Testosterone Therapy 21 Eberhard Nieschlag and Hermann M. Behre Contents 21.1 Indications and Preparations: An Overview 21.1 Indications and Preparations: An Overview .......................................................... 437 21.2 Pharmacology of Testosterone All forms of hypogonadism described in the previ- Preparations .......................................................... 439 ous chapters associated with Leydig cell insuffi - 21.2.1 Oral Testosterone Preparations ............... 439 ciency require testosterone therapy. In secondary 21.2.2 Buccal Administration ............................ 441 hypogonadism long-term testosterone therapy is also 21.2.3 Intramuscular Testosterone Preparations 442 indicated. This is only to be interrupted for GnRH or 21.2.4 Transdermal Testosterone Preparations .. 444 21.2.5 Testosterone Implants ............................. 445 gonadotropin therapy when offspring are desired. 21.3 Monitoring Testosterone Therapy in Hypogonadism .................................................. 446 Male hypogonadism is the main indication for testos- terone. Table 21.1 provides an overview of other pos- 21.3.1 Psyche and Sexuality .............................. 446 21.3.2 Somatic Parameters ................................. 447 sible applications. Some of these applications are 21.3.3 Laboratory Parameters ............................ 447 dealt with in other chapters of this volume, for example 21.3.4 Prostate and Seminal Vesicles ................. 449 in constitutionally delayed puberty (Chap. 12), in late- 21.3.5 Bone Mass and Muscles ......................... 450 onset hypogonadism (LOH) (Chap. 14), in male hor- 21.4 Evaluation of Testosterone monal contraception (Chap. 29) and in idiopathic Substitution Therapy ............................................ 451 male infertility (Chap. 22). In addition, this chapter 21.5 Excessive Height .................................................... 451 deals with its use in excessively tall stature (Sect. 21.6 Misuse and Abuse of Anabolic Steroids .............. 452 21.5) and with its abuse in doping and body building (Sect. 21.6). Because of its erythropoetic effect testos- References ........................................................................... 453 terone is also licensed for the treatment of aplastic and renal anemia, but lost ground to erythropoetin after the Table 21.1 Use of testosterone in men Clinical applications Hypogonadism Primary hypogonadism Secondary hypogonadism LOH Delayed puberty Aplastic and renal anemia Off-label use Excessive growth Application under discussion Aging male Experimental use Male contraception E. Nieschlag () Obsolete application Idiopathic infertility Centre of Reproductive Medicine and Andrology of the University, Domagkstr. 11, D-48149 Münster/Germany Abuse High-performance athletics e-mail: [email protected] and bodybuilding E. Nieschlag et al. (eds.), Andrology, 437 DOI: 10.1007/978-3-540-78355-8_21, © Springer-Verlag Berlin Heidelberg 2010 438 E. Nieschlag and H. M. Behre latter was introduced. For treatment of this condition, sexuality of their patients to date (Gooren et al. 2007). the reader is referred to textbooks of internal medicine. The International Recommendations for LOH also Testosterone therapy is indicated when, in cases establish 8 nmol/L as the absolute lower threshold for with androgen defi ciency, serum testosterone concen- testosterone substitution and the range between 8 and trations drop below a certain level (see Chap. 5). 12 nmol/L as relative indications (Nieschlag et al. In Germany 12 nmol/L is considered the lower level 2006; Behre et al. 2004; Wang et al 2008). In unclear of normal. Surprisingly this level is lower in other cases calculated free testosterone below 225 pmol/L countries, e.g., Spain (9.0), Great Britain (7.5–8.0) and can be considered as an indication for testosterone France (7.5 nmol/L) (Nieschlag et al. 2004; Gooren substitution. Additionally the pharmacogenetics of tes- et al. 2007). A study designed to verify these differ- tosterone increasingly play a role and must be taken ences in aging hypogonadal patients concluded that not into consideration together with symptom-specifi c one single threshold level coincided with the occur- threshold levels when substituting hypogonadal rence of symptoms of hypogonadism, but that there are patients (Zitzmann and Nieschlag 2007). symptom-specifi c threshold levels ranging between 15 and 8 nmol/L. Loss of vigor and libido are observed Thus testosterone substitution must become more even below 15 nmol/L, while erectile dysfunction oriented towards patients’ complaints than at present caused by lack of testosterone occurs only below and consider carefully symptom-specifi c threshold 8 nmol/L. The other symptoms occur between these serum levels. 12 nmol/L total serum testosterone two levels (Fig. 21.1) (Zitzmann et al. 2006). A study in continues to be a good indication for low normal lev- younger hypogonadal men came to similar conclusions els. The effectiveness of substitution can be measured (Kelleher et al. 2004). directly by testosterone concentrations in serum. The question at which testosterone levels substitu- tion is initiated has been more determined by the phy- sicians’ perception of hypogonadism than by the Since we are dealing with hormone replacement ther- patients’ complaints. The fact that physicians, when apy, its effectiveness can be measured directly by questioned, mentioned the loss of libido as the most checking serum testosterone concentrations. frequent symptom of testosterone defi ciency shows how little importance physicians have attached to the According to international consensus which remains valid, the major goal of testosterone therapy is to Total testosterone nmol / L replace testosterone levels at as close to physiologi- 20 cal concentrations as is possible (Nieschlag et al. 74 1992). Furthermore, the naturally occurring testos- Normal terone molecule should be used for substitution in order to guarantee the broad spectrum of testosterone 69 effects. Available testosterone preparations should be 15 judged according to these criteria. Loss of libido 84 Loss of vigor 12 Certain target organs are able to use testosterone directly, Obesity 65 while for others it must fi rst be converted to 5a-DHT or 10 estradiol in order for them to become effective (Chap. 2). Feeling depressed, disturbed sleep Lacking concentration 67 To achieve a physiological balance between testoster- Diabetes mellitus type 2 (also non-obese men) 8 one and its active metabolites, natural testosterone Hot flushes should be used and not synthetic androgens which are 75 Erectile dysfunction metabolized into other forms (e.g., 19-nortestosterone) 0 or are direct derivatives of the metabolites (e.g., mester- olone). In the same vein there is little purpose in apply- Fig. 21.1 Threshold levels of serum testosterone for various symptoms of late onset hypogonadism (LOH) in 434 patients ing estrogens either directly or exclusively to the (Zitzmann et al. 2006) hypogonadal male. Nor has any rational basis for the 21 Testosterone Therapy 439 use of testosterone precursors such as DHEA or andros- described below, nasal, conjunctival or rectal routes of tendione been established to date. The use of natural application can be chosen; however, at present these testosterone allows all androgen-dependent functions to forms play no role in clinical use. be induced or maintained in the safest way possible and This chapter deals with aspects relevant to andro- side effects to be avoided. gen therapy. For further reading reference is made to Testosterone was fi rst synthesized in 1935 current monographs (Nieschlag and Behre 2004). (Butenandt and Hanisch 1935; Ruzicka and Wettstein Table 21.1 and Fig. 21.3 provide an overview of avail- 1935) and used clinically shortly thereafter; thus it is able preparations and dosages. one of the oldest hormones in clinical use. First testos- terone implants were used, and since the 1950s testos- terone enanthate or cypionate were applied as i.m. injections. In the 1970s orally effective testosterone 21.2.1 Oral Testosterone Preparations undecanoate followed, and in the 1990s the fi rst trans- dermal testosterone substitution appeared in the form It would seem obvious to use natural testosterone in of a testosterone fi lm applied to the scrotum. Further the form it is secreted by the testes for substitution transdermal applications were membranes for non- therapy. In fact, orally applied free testosterone is well scrotal skin and fi nally testosterone gels were intro- absorbed from the intestine, but is completely metabo- duced. Injectable testosterone undecanoate represents lized by the liver in the fi rst pass effect, so that it does a real depot preparation. A mucoadhesive buccal tes- not reach target organs. About 400–600 mg testoster- tosterone tablet completes the spectrum of currently one would have to be given orally, i.e., about 100-fold available preparations (Nieschlag 2006). of the amount normally secreted by the testis daily, in The experienced physician must select the form order to exceed the testosterone-metabolizing capacity most suitable for the patient, considering both his of the liver and to achieve normal peripheral serum symptoms and phase of life. Often several preparations levels. As administering such great amounts of testos- will have to be tried before fi nding an optimal choice terone seems uneconomical and as possible long-term for the individual patient. side effects are