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Androgens (Systemic)

This monograph includes information on the following:

1) Fluoxymesterone
2) Methyltestosterone
3) Testosterone

VA CLASSIFICATION
Fluoxymesterone
Primary: HS101
Secondary: AN900; BL400

Methyltestosterone
Primary: HS101
Secondary: AN900

Testosterone
Primary: HS101
Secondary: AN900

Testosterone cypionate
Primary: HS101
Secondary: AN900; BL400

Testosterone enanthate
Primary: HS101
Secondary: AN900; BL400

Testosterone propionate
Primary: HS101
Secondary: AN900

Testosterone undecanoate
Primary: HS101


Note: Controlled substance classification—

Note: Controlled substance classification


U.S.—Schedule III {108}6 {108}5
Commonly used brand name(s): Andriol3; Andro L.A. 2003; AndroGel3; Androderm3; Android2; Android-F1; Andronate 1003; Andronate 2003; Andropository 2003; Andryl 2003; Delatest3; Delatestryl3; Depo-Testosterone3; Depo-Testosterone Cypionate3; Depotest3; Everone 2003; Halotestin1; Malogen in Oil3; Metandren2; ORETON Methyl2; Scheinpharm Testone-Cyp3; T-Cypionate3; Testamone 1003; Testaqua3; Testex3; Testoderm3; Testoderm TTS3; Testoderm with Adhesives3; Testopel Pellets3; Testred2; Testred Cypionate 2003; Testrin-P.A3; Virilon2; Virilon IM3.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Androgen—Fluoxymesterone; Methyltestosterone; Testosterone; Testosterone Undecanoate;

Antineoplastic—Fluoxymesterone; Methyltestosterone; Testosterone;

Antianemic—Fluoxymesterone; Testosterone Cypionate; Testosterone Enanthate;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

General considerations
Whenever long-term therapy is needed in men, testosterone or a testosterone ester is preferred over the oral methylated androgens (fluoxymesterone and methyltestosterone) because hepatotoxicity is less likely to occur{108}4{108}3{108}2{108}1{108}0{121}9.

Accepted

Androgen deficiency, due to primary or secondary hypogonadism (treatment)—Androgens are primarily indicated in males as replacement therapy when congenital or acquired endogenous androgen absence or deficiency is associated with primary or secondary hypogonadism. Primary hypogonadism includes conditions such as: testicular failure due to cryptorchidism, bilateral torsion, orchitis, or vanishing testis syndrome; inborn errors in testosterone biosynthesis; or bilateral orchidectomy {121}8. Hypogonadotropic hypogonadism (secondary hypogonadism) conditions include gonadotropin-releasing hormone (GnRH) deficiency or pituitary-hypothalamic injury as a result of surgery, tumors, trauma, or radiation and are the most common forms of hypogonadism seen in older adults.{121}7{121}6{121}5{121}4{121}3{121}2{121}1{121}0{136}9{136}8{136}7{136}6{136}5{136}4{136}3{136}2{136}1{136}0{182}9{182}8{182}7{182}6 Dosage adjustment is needed to accommodate individual clinical requirements for such life changes as induction of puberty, development of secondary sexual characteristics, impotence due to testicular failure, or infertility due to oligospermia.{182}5{182}4{182}3{182}2{182}1{182}0

Puberty, delayed male (treatment)—A 6-month-or-shorter course of an androgen is indicated for induction of puberty in patients with familial delayed puberty, a condition characterized by spontaneous, nonpathologic, late-onset puberty, if the patient does not respond to psychological treatment.{193}9 {193}8{193}7{193}6{193}5 {193}4{193}3{193}2{193}1{193}0{221}9{221}8{221}7{221}6{221}5{221}4 Testosterone transdermal products are not presently indicated for treatment of delayed male puberty{221}3{221}2.

Carcinoma, breast (treatment)—Androgens are indicated as secondary or tertiary hormonal treatment for palliation of metastatic breast cancer in women who have been postmenopausal for 1 to 5 years or who are surgically menopausal, who have hormone receptor–positive tumors, or who have previously demonstrated a response to hormone therapy{221}1{221}0{109}9{109}8{109}7{109}6{109}5{109}4{109}3{109}2{109}1{109}0{121}9. Androgens have also been used in the treatment of metastatic breast cancer as a supplement to chemotherapy{121}8{121}7{121}6{121}5{121}4{121}3. Transdermal testosterone systems and subcutaneous implants are not indicated for these uses and should not be used by females{121}2{121}1{121}0.

[Anemia (treatment)]1—Fluoxymesterone and testosterone cypionate or enanthate have been used to treat certain types of anemia, such as aplastic anemia, myelofibrosis, myelosclerosis, agnogenic myeloid metaplasia, and hypoplastic anemias caused by malignancy or myelotoxic drugs{182}9.

[Constitutional delay in growth (treatment) ]1—Androgens are used in the treatment of constitutional delay in growth{182}8{182}7{182}6. However, they are no longer considered the treatment of choice for most patients{182}5{182}4{182}3{182}2{182}1{182}0.

[Gender change, female-to-male]1—Testosterone is used for the development and maintenance of secondary sexual characteristics in female-to-male transsexuals{221}9{221}8{221}7{221}6{221}5.

[Lichen sclerosus (treatment adjunct) ]1—Extemporaneously compounded topical testosterone is used for the treatment of itching resulting from lichen sclerosus.{221}4{221}3{221}2{221}1{221}0{112}9

[Microphallus (treatment)]1—Intramuscular preparations of testosterone and testosterone esters, and extemporaneously compounded topical testosterone are used in the treatment of microphallus{112}8{112}7{112}6{112}5{112}4{112}3.

Acceptance not established
Although testosterone cypionate and testosterone undecanoate are indicated in Canada for the following conditions if they are not due to primary or secondary hypogonadism, further studies are needed to define the role, safety, and efficacy{112}2 of androgens to treat male climacteric symptoms and male infertility due to oligospermia.{112}1{112}0 Further studies are also needed to assess androgens as adjunctive treatment for male or female osteoporosis{136}9{136}8.

Unaccepted
Use of androgens to enhance athletic performance is illegal{136}7{136}6{136}5{136}4{136}3{136}2{136}1. Increases in muscle mass and muscle strength can be sufficient to enhance athletic performance{136}0. However, the risk of unwanted effects, such as suppression of spermatogenesis, testicular atrophy, menstrual disturbances, virilization in females, peliosis hepatis (hepatic parenchymal injury), hepatotoxicity, potential adverse effects on cardiovascular health, and development of hepatic cancer, counter athletic benefits received from androgens and make their use in athletes inappropriate{182}9{182}8{182}7{182}6{182}5{182}4. Furthermore, behavioral disturbances, including aggressive or violent behavior, have been reported with supraphysiological self-administered doses in athletes{182}3{182}2{182}1.

Androgens are not recommended for accelerating the healing of fractures or shortening the duration of postsurgical convalescence. {182}0{97}9

The use of androgens for the prevention of postpartum breast engorgement is not recommended. In most patients, postpartum breast engorgement is a benign, self-limiting condition that may respond to breast support and mild analgesics, such as acetaminophen and ibuprofen. Evidence supporting the efficacy of androgens for this indication is lacking.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:


Description
    Testosterone implants are compressed crystalline testosterone, cylindrically shaped, measuring 3.2 millimeters (mm) in diameter and 8 to 9 mm in length.{97}8
    Two types of testosterone transdermal systems are available:

• Drug-in-adhesive matrix on film (matrix-type)— Testoderm contains three layers: a polyester liner that must be removed before using; an adhesive matrix containing testosterone; and the back outermost layer, a flexible polyurethane protective film with epoxy resin.{97}7 Testoderm with Adhesives incorporates five additional adhesive strips onto the adhesive matrix of the drug film{97}6.


• Membrane-controlled drug reservoir (reservoir-type)— Androderm contains: a protective liner that must be removed before using; a disc, matted between adhesive layers, that protects the central drug reservoir and is removed before using; an adhesive layer; a membrane providing extended release of testosterone; a drug reservoir holding the testosterone, glycerin, glycerol monooleate, methyl laurate, purified water and alcohol gelled with an acrylic acid copolymer; and the back outermost layer, a polyester protective film.{97}5 Testoderm TTS is similar but does not contain the protective disc{97}4.
The matrix-type transdermal system is thinner than the reservoir-type.{97}3{97}2
    Transdermal testosterone gel is a clear, colorless hydroalcoholic gel containing 1% testosterone. The gel provides continuous transdermal delivery of testosterone for 24 hours following a single application{97}1.

Chemical group—
    Naturally occurring androgens include testosterone.
    Semi-synthetic androgens are testosterone cypionate, testosterone enanthate, and testosterone propionate.
    Synthetic androgens include fluoxymesterone and methyltestosterone.
    Oral methylated androgens (17-alpha-alkylated androgens) include fluoxymesterone and methyltestosterone{97}0{102}9{102}8 {102}7.
Molecular weight—
    Fluoxymesterone: 336.45{102}6
    Methyltestosterone: 302.46{102}5
    Testosterone: 288.43{102}4
    Testosterone cypionate: 412.62{102}3
    Testosterone enanthate: 400.6{102}2
    Testosterone propionate: 344.5{102}1
    Testosterone undecanoate: 456.7{102}0

Mechanism of action/Effect:

Endogenous plasma testosterone is maintained and regulated by gonadotropins within a normal range by a negative feedback system involving the hypothalamus and pituitary{108}9. Supraphysiologic doses of testosterone can effectively suppress the gonadotropins and spermatogenesis in eugonadal men{108}8{108}7{108}6{108}5{108}4.

Androgens are highly lipid-soluble and enter cells of target tissues by passive diffusion{108}3. Testosterone or 5-alpha-dihydrotestosterone (DHT), a metabolite produced from testosterone by the enzyme 5-alpha-reductase, binds to an intracellular androgen receptor{108}2{108}1{108}0. The hormone receptor complex translocates into the nucleus and attaches to specific hormone receptor elements on the chromosome to initiate or suppress transcription and protein synthesis{111}9. Testosterone can produce estrogenic effects as a result of its conversion to estrogen{111}8.



Androgen deficiency:

Physiologic concentrations of androgens stimulate spermatogenesis and male sexual maturity at puberty, and develop and maintain male secondary sexual characteristics. These effects include growth and maturation of the prostate, seminal vesicles, penis, and scrotum; male hair and muscle-to-fat body mass distribution; enlargement of the larynx; and thickening of vocal cords{111}7{111}6 {111}5 {111}4. In children, exogenous androgens increase linear bone growth rates and help fuse the epiphyseal growth centers. An increase in bone growth rate can also correspond to a disproportionate advancement of bone maturation.{111}3



Microphallus:

Intramuscular administration of testosterone or testosterone esters or local application of testosterone propionate ointment may result in an increase in circulating serum concentrations of DHT, which is principally responsible for phallic growth {111}2{111}1{111}0{121}9{121}8{121}7.



Lichen sclerosus:

The signs and symptoms of lichen sclerosus (vulvar itching, abnormal vulvar skin histology) may be the result of a deficiency of 5-alpha-reductase activity and subsequently reduced local DHT concentrations{121}6. Local application of testosterone propionate ointment may correct this deficiency in 5-alpha-reductase activity{121}5{121}4{121}3. Testosterone may cause a slight increase in local DHT concentrations, which may induce 5-alpha-reductase activity, and further increase local DHT concentrations{121}2{121}1{121}0{76}9.



Antianemic:

Androgens stimulate the production of red blood cells by enhancing production of erythropoietic stimulating factors.{76}8{76}7{76}6{76}5{76}4


Absorption:


Methyltestosterone:

Absorbed from oral mucosa and gastrointestinal tract{76}3.



Testosterone:


• Matrix-type transdermal system: The patch must be applied to scrotal skin (5 to 30 times more permeable to testosterone than other skin sites) to produce an adequate testosterone serum concentration{76}2. A matrix transdermal system will not produce adequate serum testosterone concentrations if applied to nonscrotal skin. Serum testosterone concentrations reach a plateau at 3 to 4 weeks{76}1 and, although testosterone is absorbed throughout a 24-hour period, concentrations do not simulate the circadian rhythm of endogenous testosterone in normal males{76}0. Interpatient variation in total plasma testosterone concentrations is high, approximately 35 to 49%; the average variation of concentration in a patient is approximately 30 to 41%{76}9.


• Reservoir-type transdermal system: Patients should avoid applying the reservoir-type patch to scrotal skin. The reservoir transdermal systems have similar sites of application, but manufacturers, depending on their clinical studies, recommend different sites and times for patch application. Since the reservoir patches show differences in time to peak effect, applying them either in the morning or at night, depending on the reservoir transdermal system and manufacturer instructions, achieves normal serum testosterone concentrations of circadian rhythm, peaking in the morning and decreasing throughout the rest of the day to plateau at night{76}8{76}7. Normal serum testosterone concentrations are reached during the first day of dosing, and drug accumulation does not occur with repeated applications{76}6{76}5.

• For Androderm—Using two transdermal systems that deliver 2.5 mg of testosterone per day each, hypogonadal men absorb 4 to 5 mg of testosterone in 24 hours, and, if the patches are applied at 10 p.m. to the abdomen, back, thighs, or upper arms, concentrations simulate the circadian rhythm of endogenous testosterone in normal males. Similar results are expected with use of a single 5-mg patch{76}4. Hypogonadal men applying the patch to the chest or shin absorb 3 to 4 mg of testosterone in 24 hours{76}3.


• For Testoderm TTS—Studies of the three application sites (upper buttocks, arm, and back) showed that when a 5-mg patch was applied at 8 a.m., testosterone concentrations simulated the circadian rhythm of endogenous testosterone in normal males{76}2.



• Subcutaneous implant: Approximately one third of the testosterone dose is absorbed in the first month, one fourth in the second month, and one sixth in the third month. Absorption continues until the implant completely dissolves, which may take up to 6 months.{76}1


• Testosterone gel: In a study with the 10-gram dose (to deliver 100 mg testosterone), all patients showed an increase in serum testosterone within 30 minutes, and 8 of 9 patients had a serum testosterone concentration within the normal range by 4 hours after the initial application. Absorption of testosterone into the blood continues for the entire 24-hour dosing interval. Serum concentrations approximate the steady state level by the end of the first 24 hours and are at steady state by the second or third day of dosing{76}0.


Protein binding:

Testosterone—Very high (approximately 99%; 80% to sex hormone–binding globulin [SHBG], 19% to albumin, and 1% free{76}9{76}8{76}7{76}6{76}5{76}4{76}3{76}2{76}1). The metabolite DHT has greater affinity for SHBG than does testosterone{76}0.

Biotransformation:

Hepatic{76}9{76}8.

Fluoxymesterone; methyltestosterone—Presence of 17-alpha alkyl group reduces susceptibility to hepatic enzyme degradation, which slows metabolism and allows oral administration{76}7{76}6{76}5.

Testosterone—Free testosterone is further converted into two of the major active metabolites, DHT and estradiol. Orally administered testosterone, but not testosterone undecanoate, undergoes nearly complete first-pass metabolism; both intramuscular and transdermal administration avoid first-pass metabolism{76}4{76}3{76}2{76}1{76}0{76}9{76}8.

• Oral: In first-pass metabolism, 90% of the oral testosterone dose is metabolized primarily to etiocholanolone, androsterone, and androstanediol, which are then conjugated{76}7{76}6. Unlike oral testosterone, oral testosterone undecanoate does not undergo hepatic first-pass metabolism{76}5.


• Injection: Testosterone esters (cypionate, enanthate, propionate) first undergo hydrolysis of the ester to the active form, free testosterone{76}4{76}3{76}2{76}1.


• Matrix-type transdermal systems: A threefold increase in DHT serum concentrations has been reported with the matrix-type testosterone transdermal system applied to scrotal skin due to high conversion to DHT by 5-alpha-reductase in the scrotal tissue{76}0. Normal ranges of estradiol concentrations are produced; however, 3 of 72 male patients using the matrix patch experienced sporadic elevations of serum estradiol concentrations that were not associated with feminizing adverse effects{76}9.


• Reservoir-type transdermal systems: The reservoir-type patch applied to nonscrotal skin produced normal DHT and estradiol serum concentrations.{76}8{76}7{76}6{76}5


• Testosterone gel: DHT concentrations increased in parallel with testosterone concentrations during testosterone gel treatment. After 180 days of treatment, mean DHT concentrations were within the normal range with a 5–gram dose ofAndrogel and were about 7% above the normal range after a 10–gram dose. The mean steady state DHT/T ratio during 180 days of treatment remained within normal limits and ranged from 0.23 to 0.29 (5 grams/day) and from 0.27 to 0.33 (10 grams/day){76}4.


Half-life:

The activity of testosterone in many tissues appears to be dependent on its reduction to DHT and the binding capacity of sex hormone–binding globulin (high in prepubertal children, declining through puberty and adulthood, and increasing again later in life){76}3{76}2{76}1.

Fluoxymesterone—Approximately 9.2 hours{76}0.

Methyltestosterone—2.5 to 3.5 hours.

Testosterone (intramuscular injection and matrix-type and reservoir-type transdermal systems and transdermal gel)—10 to 100 minutes (plasma){225}9{225}8{225}7{225}6{225}5.

Testosterone cypionate (intramuscular)—Approximately 8 days{225}4.

Time to peak concentration:


Methyltestosterone:

Tablets: 2 hours.



Testosterone undecanoate:

Capsules: 4 to 5 hours{225}3.



Testosterone:

Matrix-type transdermal systems: At steady state, approximately 2 to 4 hours after application{225}2.

Reservoir-type transdermal systems:

• For Androderm: Approximately 6 to 10 hours after application. {225}1When the reservoir-type transdermal system was applied to the back, peak serum testosterone concentrations were achieved 6 to 12 hours after the application.{225}0


• For Testoderm TTS: At steady state, approximately 4 hours after application{223}9.


• For AndroGel: Approximately 2 hours after application{223}8.



Peak serum concentration:


For testosterone transdermal systems:

For matrix-type:

• Testosterone, serum concentration—593 nanograms of testosterone per deciliter (nanograms/dL) (20.6 nanomoles per liter [nanomoles/L]), mean serum concentration{223}7. At steady state (up to 3 weeks), approximately 60% of 30 hypogonadal males in a study had maximum testosterone serum concentrations reaching higher than 500 nanograms/dL (17.3 nanomoles/L, ranging from 11.5 to 44.9 nanomoles/L){223}6{223}5.


• DHT, serum concentration—Mean serum concentrations were elevated for the matrix-type transdermal system (range, 134 to 162 nanograms/dL [5.2 to 6.3 nanomoles/L] compared with the normal range of 30 to 85 nanograms/dL [1.2 to 3.3 nanomoles/L]). One 6-year study of hypogonadal men using scrotal transdermal systems reported normal serum testosterone concentrations from 306 to 1031 nanograms/dL (10.6 and 35.8 nanomoles/L) with the elevated DHT serum concentrations remaining stable{223}4.


• Estrogen, serum concentration—Serum concentrations of estrogen in patch users were normal{223}3. However, sporadic elevations above the normal range occurred in 3 of 72 patients using the matrix patch, but were not associated with feminizing side effects{223}2.


For reservoir-type:

• Unlike the matrix-type system, which is placed on the scrotum, the reservoir-type system showed an average DHT and estrogen serum concentrations comparable to that of normal men{223}1.


• Testosterone, serum concentrations—

• For Androderm, beginning with a mean serum testosterone baseline of 76 nanograms/dL (2.6 nanomoles/L):

• 2.5 mg patch—424 nanograms/dL (14.7 nanomoles/L), average peak serum concentration (Cavg).{223}0


• 5 mg patch—584 nanograms/dL (20.2 nanomoles/L), C avg;{223}9 in another study of hypogonadal men (unknown baseline), 753 ± 276 nanograms/dL (26.1 nanomoles/L), mean peak serum concentration (Cmax).


• 7.5 mg patch—766 nanograms/dL (26.6 nanomoles/L), C avg.{223}8



• For Testoderm TTS, beginning with a mean serum testosterone baseline of 150 nanograms/dL (5.2 nanomoles/L):

• 5 mg patch—366 nanograms/dL (12.7 nanomoles/L), C avg; 462 to 499 nanograms/dL (16 to 17.3 nanomoles/L), mean Cmax.




For transdermal gel:

• Mean peak concentrations at steady state: 5 grams—830 ± 347 ng/dL; 7.5 grams—901 ± 471 ng/dL; and 10 grams—1083 ± 434 ng/dL{223}7.



Duration of action:

Testosterone—Dependent upon the ester, dosage form, and route of administration{223}6{223}5.

• Injection: Enanthate and cypionate esters are longer acting than propionate ester and base{223}4{223}3.


• Oral: Undecanoate ester action continues for about 10 hours{223}2.


• Subcutaneous implants: Three to 4 months, but may continue for 6 months.{223}1


• Transdermal systems (matrix-type and reservoir-type): At 22 hours after application, serum testosterone concentration gradually falls to 60 to 80% of the peak serum concentration. On removal of the systems, testosterone serum concentration declines to baseline within 2 hours.


• Transdermal gel: When treatment is discontinued after achieving steady state, serum testosterone levels remain in the normal range for 24 to 48 hours but return to their pretreatment levels by the fifth day after the last application{223}0.


Elimination:
    Generally renal excretion of metabolites{223}9{223}8. Approximately 90% of the administered dose is excreted in the urine, primarily as glucuronide or sulfated conjugates of the metabolites{223}7{223}6{223}5{223}4. Some fecal excretion due to enterohepatic circulation{223}3{223}2.
    Fluoxymesterone—Less than 5% is excreted in urine as free steroid and glucuronide conjugate over a 24-hour period after oral doses of 20 to 200 mg.
    Testosterone—Approximately 6% of dose is excreted in the feces{223}1{223}0{76}9, primarily in unconjugated form{76}8{76}7.
    Testosterone undecanoate—Approximately 77 to 93% of an orally administered dose is excreted in the urine and feces within 3 to 4 days{76}6.


Precautions to Consider

Carcinogenicity/Tumorigenicity

Hepatic neoplasms have been associated with long-term, high-dose androgen therapy in humans; some cases were irreversible after androgen withdrawal{76}5{76}4{76}3. This effect is more likely with oral methylated androgens{76}2{76}1{76}0{223}9.

It has been suggested that some strains of female mice injected with testosterone are at greater risk of hepatoma{223}8{223}7. When liver tumors were chemically induced in rats, testosterone increased the number of tumors and decreased tumor cell differentiation{223}6.

For testosterone—Studies in female mice given subcutaneous implants of testosterone showed an increase in cervical-uterine tumors{223}5{223}4{223}3{223}2. Some of these tumors metastasized{223}1{223}0{223}9{223}8. This effect was not seen in mice and rats given subcutaneous injections of testosterone or in rats given subcutaneous implants{223}7{223}6{223}5{223}4{223}3.

Pregnancy/Reproduction
Fertility—
In males, oligospermia, azoospermia, or reduced sperm function or ejaculatory volume resulting in possible infertility may occur during high-dose therapy with androgens if spermatogenesis is suppressed by a negative feedback mechanism{223}2{223}1{223}0{76}9{76}8{76}7{76}6{76}5{76}4. In females treated with androgens, amenorrhea may result, impairing fertility{76}3. In both females and males, fertility usually returns following cessation of therapy in females and dosage reduction or discontinuation in males{76}2{76}1{76}0{223}9{223}8.

Pregnancy—
Androgens are contraindicated during pregnancy{223}7{223}6{223}5{223}4. Studies in humans have shown that androgens cause masculinization of the external genitalia of the female fetus, including clitoromegaly, abnormal vaginal development, and fusion of genital folds to form a scrotal-like structure{223}3{223}2{223}1{223}0. The degree of masculinization is dose-related{76}9{76}8{76}7.

FDA Pregnancy Category X{76}6{76}5{76}4{76}3{76}2{76}1.

Breast-feeding

It is not known whether androgens are distributed into breast milk{76}0{18}{68}. Problems in humans have not been documented. However, androgens are rarely used by breast-feeding women{122} and are not recommended. Potential adverse effects in infants include precocious sexual development in males and virilization of external genitalia in females.

Pediatrics

Androgens should be used with caution in children and adolescents who are still growing because of possible premature epiphyseal closure in males and females, precocious sexual development in prepubertal males, or virilization in females{16}{18}{41}{68}{74}{78}{116}{117}{122}{124}{136}{162}{163}{166}{170}. Skeletal maturation should be monitored at 6-month intervals by an x-ray of the hand and wrist{16}{18}{41}{68}{73}{74}{116}{136}{162}{166}. None of the Testoderm products have been evaluated in children up to 18 years of age{76}. Androderm has not been evaluated in children up to 15 years of age{223}.


Geriatrics


Treatment of male patients 50 years of age and older with androgens should be preceded by a thorough examination of the prostate and baseline measurement of prostate-specific antigen serum concentration, since androgens may increase the risk of hyperplasia or may stimulate the growth of occult prostatic carcinoma{16}{18}{41}{65}{73}{76}{86}{122}{124}{136}{143}{160}{164}{166}{172}{182}{183}{214}. Periodic evaluation of prostate function also should be performed during the course of therapy{196}{214}.

For the testosterone transdermal system (reservoir-type)—No age-related differences in men up to 65 years of age were seen in clinical trials{223}{76}; however, absorption was 20% lower when the Androderm transdermal system was applied to the backs of men between 65 and 79 years of age{223}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Anticoagulants, coumarin- or indandione-derivative{16}{18}{41}{68}{74}{76}{136}{181}{223}    (anticoagulant effect may be increased because of decreased procoagulant factor concentration caused by alteration of procoagulant factor synthesis or catabolism and increased receptor affinity for the anticoagulant{18}{76}{136}{181}; anticoagulant dosage adjustment may be required during and following concurrent use{18}{76}{136}{181}{223})


Antidiabetic agents, sulfonylurea or{18}{68}{74}{136}{181}
Insulin{16}{18}{41}{68}{73}{74}{180}{223}    (androgens may increase or decrease blood glucose; doses of insulin{223} or antidiabetic sulfonylurea medications may need to be adjusted, especially if hypoglycemia occurs)


Corticosteroids or
Corticotropin    (testosterone may contribute to the edema that can occur with administration of corticotropin or corticosteroids; caution is recommended during concomitant administration in patients who have special risks, such as patients who have cardiac or hepatic disease{76})


Cyclosporine    (methyltestosterone has been reported to increase plasma concentrations of cyclosporine and may increase the risk of nephrotoxicity{167}; other androgens may have the same effect{02}{04})


» Hepatotoxic medications, other (see Appendix II)    (may result in an increased incidence of hepatotoxicity; patients should be carefully monitored, especially those undergoing long-term therapy or those with a history of liver disease)


Human growth hormone (somatrem or somatropin){183}{196}{198}{200}{202}{221}    (use of excessive doses of androgens in prepubertal males may accelerate epiphyseal maturation, although supplemental use of androgens may be necessary in patients with androgen deficiency to continue the growth response to human growth hormone{183}{196}{198}{200}{202}{209}{221})


Propranolol    (testosterone cypionate increases the clearance of propranolol; appropriate patient monitoring may be needed{76})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Fasting blood sugar (FBS) and{74}
Glucose tolerance test{74}{122}    (may be altered)

With physiology/laboratory test values
Alkaline phosphatase{74}{122}{124}{136}{139}{140}    (value may be increased{122}{124}{136}{140})


Aspartate aminotransferase (AST [SGOT]), serum and{41}{84}{74}{124}{139}
Calcium, chloride, inorganic phosphates, potassium, and sodium, serum and{16}{18}{74}{79}{122}{166}
17-Ketosteroid (17-KS), urine{74}{79}    (concentrations may be increased)


Bilirubin{74}{122}{136}{138}{140}    (serum concentrations may be increased{122}{136} {138}{140})


Clotting factors II, V, VII, and X{16}{18}{41}{74}{136}    (may be suppressed{136})


Corticosteroid-binding globulin    (concentration may be decreased; free hormone concentration remains unchanged{20}{21})


Creatinine{74}{79}    (serum concentrations may be increased; effect usually lasts up to 2 weeks after discontinuation of therapy)


Follicle-stimulating hormone (FSH) and{122}{134}{170}
Luteinizing hormone (LH){18}{122}{134}{170}    (serum concentrations may decrease{14}{18}{84}{122}{134}{170})

    (in one small study that used the testosterone transdermal system [reservoir-type], the LH serum concentrations decreased to normal within 6 to 12 months for 48% of the males with hypergonadotropic hypogonadism{223}. For some men, the LH concentration may continue to be high despite normal testosterone concentrations{223})


Glucose    (blood concentrations may be increased or decreased, especially with pharmacologic doses or oral formulations; physiologic doses of androgens rarely cause hypoglycemia or hyperglycemia{39}{207}{212}{221})


Hamster ova penetration test (HOPT) and
Spermatozoa count{18}{122}{124}{134}{144}{170}    (may be severely reduced at high doses{16}{18}{25}{82}{45}{122}{124}{144})


Hematocrit and{41}{68}{76}{122}{136}
Hemoglobin{41}{68}{76}{136}    (values may be increased with high-dose or long-term therapy{76}{122}{136})


High density lipoproteins (HDL){122}{124}{134}{169}{171}    (serum concentrations may be decreased, especially with pharmacologic doses and oral formulations{84}{86}{87}{122}{124}{129}{134}{169}{171})


Low density lipoproteins (LDL){122}{124}{134}{169}{171}    (serum concentrations may be increased{122}{124}{129}{134}{169}{171}, especially with pharmacologic doses and oral formulations; one study showed a slight reduction with testosterone{76}{170})


Sex steroid–binding globulin    (concentration may be decreased; free hormone concentration remains unchanged{20}{21}{76})


Thyroxine-binding globulin{18}{76}{136}{223}    (may be decreased, resulting in decreased total T 4 serum concentrations and increased resin uptake of T 3 and T4{18}{76}{136}{223}; free thyroid hormone levels remain unchanged{16}{18}{41}{74}{76}{223}, showing no clinical evidence of thyroid impairment)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, these medications should not be used when the following medical problems exist:
» Breast cancer in males{18}{74}{75}{76}{79}{136}{223} or
» Prostate cancer, known or suspected{18}{74}{75}{76}{79}{86}{122}{124}{136}{143}{160}{164}{166}{172}{223}    (tumor growth may be promoted{86}{122}{124}{136}{143}{160}{164}{166})


Risk-benefit should be considered when the following medical problems exist
» Cardiac failure or{76}{136}{204}
Cardiac function impairment or{16}{18}{41}{75}{79}{136}{166}{204}{223}
» Cardiorenal disease, severe or{76}{78}
Edema or{76}{136}
Hepatic function impairment or{16}{18}{61}{41}{75}{76}{79}{136}{223}
» Nephritis or{74}{136}
» Nephrosis or{74}{136}
Renal function impairment{16}{18}{41}{75}{76}{79}{223}    (may cause fluid retention, resulting in edema with or without congestive heart failure{18}{76}{136}{204}; diuretics may be required before and during therapy{18}{76}{204}{223})


Coronary artery disease or{68}{74}{79}{122}{124}{132}{135}{169}
» Myocardial infarction, history of{68}{74}{79}{135}{169}    (may be worsened, due to hypercholesterolemic effects of androgens{122}{124}{129}{130}{135}{169})


Diabetes mellitus    (use of androgens may increase or decrease blood glucose and produce an unfavorable profile of lipoprotein metabolism in patients without diabetes mellitus; a more exaggerated response can be expected in patients with diabetes mellitus, especially in obese patients. Effects may be greater for oral formulations or when pharmacologic doses of androgens are used. Doses of insulin or antidiabetic sulfonylurea medications may need to be adjusted, especially if hypoglycemia occurs. Physiologic doses of androgens rarely cause hypoglycemia or hyperglycemia{39}{40}{51}{136}{211})


» Hepatic function impairment{75}{76}{136}{168}    (biotransformation of androgens may be impaired, resulting in increased elimination half-life and increase in the incidence of gynecomastia {122}{136}{168})


» Hypercalcemia, due to metastatic breast cancer{16}{18}{75}{78}{166}    (may be exacerbated{18}{166}{195})


» Prostatic hyperplasia, benign with urethral obstructive symptoms{74}{76}{122}{136}{164}{183}    (further enlargement may occur{136}{164})


Sensitivity to anabolic steroids or androgens{76}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Bone age determinations{18}{162}{166}    (x-rays of hand and wrist are recommended every 6 months for children and growing adolescents to determine rate of bone maturation and effects on epiphyseal centers{29}{16}{18}{68}{101}{166})


Cholesterol and/or{56}{76}{223}
High density lipoproteins and{95}{51}{56}{76}{221}{223}
Low density lipoproteins{51}{56}{95}{221}    (serum profile determinations are recommended prior to initiation of therapy and, in some patients, at regular intervals during therapy{51}{56}{76}{213}{221})


Dihydrotestosterone, serum or{76}
Testosterone, total, serum{76}{223}    (concentrations may be determined to ensure proper dosing;{223} when done for Testoderm products, measurements are recommended after the patch has been used for 3 to 4 weeks and should be performed 2 to 4 hours after patch application{76})


Hematocrit determinations and{18}{76}{205}{223}
Hemoglobin{18}{76}{205}{223}    (recommended at regular intervals in patients receiving prolonged therapy or high doses of androgens to check for possible erythrocytosis{16}{18}{76}{87}{203}{205})


Hepatic function determinations{18}{76}{124}{136}{223}    (recommended at regular intervals during therapy, especially with oral methylated androgens{16}{18}{76}{124}{136})


Prostate-specific antigen and{76}{223}
Prostatic acid phosphatase{76}    (recommended at regular intervals during therapy{223})


For treatment of breast carcinoma
Alkaline phosphatase, serum values and
Physical examination and
X-rays of known or suspected metastases    (recommended at regular intervals during therapy to monitor objective evidence of tumor response{203})


Calcium{16}{18}{68}{86}{142}    (measurement of serum concentrations recommended at regular intervals in women with disseminated breast carcinoma{18}{86}{142})


For gender change androgen therapy
» Luteinizing hormone{94}{95}    (measurement of serum concentrations is recommended every 6 months to monitor success of therapy{94}{95})


» Alanine aminotransferase (ALT [SGPT]){94}{95}    (measurement of serum values is recommended every 6 months to monitor for adverse effects{94}{95})




Side/Adverse Effects

Note: The side effects of testosterone enanthate and testosterone cypionate cannot be quickly reversed by discontinuing medication due to the long durations of action of these medications.
Replacement doses of androgens return the prostate to normal size and function for hypogonadal males{49}. Although there is no evidence that exogenous androgens can induce development of prostate carcinoma, long-term androgen therapy or normal prostate activity carries a theoretical risk of prostatic hyperplasia or growth of occult prostatic carcinoma{16}{18}{41}{73}{76}{86}{122}{124}{136}{143}{160}{164}{166}{172}{182}{183}{214}.
Behavioral disturbances, including aggressive or violent behavior, have been reported with self-administered supraphysiologic doses in athletes{216}{219}{220}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
In females only
    
Amenorrhea or oligomenorrhea {16}{18}{68}{170}( absence of or unusual menstrual periods)
    
virilism {16}{18}{68}{76}{97}{108}{121}{122}{124}{134}{136}{141}{160}{170}{204}{205}( acne; decreased breast size; enlarged clitoris; hoarseness or deepening of voice; male pattern baldness; oily skin; unnatural and excessive hair growth)

Note: Virilism may occur with usual systemic doses, as well as with excessive doses of topical testosterone{121}{122}{124}{141}. Hoarseness or deepening of voice and enlarged clitoris may not be reversible even after the medication has been discontinued{16}{18}{68}{124}{170}. Virilism has also been reported in the female sexual partner of a male patient during his treatment with topical testosterone{141}. The reservoir-type of testosterone transdermal system has a protective film that makes testosterone transfer between sexual partners unlikely{223}.


In males only
    
Bladder irritability or urinary tract infection {74}{76}(frequent urge to urinate)— may be asymptomatic
    
blistering of skin, local {223}
    
breast soreness
    
erythema or pruritus, local (itching of skin under skin patch, mild to severe; redness of skin under patch or at implant insertion site, mild to severe){223}
    
gynecomastia {18}{76}{122}{124}{134}{136}{164}{170}{171}{173}{223}( enlargement of breasts)
    
penile erections, frequent or continuing {16}{18}{41}{68}{125}{127}{136}{164}(penile erections lasting up to 4 hours)
    
priapism (painful erections lasting longer than 4 hours)—sign of excessive dosage {16} {18} {41} {68} {125} {127} {136} {164}


Note: Blistering of skin occurred as a single incident on one skin site in many patients; in most cases, it occurred when the reservoir-type of testosterone transdermal system was applied to skin over a bony prominence. This effect is less likely if such areas are avoided. It should be treated like a burn.{223}
Medication should be discontinued and the patient given immediate medical attention if priapism occurs{16}{18}{41}{68}{125}{127}{136}{164}. If tumescence is not reversed, interruption of blood flow may result in penile tissue ischemia and permanent tissue damage.

In prepubertal males only
    
Virilism (acne ; enlargement of penis; frequent or continuing erections; early growth of pubic hair{18}{136}{170})


Incidence less frequent
In females and males{206}
    
Asthenia {224}(lack or loss of strength)
    
edema {16}{18}{41}{74}{128}{136}{164}{166}{170}( rapid weight gain; swelling of feet or lower legs)
    
breast pain {224}
    
emotional lability {224}(crying; depersonalization; dysphoria ; euphoria; mental depression; paranoia; quick to react or overreact emotionally ; rapidly changing moods)
    
erythrocytosis or secondary polycythemia (dizziness; flushing or redness of skin; headache, frequent or continuing; unusual bleeding ; unusual tiredness)—in severe cases using oral or injection dosage forms{16}{18}{41}{76}{136}{164}{166}{203}{207}{208}
    
gastrointestinal irritation {16}{73}{74}(nausea; vomiting)
    
headache {223}
    
hepatic dysfunction, including cholestatic jaundice{18}{47} (yellow eyes or skin; itching of skin)— more likely with the oral methylated androgens{16}{18}{41}{74}{76}{122}{124}{136}{138}{139}{164}{166}{170}
    
hypercalcemia {142}( confusion; constipation; increased thirst; mental depression; nausea; increased frequency of urination and quantity of urine ; unusual tiredness; vomiting)—in females with breast cancer or immobilized patients{195}
    
hypertension {224}(high blood pressure)
    


In males only
    
Benign prostatic hyperplasia{16}{76}{100}{136}{164} (difficulty urinating{76}{100}{136}{164}{224})
    
burning sensation at transdermal application site —incidence of 3%{223}
    
contact dermatitis, allergic (itching and redness of skin, severe; skin rash, severe)—incidence of 4% with use of testosterone transdermal system (reservoir-type){223}{22}
    
epididymitis, acute, nonspecific {74}{82}(chills; pain in scrotum or groin)
    
gastrointestinal bleeding {223}(black, tarry stools; vomiting of blood or material that looks like coffee grounds)
    
induration, local ( hardening or thickening of skin under patch)—with use of testosterone transdermal system (reservoir-type){223}
    
pain at implant insertion site, continuing —for subcutaneous implants {03}
    
testis disorder {224}


Incidence rare
In females and males—more likely with oral or injection dosage forms, usually associated with long-term use or high doses
    
Depression {224}(mood or mental changes)
    
hepatic necrosis {74}{134}(abdominal or stomach pain, continuing; black, tarry stools; headache, continuing; malaise, continuing ; unpleasant breath odor, continuing ; vomiting of blood)
    
hepatocellular tumor {16}{18}{41}{122}{124}{134}{136}{163}{164}{170}( pain or tenderness in upper abdomen; swelling of abdomen)
    
leukopenia {74}{79}(fever; sore throat)
    
peliosis hepatis {16}{18}{41}{122}{124}{134}{136}{163}{164}{170}(continuing loss of appetite; darkened urine; fever; hives; light-colored stools; nausea; purple or red spots on body or inside the mouth or nose; sore throat; vomiting)




Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
In females and males
    
Acne, mild{18}{74}{76}{121}{122}{128}{136}{171}{173}{224}
    
alopecia{224} ( hair loss; thinning of hair)
    
decrease or increase in libido{18}{33}{16}{41}{74}{97}{121}{134}{136}{166}{171}{224}
    
diarrhea
    
increase in pubic hair growth{112}{121}{187}
    
infection, pain, redness or other irritation at site of injection —for intramuscular injection only{41}{73}{79}{136}
    
nervousness {224}
    
stomach pain{74}
    
trouble in sleeping{74}{136}

In males only
    
Infection, pain, redness, swelling, sores or other skin irritation, local{223}{76} — for transdermal systems
    
testicular atrophy {122}{134}{166}{170}{171}(decrease in testicle size)—usually associated with high doses for oral or injection dosage forms






Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
For testosterone enanthate
    
Cerebrovascular accident{223} ( blurred vision; headache; sudden and severe inability to speak; seizures; slurred speech; temporary blindness; weakness in arm and/or leg on one side of the body, sudden and severe)

Note: One report has described acute overdosage with testosterone enanthate. Testosterone concentrations of up to 11,400 ng/dL were implicated in a cerebrovascular accident.{223}



Treatment of overdose
Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Androgens (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to androgens or anabolic steroids



Carcinogenicity—
Hepatocellular carcinoma is associated with long-term, high-dose therapy



Tumorigenicity—
Hepatic neoplasms are associated with long-term, high-dose therapy



Fertility—
May be severely impaired in males

Pregnancy—Contraindicated for use during pregnancy because of possible masculinization of female fetus





Breast-feeding—Not recommended





Use in children—Cautious use due to effects on growth and sexual development (precocious sexual development in males, virilization in females)






Use in the elderly—Increased risk of prostatic hyperplasia or occult prostatic carcinoma
Other medications, especially anticoagulants (coumarin- or indandione-derivative) or hepatotoxic medications
Other medical problems, especially breast cancer (male), cardiac failure, cardiorenal disease (severe), hepatic function impairment, hypercalcemia due to breast cancer, myocardial infarction (history of), nephritis, nephrosis, prostate cancer (known or suspected), or prostatic hyperplasia

Proper use of this medication
» Importance of not taking or using more medication than the amount prescribed

Understanding difference between the two types of testosterone patches; reading patient directions carefully before using the patch

Taking fluoxymesterone and methyltestosterone with food to minimize possible stomach upset

Proper administration of testosterone transdermal systems
For the matrix-type transdermal system—Applying to dry, clean, and hairless skin of scrotum; may be removed and reapplied after bathing, swimming, showering, or sexual activity

For the reservoir-type transdermal system—Applying Androderm to abdomen, back, thighs, or upper arms; rotating site. Applying Testoderm TTS to back, arms, or upper buttocks. Not applying the patches to the scrotum, chest, shin, bony prominences, or areas subject to prolonged pressure when sleeping or sitting. Not removing for showering, bathing, swimming, or sexual activity

» Proper dosing
For injection or oral dosage forms—Taking or using as soon as possible; not taking or using if almost time for next dose; not doubling doses

For transdermal patches—If dose is missed or patch falls off after being worn for 12 hours and cannot be reapplied, not using a new patch, returning to regular dosing schedule; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress during therapy

Diabetics: May alter blood sugar concentrations at high doses; minimal effect at physiologic doses

For testosterone transdermal system (matrix-type)—Checking with doctor if female sexual partner develops mild virilization when male partner uses the scrotal patch


Side/adverse effects
Signs of potential side effects, especially:

• In females only—Amenorrhea, oligomenorrhea, or virilism


• In males only—Bladder irritability or urinary tract infection; blistering of skin, local; breast soreness; erythema or pruritus of skin, mild to moderate, local; gynecomastia; penile erections, frequent or continuing; priapism; benign prostatic hyperplasia; burning sensation at transdermal application site; contact dermatitis, allergic; epididymitis, acute, nonspecific; gastrointestinal bleeding; induration, local; pain at implant insertion site, continuing , testis disorder


• In prepubertal males only—Virilism


• In all patients—Asthenia, breast pain, edema, emotional lability, erythrocytosis or secondary polycythemia, gastrointestinal irritation, headache, hepatic dysfunction, hepatic necrosis, hepatocellular tumor, hypercalcemia (in patients with breast cancer or immobilized patients), hypertension, leukopenia, or peliosis hepatis



General Dosing Information
The dosage and duration of therapy depend on the patient's age, sex, diagnosis, and response to therapy, and the appearance of adverse effects.{16} {18}

It is usually preferable to begin treatment for anemia and carcinoma with full therapeutic doses and to adjust later to individual requirements{221}.

For treatment of delayed puberty
The dosage used in delayed puberty generally is in the lower range of the usual adult dose for androgen replacement therapy and is given for a limited duration, usually 3 to 6 months{16}{18}{185}. The chronologic and skeletal ages should be considered, both in determining the initial dose and in adjusting the dose{16}{18}. After 3 to 6 months of therapy, the medication should be discontinued for 1 to 3 months and x-rays taken to determine the effect on bone growth or maturation{18}{34}{83}{185}.

Various dosage regimens have been used to induce pubertal changes in hypogonadal males{16}{18}{41}. Some physicians prescribe a lower dose initially, gradually increase the dose as puberty progresses, and follow with a maintenance dose, which may be decreased.{16}{18}{41}{103} Other physicians use high initial doses to induce puberty, then decrease to an adjusting maintenance dose as puberty progresses.{03}

Transdermal systems have not been investigated for this use{76}.

For treatment of breast cancer
To determine whether there will be an objective response to antineoplastic therapy, treatment should be continued for at least 3 months, during which time a response to therapy is usually apparent. Therapy should be discontinued if the disease becomes progressive again. If clinical circumstances allow for an observation period, the patient should be observed for a period of improvement known as rebound regression{203}.

Women should be checked for signs of virilization during androgen therapy{16}{18}. Some effects, such as voice changes or clitoromegaly, may not be reversible{18}. A decision should be made by the patient and physician as to how much virilization will be tolerated as a result of androgen therapy{16}{18}. Alternatively, the drug should be discontinued or the dosage reduced. If virilization is to be prevented, medication must be discontinued when signs of mild virilization appear and before the process becomes irreversible{16}{18}.

Women with metastatic breast cancer should be followed closely because androgen therapy occasionally accelerates the disease{16}{18}. A shorter-acting androgen is preferred over one with prolonged activity, especially during the early stages of androgen therapy{16}{18}.

For testosterone injection dosage form
The suspension dosage form is absorbed relatively slowly; therefore, frequent injections may cause overdosage.

Testosterone cypionate or testosterone enanthate should not be used interchangeably with testosterone propionate or testosterone base because of different durations of action{24}.

The intramuscular injections should be administered deeply into the gluteal muscle or the deltoid muscle in larger men. Injections should not be administered intravenously{34}.

For testosterone implant dosage form
Insertion of testosterone implants requires a 15-minute procedure using local anesthesia. The number of implants inserted can vary according to patient need, diagnosis, and tolerance of testosterone. A good way to establish a proper testosterone dose for the implant is to assess patient response to a short-acting injectable form of testosterone. A 25-mg dose of testosterone propionate per week is equivalent to two 75-mg implants that last for 3 months{03}{23}.

The preferred application site is the lower abdomen, 5 cm away from the umbilicus; other sites used include the deltoid and gluteal muscles, and upper thigh. The clinician inserts and releases each implant into separate fan-like tracks using a trocar that is inserted into the 1-cm incision{23}.

Afterwards, the patient should feel only minor discomfort and can apply pressure to stop minor bleeding at the incision site. Use of steri-strips covered by a water-resistant dressing for one week adequately closes and protects the incision without sutures. Postsurgical use of antibiotics is not needed{23}.

The crystallized testosterone implants dissolve subcutaneously and rarely require removal. If needed, minor surgery to remove implants can rapidly terminate the effect of the medication{23}.

For testosterone transdermal system dosage forms
There is a potential for transfer of testosterone from the matrix-type, scrotal transdermal system, or testosterone gel to the female sexual partner, resulting in mild virilization, such as changes in body hair distribution and increase in acne{76}. The reservoir-type transdermal system includes a protective liner that makes transfer to a sexual partner unlikely{223}. To avoid transfer while using testosterone gel, patients should wash their hands immediately with soap and water after application; the application site should be covered with clothing after the gel has dried; if contact with another person does occur, the area of contact should be washed with soap and water as soon as possible{224}.

The matrix-type transdermal system should be applied to clean, dry, and dry-shaved scrotal skin for optimal skin contact. Chemical depilatories should not be used{76}.

The reservoir-type transdermal system should not be applied to scrotal skin. Instead, the abdomen, back, thighs, and upper arms are the optimal areas for application for Androderm and the arm, back, or upper buttocks for Testoderm TTS. Application areas for Androderm should be rotated, and a site should not be reused for 7 days. A patch added to or removed from the treatment regimen can change the testosterone concentrations by 27 to 37%. In addition, a 20% decrease in serum testosterone concentration was demonstrated in men over 65 years of age who applied Androderm to their backs{223}.

For treatment of adverse effects


For all androgens:


For prolonged erection or priapism—
A prolonged erection should be treated if it persists for longer than 4 hours{47}; priapism should be treated promptly{47}. If tumescence is not reversed, interruption of blood flow may result in penile tissue ischemia and permanent tissue damage.

Treatment of adverse effects should be initiated by a physician trained in treating drug-induced tumescence. Depending on the severity, treatment may include:    • Application of ice packs to inner thigh, alternating between thighs, for no more than 10 minutes to shorten the time of a prolonged erection{53}.
   • Aspiration of intracavernosal blood{47}.
   • Intracavernosal administration of an alpha-adrenergic agonist; phenylephrine is preferred over epinephrine. While monitoring blood pressure, an injection of 0.5 mg/mL Phenylephrine Hydrochloride Injection USP{47} is given, followed by a second dose, if needed, in 15 minutes.{47}
   • Irrigation of the corpus cavernosum with 0.9% Sodium Chloride Irrigation USP or 20 mL of dilute solutions of phenylephrine (20 mg Phenylephrine Hydrochloride Injection USP in 500 mL of 0.9% Sodium Chloride Irrigation USP) or epinephrine (1 mL 1:1000 Epinephrine Injection USP in 1 liter of 0.9% Sodium Chloride Irrigation USP) using a 19-gauge needle to remove clotted blood.{46}{48}
   • Surgery (rarely needed){47}.





For testosterone transdermal system (reservoir-type):
For chemical-induced blistering—Symptomatic relief can be provided by administering a corticosteroid cream (not an ointment because ointments significantly reduce testosterone absorption) to relieve mild skin irritation underneath the patch. If burn-like blisters appear under the patch, use of patch should be discontinued and treatment of skin area should follow standard guidelines for treatment of burns.{223}


FLUOXYMESTERONE

Summary of Differences
Indications: Also used as an antianemic.

Side/adverse effects: Methylated androgens are more likely to cause jaundice.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

FLUOXYMESTERONE TABLETS USP

Usual adult dose
Androgen deficiency, due to primary or secondary hypogonadism
Oral, 5 mg one to four times a day.{16}{14}{74}{136}{166} Replacement therapy is usually started at 10 mg per day, with subsequent adjustments as necessary.

Breast cancer in females
Oral, 10 to 40 mg per day{14}{74}{83}{84}{86} in divided doses{14}{74}.

[Antianemic ]1
Oral, 20 to 50 mg per day, for minimum trial of two to six months.


Usual pediatric dose
Delayed puberty in males
Oral, 2.5 to 10 mg per day{136}{166} titrated to the lowest dose and to skeletal monitoring{47} for a limited duration, usually four to six months{136}{166}.


Strength(s) usually available
U.S.—


2 mg (Rx) [Halotestin (scored) ( lactose) (sucrose) (tartrazine )]{14}


5 mg (Rx) [Halotestin (scored) ( lactose) (sucrose) (tartrazine ){14}]


10 mg (Rx) [Android-F (scored {16})] [Halotestin (scored) (lactose) (sucrose) (tartrazine){14}][Generic] (scored)(may contain lactose and tartrazine{10}{50})

Canada—


5 mg (Rx) [Halotestin (scored){74} (tartrazine)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container. Protect from light.{09}

Auxiliary labeling:
   • Take with food.


METHYLTESTOSTERONE

Summary of Differences
Side/adverse effects: Methylated androgens are more likely to cause jaundice.


Oral Dosage Forms

METHYLTESTOSTERONE CAPSULES USP

Usual adult dose
Androgen deficiency, due to primary or secondary hypogonadism
Oral, 10 to 50 mg per day{15}{18}{19}{75}{136}{166}.

Breast cancer in females
Oral, 50 mg one to four times a day{15}{18}{19}{75}. After two to four weeks, dose may be decreased to 50 mg two times a day if response occurs{75}.


Usual pediatric dose
Delayed puberty in males
Oral, 5 to 25 mg per day for a limited duration, usually four to six months.{19}{136}


Strength(s) usually available
U.S.—


10 mg (Rx) [Android{04}] [Testred{19}] [Virilon{12}]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.{09}

Auxiliary labeling:
   • Take with food.


METHYLTESTOSTERONE TABLETS (Oral) USP

Usual adult dose
Androgen deficiency, due to primary or secondary hypogonadism or
Breast cancer in females
See Methyltestosterone Capsules USP.{15}{18}{75}


Usual pediatric dose
Delayed puberty in males
See Methyltestosterone Capsules USP{19}.


Strength(s) usually available
U.S.—


10 mg (Rx) [Android{15}] [ORETON Methyl{18} (lactose)][Generic]{07}


25 mg (Rx) [Android{15}][Generic]{54}

Canada—


10 mg (Rx) [Metandren{75} (scored) (lactose)]


25 mg (Rx) [Metandren{75} (scored) (lactose)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container. {09}

Auxiliary labeling:
   • Take with food.


TESTOSTERONE

Summary of Differences
Indications: Testosterone cypionate and testosterone enanthate are used as antianemics and in androgen replacement in impotence or for male climacteric symptoms. Testosterone cypionate and testosterone enanthate are also used for female-to-male gender change. Intramuscular testosterone and testosterone esters, and extemporaneously compounded testosterone propionate ointments are used in the treatment of microphallus. Extemporaneously compounded testosterone propionate ointments are used in the treatment of lichen sclerosus.

Side/adverse effects: Side effects of the enanthate and cypionate forms cannot be quickly reversed because of the long duration of action of medication form and can include hives, infection, pain, redness, or irritation at site of injection.


Oral Dosage Forms

TESTOSTERONE UNDECANOATE CAPSULES

Usual adult dose
Androgen deficiency, due to primary or secondary hypogonadism
Oral, 120 to 160 mg divided into two doses a day with meals for two to three weeks. The dose may be decreased to 40 to 120 mg a day in divided doses, as appropriate, with meals.{176}


Usual pediatric dose
Androgen deficiency, due to primary or secondary hypogonadism
Use and dose have not been established{176}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


40 mg (Rx) [Andriol{176}]

Packaging and storage:
Before dispensing, store between 2 and 8 °C (36 and 46 °F). Protect from freezing. Store in a well-closed container. Protect from light.{176}

After dispensing, store between 15 and 25 °C (59 and 77 °F). Protect from light.{176}

Stability:
After the bottle is opened, capsules retain their potency for 90 days {176}.

Auxiliary labeling:
   • Take with food.
   • Beyond use date.



Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

TESTOSTERONE INJECTABLE SUSPENSION USP

Note: Formerly known as Sterile Testosterone Suspension USP{09}.


Usual adult dose
Androgen deficiency, due to primary or secondary hypogonadism
Intramuscular, 25 to 50 mg two or three times a week.{07}{57}{166}

Breast cancer in females
Intramuscular, 50 to 100 mg three times a week.{57}


Usual pediatric dose
Delayed puberty in males
Intramuscular, 100 mg (maximum) per month for a limited duration, usually four to six months{216}.


Strength(s) usually available
U.S.—


25 mg per mL (Rx)[Generic]{07}(may contain thimerosal {59})


50 mg per mL (Rx) [Testaqua{07} (thimerosal )][Generic]( may contain thimerosal{59})


100 mg per mL (Rx) [Testamone 100{10} ( thimerosal){10}] [Testaqua{07} (thimerosal)][Generic](may contain thimerosal{59})

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.{57}

Auxiliary labeling:
   • Shake well.{57}


TESTOSTERONE CYPIONATE INJECTION USP

Usual adult dose
Androgen deficiency, due to primary or secondary hypogonadism
Intramuscular, 50 to 400 mg every two to four weeks.{07}{41}{78}{166}

Breast cancer in females
Intramuscular, 200 to 400 mg every two to four weeks. {07}

[Gender change ]1
Intramuscular, 200 mg every two weeks{94}{96}{182}. Occasional patients may require a higher dose to cause cessation of menses{94}{96}{182}.


Usual pediatric dose
Delayed puberty in males
Intramuscular, 100 mg (maximum) per month for a limited duration, usually four to six months.{07}{118}{136}{161}{216}


Strength(s) usually available
U.S.—


100 mg per mL (Rx) [Andronate 100{07} ( benzyl alcohol)] [Depotest{10} (benzyl alcohol)] [Depo-Testosterone{07}{41} (benzyl alcohol 9.45 mg per mL) (benzyl benzoate 0.1 mL per mL) (cottonseed oil)][Generic]( may contain benzyl alcohol and benzyl benzoate{07} {64})


200 mg per mL (Rx) [Andronate 200{07} ( benzyl alcohol) (benzyl benzoate)] [Depotest{07} (benzyl alcohol) ( benzyl benzoate)] [Depo-Testosterone{07}{41} (benzyl alcohol 9.45 mg per mL) (benzyl benzoate 0.2 mL per mL) (cottonseed oil)] [T-Cypionate{10}] [Testred Cypionate 200{63} (benzyl alcohol 0.9%) (benzyl benzoate 20%)] [Virilon IM{13}][Generic](may contain benzyl alcohol and benzyl benzoate ){07}{64}

Canada—


100 mg per mL (Rx) [Depo-Testosterone Cypionate{78} (benzyl alcohol) (benzyl benzoate) (cottonseed oil)] [Scheinpharm Testone-Cyp{78} (benzyl alcohol) ( cottonseed oil){175}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light{09}. Protect from freezing.

Stability:
Crystals may form at low temperatures; warming and shaking the vial will redissolve any crystals.{41}

Use of a wet needle or wet syringe may cause solution to cloud; however, potency of the medication will not be affected.


TESTOSTERONE ENANTHATE INJECTION USP

Usual adult dose
Androgen deficiency, due to primary or secondary hypogonadism or
Breast cancer in females or
[Gender change]1
See Testosterone Cypionate Injection USP .

[Antianemic ]1
Intramuscular, 400 mg a day for one week, then 400 mg one or two times a week. The maintenance dose is 200 to 400 mg every four weeks.{06}


Usual pediatric dose
Delayed puberty in males
See Testosterone Cypionate Injection USP .

[Microphallus ]1
Intramuscular, 25 to 50 mg every month for 3 to 6 months{185}{187}{189}.


Strength(s) usually available
U.S.—


100 mg per mL (Rx) [Delatest{10} (chlorobutanol )][Generic]( may contain benzyl alcohol {69})


200 mg per mL (Rx) [Andro L.A. 200{07}{67} (chlorobutanol 0.5%)] [Andropository 200{07}] [Andryl 200{07} (chlorobutanol)] [Delatestryl{68} (chlorobutanol 5 mg per mL)] [Everone 200{07} (chlorobutanol)] [Testrin-P.A{10} (chlorobutanol)][Generic](may contain benzyl alcohol{69})

Canada—


200 mg per mL (Rx) [Delatestryl{79} (chlorobutanol 0.5%)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.{68}

Stability:
Crystals may form at low temperatures; warming and shaking the vial will redissolve any crystals.{68}{79}

Use of a wet needle or wet syringe may cause solution to cloud; however, potency of the medication will not be affected.{68}{79}


TESTOSTERONE PROPIONATE INJECTION USP

Usual adult dose
Androgen deficiency, due to primary or secondary hypogonadism or
Breast cancer in females
See Testosterone Injectable Suspension USP .{73}{82}{166}


Usual pediatric dose
Delayed puberty in males
See Testosterone Injectable Suspension USP .


Strength(s) usually available
U.S.—


100 mg per mL (Rx) [Testex{07} (benzyl alcohol )][Generic]{64}{72}

Canada—


100 mg per mL (Rx) [Malogen in Oil{82}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Stability:
Crystals may form at low temperatures; warming and shaking the vial will redissolve any crystals.

Use of a wet needle or wet syringe may cause solution to cloud; however, potency of the medication will not be affected.



Subcutaneous Dosage Forms

TESTOSTERONE IMPLANTS

Usual adult dose
Androgen deficiency, due to primary or secondary hypogonadism
Subcutaneous, 150 to 450 mg every three to four months or, in some cases, as long as six months{03}.


Usual pediatric dose
Puberty, delayed, male
Subcutaneous, dose to be determined by the physician{03}. Low doses are used initially and increased gradually as puberty progresses{03}.


Strength(s) usually available
U.S.—


75 mg (Rx) [Testopel Pellets{03}]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.



Topical Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

TESTOSTERONE GEL

Usual adult dose
Androgen deficiency, due to primary or secondary hypogonadism (congenital or acquired)
Topical, recommended starting dose is 5 grams (to deliver 50 mg of testosterone) applied once daily in the morning to clean, dry, intact skin of the shoulders and upper arms and/or abdomen{224}


Usual pediatric dose
Androgen deficiency, due to primary or secondary hypogonadism (congenital or acquired)
Use and dose have not been established{224}.


Strength(s) usually available
U.S.—


2.5 grams per packet to deliver 25 mg of testosterone (Rx) [AndroGel{224}]


5 grams per packet to deliver 50 mg of testosterone (Rx) [AndroGel]

Canada—
Not commercially available.

Packaging and storage:
Store at controlled room temperature 20 to 25 °C (68 to 77 °F)

Auxiliary labeling:
   • When dispensed, include patient instructions.
   • For topical use only.

Note: AndroGel should not be applied to the genitals. Application sites should be allowed to dry prior to dressing. Hands should be washed with soap and water after Androgel has been applied{224}.



TESTOSTERONE PROPIONATE OINTMENT

Usual adult dose
[Lichen sclerosus ]1
Initial, topical, to the vulva, as a 1 or 2% ointment, two times a day for six weeks or until relief of itching occurs{97}{108}{121}{136}{182}{193}{221}. Dosage should be decreased to the minimum effective dose{109}{121}{182}{221}.


Usual pediatric dose
[Microphallus ]1
Topical, to the penis, as a 5% ointment, two times a day for three months{112}{136}{182}.


Strength(s) usually available
U.S.—
Not commercially available. Compounding required for prescription.

Canada—
Not commercially available. Compounding required for prescription.

Preparation of dosage form:
Formulations that have been used for the extemporaneous compounding of testosterone propionate ointments are as follows: For 15 grams of 2% testosterone propionate ointment

   • 3 mL of 100-mg-per-mL testosterone propionate injection
   • 12 grams of white petrolatum.{97}{102}{108}{111}{121}
For 15 grams of 5% testosterone propionate ointment

   • 7.5 mL of 100-mg-per-mL testosterone propionate injection
   • 7.5 grams of white petrolatum.



TESTOSTERONE TRANSDERMAL SYSTEMS (Matrix-type)

Usual adult dose
Androgen deficiency, due to primary or secondary hypogonadism
Topical, one 6-mg transdermal dosage system (15 mg per sixty-centimeters-squared patch) applied to clean, dry and hairless skin of scrotum at approximately 8 a.m., every twenty-two to twenty-four hours. If scrotal area is inadequate, the smaller-sized 4-mg transdermal dosage system (10 mg per forty-centimeters-squared patch) should be used every twenty-two to twenty-four hours {76}.


Note: Discontinue if desired response is not reached by six to eight weeks{76}.


Usual pediatric dose
Children up to 18 years of age—Dosage has not been established {76}.

Strength(s) usually available
U.S.—


4 mg delivered per system per day (Rx) [Testoderm{76}]


6 mg delivered per system per day (Rx) [Testoderm{76}] [Testoderm with Adhesives{76}]

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F).

Auxiliary labeling:
   • For external use only.
   • Apply patch to a clean, dry, hair-free area of the skin.

Note: The manufacturer's directions for the patient should be dispensed with the product.
Patients should be instructed to apply the patches to the scrotum.



TESTOSTERONE TRANSDERMAL SYSTEMS (Reservoir-type)

Usual adult dose
Androgen deficiency, due to primary or secondary hypogonadism
Topical, 5 mg applied to clean, dry skin of the back, abdomen, upper arms, or thighs for Androderm at 10 p.m. every twenty-four hours {225}and to the back, arms, or upper buttocks for Testoderm TTS at 8 a.m. every twenty-two to twenty-four hours. 2.5 mg may be used for nonvirilized patients or dose may be increased to 7.5 mg as appropriate.


Note: Patients should not apply the patches to the scrotum, bony prominences (deltoid region of the upper arm, the greater trochanter of the femur, and the ischial tuberosity), chest, or shin, or areas subject to prolonged pressure while sleeping or sitting.{223}


Usual pediatric dose
Androgen deficiency, due to primary or secondary hypogonadism


For Androderm:
Children up to 15 years of age—Use and dose have not been established {223}.

Children 15 years of age and older—See Usual adult dose{223}.



For Testoderm TTS:
Children up to 18 years of age—Use and dose have not been established{76}.



Usual geriatric dose
Androgen deficiency, due to primary or secondary hypogonadism
See Usual adult dose .


Strength(s) usually available
U.S.—


2.5 mg delivered per system per day (Rx) [Androderm{223}]


5 mg delivered per system per day (Rx) [Androderm{223}] [Testoderm TTS{76}]

Canada—
Not commercially available.

Packaging and storage:
For Androderm, store between 15 and 30 °C (59 and 86 °F){223}. For Testoderm TTS, store below 25 °C (77 °F){76}.

Auxiliary labeling:
   • For external use only.
   • Apply patch to a clean, dry, hair-free area of the skin.

Note: The manufacturer's directions for the patient should be dispensed with the product.




Revised: 01/25/2001



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  1. DeSai M, Colberg C, Ranney B, et al. Testicular feminization: patient report and brief review of the literature. S D J Med 1980 Apr; 29-31.
  1. Glenn JF. Testicular feminization syndrome: current clinical considerations. Urology 1976; 7(6): 569-77.
  1. Hammar B, Michowitz M, Solowiejczyk M. Testicular feminization syndrome. Am Surg 1980 Aug: 457-60.
  1. Shull BL, Taylor PT. Testicular feminization syndrome: a case study of four generations. South Med J 1989; 82(2): 251-4.
  1. Scully RE, Mark EJ, McNeely WF, et al. Weekly clinicopathological exercises: case 13-1990. N Engl J Med 1990; 322(13): 917-25.
  1. Savage MO, Grant DB. The incomplete male. Arch Dis Child 1978; 53: 701-3.
  1. Tsega E, Damtew B. Testicular feminization syndrome: a report of three Ethiopian patients and a brief review. Postgrad Med J 1979; 55: 844-8.
  1. Himathongkam T, Berger MJ, Williams GH, et al. Incomplete testicular feminization syndrome with pubertal virilization. Am J Obstet Gynecol 1974; 118(2): 288-90.
  1. Kutten F, Mauvais-Jarvis P. Testosterone 5-alpha-reduction in the skin of normal subjects and of patients with abnormal sex development. Acta Endocrinol 1975; 79: 164-76.
  1. Zarate A, Canales ES, Soria J, et al. Studies on the luteinizing hormone- and follicle-stimulating hormone-releasing mechanism in the testicular feminization syndrome. Am J Obstet Gynecol 1974; 119(7): 971-7.
  1. Morris JM. The syndrome of testicular feminization in male pseudohermaphrodites. Am J Obstet Gynecol 1953; 65(6): 1192-211.
  1. Perez-Palacios G, Jaffe RB. The syndrome of testicular feminization. Pediatr Clin North Am 1972; 19(3): 653-67.
  1. Boczkowski K. Testicular feminization syndrome with and without sexual hair. Obstet Gynecol 1971; 38(5): 719-23.
  1. Quattrin T, Aronica S, Mazur T. Management of male pseudohermaphroditism: a case report spanning twenty-one years. J Pediatr Psychol 1990; 15(6): 699-709.
  1. Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med 1990; 112(5): 352-64.
  1. Baylink D. Steroid-induced osteoporosis. American Academy of Allergy and Immunology. Asthma: advanced level course: course syllabus of 47th annual meeting, March 1991; p. 19-28.
  1. Jackson JA, Kleerekoper M. Osteoporosis in man: diagnosis, pathophysiology, and prevention. Medicine 1990; 69(3): 137-52.
  1. Rosenfield RL. Diagnosis and management of delayed puberty. J Clin Endocrinol Metab 1990; 70(3): 559-62.
  1. Styne DM. Puberty and its disorders in boys. Endocrinol Metab Clin North Am 1991; 20(1): 43-69.
  1. Schwartz ID, Root AW. The Kleinfelter syndrome of testicular dysgenesis. Endocrinol Metab Clin North Am 1991; 20(1): 153-63.
  1. Haidl G, Schill W-B. Guidelines for drug treatment of male infertility. Drugs 1991; 41(1): 60-8.
  1. Schoen EJ. Treatment of diseases of the testes affecting growth and development. Mod Treat 1968; 5(1): 184-204.
  1. Yee GC, McGuire TR. Pharmacokinetic drug interactions with cyclosporin (Part I). Clin Pharmacokinet 1990; 19(4): 319-32.
  1. Bass NM, Williams RL. Guide to drug dosage in hepatic disease. Clin Pharmacokinet 1988; 15(6): 396-420.
  1. Lorimer DA, Hart LL. Cardiac dysfunction in athletes receiving anabolic steroids. Drug Intell Clin Pharm 1990; 24: 1060-1.
  1. AMA Council on Scientific Affairs. Medical and nonmedical uses of anabolic-androgenic steroids. JAMA 1990; 264(22); 2923-7.
  1. Van der Zon P. Safety of testosterone enanthate [letter]. Lancet 1990 Dec 15; 336: 1517-8.
  1. Pollard M. Tumorigenic effect of testosterone [letter]. Lancet 1990 Dec 15; 336: 1518.
  1. Nieschlag E, Waites GMH, Paulsen, et al. Tumorigenic effect of testosterone [letter]. Lancet 1990 Dec 15; 336: 1518.
  1. National Association of Boards of Pharmacy. NABP Newsletter 1991 March: 27.
  1. Testosterone cypionate (Scheinpharm Testone-Cyp—Schein). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 1512.
  1. Testosterone undecanoate (Andriol—Organon). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 84-5.
  1. Testosterone cypionate package insert (Depo-Testosterone, Upjohn—US), Rev 9/90, Rec 12/17/90.
  1. Testosterone cypionate package insert (Depo-Testosterone, Upjohn—US), Rev 4/90, Rec 8/13/90.
  1. Manufacturer"s letter, Rec 4/94. Discontinued Android 5 mg 8/4/93—ICN (US).
  1. Hansten PD, Horn JR. Drug interactions. 6th ed. Philadelphia: Lea & Febiger; 1989.
  1. Tatro DS, editor. Drug interaction facts. St. Louis: Facts and comparisons; 1990.
  1. Panel comments, 9/13/91.
  1. Manufacturer comment, 9/13/91.
  1. Panel comment, 9/13/91.
  1. Panel comment, 9/13/91.
  1. Panel comment, 9/13/91.
  1. Panel comment, 9/13/91.
  1. Hung W, August GP, Glasgow AM. Pediatric endocrinology. Garden City, NY: Medical Examination Publications; 1978.
  1. Guthrie RD, Smith DW, Graham CB. Testosterone treatment for micropenis during early childhood. J Pediatr 1973; 83(2): 247-52.
  1. Reviewers" responses to panel ballot 3/90.
  1. Panel comment, 9/13/91.
  1. Panel comment, 9/13/91.
  1. Panel comment, 9/13/91.
  1. Panel comment, 9/13/91.
  1. Panel comment, 9/13/91.
  1. Panel comment, 9/13/91.
  1. Panel comments.
  1. LaFranchi S, Hanna CE, Illingworth DR. Effect of growth hormone replacement on development of hypothyroidism and hyperlipidemia. J Pediatr 1985 Apr; 106(4): 588-93.
  1. Linet O. Interactions between androgenic-anabolic steroids and glucocorticoids. Prog Drug Res 1970; 14: 139-95.
  1. MacGillivray MH, Kolotkin M, Muschauer RW. Enhanced linear growth responses in hypopituitary dwarfs treated with growth hormone plus androgen versus growth hormone alone. Pediatr Res 1974; 8: 103-8.
  1. Kirkland R, Clayton GW. Growth increments with low dose intermittent growth hormone and fluoxymesterone in first year of therapy in hypopituitarism. Pediatrics 1979; 63: 386-8.
  1. Kirkland R, Clayton GW. Intermittent human growth therapy (IGH) and fluoxymesterone (F) in hypopituitarism: 4 years experience. Clin Res 1978; 26.
  1. Panel comment, 9/13/91.
  1. Kennedy BJ, Nathanson IT. Effects of intensive sex steroid hormone therapy in advanced breast cancer. JAMA 1953; 152: 1135-41.
  1. Kennedy BJ. Stimulation of erythropoiesis by androgenic hormones. Ann Intern Med 1962; 57(6): 917-36.
  1. Panel comment, 9/13/91.
  1. Panel comment, 9/13/91.
  1. Panel comment, 9/13/91.
  1. Panel comment, 3/16/92.
  1. Manufacturer comment (Ciba-Geigy—Canada), telephone call 4/2/92. Metandren.
  1. Cohen JC, Hickman R. Insulin resistance and diminished glucose tolerance in powerlifters ingesting anabolic steroids. J Clin Endocrinol Metab 1987; 64(5): 960-3.
  1. Woodard TL, Burghen GA, Kitabchi AE, et al. Glucose intolerance and insulin resistance in aplastic anemia treated with oxymetholone. J Clin Endocrinol Metab 1981; 53(5): 905-8.
  1. Panel comment, 9/13/91.
  1. Panel comments, 11/25/91.
  1. Panel comments, 11/26/91.
  1. Panel comments, 11/26/91.
  1. Kaplan SA. Clinical pediatric endocrinology. Philadelphia: W.B. Saunders Company; 1990. p. 52-4.
  1. Lipschitz F, editor. Pediatric endocrinology. New York: Marcel Dekker; 1990. p. 17.
  1. Pope HG, Katz DL. Affective and psychotic symptoms associated with anabolic steroid use. Am J Psychiatry 1988; 145(4): 487-90.
  1. Lubell A. Does steroid abuse cause or excuse violence? Phys Sports Med 1989; 17(2): 176-85.
  1. Panel consensus, panel survey date 3/16/92.
  1. Manufacturer comment (Ciba-Geigy—US), panel survey date 3/16/92. Metandren discontinued.
  1. Product Information: Androderm®, testosterone transdermal system. Watson Pharma, Corona, CA (PI revised 8/1999) reviewed 4/2000.
  1. Product Information: AndroGel™ 1%, testosterone gel. Unimed Pharmaceuticals, Buffalo Grove, IL reviewed 8/2000.
  1. Product Information: Androderm®, testosterone transdermal system. Watson Pharma, Corona, CA, (PI revised 12/1999) reviewed 01/2001.
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