madman
Super Moderator
The real epidemiology and the possible consequences of anabolic-androgenic steroids (AAS) use still represent a very tricky task due to the difficulties in the quantification and detection of these drugs. Chronic use of AAS, frequently combined with other illicit substances, can induce tremendous negative effects on the reproductive system, but it is also associated with an increased overall and cardiovascular mortality risk. In the present review, we summarize and discuss the available evidence regarding the negative impact of AAS on the male reproductive system, providing practical suggestions to manage these problems. For this purpose, a meta-analysis evaluating the effects of AAS abusers vs. controls on several hormonal, reproductive and metabolic parameters was performed. In addition, in order to overcome possible limitations related to the combined use of different AAS preparations, we also retrospectively re-analyzed data on animal models treated with a supraphysiological dosage of testosterone (T), performed in our laboratory. Available data clearly indicated that AAS negatively affects endogenous T production. In addition, increased T and estradiol circulating levels were also observed according to the type of preparations used. The latter leads to an impairment of sperm production and to the development of side effects such as acne, hair loss, and gynecomastia. Furthermore, a worse metabolic profile, characterized by reduced high-density lipoprotein and increased low-density lipoprotein cholesterol levels along with an increased risk of hypertension has been also detected. Finally sexual dysfunctions, often observed upon doping, represent one of the most probable unfavorable effects of AAS abuse.
INTRODUCTION
Anabolic-androgenic steroids (AAS) represent a group of heterogeneous compounds, which include testosterone (T) and its derivate substances, largely used to enhance physical performance, sense of well-being, and cosmetic appearance among athletes [1-4]. Some years after T isolation and synthesis in 1935 [5], Bøje [6] had already discussed the possible use of sex steroids in athletes. Alleged information suggests that the Germans gave AAS to soldiers during World War II and to athletes in preparation for the 1936 Berlin Olympic Games [4]. The first documented use of AAS in an athletic competition dates back to a Russian team at the weightlifting championship during the 1954 Vienna Olympic Games [4]. From strength-intensive sports, the use of AAS gradually spread to other disciplines and to non-professional competitions. In 1990, the possibility of having open access to classified documents, after the fall of the Communist government in the German Democratic Republic, allowed for the discovery of a secret State program to improve national athletes’ performance using AAS during the 1970s and 1980s [4]. Similarly, more recently, the Russian track and field team was banned from the 2016 Olympic Games due to suspicions about a State program supporting the use of illicit drugs among their athletes [3]. The epidemiology of AAS use, either in professional athletes or in the general population is a difficult task due to reluctance to declare openly the consumption and the introduction of chemical modifications in order to reduce the detection of AAS [3,4]. For the first time in 1975, the International Olympic Committee created a list of banned illicit substances including stimulants and narcotics, which, since 2004, are nowadays under the responsibility of the World Anti-Doping Agency (WADA) [3,4].
Official data resulting from Olympic-level athletes, tested between 1987 and 2013, indicated a prevalence of positive tests, ranging from 0.96% to 2.45% [7]. However, WADA data showed that, of elite professional athletes, from 44% up to 70% have declared past use of illicit drugs, although only less than 1% of those tested were caught [7]. The figure is even more impressive considering that more than 75% of AAS users are noncompetitive athletes [1-4]. A meta-analysis, including 187 studies and providing data from 271-lifetime prevalence rates indicated a global rate of AAS use of 3.3%, being four times higher in males than in females (6.4% vs. 1.6%) [1]. In addition, data derived from ten studies, investigating AAS dependence, concluded that 32.5% of AAS users developed, at some time, a drug dependence [4]. Applying these data to the US population, the prevalence of AAS users is similar to that observed for other diseases such as Human Immunodeficiency Virus infection or type 1 diabetes [4].
Due to their influence on the hypothalamus-pituitary testis axis, the chronic use of AAS could have a tremendous impact on endogenous T production, fertility, and general well-being. In addition, the combination with the abuse of other substances such as opiates, other anabolic drugs (human chorionic gonadotropin hormone [hCG], growth hormone [GH], insulin) can have even more deleterious effects not only on the reproductive system but also increasing overall and cardiovascular (CV) mortality risk [1-4]. A previous meta-analysis, including 11 studies and less than 100 abusers, has documented that the use of AAS resulted in a rapid reduction in gonadotropins and T levels, which gradually return to the baseline within 13–24 weeks [8]. No data on comparisons between AAS-abusers and non-abuser athletes were reported.
*The aim of the present study is to summarize and critically discuss the available evidence regarding the impact of AAS on the male reproductive system providing practical suggestions to manage these problems. A meta-analysis including those studies comparing the effects of AAS vs. controls on reproductive systems will be also provided.
CONCLUSIONS
T often considered the hormone for youthful vigor and sexual potency could be indeed venom for fertility and sexuality if abused. The animal models here described demonstrated that the decrease in gonadotrophins and testis volume, as well as in alterations in sperm parameters, i.e., sperm concentration and normal morphology, are genuine effects of supraphysiological dosing of androgens [57-61]. In contrast, a supraphysiological dose of T in animal studies resulted in a modest or null effect on erection, in contrast to that observed in some, but not all clinical studies (Fig. 1 and Supplement Fig. 2G). It should be recognized that changes in sexuality are not a primary endpoint in such clinical studies and that, quite often, androgens are not the only substance abused. This might justify the negative effect of androgen abuse recorded in the present meta-analysis. In fact, in clinical trials, where a standardized dose of T was administered to otherwise eugonadal subjects or in mixed populations, libido increased and did not decrease [43-46] with a null effect on erections. In our animal models, modifications in sexual desire were not investigated and, therefore, final conclusions cannot be drawn. Clinical studies, here scrutinized and summarized in a meta-analysis, indicated that AAS was associated with an unfavorable lipid profile and with an increase in blood pressure. All these conditions might be associated with a decreased blood flow within cavernous arteries, finally leading to erectile dysfunction. We did not observe such changes in the rabbit model, where all the animals were maintained in a standardized condition and fed a regular diet. Hence, it is possible that the adverse modifications in lipid metabolism and in the blood pressure observed in clinical trials were most probably due to abuse of other doping substances or to an unhealthy lifestyle.
Nonetheless, as universally observed in all meta-analyses involving TRT in hypogonadal individuals [49,50], we here report a parallel decrease in fat mass and an increase in lean mass induced by AAS. Accordingly, histomorphological analysis of rabbit vastus medialis sections indicates a T-induced increase in muscle fiber diameter with an exercise-associated additive effect.
Results on sperm parameters were clearly concordant between pre-clinical and clinical observations. Chronic exposure to androgens not only resulted in a reduced testis size but also in a reduction of sperm number and normal morphology, supporting fertility problems in androgen abusers.
Finally, due to the activation of androgenic and/or estrogenic signaling, AAS was significantly associated with in one-way acne and baldness and, in the other one, with gynecomastia, respectively. Some, but not all, of these conditions can be reversed by AAS withdrawal. To restore testicular function after doping, direct (hCG) or indirect (antiestrogen) stimulators of endogenous T synthesis have been suggested, but clear evidence of their efficacy over a natural course is scanty.
In conclusion, illicit use of supraphysiological doses of androgens for non-medical purposes, including increasing muscular performances, is associated with several androgen-dependent consequences, such as acne, gynecomastia, and baldness. In addition, due to the well-known negative feedback on the HPT axis, it is associated with a fall in gonadotrophin levels and a reduction in testis size and sperm production. In fact, T is the cornerstone for all male contraceptive preparation. Sexual dysfunctions often observed upon doping with androgens are most probably related to the unfavorable effect of AAS on blood pressure and lipid profile recorded in clinical studies and most probably related to the concomitant abuse of other substances or to an unhealthy lifestyle.
INTRODUCTION
Anabolic-androgenic steroids (AAS) represent a group of heterogeneous compounds, which include testosterone (T) and its derivate substances, largely used to enhance physical performance, sense of well-being, and cosmetic appearance among athletes [1-4]. Some years after T isolation and synthesis in 1935 [5], Bøje [6] had already discussed the possible use of sex steroids in athletes. Alleged information suggests that the Germans gave AAS to soldiers during World War II and to athletes in preparation for the 1936 Berlin Olympic Games [4]. The first documented use of AAS in an athletic competition dates back to a Russian team at the weightlifting championship during the 1954 Vienna Olympic Games [4]. From strength-intensive sports, the use of AAS gradually spread to other disciplines and to non-professional competitions. In 1990, the possibility of having open access to classified documents, after the fall of the Communist government in the German Democratic Republic, allowed for the discovery of a secret State program to improve national athletes’ performance using AAS during the 1970s and 1980s [4]. Similarly, more recently, the Russian track and field team was banned from the 2016 Olympic Games due to suspicions about a State program supporting the use of illicit drugs among their athletes [3]. The epidemiology of AAS use, either in professional athletes or in the general population is a difficult task due to reluctance to declare openly the consumption and the introduction of chemical modifications in order to reduce the detection of AAS [3,4]. For the first time in 1975, the International Olympic Committee created a list of banned illicit substances including stimulants and narcotics, which, since 2004, are nowadays under the responsibility of the World Anti-Doping Agency (WADA) [3,4].
Official data resulting from Olympic-level athletes, tested between 1987 and 2013, indicated a prevalence of positive tests, ranging from 0.96% to 2.45% [7]. However, WADA data showed that, of elite professional athletes, from 44% up to 70% have declared past use of illicit drugs, although only less than 1% of those tested were caught [7]. The figure is even more impressive considering that more than 75% of AAS users are noncompetitive athletes [1-4]. A meta-analysis, including 187 studies and providing data from 271-lifetime prevalence rates indicated a global rate of AAS use of 3.3%, being four times higher in males than in females (6.4% vs. 1.6%) [1]. In addition, data derived from ten studies, investigating AAS dependence, concluded that 32.5% of AAS users developed, at some time, a drug dependence [4]. Applying these data to the US population, the prevalence of AAS users is similar to that observed for other diseases such as Human Immunodeficiency Virus infection or type 1 diabetes [4].
Due to their influence on the hypothalamus-pituitary testis axis, the chronic use of AAS could have a tremendous impact on endogenous T production, fertility, and general well-being. In addition, the combination with the abuse of other substances such as opiates, other anabolic drugs (human chorionic gonadotropin hormone [hCG], growth hormone [GH], insulin) can have even more deleterious effects not only on the reproductive system but also increasing overall and cardiovascular (CV) mortality risk [1-4]. A previous meta-analysis, including 11 studies and less than 100 abusers, has documented that the use of AAS resulted in a rapid reduction in gonadotropins and T levels, which gradually return to the baseline within 13–24 weeks [8]. No data on comparisons between AAS-abusers and non-abuser athletes were reported.
*The aim of the present study is to summarize and critically discuss the available evidence regarding the impact of AAS on the male reproductive system providing practical suggestions to manage these problems. A meta-analysis including those studies comparing the effects of AAS vs. controls on reproductive systems will be also provided.
CONCLUSIONS
T often considered the hormone for youthful vigor and sexual potency could be indeed venom for fertility and sexuality if abused. The animal models here described demonstrated that the decrease in gonadotrophins and testis volume, as well as in alterations in sperm parameters, i.e., sperm concentration and normal morphology, are genuine effects of supraphysiological dosing of androgens [57-61]. In contrast, a supraphysiological dose of T in animal studies resulted in a modest or null effect on erection, in contrast to that observed in some, but not all clinical studies (Fig. 1 and Supplement Fig. 2G). It should be recognized that changes in sexuality are not a primary endpoint in such clinical studies and that, quite often, androgens are not the only substance abused. This might justify the negative effect of androgen abuse recorded in the present meta-analysis. In fact, in clinical trials, where a standardized dose of T was administered to otherwise eugonadal subjects or in mixed populations, libido increased and did not decrease [43-46] with a null effect on erections. In our animal models, modifications in sexual desire were not investigated and, therefore, final conclusions cannot be drawn. Clinical studies, here scrutinized and summarized in a meta-analysis, indicated that AAS was associated with an unfavorable lipid profile and with an increase in blood pressure. All these conditions might be associated with a decreased blood flow within cavernous arteries, finally leading to erectile dysfunction. We did not observe such changes in the rabbit model, where all the animals were maintained in a standardized condition and fed a regular diet. Hence, it is possible that the adverse modifications in lipid metabolism and in the blood pressure observed in clinical trials were most probably due to abuse of other doping substances or to an unhealthy lifestyle.
Nonetheless, as universally observed in all meta-analyses involving TRT in hypogonadal individuals [49,50], we here report a parallel decrease in fat mass and an increase in lean mass induced by AAS. Accordingly, histomorphological analysis of rabbit vastus medialis sections indicates a T-induced increase in muscle fiber diameter with an exercise-associated additive effect.
Results on sperm parameters were clearly concordant between pre-clinical and clinical observations. Chronic exposure to androgens not only resulted in a reduced testis size but also in a reduction of sperm number and normal morphology, supporting fertility problems in androgen abusers.
Finally, due to the activation of androgenic and/or estrogenic signaling, AAS was significantly associated with in one-way acne and baldness and, in the other one, with gynecomastia, respectively. Some, but not all, of these conditions can be reversed by AAS withdrawal. To restore testicular function after doping, direct (hCG) or indirect (antiestrogen) stimulators of endogenous T synthesis have been suggested, but clear evidence of their efficacy over a natural course is scanty.
In conclusion, illicit use of supraphysiological doses of androgens for non-medical purposes, including increasing muscular performances, is associated with several androgen-dependent consequences, such as acne, gynecomastia, and baldness. In addition, due to the well-known negative feedback on the HPT axis, it is associated with a fall in gonadotrophin levels and a reduction in testis size and sperm production. In fact, T is the cornerstone for all male contraceptive preparation. Sexual dysfunctions often observed upon doping with androgens are most probably related to the unfavorable effect of AAS on blood pressure and lipid profile recorded in clinical studies and most probably related to the concomitant abuse of other substances or to an unhealthy lifestyle.
