madman
Super Moderator
Anabolic androgenic steroid-induced liver injury: An update (2022)
Ana Petrovic, Sonja Vukadin, Renata Sikora, Kristina Bojanic, Robert Smolic, Davor Plavec, George Y Wu, Martina Smolic
Abstract
Anabolic androgenic steroids (AASs) are a group of molecules including endogenous testosterone and synthetic derivatives that have both androgenic and anabolic effects. These properties make them therapeutically beneficial in medical conditions such as hypogonadism. However, they are commonly bought illegally and misused for their anabolic, skeletal muscle-building, and performance-enhancing effects. Supraphysiologic and long-term use of AASs affect all organs, leading to cardiovascular, neurological, endocrine, gastrointestinal, renal, and hematologic disorders. Hepatotoxicity is one of the major concerns regarding AASs treatment and abuse. Testosterone and its derivatives have been most often shown to induce a specific form of cholestasis, peliosis hepatis, and hepatic benign and malignant tumors. It is currently believed that mechanisms of pathogenesis of these disorders include disturbance of antioxidative factors, upregulation of bile acid synthesis, and induction of hepatocyte hyperplasia. Most toxicity cases are treated with supportive measures and liver function normalizes with discontinuation of AAS. However, some long-term consequences are irreversible. AAS-induced liver injury should be taken into consideration in patients with liver disorders, especially with the increasing unintentional ingestion of supplements containing AAS. In this paper, we review the most current knowledge about AAS-associated adverse effects on the liver, and their clinical presentations, prevalence, and pathophysiological mechanisms.
INTRODUCTION
Anabolic androgenic steroids (AASs) are a group of compounds that include endogenous androgens, most importantly testosterone, and their synthetic derivatives[1]. Testosterone and synthetic AASs have been commonly used for their androgenic masculinizing effects resulting in male secondary characteristics, as well as anabolic skeletal muscle building effects due to enhanced protein utilization and synthesis mechanisms[2,3]. AASs are medically indicated in conditions such as male primary and secondary hypogonadism, aplastic anemia, muscle wasting in human immunodeficiency virus-infected patients, osteoporosis, libido dysfunction, chronic kidney disease, and breast cancer[4]. However, they are often misused because of their performance-enhancing and anabolic effects resulting in increased fat-free mass and improved muscle fiber size and strength. Abuse of AASs for aesthetic purposes and athletic performance improvement has surged as a public health problem in the past few decades among both professional and recreational athletes and bodybuilders[5,6]. Unmodified testosterone is rapidly metabolized when administered orally or parenterally and exerts a similar proportion of anabolic and androgenic effects. Chemical modifications of testosterone allow prolonged effective blood concentrations and changes to its pharmacodynamic properties, therefore enhancing desired anabolic or androgenic effects. In its synthetic derivatives used for aesthetic and performance-enhancing purposes, testosterone is altered mainly through alkylation and esterification to enhance bioavailability by reducing hepatic metabolism, prolonging the duration of action, and maximizing anabolic properties, though all of the synthetic compounds still exert significant androgenic effects. Supraphysiologic doses and prolonged unsupervised use of AASs have major impacts on users, affecting all organs and causing cardiovascular, neuroendocrine, neuropsychiatric, renal, gastrointestinal, musculoskeletal, dermatologic, immune, and hematologic disorders. Testosterone has a major impact on the homeostasis of electrolytes, macromolecules, and micromolecules, including alterations in systemic iron balance and erythropoiesis. It has been established that AAS-induced erythropoiesis is mediated by erythropoietin [7]. Most recent studies also imply suppression of hepcidin (a negative regulator of the iron transporter ferroportin) as a mechanism of androgen-induced enhanced iron absorption and incorporation into red blood cells[8]. Some of the most common adverse effects related to AASs are dyslipidemia, hypertension, hypogonadism and infertility, aggression and mood disorders, addiction, and liver and kidney injury[9-11]. This has led to stricter laws regarding the availability of AASs, mainly in professional sports organizations which ban anabolic steroid use, and test competitors for the presence of illegal steroids not only because of their unfair advantage in performance but also because of their potentially dangerous side effects. In legal terms, AASs have been classified in the United States as schedule 3 drugs by the Drug Enforcement Agency, meaning that they can be legally obtained as prescription-only drugs. However, they are illegally sold among teammates, trainers, and fitness centers, through the black market or counterfeit prescriptions. Furthermore, many AASs are legally bought and consumed unknowingly in over-the-counter dietary supplements advertised as energy, virility, and muscle strength enhancers [12-14]. Although the precise number of AAS users is difficult to determine, it is estimated that the prevalence across the world is 1%-5%[15]. A study in 2013 found that the prevalence of AAS use among male elite college students in the United States during their lifetime is about 20%[16]. In Norway's high school population, a prevalence of 4% was found[17]. While it is difficult to establish a true prevalence of AAS use due to underreporting of this socially undesirable behavior, all the surveys nevertheless found significantly higher AAS use in male compared to female persons and the majority of AAS users are or were professional or near-professional athletes[15]. With the liver being the main site of steroid clearance, hepatotoxicity is one of the major adverse effects of chronic AAS use. The aim of this paper is to focus on the most recent studies and knowledge obtained regarding AAS-induced liver injury.
*HEPATOTOXICITY
*CHOLESTASIS
*PELIOSIS HEPATIS
*NEOPLASMS
*ADDITIONAL CONCERNS REGARDING AASS AND THE LIVER
CONCLUSION
AAS use is closely linked to hepatotoxicity and serious hepatic conditions such as cholestasis, peliosis hepatis, and benign and malignant hepatic tumors, as well as steatohepatitis and dyslipidemia with multiple studies supporting a causal association. Several pathophysiological mechanisms have been proposed including AR receptor-mediated inflammatory response, disturbance of hepatic antioxidant factors, promotion of hepatocyte hyperplasia, and upregulation of bile acid synthesis. Most of these conditions have been reported with 17-alpha-alkylated steroids. Liver function usually returns to normal with discontinuation of use, but a higher HCC prevalence with AASs is concerning. Another important fact is the increasing number of case reports presenting patients with dietary supplement-associated liver conditions that are still underreported. Given all of the above, screening for liver pathology in known AAS users should be considered in order to possibly reverse the condition. Also, if certain liver pathology is diagnosed incidentally, a history of AAS as a potential causal agent should be actively sought, and if found, addressed promptly.
Ana Petrovic, Sonja Vukadin, Renata Sikora, Kristina Bojanic, Robert Smolic, Davor Plavec, George Y Wu, Martina Smolic
Abstract
Anabolic androgenic steroids (AASs) are a group of molecules including endogenous testosterone and synthetic derivatives that have both androgenic and anabolic effects. These properties make them therapeutically beneficial in medical conditions such as hypogonadism. However, they are commonly bought illegally and misused for their anabolic, skeletal muscle-building, and performance-enhancing effects. Supraphysiologic and long-term use of AASs affect all organs, leading to cardiovascular, neurological, endocrine, gastrointestinal, renal, and hematologic disorders. Hepatotoxicity is one of the major concerns regarding AASs treatment and abuse. Testosterone and its derivatives have been most often shown to induce a specific form of cholestasis, peliosis hepatis, and hepatic benign and malignant tumors. It is currently believed that mechanisms of pathogenesis of these disorders include disturbance of antioxidative factors, upregulation of bile acid synthesis, and induction of hepatocyte hyperplasia. Most toxicity cases are treated with supportive measures and liver function normalizes with discontinuation of AAS. However, some long-term consequences are irreversible. AAS-induced liver injury should be taken into consideration in patients with liver disorders, especially with the increasing unintentional ingestion of supplements containing AAS. In this paper, we review the most current knowledge about AAS-associated adverse effects on the liver, and their clinical presentations, prevalence, and pathophysiological mechanisms.
INTRODUCTION
Anabolic androgenic steroids (AASs) are a group of compounds that include endogenous androgens, most importantly testosterone, and their synthetic derivatives[1]. Testosterone and synthetic AASs have been commonly used for their androgenic masculinizing effects resulting in male secondary characteristics, as well as anabolic skeletal muscle building effects due to enhanced protein utilization and synthesis mechanisms[2,3]. AASs are medically indicated in conditions such as male primary and secondary hypogonadism, aplastic anemia, muscle wasting in human immunodeficiency virus-infected patients, osteoporosis, libido dysfunction, chronic kidney disease, and breast cancer[4]. However, they are often misused because of their performance-enhancing and anabolic effects resulting in increased fat-free mass and improved muscle fiber size and strength. Abuse of AASs for aesthetic purposes and athletic performance improvement has surged as a public health problem in the past few decades among both professional and recreational athletes and bodybuilders[5,6]. Unmodified testosterone is rapidly metabolized when administered orally or parenterally and exerts a similar proportion of anabolic and androgenic effects. Chemical modifications of testosterone allow prolonged effective blood concentrations and changes to its pharmacodynamic properties, therefore enhancing desired anabolic or androgenic effects. In its synthetic derivatives used for aesthetic and performance-enhancing purposes, testosterone is altered mainly through alkylation and esterification to enhance bioavailability by reducing hepatic metabolism, prolonging the duration of action, and maximizing anabolic properties, though all of the synthetic compounds still exert significant androgenic effects. Supraphysiologic doses and prolonged unsupervised use of AASs have major impacts on users, affecting all organs and causing cardiovascular, neuroendocrine, neuropsychiatric, renal, gastrointestinal, musculoskeletal, dermatologic, immune, and hematologic disorders. Testosterone has a major impact on the homeostasis of electrolytes, macromolecules, and micromolecules, including alterations in systemic iron balance and erythropoiesis. It has been established that AAS-induced erythropoiesis is mediated by erythropoietin [7]. Most recent studies also imply suppression of hepcidin (a negative regulator of the iron transporter ferroportin) as a mechanism of androgen-induced enhanced iron absorption and incorporation into red blood cells[8]. Some of the most common adverse effects related to AASs are dyslipidemia, hypertension, hypogonadism and infertility, aggression and mood disorders, addiction, and liver and kidney injury[9-11]. This has led to stricter laws regarding the availability of AASs, mainly in professional sports organizations which ban anabolic steroid use, and test competitors for the presence of illegal steroids not only because of their unfair advantage in performance but also because of their potentially dangerous side effects. In legal terms, AASs have been classified in the United States as schedule 3 drugs by the Drug Enforcement Agency, meaning that they can be legally obtained as prescription-only drugs. However, they are illegally sold among teammates, trainers, and fitness centers, through the black market or counterfeit prescriptions. Furthermore, many AASs are legally bought and consumed unknowingly in over-the-counter dietary supplements advertised as energy, virility, and muscle strength enhancers [12-14]. Although the precise number of AAS users is difficult to determine, it is estimated that the prevalence across the world is 1%-5%[15]. A study in 2013 found that the prevalence of AAS use among male elite college students in the United States during their lifetime is about 20%[16]. In Norway's high school population, a prevalence of 4% was found[17]. While it is difficult to establish a true prevalence of AAS use due to underreporting of this socially undesirable behavior, all the surveys nevertheless found significantly higher AAS use in male compared to female persons and the majority of AAS users are or were professional or near-professional athletes[15]. With the liver being the main site of steroid clearance, hepatotoxicity is one of the major adverse effects of chronic AAS use. The aim of this paper is to focus on the most recent studies and knowledge obtained regarding AAS-induced liver injury.
*HEPATOTOXICITY
*CHOLESTASIS
*PELIOSIS HEPATIS
*NEOPLASMS
*ADDITIONAL CONCERNS REGARDING AASS AND THE LIVER
CONCLUSION
AAS use is closely linked to hepatotoxicity and serious hepatic conditions such as cholestasis, peliosis hepatis, and benign and malignant hepatic tumors, as well as steatohepatitis and dyslipidemia with multiple studies supporting a causal association. Several pathophysiological mechanisms have been proposed including AR receptor-mediated inflammatory response, disturbance of hepatic antioxidant factors, promotion of hepatocyte hyperplasia, and upregulation of bile acid synthesis. Most of these conditions have been reported with 17-alpha-alkylated steroids. Liver function usually returns to normal with discontinuation of use, but a higher HCC prevalence with AASs is concerning. Another important fact is the increasing number of case reports presenting patients with dietary supplement-associated liver conditions that are still underreported. Given all of the above, screening for liver pathology in known AAS users should be considered in order to possibly reverse the condition. Also, if certain liver pathology is diagnosed incidentally, a history of AAS as a potential causal agent should be actively sought, and if found, addressed promptly.
