Pharmacology of anabolic steroids
In target tissues, that is, the cells that contain steroid receptors, the hormone binds to the receptor ligand-binding domain, causing dissociation of the receptor—Hsp90 complex, the resultant conformational allosteric change making the receptor active. Steroids can display differing pharmacokinetic characteristics depending on their structure, which in turn determines their behavior and therefore concentration in the blood. Clin Lab Med 7: Aromatase in skeletal muscle.
Biopharmacology of Testosterone
The third compound is structurally identical to testosterone except for the deletion of the 19th carbon hence its name. Women who chronically administer large doses of weaker androgens that can be converted to more potent steroids would be expected to suffer from virilizing effects. Psychiatric and medical effects of anabolic—androgenic steroid use. The chronic use of AASs can cause various pathologic alterations, which are related to dose, frequency, and patterns of use. Since short acting steroids are cleared from the body more rapidly, they need to be given in regular doses to build up and maintain a high enough concentration in the blood to be therapeutically effective. The endocrine system has a remarkable array of checks and balances that ensure the human body is at or near homeostasis at any point in time. A loading dose is one dose or a series of doses given at the onset of a cycle with the aim of achieving the target concentration rapidly.
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Cocaine, Marijuana, Designer Drugs: Chemistry, Pharmacology and Behavior. A review of the literature. Am J Sports Med The effect of male hormone on problem and energy metabolism of castrated dogs.
The history of anabolic steroids and a review of clinical experience with anabolic steroids. Acta Endocrinol Suppl Androgen abuse by athletes. Anabolic steroids in athletics: How well do they work and how dangerous are they? Murad F, Haynes RC A Textbook of Clinical Pharmacology. Council on Scientific Affairs Drug abuse in athletes: Anabolic steroids and human growth hormone. How an anabolic steroid may affect androgen receptor conformation and interaction with particular coregulators is of obvious interest, as such knowledge may eventually offer an additional mechanism for anabolic—androgenic dissociation.
The development of nonsteroidal selective androgen receptor modulators SARMs may offer better dissociation of biological effects than anabolic steroids and possibly even permit the therapeutic targeting of specific tissues and organs.
Potential therapeutic modalities could then be specific agonists for restoration of fat-free muscle mass and strength in those with chronic illnesses such as HIV and specific antagonists for the treatment of prostate cancer in men or hirsutism in women Wolf and Obendorf, ; Bhasin et al.
In anticipation of the potential of such agonists for performance enhancement in sport, SARMs have been added to the World Anti-Doping Agency's WADA's list of prohibited substances in sport, despite none yet being available on the market.
Anabolic steroids are controlled substances in several countries, including Australia, Argentina, Brazil, Canada, the United Kingdom and the United States. Even so, there is a readily available supply of steroids worldwide for non-medicinal purposes, because, in most countries, anabolic steroids can be sold legally without a prescription Hermansson, ; Cramer, Thus, many foreign distributors do not violate the laws of their own country when they sell these substances to customers overseas via the Internet and by e-mail orders.
The majority of the hormone products in the European market come from countries within the European Union and Russia, but also sometimes from Thailand, Turkey, Egypt, India and Pakistan Hermansson, In the United States, significant quantities of anabolic steroids come from Mexico, as well as other countries such as Russia, Romania and Greece Cramer, In the United Kingdom, anabolic steroids are controlled under Schedule IV Part 2 of the Misuse of Drugs Act; the Act includes most of the anabolic steroids, together with clenbuterol adrenoreceptor stimulant and human growth hormone.
There is no restriction on the possession of these substances when they are part of a medicinal product and are for self-administration. However, prosecutions of intent to supply have been made of individuals found in possession of large quantities of these substances without a prescription for them. A Home Office licence is required for importation and exportation of anabolic steroids, except in cases of small quantities for legitimate purposes.
In , WADA was set up as a foundation under the initiative of the IOC with the support and participation of intergovernmental organizations, governments, public authorities, and other public and private bodies fighting against doping in human sport. Under WADA, the rules and technical documents concerning anabolic steroids and other drugs are constantly evolving and for up to date information the reader is strongly advised to access the WADA web site http: The use of anabolic steroids for cosmetic benefits among both adults and adolescents in society may be incorrectly regarded as a comparatively harmless pharmacological manipulation that can aid the development of bulging muscles and a well-toned figure.
Nevertheless, it is difficult to estimate the true number of anabolic steroid users in the whole of the United Kingdom but these drugs are used on a nationwide basis, as discussed in depth by the report from the British Medical Association BMA, Similar surveys indicate a high prevalence of use in the United States Yesalis et al.
For drug control in sport, anabolic steroids are regarded correctly as performance enhancers, as well as harmful to health. Comparison of the adverse findings for worldwide testing for over a decade show that there has been little change year after year, the most common steroids being testosterone, nandrolone, stanozolol and methandienone.
Testosterone has an unfavourable anabolic—androgenic dissociation compared with other anabolic steroids, but it is more difficult to prove its administration, as it is also produced endogenously. Some consider that the WADA statistics do not reflect the real extent of doping with anabolic steroids, particularly within top-level athletics but few would dispute that the urge to succeed and the rewards of success, both financial and otherwise, have provided powerful incentives to some competitors to look for every possible means of improving their performance, despite the risk of denunciation and penalties.
Some of the structural modifications that have been introduced into the testosterone in an attempt to maximize the anabolic effect and minimize the androgenic are shown in Figure 2 , and examples of anabolic steroids are given in Figure 3. Many of these steroids have been withdrawn as licensed products in numerous countries worldwide but they continue to be available as pharmaceutical preparations in others, for example, methandienone, methyltestosterone, oxandrolone and stanozolol.
The only preparations currently available as licensed products for human use within the United Kingdom are testosterone and its esters, nandrolone as the decanoate ester , mesterolone and oxymetholone named patient basis only. Boldenone and trenbolone are restricted to veterinary purposes only in some countries, but, nonetheless, sports competitors and bodybuilders have been known to administer these anabolic steroids.
A methyl group attached to C-1 can also confer oral activity, as in methenolone or mesterolone, but these two anabolic steroids are considered to be relatively weak in pharmacological activity. Once in the circulation, hydrolysis rapidly occurs by the action of blood esterases to yield the active compound. The esters include cyclohexylpropionate, decanoate, laurate and phenylpropionate for nandrolone; acetate, cypionate, decanoate, enanthate, isocaproate, phenylpropionate, propionate and undecanoate for testosterone, undecylenate for boldenone and acetate for trenbolone.
The mechanism of action of the nandrolone esters and other anabolic steroids, and the effect of drug delivery systems on their biological activity have been studied by van der Vies The duration of action of the esters depends upon the rate of absorption from the site of administration.
This is dependent on the chain length of the acid moiety and also the formulation, being related to the partition coefficient of the derivatives between the oil used in the formulation and plasma. In general, the longer the chain length, the more slowly the preparation is released into circulation, thus prolonging the duration of action. Furthermore, testosterone undecanoate is also orally active, the 11 carbon chain ester making the molecule so lipophilic that its route of absorption is partially shifted from the hepatic portal vein to the lymph system, thus bypassing first-pass metabolism to some extent, it being released into the circulation via the thoracic duct Coert et al.
Non-pharmaceutical water-based testosterone suspensions for injection are advertised on bodybuilding web sites and cheats in sport may find these attractive as, in theory, these should be relatively short acting. Non-pharmaceutical-based preparations, whether oil or water based, may be a particular hazard to health as the contents may not have been prepared under sterile conditions. Other short-acting testosterone preparations include those that are designed to be administered by the sublingual or buccal route.
Such short-acting formulations are of particular concern in sport, as the exogenous source of testosterone is rapidly eliminated following cessation of treatment. Increased out-of-competition testing helps to combat the cheat who is using short-acting preparations and ceasing administration prior to competition in anticipation of testing. A current cause for concern is the recent manufacture of analogues of established anabolic steroids to tap into the bodybuilding market. It is a consequence of their widespread availability that a minority of athletes will also use these steroids in an attempt to improve sporting performance, and because they are structurally related to mainstream anabolic steroids, sports antidoping laboratories are made to incorporate such compounds into their drug screens under the WADA rules.
These steroids are supplied for oral administration, and are therefore subject to first-pass metabolism, a very important factor as to the extent the steroid is deactivated or converted to a more active form. Some of the putative metabolites of dietary supplements have been identified by mass spectrometry, but not by other analytical techniques such as nuclear magnetic resonance spectroscopy to confirm configuration of the structure; the interested reader is referred to the extensive review by Van Eenoo and Delbeke With respect to prohormone supplements of testosterone, as recently reviewed by Brown et al.
However, supplements of the weaker androgens DHEA or androstenedione may be of little or no benefit to healthy young men who wish to improve their strength and sporting performance if, as would be expected, any anabolic effect is primarily mitigated through peripheral conversion to testosterone.
Ingestion of DHEA can result in an increase in circulating DHEA and androstenedione, but it is not resolved as to whether there is an increase in plasma testosterone, see for example Brown et al. This is not surprising because in the adult men the overall peripheral contribution of these precursor steroids to circulating testosterone is small.
Any contribution from exogenous DHEA or androstenedione will be largely moderated by the large amount of testosterone contributed by the testis. In women, an increase in performance may be possible following ingestion of these supplements, as circulating testosterone would be expected to increase. There are modest-to-large increases in circulating testosterone following androstenedione administration to women Leder et al. Women who chronically administer large doses of weaker androgens that can be converted to more potent steroids would be expected to suffer from virilizing effects.
In , the FDA Food and Drug Administration , as part of its public health mission, sent warning letters to 23 companies in the United States requesting them to cease distributing androstenedione as dietary supplements FDA, Designer anabolic steroids are considered as ones that are manufactured specifically to circumvent doping tests in human sport, and, therefore, for obvious reasons, they are supplied in a clandestine fashion.
There are few examples to draw on. Classified documents Franke and Berendonk, saved after the collapse of the German Democratic Republic revealed that, since , a pharmaceutical company had produced preparations of epitestosterone propionate exclusively for the governmental doping programme.
Tetrahydrogestrinone can be easily manufactured by the catalytic hydrogenation of the ethynyl group of the progestogen gestrinone Figure 5. This relatively simple synthetic step hides the thinking that probably lay behind the design of THG.
Given the close homology of their receptors, there is an overlap between the activity of progestogens and androgens, especially those xenobiotic steroids that lack the C methyl group, but which activity predominates depends on whether the alkyl substituent at carbon is ethynyl or ethyl.
The synthetic route is described in a seminal paper by Djerassi et al. However, substitution with an ethyl group on nandrolone rather than ethynyl group results in another anabolic steroid known as norethandrolone, which also has oral activity.
This is indeed the case, as subsequently THG was found to be a highly potent androgen and progestogen in an in vitro bioassay system expressing human steroid receptors Death et al. Underground chemists appear also to be accessing information concerning other steroids that were synthesized several decades ago by pharmaceutical companies but were never marketed. Such steroids that have been detected until recently are norbolethone Catlin et al.
Although the extent of this activity appears to be limited, as screening procedures rely on targeting selecting ions for monitoring by mass spectrometry, unknown steroids may escape detection. To demonstrate how this problem may be addressed, Thevis et al. Anabolic steroids are thought to exert their actions by several different mechanisms. These mechanisms include modulating androgen receptor expression as a consequence of i intracellular metabolism and by ii directly affecting the topology of the androgen receptor and thus subsequent interaction with co-activators and transcriptional activity.
Other mechanisms include iii an anticatabolic effect by interfering with glucocorticoid receptor expression; and iv by non-genomic, as well as by genomic pathways, in the CNS resulting in behavioural changes.
These mechanisms are discussed herein. As an adjunct, much of the physiological importance of non-genomic actions of androgens is still to be elucidated, not least with respect to androgen-induced cell-cycle progression. Regarding androgens, several non-genomic mechanisms appear to be involved, including mediation by the membrane-bound sex hormone-binding globulin receptor and also a putative G-protein-coupled receptor that androgens directly bind with, as well as through stimulation of nonreceptor tyrosine kinase c-SRC.
The complexity of these mechanisms is described in detail elsewhere Cato et al. It is not currently known whether non-genomic actions of androgens at physiological concentrations are important in skeletal muscle growth, let alone what the non-genomic effects may be evoked by the administration of anabolic steroids. The structural changes to testosterone by medicinal chemists were designed to enhance the protein anabolic effect relative to the androgenic effect.
Unfortunately, the anabolic effects could not be divorced entirely from the androgenic effects, although some synthetic steroids present a remarkable dissociation, at least based on the myotrophic—androgenic index. It may be argued that by today's standards this in vivo approach, which was developed over 50 years ago, is unsophisticated given the huge developments in molecular biology since that time.
Despite the criticism that this approach has attracted, it is of note that anabolic steroids with high myotrophic activity and favourable index values, for example, nandrolone esterified , oxymetholone, methandienone and stanozolol are still available as medicines in many countries.
These steroids remain desirable as a doping agent to enhance sporting performance as evident by the statistics collated by WADA and for bodybuilding purposes. For this reason, it is logical to summarize this approach, based on growth of a particular skeletal muscle called the levator ani relative to that of androgenic target tissue, usually the prostate gland, and attempt to explain the underlying mechanism of dissociation of the growth of the two tissues compared with controls.
Eisenberg and Gordan proposed the use of the rat levator ani muscle as a bioassay of protein anabolic activity; the anatomical drawings from the dissection of the male rat, displaying the location of this muscle, the prostate and seminal vesicles are displayed in this paper. The rat levator ani muscle is part of the perineal complex of striated muscles that envelope the rectum.
This muscle was chosen because previous workers had reported that testosterone propionate stimulated the growth of the perineal complex in infantile rats, and, additionally, this complex was easily separated from other tissues. In contrast, there was a much smaller unparalleled increase in the weight of the seminal vesicles. The foundation of the commonly used procedure of the myotrophic—androgenic index was based on a modification of the Eisenberg and Gordan method by Hershberger et al.
Hershberger and co-workers preferred the use of the ventral part of the prostate rather than the seminal vesicles as a measure of tissue androgenic response in immature gonadectomized rats. They proposed a measure of hormonal myotrophic-to-androgenic activity using the following ratio:. Many investigators employed the approach proposed by Hershberger et al.
A comprehensive comparison of the anabolic and androgenic activities of many anabolic steroids and their dissociation index is given elsewhere Potts et al. Kruskemper discusses the many failings of the procedures used for determining the myotrophic—androgenic index, for example, the seminal vesicles react more slowly to certain androgens, so that with short test administration, distortions can arise in favour of the myotrophic effect. The harshest criticism of this index was given by Nimni and Geiger , Scow and Hagan and Hayes Testosterone administration for 56 days to young gonadectomized rats castrated at 20—23 days of age had no effect on the growth of the thigh muscle compared with controls, yet there was considerable growth in the perineal musculature Scow, ; Scow and Hagan, Hayes stated that the rat levator ani muscle is not homologous to this muscle in other species, that is, it is not a typical sphincter muscle and does not lift the anus in rodents but is part of the male reproductive system.
Thus, Hayes renamed the levator ani muscle, calling it the dorsal bulbocavernosus. All three groups of workers showed that the levator ani muscle reflects a general genitomyotrophic response rather than an overall response to androgens. Later, Hervey claimed that the male rat's characteristics are determined shortly after birth due to a brief secretion of testosterone , and, thereafter, any increase in body mass is not affected by androgens. Contrary to the opinions described above, there is nonetheless biochemical evidence that suggests that the genitomyotrophic response of the levator ani muscle may serve as an indicator of the general myotrophic responses in the developing rat for the following reasons.
Celotti and Cesi , in their review of possible mechanisms of action of anabolic steroids, discuss that the peculiar androgen sensitivity of this muscle is intermediate between that present in the skeletal muscles and that of the prostate.
The myotrophic effect of anabolic steroids may be reflected by the amplified response of the levator ani muscle due to its higher concentration of androgen receptors, an effect that is not apparently sufficient in other typical rat skeletal muscles to be observed using differences in weight compared with controls as the measurand. Among the anabolic steroids, nortestosterone nandrolone was one of the first synthesized, the most used and probably the best studied.
Hence, in androgenic tissue, testosterone is converted to a more potent metabolite, whereas nortestosterone is converted to a less potent one. If the model is correct, such a diminishment in androgenic activity should not be confined to the accessory reproductive tissues in the human such as the prostate, but also in non-genital target tissues where clear roles for the metabolism to DHT have been defined such as the male patterns of facial and body hair growth, thus allowing more muscle per whisker.
This suggests that further work at the molecular level is required to better understand the action of androgens on sebaceous gland function. Recently, as part of investigations to assess whether the designer steroid THG had anabolic and androgenic properties see also next section , three papers report the effects of its administration on the growth of the levator ani, prostate and seminal vesicles compared with control steroids Jasuja et al.
Notwithstanding the possible differences in pharmacokinetics and bioavailability between THG and the control steroids administered, there appeared to be little myotrophic—androgenic dissociation, but, nonetheless, the bioassays clearly demonstrated that THG had anabolic and androgenic activity in vivo , and, therefore, belonged within the banned doping class of anabolic agents in sport, as defined by WADA.
As a final and very important point, it is of note that complete dissociation has not been achieved with any anabolic steroid synthesized, and, therefore, the chronic administration of these drugs, even those with a very high myotrophic—androgenic index value, such as found with nandrolone nortestosterone , will result in hirsutism and, eventually, virilization of women and children.
The androgen receptor belongs to the family of nuclear receptor superfamily Mangelsdorf et al. A DNA-binding domain, a ligand-binding domain and at least two transcriptional activation domains, characterize these receptors.
Apart from binding with the steroid, the ligand-binding domain also functions in dimer formation and mediates transcriptional activation. The zinc-fingers are inserted between specific grooves of the DNA helix, thus, allowing maintenance of DNA-binding activity.
A general model of steroid receptor action is displayed in Figure 7. In the absence of hormone, it is by and large accepted that steroid receptors exist as an inactive oligomeric complex, being sequestered by the heat-shock protein Hsp , Hsp90, which acts as a molecular chaperone.
Hsps are so-called because they were discovered to accumulate under stress conditions including within heat-traumatized cells, but many are present and functionally important under normal conditions; they are named according to their molecular weight in kilodaltons. Another chaperone called p23 stabilizes the aporeceptor complex by blocking Hsp90 in the ATP-bound substrate conformation.
Co-chaperones utilizing tetratricopeptide repeat motifs are necessary for docking of the Hsp As an adjunct, other chaperones, called Hsp40 and Hsp70 and an organizing protein called Hop heat-shock organizing protein are important in the assembly of the steroid receptor—Hsp90 complex. Picard gives a clear overview of molecular chaperones and cofactors that are relevant to steroid receptor action. Phosphorylation of the receptors is also important in regulation of receptor function Weigel and Moore, The steroid receptor—Hsp90 complex appears to be necessary for the receptor to stabilize in a conformation for binding to the ligand with high affinity and also to maintain its solubility in the cell.
It is generally accepted that, although the receptor is held in this complex, it is inactive as a transcription factor, that is, the Hsp90 complex acts as a repressor of transcriptional activity by preventing one or several of the following: Steroids are relatively small molecules, for example, testosterone has a molecular weight of , and they can passively diffuse into cells.
In target tissues, that is, the cells that contain steroid receptors, the hormone binds to the receptor ligand-binding domain, causing dissociation of the receptor—Hsp90 complex, the resultant conformational allosteric change making the receptor active. In the case of the androgen and glucocorticoid receptor, the chaperone complex resides in the cytoplasm, and following dissociation from the chaperone the activated receptor is translocated into the nucleus.
Activated receptors interact as homodimers with the steroid response element on the chromatin, the effect of two receptors binding being cooperative greater affinity and stability.
Coregulators can be either positive or negative regulatory proteins, referred to as co-activators or corepressors, respectively Perissi and Rosenfeld, Co-activator and corepressor complexes are required for nuclear receptor-mediated transcriptional regulation, generally liganded receptors recruiting co-activators resulting in gene activation, transcription of the gene, translation and a resultant alteration in cell function, growth or differentiation.
The function of the transcriptional activation domains on the receptor is to mediate the binding of the receptor to the comodulators. The receptor has an N-terminal activation function-1 AF-1 and a second activation function-2 AF-2 in the C-terminal ligand-binding domain.
The mechanism of AF-1 gene activation is not well understood due to the lack of conformational information but, by contrast, many crystal structures of the ligand-binding domain of different nuclear receptors have been achieved, allowing a fuller understanding of AFmediated transcriptional activation.
AF-2 is dependent on ligand binding to the receptor for its activity, which causes the folding of a C-terminal helix helix , acting as a lid over the ligand pocket upon ligand binding. The molecular biology of the androgen receptor has been reviewed by Klocker et al. In contrast to other steroid receptors, most of its transcriptional activity is mediated through the N-terminal AF-1 domain, there being a reduced capacity of AF-2 in the androgen receptor to recruit LXXLL-containing co-activators.
Instead, it has been suggested that the AF-2 of the androgen receptor acts primarily as an interaction platform for the recruitment of co-activators to the N-terminal region, this regulation of gene expression through the intradomain interaction and communication being unique to this receptor. To date, several families of co-activator proteins have been identified but only two direct inhibitors of androgen receptor function have been identified in vivo , SHP and DAX-1, these being atypical orphan receptors that lack DNA-binding domains.
Using X-ray crystallography, the interaction between peptide segments of SHP containing LXXLL-like motifs and the ligand-binding domain on the androgen receptor was investigated, and it was found that the LKKIL motif formed a complex, binding with a hydrophobic groove on the androgen receptor Jouravel et al. It was suggested that this transcriptional activity of androgen receptors might be inhibited by SHP competing for binding to androgen receptor co-activators.
The binding motif to the androgen receptor by DAX-1 is still to be elucidated. Another corepressor, FoxG1, appears to be a likely candidate for interaction with the androgen receptor in vivo but studies are necessary to prove whether this is the case Obendorf et al. Anabolic steroids bind to the androgen receptor with different affinities. The relative binding with fluoxymesterone, methandienone and stanozolol was much weaker and that with oxymetholone and ethylestrenol was too low to be determined.
There is a large discrepancy as to what is known about the in vivo activities of these steroids compared with their in vitro activity, even taking into account possible differences in the bioavailability and clearance of these steroids not least determined by the affinity to sex hormone-binding globulin in the blood circulation. Furthermore, Feldkoren and Andersson found that stanozolol and methandienone have significantly lower binding affinities compared with testosterone but all three steroids were potent activators in a cell-based androgen receptor-dependent transactivation assay.
Clearly, the degree of physical binding to the androgen receptor, as measured by ligand-binding assays, does not fully explain the biological activity of anabolic steroids. Distinct target gene expression profiles due to androgen receptor activation by structurally different androgens has also been reported Holterhus et al. The model used was three structurally different androgen promoter constructs in co-transfected Chinese hamster ovary cells.
All the steroids proved to be potent activators of the androgen receptor, but the anabolic steroids and the testosterone precursors showed characteristic promoter activation profiles distinct from the virilizing androgens. Additionally, DHT cannot undergo further reduction, nor is it a substrate for aromatase; thus, it is not converted to estrogenic metabolites. DHT has been shown to bind avidly to receptors in tissues, such as skin, scalp, and prostate, and to exert times the androgenic effect of testosterone.
Thus, the primary hormone mediating the androgenic effects of testosterone is actually the 5-alpha reduced DHT. At physiologic testosterone levels, nearly all androgen receptors are engaged. Therefore, supraphysiologic doses of testosterone or AASs would have no increased anabolic effect in healthy athletes unless other mechanisms of action existed.
Because there are many agents in production and literally hundreds more that have been synthesized, this discussion focuses on the basics involving the steroid ring substitutions and how these substitutions affect the properties of the drug. Detailed analysis is limited to those agents that are available or have been approved for use in the United States.
Anabolic-androgenic steroid AAS development was centered on the need for agents that exhibited different characteristics than did testosterone. In general, the goal was to develop agents that were more anabolic and less androgenic than testosterone, that were capable of being administered orally, and that had less effect upon the hypothalamic-pituitary-gonadal axis.
Most AASs are derived from 3 compounds: The third compound is structurally identical to testosterone except for the deletion of the 19th carbon hence its name. These parent compounds offer different properties with regard to action and metabolism that are generally constant throughout the entire family of compounds. One of the first changes made to the testosterone molecule was the addition of a methyl group or an ethyl group to the carbon position.
This addition was noted to inhibit the hepatic degradation of the molecule, greatly extending the molecule's half-life and making it active when administered orally. Prior to this, testosterone, dihydrotestosterone, and nortestosterone all required parenteral administration due to hepatic metabolism of ketosteroids; this metabolism occurred on the first pass, when the drugs were administered orally.
However, adding a methyl group or an ethyl group did not produce a drug with the exact properties of the parent compound. The alteration of hepatic metabolism was noted to cause strain on the liver, and indeed all oral compounds with this C addition were found to cause dose-related hepatotoxicity. This small change was also found to lower these agents' interaction with aromatase. Testosterone esters have increasingly been used in replacement therapy, but abuse of these compounds has risen as well.
A feature that all testosterone esters have in common is a testosterone molecule with a carboxylic acid group ester linkage attached to the beta hydroxyl group.
These esters differ in structural shape and size; they function only to determine the rate at which the testosterone is released from tissue. Generally, the shorter the ester chain, the shorter the drug's half-life and quicker the drug enters the circulation.
Once in the circulation, the ester is cleaved, leaving free testosterone. Methyltestosterone is a very basic anabolic-androgenic steroid AAS , with the only addition being a methyl group at C This eliminates first-pass degradation in the liver, making oral dosing possible.
It also causes dose-related hepatotoxicity. Methyltestosterone is metabolized by aromatase to the potent estrogen alpha methyl estradiol and is also reduced by 5AR to alpha methyl dihydrotestosterone. This compound exhibits very strong androgenic and estrogenic side effects and is generally a poor choice for most, if not all, uses. Methandrostenolone has an added cis- 1 to cis- 2 double bond that reduces estrogenic and androgenic properties.
However, it does undergo aromatization to the rather potent estrogen alpha methyl estradiol, but curiously, it does not show the in-vivo propensity for reduction by 5AR to alpha dihydromethandrostenolone to any large degree. This steroid was first commercially manufactured in by Ciba under the brand name Dianabol and quickly became the most used and abused steroid worldwide, remaining so to date. It jokingly came to be known as "the breakfast of champions" in sports circles.
This agent is very anabolic, with a half-life of approximately 4 hours. The methyl group at C makes this AAS an oral preparation and potentially hepatotoxic. Ciba, as well as generic firms in the United States, discontinued methandrostenolone in the late s, but over 15 countries worldwide still produce it in generic form. Fluoxymesterone is a potent androgen that is produced under the brand name Halotestin.
With the addition of a 9-fluoro group, it is a very potent androgen that has little anabolic activity. An added beta hydroxyl group inhibits its aromatization. Again, the C methyl group makes oral administration possible, but with hepatic concerns. Nandrolone decanoate is simply a nortestosterone molecule in which a carbon decanoate ester has been added to the beta hydroxyl group. This addition extends the half-life of the drug considerably.
Nandrolone is a potent anabolic with a relatively favorable safety profile. Nandrolone is reduced by 5AR in target tissues to the less potent androgen dihydronandrolone. Its affinity for aromatization to estrogen is low, being perhaps times less than that of testosterone.
Nandrolone and its several esters decanoate, phenylpropionate differ only in their half-lives, due to the difference in ester properties. Nandrolone is a relatively safe drug with minimal androgenic concerns and ample anabolic action at therapeutic doses. Nandrolone decanoate is an intramuscular IM preparation and lacks the hepatotoxic C group; however, this agent is one of the most widely abused AASs, due to its efficacy, safety profile, and worldwide manufacture.
Ethylestrenol is an oral nortestosterone derivative and was marketed in the United States under the brand name Maxibolin, but it has since been discontinued. This agent differs from nandrolone by the addition of a alpha ethyl group to reduce first-pass metabolism, as well as by the deletion of the 3-keto group.
This latter omission seems to reduce androgen receptor binding. Ethylestrenol is a mild AAS, having very little anabolic or androgenic effect at therapeutic doses. Trenbolone is a derivative of nandrolone with several additions. The addition of a cis- 9 to cis- 10 double bond inhibits aromatization, while a cis- 11 to cis- 12 double bond greatly enhances androgen receptor binding. This drug is androgenically and anabolically potent. It is comparably more androgenic than nandrolone due to its lack of conversion to a weaker androgen by 5AR, as is seen with nandrolone.
Trenbolone is a European drug with a very high abuse record. In the United States, it is used in veterinary preparations as trenbolone acetate; as such, it has found its way into the hands of persons who wish to exploit its androgenic and anabolic potential. The second carbon substitution with oxygen is thought to increase the stability of the 3-keto group and greatly increase its anabolic component. This AAS is very anabolic, with little androgenic effect at a therapeutic dose.
First marketed by Searle, DHT was discontinued in the mids. Due to its mild androgenic properties, oxandrolone is one of the few agents to be routinely abused by female athletes. Athletes, from weightlifters to boxers, use oxandrolone, seeking to increase strength without experiencing additional weight gain. Stanozolol is an active AAS, due to the stability afforded by the 3,2 pyrazole group on the A-ring, which greatly enhances androgen receptor binding.
The C methyl group enhances oral availability. Stanozolol is highly active in androgen- and anabolic-sensitive tissue. It is a weaker androgen than DHT and exerts comparatively less androgenic effect.
It will not aromatize to estrogenic metabolites. Athletes, many in track and field, have abused it. In , Canadian sprinter Ben Johnson was stripped of his Olympic gold medal after testing positive for stanozolol.
This quite potent AAS is a unique agent. Oxymetholone is C methylated and, thus, is an oral agent. The 3-keto stability added by the 2-hydroxymethylene group greatly enhances the drug's anabolic properties. The action of this agent in androgen-sensitive tissues is much like that of DHT and is quite androgenic. Oxymetholone is the only AAS to date to be considered a carcinogen.
Like this entire class, oxymetholone does not aromatize. It is thought to activate estrogen receptors via the 2-hydroxymethylene group, and it can exert many estrogenic side effects. Oxymetholone is marketed in the United States as Anadrol and has been abused the world over by weight lifters and strength athletes for its strong anabolic and pronounced androgenic effects.
The use of anabolic-androgenic steroids AASs to improve performance and acquire more muscular bodies is on the rise worldwide. In the US, it is estimated that between 2. Men use AASs significantly more than women, although use among females is increasing. The global lifetime prevalence for males is 6.
The chronic use of AASs can cause various pathologic alterations, which are related to dose, frequency, and patterns of use. Adverse effects include the hepatic, cardiovascular, reproductive, musculoskeletal, endocrine, renal, immunologic, and hematologic systems, as well as psychological and psychiatric effects. An increase in suicide and violent death has been demonstrated in individuals with a history of long-term AAS use.
In the suicides, AAS-related impulsive behavior characterized by violent rage, mood swings, and propensity to depression was also noted. Most of the adverse effects of anabolic-androgenic steroid AAS use are dose dependent, and some are reversible with cessation of the offending agent or agents. Vital signs, including heart rate and blood pressure, and basic chemistries, such as sodium, potassium, hemoglobin, hematocrit, BUN blood urea nitrogen , creatinine, hepatic, and lipid profiles, must be monitored carefully.
Monitoring these parameters will help the clinician to determine drug choice, treatment dose, and duration, and will help to alert the prescriber to potentially serious adverse effects that necessitate the discontinuation of therapy.
The most common deleterious effects of AAS use on the cardiovascular system include increased heart rate, increased blood pressure, and changes in lipid metabolism, including lowered high-density lipoprotein HDL and increased low-density lipoprotein LDL. The increase in heart rate is thought to be more profound with the androgens, especially those resistant to aromatase, and is believed to be due to the inhibition of monoamine oxidase MAO.
This effect, when combined with the increased renal recovery of ions, such as sodium, causing subsequent fluid retention, can lead to dramatic increases in blood pressure. Combine this with a tendency to lower HDL and raise LDL, and the stage is set for untoward atherogenic and cardiac effects. Anabolic steroid users can have a lower left ventricle ejection fraction. Anabolic steroid abuse has been associated with ventricular arrhythmias.
The changes made to C to inhibit hepatic degradation make nearly all oral preparations hepatotoxic. Levels approaching times baseline are often set as upper limits of reference ranges when administering oral AASs, but the risk-to-benefit ratio must be constantly evaluated.
Iamges: pharmacology of anabolic steroids
Athletes and bodybuilders have recognized for several decades that the use of anabolic steroids can promote muscle growth and strength but it is only relatively recently that these agents are being revisited for clinical purposes. Selective androgen receptor modulators SARMs: In bone, the mechanism of action of the anabolism of androgens has not been entirely elucidated but both a direct effect of testosterone and a mediated effect by aromatization to oestradiol are important Orwoll, ; Zitzmann and Nieschlag,
In vitro metabolism of 7-alpha-methylnortestosterone by rat-liver, prostate, and epididymis.
The influence of 6 months of oral anabolic steroids on body mass and respiratory muscles in undernourished COPD patients. Modulation of the cytosolic androgen receptor in striated-muscle by sex steroids. The endocrine system has a remarkable array of checks and balances that mast prop frequency the human body is at parmacology near homeostasis at any point in time. Dissociation of the androgenic and other hormonal activities from the protein anabolic effects of steroids Handbook of Experimental Pharmacology 43 Springer-Verlag: This unsightly growth is termed gynecomastia and can be treated pharmacology of anabolic steroids or surgically. Knowing this trend, one can reasonably interpolate the half—life of any oil-based steroid given its logP value boldenone appears anomalous in this regard, but the study was performed in horses, so we can't make a direct comparison with human data. As steroies adjunct, other chaperones, called Hsp40 and Hsp70 and pharmacology of anabolic steroids organizing protein called Hop heat-shock organizing protein are important in the assembly of the steroid receptor—Hsp90 o.
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