Mechanism of action bound to
testosterone The protein is shown as a
ribbon diagram in red, green, and blue, with the steroid shown in white. The
pharmacodynamics of AAS are unlike
peptide hormones. Water-soluble peptide hormones cannot penetrate the fatty
cell membrane and only indirectly affect the
nucleus of target
cells through their interaction with the cell's surface
receptors. However, as fat-soluble hormones, AAS are membrane-permeable and influence the nucleus of cells by direct action. The pharmacodynamic action of AAS begin when the exogenous hormone penetrates the membrane of the target cell and binds to an
androgen receptor (AR) located in the
cytoplasm of that cell. From there, the compound hormone-receptor diffuses into the nucleus, where it either alters the
expression of
genes or activates processes that
send signals to other parts of the cell. Different types of AAS bind to the AAR with different
affinities, depending on their chemical structure. first, they increase the
production of proteins; second, they reduce recovery time by blocking the effects of stress hormone
cortisol on muscle tissue, so that
catabolism of muscle is greatly reduced. It has been
hypothesized that this reduction in muscle breakdown may occur through AAS inhibiting the action of other steroid hormones called
glucocorticoids that promote the breakdown of muscles.
Molecular interaction of AAS with androgen receptors Anabolic steroids interact with ARs across various tissues, including muscle, bone, and reproductive systems. Anabolic steroids influence cellular differentiation while favoring the development of muscle cells over fat-storage cells. Research in this field has shown that structural modifications in anabolic steroids are critical in determining their binding affinity to ARs and their resulting anabolic and androgenic activities.
Anabolic and androgenic effects As their name suggests, AAS have two different, but overlapping, types of effects:
anabolic, meaning that they promote anabolism (cell growth), and
androgenic (or
virilizing), meaning that they affect the development and maintenance of masculine characteristics. Some examples of the anabolic effects of these hormones are increased
protein synthesis from
amino acids, increased appetite, increased bone remodeling and growth, and stimulation of
bone marrow, which increases the production of
red blood cells. Through a number of
mechanisms AAS stimulate the formation of muscle cells and hence cause an increase in the size of
skeletal muscles, leading to increased strength. The androgenic effects of AAS are numerous. Depending on the length of use, the side effects of the steroid can be irreversible. Processes affected include pubertal growth,
sebaceous gland oil production, and sexuality (especially in fetal development). Some examples of virilizing effects are
growth of the clitoris in females and the
penis in male children (the adult penis size does not change due to steroids), increased
vocal cord size, increased
libido, suppression of
natural sex hormones, and impaired
production of sperm. Effects on women include deepening of the voice, facial hair growth, and possibly a decrease in breast size. Men may develop an enlargement of breast tissue, known as gynecomastia, testicular atrophy, and a reduced sperm count. The androgenic:anabolic ratio of an AAS is an important factor when determining the clinical application of these compounds. Compounds with a high ratio of androgenic to an anabolic effects are the drug of choice in androgen-replacement therapy (e.g., treating
hypogonadism in males), whereas compounds with a reduced androgenic:anabolic ratio are preferred for anemia and osteoporosis, and to reverse protein loss following trauma, surgery, or prolonged immobilization. Determination of androgenic:anabolic ratio is typically performed in animal studies, which has led to the marketing of some compounds claimed to have anabolic activity with weak androgenic effects. This disassociation is less marked in humans, where all AAS have significant androgenic effects. A commonly used protocol for determining the androgenic:anabolic ratio, dating back to the 1950s, uses the relative weights of ventral
prostate (VP) and
levator ani muscle (LA) of male
rats. The VP weight is an indicator of the androgenic effect, while the LA weight is an indicator of the anabolic effect. Two or more batches of rats are
castrated and given no treatment and respectively some AAS of interest. The
LA/VP ratio for an AAS is calculated as the ratio of LA/VP weight gains produced by the treatment with that compound using castrated but untreated rats as baseline: (LAc,t–LAc)/(VPc,t–VPc). The LA/VP weight gain ratio from rat experiments is not unitary for testosterone (typically 0.3–0.4), but it is normalized for presentation purposes, and used as basis of comparison for other AAS, which have their androgenic:anabolic ratios scaled accordingly (as shown in the table above). In the early 2000s, this procedure was standardized and generalized throughout
OECD in what is now known as the Hershberger assay.
Body composition and strength improvements Anabolic steroids notably influence muscle fiber characteristics, affecting both the size and type of muscle fibers. This alteration significantly contributes to enhanced muscle strength and endurance. Anabolic-androgenic steroids (AAS) cause these changes by directly impacting the muscle tissue's cellular components. Studies have shown that these changes are not merely superficial but represent a profound transformation in the muscle's structural and functional properties. This transformation is a key factor in the steroids' ability to enhance physical performance and endurance. Body weight in men may increase by 2 to 5 kg as a result of short-term (<10 weeks) AAS use, which may be attributed mainly to an increase of lean mass. Animal studies also found that fat mass was reduced, but most studies in humans failed to elucidate significant fat mass decrements. The effects on lean body mass have been shown to be dose-dependent. Both
muscle hypertrophy and the formation of new
muscle fibers have been observed. The hydration of lean mass remains unaffected by AAS use, although small increments of blood volume cannot be ruled out. 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. This dose is sufficient to significantly improve lean muscle mass relative to placebo even in subjects that did not exercise at all.
Dissociation of effects Endogenous/natural AAS like testosterone and DHT and synthetic AAS mediate their effects by binding to and activating the AR. Males with this condition are born with
ambiguous genitalia and a severely underdeveloped or even absent prostate gland. They also notably do not develop gynecomastia as a consequence of their condition.
Functional selectivity An animal study found that two different kinds of
androgen response elements could differentially respond to testosterone and DHT upon activation of the AR. Whether this is involved in the differences in the ratios of anabolic-to-myotrophic effect of different AAS is unknown however. It has been proposed that differential signaling through mARs may be involved in the dissociation of the anabolic and androgenic effects of AAS. These women have little or no
sebum production, incidence of
acne, or body hair growth (including in the pubic and axillary areas). These observations suggest that the AR is mainly or exclusively responsible for masculinization and myotrophy caused by androgens. The mARs have however been found to be involved in some of the health-related effects of testosterone, like modulation of prostate cancer risk and progression.
Antigonadotropic effects Changes in endogenous testosterone levels may also contribute to differences in myotrophic–androgenic ratio between testosterone and synthetic AAS. As such, combined progestogenic activity may serve to further increase the myotrophic–androgenic ratio for a given AAS.
Comparison of AAS AAS differ in a variety of ways including in their capacities to be
metabolized by
steroidogenic enzymes such as
5α-reductase,
3-hydroxysteroid dehydrogenases, and
aromatase, in whether their potency as AR agonists is potentiated or diminished by 5α-reduction, in their ratios of
anabolic/
myotrophic to
androgenic effect, in their
estrogenic,
progestogenic, and
neurosteroid activities, in their
oral activity, and in their capacity to produce
hepatotoxicity.
5α-Reductase and androgenicity Testosterone can be robustly converted by
5α-reductase into DHT in so-called androgenic tissues such as
skin,
scalp,
prostate, and
seminal vesicles, but not in
muscle or
bone, where 5α-reductase either is not expressed or is only minimally expressed. Conversely, certain 17α-alkylated AAS like methyltestosterone are 5α-reduced and potentiated in androgenic tissues similarly to testosterone.
voice deepening, and changes in
sex drive show no difference.
Aromatase and estrogenicity Testosterone can be
metabolized by
aromatase into
estradiol, and many other AAS can be metabolized into their corresponding
estrogenic metabolites as well. 4,5α-Dihydrogenated derivatives of testosterone such as DHT cannot be aromatized, whereas 19-nortestosterone derivatives like nandrolone can be but to a greatly reduced extent. Some 19-nortestosterone derivatives, such as dimethandrolone and 11β-MNT, cannot be aromatized due to
steric hindrance provided by their 11β-methyl group, whereas the closely related AAS trestolone (7α-methyl-19-nortestosterone), in relation to its lack of an 11β-methyl group, can be aromatized. However, it is notable that estrogens that are 17α-substituted (e.g.,
ethinylestradiol and methylestradiol) are of markedly increased estrogenic potency due to improved
metabolic stability,
Progestogenic activity Many 19-nortestosterone derivatives, including nandrolone,
trenbolone,
ethylestrenol (ethylnandrol),
metribolone (R-1881), trestolone, 11β-MNT, dimethandrolone, and others, are potent agonists of the
progesterone receptor (PR) and hence are
progestogens in addition to AAS. Similarly to the case of estrogenic activity, the progestogenic activity of these drugs serves to augment their antigonadotropic activity. AAS that are not orally active are used almost exclusively in the form of
esters administered by
intramuscular injection, which act as
depots and function as long-acting
prodrugs. In contrast to most other AAS, 17α-alkylated testosterone derivatives show resistance to metabolism due to steric hindrance and are orally active, though they may be esterified and administered via intramuscular injection as well. with hepatotoxicity. In contrast,
testosterone esters have only extremely rarely or never been associated with hepatotoxicity, Aside from prohormones and testosterone undecanoate, almost all orally active AAS are 17α-alkylated. A few AAS that are not 17α-alkylated are orally active. ==Chemistry==