Testosterone undecanoate in the treatment of male ...

Drug Evaluation

Testosterone undecanoate in the treatment of male hypogonadism Daniel Edelstein† & Shehzad Basaria †

1.

Male hypogonadism

2.

Current testosterone

Johns Hopkins School of Medicine, Division of Endocrinology and Metabolism, 550 N. Broadway Suite 108, Baltimore, MD, USA

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by JHU John Hopkins University on 10/14/14 For personal use only.

replacement therapies 3.

Chemistry of testosterone undecanoate

4.

Pharmacokinetics and metabolism

5.

Clinical efficacy of testosterone undecanoate

6.

Safety and tolerability

7.

Expert opinion

Importance of the field: Testosterone undecanoate (TU) represents an exciting new testosterone replacement therapy for hypogonadal men due to its convenient dosing schedule and favorable pharmacokinetic and safety profiles. Areas covered in this review: Clinical, pharmacokinetic and safety characteristics of TU will be reviewed. The characteristics of currently approved testosterone therapies will be reviewed and compared with those of TU in order to determine which therapy most appropriately meets the clinical objective of properly matching a patient with a therapy that is best able to deliver physiological levels of testosterone for prolonged periods of time, while at the same time being safe, effective, inexpensive, simple to use, and with few side effects. What the reader will gain: TU represents the first long-acting injectable with an excellent safety profile that can be administered only four times annually to produce stable levels of testosterone. Long-term studies have validated the clinical efficacy of TU in maintaining therapeutic levels of testosterone. Patient preference for the convenient dosing schedule might also lead to better compliance and therapeutic benefit. No serious side effects have been noted with the use of TU, including long-term data on patients treated with TU over 8 years. Take home message: TU is both a desirable and safe option for the treatment of hypogonadal men. Patients will benefit from the stable testosterone levels and fewer required injections, while achieving the desired benefits of androgen replacement. Keywords: androgen replacement, male hypogonadism, testosterone, testosterone undecanoate Expert Opin. Pharmacother. (2010) 11(12):2095-2106

1.

Male hypogonadism

Male hypogonadism is a common endocrine problem that affects an estimated 4 -- 5 million men in the United States. Male hypogonadism is characterized by defects in spermatogenesis and failure of the testes to produce an adequate amount of testosterone (T). Testosterone production is necessary for the development of external genitalia and secondary sex characteristics in children and adolescents. The timing of the onset of hypogonadism directly influences the resulting phenotype. Testosterone deficiency in utero results in ambiguous genitalia. Prepubertal testosterone deficiency can result in small testis and penis, lack of development of secondary sexual characteristics, eunuchoidal body habitus, and delayed bone age. In adults, androgen production is necessary for maintenance of lean body mass (LBM), libido, bone mass, spermatogenesis and sexual function. Hypogonadism is typically classified according to the resulting defect in the reproductive system. Respective levels of gonadotropins are used to distinguish primary hypogonadism, characterized by testicular failure, from secondary hypogonadism, which often results from hypothalamic or pituitary disorders [1]. In primary hypogonadism, 10.1517/14656566.2010.505920 © 2010 Informa UK Ltd ISSN 1465-6566 All rights reserved: reproduction in whole or in part not permitted

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Testosterone undecanoate

Box 1. Drug summary.


Drug name Phase Launched indication Pharmacology description Route of administration Chemical structure

Testosterone undecanoate Launched Hypogonadism Testosterone receptor agonist Parenteral, intramuscular O O-C-(CH2)9-CH3

O

Pivotal trial(s)

[3,13-15,21,27]

Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com).

serum testosterone is low but the gonadotropins (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) are elevated due to the loss of negative feedback (hypergonadotropic hypogonadism). Testicular trauma (surgery, chemotherapy, radiation) or genetic disorders such as Klinefelter’s syndrome often result in hypergonadotropic hypogonadism. Secondary hypogonadism (hypogonadotropic hypogonadism) is indicated by low to inappropriately normal levels of both LH and FSH in the presence of low testosterone levels. Any injury to the hypothalamus or the pituitary gland (tumor, infiltrative diseases, trauma, radiation) can result in hypogonadotropic hypogonadism. Other causes of male hypogonadism include hyperprolactinemia, hypercortisolism (exogenous or endogenous), opioid use, and hemochromatosis. In addition to pathological hypogonadism, another clinical condition that is frequently diagnosed is ‘andropause’ -- lateonset hypogonadism, an age-related decline in testosterone levels [2]. Approximately 20% of men over the age of 60 have serum testosterone levels that are below the lower limit of normal for young men. This form of hypogonadism is multifactorial and results from a combination of testicular and pituitary insufficiency. Andropause can be associated with osteoporosis, as well as with decreased LBM and sexual dysfunction.

Current testosterone replacement therapies

irreversible. Hence, the clinical objective for utilizing one testosterone formulation over another is to properly match the patient with a therapy that is best able to provide physiological levels of testosterone for prolonged periods of time, while at the same time being safe, efficacious, inexpensive, simple to use, and with few side effects. Testosterone replacement therapies have been available for the past 70 years, though earlier modalities are considered to be suboptimal by current standards. Testosterone therapies have evolved since their initial clinical introduction, beginning in the 1940s with the development of subdermal testosterone implants. Testosterone esters were developed in the 1950s and remain a common and inexpensive modality, though they require intramuscular administration and result in undesirable pharmacokinetics. Oral testosterone undecanoate (TU) became available in the 1970s; however, it requires frequent daily dosing with fatty meals. Transdermal delivery of testosterone became available in 1994 with the introduction of the scrotal patch (Testoderm, Alza Corp., Mountain View, CA, USA). This was the first treatment modality that was able to deliver consistent physiological levels of testosterone. The drawbacks included frequent clipping of scrotal hair and difficulty adhering to underdeveloped scrotums. Androderm (Watson Pharm., Corona, CA, USA), a non-scrotal patch, followed soon after and is still available today, though associated with skin reactions in 30% of patients. Testosterone gel was introduced in 2000, and has become the most popular treatment available due to its simple daily application and consistent maintenance of stable physiological levels of testosterone. A mucoadhesive buccal testosterone tablet was recently introduced and offers the benefit of sustained testosterone release, though it requires twice daily administration. A long-acting injectable form of TU known as Nebido (Bayer Schering Pharma AG) is available in 86 countries (outside the US) and is currently being developed under the name Aveed (Endo Pharmaceuticals) for approval in the US. TU was initially licensed from Bayer Schering Pharma AG by Indevus Pharmaceuticals in 2005. Indevus faced a protracted development environment in the US and Endo Pharmaceuticals acquired the rights to TU upon their purchase of Indevus in 2008. TU is the first intramuscular agent that can be taken every 3 months, and may prove to be most convenient for patients who are diagnosed at younger ages who require lifelong testosterone therapy. Table 1 summarizes the currently available testosterone therapies and their clinical implications.

Chemistry of testosterone undecanoate

2.

3.

Presently, several modalities of testosterone replacement are available, each differentiated by their route of delivery, half-life, cost, and ability to deliver physiological levels of testosterone. Testosterone replacement is often a lifelong therapy, since many of its underlying etiologies are generally

Testosterone undecanoate (3-oxoandrost-4-en-17-ylundecanoate, TU; Box 1) is a semi-synthetic androgen with a molecular weight of 456.7 Da. TU is prepared through the 17-b position esterification of natural testosterone with undecanoic acid. In screening for improved long-acting intramuscular testosterone formulations for male

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Expert Opin. Pharmacother. (2010) 11(12)

Edelstein & Basaria

Table 1. Currently approved testosterone replacement therapies. Delivery system (drug)

Route of delivery

Standard dosage for androgen deficiency

Clinical considerations

Testosterone Testosterone Testosterone Testosterone

Intramuscular Intramuscular Intramuscular

10 -- 25 mg 2 -- 3/week 200 mg every 2 -- 4 week 200 mg every 2 -- 4 week

Intramuscular

1000 mg every 12 week

Inexpensive Administered every 2 weeks ‘Roller-coaster’ pharmacokinetics Requires injections Expensive Long-acting Less frequent administration

Testosterone undecanoate Testosterone undecanoate

Intramuscular

1000 mg every 12 week

Andridiol Testocaps

40 -- 80 mg 2 -- 3/day

40 -- 80 mg 2 -- 3/day

Testosterone patch Androderm Andropatch

Skin patch Skin patch

5 mg/day 5 mg/day

Expensive Mimics circadian rhythm Daily administration Skin irritation

Testosterone gel Androgel/Testogel Testim

Topical Topical

5 g/day 5 g/day

Expensive Testosterone levels within physiological range Daily administration Possible transference to intimate contacts

Buccal testosterone Striant

Buccal

30 mg b.i.d.

Expensive Testosterone levels within physiological range Twice-daily dosing Possible oral irritation

Testosterone pellets Testopel

Implant

800 mg 5 -- 7 months

Expensive Convenient 6-month biological duration Requires small incision Possible pellet extrusion Infection

esters propionate enanthate cypionate



contraception, TU exhibited the most favorable kinetics compared with traditional testosterone esters due to the considerably long-term kinetics involved in cleaving TU’s extended hydrophobic side chain consisting of the saturated aliphatic fatty acid undecanoic acid (composed of 11 carbon atoms compared with the 7 and 8 carbons in other esters) [3-5]. This favorable profile allowed for much longer dosing intervals and a sustained normalized testosterone level, avoiding the flux of supra- and subphysiological testosterone levels typical of traditional esters. Since testosterone is the active pharmacological agent of TU, the toxicology of TU is the same as other cleavable testosterone fatty acid esters -- such as testosterone cypionate, enanthate and propionate, each with 9, 7, and 3 carbon atoms, respectively. There are no particular precautions for storing TU, as it has a shelf life of 3 years and is stable at a temperature of 40 C for ‡ 6 months and at a temperature of 30 C for ‡ 24 months [6].

4.

Expensive Long-acting Less frequent administration Expensive Frequent dosing with meals Nausea and GI complaints common

Pharmacokinetics and metabolism

Physiological characteristics of testosterone Testosterone is required for the development of male secondary sexual characteristics, spermatogenesis, maintenance of body composition, and sexual function. Plasma T increases in males until they reach the age of 17, when they stabilize at normal male adult levels of approximately 10 -- 35 nmol/l. In healthy adults, testosterone levels remain stable until men are between the ages of 35 and 40, when levels begin to decline by around approximately 1.2% per year. [7]. Native testosterone is well absorbed from the intestine, yet it undergoes hepatic metabolism so rapidly that maintenance of normal serum T levels in a hypogonadal patient with oral testosterone is practically impossible. In an attempt to improve its bioavailability and pharmacokinetics, several structural modifications of testosterone have been performed, including 17a-alkylation, 17b-esterification, 7a-methylation, 4.1


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1-methylation and addition of a 19-normethyl group (Figure 1). There are generally three criteria when evaluating or designing a particular testosterone modality to be therapeutically effective: route of administration, esterification of the 17b-position, and chemical modification of the molecule [8].

the 17-ketosteroids androsterone and etiocholanolone, which are secreted in the urine and bile. Testosterone and its metabolites can also be hydroxylated by glucuronyltransferases and sulfotransferases to produce water-soluble conjugates that are excreted in the urine and bile. Approximately 2% of testosterone is excreted unchanged in the urine.

Endogenous testosterone synthesis and metabolism

Testosterone undecanoate Intramuscular TU is administered in a castor oil depot in order to decrease absorption rate. Upon entering systemic circulation, TU is cleaved by serum esterases into undecanoic acid and testosterone. Treatment with intramuscular TU has been evaluated in several studies in order to determine its half-life, Cmax and dosing frequency. An early pharmacological study showed that serum levels of testosterone increased from basal levels of 5.0 ± 0.8 to 12.3 ± 1.7 nmol/l, 2 days after injection. Cmax of 22.0 ± 2.0 nmol/l was achieved between days 7 and 14. Mean levels of testosterone were significantly higher than basal values and low normal testosterone levels were maintained in all patients up to 8 weeks following injection (Figure 2) [13]. In an initial pharmacokinetic study, 13 hypogonadal men received four intramuscular injections of TU (1000 mg in 4 ml castor oil) every 6 weeks for 4.5 months [14]. While testosterone levels initially fluctuated, they increased steadily over the 24-week study period and remained within a clinically therapeutic range. Serum DHT and estradiol levels followed a similar pattern. A subsequent study was conducted to determine a dosing interval for TU in seven hypogonadal men receiving injections at 6-week intervals over 3 years. After the tenth injection, TU was administered at 12-week intervals [15]. Testosterone levels increased from 5.2 ± 3.1 to 23.8 ± 7.8 nmol/l after four injections at 6-week intervals. Steady-state kinetics measured after the 13th dose showed that Cmax was 32.0 ± 11.7 nmol/l and half-life was 70.2 ± 21.1 days. In comparison to Testogel (Bayer Schering) 100 mg/day (37.5 nmol/l), TU exhibited a lower mean Cmax, though it was higher than with Testogel 50 mg/day (28.8 nmol/l) and Androderm (26.5 nmol/l) patch 5 mg/day [16,17]. Injections given at gradually increasing intervals, eventually reaching a schedule of once every 12 weeks, were shown to maintain serum testosterone values at the lower limit of normal at 12.6 ± 3.7 nmol/l. Based on these results, a dosing regimen of 1000 mg TU every 12 weeks was recommended and evaluated to be safe and efficacious over a 3-year period [15]. A subsequent trial compared TU (1000 mg TU i.m. every 6-weeks for three doses, followed by 1000 mg every 9 weeks thereafter) with TE (250 mg every 3 weeks) administered to two groups of 20 hypogonadal men with baseline serum T values < 5 nmol/l [3]. The trough testosterone values for TU were 14.1 ± 4.5 nmol/l after the first two doses and 16.3 ± 5.7 nmol/l after week 30. These levels were well within the physiological range and significantly higher than mean trough levels in the TE group, which were consistently


4.2

Testosterone, estradiol, and dihydrotestosterone (DHT) have important roles in male reproductive function. Over 95% of testosterone synthesis occurs in the Leydig cells of the testes, with a very small fraction being produced by the adrenal cortex. Testosterone is synthesized through a series of enzymatic reactions that convert cholesterol to testosterone. A small amount of estradiol, estrone, DHT, and dehydroepiandrosterone (DHEA) are also directly secreted by the testes. Testosterone synthesis relies on complex interaction among the hormones secreted along the hypothalamic--pituitary--Leydig cell axis. Gonadotropin-releasing hormone (GnRH) is secreted by the hypothalamus and stimulates the pituitary to secrete gonadotropins. LH stimulates Leydig cells to synthesize testosterone, while FSH stimulates the seminiferous tubules to initiate spermatogenesis. In healthy men, approximately 3 -- 10 mg/day of testosterone is produced daily under the stimulation of GnRH pulses every 60 -- 90 min. In young men, there is a diurnal rhythm of testosterone secretion, with peak levels in the morning. In older men, this circadian pattern is lost [9,10]. However a recent report suggests that this diurnal rhythm of androgen status is maintained in healthy, fit individuals into their 70s [11]. At the target tissues, testosterone crosses the cell membrane via passive diffusion due to its lipophilic nature [12]. Testosterone may directly activate its receptor or may first be metabolized to DHT by the enzyme 5a-reductase. DHT has a much higher binding affinity for the androgen receptor. Testosterone or DHT bind the androgen receptor in the cytoplasm, and then the complex crosses the nuclear membrane and associates with a hormone-specific receptor and modulates DNA transcription. Testosterone is also converted to estradiol by aromatase, an enzyme that is ubiquitous, but most abundant in adipose tissue. The effect of androgen-induced transcriptional modulation depends upon the target tissue. Testosterone is 98% bound to plasma proteins; hence, only 2% circulates in free form (biologically active). Of the 98% bound testosterone, approximately 40% is bound to sex hormone binding globulin (SHBG) and 60% is bound to albumin. The affinity of testosterone for SHBG is 1000-fold that of albumin; hence it is tightly bound to SHBG. In contrast, testosterone is loosely bound to albumin and is readily available to the tissues. This albuminbound testosterone, along with the free form, is known as bioavailable testosterone. The hepatic CYP P450 3A enzyme converts testosterone and DHT to inactive products. Oxidation of the D ring produces 2098

4.3


Edelstein & Basaria

Esterification of 17β-hydroxyl improves lipophilicity, enabling parenteral use (i.e., intramuscular) Substitution with 9α-fluoro increases activity by increasing affinity for AR

OH

17α-alkylation retards hepatic catabolism and imparts oral activity

Reduction of 3-ketone is essential for metabolism

Figure 1. Common structure--function relationships of androgens.

45 40 35 Testosterone (nmol/l)


O

30 25 20 15 10 5 0 Init.

0

2

4

6

8

10

12

14

16

18

20

22

24

Weeks

Figure 2. Mean values of serum testosterone, levels in 13 hypogonadal men before and during substitution therapy with intramuscular testosterone undecanoate. Injections of 1000 mg were given at weeks 0, 6, 12 and 18. T levels increased significantly from baseline of 5.3 nmol/l (Init.) to T levels of 24.3 nmol/l 1 week following the first injection of TU. Serum levels 6 weeks following the third and fourth injections were not significantly different. Figure adapted with permission from [14].

< 10 nmol/l, demonstrating a more stable elevation of testosterone levels with TU compared with TE. The mean testosterone levels throughout the study for TU administration was 16.17 ± 4.99 nmol/l. Several patients developed supraphysiological testosterone levels with 6-week intervals of TU injection; extending the injection interval prevented this effect. As a follow-up, this study was extended for 2.5 years of further treatment, with all patients receiving 1000 mg TU

every 12 weeks. Two loading doses of 1000 mg TU every 8 weeks were given to patients who previously received TE. This dosing regimen resulted in stable serum trough T levels ranging from 14.9 ± 5.2 to 16.5 ± 8.0 nmol/l. The mean serum levels of DHT and estradiol also increased in parallel with serum T levels and remained within the normal range. Additionally, it was demonstrated that patients receiving TE could be transitioned to TU without interruption in therapy, though an additional loading dose of TU was necessary.


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Long-term data from a study of 22 hypogonadal men receiving 1000 mg TU every 10 -- 14 weeks resulted in adequate substitution with serum trough T levels within the lownormal range [18]. The resulting total and free testosterone levels of patients in this study over 8.5 years confirm that long term substitution with TU results in clinically therapeutic testosterone substitution (Figure 3) [19]. TU appears to be equally effective in both younger and elderly men, as evidenced in a study of 21 men with primary, secondary and late-onset hypogonadism between the ages of 45 -- 79 years, treated with TU over 6 months [20]. Testosterone levels increased from a baseline level of 9.02 ± 3.78 nmol/l to 13.54 ± 4.68 nmol/l after 6 weeks and to 46.41 ± 6.42 nmol/l after 30 weeks of treatment. DHT levels increased from a baseline level of 286 ± 141 pg/ml to 905 ± 299 pg/ml and in two patients, injections were able to be extended from 12 to 14 weeks, while still maintaining efficacy. On average, PSA levels fluctuated and increased minimally, while remaining in the normal range. The study investigators concluded that TU is safe for treating hypogonadal men. A recent study of 117 hypogonadal men receiving 750 mg of TU at 0, 4, and 14 weeks showed that administration of TU at baseline and again at 4 weeks quickly achieved therapeutic testosterone levels [21]. Of the 117 patients, 110 patients (94%) had an average testosterone concentration (Cavg) within the clinically therapeutic range of 10.41 -- 34.7 nmol/l during the 10 weeks following the third injection. Additionally, 92% of patients had a Cmax < 52 nmol/l throughout the study. Based on the results of this study, it is clear that TU therapy exceeded the FDA’s two threshold criteria for therapeutic success, as the Cavg was well within the young healthy adult male reference range of 10.41 -- 34.7 nmol/l and the Cmax did not exceed the upper limit of 52 nmol/l for the vast majority of patients. In a study measuring the impact of testosterone substitution on circulating levels of DHT, 32 men treated for 15 months with TU were compared with 23 men treated for 9 months with T-gel (Testogel) [22]. Plasma T rose higher in the TU group, rising from a baseline of 7.2 ± 1.7 to 19.3 ± 4.1 nmol/l following treatment, while in the T-gel group the rise of testosterone was from 7.8 ± 1.6 to 15.3 ± 3.2 nmol/l. Surprisingly, mean plasma DHT levels declined similarly between the two groups following testosterone administration, from 0.95 ± 0.50 to 0.55 ± 0.30 nmol/l, coinciding with a declining ratio of DHT/T. This finding is in contrast to previous studies that have shown an increase in plasma DHT levels upon administration of testosterone [16,17,23]. The authors speculate that the unusual observation of declining DHT may be attributed to the older age of study subjects, though previous studies also included elderly men. Based on the data from several key studies and longterm clinical observations, an initial dose of 1000 mg TU has been determined to be most optimal and should be followed by a second injection 6 weeks later [3,18]. After this 2100

loading dose period, injections may resume every 12 weeks as long as the patient’s serum T levels are in the range of 10 -- 15 nmol/l. It is possible to extend the dose to 14-week intervals if serum T concentrations are > 15 nmol/l before the fourth injection. However, if the serum T levels are < 10 nmol/l, then the injection schedule of TU should be shortened to every 10 weeks [18]. There have been reports of men with accelerated rates of testosterone metabolism who may require an injection of TU 1000 mg every 10 -- 11 weeks [24]. Intramuscular TU offers the dual benefit of long-term stabilization of testosterone levels while concurrently being amenable to flexible dose modifications with individualized injection intervals.

Clinical efficacy of testosterone undecanoate

5.

Initial studies The efficacy of TU in preclinical Phase I studies has been extensively reviewed elsewhere [25]. Several Phase II trials have evaluated the efficacy and safety of TU in hyopogonadal men. An initial open-label, nonrandomized clinical trial investigated the administration of TU 1000 mg in castor oil (250 mg/ml) injected intramuscularly at 6-week intervals for 24 weeks in 13 hypogonadal men, aged 19 -- 57 years, with baseline serum T levels < 10 nmol/l [14]. Previous androgen replacement therapy was discontinued for 4 weeks preceding the study. No patient reported any injection-site pain or swelling, despite the large volume of injection (4 ml). Testosterone levels increased from a baseline of 5.3 ± 0.9 to 24.3 ± 2.9 nmol/l on day 7. Levels decreased linearly from day 7 to a value of 12.4 ± 1.2 nmol/l immediately before the second injection. Maximal serum T levels after the third and fourth injection were 37.2 ± 3.9 and 40.8 ± 3.9 nmol/l, respectively. DHT and estradiol both increased significantly, remaining within the normal range. Patients with primary hypogonadism (n = 7) showed significant suppression of LH and FSH secretion. Routine serum chemistries did not change during the course of treatment. Levels of HDL and total cholesterol decreased significantly; LDL cholesterol and triglycerides were unchanged. Hemoglobin increased significantly from a baseline value of 142 ± 3 to 154 ± 4 g/l. Hematocrit also increased from 42.5 ± 1.1% to 45.7 ± 1.0%. There was a significant increase in erythrocytes from 4.8 ± 0.1 10 -- 12/l to 5.1 ± 0.1 10 -- 12/l, still within the normal range. Patients showed a significant increase in weight, from a baseline value of 82.3 ± 3.8 to 85.8 ± 3.7 kg at the completion of the study, most likely due to the anabolic effects of testosterone on LBM. Patients also reported an improvement in emotional stability, improved sense of wellbeing and improved sexual function. The prostate size and PSA levels did not exceed the normal range, though there was a slight but notable increase in prostate volume from 13.6 ± 2.4 ml at baseline to 15.7 ± 2.0 ml at the end of the study. PSA levels also increased significantly from 5.1


Edelstein & Basaria

600


Free testosterone (pmol/l)

Total testosterone (nmol/l)

30 25 20 15 10 5

500 400 300 200 100

0

0 0

50

0

100 150 200 250 300 350 400 450 500

50

Weeks

100 150 200 250 300 350 400 450 500 Weeks

Figure 3. Eight years of experience with testosterone undecanoate i.m.: free testosterone levels. Data from the Muenster group [19].

0.6 ± 0.3 µg/l to maximal levels of 1.2 ± 0.7 µg/l at week 19. Patients did not report mood swings or emotional instability (a common complaint with TE), suggesting that TU allows for more stable levels of testosterone compared with the rapid fluctuations in testosterone levels seen with TE. No serious adverse events occurred. Two patients reported mild acne, one patient experienced gynecomastia, and a further two complained of breast tenderness. In a subsequent open-label, nonrandomized clinical trial, seven hypogonadal men were treated with TU 1000 mg in castor oil at increasing intervals over a 3.2-year period [15]. Gonadotropin levels decreased significantly with TU treatment. A small increase in hemoglobin, hematocrit and erythrocytes occurred from the baseline values; only one patient developed levels above the upper limit of normal. This is in contrast to TE, which is almost three times as likely to cause polycythemia compared with transdermal testosterone replacement. No changes were observed in serum electrolytes, liver function or prothrombin time. Changes in lipid parameters did not reach statistical significance; however, a slight decrease in HDL cholesterol (-13.8%) and LDL cholesterol (-10.4%) was noted. There was a slight and insignificant increase in prostate volume from a baseline of 13.6 ± 6 to 23.1 ± 6.1 ml at study completion. PSA levels remained within the normal range but did show a small increase during the 6-week injection period. Body weight increased slightly, but the increase was not statistically significant. Patients reported a general sense of well-being and normal sexual function during treatment. These parameters were not different when evaluated at the half-point of injection intervals versus the end of the interval period. This suggests that physiologically normal testosterone values were maintained throughout the 12-week period with no major fluctuations. No serious adverse events occurred. One patient experienced mild acne, but this resolved with longer interval periods (12-week intervals). This same patient also developed gynecomastia.

Later studies Schubert and colleagues compared the efficacy of TU with TE in 40 hypogonadal men, assessing sexual function, body composition, muscle strength and hematological parameters. In a follow-up trial, 40 hypogonadal men initially randomized to receive either TE or TU for 30 weeks, was extended to 32 patients who continued receiving TU 1000 mg every 12 weeks for an additional 114 weeks [3,26]. Grip strength was not shown to increase during the 30-week period in either TU- or TE-treated patients, but did show a marked improvement after 114 weeks of TU treatment, rising by 3.8 ± 2.9 kg in the left and 4.2 ± 2.9 kg in the right hand. Body mass index (BMI) was not affected in either group during the initial or follow-up treatment periods. Average leptin levels decreased significantly in both groups within the first 30 weeks, from an average of 14.2 ± 11.3 to 6.8 ± 41 ng/ml, though no further decline was noted in long-term treatment with TU. Total cholesterol levels declined significantly in both groups during the first 30 weeks: 8.6% in the TU group and 6.1% in the TE group. Mean serum high-density lipoprotein (HDL) cholesterol declined significantly following testosterone therapy by 13.9% in the TU group and 12.2% in the TE group. Low-density lipoprotein (LDL) cholesterol also declined by 6.4% in the TU group and 3.3% in the TE group. The cholesterol-lowering effect remained after all patients were switched to TU therapy, with total serum cholesterol declining by 14% compared with baseline over the full period of observation. Within the 30-week study period, both hemoglobin and hematocrit levels increased by 9.4 and 7.8%, respectively, in the TU group compared with increases in hemoglobin and hematocrit of 7.9 and 8% in the TE group. Both hemoglobin and hematocrit levels remained stable throughout the 114-week study period, with no further increases attained beyond the values achieved at 30 weeks. Patients receiving TU experienced half the adverse events (AE) as those treated with TE (2 vs 4 AE, respectively). The two AE for the TU group were reports of increased snoring 5.2


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during sleep and pain at the injection site. The AE for the TE group included one report of hair loss, two reports of mild acne or skin discoloration, and one report of pain at the injection site. Over the 114-week treatment with TU, one patient experienced convulsions, considered a serious AE. In both treatment groups, serum PSA values rose significantly, though remained within the normal range throughout the course of treatment (< 2.5 µg/l). PSA levels in the TU group increased from 0.27 ± 0.19 to 0.73 ± 0.38 µg/l and in the TE group from 0.35 ± 0.24 to 0.53 ± 0.35 µg/l after 29 months. This investigation revealed that TU is as efficacious as TE, with the benefits of a more convenient dosing schedule and a slightly lower risk profile based on the decreased occurrence and lesser severity of AEs. The second investigation utilizing the same patient population evaluated the sexual function and mood of 40 men randomized to receive either TE (n = 20) or TU (n = 20) over 30 weeks [27]. After completing the comparison study over 30 weeks, 16 patients from the TE group and all 20 from the TU group agreed to receive TU for an additional 65 weeks. Assessment of psychosexual effects was made using a standardized questionnaire to assess general mood, sexual activity, frequency of erections and ejaculations, number of early-morning erections, and various components of sexual interest and desire. Both TU and TE were shown to improve all assessed parameters of sexual activity and general mood, with no significant differences between the two treatment groups. Results were maintained throughout the 65-week period when all subjects received TU. Erectile function improved in 85% of patients during therapy in both groups. All parameters of sexual well-being were greatly improved during therapy and continued to improve significantly during the follow-up period with TU administration. A general mood assessment also showed significant improvements in general well-being parameters, including decreased agitation and listlessness and increased self-confidence, activation, concentration and good mood. These parameters showed even greater improvement during the follow-up period with TU. A long-term follow-up study comparing TU with TE evaluated the safety and efficacy of TU [28]. Over the 4-year course of treatment, plasma T before injection remained above the lower limit of normal, 11.9 -- 15.9 nmol/l, and no patients experienced supraphysiological plasma levels of testosterone, nor did the injection interval have to be extended longer than 12 weeks for any patient. Plasma levels of estradiol and SHBG were stable, while plasma LH and FSH declined over the study period. Body weight, BMI, and waist-to-hip ratio all remained stable. Treatment with TU decreased LDL, while HDL increased significantly. Triglycerides and total plasma cholesterol also remained stable. Apolipoprotein A1 and B decreased slightly, while lipoprotein(a) was stable. Leptin levels, which had initially decreased by 50% during the first 30 weeks, remained stable over the longer term. A small but significant increase in bone mineral density was observed. 2102

The extended observation period of this study provides important information on the long-term administration of TU, the results of which are summarized in Table 2. It seems likely that though the majority of beneficial effects of TU were experienced during the first 30 weeks of therapy, some androgen-dependent functions may require longer-term administration of TU before the beneficial effects of testosterone are fully realized. Several studies have shown improved levels of libido and sexual desire during TU therapy. A recent prospective open-label study compared the effects of TU administration (1000 mg/interval) in 28 hypogonadal men to T-gel (50 mg/day) in 27 hypogonadal men over 9 months of treatment on symptoms of sexual dysfunction [29]. In men treated with T-gel, plasma T levels rose from 7.77 ± 1.42 to 13.90 ± 2.50 nmol/l at 9 months, within the lower limit of normal, while plasma T levels of men receiving TU increased significantly higher from a baseline of 7.22 ± 1.94 to 18.74 ± 2.67 nmol/l, within the middle range of normal. All patients were assessed at baseline and every 3 months on the following variables: International Index of Erectile Function (IIEF) function, aging male score (AMS), waist circumference, blood pressure and various hematological parameters, and liver function. In all patients, sexual parameters showed significant improvement at each assessment interval, with the TU group experiencing the greatest benefit. A testosterone dose--effect relationship was indicated, as TU’s ability to generate higher plasma T levels was markedly more effective than T-gel at producing better results for all efficacy parameters. A number of studies have reported on the potential use of TU in treatment of erectile dysfunction (ED). Testosterone is known to exert significant effects on the physiological and anatomical properties of erectile tissue [30,31]. TU therapy has been shown to improve veno-occlusive dysfunction in patients with severe ED as a result of diabetes mellitus, obesity, and metabolic syndrome who did not respond to prior PDE5 inhibitors and alprostadil injections [32,33]. A recent study evaluated the impact of TU on 22 hypogonadal men with ED. In 12 of the 22 patients (54%), TU was shown to significantly improve the sexual desire domain of the IIEF, as well as improve the erectile function domain after 24 weeks of therapy. The other 10 patients did report an improvement of sexual desire, though a significant increase in erectile function was not achieved. An important observation from this study was that the effect of testosterone on erectile function does not occur rapidly and may take as long as 12 -- 24 weeks to become apparent. Therefore, testosterone therapy should be evaluated after a sufficient period of observation, in some cases at least 24 weeks. Overall, restoration of normal testosterone levels in hypogonadal men receiving TU therapy appears to significantly improve sexual dysfunction and to have a direct and positive impact on the physiological characteristics of ED.



15.8 ± 1.2 47.3 ± 3.3 19.7 ± 8.8 0.67 ± 0.38

Hemoglobin g/dl (n = 13.5 -- 18.0)

Hematocrit % (n = 42 -- 50)

Prostate volume (ml)

PSA µg/dl (n < 3.5)

Adapted from [28].

43 ± 9

212 ± 38

Cholesterol ng/dl (n < 200) 153.7 ± 78.7

1.1 ± 0.2

Bone mineral density g/cm2

Triglycerides mg/dl (n < 200)

26.5 ± 11.8

SHBG (15 -- 70 nmol/l)

HDL ng/dl (n = 35 -- 55)

14.3 ± 7.7

Testosterone (10 -- 30 nmol/l)

0 week

0.75 ± 0.36

46.3 ± 2.9

16.0 ± 1.0

161.2 ± 71.4

43 ± 10

202 ± 36

25.8 ± 11.2

16.1 ± 4.9

84 weeks

0.79 ± 0.42

22.0 ± 8.4

46.4 ± 2.9

16.0 ± 1.0

174.3 ± 110.6

43 ± 9

206 ± 36

1.2 ± 0.2

25.9 ± 10.9

15.9 ± 5.7

96 weeks

Table 2. Laboratory variables during 228 weeks of TU administration.

0.73 ± 0.40

21.4 ± 8.5

46.6 ± 3.2

16.2 ± 1.1

190.5 ± 105.4

41 ± 12

201 ± 33

1.2 ± 0.2

27.2 ± 12.3

15.1 ± 4.9

120 weeks

47.8 ± 3.7

16.5 ± 1.3

177.3 ± 90.8

42 ± 10

207 ± 39

132 weeks

46.8 ± 2.6

16.4 ± 0.9

174.7 ± 74.6

43 ± 11

209 ± 38

144 weeks


0.87 ± 0.53

24.3 ± 8.7

46.3 ± 2.5

16.3 ± 1.0

184.5 ± 95.9

43 ± 12

204 ± 44

1.2 ± 0.2

27.9 ± 15.9

12.5 ± 4.0

164 weeks

0.85 ± 0.58

23.1 ± 7.8

45.6 ± 2.9

16.0 ± 1.0

177.6 ± 126.7

55 ± 11

208 ± 46

1.2 ± 0.2

25.3 ± 10.4

11.7 ± 4.1

228 weeks

Edelstein & Basaria

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Table 3. Clinically significant outcomes of testosterone therapy.


Improvements

Complications

" Strength and muscle mass

" PSA and prostate volume

" Sense of well-being

Lipid abnormalities #HDL

" Hemoglobin levels

" Risk of infertility

" Lean body mass

Acne or oily skin

Normal virilization

Testicular atrophy

# Overall body fat

Skin reactions

" Sexual activity

Gynecomastia

" Energy

Polycythemia

" Libido

Sleep apnea

6.

Safety and tolerability

So far TU has shown a good safety profile; no major adverse events were seen in any studies, including long-term data collected over 8 years of treatment. TU should be injected deep into the gluteal muscle and though few patients report injection-site pain, concerns of local irritation at the injection site could be reduced by slow administration. A recent study reported that 80% of men experienced pain of moderate severity following an injection of TU [34]. This pain peaked immediately after injection and lasted no longer than 1 -- 2 days, returning to baseline on day 4. These results correspond with previous evidence suggesting that local irritation does not typically last longer than 3 days. No patients voluntarily discontinued TU therapy as a result of injection-site pain or local discomfort. Increase in PSA and prostate size was within the normal range. Though several studies have demonstrated an increased PSA velocity, in comparative studies, PSA values and prostate size were not higher for TU than for other testosterone therapies. As with any testosterone replacement therapy, serum PSA, prostate size and erythropoiesis parameters should be monitored in men aged > 45 years at quarterly intervals for the first year and then annually throughout the duration of therapy [35]. Side effects such as gynecomastia, breast tenderness and acne were reported in a minority of patients on TU. These side effects are not unique to TU therapy and occur more frequently among patients receiving other testosterone therapies. The relative absence of side effects in TUtreated patients is thought to be due to TU’s ability to improve and maintain normal physiological levels of T, DHT and estradiol. TE in contrast to TU commonly causes fluxes of supra- and subphysiological peaks shortly after and before injections. This flux often leads to mood swings and emotional imbalance, as well as elevated hematocrit levels [16,36,37]. Increases of hematological parameters to eugonadal levels were seen in several studies of TU, but there was no occurrence of polycythemia, as observed in studies with traditional testosterone esters [16,36,37]. 2104

Though rare, TU has been associated with reports of pulmonary oily microembolism (POME), causing symptoms such as the urge to cough and respiratory distress. POME is probably due to the improper injection of TU, in which the drug was injected too quickly, rather than due to TU itself. Current recommendations call for patients to receive TU in the clinic to avoid potential injection reactions. In the US clinical trials of TU, which included approximately 500 patients, there was one report of POME in a patient receiving a 750-mg dose of TU. The symptoms resolved within a few minutes and the patient did not need further medical attention. Instances of POME have also been reported since TU’s approval in Europe, though they were associated with a larger dose (1000 mg). Side effects beyond a shortness of breath due to POME include dizziness, flushing and rare instances of fainting. Due to the rare instances of POME, TU has not been readily approved in the US and is facing further scrutiny by regulatory authorities, despite its European approval in 2003. 7.

Expert opinion

Testosterone modalities are differentiated by their route of administration, ability to maintain stable physiological levels of testosterone, safety profile, and dosing schedule convenience. Testosterone therapy is successful at reversing many of the symptoms associated with hypogonadism in both younger and older men (Table 3). As the majority of hypogonadal men require lifelong treatment with testosterone, it is important to utilize a therapy that is effective, safe, and convenient to use. A variety of testosterone replacement modalities are available today, though each modality has inherent deficiencies (Table 1). The shortcomings of testosterone esters are abundantly clear, as these injections do not provide physiological testosterone levels and require frequent administration. Testosterone gels are widely prescribed due to their favorable pharmacokinetic profile and positive long-term clinical results. Testosterone gels, however, require daily administration, which some patients find cumbersome. Additionally, testosterone gels have received a black box warning due to the potential risk of transference of unabsorbed gel from the patient to their spouse or young children. TU, by contrast, is administered only four times annually, produces stable levels of testosterone, and thus far has an excellent safety profile. From the standpoint of a physician, testosterone gel and TU are pharmacokinetically very similar in their ability to produce physiological levels of testosterone. Patients, however, may prefer the convenient dosing schedule of TU, which may lead to better compliance and therapeutic benefit. Initial consensus regarding restricting use of TU in older hypogonadal men due to the increased potential risks of polycythemia and prostate-related adverse effects have not been substantiated in long-term studies. No events of polycythemia have been recorded with TU administration; indeed, polycythemia is much more common with administration



Edelstein & Basaria

of traditional esters. Though no serious side effects have been noted with TU, there are still unquantified risks in terms of its impact on prostate size and potential cancer development, though these risks apply to all testosterone therapies. Careful scrutiny of patients experiencing episodes of POME following injection of TU is recommended since the precise cause of POME is not yet fully understood. Studies using TU did raise PSA levels and increased prostate size; however, these levels were well within the normal range and were not increased preferentially more than other testosterone modalities. It is strongly recommended that standard practice clinical guidelines for monitoring elderly patients be closely followed in elderly men receiving TU. Consideration should also be given to initially administer T-gel to new elderly patients, allowing for the monitoring of potential adverse reactions to testosterone replacement, especially considering the potential for effects on prostate health. After an initial monitoring period proves successful, patients may be transitioned to TU. Younger patients with little risk of prostate issues can be started on TU right away. TU can be taken every 3 months (after two loading doses), representing a significant convenience to patients. Positive clinical symptoms and stable trough plasma T levels measured before subsequent injections may enable the extension of the Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Affiliation

Daniel Edelstein†1 BS & Shehzad Basaria2 MD † Author for correspondence 1 Johns Hopkins School of Medicine, Division of Endocrinology and Metabolism, 550 N. Broadway Suite 108, Baltimore, MD, USA E-mail: [email protected] 2 Boston University School of Medicine, Boston Medical Center, Division of Endocrinology and Metabolism, Androgen Clinical Research Unit, 670 Albany Street, 2nd Floor, USA