Androgenic-anabolic steroids (AAS) are widely missed worldwide as performance-enhancing agents. The use of AAS started in competitive sports and spread to non-competitive athletes. The World Anti-Doping Agency banned AAS since the 1950s and has continued adding new methods and new variations of AAS. Currently, the CDC estimates that the majority of AAS users are adolescent males.
The hypothalamus is the integrating center for the reproductive axis (HPG). It receives signals from the amygdala, olfactory, and visual cortex. Gonadotropin-releasing hormone (GnRH) then gets released into a venous portal system that carries it to adenohypophysis of the pituitary gland. In addition to signals from the CNS, humoral factors from the testes also play a role in modulating the release of GnRH. Gonadotropin-releasing hormone release is pulsatile, seasonal, and circadian. Levels of GnRH are highest during spring and in the morning with peaks occurring every 90 to 120 minutes. Once released, GnRH acts on the pituitary gland and promotes the production and release of luteinizing hormone (LH) and to a lesser extent, follicle-stimulating hormone (FSH). Luteinizing hormone, in turn, acts on Leydig cells in the testes, which are the site of production of most of the endogenous androgens. Androgen production also occurs in the adrenal cortex and the conversion of androstenedione peripherally. Testosterone, in turn, inhibits the production of GnRH in the hypothalamus.
Testosterone is a 19-carbon steroid and is the most potent endogenous androgen. As such, it is the basis of most AAS. Addition of various functional groups to this basic 19-carbon structure changes androgenic, anabolic, and toxicity profiles of AAS.
Testosterone and other AAS act to increase muscle hypertrophy through modulating androgen receptor and its interaction with co-activators. It also increased muscle hypertrophy through modulation of receptor expression through intercellular metabolism, an anti-catabolic effect, by interfering with glucocorticoid receptor expression and various genomic and non-genomic pathways that act on the central nervous system.
Studies of long term AAS users showed an increase in muscle fiber hypertrophy. Both Type I and Type II had significant hypertrophy. Even though Type II muscle fibers compose the majority of muscle mass in power-lifters, it was Type I fibers that enlarged the most with a 33% increase in size. Additionally, Type II fibers require a lesser dose of testosterone 300 mg vs. 600 mg for Type I to exhibit hypertrophy.
One of the critical mechanisms by which AAS induces muscle hypertrophy is by increasing the synthesis of contractile proteins. Injections (IM) of 200 mg of testosterone enanthate increased synthesis two-fold by increasing the rate at which amino acids underwent reuse, while protein turnover rate was unchanged. Each muscle fiber contains multiple myonuclei that can support a certain level of protein synthesis. With resistance training, these myonuclei increase in size and can support an increase in protein synthesis and cross-sectional area of a muscle fiber. On average, this increase is no more than 26% for Type II muscle fiber, which is termed “ceiling theory,” however, with AAS supplementation, researchers observed a significant increase of 36%. This effect is even higher for Type I muscle fibers.
Short term administration of androgenic-anabolic steroids (300 mg per week for 20 weeks) increases the number of muscle satellite cells; this is thought to be because testosterone promotes satellite cell proliferation and entry into the cell cycle. As these cells enter the cell cycle, some daughter cells don’t differentiate and become quiescent cells. Other satellite cells while dividing may become new myonuclei or proceed to form new myotubules.
While the exact mechanism remains unclear, murine models showed that testosterone-treated C3H 10T1/2 pluripotent mesenchymal cells showed increases in MyoD and myosin heavy chains. Testosterone supplementation is a potent regulator of lipolysis via influencing catecholamine signal transduction. Testosterone also inhibits adipocyte precursor cells from differentiation.
Finally, there may be an androgen receptor-independent pathway through which testosterone may act. AAS may work on G-protein coupled receptor at the plasma membrane, which would increase Ca2+ concentration and activate ERK1/2 kinases, which then would phosphorylate transcription factors.
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