New Long-Acting Androgens

World J Urol (2003) 21: 306–310 DOI 10.1007/s00345-003-0364-x TOPIC PAPER Louis J. Gooren New long-acting androgens Received: 16 September 2003 / Accepted: 17 September 2003 / Published online: 9 October 2003 Ó Springer-Verlag 2003 Abstract Testosterone substitution treatment aims to are usually irreversible. The consequence is that life-long replace physiological actions of endogenous testosterone androgen replacement is required. Patient compliance by steadily maintaining physiological blood levels of with life-long androgen replacement depends on conve- testosterone. The underlying conditions rendering nient pharmaceutical formulations ensuring continuity androgen replacement necessary are usually irreversible. of androgen replacement. The benefits of androgen The consequence is that almost life-long androgen replacement therapy are clear, but the delivery of tes- replacement is required. Patient compliance with life- tosterone to hypogonadal men in a way that approxi- long androgen replacement depends on convenient mates normal levels and patterns still poses a therapeutic pharmaceutical formulations ensuring continuity of challenge. Among experts, there is consensus that the androgen replacement. Therefore, they must be conve- major goal of testosterone substitution is ‘‘to replace nient in usage with a relative independence of medical testosterone levels at as close to physiological concen- services. In elderly man, safety of androgen replacement trations as is possible’’ [18]. General agreements about therapy is a concern but in younger subjects (below the such an androgen replacement therapy are (1) a delivery age of 50 years) side effects of androgens are usually of the physiological amount of testosterone (3-10 mg/d); minimal. For them, long-acting testosterone prepara- (2) consistent levels of testosterone, 5a-dihydrotestos- tions are well suited. Testosterone implants generate, terone (DHT) and 17b-oestradiol (E2) within normal depending on the dose of implants, 3–6 months of nor- physiological ranges; (3) a good safety profile without mal plasma testosterone. This method requires minor adverse effects on the prostate, serum lipids, liver or surgery. Injectable testosterone undecanoate maintains respiratory function; and (4) convenience in usage, pa- plasma testosterone in the normal range for 12 weeks. tient-friendly, with a relative independence of medical services. Keywords Testosterone Æ Replacement therapy Æ It is also generally accepted that testosterone, natu- Parenteral androgen Æ Testosterone implant Æ Aging rally produced by the testis, is viewed as the best male androgen for substitution in hypogonadal men. The reason behind the selection is that testosterone can be converted to DHT and E2, thus developing the full spectrum of testosterone activities in long-term substitution. In cases of androgen deficiency, testosterone replacement therapy aims to replace physiological actions of endogenous testosterone by steadily maintaining physi- Quantitative aspects of androgen action ological blood levels of testosterone [18]. The underlying conditions rendering androgen replacement necessary One of the pharmaceutical problems of androgen therapy is the vast amount of androgen molecules to be administered for replacement. The daily testosterone production in the eugonadal adult man lies in the range L. J. Gooren of 4–7 mg, as opposed to daily production of E2 which Department of Endocrinology, lies at its peak in the late follicular phase of the men- Section of Andrology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands strual cycle and amounts to 0.5–1.0 mg/day. The E-mail: [email protected] challenge in androgen replacement treatment has been Fax: +31-20-4440502 to deliver a sufficiently large amount of androgen 307 molecules to the circulation. This difficulty can be injection are low [20, 24]. The normal pattern of cir- demonstrated by comparing transdermal delivery of cadian rhythm of testosterone is not provided and the testosterone with that of E2. The latter has been rela- injections are painful [14]. A vast number of patients tively easy (two patches per week containing 50–100 lg experience these strongly fluctuating levels as unpleas- E2), while with transdermal testosterone treatment this ant (Ôroller coaster effectÕ). is relatively difficult (daily scrotal or large nonscrotal Thus, most intramuscular presentations of testos- patch containing 8–14 mg of testosterone). The large terone are associated with a number of disadvantages. quantities of testosterone needed for their biological The profile of testosterone levels may be accompanied actions as compared with E2 may be explained by the by disturbing fluctuations in sexual function, energy properties of the androgen receptor. It is conceivable level, and mood [15]. Although levels of DHT are that an androgen can be designed that retains (most of) normal, androgen metabolites are frequently not its properties, but which has a hormone-receptor physiological and E2 concentrations may become interaction in a way comparable to oestrogen action, excessive in some men. High post-injection levels of where relatively few oestrogen molecules achieve pow- testosterone predispose the patient to acne and poly- erful biological effects. cythaemia, and E2 causing gynaecomastia. In some patients, injections may be associated with bleeding or bruising [14]. Available preparation for testosterone replacement Therefore, there is a clear need for testosterone preparations which are longer-acting with more stable Three approaches are used to make testosterone thera- plasma testosterone levels and which require less fre- peutically effective: routes of administration, esterifica- quent administration. tion in the 17b position and chemical modification of the molecule, or a combination of approaches. This contri- bution will focus on the long-acting forms of testoster- Parenteral testosterone undecanoate one replacement. Oral testosterone undecanoate dissolved in oil and encapsulated has been available since the early 1970s. Parenteral testosterone esters A study from China [28] revealed that that this com- pound administered parenterally had a significantly Parenteral testosterone preparations have for a long longer half-life than the conventional parenteral tes- time been the mainstay of testosterone treatment and tosterone esters. After experimentation comparing dif- they are the most cost-effective methods. The most ferent concentrations and solutions, 1000 mg commonly used forms include 17b-hydroxyl esters of testosterone undecanoate in 4 ml castor oil proved to testosterone, which are administered with slow-release, deliver an attactive pharmacokinetic profile: the ter- oil-based vehicles. Commonly used intramuscular minal half life was 33.9±4.9 days, with maximal levels injectable testosterone esters are short-acting testoster- of 19.3±2.1 nmol/L reached after 11.4±1.5 days [3]. one propionate and longer-acting testosterone enanthate Later studies with four injections of 1000 mg testos- and cypionate. terone undecanoate in 4 ml castor oil at 6-week inter- Testosterone enanthate is one of the most commonly vals in hypogonadal men showed that intervals between used intramuscular testosterone esters. After a single two injections may be as long as 13 weeks. Serum injection of 250 mg, maximal testosterone concentra- testosterone levels were never found to lie below the tions are reached after 10 h; the terminal half life is lower limit of normal, while only short-lived peaks 4.5 days [17]. At a dose of 200 –250 mg, the optimal above normal (40.8±3.8 nmol/L) were observed after injection interval is 2–3 weeks but peak and through the third and fourth injection interval [19]. In a study values are clearly above and below the normal range, of testosterone undecanoate given to seven hypogo- so that only 45–55% of the injection interval plasma nadal men with intervals of 12 weeks, serum testoster- testosterone levels are in the normal range. Other tes- one, DHT and E2 were mostly within the normal range tosterone esters are testosterone cypionate and testos- and showed a tendency to decrease with longer inter- terone cyclohexanocarboxylate. The pharmacokinetics vals. Safety parameters such as body weight, hemo- of these testosterone esters are very similar to those globin, serum lipids and PSA and prostate volume did of testosterone enanthate [21, 22]. Administration of not change significantly during 3.2 years of observa- 200 mg every 2 weeks provides an acceptable form of tion. Maximum testosterone levels during steady state testosterone replacement. With most of the latter tes- were measured after 1 week and amounted to tosterone esters, a maximum concentration follows 32±11.7 nmol/L. The investigators concluded that this approximately 72 h after injection. Testosterone levels preparation had significant advantages over the con- slowly diminish during the following 10–14 days, ventional parenteral testosterone esters such as con- showing an exponential decline of serum testosterone siderably longer intervals between injections and levels reaching baseline at approximately day 21 [25]. significantly less severe and frequent supraphysiological As a result, the testosterone levels before the next plasma testosterone levels [23, 27]. 308 smoothness/hardness, the site of implantation with its Testosterone buciclate local blood flow and reaction of the surrounding tissue, which may lead to encasing of the pellet. Testosterone buciclate is long-acting, slow-release

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