1. Natural and Synthetic Androgens
As reviewed in Chapter 2, the naturally occurring androgens are 19-carbon steroids. Testosterone is the principal male androgen produced and secreted by the testes. An important biologically active metabolite of testosterone, produced in certain target tissues, is 5α-dihydrotestosterone. The structures of these androgens are presented in Figure 1. Table 1 summarizes some of the major steroids and androgenic intermediates found in significant concentrations in the blood of normal adult males.
Fig1. Androgen-related molecules. The structures of the naturally occurring androgens, testosterone and 5α-dihydrotestosterone are shown. Below are shown chemically synthesized compounds that mimic some of the effects of the natural androgens (synthetic androgens and SARMs, Selective Androgen Receptor Modifiers) as well as anti-androgens that oppose the effects of the natural androgens.
Table1. Production and Circulation of Sex Steroids in the Adult Human Male
As discussed in more detail in section V, the bio logical actions of androgens can be divided into those directed towards the development and maintenance of the male reproductive system and those that have anabolic effects on skeletal muscle. Anabolic steroids are synthetic analogs of testosterone whose actions are selective for the anabolic effects on muscle rather than, for example, growth effects on the prostate gland. The reasons for this selectivity have to do with the resistance of the molecule to metabolism into dihydrotesterone or estradiol, as well as its interaction with the androgen receptor (AR) in specific target tissues.
Three examples of the many anabolic testosterone derivatives that have been synthesized are shown in the middle section of Figure 1.
Anabolic androgens are used as adjuvant treatments in diseases with muscle wasting, such as cancer and AIDS, and in glucocorticoid-induced osteoporosis. Anabolic androgens are misused through prescription for nonindicated purposes and abused by athletes who use them to build muscle mass and strength. This topic will be discussed in more detail in section VI.C.
2. Androgen Antagonists
Some synthetic analogs of testosterone compete for binding to the AR, but do not generate androgenic effects; such analogs are termed androgen antagonists or anti-androgens. Examples including one steroidal and two nonsteroidal anti-androgens are shown in the third row of Figure 1. Some steroidal androgen antagonists tend to interact with the glucocorticoid receptor, which can lead to undesirable side effects. Others, such as cyproterone acetate, in addition to inhibiting androgen action at the AR, also interact with the progesterone receptor, decreasing LH secretion from the pituitary.
Androgen antagonists are used in the treatment of both benign prostate hyperplasia as well as androgen-dependent prostate carcinoma. Because of its favorable side effect profile, bicalutamide is currently the drug of choice for treating prostate cancer. Anti androgens are also useful in treating females with excessive androgen levels, such as in polycystic ovary syndrome.
3. SARMs (Selective Androgen Receptor Modifiers)
SARMs are defined as molecules that interact with the AR, eliciting biological responses in the bone and muscle, for example, but not in the prostate; thus the term “selective.” According to this definition, they include some of the synthetic androgens described above, but there are also a number of nonsteroidal SARMs. The effectiveness of a SARM will depend on its affinity for the AR and the degree of its selectivity. Two examples of nonsteroidal SARMs are shown in Figure 1. S-4 (Andarine) has gone through extensive preclinical testing and LGD-2941 has entered a Phase I clinical trial. Many other nonsteroidal SARMs are currently being synthesized and tested.
