Vademecum

TESTOSTERONA

DESCRIPCION

Testosterone is the primary androgen found in the body. Endogenous testosterone is synthesized by cells in the testis, ovary, and adrenal cortex. Therapeutically, testosterone is used in the management of hypogonadism, either congenital or acquired. Testosterone is also the most effective exogenous androgen for the palliative treatment of carcinoma of the breast in postmenopausal women. Anabolic steroids, derivatives of testosterone, have been used illicitly and are now controlled substances. Testosterone was in use in 1938 and approved by the FDA in 1939. Testosterone is administered parenterally in regular and delayed-release (depot) dosage forms. Two transdermal forms are available for the treatment of male hypogonadism. Testopelï¿½ Implants contain testosterone in sterile pellets that are implanted subcutaneously for extended-release over 3ï¿½6 months time. Androgelï¿½ (testosterone topical skin gel) was approved in February 2000. Other topical dosage forms and a sublingual tablet are under investigation. Mechanism of Action: Endogenous testosterone is responsible for sexual maturation at all stages of development throughout life. Synthetically, it is prepared from cholesterol. The function of androgens in male development begins in the fetus, is crucial during puberty, and continues to play an important role in the adult male. Women also secrete small amounts of testosterone from the ovaries. The secretion of androgens from the adrenal cortex is insufficient to maintain male sexuality. Increased androgen plasma concentrations suppress gonadotropin-releasing hormone (reducing endogenous testosterone), luteinizing hormone, and follicle-stimulating hormone by a negative-feedback mechanism. Testosterone also affects the formation of erythropoietin, the balance of calcium, and blood glucose. Androgens have a high lipid solubility, enabling them to rapidly enter cells of target tissues. Within the cells, testosterone undergoes enzymatic conversion to 5-alpha-dihydrotestosterone and forms a loosely bound complex with cystolic receptors. Androgen action arises from the initiation of transcription and cellular changes in the nucleus brought about by this steroid-receptor complex. Normally, endogenous androgens stimulate RNA polymerase, resulting in an increased protein production.These proteins are responsible for normal male sexual development, including the growth and maturation of the prostate, seminal vesicle, penis, and scrotum. During puberty, androgens cause a sudden increase in growth and development of muscle, with redistribution of body fat. Changes also take place in the larynx and vocal cords, deepening the voice. Puberty is completed with beard development and growth of body hair. Fusion of the epiphyses and termination of growth is also governed by the androgens, as is the maintenance of spermatogenesis. When endogenous androgens are unavailable, use of exogenous androgens are necessary for normal male growth and development. Pharmacokinetics: Testosterone is administered IM, as a topical gel or ointment, by implantation of long-acting pellets, or via transdermal systems. Testosterone is absorbed from the GI tract, but because of extensive first-pass metabolism, oral bioavailability is poor. ï¿½Intramuscular absorption: Parenteral formulations have been developed that reduce the rate of testosterone secretion, with esters being less polar and slowly absorbed from intramuscular sites. Esters have a duration of action of 2ï¿½4 weeks following IM administration. The esters are hydrolyzed to free testosterone, which is inactivated in the liver. ï¿½Subcutaneous implantable pellets: The duration of action of testosterone pellets (Testopelï¿½) is usually 3ï¿½4 months, but may last as long as 6 months. ï¿½Topical skin gel/ointment absorption: Roughly 10% of an applied topical dosage of testosterone skin gel or ointment is systemically absorbed with once daily dosing; absorption of the gel from the skin occurs continually over the 24 hour dosing interval which indicates that the skin acts as a reservoir for sustained-release. ï¿½Transdermal patch absorption: There are three brands of testosterone patches available. Testodermï¿½ patches are applied to the scrotum and serum concentrations of testosterone rise to a maximum after 2ï¿½4 hours, returning to baseline two hours after patch removal. Serum concentrations of testosterone approach those of normal males, and reach a plateau after 3ï¿½4 weeks. The scrotal skin is about five times more permeable than normal skin and Testodermï¿½ will not achieve desired serum concentrations if applied to other skin sites. Testodermï¿½ TTS patches achieve adequate serum concentrations when applied to the arm, back, or upper buttocks; serum testosterone concentrations peak at 2ï¿½4 hours and return towards baseline within roughly 2 hours of patch removal. Androdermï¿½ patches can be applied to any healthy skin site other than on the scrotum or bony areas. Daily application of two Androdermï¿½ skin patches at 10 PM results in serum testosterone concentrations that approach those of healthy young men and follow normal circadian variation. The first day of dosing results in morning serum testosterone concentrations within the normal range. There is no testosterone accumulation with continued use. Following removal of Androdermï¿½, hypogonadal status returns within 24 hours. Baseline serum testosterone concentrations may be reduced because endogenous secretion of testosterone may be suppressed by Androdermï¿½. ï¿½Distribution, metabolism and excretion: In serum, testosterone is bound to protein. Testosterone has a high affinity for sex hormone binding globulin (SHBG) and a low affinity for albumin. The albumin-bound portion freely dissociates. The affinity for SHBG changes throughout life. It is high during prepuberty, declines during adolescence and adult life, then rises again in old age. The active metabolite DHT has a greater affinity for SHBG than testosterone. Elimination half-life is 10ï¿½100 minutes and is dependent on the amount of free testosterone in the plasma. Testosterone is metabolized in the liver to various 17-keto steroids. Estradiol and dihydrotestosterone (DHT) are the major active metabolites, and DHT undergoes further metabolism. Testosterone activity appears to depend on formation of DHT, which binds to cytosol receptor proteins. Further metabolism of DHT takes place in reproductive tissues. About 90% of a testosterone dose is excreted in the urine as conjugates of glucuronic and sulfuric acids. About 6% is excreted in the feces, largely unconjugated.

Indications...Dosage For androgen replacement therapy: ï¿½For the treatment of impotence: Intramuscular dosage (testosterone suspension or testosterone propionate): Adults: 10ï¿½25 mg IM two or three times a week. Intramuscular dosage (testosterone cypionate or testosterone enanthate): Adults: 50ï¿½400 mg IM once every 2ï¿½4 weeks. ï¿½For the treatment of hypogonadism (primary and hypogonadotropic types): Intramuscular dosage (testosterone suspension or testosterone propionate): Adults: 10ï¿½25 mg IM two or three times per week. Intramuscular dosage (testosterone cypionate or testosterone enanthate): Adults: 50ï¿½400 mg IM once every 2ï¿½4 weeks. Children: For the initiation of pubertal growth: 40ï¿½50 mg/m2 IM monthly until the growth rate falls to prepubertal levels. For the terminal growth phase: 100 mg/m2 IM monthly until growth ceases. Maintenance of virilization may be achieved with a dose of 100 mg/m2 twice monthly. Topical gel dosage (only for AndroGelï¿½): Adults over age 18 years: Initially, 50 mg of testosterone (5 g of 1% skin gel) to the skin of the shoulder, arm, or abdomen once daily, preferably in the morning. The serum testosterone level should be measured 14 days after the initiation of therapy to ensure proper dosage. If the serum testosterone level is below the normal range or if the desired clinical response is not achieved, the testosterone dosage may be increased to 75 mg/day (7.5 g of gel once daily) and then to 100 mg/day (10 g of gel once daily) as clinically indicated. The maximum recommended testosterone dosage is 100 mg/day (10 g of gel) based on clinical trials. Transdermal dosage (only for Testodermï¿½): Adults over age 18 years: Apply a 60 cm2 patch to the scrotal area, changed daily. For optimal contact the skin should be dry, clean, and dry-shaved if necessary. This patch will deliver 6 mg of testosterone per day. If the scrotal area is inadequate, a 40 cm2 patch, delivering 4 mg of testosterone per day, may be applied. The patch should be worn for 22 hours out of 24. Serum testosterone levels should be determined after 3ï¿½4 weeks of daily system use. If results are inadequate after 6ï¿½8 weeks, another form of replacement therapy should be used. Children up to age 18 years: Safety and efficacy have not been established. Transdermal dosage (only for Testoderm TTSï¿½): Adults over age 18 years: Apply a patch (one system) to an area of dry, clean skin on the arm, back, or upper buttocks every 24 hours. This patch will deliver 5 mg of testosterone per day. Serum testosterone concentrations should be taken to determine whether normal serum testosterone levels have been achieved. Dose may be increased as appropriate. Children up to age 18 years: Safety and efficacy have not been established. Transdermal dosage (only for Androdermï¿½): Adults: Apply a patch (one system) nightly to an area of dry, clean skin on the upper arms, thighs, back or abdomen. The patch should be worn for 24 hours. The usual dose is 5 mg, changed daily, provided by two patches worn simultaneously at different sites. Serum testosterone concentrations should be taken to determine whether normal serum testosterone levels have been achieved. Depending on these results, the maintenance dose may be increased to 3 systems or reduced to one system daily. Therapy for non-virilized patients should be started at 1 system nightly. Children up to age 18 years: Safety and efficacy have not been established. For the treatment of delayed puberty in males: Intramuscular dosage (testosterone suspension or testosterone propionate) Adolescents: Up to 100 mg IM per month for a limited period, usually between 4ï¿½6 months. Different dosage schedules have been employed dependent on patients chronological and skeletal age, and response. Intramuscular dosage (testosterone cypionate or testosterone enanthate): Adolescents: 50ï¿½200 mg IM once every 2ï¿½4 weeks for a limited period. Or, 40ï¿½50 mg/m2/dose IM monthly for 6 months. For palliative treatment of inoperable breast cancer in women: Intramuscular dosage (testosterone suspension or testosterone propionate): Adults: 50ï¿½100 mg IM three times a week. Intramuscular dosage (testosterone cypionate or testosterone enanthate): Adults: 200ï¿½400 mg IM once every 2ï¿½4 weeks. For the treatment of postpubertal cryptorchidismï¿½: Intramuscular dosage (testosterone suspension or testosterone propionate): Adults: 10ï¿½25 mg IM two or three times per week. For the treatment of microphallusï¿½: Intramuscular dosage (testosterone enanthate): Children: 25ï¿½50 mg IM once a month for 3ï¿½6 months. Topical dosage (testosterone propionate): Children: Apply a 5% ointment topically to the penis twice daily for three months. For the treatment of anemiaï¿½ in patients with chronic renal failure: Intramuscular dosage (testosterone enanthate): Adults: Initially, 400 mg IM daily for one week, then 400 mg IM once or twice a week. Maintenance dose is 200ï¿½400 mg IM once every 4 weeks. For female-to-male gender changeï¿½: Intramuscular dosage (testosterone cypionate; or testosterone enanthate): Adults: 200 mg IM once every 2 weeks. Higher doses may be required for cessation of menses. For the treatment of lichen sclerosusï¿½: Topical dosage (testosterone ointment): Adults: Apply a 1% or 2% ointment topically to the vulva twice daily for six weeks or until itching is relieved. Decrease dosage to minimum effective dose. For the treatment of AIDS-associated wasting syndromeï¿½: Intramuscular dosage: Adults: In a randomized double-blind, placebo-controlled study, 51 HIV-positive men with AIDS-associated wasting syndrome were randomly assigned to receive testosterone enanthate 300 mg IM or placebo every 3 weeks for 6 months. Compared to patients treated with placebo, testosterone-treated patients had significant increases in lean body mass and an overall improvement in quality of life.[2177] Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. ï¿½non-FDA-approved indication

Administration Intramuscular Administration ï¿½Testosterone injections are administered intramuscularly. Do not inject intravenously. ï¿½If crystals form in the vial of the injection, warm and shake the vial to dissolve. Intramuscular injection (testosterone injection or suspension for injection): ï¿½Use of a wet needle will cause a cloudy solution but will not alter potency. ï¿½Inject IM deeply into the upper outer quadrant of the gluteal muscles. Aspirate prior to injection to avoid injection into a blood vessel. Topical Administration ï¿½Testosterone is applied topically for subcutaneous absorption as transdermal patches, as skin gels, or as ointments. ï¿½Wash hands before and after application of any of these dosage forms. Take care not to touch the eyes or other mucous membranes. Topical skin gel (AndroGelï¿½): ï¿½AndroGelï¿½ is applied once daily (preferably in the morning) to clean, dry skin on the shoulders, upper arm or the abdomen. Do not apply to the scrotum or genitals. ï¿½Open packet(s) needed for proper dosage. Squeeze the entire contents of the dose into the palm of the hand and then immediately apply to the skin site. ï¿½ Allow the site to dry a few minutes before putting on clothing. ï¿½Wash hands after application. ï¿½For optimal response, do not shower or swim for 5ï¿½6 hours after application of the gel. ï¿½Direct contact of the gel-medicated skin with the skin of another person can result in the transfer of residual testosterone and absorption by the other person. It is recommended that the treated area be clothed at all times prior to washing off residual drug. In clinical studies, vigorous contact with a female partner for 15 minutes resulted in serum female testosterone levels > 2 times normal values. In the case of direct contact, the other person should wash the area of contact with soap and water as soon as possible. Transdermal systems: NOTE: Mild skin irritation may be ameliorated by treatment of the affected skin with over-the-counter topical hydrocortisone cream applied after system removal. Additionally, applying a small amount of 0.1% triamcinolone acetonide cream to the skin under the central drug reservoir of the transdermal system has been shown to reduce the incidence and severity of skin irritation. The administration of 0.1% triamcinolone acetonide cream does not significantly alter transdermal absorption of testosterone from the system. Ointment formulations should not be used for pretreatment as they may significantly reduce testosterone absorption. ï¿½Testodermï¿½: Apply patch to a dry, clean, dry-shaved area on the scrotum. Do not use chemical depilatories to remove hair. ï¿½Androdermï¿½: Apply patch to a dry, clean area of skin on the upper arms, thighs, back or abdomen. Rotate sites daily and do not reuse a site for 7 days. Do not apply to the scrotum or bony areas of the body. Extemporaneous compounding of a Testosterone Ointmentï¿½: ï¿½Extemporaneously prepare 15 grams of a 2% ointment by using 3 ml of 100 mg/ml testosterone propionate injection and 12 grams of white petrolatum. To make 15 grams of a 5% ointment, use 7.5 ml of 100 mg/ml testosterone propionate injection and 7.5 grams of white petrolatum. ï¿½non-FDA-approved indication

Contraindications Testosterone injections are administered intramuscularly. Do not inject via intravenous administration. Testosterone can stimulate the growth of cancerous tissue and should not be used to treat male patients with prostate cancer or breast cancer. Patients with prostatic hypertrophy should be treated with caution because of the possible development of malignancy. During treatment with androgens, edema occurs because of water retention in association with sodium retention. Testosterone is therefore contraindicated in patients with severe cardiac disease, severe hepatic disease, or severe renal disease because of possible exacerbation of these conditions. In addition, patients with heart failure, nephritis, nephrosis, coronary artery disease, myocardial infarction, or existing edema should be treated with caution. Patients with severe hepatic disease or hepatic dysfunction also can be at risk of drug accumulation because of reduced clearance. Patients receiving high doses of testosterone are at risk for polycythemia. Testosterone is absolutely contraindicated during pregnancy because of probable adverse effects on the fetus (FDA pregnancy category X). Females of childbearing potential who are receiving testosterone treatments should utilize adequate contraception. Women should be aware that accidental exposure to some testosterone dosage forms (i.e., ointments and gels) may occur if they come into direct contact with a treated patient. In clinical studies, within 2ï¿½12 hours of gel application by male subjects, 15-minute sessions of vigorous skin-to-skin contact with a female partner resulted in serum female testosterone levels > 2 times the female baseline values. When clothing covered the treated site on the male, the transfer of testosterone to the female was avoided. In the case of direct skin-to-skin contact with the site of gel or ointment application, the non-treated person should wash the area with soap and water as soon as possible. Testosterone distribution into breast milk has not been determined, but it may have adverse effects on the infant. Alternative methods to breast-feeding are recommended in lactating women receiving testosterone therapy. Androgen therapy can result in loss of diabetic control and should be used with caution in patients with diabetes mellitus. Close monitoring of blood glucose is recommended. Testosterone has induced osteolysis and should be used with caution in patients with hypercalcemia, which can be exacerbated in patients with metastatic breast cancer. Use of testosterone in children should be undertaken only with extreme caution. Testosterone may accelerate bone maturation without stimulating compensatory linear growth, sometimes resulting in compromised adult stature. If testosterone is administered to prepubertal males, radiographic examinations of the hand and wrist should be performed every 6 months to assses the rate of bone maturation and the effect of the drug on epiphyseal centers. Once the epiphyses have closed, growth is terminated. Even after discontinuation of treatment, epiphyseal closure can be enhanced for several months. Some preparations of testosterone contain tartrazine dye and should be used with caution in patients with a known tartrazine dye hypersensitivity. Patients allergic to aspirin are often at risk.

Interactions Testosterone can increase the anticoagulant action of warfarin. Serious bleeding has been reported with this drug-drug interaction. Although the mechanism is unclear, testosterone may reduce procoagulant factors. Reduction of warfarin dosage may be necessary if testosterone therapy is coadministered. It is unclear if testosterone can augment the anticoagulant response to heparin therapy in a similar manner. Testosterone has been shown to increase plasma concentrations of cyclosporine, leading to a greater risk of nephrotoxicity. Androgens can increase the risk of hepatotoxicity and therefore should be used with caution when administered concomitantly with other hepatotoxic medications. Patients should be monitored closely for signs of liver damage, especially those with a history of liver disease. Androgens may be necessary to assist in the growth response to human growth hormone, but excessive doses of androgens in prepubescent males can accelerate epiphyseal maturation. Androgens are known to stimulate erythropoiesis. Despite the fact that endogenous generation of erythropoietin is depressed in patients with chronic renal failure, other tissues besides the kidney can synthesize erythropoietin, albeit in small amounts. Concurrent administration of androgens can increase the patient's response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made. Theoretically, because the soy isoflavones appear to inhibit type II 5-alpha-reductase, the soy isoflavones may counteract the activity of the androgens. The actions of androgens could be antagonized by finasteride or saw palmetto. Avoid concurrent use of androgens and saw palmetto, Serenoa repens.

Adverse Reactions In females Disruption of the regular menstrual cycle secondary to testosterone-induced suppression of gonadotropin secretion can lead to amenorrhea or oligomenorrhea. When androgens are given to women, virilization, manifested by acne, growth of facial hair, enlarged clitoris, reduced breast size, and deepening of the voice, can occur. If treatment is discontinued when these symptoms first appear, they usually subside. Prolonged treatment can lead to irreversible masculinity, so the benefit of treatment should be measured against the risk. In males Male patients can experience feminization during prolonged therapy with testosterone, which is believed to result from inhibition of gonadotropin secretion and conversion of androgens to estrogens. These effects are more pronounced in patients with concurrent hepatic disease and include breast soreness and gynecomastia. Feminizing effects are generally reversible. Priapism and excessive sexual stimulation, more common in geriatric males, are generally the effect of excessive testosterone dosage. Oligospermia and decreased ejaculatory volume may occur in patients receiving long-term therapy or excessive doses. Alopecia resembling male pattern baldness has also occurred. Prostate cancer as a secondary malignancy or prostatic hypertrophy can develop during prolonged therapy with testosterone and are more likely to occur in eldery male patients. Signs of acute epididymitis (e.g., fever, chills, pain in the inguinal region) and/or urinary urgency should prompt withdrawal of the drug and reevaluation of dosage. Testosterone patches can cause scrotal skin irritation, erythema, and/or pruritus at site of application. Blister reactions may occur under the system. These reactions will usually decrease or disappear over time. The patches can also cause skin discoloration. Chronic skin irritation resulted in 5% of patients to discontinue treatment. Mild skin irritation may be ameliorated by treatment of affected skin with over-the-counter topical hydrocortisone cream applied after transdermal system removal. Additionally, applying a small amount of 0.1% triamcinolone acetonide cream to the skin under the central drug reservoir of the transdermal system has been shown to reduce the incidence and severity of skin irritation. The administration of 0.1% triamcinolone acetonide cream does not significantly alter transdermal absorption of testosterone from the system. Ointment formulations should not be used for pretreatment as they may significantly reduce testosterone absorption. Similar to other testosterone products, the patches can cause nausea/vomiting, priapism, edema, urinary difficulties, and mastalgia. Headache has been reported in about 5% of patients during use of testosterone patches. In prepubescent males When androgens are used in the treatment of immature males, early virilism can be a disadvantage because it is accompanied by premature epiphyseal closure. Monitoring of skeletal maturation should be undertaken at about 6-month intervals. Once the epiphyses have closed, growth is terminated. Even after discontinuation of treatment, epiphyseal closure can be enhanced for several months. In males and females Peripheral edema can occur as the result of increased water retention (in association with sodium chloride) and is manifested by weight gain. If normal therapeutic doses are used in the treatment of hypogonadism, only a moderate amount of fluid retention occurs. In the treatment of patients with impaired renal function or congestive heart failure, the water retention is of greater significance. Androgen therapy is related to growth and secretion of the sebaceous glands, which can cause an acne indistinguishable from acne vulgaris. Hepatic dysfunction can occur from use of testosterone. Elevated hepatic enzymes are more common than overt jaundice. Hepatic effects have been shown to be more likely with administration 17-alpha-alkylandrogens such as methyltestosterone. The drug should be discontinued if cholestatic jaundice or hepatitis occurs. Peliosis hepatis and hepatic neoplasms occur rarely, but when they do, they are potentially life-threatening. Androgen therapy has induced osteolysis and can exacerbate hypercalcemia. Androgen-induced hypercalcemia occurs especially in immobile patients and those with metastatic carcinoma of the breast. Testosterone has a stimulatory effect on the formation of erythropoietin. Increased erythropoiesis, especially in women, can lead to erythrocytosis (polycythemia) and its complications including: dizziness, headache, tiredness, unusual bleeding, flushing, or redness of the skin. Periodic hemoglobin and hematocrit determinations should be considered in patients receiving long-term therapy. Observational studies in post-menopausal women, bodybuilders, and weightlifters using anabolic steroids have revealed "pro-atherogenic" changes in lipid profiles, including decreases in HDL concentrations and increases in LDL concentrations. Synthetic androgens may produce a greater lowering of the HDL-C:LDL-C ratio than does testosterone. Oral dosage forms may produce greater changes than parenteral dosage forms. Although the implications of androgen-induced hypercholesterolemia are unclear, caution should be exercised, particularly in patients predisposed to dyslipidemias or atherosclerosis. Androgen therapy can produce libido decrease or libido increase. Geriatric males have been found to be more likely to experience excessive sexual stimulation. Miscellaneous adverse reactions to testosterone therapy have included nausea/vomiting, chills, bladder irritability, insomnia, anxiety, and mental depression. Intramuscular administration of anabolic steroids can cause inflammation, uticaria, postinjection iduration and furunculosis. Patients should be observed for any signs of an injection site reaction.

2177. Grinspoon S, Corcoran C, Askari H, et al. Effects of androgen administration in men with the AIDS wasting syndrome: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;129:18ï¿½26.