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Most clinical trials with testosterone replacement treatment have been done in postpubertal males with hypogonadism from various causes. With few exceptions, they have been open-label; double-blind studies would be a challenge, although preferable. Total testosterone concentrations have generally been used for the diagnosis of androgen deficiency and for adequacy of replacement testosterone therapy. Free or bioavailable testosterone concentrations may provide a better basis for diagnosis of deficiency and for adequate replacement therapy. Intrinsic potency, bioavailability, and rate of clearance from the circulation are determinants of the biological actions of androgens. Goal of Androgen Therapy

A safe general principle in androgen replacement therapy is to approach normal physiology with concentrations of testosterone (350-1050 ngdL_ 1) and its active metabolites3 and this should not have untoward health hazards on the prostate, serum lipids, and cardiovascular, liver, and lung function. Thus, unphysiologically high or low serum testosterone concentrations should be avoided. Normal physiological responses to androgen replacement therapy allow virilization in prepubertal males and restoration or preservation of virilization in postpubertal males. Self-administration that is convenient, causes minimal discomfort, and results in reproducible daily pharmacokinetics at a reasonable cost is preferred. None of the currently available androgen replacement therapies achieves the ideal, but improvements have been made in achieving these goals. Historical Aspects

Oral pure testosterone was ineffective, but the methyl derivative (methyltestostereone) was effective orally, as were implanted subcutaneous testosterone pellets. Testosterone ester injections gained widespread acceptance in the 1950s.19 Other testosterone derivatives were made for their anabolic properties. Testosterone undecanoate (TU) administered orally became available for clinical use in some countries in the 1970s. Developers of androgens have avoided derivatives of testosterone with hepatic toxicity and have focused on delivering pure testosterone by oral, injectable, or transdermal preparations. Testosterone is metabolized to potent metabolites by steroid 5-a-reductase to form DHT and aromatase to form estradiol and chemical modification of testosterone results in substances that are poor substrates for these enzymes. Adults

A 5 mg delivery dose of a patch or gel system or 200 mg of either testosterone enanthate or cypionate intramuscularly (IM) every 2 weeks is administered for androgen replacement therapy in males with hypogonadism. If IM testosterone enanthate or cypionate is used, an injection of 100 mg produces a better pattern of testosterone levels, but higher doses at less frequent intervals deviate much more from the physiologic normal testosterone range.3

The efficacy of androgen replacement therapy is best assessed by monitoring the patient's serum testosterone responses,1'2 because variability in response to testosterone therapy in hypogonadal males in libido, potency, sexual activity, feeling of well-being, motivation, energy level, aggressiveness, stamina, and hematocrit is considerable. Increases in body hair, muscle mass and strength, and bone mass may require months to years of therapy. In sexually immature, eunuchoidal males, androgen replacement therapy may also cause secondary sexual characteristics and long bone growth.

When injectable forms of testosterone are administered, testosterone levels during therapy should be in the mid to normal range 1 week after an injection. Some hypogonadal males treated with testosterone esters experience fluctuations in sexual function, energy level, and mood, which are associated with fluctuations in serum testosterone concentrations between injections.

With patch and gel systems the recommended beginning dose is 5 mg testosterone for adults; smaller doses are recommended for some elderly males. Measurement of serum testosterone concentrations about 12 h after application after daily treatment for 7-14 days will provide information about adequate dosing. Then dosing adjustments can be made. Counseling of patients and their partners before beginning androgen replacement is recommended to help reduce or alleviate adjustment problems of increased sexual interest and performance.

Males with prepubertal hypogonadotropic hypogonadism require the combined treatment with human chorionic gonadotropin (hCG) plus human menopausal gonadotropins to initiate sperm production and fertility. In those with a selective deficiency of GnRH, such as Kallmann's syndrome, pulsatile GnRH therapy has been shown to stimulate testosterone production and spermatogenesis. Prepubertal

Initiation of androgen replacement therapy in prepubertal hypogonadism is usually begun at about 14 years of age, and earlier if clinically indicated.1'2 Growth, virilization, and psychological adjustment should be monitored. Distinguishing between simple delayed puberty and hypogonadism is often a challenge, and transient androgen therapy can be given until permanent hypogonadism is established.1,2

In boys gradual replacement therapy with testosterone less than an adult replacement dose is justified (50 or 100 testosterone enanthate or cypionate IM monthly1'2 or 2.5 mg daily of transdermal testosterone), and the goal is to duplicate the changes in testosterone occurring naturally in normal boys and resulting in gradual virilization and progression of secondary sexual development. Then, the dosage of testosterone ester may be 50-100 mg every 2 weeks or 2.5 mg Androderm nightly for 12 h for approximately 6 months.3 Stopping replacement for 3-6 months allows an assessment of the spontaneous onset and progression of puberty. If spontaneous puberty is not in evidence, androgen therapy is reinstituted for another 6 months with 100 mg testosterone ester every 2 weeks or 2.5 mg Androderm daily. Testosterone Preparations Intramuscular preparations Testosterone esters: overview

Testosterone fatty acid esters at the 17 position prolongs IM retention and duration of activity of testosterone commensurate with fatty acid length (Figure 1).49 When administered IM,3 the androgen ester is slowly absorbed into the circulation where it is then rapidly metabolized to active unesterified testosterone. Testosterone propionate, a short fatty acid, releases testosterone for only 2-3 days and is not suitable for long-term replacement therapy. Intermediate-acting preparations, including testosterone enanthate, cypionate, and cyclohexane carboxylate are suitable for clinical use and have similar steroid release profiles when injected IM. Common regimens are administration of 200 mg of either testosterone enanthate or cypionate once every 2 weeks IM or 100 mg weekly.3 T-tra«i-4-n-butylcyclohexyl-carboxylate and TU are even longer-acting preparations with sustained therapeutic blood levels for about 6-12 weeks depending on the dose.20 As summarized in Figure 1, injections of testosterone enanthate (200-250 mg injected every 2 weeks) result in a maximal supraphysiological testosterone serum concentration as high as 51 nmol L _ 1 shortly after injection and then decline to the lower range of normal testosterone serum concentration (12 nmol L_ 1) before 2 weeks.3 Nandrolone phenylpropionate and decanoate

Nandrolone phenylpropionate and decanoate are 17^-hydroxyl esters of 19-norT that have prolonged action following injection, and are used primarily to treat refractory anemias rather than for androgen replacement therapy.3 Testosterone buccilate

A dose of 600 mg testosterone buccilate injected IM in hypogonadal males produced serum testosterone concentrations within the normal range for about 8 weeks with a half-life of 29.5 days. Serum DHTand SHBG concentrations were within the normal range; estradiol was only slightly increased and gonadotropins were significantly suppressed. No adverse biochemical and prostate effects were reported. This preparation may be used for male contraceptive therapy or replacement for hypogonadism. Testosterone undecanoate

Testosterone undecanoate (TU) injections of 500 and 1000 mg in hypogonadal males resulted in increased mean serum testosterone levels from less than 10 nmol L _ 1 to 47.8+ 10.1 and 54.2 + 4.8 nmol L _ 1, respectively, after about 1 week. By 50-60 days, serum testosterone levels decreased and reached the lower normal limit for adult males with a terminal

Figure 1 Serum testosterone concentrations during testosterone replacement therapy in adult primary hypogonadal men. Testosterone enanthate was administered by IM injection (arrows) for 12 weeks in four dosage regimens: 100 mg weekly; 200 mg every 2 weeks; 300 mg every 3 weeks; and 4000 mg every 4 weeks. Blood was sampled weekly until the last dose and more frequently thereafter. (Reproduced with permission from Snyder, P. J.; Lawrence, D. A. J. Clin. Endocrinol. Metab. 1980, 51, 1335-1339. Copyright 1980, The Endocrine Society.)


Figure 1 Serum testosterone concentrations during testosterone replacement therapy in adult primary hypogonadal men. Testosterone enanthate was administered by IM injection (arrows) for 12 weeks in four dosage regimens: 100 mg weekly; 200 mg every 2 weeks; 300 mg every 3 weeks; and 4000 mg every 4 weeks. Blood was sampled weekly until the last dose and more frequently thereafter. (Reproduced with permission from Snyder, P. J.; Lawrence, D. A. J. Clin. Endocrinol. Metab. 1980, 51, 1335-1339. Copyright 1980, The Endocrine Society.)

elimination half-life of 18.3 + 2.3 and 23.7 + 2.7 days.21 Estradiol and DHT paralleled testosterone and remained within normal limits. In these short-term studies, no serious side effects were reported. IM TU has promise for long-term substitution therapy in hypogonadism and hormonal male contraception.21 Subcutaneous testosterone implants

Pure fused pellets or Silastic capsules implanted subcutaneously release testosterone in amounts to maintain physiologic concentrations of testosterone for between 4 and 6 months.22

Jockenhovel et al.23 implanted 6-200 mg fused crystalline testosterone pellets in the subdermal fat tissue of the abdomen in hypogonadal males, and after an initial peak on the first day of administration a stable plateau lasted for 63 days. Testosterone values fell below the normal range by 180 days but took about 300 days to reach baseline. However, serum estradiol and DHTwere elevated from day 21 to 105, and SHBG was decreased from day 21 to 168. Implants of testosterone pellets could be used for testosterone replacement therapy as well as for reversible male contraception. Transdermal testosterone

Transdermal testosterone creams have been used in the treatment of microphallus in children and hypogonadism in adults.3 Percutaneous Dihydrotestosterone in hypogonadal males

A 125 mg dose of hydroalcoholic gel of DHT applied twice daily to the skin can result in sustained concentrations of DHT.24 As expected, the ratio of DHT to testosterone increased to around 5 (normal ranges between 0.1 and 0.2); serum testosterone, estradiol, and SHBG concentrations did not rise and gonadotropins were unchanged. Treatment of testosterone-deficient hypogonadal males reportedly improved virilization and sexual function and decreased plasma low- and high-density lipoprotein (HDL) cholesterol levels moderately without causing enlargement of the prostate as determined by ultrasound study.24 Transscrotal testosterone

Scrotal skin is at least five times more permeable to testosterone than other skin sites. Testoderm and Testoderm with adhesive applied to the scrotum of hypogonadal males delivers 4 and 6 mg of testosterone daily. Peak testosterone concentrations occurred at 3 weeks and then remained stable. DHT concentrations were elevated, and normal-range androgen concentrations (testosterone plus DHT) and estradiol were achieved in 80% of hypogonadal males.3 Nonscrotal testosterone patch therapy (Androderm)

After a 5 mg Androderm system was applied daily to nonscrotal skin (back, abdomen, thighs, and upper arms) at about 22:00 h, testosterone was continuously absorbed during the 24-h dosing period, and the serum testosterone concentration profile for more than 90% of males resembled the normal circadian variation in healthy young males (Figure 2).3 In addition, bioavailable testosterone (BT), DHT and estradiol serum testosterone concentrations paralleled the serum testosterone profile (Figure 2) after patch application and remained within the normal reference range.

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