sign in sign up
<<
Home , Jenapharm, Nandrolone decanoate, Testosterone undecanoate

DRUG PROFILE

Long-acting undecanoate for parenteral testosterone therapy

Aksam A Yassin†, Testosterone as a compound for the treatment of testosterone deficiency has been Doris Huebler & available for almost 70 years; however, the pharmaceutical formulations have been less Farid Saad than ideal. Injectable testosterone have been used traditionally for treatment, but †Author for correspondence Clinic of Urology/Andrology, they generate supranormal testosterone levels shortly after the 2–3-weekly injections, Segeberger Kliniken, when testosterone levels then decline very rapidly becoming subnormal in the days Department of Urology, before the next . is a new injectable testosterone Rathausallee 94 a, 22846 Norderstedt-Hamburg, preparation with a considerably better pharmacokinetic profile. After two initial ; and Gulf Medical injections with a 6-week interval, the following intervals between two injections are College School of , almost always 12 weeks. Plasma testosterone levels with this preparation are almost Ajman, United Arab Emirates always in the normal range. Side effects experienced with conventional testosterone Tel.: +49 405 262 157 Fax: +49 405 262 820 esters are almost nil with this preparation. [email protected]

Soon after its chemical identification more than Most forms of oral testosterone are alkylated 70 years ago, the male testosterone at the 17α- position, greatly reducing became pharmaceutically available. However, it their hepatic and improving their has taken a considerable time for convenient oral . Unfortunately, these com- and safe preparations to be developed. The low pounds, such as 17α-methyl testosterone, are bioavailability, after both oral and parenteral associated with an unacceptably high rate of administration due to the short circulating half- hepatotoxic effects, including cholestatic jaun- life of testosterone, hampered its therapeutic use dice, and even tumors in a [1,2]. Among ways to circumvent these limita- third to half of long-term users [9–11]. As a result, tions, chemical modifications of the testoster- such 17α-alkylated forms of testosterone are not one molecule were developed allowing oral use, considered safe for long-term use by most although part some these turned out to be hepa- experts in the field [12]. totoxic. Subsequently, various parenteral testo- The only of testosterone sterone preparations were developed. Among that is currently safe is testosterone undecanoate the earliest were intramuscular injectable for- (TU), which is commercially available in many mulations of testosterone esterified with fatty countries. When administered orally, a portion of acids dissolved in a vegetable oil vehicle [3]. TU is absorbed via lymphatics and thereby These preparations remain the most cost-effec- bypasses hepatic first-pass metabolism [13–15]. TU tive and widely used worldwide. However, is lymphatically absorbed due to its long lipophilic injections of conventional testosterone fatty side chain. However, the absolute bioavailability acid esters (enanthate, cypionate, decanoate and of testosterone after oral TU administration is propionate) have an effective duration of action only approximately 6% [15], implying that most of of 1–2 weeks [4], as wider or narrower spacing an oral TU dose is absorbed via the portal circula- between injections leads to progressively more tion and metabolized by the liver. TU must be extreme excursions in serum testosterone con- administered orally in doses of 120–240 mg/day Keywords: injection interval, centrations with substantial supra- and sub- (divided in two-to-three administrations per day). pharmacokinetic profile, physiological serum concentrations, less well- The route for testosterone admin- testosterone esters, [5] testosterone treatment, sustained suppression and istration generates excellent pharmacokinetic testosterone undecanoate greater subjective symptoms of these wide fluc- profiles; however, patches can cause moderate to tuations [2]. Subdermal testosterone pellet severe reaction due to the vehicles (enhanc- implants or biodegradable microspheres allow ers) that facilitate testosterone absorption across longer application intervals, although handling the skin [16]. The newly available testosterone Future Drugs Ltd of these preparations is relatively difficult [6–8]. gels are safe and effective, but must be applied to

10.1586/14750708.3.6.709 © 2006 Future Drugs Ltd ISSN 1475-0708 Therapy (2006) 3(6), 709–721 709 DRUG PROFILE – Yassin, Huebler & Saad

a fairly large area of skin and care must be taken able to develop a suitable intramuscular testo- to avoid inadvertent exposure to women and sterone preparation with a volume of 4 ml con- children [17–21]. taining 1000 mg of TU. At present, the Sustained- and controlled-release testoster- stability in climate zone II (25oC) lasts one buccal systems, including mucoadhesive 60 months [37]. Intramuscular TU is currently , are now available in some countries not approved for use in the USA, but is pre- but require twice-daily administration. Venous scribed in , and drainage from the oral cavity flows directly to under the trade name Nebido®, and in Aus- the superior vena cava and, thus, hepatic first- tralia under the trade name Reandron 1000® pass metabolism is circumvented with these for the treatment of male . preparations [22–25]. In summary, each of these modes of testoster- Toxicology & pharmacology one delivery has drawbacks. The recent discov- The active pharmacological principle of LA-TU ery of steroidal and selective is testosterone itself. After entering the periph- receptor modulators (SARMs) could eral circulation, TU (molecular weight provide a promising alternative for testosterone 456.7 Da) is hydrolyzed to testosterone, which therapy, including hormonal male contracep- exerts its androgenic activity [14,38]. Therefore, tion. The identification of an orally bioavailable the toxicology of TU is the same as for other SARM with the ability to mimic the desired cleavable testosterone esters, such as central and peripheral androgenic and anabolic (three carbon ), effects of testosterone in a tissue-specific manner (TE; seven carbon atoms) and simultaneously avoid the undesirable or (eight carbon atoms). androgen effects (e.g., on and skin) In contrast to these fatty acid esters, the kinetics would represent an important step in androgen for side-chain cleavage of the saturated aliphatic therapy [26–30]. However, most of these com- fatty acid undecanoic acid with 11 carbon atoms pounds are in very early phases of pharmaceuti- turned out to be considerably longer, permitting cal development and the availability on the much longer injection intervals and at the same market is expected in the more or less distant time preventing supra- or subphysiological future. That also applies to microencapsulation serum testosterone levels. of Leydig cells [31] and some possibilities of stem Nahrendorf and colleagues evaluated the influ- cell technology. ence of LA-TU treatment on left ventricular In a search for medium-term solutions to key remodeling following experimental myocardial problems of testosterone therapy, TU, for intra- infarction in male rats, as assessed by magnetic res- muscular administration was developed by onance imaging and in vivo hemodynamics [39]. Jenapharm GmbH & Co. KG, a subsidiary of The authors found no evidence for cardiac toxic- Schering AG in Berlin, Germany. The develop- ity of testosterone administration, despite a ten- ment of this long-acting TU (LA-TU) will now fold increase in testosterone serum levels, after be presented and discussed. TU administration compared with placebo administration. Neither infarct size nor proce- Development of LA-TU dure-related mortality was influenced by TU. For the development of an intramuscular long- On the contrary, there was a tendency to an acting testosterone preparation for male contra- improved hemodynamic outcome: left ventricu- ception, the WHO Special Programme of lar end diastolic pressure was reduced signifi- Research, Development and Research Training cantly in TU-treated animals together with wall in Human Reproduction initiated search activi- stress without differences in diastolic filling rates ties for identifying suitable fatty acid side chains following myocardial infarction. for esterification of testosterone [32]. It appeared Despite the fact that, after oral administra- that testosterone esterified with undecanoic acid tion, TU is well tolerated, the bioavailability shows ideal long-term kinetics [4,33–34]. The first leaves much to be desired. Täuber and colleagues TU preparation was developed in [35–36]. reported that the mean absolute bioavailability Unfortunately, the injection volume of 8 ml for of testosterone after oral administration of TU to TU 1000 mg caused some problems at the local women was 6.83 ± 3.32%, whereas the mean injection site. Therefore, by use of a special absolute bioavailability of orally administered galenic formulation based on free testosterone was 3.64 ± 2.45% [15]. The and refined , Jenapharm/Schering were absorption of TU by the gut is erratic, resulting

710 Therapy (2006) 3(6) Testosterone undecanoate – DRUG PROFILE

in a great inter- as well as intra-individual varia- highly individual variations. Prostate volumes bility in serum levels. TU is metabolized partly increased equally in all groups after administra- in the intestinal wall [14]. tion and declined to castrate levels after with- With the present state of available testosterone drawal. The results suggest that TU in soybean preparations, the parenteral administration of oil produces similar effects as TU in other vehi- TU will receive growing interest. cles. The authors conclude that this study in nonhuman primates warranted testing of this new preparation in humans [42]. The relationships between intramuscular TU dose (31, 62.5, 125, 250 and 500 mg/kg body Pharmacokinetics in men weight subcutaneously) and testosterone serum Zhang and colleagues presented the first levels was investigated in male rats [40]. A single detailed pharmacokinetic investigation of the injection of TU 125 mg/kg body weight is injectable Chinese TU preparation administer- effective in inducing physiological testosterone ing two single doses in hypogonadal men [43]. levels in orchiectomized rats for a minimum of Eight patients with Klinefelter’s syndrome 4 weeks. High-dose TU (500 mg/kg body received either TU 500 or 1000 mg by intra- weight) administered as a single injection results muscular injection; and 3 months later, the in supraphysiological testosterone serum con- other dose was administered to each of the par- centrations for up to 6 weeks in nonorchiect- ticipants. Every week or second week after the omized animals. TU was superior to other injections, the serum total testosterone concen- preparations releasing testosterone (subcutane- trations were measured. The whole observation ous testosterone pellets, testosterone-filled sub- period was only 8–9 weeks. The single-dose cutaneous Silastic® implants and subcutaneous injections maintained serum testosterone levels testosterone propionate). within the normal range for at least 7 weeks, In five long-term orchidectomized cynomol- without immediately apparent side effects. Of gus monkeys (Macaca fascicularis), Partsch and considerable interest was the observation that colleagues compared the testosterone serum lev- the pharmacokinetic profiles of testosterone els after single intramuscular injections of TU or were different when TU 500 mg was adminis- TE 10 mg/kg body weight [41]. With respect to tered as the first injection or when it was given pharmacokinetic characteristics, such as AUC as the second. Somewhat unexpectedly, the (4051 vs 1771 nmol × h/l), residence time (41 vs peak testosterone values obtained were lower 12 days), terminal half-life (26 vs 10 days), max- when the 500 mg dose given as the second imal testosterone concentration (73 vs injection, compared with when the 500 mg 177 nmol/l) and time to maximal testosterone dose was administered first. The authors specu- concentration (11 vs 1 days), TU showed phar- late that long-term hypogonadism of these men macokinetic and pharmacodynamic properties may have induced faster cleavage or clearance clearly superior to those of TE. Animals treated mechanisms for TU and testosterone by the with TU also demonstrated a significantly longer time of the second injection. Another explana- ejaculatory response (14 weeks) than those tion proposed was that the residual endogenous treated with TE (7 weeks). testosterone is suppressed by the first injection A group headed by Eberhard Nieschlag in (decreasing of luteinizing hormone [LH] and Germany, together with the National Research follicle-stimulating hormone [FSH]) and that, Institute for Familiy Planning in China, exam- after the second injection, only exogenous ined the pharmacokinetics of parenteral TU dis- testosterone is measured. solved in soybean oil, castor oil or . Behre and colleagues, from the group in Five castrated male cynomolgus monkeys Muenster, compared the Chinese preparation (Macaca fascicularis) received a single intramus- (TU 125 mg/ml in tea seed oil) with TU cular injection of TU 10 mg/kg body weight 250 mg/ml in castor oil [44]. TU 125 mg/ml in (nonesterified testosterone 6.3 mg/kg body tea seed oil was injected in two volumes of 4 ml weight for all preparations). After injection, sup- at two sites, while TU 250 mg/ml in castor oil raphysiological testosterone levels were induced. was a single injection of 4 ml. It appeared that There were no significant differences in the TU 250 mg/ml in castor oil had a longer half-life pharmacokinetics of the three TU preparations than the tea seed preparation (33.9 ± 4.9 vs with regard to plasma testosterone and . 20.9 ± 6.0 days). This observation is in agree- The suppression of gonadotropin levels showed ment with an interesting study on the possible www.future-drugs.com 711 DRUG PROFILE – Yassin, Huebler & Saad

influence of injection volume on the pharma- In contrast to the group treated with TE, cokinetics of esters. Comparing trough testosterone levels (measured immedi- intramuscular 1000 mg in ately before the new injection) in patients 1 vs 4 ml oily solution, the bioavailability of the receiving LA-TU remained within the physio- in the smaller injection volume was larger logical (eugonadal) range. This study was than in the larger volume [45]. This underlines extended as a follow-up study for approxi- the relevance of an injection volume of this type mately 2.5 years of treatment [50]. All the of drug. In the case of LA-TU the well-estab- patients in this study phase received TU lished injection volume of 4 ml should not be 1000 mg every 12 weeks (the former LA-TU modified, for example, by administering 2 ml patients) or TU 2 × 1000 mg every 8 weeks, twice at different sites at the same time. followed by TU 1000 mg every 12 weeks (the In the next study from the Muenster group, 13 former TE patients). This regimen resulted in hypogonadal men received four intramuscular stable mean serum trough levels of testosterone injections of LA-TU at 6-week intervals [46]. Tes- (ranging from 14.9±5.2 to 16.5±8.0nmol/l) tosterone serum levels were never found to lie and estradiol (ranging from 98.5 ± 45.2 to below the lower limit of normal, and only briefly 80.4 ± 14.4 pmol/l). For testosterone therapy after the third and fourth injections were testo- with LA-TU, the authors recommended an ini- sterone serum levels above the upper limit of nor- tial loading dose of TU 3 × 1000 mg every mal, while peak and trough values increased over 6 weeks, followed by TU 1000 mg every the 24-week observation period. Serum estradiol 12 weeks. It was demonstrated that patients and dihydrostestosterone (DHT) followed this receiving TE could be switched to LA-TU pattern, not exceeding the normal limits. The without interruption in therapy, but with an same group performed a study for finding suita- additional loading dose of LA-TU 2 × 1000 mg ble injection intervals for LA-TU [47]. In seven every 8 weeks after switching from the hypogonadal men, injections were administered short-acting TE to TU. at gradually increasing intervals between the fifth Clinical long-term experience up to 120 and tenth injections (starting with a 6-week weeks was also published in 2004 by another injection interval) and from then on every group [51]. A total of 26 hypogonadal patients 12 weeks. Steady-state kinetics were assessed received LA-TU (TU 1000 mg/4 ml) in a first after the thirteenth injection. Cmax was stage of the study in weeks 0, 6, 16, 26 and 36, 32.0 ± 11.7 nmol/l and the half-life was followed by an additional stage of up to 70.2 ± 21.1 days. The mean Cmax of 32 nmol/l 120 weeks with injections every 12 weeks. The seen during steady-state with LA-TU adminis- supranormal peak concentrations of total and tration was lower than that achieved by Testo- free testosterone occurred 2 weeks after the first gel® 100 mg/day (37.5 nmol/l); however, it was injection, then decreased to within the physio- higher than with Testogel 50 mg/day logical range. At the end of the study, during (28.8 nmol/l) and Androderm® patch 5 mg/day washout period, serum testosterone levels (26.5 nmol/l). Prior to the next injection, the declined to the low pretreatment levels serum levels for testosterone and its metabolites, 14 weeks after the final injection. A parallel DHT and estradiol, were mostly within the nor- increase of 17β-estradiol levels was seen, but mal (eugonadal) range and showed a tendency to there was an earlier decrease to pre-treatment decrease with increasing injection intervals. The levels by 4 weeks after the last injection. Serum study concluded that, after initial loading doses LH and FSH were suppressed during the treat- at 0 and 6 weeks, injection intervals of 12 weeks ment period, while -binding glob- establish eugonadal values of serum testosterone ulin (SHBG) remained stable. Serum prostate- in almost all men. Also, Yassin and Saad analyz- specific antigen (PSA) rose from 0.660 to ing 58 hypogonadal men on LA-TU treatment 0.976 ng/ml (p < 0.01) after 120 weeks, but every 3 months, and did not notice any elevation did not exceed the normal range. Prostate vol- of DHT levels exceeding the physiological ume increased from 19.6 to 26 ml (p < 0.05). threshold [48]. Osteocalcin rose from 0.734 to 1.049 nmol/l In an open-label, randomized, prospective (p < 0.01). Bone mineral density (BMD) did study, Saad and colleagues compared LA-TU not change. Standard laboratory tests und uro- (TU 1000 mg three-times every 6 weeks, there- flow did not change. Sexual interest (assessed after every 9 weeks) with TE (250 mg every by use of the aging males’ symptom [AMS] 3 weeks) in 40 hypogonadal men (Figure 1) [49]. questionnaire) increased.

712 Therapy (2006) 3(6) Testosterone undecanoate – DRUG PROFILE

Figure 1. Trough levels of testosterone after repeated injection intervals with LA-TU therapy. The injections of testosterone enanthate and testosterone loading dose of TU achieved by the first two undecanoate in 40 hypogonadal men. injections with an interval of 6 weeks is also rec- ommended for patients who are being trans- ferred from short-acting testosterone injections 40 (e.g., testosterone enanthate 250 mg) to TU treatment with LA-TU. TE Whereas all known papers on the pharmacok- 30 inetics of LA-TU show that, after of TU 1000 mg, serum testosterone concentrations are still in the physiological (eug- 20 onadal) range, Hay and Wu report that adminis- tration of TU 1000 mg every 12 weeks and 10 TU 750 mg every 9 weeks causes periodical supraphysiological excursions of testosterone Testosterone level (nmol/l) level Testosterone levels in ten hypogonadal men [53,54]. TU 0 500 mg every 6 weeks provided the most physi- 0 6 12 18 24 30 ological androgen replacement, with testoster- Time (months) one levels within the normal range at all time Mean age: 41 years; range: 18–74 years. points. However, these findings with LA-TU TE: Testosterone enanthate;TU: Testosterone undecanoate. were not replicated by other groups.

Long-term experience (up to more than Therapy of hypogonadism with LA-TU 8 years) with LA-TU in 22 hypogonadal men has Several treatment options exist for hypogonadal been presented by Zitzmann and Nieschlag [52]. patients. The most commonly used include Individual dosing intervals ranged from 10 to injectable intramuscular testosterone esters, such 14 weeks. Serum trough levels of testosterone as TE, administered at injection intervals of were generally within the low normal range, 2–3 weeks, which is associated with supraphysio- indicating sufficient substitution. In contrast to logical peak values shortly after the injection and short-acting testosterone esters, sensations of to subphysiological levels in the days before the fluctuations in androgen serum concentrations new injection. This often leads to mood swings were rarely observed. If this was the case, it or emotional instability. Another important con- occurred during the last 2 weeks before the next sequence of the supraphysiological testosterone injection, indicating loss of androgenic psycho- levels treatment with TE is the periodic elevation tropic effects. Summarizing the two key studies in . From 70 older men with low by Zitzmann and Nieschlag [52] and Schubert serum testosterone receiving TE 200 mg every and colleagues [50], the following administration 2 weeks, 30% developed a hematocrit greater regimen is recommended for LA-TU therapy in than 52% [55,56]. In another study of 32 hypo- hypogonadal men: after the first injection of gonadal men receiving TE 200 mg every TU 1000 mg, the second injection of 2 weeks, 14 patients (43.8%) had at least one TU 1000 mg is to be administered 6 weeks after occurrence of an elevated hematocrit value [59]. the first injection (loading dose), followed by Elevated hematocrit values may lead to throm- injections every 12 weeks (Figure 2). An individu- boembolic events. It is now clear that LA-TU is alization of the LA-TU therapy is recommended at least as effective and safe as the standard by Zitzmann and Nieschlag [52]. If before the injectable formulation and requires only four fourth injection the testosterone serum concen- injections per year in long-term treatment while tration lies between 10 and 15 nmol/l, the injec- maintaining serum testosterone levels within the tion interval should be every 12 weeks. Should physiological range. The data confirm the safety the testosterone serum concentration at this and efficacy of long-term LA-TU therapy in time be lower than 10 nmol/l, the injection hypogonadal patients treated over a period of interval is shortened to every 10 weeks. If the more than 8 years. testosterone level is greater than 15 nmol/l, the The two key studies on TU have been per- injection interval should be extended to every formed in Muenster, Germany, by the group 14 weeks. Additionally, clinical symptoms headed by Nieschlag, and in Cologne, Germany, should be considered for individualization of headed by Jockenhoevel and Schubert. The results www.future-drugs.com 713 DRUG PROFILE – Yassin, Huebler & Saad

Figure 2. Dosage scheme of remained within the normal range over the intramuscular testosterone entire treatment period. Computed tomo- undecanoate 1000 mg. graphy of the lumbar spine showed that improved in all patients during the first 2 years and remained stable thereafter. Body Initial dosage TU mass index (BMI) decreased during the first Control: Hb Control: T 2 years of treatment. Serum total PSA Hb levels did not change over the treatment period DRE PSA and serum LDL levels decreased slightly, con- curring with the decrease of BMI, and serum HDL levels increased slightly over time. There were no relevant changes in pressure or heart rate. Overall, treatment with intramuscu- lar TU demonstrated beneficial effects on body 0 6 18 30 composition and lipid profile [58]. Weeks

The second injection should be administered after Cologne study an interval of 6 weeks, and thereafter every The efficacy of LA-TU was compared with the 12 weeks. Recommended scheme of checks in gold standard of TE 250 mg intramuscularly in patients aged over 45 years. a 30-week controlled, prospective, randomized, DRE: Digital rectal examination; Hb: ; PSA: Prostate-specific antigen; T: Testosterone; parallel-group study that was followed by a TU: Testosterone undecanoate. long-term open-label study over 5 years. During the first 30 weeks of the comparative phase, 40 hypogonadal men with testosterone levels have been presented by Zitzmann [52] and Schu- below 5 nmol/l were randomly assigned to bert [58] at the Fifth World Congress on the Aging either TE 250 mg intramuscularly every Male, 2006, in Salzburg, Austria. These studies 3 weeks (n = 20) or LA-TU three times in are summarized by Schubert and colleagues [Schu- 6-week intervals, followed by a 9-week interval. bert M, Zitzmann M. Unpublished Data]. LA-TU was gener- Following the first 30 weeks of the comparative ally well tolerated. Local irritation at the site of part of the study, all patients received LA-TU injection was moderate, did not last longer than every 12 weeks in a one-arm follow-up study 3 days and could be minimized by administering over an additional 30 months. In the first LA-TU slowly over a period of approximately 30 weeks, there were no differences in sexual 1 min. No patients discontinued treatment due to parameters (spontaneous morning , problems of local discomfort. LA-TU should be total erections and ejaculations) between the injected deeply into the gluteal muscle with the two groups (Figure 3). After 30 weeks, serum PSA patient in a prone position. During the first year levels in both treatment groups had risen of LA-TU treatment, erythropoiesis parameters, slightly, but remained stable during long-term prostate size and serum PSA should be monitored LA-TU administration and stayed within the for safety reasons in men above the age of 45 years normal range over the entire observation period. at quarterly intervals and then yearly thereafter. Prostate volume increased during the first 30 weeks but then remained stable until the end Muenster study of the follow-up study (Figure 4) [59]. Compar- The study included 14 patients who received ing the mean baseline levels with the mean lev- LA-TU up to 8.5 years at injection intervals of els after follow-up, there was an increase in approximately 12 weeks. Patients reported res- serum testosterone (from 3.9 to 16.2 nmol/l), toration of sexual function and positive changes PSA serum levels (from 0.27 to 0.75 ng/ml) and in mood patterns. In contrast to short-acting prostate volume (from 14.5 to 20.2 ml), TE preparations, patient-reported perception whereas a decline of serum total cholesterol of fluctuations in androgen concentrations (from 235.3 to 202.4 mg/dl), LDL cholesterol were rarely reported. Over the whole treatment (from 158.8 to 134.9 mg/dl), HDL cholesterol period, PSA concentrations did not exceed the (from 46.1 to 42.8 mg/dl) and triglycerides normal range and prostate size remained below (from 199.9 to 161.2 mg/dl) was observed. 30 ml in all patients. Hemoglobin and hemat- Taken together, there were no serious side ocrit increased initially during treatment, but effects of LA-TU treatment.

714 Therapy (2006) 3(6) Testosterone undecanoate – DRUG PROFILE

Figure 3. Sexual parameters in 40 hypogonadal men treated with testosterone or testosterone undecanoate.

10 4 8 *** * * * * * * 3 * * * * * * * * * 6 * * * * * * * * * * 2 * * * 4 ***

Total erections Total * Spontaneous morning erections * 1 2

0 0 S 0 3 6 9 12 15 18 21 24 27 30 S 0 3 6 9 12 15 18 21 24 27 30 Weeks Weeks 4

* * * 3 * * * * * * Testosterone enanthate * * * 2 * * * Testosterone undecanoate * * * *p < 0.05 *

Ejaculations * 1

0 S 0 3 6 9 12 15 18 21 24 27 30 Weeks

Mean age: 41 years; range: 18–74 years.

Using a standardized self-evaluation ques- The Muenster and Cologne studies were con- tionnaire for assessing psychosexual effects of firmed recently by a study conducted by Jacobeit LA-TU treatment [60], it was found that scores and colleagues [61]. A total of 33 hypogonadal men for sexual thoughts/fantasies and sexual inter- with primary, secondary or late-onset hypogonad- est/desire doubled. Also, the score for satisfac- ism between the ages of 45 and 79 years, were tion of sex life increased. Improvements were treated with LA-TU. Serum testosterone levels seen for waking erections, total number of erec- increased from 9.0 ± 3.8 nmol/l at baseline to tions and ejaculations. The psychological 13.5 ± 4.6 nmol/l after 6 weeks and to parameters for depression, and anxiety 16.4 ± 6.4 nmol/l after 30 weeks of treatment. decreased within the first 3–6 weeks and DHT levels increased from 0.98 ± 0.48 to remained stable. There were no statistically sig- 3.1 ± 1.0 nmol/l. Serum PSA levels fluctuated nificant differences between TE and TU. No minimally in the normal range. In two patients, the significant change was observed in the score for length between two injections could be prolonged aggressiveness in either group, indicating that from 12 to 14 weeks. All patients reported this parameter was not affected by the treat- improved mood, sexual function and quality of life. ment provided. These results obtained in In contrast to the short-acting testosterone hypogonadal men are paralleled in some esters with LA-TU, the FSH and respects in the study by O’Connor and col- luteinizing hormone LH are permanently sup- leagues showing that a single injection of TU pressed. This suppression of gonadotropins is 1000 mg to 28 eugonadal young men, elevating desired for male contraception, for which mean testosterone levels above normal, was LA-TU is a potential candidate. associated with significant increases in anger/hostility from baseline to week 2 after the Treatment of injection [60]. It was accompanied by an overall with LA-TU reduction in fatigue/inertia and did not The influence of LA-TU on erectile dysfunction increase aggressive behavior or induce any (ED) has been investigated extensively by Yassin changes in nonaggressive or sexual behavior. and colleagues [62–66]. In a study assessing the

www.future-drugs.com 715 DRUG PROFILE – Yassin, Huebler & Saad

Figure 4. Effect of testosterone undecanoate (intervals disappearance of venous leakage suggests that of 12 weeks) on prostate-specific antigen in LA-TU treatment may have beneficial effects on 40 hypogonadal men. penile anatomical/physiological substrate, facili- tating the veno-occlusive mechanism. This find- ing has been replicated in five out of 12 hypogonadal patients [64]. These results confirm data obtained from animal studies showing that 1 androgen insufficiency leads to veno-occlusive dysfunction that cannot be restored with PDE5 inhibitor treatment alone [67].

Suitability of LA-TU for the PSA (ng/ml) 0.5 management of transgender patients Despite the current limited experience (13 patients), the treatment of female-to-male Testosterone undecanoate 1000 mg i.m. Testosterone enanthate 250 mg i.m. transgender individuals with LA-TU appears to 0 be a safe and effective therapy. Undesirable side 0 6 12 18 24 30 effects have not been observed. Total cholesterol Time (months) and LDL were lowered and HDL remained unchanged. The use of LA-TU did not lead to Mean age: 41 years; range: 18–74 years. , seborrhoea and balding. In two patients it i.m.: Intramuscular; PSA: Prostate-specific antigen. From [59]. was possible to prolong the injection interval from 12 to 14 weeks [68,69]. impact of testosterone therapy only on ED, 22 hypogonadal men with ED received injections of Use of LA-TU for male contraception LA-TU on day 1, again after 6 weeks and then in Exogenous administration of testosterone func- intervals of 12 weeks. Sexual function was tions as a contraceptive in the male by suppress- assessed using the International Index of Erectile ing the secretion of LH and FSH from the Function (IIEF) [65]. While in all patients testo- pituitary. After 2–3 months of treatment, low sterone therapy alone significantly improved the levels of FSH and LH lead to markedly sexual desire domain of the IIEF (from 4.5 to 8.4 decreased sperm concentrations. This approach on a scale of 10), in 12 out of 22 patients (54%) to contraceptive development appears safe and the erectile function domain score increased from fully reversible; however, sperm concentrations 12 at baseline (moderate ED) to 25 (indicating are not suppressed to zero in all men. There- normal erectile function) at week 24. It is of note fore, researchers have combined testosterone that the effect of testosterone on erectile function with progestins to further suppress pituitary may appear as late as after 12–24 weeks of gonadotropins and optimize contraceptive effi- administration of testosterone. cacy [70–79]. Surprisingly, studies in Chinese men Evaluation of the role of testosterone therapy show that intramuscular TU alone affords bet- on veno-occlusive dysfunction showed caverno- ter suppression of and protec- sographic changes in hypogonadal patients with tion against than male condom use severe ED, diabetes mellitus, obesity and/or met- and, thus, use of TU alone could suffice for abolic syndrome who did not respond to phos- contraceptive use in Chinese men and may phodiesterase (PDE)5 inhibitors and alprostadil receive registration in China [80]. injections [64–66]. One patient who had venous In contrast to East Asians, only approximately leakage prior to testosterone received treatment 50% of Caucasian volunteers exhibited with LA-TU at 12–14-week intervals following a azoospermia following treatment with LA-TU loading dose of 6 weeks. The patient showed alone administered every 6 weeks [81]. However, improved sexual function after 9 weeks of treat- these results with LA-TU, which are comparable ment and repeated cavernosography after to those obtained following weekly injections of 12 weeks revealed that the venous leakage had TE [82], offer the advantage of longer injection receded (Figure 5) [66]. The results from this case intervals and, therefore, TU is the most promis- study suggest that LA-TU has a positive impact ing androgen preparation for further develop- on the veno-occlusive properties of penile trabec- ment as a if combined with ular tissues in hypogonadal ED patients. The potent progestins [83–87]. To increase long-term

716 Therapy (2006) 3(6) Testosterone undecanoate – DRUG PROFILE

Figure 5. Cavernosography images before and after physiological testosterone levels. Very few testosterone undecanoate treatment. patients reported irritation or pain at the sight of injection despite the large volume of injec- tion (4 ml). Significant increases in PSA and prostate size were noted in some of these trials; however, this is probably due to the fact that hypogonadal men have subnormal PSA values and small prostate size at baseline and is observed with every kind of testosterone administration that normalizes plasma testo- sterone levels. Furthermore, PSA levels and A prostate size remained within the normal range. Similarly, increases of parameters of erythro- poiesis to the eugonadal values were observed, B but there was no occurrence of polycythemia as observed in studies with the more traditional (A) Cavernosography before testosterone undecanoate treatment clearly showing venous leakage (arrows). (B) Repeat cavernosography after 12 weeks testosterone esters. Only one study demon- testosterone undecanoate treatment showing no signs of venous leakage. strated a transient decline in serum HDL cho- From [66]. lesterol; however, its value remained within the normal range [88]. acceptability of the regimen, TU injection inter- vals might even be prolonged to 8 or 12 weeks. Expert commentary Meriggiola and colleagues demonstrated that Most medical conditions requiring androgen injections of LA-TU every 8 weeks, combined therapy are irreversible. As a consequence, with 200 mg of the long-acting parenteral nore- androgen-replacement therapy often extends thisterone enanthate (NETE), very effectively over many decades. Therefore, patient compli- suppresses spermatogenesis in normal men [86]. ance is of utmost importance. Treatment with For many years, the lack of suitable testosterone the unmodified testosterone molecule is pre- formulations, in terms of pharmacokinetics and ferred by opinion leaders, with a treatment convenience of administration, has hampered the modality and in a dose that maintains serum development of male hormonal contraceptives. testosterone in the physiological range for the The recent studies with LA-TU represent a turning full 24 h of the day. To date, studies show that point in the development of male hormonal con- LA-TU represents an effective, safe and well traceptives [87]. Despite the requirement of regular tolerated means of androgen treatment in injections, the acceptability of this regimen hypogonadal men. At present, clinical experi- (LA-TU combined with NETE) is high [87]. ence is available with LA-TU treatment over Although there are now many studies showing the 9years [89]. suitability of LA-TU combined with a progestin for After a recommended loading dose of two male contraception, it is currently too early to rec- injections with a 6-week interval, LA-TU is the ommend a definitive regimen for male hormonal first intramuscular agent that can be adminis- contraception. Further studies are required. tered every 12 weeks, thus maintaining physio- logical plasma testosterone levels. Depending on Safety & tolerability the trough plasma testosterone level immedi- No major adverse effects were encountered in ately before the next injection and clinical the clinical trials of TU. This is not surprising symptoms of the patient, adjustment of the since the pharmaceutically active component is injection interval is desirable, rarely by shorten- testosterone itself. Common side effects of testo- ing (every 10–11 weeks), or more often by pro- sterone administration, such as , longing (every 13–14 weeks) the interval breast tenderness and acne, were reported in between two injections. LA-TU produces fewer only a minority of patients, which is probably to peaks and troughs in serum testosterone levels be ascribed to the largely normal physiological in comparison to the traditional testosterone levels achieved with LA-TU. Adverse effects esters. Hypogonadal men treated with LA-TU observed in the initial studies were less frequent report a general sense of well-being and normal when the dosing frequency was decreased from sexual function during treatment. These para- 6 and 8 weeks to 12 weeks, generating more meters were not different when evaluated at the www.future-drugs.com 717 DRUG PROFILE – Yassin, Huebler & Saad

half point of injection intervals compared with The open questions are related to testosterone the end of the injection interval period. This therapy in general and also apply to other testo- suggests that normal physiological testosterone sterone preparations. Larger, longer-term clinical values were maintained throughout the 12-week studies with more patients are required to find period, without major fluctuations. As a result, definitive answers regarding the inter-relation- patients did not report mood swings or emo- ships between testosterone serum levels and the tional instability, which is a common complaint pathophysiology of . However, with other testosterone preparations. experts agree that it is responsible clinical practice A major advantage of LA-TU is that it only to treat elderly hypogonadal men with testoster- requires four injections per year compared with one provided the existing guidelines for monitor- 26 injections per year for TE (if taken at a dose ing are followed. Specific questions with regard of 200 or 250 mg every 2 weeks). Every to LA-TU are related to the different pharmacok- 12 weeks, the physician sees the patient for inetics after single and multiple injections in safety and efficacy monitoring. The clinical comparison to other testosterone preparations. experience with LA-TU meets the requirements spelled out in the consensus on testosterone as Outlook well as other recommendations regarding safety In view of its favorable pharmacokinetic profile, and efficacy monitoring of testosterone adminis- LA-TU has been well received. Its advantages tration. Therefore, LA-TU is also well suited for over the more conventional injectable testoster- elderly men since these patients will be exam- one preparations are obvious. The injection fre- ined four times per year and a prostate malig- quency is as little as four per year. The large nancy and other reasons for the discontinuation fluctuations of plasma testosterone with the con- of the therapy can be timely diagnosed. ventional testosterone esters are subjectively LA-TU treatment is indicated for all forms of experienced as unpleasant by many patients. hypogonadism. Men with ED and low testoster- LA-TU, with its more favorable pharmoco- one may also benefit from LA-TU administra- kinetic profile, did not have these side effects in tion, and the combination of PDE5 inhibitors clinical trials. Thus, the merits of LA-TU have and LA-TU may be indicated in men who do manifested themselves. The traditional testoster- not respond sufficiently to PDE5 inhibitors one esters developed some 50–60 years ago are alone. The results of use of LA-TU for male con- relatively cheap. Health economics may delay a traception, for example, in combination with wide introduction of LA-TU in the short-term progestins, are quite encouraging. However, this in spite of the improvements in comparison to subject needs further study. the traditional testosterone esters.

Highlights

• Traditional testosterone preparations have been available for more than 50 years, although their pharmacokinetic properties have been less than ideal. • Injectable testosterone esters, to be administered at 2–3-week intervals, have been traditionally used but they generate supranormal testosterone levels shortly after the injection and then testosterone levels decline very rapidly, becoming subnormal in the days before the next injection. • Testosterone undecanoate is a new injectable testosterone preparation with a considerably better pharmacokinetic profile. After two initial injections with a 6-week interval, the following intervals between two injections is usually 12 weeks. • Plasma testosterone levels with testosterone undecanoate treatment are almost always in the range of normal men. • Side effects experienced with the conventional testosterone esters are almost nil with this preparation.

Bibliography 3. Junkmann K. Long-acting in 5. Snyder PJ, Lawrence DA. Treatment of male 1. Hamilton JB. Treatment of sexual reproduction. Rec. Prog. Horm. Res. 13, hypogonadism with testosterone enanthate. J. underdevelopment with synthetic male 380–419 (1957). Clin. Endocrin. Metab. 51, 1335–1339 (1980). hormone substance. Endocrinology 97, 4. Behre HM, Nieschlag E. Comparative 6. Bhasin S, Swerdloff RS, Steiner B et al. A 917–921 (1937). pharmacokinetics of testosterone esters. In: biodegradable testosterone microcapsule 2. Handelsman DJ. Androgen action and Testosterone: Action Deficiency Substitution formulation provides uniform eugonadal levels pharmacological uses. In: Endocrinology (4th (2nd Edition). Nieschlag E, Behre HM of testosterone for 10–11 weeks in Edition). DeGroot LJ (Ed.). WB Saunders, (Eds). Springer, Berlin, Germany 329–348 hypogonadal men. J. Clin. Endocrinol. Metab. PA, USA 2232–2242 (2001). (1998). 74, 75–83 (1992).

718 Therapy (2006) 3(6) Testosterone undecanoate – DRUG PROFILE

7. Amory JK, Anawalt BD, Blaskovich PD, males with improvements in body composition and prevents bone loss in Gilchriest J, Nuwayser ES, Matsumoto composition and sexual function. J. Clin. orchidectomized rats. Endocrinology 146, AM. Testosterone release from a Endocrinol. Metab. 88, 2673–2681 (2003). 4887–4897 (2005). subcutaneous, biodegradable microcapsule 20. Schreiber G, Ebert T, Matheis K. 31. Machluf M, Orsola A, Boorjian S, formulation (Viatrel) in hypogonadal men. Erfahrungen mit der transdermalen Kershen R, Atala A. Microencapsulation of J. Androl. 23, 84–91 (2002). testosterongel-therapie des klassischen Leydig cells: a system for testosterone 8. Kelleher S, Howe C, Conway AJ, und des altershypogonadismus. Blickpunkt supplementation. Endocrinology 144, Handelsman DJ. Testosterone release rate DER MANN 2, 29–33 (2004). 4975–4979 (2003). and duration of action of testosterone 21. Kühnert B, Byrne M, Simoni M et al. 32. Crabbé P, Diczfalusy E, Djerassi C. implants. Clin. Endocrinol. 60, 420–428 Testosterone substitution with a new Injectable contraceptive synthesis: an (2004). transdermal, hydroalcoholic gel applied to example of international cooperation. 9. Westaby D, Ogle SJ, Paradinas FJ, scrotal or non-scrotal skin: a multicenter Science 209, 992–994 (1980). Randell JB, Murray-Lyon IM. Liver trial. Eur. J. Endocrinol. 153, 317–326 33. Herz JE, Torres JV, Murillo A et al. Potential damage from long-term (2005). long-acting contraceptive agents: esters and . Lancet 2, 262–263 22. Slater CC, Souter I, Zhang C, Guan C, ethers of testosterone with α- and/or β-chain (1977). Stanczyk FZ, Mishell DR. branching. Steroids 46, 947–953 (1985). 10. Turani H, Levi J, Zevin D, Kessler E. Pharmacokinetics of testosterone after 34. Waites GM. Methods for the regulation of Hepatic lesions in patients on anabolic percutaneous gel or . male fertility. In: Annual Technical Report androgenic therapy. Isr. J. Med. Sci. 19, Fertil. Steril. 76, 32–37 (2001). 1992; World Health Organization (WHO) 332–337 (1983). 23. Korbonits M, Slawik M, Cullen D et al. A Special Programme of Research, Development 11. Lowdell CP, Murray-Lyon IM. Reversal of comparison of a novel testosterone and Research Training in Human liver damage due to long term bioadhesive buccal system, Striant, with Reproduction. World Health Organization, methyltestosterone and safety of non-17-α testosterone adhesive patch in Geneva, Switzerland, alkylated . BMJ 291, 637–645 hypogonadal males. J. Clin. Endocrinol. (WHO/HRP/ATR/92/93) 63–78 (1993). (1985). Metab. 89, 2039–2043 (2004). 35. Gu YQ, Wang XH, Xu D et al. A 12. Gooren LJ, Bunck MC. Androgen 24. Ross RJM, Jabbar A, Jones TH et al. multicenter contraceptive efficacy study of replacement therapy, present and future. Pharmacokinetics and tolerability of a injectable testosterone undecanoate in Drugs 64, 1861–1891 (2004). bioadhesive buccal testosterone tablet in healthy Chinese men. J. Clin. Endocrinol. 13. Nieschlag E, Mauss J, Coert A, Kicovic P. hypogonadal men. Eur. J. Endocrinol. 150, Metab. 88, 562–568 (2003). Plasma androgen levels in men after oral 57–63 (2004). 36. Zhang L, Shah IH, Liu Y, Vogelsong KM, administration of testosterone and 25. Wang C, Swerdloff R, Kipnes M et al. New Zhang L. The acceptability of an injectable, testosterone undecanoate. Acta Endocrinol. testosterone buccal system (Striant) once-a-month male contraceptive in China. (Copenh.) 79, 366–374 (1975). delivers physiological testosterone level: Contraception 73, 548–553 (2006). 14. Horst HJ, Höltje WJ, Dennis M, Coert A, pharmacokinetics study in hypogonadal 37. PCT Patent Application WO 2004/080383 Geelen J, Voigt KD. Lymphatic absorption men. J. Clin. Endocrinol. Metab. 89, Methods and pharmaceutical compositions and metabolism of orally administered 3821–3829 (2004). for reliable achievement of acceptable serum testosterone undecanoate in man. Klin. 26. Hanada K, Furuya K, Yamamoto N et al. testosterone levels. International Filing Date Wochenschr. 54, 875–879 (1976). Bone anabolic effects of S-40503, a novel 15 March (2004). 15. Täuber U, Schröder K, Düsterberg B, nonsteroidal selective 38. De Nijs H. Targeting of drugs to the lymph. Matthes H. Absolute bioavailability of modulator (SARM), in rat models of Acta Pharm. Technol. 33, 163–168 (1987). testosterone after oral administration of . Biol. Pharma. Bull. 26, 39. Nahrendorf M, Frantz S, von zur Mühlen C testosterone undecanoate and testosterone. 1563–1569 (2003). et al. Effect of testosterone on post- Eur. J. Drug Metab. Pharmacokinet. 11, 27. Marhefka CA, Gao W, Chung K et al. myocardial infarction remodelling and 145–149 (1986). Design, synthesis, and biological function. Cardiovasc. Res. 57, 370–378 16. Amory JK, Matsumoto AM. The characterization of metabolically stable (2003). therapeutic potential of testosterone selective androgen receptor modulators. 40. Callies F, Kollenkirchen U, patches. Exp. Opin. Invest. Drugs 7, J. Med.Chem. 47, 993–998 (2004). von zur Mühlen C, Tomaszewski M, Beer S, 1977–1985 (1998). 28. Smith CL, O’Malley BW. Coregulator Allolio B. Testosterone undecanoate: a 17. Swerdloff RS, Wang C, Cunningham G function: a key to understanding tissue useful tool for testosterone administration in et al. Long-term pharmacokinetics of specificity of selective receptor modulators. rats. Exp. Clin. Endocrinol. Diabetes 111, transdermal testosterone gel in Endocr. Rev. 25, 45–71 (2004). 203–208 (2003). hypogonadal men. J. Clin. Endocrinol. 29. Chen JC, Hwang DJ, Bohl CE, 41. Partsch CJ, Weinbauer GF, Fang R, Metab. 85, 4500–4510 (2000). Miller DD, Dalton JT. A selective Nieschlag E. Injectable testosterone 18. Gooren LJG, Bunck MCM. Transdermal androgen for undecanoate has more favourable testosterone delivery: testosterone patch hormonal male contraception. J. pharmacokinetics and and gel. World J. Urol. 21, 316–319 Pharmacol. Exp. Ther. 312, 546–553 than testosterone enanthate. Eur. J. (2003). (2005). Endocrinol. 132, 514–519 (1995). 19. Steidle C, Schwartz S, Jacoby K, Sebree T, 30. Gao W, Reiser PJ, Coss CC et al. Selective 42. Wistuba J, Luetjens CM, Kamischke A et al. Smith T, Bachand R. AA2500 testosterone androgen receptor modulator treatment Pharmacokinetics and pharmacodynamics gel normalizes androgen levels in aging improves muscle strength and body of injectable testosterone undecanoate in www.future-drugs.com 719 DRUG PROFILE – Yassin, Huebler & Saad

castrated cynomolgus monkeys (Macaca undecanoate (Nebido) in substitution 61. Jacobeit JW, Schulte HM. Long-acting fascicularis) are independent of different oil therapy of hypogonadal men. Aging Male 9, intramuscular testosterone undecanoate vehicles. J. Med. Primatol. 34, 178–187 5 (2006). (TU, Nebido®) in treatment of aging males (2005). 53. Hay CJ, Wu FCW. Intramuscular with hypogonadism. Presented at: 8th 43. Zhang GY, Gu YQ, Wang XH, Cui YG, testosterone (T) undecanoate for the European Congress of Endocrinology. Bremner WJ. A pharmacokinetic study of treatment of male hypogonadism: a Glasgow, UK, April 1–5 2006 (Poster injectable testosterone undecanoate in parallel-group randomised open-label P184). hypogonadal men. J. Androl. 19, 761–768 pharmacokinetic study. Endocrine Abstracts 62. Yassin A, Saad F. Modulation of erectile (1998). 7, P292 (2004). function with long-acting testosterone 44. Behre HM, Abshagen K, Oettel M, 54. Hay C, Wu F. Intramuscular testosterone injection (Nebido®) i.m. in hypogonadal Hübler D, Nieschlag E. Intramuscular undecanoate (TU) for the treatment of patients. Presented at: 8th International injection of testosterone undecanoate of male hypogonadism: a pharmacokinetic Congress of Andrology. Seoul, Korea, male hypogonadism: Phase I studies. Eur. J. study to determine the optimal dose and June 12–16 2005. Int. J. Androl. 28, 14 Endocrinol. 140, 414–419 (1999). frequency of administration. Presented at: (2005) (Abstract P045). 45. Minto CF, Howe C, Wishart S, Conway AJ, 12th International Congress on 63. Yassin AA, Saad F, Diede HE. Testosterone Handelsman DJ. Pharmacokinetics and Endocrinology. Lisbon, and erectile function in hypogonadal men pharmacodynamics of nandrolone esters in 31 August–4 September 2004. (Poster unresponsive to tadalafil: results from an oil vehicle: effects of , injection site and Presentation, Series B- Repro, P1221). open-label uncontrolled study. Andrologia injection volume. J. Pharmacol. Exp. Ther. 55. Amory JK, Watts NB, Easley KA et al. 38, 61–68 (2006). 281, 93–102 (1997). Exogenous testosterone or testosterone 64. Yassin A, Saad F, Traish A. Testosterone 46. Nieschlag E, Büchter D, von Eckardstein S, with increases bone mineral undecanoate restores erectile function in a Abshagen K, Simoni M, Behre HM. density in older men with low serum subset of patients with venous leakage: a Repeated intramuscular injections of testosterone. J. Clin. Endocrinol. Metab. 89, series of case reports. J. Sex Med. 3, 727–735 testosterone undecanoate for substitution 503–510 (2004). (2006). therapy in hypogonadal men. Clin. 56. Dobs AS, Meikle AW, Arver S, Sanders SW, 65. Yassin A, Saad F. Changes in penile Endocrinol. 51, 757–763 (1999). Caramelli KE, Mazer NA. cavernosography and venous leakage under 47. von Eckardstein S, Nieschlag E. Treatment Pharmacokinetics, efficacy, and safety of a testosterone therapy in hypogonadal of male hypogonadism with testosterone permeation-enhanced testosterone patients with ED. “Case Report”. Presented undecanoate injected at extended intervals transdermal system in comparison with bi- at: 8th International Congress of Andrology. of 12 weeks: a Phase II study. J. Androl. 23, weekly injections of testosterone enanthate Seoul, Korea, June 12–16 2005. Int. J. 419–425 (2002). for the treatment of hypogonadal men. Androl. 28, 16 (2005) (Abstract P022). 48. Yassin AA, Saad F. Does long-acting J. Clin. Endocrinol. Metab. 84, 3469–3478 66. Yassin AA, Saad F. Dramatic improvement testosterone injection (Nebido) have an (1999). of penile venous leakage upon testosterone impact on DHT? Int. J. Androl. 57. Schubert M. Comparison of kinetics, administration. A case report and review of 28(Suppl. 1), 63 (2005). efficacy and safety of the long-acting literature. Andrologia 38, 34–37 (2006). 49. Saad F, Huebler D, Ernst M et al. A novel testosterone undecanoate formulation with 67. Traish AM, Toselli P, Jeong SJ, Kim NN. injectable testosterone undecanoate (TU) standard testosterone enanthate. Aging Adipocyte accumulation in penile corpus does not lead to supraphysiological Male 9, 6 (2006). cavernosum of the orchiectomized rabbit: a testosterone concentrations in the treatment 58. Zitzmann M, von Eckardstein S, Saad F, potential mechanism for veno-occlusive of male hypogonadism. J. Androl. Nieschlag E. Long-term experience with dysfunction in . (Suppl. 132) (2001) (Abstract P3/4–055). injections of testosterone undecanoate for J. Androl. 26, 242–248 (2005). 50. Schubert M, Minnemann T, Hübler D substitution therapy in hypogonadal men. 68. Jacobeit JW, Hugo U, Schulte HM, et al. Intramuscular testosterone Presented at: 87th Annual Meeting of the Ludwig M. Wenn der zweite schritt vor dem undecanoate: Pharmacokinetic aspects of a Endocrine Society. San Diego, CA, USA, ersten…grundlagen der behandlung von novel testosterone formulation during long- June 4–7 2005. frau-zu-mann-transgendern. Gynäkol. term treatment of men with hypogonadism. 59. Sommer F, Schwarzer U, Christoph A, Endokrinol. 3, 140–144 (2005). J. Clin. Endocrinol. Metab. 89, 5429–5434 Hübler D, Engelmann U, Jockenhövel F. 69. Jacobeit JW, Epe M, Hugo U, Ludwig M, (2004). The effect of long-term testosterone Schulte HM. Long-acting intramuscular 51. Bueber V, Gerke O, Grote M, Preuss RA, replacement therapy on prostate specific testosterone undecanoate (TU, Nebido®) in Saad F, Witte MF. Treatment of antigen and prostate volume in the treatment of female-to-male transgender hypogonadal men with long-acting hypogonadal men – results of a prospective individuals. 8th European Congress of testosterone undecanoate (TU): clinical and study. Eur. Urol. 1(Suppl. 1), 61 (2002) Endocrinology, Glasgow, UK, April 1–5 pharmacokinetic results after intramuscular (Abstract 235). 2006 (Poster P183). application of 1000 mg TU every three 60. O’Connor DB, Archer J, Wu FCW. Effects 70. Roy S, Kapilashrami MC, Shrivastav TG, months up to 120 weeks. The Endocrine of testosterone on mood, aggression, and Roy S, Basu A. Recent advances in Society’s 86th Annual Meeting, June 16–19 sexual behavior in young men: a double- hormonal male contraception. Health Popul. 2004, 445 (PS–556) (2004). blind, placebo-controlled, cross-over study. Perspect. Issues 25, 159–176 (2002). 52. Zitzmann M, Nieschlag E. Long term J. Clin. Endocrinol. Metab. 89, 2837–2845 71. Behre HM, Nashan D, Hubert W, experience of more than 8 years with a (2004). Nieschlag E. Depot gonadotropin-releasing novel formulation of testosterone hormone blunts the androgen-

720 Therapy (2006) 3(6) Testosterone undecanoate – DRUG PROFILE

induced suppression of spermatogenesis in a 81. Ng CM, Qoubaitary A, Swerdloff RS et al. 87. Meriggiola MC, Cerpolini S, Bremner WJ of male contraception. J. Clin. Pharmacokinetics and pharmacodynamics et al. Acceptability of an injectable male Endocrinol. Metab. 74, 84–90 (1992). of intramuscular injections of testosterone contraceptive regimen of 72. Meriggiola MC, Farley TMM, Mbizvo MT. undecanoate in healthy male volunteers. enanthate and testosterone undecanoate for A review of androgen-progestin regimens for Presented at: The Endocrine Society’s 87th men. Hum. Reprod. 21, 2033–2240 (2006). male contraception. J. Androl. 24, 466–483 Annual Meeting, San Diego, CA, USA 88. Harle L, Basaria S, Dobs AS. Nebido: a (2003). June 4–7, 2005. (P1–564). long-acting injectable testosterone for the 73. Nieschlag E, Zitzmann M, Kamischke A. 82. World Health Organization. Contraceptive treatment of male hypogonadism. Expert Use of progestins in male contraception. efficacy of testosterone-induced azoospermia Opin. Pharmacother. 6, 1751–1759 (2005). Steroids 68, 965–972 (2003). in normal men. Fertil. Steril. 65, 821–829 89. Zitzmann M, Saad F, Nieschlag E. Long- 74. Amory JK. Testosterone/progestin regimens: (1996). term experience and safety of 44 treatment- A realistic option for male contraception? 83. Kamischke A, Plöger D, Venherm S, years with a long-acting formulation of Curr. Opin. Invest. Drugs 5, 1025–1030 von Eckardstein S, von Eckardstein A, testosterone undecanoate in substitution (2004). Nieschlag E. Intramuscular testosterone therapy of hypogonadal men. Poster 75. Kamischke A, Nieschlag E. Progress towards undecanoate with or without oral P2–547. Presented at: Endocrine Society, hormonal male contraception. Trends : a randomized placebo- Annual Meeting, Boston, MA, USA Pharmacol. Sci. 25, 49–57 (2004). controlled feasibility study for male June 24–27 2006. 76. Nieschlag E. Entwicklungsstand der contraception. Clin. Endocrinol. 53, 43–52 hormonellen männlichen Kontrazeption. (2000). Affiliations Deutsches Ärzteblatt. 102, A3506–A3512 84. Kamischke A, Venherm S, Plöger D, Aksam A Yassin, MD PhD EdD FEBU (2005). von Eckardstein S, Nieschlag E. Clinic of Urology/Andrology, Segeberger Kliniken, 77. Cornia PB, Anawalt D. Male hormonal Intramuscular testosterone undecanoate and Department of Urology, Rathausallee 94 a, contraceptives: a potentially patentable and in a clinical trial 22846 Norderstedt-Hamburg, Germany; profitable product. Exper. Opin. Ther. for male contraception. J. Clin. Endocrinol. and Gulf Medical College School of Patents 15, 1727–1737 (2005). Metab. 86, 303–309 (2000). Medicine, Ajman-UAE 78. Hoesl CE, Saad F, Poeppel M, Altwein JE. 85. Kamischke A, Heuermann T, Krüger K et al. Tel.: +49 405 262 157 Reversible, non-barrier male contraception: An effective hormonal male contraceptive Fax: +49 405 262 820 status and prospects. Eur. Urol. 48, 712–723 using testosterone undecanoate with oral or [email protected] (2005). injectable norethisterone preparations. Doris Huebler 79. Meriggiola MC, Pelusi G. Advances in male J. Clin. Endocrinol. Metab. 87, 530–539 Schmieden, 12; 07407 Uhlstaedt-Kirchhasel, . Expert Opin. (2002). Germany Investig. Drugs 15, 389–397 (2006). 86. Meriggiola MC, Constantino E, Saad F 80. Gui YL, He CH, Amory JK et al. Male et al. Norethisterone enanthate plus Farid Saad hormonal contraception: Suppression of testosterone undecanoate for male Research Department, Gulf Medical College spermatogenesis by injectable testosterone contraception: effects of various injection School of Medicine, Ajman-UAE; undecanoate alone or with levonorgestrel intervals on spermatogenesis, reproductive Andrology Department, Schering AG, implants in Chinese men. J. Androl. 25, , testis, and prostate. J. Clin. 13342 Berlin, Germany 720–727 (2004). Endocrinol. Metab. 90, 2005–2014 (2005).

www.future-drugs.com 721