Possibly Everything You Might Wanto to Know about Testosterone I

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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.