In addition, some 19-nortestosterone derivatives, including trestolone (7α-methyl-19-nortestosterone (MENT)), 11β-methyl-19-nortestosterone (11β-MNT), and dimethandrolone (7α,11β-dimethyl-19-nortestosterone), cannot be 5α-reduced. 19-Nortestosterone derivatives like nandrolone can be metabolized by 5α-reductase similarly to testosterone, but 5α-reduced metabolites of 19-nortestosterone derivatives (e.g., 5α-dihydronandrolone) tend to have reduced activity as AR agonists, resulting in reduced androgenic activity in tissues that express 5α-reductase. In contrast to testosterone, DHT and other 4,5α-dihydrogenated AAS are already 5α-reduced, and for this reason, cannot be potentiated in androgenic tissues. This dose is sufficient to significantly improve lean muscle mass relative to placebo even in subjects that did not exercise at all. A randomized controlled trial demonstrated, however, that even in novice athletes a 10-week strength training program accompanied by testosterone enanthate at 600 mg/week may improve strength more than training alone does. For almost two decades, it was assumed that AAS exerted significant effects only in experienced strength athletes. Strength improvements in the range of 5 to 20% of baseline strength, depending largely on the drugs and dose used as well as the administration period. After drug withdrawal, the effects fade away slowly, but may persist for more than 6–12 weeks after cessation of AAS use. Testosterone is important for promoting and maintaining muscle growth and developing secondary male sex characteristics, such as a deep voice and facial hair. This is especially true if the steroids are in a supplement or injection that contains high concentrations. Testosterone is most known for causing changes to the male body during puberty, making the voice deeper and the body hairier. The World Anti-Doping Agency (WADA) maintains the list of performance-enhancing substances used by many major sports bodies and includes all anabolic agents, which includes all AAS and precursors as well as all hormones and related substances. According to Handelsman, the pharmaceutical industry attempted to dissociate the so-called "androgenic" and "anabolic" effects of AAS in the mid-20th-century in order to create non-masculinizing anabolic agents that would be more suitable for use in women and children. (Likewise, all "androgens" are inherently anabolic.) Indeed, it is likely impossible to fully dissociate anabolic effects from androgenic effects, as both types of effects are mediated by the same signaling receptor, the AR. Norethandrolone was introduced for medical use in 1956, and was quickly followed by numerous similar steroids, for instance nandrolone phenylpropionate in 1959 and stanozolol in 1962. It was the first steroid with a marked and favorable separation of anabolic and androgenic effect to be discovered, and has accordingly been described as the "first anabolic steroid". Subsequently, in 1955, it was re-examined for testosterone-like activity in animals and was found to have similar anabolic activity to testosterone, but only one-sixteenth of its androgenic potency. Androgens were discovered in the 1930s and were characterized as having effects described as androgenic (i.e., virilizing) and anabolic (e.g., myotrophic, renotrophic). The development of muscle-building properties of testosterone was pursued in the 1940s, in the Soviet Union and in Eastern Bloc countries such as East Germany, where steroid programs were used to enhance the performance of Olympic and other amateur weight lifters. Studies in the United States have shown that AAS users tend to be mostly middle-class men with a median age of about 25 who are noncompetitive bodybuilders and non-athletes and use the drugs for cosmetic purposes. Ergogenic uses for AAS in sports, racing, and bodybuilding as performance-enhancing drugs are controversial because of their adverse effects and the potential to gain advantage in physical competitions. These effects include harmful changes in cholesterol levels (increased low-density lipoprotein and decreased high-density lipoprotein), acne, high blood pressure, liver damage (mainly with most oral AAS), and left ventricular hypertrophy. Aromatase is highly expressed in adipose tissue and the brain, and is also expressed significantly in skeletal muscle. 5α-reductase is widely distributed throughout the body, and is concentrated to various extents in skin (particularly the scalp, face, and genital areas), prostate, seminal vesicles, liver, and the brain. In addition, DHT is metabolized by 3α-hydroxysteroid dehydrogenase (3α-HSD) and 3β-hydroxysteroid dehydrogenase (3β-HSD) into 3α-androstanediol and 3β-androstanediol, respectively, which are metabolites with little or no AR affinity. AR agonists are antigonadotropic – that is, they dose-dependently suppress gonadal testosterone production and hence reduce systemic testosterone concentrations. However, women with complete androgen insensitivity syndrome (CAIS), who have a 46,XY ("male") genotype and testes but a defect in the AR such that it is non-functional, are a challenge to this notion. Indeed, DHT has less than 1% of the affinity of testosterone for ZIP9, and the synthetic AAS metribolone and mibolerone are ineffective competitors for the receptor similarly. Testosterone signals not only through the nuclear AR, but also through mARs, including ZIP9 and GPRC6A. Whether this is involved in the differences in the ratios of anabolic-to-myotrophic effect of different AAS is unknown however. An animal study found that two different kinds of androgen response elements could differentially respond to testosterone and DHT upon activation of the AR. This can stimulate the body to produce more testosterone and help improve sperm production. Medicinal treatment of steroid abuse, especially if that use lasts longer than a year, can include clomiphene. Some steroid users experience sudden, extreme bouts of aggression, commonly known as "roid rage".
