Review 14 February 2021, and 1 Department of Food Science, Faculty of Agrobiology, Food, and Natural Resources, Czech University of Life Sciences Prague, Kamýcká 129, 165 00 Prague-Suchdol, Czech Republic 2 Department of Chemistry of Natural Compounds, University of Chemistry and Technology Prague, Technická 5, Prague 6, 166 28 Prague, Czech Republic 3 Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technická 5, Prague 6, 166 28 Prague, Czech Republic * Author to whom correspondence should be addressed.
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 AAS misuse. 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.
Graphical Abstract
Testosterone (T) derivatives and their (semi-)synthetic analogues (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 as 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 one symptom. 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 analogues, 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 centres.
This review principally aims to summarize particular examples of T analogues 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.
Medicinal application, routes of administration, and available forms of compounds discussed in this review are summarized in Table 1.
Medicinal use, usual routes of administration, and available forms of compounds discussed in this review.
Androgens generally consist of a C 19 androstane skeleton without a side chain and they have Δ 4-3-keto and 17β-hydroxyl functional groups. The primary natural androgen is T (Figure 1 and Figure 2).
Scheme of testosterone biosynthesis.
Microbial production of testosterone (A) and stereoselective introduction of alkyl (methyl) group to C 17 position (B).
T is synthesized de novo from cholesterol via several enzymatic transformations where dehydroepiandrosterone (DHEA) 1, androstenediol 2, and androstenedione 3 play a key role (Figure 1). T may be subject to further structural changes leading to the production of dihydrotestosterone 4 or estradiol (Figure 1). T can be produced pharmaceutically from androstenolone (5, Figure 2) by the reduction of 17-carbonyl and oxidation of the 3-hydroxyl with the use of necessary protecting groups. This structural conversion is attained by the use of yeasts, which first oxidize the 3-hydroxyl under aerobic conditions, then reduce the 17-keto group under anaerobic conditions (Figure 2A). Androstenolone may be obtained from plant-derived steroids, such as diosgenin from Dioscorea species (Dioscoreaceae), Trigonella foenum-graecum (Fabaceae), and solasodine or tomatidine from various Solanum and Lycopersicon species (Solanaceae) by marker degradation and side-chain removal. Additionally, 5 can be further synthetically modified by alkylation at the C-17 position and successive oxidation resulting in potent anabolics 17α-methyltestosterone 6 or methandienone 7 (Figure 2B).
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 Δ 4 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 oestrogenic activity and shows only slight hepatotoxicity. The introduction of a methyl group in position 1α leads to an 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].
Some of the synthetic testosterone analogues (synthetic anabolic steroids).
All of the aforementioned derivatives have an androgenic to the 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 introduction of a double bond between the C 1 and C 2 (e.g., metandienone, turinabol), between the C 9 and C 10 and the C 11 and C 12 positions (e.g., trenbolone, metribolone, tetrahydrogestrinone), introduction of a substituent such as a hydroxyl group or chlorine atom at the C 4 position (e.g., turinabol), substitutions at the C 2 or C 2 α position such as methyl (e.g., drostanolone), hydroxymethylene (e.g., oxymetholone), or a fused ring (e.g., stanozolol), and removal of the C 19 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 oedema 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 C 2 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 c
