia resulting from osteolysis, especially in immobile patients and those with metastatic carcinoma of the breast, has been reported in patients receiving testosterone. 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.

•Nervous System Effects

Sleep apnea has occurred occasionally in men receiving testosterone replacement. 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. In addition, loud snoring is more common in untreated men than in women, and physiologic mechanisms for snoring and obstructive sleep apnea are similar. 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. 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. In addition, patients receiving testosterone replacement should be advised to report any sleep-associated changes such as snoring, daytime somnolence, and emotional disturbances.

Sleeplessness, headache, anxiety, mental depression, and generalized paresthesia also have occurred in patients receiving testosterone.

•Sensitivity Reactions

Hypersensitivity reactions, including skin manifestations and anaphylactoid reactions, have occurred rarely with testosterone. Allergic contact dermatitis has been reported with topical administration (e.g., as transdermal systems) of testosterone. (See Cautions: Local Effects.)

•Hematologic Effects

Supraphysiologic concentrations of testosterone can stimulate erythropoiesis. Increased hematocrit and possibly adverse effects secondary to hyperviscosity may result. In addition, leukopenia, polycythemia, and suppression of clotting factors II, V, VII, and X also have occurred in patients receiving testosterone.

•Hepatic Effects

Cholestatic hepatitis and jaundice and abnormal liver function test results have occurred in patients receiving androgens, principally 17-***945;-alkylandrogens such as fluoxymesterone or methyltestosterone. (See Cautions in Fluoxymesterone 68:08 and in Methyltestosterone 68:08.)

•Other Adverse Effects

Other adverse effects associated with testosterone therapy include nausea, chills and excitation.

•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 a testosterone ester in combination with an estrogen should be given a copy of the patient labeling for the combination.

Patients receiving testosterone replacement therapy should be monitored periodically for response and tolerance. Some clinicians recommend that patients be monitored every 3–4 months during the first year of testosterone replacement, and periodically thereafter. Rectal prostate examination should be performed routinely at baseline and periodically thereafter and annual determination of PSA should be performed at baseline, 3–6 months after initiating therapy, and annually thereafter in older men, particularly in those older than 50 years of age. In addition, annual determination of hematocrit is recommend during testosterone replacement therapy because of the hormone’s eryhthropoietic potential. Patients receiving testosterone replacement also should have a lipid profile performed at baseline and repeated after 6–12 months.

Because of the long duration of implanted testosterone pellets (implants), removal of the implants is necessary if testosterone-induced effects that must be terminated occur. In addition, because pellet implantation is much less flexible for adjusting dosage than other routes of administration, dosage requirements of testosterone implants should be estimated carefully.

Testosterone should be used with caution in patients with cardiac, renal, or hepatic dysfunction since edema, with or without congestive heart failure, may occur as a result of sodium and water retention. If edema occurs during testosterone therapy and it is considered a serious complication, the drug should be discontinued; diuretic therapy may also be necessary.

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 climacteric in males. 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.

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.

Some clinicians also state that a history of sleep apnea is a relative contraindication to testosterone therapy. (See Cautions: Systemic Effects.)

Testosterone is contraindicated in males with carcinoma of the breast or known or suspected carcinoma of the prostate. Testosterone also is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the respective formulation. Some manufacturers state that the drug is also contraindicated in patients with cardiac, renal, or hepatic decompensation; hypercalcemia; impaired liver function; and in patients who are easily sexually stimulated. Other manufacturers state that the drug is also contraindicated in patients with serious cardiac, renal, or hepatic disease and in patients with known hypersensitivity to the drug. Because of the potential risk of serious adverse health effects, testosterone should not be used for enhancement of athletic performance or physique. (See Uses: Misuse and Abuse.)

•Pediatric Precautions

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 Testoderm® transdermal system formulations in pediatric patients have not been established and those of Androderm® transdermal systems have not been established in males younger than 15 years of age. Safety and efficacy of topical testosterone gel in pediatric patients younger than 18 years of age also have not been established.

•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. The prostate and breasts should be examined carefully prior to initiating testosterone therapy in men and at follow-up visits. 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.

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

Pregnancy

Testosterone may cause fetal harm when administered to pregnant women. 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. Women who become pregnant while receiving the drug should be informed of the potential hazard to the fetus.

The possibility that testosterone could be transferred from patients treated with topical or transdermal preparations of the drug to their sexual partners or other individuals in close physical contact should be considered. Certain testosterone transdermal systems have an occlusive backing (e.g., Androderm®, Testoderm® TTS) that prevents the partner from coming in contact with active ingredient in the system. However, scrotal transdermal systems (i.e., Testoderm® with or with Adhesive) do not include such an occlusive backing, and the potential for transfer of testosterone to a sexual partner was 6 mcg (1/45th the daily endogenous testosterone production in females) in one study. Transdermal systems that inadvertently are transferred to a sexual partner should be removed immediately and the contacted skin washed. Pregnant women should avoid skin contact with testosterone topical gel application sites in men. If unwashed or unclothed skin to which tetosterone 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 as soon as possible. In vitro studies show that residual testosterone is removed by such washing.

Fertility

Although the effect of testosterone on fertility in humans has not been conclusively determined, the drug produces oligospermia and decreased ejaculatory volume in males. Priapism and excessive sexual stimulation have also occurred in males receiving the drug. (See Cautions: Precautions and Contraindications.) Increased or decreased libido has also been reported.

Lactation

It is not known whether testosterone is distributed into milk. Because of the potential for serious adverse reactions to androgens in nursing infants, a decision should be made whether to discontinue nursing or to not use testosterone, taking into account the importance of the drug to the woman.

Drug Interactions

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. Patients receiving oral anticoagulants should also be closely monitored when androgen therapy is discontinued.

Increased serum oxyphenbutazone concentrations have reportedly occurred in patients receiving androgens concurrently with oxyphenbutazone.

The metabolic effects of androgens may decrease blood glucose concentrations and insulin requirements in patients with diabetes.

Laboratory test Interferences

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.

Testosterone may cause a decrease in creatinine and creatine excretion and increase the excretion of 17-ketosteroids.

Pharmacology

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. Serum concentrations of the hormone exhibit diurnal variation, with highest concentrations of circulating testosterone occurring in the early morning hours. For a reliable testosterone determination, use of 3 pooled morning serum testosterone samples can minimize errors attributable to variation in concentrations of the hormone. Testosterone circulates principally in bound form, mainly to sex hormone binding globulin (SHBG; testosterone-estadiol binding globulin, TEBG) and albumin. 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. 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.

Pharmacokinetics

For information on the pharmacokinetics of endogenous testosterone, see Pharmacology.

•Absorption

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 cypionateand enanthate esters of testosterone are absorbed slowly from the lipid tissue phase at the IM injection site, achieving peak serum concentrations about 72 hours after IM injection; thus, these esters have a prolonged duration of action (i.e., up to 2–4 weeks) following IM administration. Testosterone propionate, however, reportedly has a shorter duration of action than that of testosterone following IM administration. Because IM injection of testosterone or its esters causes local irritation, the rate of absorption may be erratic.

Following subcutaneous implantation of testosterone pellets, approximately 33% of an implanted dose is absorbed systemically during the first month, 25% during the second month, and 17% during the third month. The duration of action of subcutaneous testosterone implants (pellets) is usually 3–4 months but occasionally may be up to 6 months.

Testosterone is absorbed systemically through the skin following topical application as a gel or transdermal system. Following topical application of a hydroalcoholic gel formulation of testoterone (AndroGel® 1%) 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. Approximately 10% of a testosterone dose applied topically to the skin as the 1% gel is absorbed percutaneously into systemic circulation. The manufacturer 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. 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. With daily topical application of the 1% gel, serum testosterone concentrations 30, 90, and 180 days after initiating treatment generally are maintained in the eugonadal range. 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. 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. 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.

Following topical application of transdermal systems of testosterone to nonscrotal or scrotal skin, the hormone is absorbed percutaneously into systemic circulation. Although interindividual variation in percutaneous testosterone absorbtion 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. Scrotal skin is at least 5 times more permeable to percutaneous testosterone absorption than other skin sites. Therefore, for nonscrotal, but not scrotal application, permeation enhancers (e.g., alcohol) are incorporated into the transdermal systems to promote percutaneous absorption of the hormone.

Because genital skin contains high concentrations of 5***945;-reductase, serum DHT concentrations generally remain in the supraphysiologic range in most men following chronic scrotal application of the transdermal systems; however, in some men, DHT concentrations may increase initially and then decrease to normal levels with continued scrotal therapy. Results of a pooled analysis of studies with Testoderm® transdermal system indicated an increase in plasma DHT concentrations during therapy with the system, as well as a change in testosterone to DHT ratios (range: 0.7–12.5) relative to those observed in men not receiving testosterone therapy (3.6–15.2). The long-term effects of the change in this ratio are as yet unknown. With nonscrotal topical application of the transdermal systems at recommended sites, there is no appreciable dermal metabolism of testosterone to DHT, presumably reflecting the relatively low concentrations of 5***945;-reductase and aromatase activity in nonscrotal skin, and mean DHT concentrations and ratios of testosterone to DHT are within the normal range.

With topical application to nonscrotal skin, the extent of percutaneous testosterone absorption varies according to the site of application, possibly secondary to regional differences in skin permeability, cutaneous blood flow, and/or degree of adhesion between the transdermal system and skin. 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. 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. Daily nighttime (at approximately10 p.m.) application of Androderm® transdermal systems results in a serum testosterone concentration profile that mimics the endogenous diurnal pattern in healthy young men. Application of Testoderm® TTS transdermal systems to the arm, back, or upper buttocks (the recommended application sites) reportedly results in areas under the serum concentration-time curve (AUC0–27) that are equivalent, making application to any of these sites interchangeable. Daily morning application of any of the Testoderm® transdermal preparations approximates the endogenous diurnal pattern of serum testosterone in healthy males, with percutaneous absorption of the hormone occurring continuously over the 24-hour dosing period. Serum testosterone concentrations peak at 2–4 hours after nonscrotal or scrotal application of Testoderm® preparations and return toward baseline within approximately 2 hours after system removal.

•Distribution

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. Because testosterone easily dissociates from albumin, the albumin-bound drug is presumed to be pharmacologically active. The SHBG-bound portion is not considered to be pharmacologically active.

In serum, testosterone is bound with high affinity to SHBG and with low affinity to albumin. The amount of SHBG in serum and the total testosterone concentration determine the distribution of pharmacologically active and non-active forms of the androgen. SHBG-binding capacity is high in prepubertal children, declines during puberty and adulthood, and increases again during the later decades of life. 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.

•Elimination

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. Testosterone released from testosterone transdermal systems has an apparent elimination half-life of 1.29 hours. 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.

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.

Chemistry and Stability

•Chemistry

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 enanthateoccurs 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 propionate occurs as white or creamy white, odorless crystals or as a crystalline powder and is insoluble in water, freely soluble in alcohol, and soluble in vegetable oils. Commercially available testosterone pellets are sterile pellets of the drug in compressed form.

Parenteral Preparations

Commercially available testosterone suspension is a sterile suspension of the drug in an aqueous medium; the suspension may also contain sodium carboxymethylcellulose, methylcellulose, povidone, docusate sodium, and thimerosal. Testosterone cypionateinjection is a sterile solution of the drug in a suitable vegetable oil (e.g., cottonseed oil); the injection may also contain a suitable solubilizing agent and benzyl alcohol or chlorobutanol as a preservative. 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. Testosterone propionate injection is a sterile solution of the drug in a suitable vegetable oil which may also contain benzyl alcohol or phenol as a preservative.

Subcutaneous Implants

Testoterone for subcutaneous implantation is commercially available as sterile pellets (implants) that are cylindrically shaped (3.2 mm diameter and 8–9 mm length) and ready for implantation. The pellets weigh approximately 77 mg, of which 75 mg is testosterone; the pellets also contain stearic acid and polyvinylpyrroidone. When implanted subcutaneously, the pellets slowly release testosterone for a long-acting androgenic effect.

Transdermal Systems

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. 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.
Transdermal testosterone (Testoderm® TTS) also is commercially available as a system that consists of an outer transparent layer of polyester/ethylene vinyl acetate laminate film, a drug reservoir of testosterone and alcohol gelled with hydroxypropyl cellulose, and an ethylene-vinyl acetate copolymer membrane coated with a layer of polyisobutylene adhesive formulation that controls the rate of drug release from the system; a protective liner of silicone-coated polyester covers the adhesive surface and should be removed prior to application.

Transdermal testosterone (Testoderm® with or without Adhesive) also is commercially available as scrotal systems that consist of a soft flexible outer layer of polyester and a ethylene-vinyl acetate copolymer film that contains testosterone; a protective liner of fluorocarbon diacrylate or silicon-coated polyester covers the drug film in the adhesive-free system and such a liner of fluorocarbon diacrylate-coated polyester covers the adhesive stripes and adhesive-free area of the drug film, and these protective liners should be removed prior to application. The surface of the drug film on the adhesive-containing scrotal Testoderm® system is partially covered by a layer that contains thin, narrow adhesive stripes composed of polyisobutylene and colloidal silicon dioxide.

Topical Gel

Testosterone topical gel is a clear, colorless, hydroalcoholic gel containing testosterone 1%. AndroGel® also contains alcohol 68.9%, purified water, sodium hydroxide, carbomer 940, and isopropyl myristate and Testim® also contains alcohol 74%, purified water, pentadecactone, carbopol, acrylates, propylene glycol, glycerin, polyethylene glycol, and tromethamine. Each g of testosterone gel 1% contains 10 mg of testosterone.

•Stability

Commercially available testosterone preparations should be stored at a temperature of 20–25°C; freezing of the sterile suspension and injections should be avoided. A precipitate may form if the injections are stored at a low temperature; however, this will dissolve after shaking and warming to room temperature. Use of a wet needle orsyringe may cause the parenteral solutions to become cloudy; however, this will not affect potency.
Testosterone implants (pellets) should be stored in a cool place (8–15°C).

Androderm® and scrotal Testoderm® transdermal systems should be stored at a room temperature of 15–30°C and nonscrotal Testoderm® TTS transdermal systems should be stored at a controlled room temperature less than 25°C. Testosterone transdermal systems should be disposed of in household trash in a manner that prevents accidental application or ingestion by children or pets.

Preparations

Most preparations containing testosterone or its esters are subject to control under the Federal Controlled Substances Act of 1970, as amended by the Anabolic Steroids Control Act of 1990, as schedule III (C-III) drugs. (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. 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.

Testosterone

Route Form Strength Brand
Powder* (C-III)
Parenteral Implants, for subcutaneous use 75 mg Testopel® Pellets (C-III; with povidone), Bartor
Injectable suspension 100 mg/mL (C-III)*
Topical Gel 1% (25 and 50 mg) AndroGel® (C-III; with alcohol 68.9%), Unimed
1% (50 mg) Testim® (C-III; with alcohol 74%), Auxilium
Transdermal System 2.5 mg/24 hour (12.2 mg/37 cm2) Androderm® (C-III; with alcohol), Watson
4 mg/24 hour (10 mg/40 cm2) Testoderm® (C-III; available with or without adhesive), Ortho-McNeil
5 mg/24 hour (24.3 mg/44 cm2) Androderm® (C-III; with alcohol), Watson
5 mg/24 hour (328 mg/60 cm2) Testoderm® TTS (C-III; with 1.2 mL alcohol), Ortho-McNeil
6 mg/24 hour (15 mg/60 cm2) Testoderm® (C-III; available with or without adhesive), Ortho-McNeil

*available by nonproprietary name


Testosterone cypionate

Route Form Strength Brand
Parenteral Injection (in oil) 100 mg/mL* Depo®-Testosterone (C-III with benzyl alcohol), Pfizer
200 mg/mL Depo®-Testosterone (C-III; with benzyl alcohol), Pfizer
Virilon® IM (C-III; with benzyl alcohol), Star

*available by nonproprietary name


Testosterone cypionate Combinations

Route Form Strength Brand
Parenteral Injection (in oil) 50 mg/mL with Estradiol cypionate 2 mg/mL* Depo-Testadiol® (C-III; with chlorobutanol), Pfizer

*available by nonproprietary name


Testosterone enanthate

Route Form Strength Brand
Parenteral Injection (in oil) 200 mg/mL* Delatestryl® (C-III; with chlorobutanol; available as Unimatic® disposable syringes and multiple-dose vials), BTG

*available by nonproprietary name


Testosterone enanthate Combinations

Route Form Strength Brand
Parenteral Injection (in oil) 90 mg/mL with Estradiol Valerate 4 mg/mL*

*available by nonproprietary name


Testosterone propionate

Route Form Strength Brand
Powder* (C-III)
Parenteral Injection (in oil) 100 mg/mL (C-III)*

*available by nonproprietary name
†Use is not currently included in the labeling approved by the US Food and Drug Administration.

"Testosterone replacement therapy is not associated with an increased risk of cancer or prostate cancer in men, based on results from a large study with a mean follow-up of nearly 9 years" ... and "When the researchers examined prostate cancer alone, they found that men on TRT had an age-adjusted SIR of 2.6 while those not on TRT had a SIR of 3.7. That particular finding is "very preliminary, but maybe there’s some possible protective effect of testosterone," said Dr. Eisenberg, who is also an assistant professor of urology at Stanford."

No higher risk of cancer after 9 years of testosterone replacement therapy : Clinical Endocrinology News

nice find ^^^