Medicinal Use of T and Related Steroids

[madman]

Abstract: Testosterone derivatives and related compounds (such as anabolic-androgenic steroids— AAS) are frequently misused by athletes (both professional and amateur) wishing to promote muscle development and strength or to cover AASmisuse. Even though these agents are vastly regarded as abusive material, they have important pharmacological activities that cannot be easily replaced by other drugs and have therapeutic potential in a range of conditions (e.g., wasting syndromes, severe burns, muscle, and bone injuries, anemia, hereditary angioedema). Testosterone and related steroids have been in some countries treated as controlled substances, which may affect the availability of these agents for patients who need them for therapeutic reasons in a given country. Although these agents are currently regarded as rather older generation drugs and their use may lead to serious side-effects, they still have medicinal value as androgenic, anabolic, and even anti-androgenic agents. This review summarizes and revisits the medicinal use of compounds based on the structure and biological activity of testosterone, with examples of specific compounds. Additionally, some of the newer androgenic-anabolic compounds are discussed such as selective androgen receptor modulators, the efficacy/adverse-effect profiles of which have not been sufficiently established and which may pose a greater risk than conventional androgenic-anabolic agents.




1. Introduction

Testosterone (T) derivatives and their (semi-)synthetic analogs (so-called androgenic anabolic steroids—AAS) have been controversial for already quite some time. These substances have become the subject of abuse by professional athletes, and currently also by a significant number of amateur athletes, to enhance performance (i.e., performance-enhancing drugs) and body aesthetics. However, T and many AAS have valuable and often irreplaceable pharmacological activities that are medicinally useful, though these compounds are currently regarded as rather older generation drugs.

T and related compounds primarily act like androgens, promoting the development and maintenance of male sex characteristics such as maturation of the sex organs, voice deepening, and growth of facial and body hair. They also have an anabolic activity that promotes the storage of protein and stimulates the growth of bone and muscles, and these functions are especially important from a medicinal standpoint [1]. Indeed, tremendous efforts have been put into developing agents with increased anabolic activity such as the recently discovered selective androgen receptors modulators (SARMs). However, there is still no single anabolic molecule from which the androgenic activity has been fully eliminated. T and other AAS still find their use in the treatment of a wide range of human diseases, including hypogonadism, male sexual impotence, and some types of breast cancer in women. They are also of value in various types of wasting syndromes, for example in patients suffering from acquired immune deficiency syndrome (AIDS) anorexia, or alcoholism, and for those with severe burns, muscle, tendon or bone injury, osteoporosis, certain types of anemias, and hereditary angioedema [2]. T has also recently been discussed in connection with longevity. As a person ages, their physiological levels of T decrease. The T decline has been associated with aging symptoms such as hypertension, obesity, diabetes, overall fatigue, depression, and cognitive decline [2,3]. The current trend in some countries is to use T with its pleiotropic effects to combat several age-related changes, rather than a combination of drugs each treating onesymptom. Supplementation with T or related compounds, however, may cause serious adverse effects, including skin disorders, hepatotoxicity (especially true for the orally-active T derivatives), altered blood lipid profiles, hypertension, cardiovascular conditions, kidney disorders, behavioral changes, and reproduction disorders [4]. Regardless of their safety and side-effect profile, T and its analogs, at the correct formulation and dose for the appropriate condition, may still offer several beneficial pharmacological responses and may be considered very valuable pharmaceutical agents.

One of the biggest current problems associated with AAS is that there has been an increasing number of recent reports of AAS abuse by non-professional athletes, mostly young people seeking to improve performance, build muscle and stamina, and have a great-looking body [5,6]. Apart from the aforementioned side effects, AAS use may lead to withdrawal symptoms after these drugs have been discontinued.These symptoms are very similar to those observed in subjects with age-related T decline, including increased fat storage, loss of muscle mass and bone strength, mood swings, irritability, extreme fatigue, restlessness, and depression. Thus, for many users, the only way to overcome these symptoms is to start taking AAS again, and ultimately, they become addicted to these drugs (however, it is a relatively special type of addiction that is different from other drugs). As there are some indications that the abuse of AAS by amateur athletes is increasing, this may pose a challenge to the health care system and addiction centers.

This review principally aims to summarize particular examples of T analogs and other androgens, including established anabolic steroids, newly introduced SARMs, T- and nandrolone-prohormones, formulations containing steroids intended to raise endogenous T levels (so-called T boosters), and drugs that act as antiandrogens based on T structure and revisits their role as therapeutic drugs. The information summarized in this review was obtained through an extensive review of the literature by searching for relevant books and articles with the Web of Knowledge, SciVerse Scopus, and PubMed databases.




2. Available Testosterone Analogues
2.1. Analogues of Testosterone with Agonistic Activity
2.2 Selective Androgen Receptor Modulators (SARMs)
2.3. Testosterone and Nandrolone Prodrugs (Prohormones)
2.4. Testosterone Boosters
2.5 Antiandrogens




5. Conclusion

T derivatives and many of its related analogs (AAS) have been primarily developed for medicinal use to treat various conditions (e.g., wasting syndromes associated with AIDS, anorexia, alcoholism, severe burns, muscle, tendon, and bone injuries, various types of anemias, and as a prophylaxis to hereditary angioedema). In due course, these drugs have been misused by athletes wishing to promote muscle development and strength and this phenomenon currently appears to be becoming considerably more frequent, especially in amateur athletes. Despite their abuse potential, these drugs are in some countries nonuniformly treated as controlled substances, while legal in others. Their legal status has also an impact on the availability of these drugs for medicinal use. Even though these agents are regarded as rather older generation drugs, and their efficacy/side-effects ratio may be in some cases viewed as disputable, they display valuable and often irreplaceable pharmacological properties, which makes them still medicinally useful. With the right type, dose, and appropriate regimen, AAS can be of value in the treatment of a relatively wide range of diseases and injuries where other drugs fail to provide the necessary therapeutic benefit. We should be especially careful with the more recent anabolic. Some SARMs are showing promising results in clinical trials, however, as of yet, they have not advanced into clinical use. Despite this, some SARMs are already appearing on the black market. T and the common steroidal anabolics have been used for more than fifty years, and we at least know what to expect from them. The new anabolics such as the SARMs could lead to unexpected and perhaps very dangerous side effects.

 

[madman]

Table 1. Medicinal use, usual routes of administration, and available forms of compounds discussed in this review

 

[madman]

Figure 1. Scheme of testosterone biosynthesis.

 

[madman]

Figure 2. Microbial production of testosterone (A) and stereoselective introduction of alkyl (methyl) group to C17 position (B).

 

[madman]

Figure 3. Some of the synthetic testosterone analogs (synthetic anabolic steroids).

 

[madman]

Figure 4. Nandrolone-based analogs with a strong pro-estrogenic effect.

 

[madman]

Figure 5. Experimental anabolic-androgenic steroids.

 

[madman]

Figure 6. Designer drugs based on testosterone structure/functionalities.

 

[madman]

Figure 7. Some of the selective androgen receptor modulators in clinical or pre-clinical development.

 

[madman]

Figure 8. Selective androgen receptor modulators that have been eliminated from further research.

 

[madman]

Figure 9. Testosterone prodrugs (prohormones)

 

[madman]

Figure 10. Plant-based steroids that are part of products marketed as testosterone boosters I.

 

[madman]

Figure 10. Plant-based steroids that are part of products marketed as testosterone boosters II.

 

[madman]

Figure 12. Molecular structures of anti-androgens.

 

[madman]

T is not orally active as it readily undergoes hepatic metabolism (though there are some oral forms, such as undecanoate ester; attachment of a very-long-chain ester at 17β position increases oral activity). The usual mode of administration includes injections or subcutaneous implants of its ester forms. Dermal patches are available and this is the method of choice for the treatment of hypogonadism [1,7]. T is also available in other therapeutic modalities, including topical hydroalcoholic gels [8], buccal [9], sublingual [10], and intranasal formulations [11].

Another compound that finds use in the management of low T levels is dihydrotestosterone (DHT, androstanolone; 4, Figure 1). It is available as injections or dermal gels. Enormous efforts have been made to produce an orally active form of T, and one successful candidate is the undecanoate ester of T [12].

Methyltestosterone (6, Figure 2) is an orally active agent that is used for hypogonadism, erectile dysfunction, suppression of menopausal symptoms (hot flashes, osteoporosis, low libido), and in the treatment of breast cancer [13,14]. Mesterolone (8, Figure 3) has a 1α-methyl group and a reduced Δ4 double bond and is also orally active. Its androgenic activity is slightly higher than the anabolic effect, and it is of value for increasing low T levels, but it is hardly ever prescribed now [15,16]. Mesterolone has very low to no estrogenic activity and shows only slight hepatotoxicity. The introduction of a methyl group in position 1α leads to increased oral activity. Oral activity may also be achieved by the introduction of the 17α-alkyl group (as seen in methyltestosterone). This modification leads to reduced metabolism in the liver and increased bioavailability, but hepatotoxicity is also increased [17,18].Methandriol (9, Figure 3) is available in both oral and injectable forms as dipropionate, propionate, and bisenanthoyl acetate esters. It has almost exclusively been used in the treatment of breast cancer in women [19,20].

All of the aforementioned derivatives have an androgenic to an anabolic activity ratio of about one to one. There have been attempts to produce steroids with low androgenic but high anabolic activity, but every anabolic steroid retains some androgenic activity. Anabolic activity may be increased by several chemical modifications, including the introduction of a double bond between the C1 and C2 (e.g., metandienone, turinabol), between the C9 and C10 and the C11 and C12 positions (e.g., trenbolone, metribolone, tetrahydrogestrinone), the introduction of a substituent such as a hydroxyl group or chlorine atom at the C4 position (e.g., turinabol), substitutions at the C2 or C2α position such as methyl (e.g., drostanolone), hydroxymethylene (e.g., oxymetholone), or a fused ring (e.g., stanozolol), and removal of the C19 methyl group (e.g., nandrolone, trenbolone, norethandrolone, ethylestrenol). Some of the agents with increased anabolic effects are described below.

Metandienone (dianabol®; 7, Figure 2) is hardly ever used now in clinical practice [21]. It is available in both oral and injectable forms. Metandienone is a strong agonist for oestrogen receptors and can cause gynecomastia and fluid retention [22]. Many users are thus forced to take selective oestrogen receptor modulators (SERMs or SORMs), such as tamoxifen, to combat these side-effects [4]. Other side-effects include mental disorders, increased aggressiveness, and hepatotoxicity.

Fluoxymesterone (halotestin; 10, Figure 3) is a 17α-methyl-9α-fluoro-11β-hydroxy derivative. It is used in the treatment of hypogonadism, delayed puberty [23], female breast cancer [24], and anemia [25]. It can cause edema because of sodium and water retention, presumably through inhibition of corticosteroid 11β-hydroxysteroid dehydrogenase enzymes [26]. It is still widely abused to improve strength and performance.

Drostanolone (11, Figure 3) is another agent that has been removed from medicinal use, although it was of value in certain types of breast cancer [27].

Metenolone (12, Figure 3) has been used in the form of acetate and enanthate esters, the former being orally active, while the latter is given by injection. Both esters have been mainly used in the treatment of anemia caused by bone marrow failure [28]. Metenolone has weak androgenic and oestrogenic activity and low hepatotoxicity and has been discontinued for medicinal use in many countries.

Oxandrolone (13, Figure 3) has a replaced carbon atom at the C2 position with an oxygen atom, which leads to reduced hepatotoxicity. It has the advantage of being primarily metabolized by the kidneys and not by the liver. It is especially useful for treating cases of severe weight loss and diseases that cause muscle wasting such as AIDS wasting syndrome, corticosteroid-induced protein catabolism, and alcoholic hepatitis [29], but also finds use in anemia, hereditary angioedema [30], severe burns, osteoporosis [31], hypogonadism, and Turner’s syndrome [32]. One of the most common side effects is a decrease in high-density lipoprotein (HDL). Oxandrolone has a high anabolic to androgenic activity ratio, which makes it especially suitable for use in women. It has low androgenic activity and relatively low hepatotoxicity.

Oxymetholone (14, Figure 3) has a strong anabolic effect and is especially of value in treating anemia. It is also used in osteoporosis [33], AIDS wasting syndrome [34], and other conditions, in which muscle growth and weight gain are needed. The most common side effect is hepatoxicity [35]. When oxymetholone is treated with hydrazine, it forms a pyrazole ring fused to a saturated A ring. An example of such a compound is stanozolol [1].

Stanozolol (15, Figure 3) has been used in the treatment of osteoporosis [36] and is currently being evaluated as a treatment for hereditary angioedema [37,38]. Unlike other anabolic steroids, it is not available in esterified form but as an aqueous solution or tablet. The use of this drug in humans was discontinued in many countries, but it is still widely used in veterinary medicine for the same conditions as in humans.

Boldenone (16, Figure 3) is a natural derivative of T, also known as Δ1-testosterone. It is available as a undecylenate ester and is exclusively used in veterinary medicine [16,39]. Among other activities, it increases appetite and also stimulates the release of erythropoietin. Boldenone has relatively low hepatotoxicity, androgenic potency and does not interact with receptors for progesterone.

Turinabol (chlorodehydromethyltestosterone; 17, Figure 3) is a 4-chloro derivative of metandienone. It was developed for the treatment of wasting diseases, especially for patients losing bone strength and mass [40].

In the course of synthesizing T analogs, compounds with the methyl group removed from position C19 were obtained and these displayed considerable progestogen activities.

Nandrolone (19-nortestosterone; 18, Figure 4) is available as decanoate and phenylpropionate esters, but these are not orally active and must be administered via subcutaneous or intramuscular injection. They are used in the treatment of anemia, severe burns, wasting syndrome in patients suffering from AIDS [41], osteoporosis [42], or breast cancer [39,43]. It is also available in the form of eye drops as nandrolone sulfate [44].

Ethylestrenol (19, Figure 4) lacks the 3-keto group. It was used for muscle promotion and weight gain, in treatment of bone pain and osteoporosis, as an adjunct therapy for corticosteroid-induced wasting and severe injuries, arthritis, aplastic anemia and anemia of chronic kidney disease [45,46,47], conditions of arteries and veins (e.g., thrombosis, Behçet’s disease, Raynaud’s disease, Degos disease) [48,49,50], and short stature in youths [51]. It is no longer used medicinally but is still available for veterinary use.

Norethandrolone (20, Figure 4) has similar properties and is also used to treat muscle wasting [52], severe burns [53], and aplastic anemia [54]. Its medicinal use has largely been discontinued, though it is still used in some countries [53].

Trenbolone (21, Figure 4) has been marketed as a variety of esters, many of which are no longer used in veterinary or medicinal practice. Trenbolone acetate is still used in animals to stimulate muscle growth and appetite [55]. Perhaps the most common trenbolone ester for human use was hexahydrobenzylcarbonate, but this is no longer prescribed. A harmless, but potentially worrying adverse effect of trenbolone is an orange coloration of body fluids, including urine, because of the presence of a strong chromophore group. Another very specific side effect is the so-called trenbolone cough (particularly prevalent in trenbolone acetate), a phenomenon whose mechanism has not yet been satisfactorily explained, and is believed to be related to the interaction with prostaglandin receptors. Among other relatively common side-effects of trenbolone use are erectile dysfunction, reduced sex drive, night sweats, insomnia, increased aggressivity, anxiety, and cardiovascular problems [56].

 

[JoeJ0eyJoeJoe]

This reply may be too lay for this discussion, but the information you published strikes my interest: I have a good friend who has been through a colectomy and a 2-month-long ICU stay at the end of 2019, resulting in whole-body muscle atrophy. He's been struggling with recovery and physical therapy for more than a year with only moderate progress (still in a wheelchair most of the time, struggles even with eating due to poor muscle tone). I suspect his bone density is suffering as well due to the inability to be active and perform any substantial load-bearing exercise.

It seems clear and evident to me that this would be a case where anabolic steroids would serve to help get him back on track before it's too late. It seems they would hasten the recovery. And to me it would seem to have a cumulative effect: build up the muscle, then he's able to do more movement/exercise, bone strength would increase as a result, along with cardiovascular endurance, mental clarity and mood.

I've discussed this with him, and he discussed it with his doctor, who prescribed T injections for a short period (totally wrong protocol in my lay opinion ... every-other-week injections, minimal TRT dosage vs. something that might simulate muscle growth. I suspect his doctor has near zero experience with these types of meds, and based on what I've read above, it's not a trivial task to comprehend.).

Unfortunately, my friend is not assertive, and even less so in his current state of mind, so he doesn't seem to have the drive to push this topic further. And, he doesn't have discretionary income to fund treatment outside of what insurance provides. Very sad to observe this.