madman
Super Moderator
ABSTRACT
Background and aim: In recent years the expanding misuse of Nandrolone among non-athletes, particularly adolescent males is a prevalent global concern due to its adverse effects. This article provides a summary of the experimental studies to clarify the relationship between Nandrolone exposure and behavioral and cognitive performances.
Materials and methods: The present systematic review was conducted using PubMed, Embase, and ScienceDirect databases, from 2000 to 2020, using the following key terms: Nandrolone AND Cognition, Nandrolone AND Learning, Nandrolone AND Memory, Nandrolone AND (Synaptic plasticity or Hippocampal synaptic plasticity), Nandrolone AND (Aggression or Aggressive-like behavior), Nandrolone AND (Anxiety or Anxiety-like behavior), Nandrolone AND (Depression or Depressive-like behavior).
Results: 33 qualified papers were selected from the 2498 sources found. Of the 33 cases, 32 (96.97%) were males while only 1 (3.03%) was female and male. From 33 selected articles 8 reported studies were related to spatial memory, 2 reported studies were related to avoidance memory, 11 studies reported information on synaptic plasticity, 11 reported studies were related to aggressive behavior, 8 reported studies were related to aggressive behavior and 6 reported studies were related to depression.
Conclusion: Nandrolone can change spatial ability, avoidance memory, and hippocampal synaptic plasticity. Also, Nandrolone exposure produces variable effects on behavioral function such as aggression, depression, and anxiety. This is despite the fact that the results are contradictory. These discrepancies might be due to the differences in sex, age, dosage and treatment duration, and administration route. However, the negative results are more common than the published positive ones.
1. Introduction
Anabolic-androgenic steroids (AASs) are a large group of synthetic derivatives of the male gonadal hormone testosterone, which has both androgenic and anabolic effects [1-3]. Based on the replacement of the base molecule, AASs are classified into 3 main classes. Esterification at C-17 is related to class I. Class II is related to a demethylated group at C-19 and may also have C-17 esters. Alkylation at C-17 creates class III. Nandrolone (19-nortestosterone) belongs to the second class of AASs [4,5]. The classification of AASs is presented in Fig. 1. Nandrolone is usually used as esters, such as Nandrolone Decanoate (ND) and Nandrolone Phenylpropionate (NPP) (Fig. 2). The most commonly used esters are ND and to a lesser extent NPP [6]. Nandrolone esters were first described and introduced for medical use in the late 1950s, but, the misuse of these compounds has increased among non-athletes to enhance physical performance [6,7]. The recommended therapeutic dose of Nandrolone for humans is 0.4 mg/kg/day, while doses used illegally commonly are up to 100 times the therapeutic dose [8]. However, due to adverse effects on cardiovascular, endocrine, reproductive, and behavioral function, the rising Nandrolone abuse is a prevalent global problem [9,10]. As a result of the absence of a methyl group in the 19-position, Nandrolone displays less androgenic activity compared with testosterone [11]. However, due to its anabolic properties and the diminished ability to convert estrogen, Nandrolone is one of the most frequently abused AASs [12,13].
*In this paper, we systematically reviewed experimental studies in order to determine whether is the possible relationship between Nandrolone exposure and behavioral and cognitive function in animal models.
1.1. Nandrolone metabolism
The half-life of Nandrolone administered by intramuscular injection is approximately 6 to 12 days. The mean half-life for release of the ester from the depot into the general circulation was 6 days, whereas the mean half-life for the combined processes of hydrolysis of ND and elimination of free Nandrolone was only 4.3 h [14]. The metabolism of Nandrolone occurs in the liver and is very similar to testosterone. Similar to testosterone, in specific tissues including, the prostate gland, liver, skin, hair follicles, and brain, 5α-reductase will reduce the C-4,5 double bond of Nandrolone, yielding low-affinity androgenic receptor (AR) ligand dihydroNandrolone (DHN) [11]. However, DHN is less androgenic than Nandrolone as opposed to the relationship between testosterone and dihydrotestosterone [11,15]. Also the aromatization of Nandrolone to the estradiol-a ligand of the estrogen receptors- occurs similar to testosterone, but to a lesser extent than that of testosterone (only about 20% of that of testosterone or possibly even lesser) [11,16]
1.2. Mechanism of action: genomic and non-genomic pathway
Nandrolone is an agonist of the androgen receptors. The anabolic-androgenic effects of Nandrolone are related to the AR-signaling action. There are three main action mechanisms: (1) direct interaction with AR; (2) through DHN produced by the action of 5- a-reductase, and (3) through estrogen receptors by estradiol produced by aromatase [17]. Previous studies have indicated that AASs, such as Nandrolone have a high affinity for the ARs [18]. In genomic mechanisms, steroid hormones mediate their effects through the activation of specific intracellular androgen receptors that act as a transcription factor. In this regard, after translocation into the cytoplasm, the steroid hormone binds to and activates the androgen receptor. The bound steroid receptors act as transcription factors and fix the hormone response element at DNA, where they activate or silence the expression of genes and subsequent protein synthesis [19,20].
Several reports have suggested that in addition to the genomic effect of steroid hormones through intracellular ARs, they have non-genomic action, as well. Non-genomic steroid function involves the rapid induction of conventional second messenger signal transduction cascades [21,22]. Accordingly, androgen interacts with a membrane-associated androgen receptor leading to the activation of L-type calcium channels and phospholipase C through an inhibitory G-protein. The resulted increases in intracellular calcium can activate protein kinase C, calmodulin, and RAS/MEK/ERK pathway, finally affecting gene transcription [23].
1.3. Administration pattern
AASs are typically administered via the intramuscular or subcutaneous route, by pellet subcutaneous implantation, or by application on the skin [24]. Some indices are used to investigate the effects of Nandrolone on brain functions. AAS should be injected directly into the brain, while in most studies, Nandrolone is administrated via subcutaneous (s.c) or intramuscular (i.m) injections. In some experiments, the direct effect of Nandrolone on brain functions was examined by intracerebroventricular (i.c.v) [25-27] and intrahippocampal injections [28]
4. Discussion
Several mechanisms are involved in Nandrolone's adverse effects and need to be better elucidated. The hippocampus is a part of the limbic system that has a well-known role in cognitive aspects of the brain [52]. The role of androgens in cognitive performance associated with the hippocampus has been suggested. The hippocampal CA1 pyramidal cell layer contains a high density of the androgen receptors, indicating that there must be a relationship between androgens and memory performance [53,54].
5. Conclusion
Even though the use of Nandrolone for medical purposes is relatively safe, it can be harmful to health and cause side effects if used improperly. Many studies have confirmed the side effects of Nandrolone abuse on the liver, kidney, cardiovascular, reproductive, musculoskeletal and endocrine systems. In addition to the general adverse effects of Nandrolone, on sexual functions, a large number of experiments have reported that administration of Nandrolone has an adverse effect on behavioral and cognitive functions.
In a systematic review of the literature on online resources, the outcomes obtained from animal experiments agrees on the fact that Nandrolone can affect spatial ability, passive avoidance memory and hippocampal synaptic plasticity. Also, the experimental results clarified that Nandrolone exposure produces variable effects on behavioral function such as aggressive behavior, depression and anxiety-like behavior.
However, despite decades of research on the relationship between Nandrolone and cognitive function, the achieved results are complex and contradictory. Some investigators have reported that treatment with Nandrolone impaired cognitive function. In contrast, some others suggest a positive correlation or no association between Nandrolone and cognitive performance. There are similar results for the effect of Nandrolone on behavioral performance. These discrepancies might be due to the differences in sex, age, dosage and treatment duration, and administration route. However, based on the published literatures, the negative results are more common than the published positive ones.
Background and aim: In recent years the expanding misuse of Nandrolone among non-athletes, particularly adolescent males is a prevalent global concern due to its adverse effects. This article provides a summary of the experimental studies to clarify the relationship between Nandrolone exposure and behavioral and cognitive performances.
Materials and methods: The present systematic review was conducted using PubMed, Embase, and ScienceDirect databases, from 2000 to 2020, using the following key terms: Nandrolone AND Cognition, Nandrolone AND Learning, Nandrolone AND Memory, Nandrolone AND (Synaptic plasticity or Hippocampal synaptic plasticity), Nandrolone AND (Aggression or Aggressive-like behavior), Nandrolone AND (Anxiety or Anxiety-like behavior), Nandrolone AND (Depression or Depressive-like behavior).
Results: 33 qualified papers were selected from the 2498 sources found. Of the 33 cases, 32 (96.97%) were males while only 1 (3.03%) was female and male. From 33 selected articles 8 reported studies were related to spatial memory, 2 reported studies were related to avoidance memory, 11 studies reported information on synaptic plasticity, 11 reported studies were related to aggressive behavior, 8 reported studies were related to aggressive behavior and 6 reported studies were related to depression.
Conclusion: Nandrolone can change spatial ability, avoidance memory, and hippocampal synaptic plasticity. Also, Nandrolone exposure produces variable effects on behavioral function such as aggression, depression, and anxiety. This is despite the fact that the results are contradictory. These discrepancies might be due to the differences in sex, age, dosage and treatment duration, and administration route. However, the negative results are more common than the published positive ones.
1. Introduction
Anabolic-androgenic steroids (AASs) are a large group of synthetic derivatives of the male gonadal hormone testosterone, which has both androgenic and anabolic effects [1-3]. Based on the replacement of the base molecule, AASs are classified into 3 main classes. Esterification at C-17 is related to class I. Class II is related to a demethylated group at C-19 and may also have C-17 esters. Alkylation at C-17 creates class III. Nandrolone (19-nortestosterone) belongs to the second class of AASs [4,5]. The classification of AASs is presented in Fig. 1. Nandrolone is usually used as esters, such as Nandrolone Decanoate (ND) and Nandrolone Phenylpropionate (NPP) (Fig. 2). The most commonly used esters are ND and to a lesser extent NPP [6]. Nandrolone esters were first described and introduced for medical use in the late 1950s, but, the misuse of these compounds has increased among non-athletes to enhance physical performance [6,7]. The recommended therapeutic dose of Nandrolone for humans is 0.4 mg/kg/day, while doses used illegally commonly are up to 100 times the therapeutic dose [8]. However, due to adverse effects on cardiovascular, endocrine, reproductive, and behavioral function, the rising Nandrolone abuse is a prevalent global problem [9,10]. As a result of the absence of a methyl group in the 19-position, Nandrolone displays less androgenic activity compared with testosterone [11]. However, due to its anabolic properties and the diminished ability to convert estrogen, Nandrolone is one of the most frequently abused AASs [12,13].
*In this paper, we systematically reviewed experimental studies in order to determine whether is the possible relationship between Nandrolone exposure and behavioral and cognitive function in animal models.
1.1. Nandrolone metabolism
The half-life of Nandrolone administered by intramuscular injection is approximately 6 to 12 days. The mean half-life for release of the ester from the depot into the general circulation was 6 days, whereas the mean half-life for the combined processes of hydrolysis of ND and elimination of free Nandrolone was only 4.3 h [14]. The metabolism of Nandrolone occurs in the liver and is very similar to testosterone. Similar to testosterone, in specific tissues including, the prostate gland, liver, skin, hair follicles, and brain, 5α-reductase will reduce the C-4,5 double bond of Nandrolone, yielding low-affinity androgenic receptor (AR) ligand dihydroNandrolone (DHN) [11]. However, DHN is less androgenic than Nandrolone as opposed to the relationship between testosterone and dihydrotestosterone [11,15]. Also the aromatization of Nandrolone to the estradiol-a ligand of the estrogen receptors- occurs similar to testosterone, but to a lesser extent than that of testosterone (only about 20% of that of testosterone or possibly even lesser) [11,16]
1.2. Mechanism of action: genomic and non-genomic pathway
Nandrolone is an agonist of the androgen receptors. The anabolic-androgenic effects of Nandrolone are related to the AR-signaling action. There are three main action mechanisms: (1) direct interaction with AR; (2) through DHN produced by the action of 5- a-reductase, and (3) through estrogen receptors by estradiol produced by aromatase [17]. Previous studies have indicated that AASs, such as Nandrolone have a high affinity for the ARs [18]. In genomic mechanisms, steroid hormones mediate their effects through the activation of specific intracellular androgen receptors that act as a transcription factor. In this regard, after translocation into the cytoplasm, the steroid hormone binds to and activates the androgen receptor. The bound steroid receptors act as transcription factors and fix the hormone response element at DNA, where they activate or silence the expression of genes and subsequent protein synthesis [19,20].
Several reports have suggested that in addition to the genomic effect of steroid hormones through intracellular ARs, they have non-genomic action, as well. Non-genomic steroid function involves the rapid induction of conventional second messenger signal transduction cascades [21,22]. Accordingly, androgen interacts with a membrane-associated androgen receptor leading to the activation of L-type calcium channels and phospholipase C through an inhibitory G-protein. The resulted increases in intracellular calcium can activate protein kinase C, calmodulin, and RAS/MEK/ERK pathway, finally affecting gene transcription [23].
1.3. Administration pattern
AASs are typically administered via the intramuscular or subcutaneous route, by pellet subcutaneous implantation, or by application on the skin [24]. Some indices are used to investigate the effects of Nandrolone on brain functions. AAS should be injected directly into the brain, while in most studies, Nandrolone is administrated via subcutaneous (s.c) or intramuscular (i.m) injections. In some experiments, the direct effect of Nandrolone on brain functions was examined by intracerebroventricular (i.c.v) [25-27] and intrahippocampal injections [28]
4. Discussion
Several mechanisms are involved in Nandrolone's adverse effects and need to be better elucidated. The hippocampus is a part of the limbic system that has a well-known role in cognitive aspects of the brain [52]. The role of androgens in cognitive performance associated with the hippocampus has been suggested. The hippocampal CA1 pyramidal cell layer contains a high density of the androgen receptors, indicating that there must be a relationship between androgens and memory performance [53,54].
5. Conclusion
Even though the use of Nandrolone for medical purposes is relatively safe, it can be harmful to health and cause side effects if used improperly. Many studies have confirmed the side effects of Nandrolone abuse on the liver, kidney, cardiovascular, reproductive, musculoskeletal and endocrine systems. In addition to the general adverse effects of Nandrolone, on sexual functions, a large number of experiments have reported that administration of Nandrolone has an adverse effect on behavioral and cognitive functions.
In a systematic review of the literature on online resources, the outcomes obtained from animal experiments agrees on the fact that Nandrolone can affect spatial ability, passive avoidance memory and hippocampal synaptic plasticity. Also, the experimental results clarified that Nandrolone exposure produces variable effects on behavioral function such as aggressive behavior, depression and anxiety-like behavior.
However, despite decades of research on the relationship between Nandrolone and cognitive function, the achieved results are complex and contradictory. Some investigators have reported that treatment with Nandrolone impaired cognitive function. In contrast, some others suggest a positive correlation or no association between Nandrolone and cognitive performance. There are similar results for the effect of Nandrolone on behavioral performance. These discrepancies might be due to the differences in sex, age, dosage and treatment duration, and administration route. However, based on the published literatures, the negative results are more common than the published positive ones.
