medicina

Review
Nandrolone Decanoate: Use, Abuse and Side Effects
Federico Giuseppe Patanè 1,† , Aldo Liberto 1,† , Andreana Nicoletta Maria Maglitto 1 ,
Pasquale Malandrino 1 , Massimiliano Esposito 1 , Francesco Amico 1 , Giuseppe Cocimano 1 ,
Giuseppe Li Rosi 2 , Dario Condorelli 1 , Nunzio Di Nunno 3 and Angelo Montana 1, *
1 Legal Medicine, Department of Medical, Surgical and Advanced Technologies, “G.F. Ingrassia”,
University of Catania, 95123 Catania, Italy; [email protected] (F.G.P.);
[email protected] (A.L.); [email protected] (A.N.M.M.);
[email protected] (P.M.); [email protected] (M.E.);
[email protected] (F.A.); [email protected] (G.C.); [email protected] (D.C.)
2 Department of Law, Criminology, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy;
[email protected]
3 Department of History, Society and Studies on Humanity, University of Salento, 73100 Lecce, Italy;
[email protected]
* Correspondence: [email protected]; Tel.: +39-328-765-5428
† These authors contributed equally to this work.




Received: 30 September 2020; Accepted: 9 November 2020; Published: 11 November 2020


Abstract: Background and Objectives: Androgens play a significant role in the development of male
reproductive organs. The clinical use of synthetic testosterone derivatives, such as nandrolone, is
focused on maximizing the anabolic effects and minimizing the androgenic ones. Class II anabolic
androgenic steroids (AAS), including nandrolone, are rapidly becoming a widespread group of
drugs used both clinically and illicitly. The illicit use of AAS is diffused among adolescent and
bodybuilders because of their anabolic proprieties and their capacity to increase tolerance to exercise.
This systematic review aims to focus on side effects related to illicit AAS abuse, evaluating the scientific
literature in order to underline the most frequent side effects on AAS abusers’ bodies. Materials and
Methods: A systematic review of the scientific literature was performed using the PubMed database
and the keywords “nandrolone decanoate”. The inclusion criteria for articles or abstracts were English
language and the presence of the following words: “abuse” or “adverse effects”. After applying
the exclusion and inclusion criteria, from a total of 766 articles, only 148 were considered eligible
for the study. Results: The most reported adverse effects (found in more than 5% of the studies)
were endocrine effects (18 studies, 42%), such as virilization, gynecomastia, hormonal disorders,
dyslipidemia, genital alterations, and infertility; cardiovascular dysfunctions (six studies, 14%) such
as vascular damage, coagulation disorders, and arteriosus hypertension; skin disorders (five studies,
12%) such as pricking, acne, and skin spots; psychiatric and mood disorders (four studies, 9%) such as
aggressiveness, sleep disorders and anxiety; musculoskeletal disorders (two studies, 5%), excretory
disorders (two studies, 5%), and gastrointestinal disorders (two studies, 5%). Conclusions: Based
on the result of our study, the most common adverse effects secondary to the abuse of nandrolone
decanoate (ND) involve the endocrine, cardiovascular, skin, and psychiatric systems. These data
could prove useful to healthcare professionals in both sports and clinical settings.

Keywords: nandrolone decanoate; drug abuse; androgenic steroids; adverse effects; steroid treatment

1. Introduction
The name “anabolic androgenic steroids” already suggests their “anabolic” (from Greek ἀναβoλή
“throw upward”) and “androgenic” (Greek ἀνδρóς “of a man” + -γενής “born”) properties.

Medicina 2020, 56, 606; doi:10.3390/medicina56110606 www.mdpi.com/journal/medicina

Medicina 2020, 56, 606 2 of 24

Androgens play a significant role in the development of male reproductive organs, such as the
prostate, penis, seminal vesicle, ductus deferens, and epididymis. Testosterone is a steroid hormone
that has an essential role in the development of the male phenotype and the regulation of reproduction
of males. This hormone is effective on puberty, fertility, and sexual function in males [1,2].
Anabolic androgenic steroids (AAS) represent a large group of synthetic derivatives of testosterone,
produced to maximize anabolic effects and minimize the androgenic ones [3]. Several structural
modifications have been introduced into testosterone in an attempt to maximize the anabolic effect and
minimize androgenic effects. Currently, AASs are classified in 3 major classes [4] based on substitution
of the base molecule. Class I is related to C-17 esterification. Class II is related to a demethylated group
at C-19 and may also have C-17 esters. Class III is related to alkylation at C-17.
The classification of anabolic steroids is given in Table 1.

Table 1. Classification of anabolic androgenic steroids (AAS).

Class Chemical Structure Examples

I Testosterone propionate

II Nandrolone decanoate

III Stanozolol

Nandrolone is included in the group of class II AASs, which is composed of

19-nortestosterone-derivates. In general, AASs is a broad and rapidly growing group of synthetic
androgens used both clinically and illicitly.
Compared to testosterone propionate, nandrolone decanoate is considered to have strong
anabolic effects but weak androgenic effects (potency ratios of 3.29–4.92 and 0.31–0.41). In particular,
nandrolone esters are thought to have the highest ratio of anabolic to androgenic effects of any AAS.
The low androgenicity of nandrolone decanoate is thought to be due to the fact that nandrolone is
inactivated by 5α-reductase via transformation into the low-affinity androgen receptor (AR) ligand
5α-dihydronandrolone. This is thought to result in a lower incidence and magnitude of side effects.
Nandrolone has very low affinity for human serum sex hormone-binding globulin (SHBG), about
5% of that of testosterone and 1% of that of dihydrotestosterone (DHT). It is mainly metabolized by the
enzyme 5α-reductase, into 5α-dihydronandrolone, 19-norandrosterone, and 19-noretiocholanolone,
which can be detected in urine [5]. Nandrolone displays a so-called flip-flop pharmacokinetics.
This means that the ascending phase of the curve represents the disposition of nandrolone, and the
descending part of the curve represents the rate-limiting process of release of nandrolone decanoate
from the muscle into the general circulation [6]. In clinical use, nandrolone is applicable in clinical
practice for burns, radiation therapy, surgery, trauma, and various forms of anemia [7]. Moreover,
it has also been used for the treatment of chronic kidney disease, osteoporosis in postmenopausal
women [8], inoperable breast cancer, and for patients on long-term corticosteroid therapy, as well as an
adjunct to therapy for conditions characterized by a negative nitrogen balance. The drug is often used
Medicina 2020, 56, 606 3 of 24

off-label to preserve lean mass in human immunodeficiency virus (HIV)/acquired immunodeficiency

syndrome (AIDS) associated wasting syndrome [9].
The compound is famous not only among adults, but also adolescents because of its anabolic,
muscle-building properties [10–13]. Skeletal muscle can be considered as the primary target tissue
for the anabolic effects of AAS, which are mediated by androgenic receptors which, after exposure to
AAS, are up-regulated, and their number increases with bodybuilding [14]. Therefore, AAS determine
an increase in muscle size as a consequence of dose-dependent hypertrophy resulting in an increase
of the cross-sectional areas of both type I and type II muscle fibers and myonuclear domains [15].
It is administered via intramuscular injection and is metabolized in a similar manner to testosterone,
with conversion into 3-norandrosterone by5α-reductase [16]. The recommended therapeutic dose
of ND for humans is 0.4 mg/kg/day [17]. Its consumption can trigger a series of adverse side effects
in the body, both acute and chronic [18]. However, acute adverse effects have also been described,
primarily consisting of headaches, fluid retention, gastrointestinal irritation, diarrhea, abdominal
pain, jaundice, menstrual abnormalities, and hypertension. The chronic effects of AAS abuse, aside
from neuropsychiatric and behavioral effects, include a wide range of somatic consequences. Many
organs and systems are targets of AAS action. Consequently, AASs may exert negative effects on
reproductive, hepatic, musculoskeletal, endocrine, renal, immunologic, cardiovascular, cerebrovascular,
and hematological systems [19–22].
Moreover, it has been reported that AASs can increase tolerance to exercise by making the muscles
more capable of resisting overload, thereby shielding them from muscle fiber damage and improving
the level of protein synthesis during recovery [23].
Nowadays, especially athletes in power sports such as bodybuilding and weightlifting administer
illegally high doses of AASs to increase their muscle mass and improve their overall performance [24].
However, also non-athletes also abuse AASs. Nandrolone decanoate (ND) injection has been classified
as a Schedule III controlled substance under the Anabolic Steroids Control Act of 1990 [25]. Due to
serious health risks, the nonmedical use of AASs is banned by most sports organizations. In addition,
AASs are listed in the WADA (World Anti-Doping Agency) prohibited list [26]. The abuse of these
drugs has become a major health problem [27].
The use of AASs in competitive bodybuilding became widespread and was often supervised
by physicians who supplied the drugs to the athletes, ensuring what they were injecting was pure
while monitoring and minimizing side effects such as infertility, liver toxicity, impaired lipid profiles,
high blood pressure, acne, hair loss or gynecomastia. During this time, there was no need for a
black market or underground laboratories (UGL) since these drugs were readily available from health
professionals. However, the situation dramatically changed after the introduction of the Anabolic
Steroid Control Act in 1990, and subsequently reinforced by the Anabolic Steroid Control Act of 2004.
In 2014, the Designer Steroid Control Act was enacted in an attempt to close loopholes for slightly
modified compounds. These events created an immense demand for black market products, which
facilitated the creation of underground laboratory products and importing drugs produced in countries
with lax AAS legislations [28].
Even though legitimate pharmaceutical grade AASs can be purchased on the black market via
several routes, physician supervision of usage is usually lacking, making a legitimate pharmaceutical
product potentially dangerous for uninformed users. Since buying and using AASs (without a medical
prescription) is a criminal act in many countries, the AAS user is often reluctant to seek advice from a
physician when health issues arise. Indeed, a survey found that AAS users very often have no trust in
physicians’ knowledge about AASs and typically do not disclose their AAS use to them [29].
The aim of this systematic review is to focus on the side effects related to illicit AAS abuse,
evaluating findings in the scientific literature, in order to underline the most frequent side effects on
AAS abuser’s bodies.
Medicina 2020, 56, 606 4 of 24

2. Materials and Methods

2.1. Database Source

We performed a systematic review of the literature on online resources using the PubMed database
for all published articles from 1 January 1900 to 22 July 2020, using the key words: “nandrolone
decanoate”.

2.2. Selection of Studies and Data Collection

A total of 766 articles were retrieved, excluding all duplicated articles, additional exclusion and
inclusion criteria were then applied: Articles or abstracts in English containing one of the following
words: “Abuse” or “Adverse effects”. A total of 479 articles did not meet these criteria and were
therefore excluded. From the remaining 278 articles a manual review was performed to remove
non-available articles, duplicate articles, articles not relevant for the study, older literature reviews
and articles not reporting adverse effects. A total of 148 articles met these inclusion criteria and were
considered eligible for the study, while 130 articles were excluded. Studies from the references of
the selected articles, and articles not meeting inclusion and exclusion criteria are discussed in this
study, but not included in the systematic review. For a more comprehensive review, we included in the
discussion the excluded but relevant articles, eventually performing a specific research for key sections.
Figure 1 summarizes the flowchart about article selection after the PubMed search. All included articles
are listed in Appendix A.

Figure 1. Included articles search strategy; (a) The flowchart about article selection used for the
literature review. (b) Time distribution of included articles: x-axis for year; y-axis for amount of articles
per year.

3. Results
A total of 115 studies reported data about animal experiments (for example rats, horses, dogs),
while 33 studies reported data about humans (409 subjects, 346 males, 63 females) as shown in Table 2.
The subjects mean age was 34.8 years (Standard Deviation: 12.8), as described in 21 articles. Males
Medicina 2020, 56, 606 5 of 24

were younger (33.3 years) than females (53.3). Eighteen articles discussed side effects of subjects
abusing nandrolone decanoate (without medical prescription), while 15 articles discussed side effects
of subjects taking it for medical treatment.

Table 2. Demographic data.

Population Age (Years) 1

Males 346 (87%) 33.3
Females 63 (13%) 53.3
Total 409 34.8 (S.D. 12.8)
Treatment 313
Non-treatment 96
1 Age is considered only when both age and gender are reported. S.D.: standard deviation.

Adverse effects were studied on these population-based studies. The results are shown in
Table 3 and Figure 2. Most reported adverse effects (more than 5% of the studies) were endocrine (18
studies, 42%), cardiovascular (six studies, 14%), skin (five studies, 12%), psychiatric (four studies, 9%),
musculoskeletal (two studies, 5%), excretory (two studies, 5%), and gastrointestinal disorders (two
studies, 5%). In order to list all adverse effects, these were grouped by affected system based on study
reports (for example, in psychiatric disorders, we grouped all behavioral, mood, and anxiety symptoms).

Table 3. Adverse effects.

Studies Common Reports

(virilization, gynecomastia, hormonal disorder, cholesterol and lipid, genital and
Endocrine 18
infertility issues)
Cardiovascular 6 (vascular damage, coagulation disorders, arterial hypertension)
Skin 5 (pricking, acne, skin spots)
Psychiatric 4 (aggressiveness, mood disorders, sleep disorders, anxiety)
Musculoskeletal 2 (tendon ruptures)
Excretory 2 (organ damage)
Gastrointestinal 2 (organ damage, liver adenomas)
Neurological 1 (seizures)
Immune 1 (chronic infection relapse)
Respiratory 1 (sleep apnea syndrome)
Genetic 1 (genetic damage)

The most common side effects were: endocrine disorders (virilization, gynecomastia, hormonal
disorders, cholesterol and lipid disorders, genital and infertility issues); cardiovascular disorders
(vascular damage, coagulation disorders, arteriosus hypertension); skin disorders (pricking, acne, skin
spots); psychiatric disorders (aggressiveness, mood disorders, sleep disorders, anxiety); musculoskeletal
disorders (tendon ruptures); excretory disorders (organ damage); gastrointestinal disorders (organ
damage and liver adenomas); neurological disorders (seizures); immune disorders (chronic infection
relapse; respiratory disorders (sleep apnea syndrome); genetic disorders (genetic damage).
We also examined the difference between reported side effects between men and women, as well
as between the medical administration and abusive use. The most reported side effect concerns the
endocrine system for both males and females; reported more frequently for females. The most reported
side effects for treatment administration were on the endocrine system (61%), while the most adverse
effects for abusive use were endocrine (19%), cardiovascular (19%), and dermatological disorders (19%).
Reports related to males were mixed between treatment and abusive use (45% were from reports of
medical treatment, while 55% were from reports of illicit or recreational use). In our data, the most
common reported side effect was the endocrine system for both males and females (60% for females,
37% for males). We think this result is caused by the number of reports: most examined female cases
were secondary to treatment side effects, while male cases were related to both treatment and abuse, as
shown in Figures 3 and 4.
Medicina 2020, 56, 606 6 of 24

Figure 2. This graph summarizes the adverse effects reported. Endocrine, cardiovascular, skin and
psychiatric disorders are the most reported.

Figure 3. Graph representing side effects for treatment or abuse related administration. (a) Treatment
related. (b) Abuse related.

Moreover, the incidence of side effects on males was more homogeneous (37% endocrine disorders,
16% cardiovascular disorders, 13% skin disorders, 10% psychiatric disorders, compared to females
where we found 61% endocrine disorders, 10% cardiovascular disorders, 10% skin disorders, 10%
psychiatric disorders). We think this difference is due to the administration dosage and pattern. In fact,
most abusers use several AAS at the same time.
Medicina 2020, 56, 606 7 of 24

Figure 4. Graph representing side effects for males and females. (a) Females. (b) Males.

4. Discussion
AASs represent a large group of synthetic derivatives of testosterone designed to maximize
anabolic effects (such as increasing muscle mass and strength and reducing fat) and to minimize
androgenic ones (such as virilization) [30–32]. There are numerous clinically proven effects: AASs
promote stimulation of growth and maturation of non-reproductive tissues and maintenance of
secondary sexual characteristics and reproductive function [33]. They also promote bone growth
in both young and adult populations; and have long been used as a treatment for growth delay
and osteoporosis [30,34]. Anabolic androgenic steroids are clinically indicated for the treatment of
chronic diseases associated with the catabolic state of the patient, in conditions of AIDS, chronic
obstructive pulmonary disease, hepatic or renal failure, cancer, and in cases of burns and postsurgical
recovery. They are also recommended for androgen replacement therapy after menopause, and during
age-related sarcopenia [35,36].
ND is the most prescribed AAS because it exhibits the lowest incidence of adverse effects
compared to beneficial effects [37]. As a result, ND had been implicated in doping, until its health
risks became evident and the International Olympic Committee (IOC) abolished the use of ND in
sports competitions [38]. While it is more common among so-called gym visitors, this substance is
also used in criminal circles and in competitive situations where personal aggressiveness could be a
determining factor.
ND is generally used in the injectable form to improve performance [23], regularly or occasionally,
with a combination of multiple AASs. Athletes tend to self-administer AASs for several weeks
before sports competitions believing in the synergic anabolic effects with minimal side effects and the
possibility of avoiding being discovered on doping tests. [39,40].
The anabolic effect on proteins requires a specific diet necessary to maintain a correct nitrogen
balance. Unfortunately, hyperproteic diets are often not balanced and excessive proteins are eliminated
through urine or converted into fat [39,41]. A summary of these effects is represented in Figure 5.
In order to investigate the side effects of such abusive administration of ND, we reviewed the
literature and studied the results systematically.
Medicina 2020, 56, 606 8 of 24

Figure 5. Where is the balance between known positive effects and underestimated or unknown side
effects? This image tries to summarize this concept, because nandrolone decanoate is a molecule that
affects several systems at the same time and sometimes in an irreversible way.

4.1. Endocrine and Genital Disorders

In our data, the most reported endocrine disorders were serum lipid alteration and virilization
(for example, gynecomastia, voice pitch alteration). Several authors, after a period of administration
of AASs, highlighted a significant increase of low-density lipoprotein (LDL) and decreasing
high-density lipoprotein (HDL). Such effects and reversibility are dependent on dosage and treatment
duration [30,42,43]. It has been shown that high doses of AASs induce adverse effects by increasing
plasma triglyceride levels and decreasing plasma HDL-C levels up to 70%, considered to provide
anti-atherosclerotic protection [44], while some studies showed contradictory results about this
aspect [45,46].
ND has important effects on the hypothalamic—pituitary—adrenal Axis (HPAA) and on lipid
metabolism. In a study by Gårevik et al., cholesterol level, steroid synthesizing enzymes in the adrenal
gland (HMGCR) mRNA and Apo-lipoprotein B (ApoB) appeared to increase after a single dose of ND
in humans, and this effect was persistent after 14 days [47]. Belgoma and colleagues [48] highlighted
the molecular mechanism behind serum lipid alteration, with a downregulation of several intracellular
factors that leads to the synthesis of sphingolipids and glycerolipids. AASs decrease lipogenesis by the
downregulation of the activity of the lipogenic liver X receptor pathway via activation of the androgen
receptor. Moreover, the androgen receptor induces de novo synthesis of fatty acids and cholesterol by
upregulated HMG-CoA (steroid synthesizing enzymes in the adrenal gland—Coenzyme A) reductase
and low-density lipoprotein (LDL) receptor.
Racca and colleagues [49], after having administered ND to rats, noted an increase in
adrenocorticotrophin (ACTH) (both in blood and in pituitary corticotropes), glucocorticoid receptor (GR)
Medicina 2020, 56, 606 9 of 24

reduction in the hippocampus and hypothalamus cytosol, and GR translocation in the hippocampus
nuclear fraction, stimulation of cortical serotonin re-uptake and activation of hippocampus cytosolic
extracellular signal-regulated kinases 2 (ERK2). Alsio and coworkers [50] noted an important reduction
in corticosterone (CORT) plasma levels in the rat after ND treatment for 14 days; Nandrolone
treatment increased HMGCR expression in the adrenal glands and reduced expression levels of the
b3-adrenoceptor in adipose tissue [51].
Cases of women with ovarian follicles maturation failure, uterus, clitoris, vagina, and mammary
gland hypertrophy, with hormonal disorders, confirmed by experiments on animals, have been reported
in the literature. ND decreased the serum level of follicle-stimulating hormone (FSH), Luteinizing
hormone (LH), progesterone and estrogen [52]. ND also promoted histological alterations in female
genital organs in a dose-independent manner, despite recovery from treatment [33,53].
Virilization in female users is a well-known side effect, characterized by voice pitch alteration,
body hair growth, hair loss, thick and greasy skin, acne, as well as increased libido and clitoris
hypertrophy [54].
AASs also affect the activity of the sexual hormone in males, causing the inhibition of reproductive
function, since the first administration [47], by turning off physiological testosterone production,
causing testis atrophy, spermatogenesis inhibition (also leading to aspermia), and erectile dysfunction.
They also cause biochemical modifications of prostatic secretion and seminal liquid. Most of these
degenerative changes are partially reversible after treatment suspension [33,55,56].
ND, among other AASs, exerts a strong negative feedback on the hypothalamic-pituitary-gonadal
axis that reduces the levels of LH and FSH and leads to a reduction of testosterone. Due to the decrease
in FSH levels, the growth and development of Sertoli cells is insufficient [56].

4.2. Cardiovascular Disorders

The effects of androgens on the cardiovascular system involve blood vessel disorders, increased
erythropoiesis, hematocrit increase, hyperviscosity and hypertension, but may have direct effects
on cardiac muscle and its function, decreasing potential duration, altering repolarization, and peak
shortening times [57,58].
In our data, the most reported cardiovascular disorders were platelet aggregation disorders and
cardiac injuries. Shirpoor and coauthors [59], through experiments on rats, showed the molecular
mechanisms underlying heart hypertrophy: chronic nandrolone treatment with or without strenuous
exercise causes a shift in the alpha and beta–myosin heavy chain (α-MHC/β-MHC) isoform expression
manifested by elevation of β-MHC mRNA and the ratio of β-MHC mRNA/α-MHC mRNA expression, as
well as an increase in the heart tissue of mono-amine oxidase (MAO) and calcium/calmodulin-dependent
protein kinase II-δ activities (CaMKII-δ). Moreover, androgens have receptors in the heart and their
action directly affects it through coupling directly with nuclear receptors and increasing the expression
of mRNA, thus stimulating cardiac protein synthesis resulting in myocardial hypertrophy [60,61].
Franquni and coauthors [62] showed the presence of cardiac remodeling and subsequent cardiac
injury as indicated by the reduction in cardiac troponin I. Additionally, a reduction in the Bezold–Jarisch
reflex (BJR) control of heart rate (HR) and blood pressure was also demonstrated. As a result of these
changes, animals treated with ND demonstrated increased blood pressure that reached hypertensive
levels. These mechanisms are related to the ability of ND to produce a reduction of the anti-inflammatory
cytokine (IL-10) and augmentation of the pro-inflammatory cytokines (IL-6 and TNF-a) causing cardiac
remodeling and injury [63–66].
In a study by Omar and colleagues, the authors suggested a mechanism of androgenic stimulation of
platelet aggregation through either increased production of thromboxane A2 or decreased prostacyclin
and cyclooxygenase activity, synergistic with polycythemia, and increased platelet count thus causing
increased blood viscosity [67]. Pro-aggregatory effects on platelets because of high dosages of androgens
could be related to a decrease in cycloxygenase activity [68]. Most of these alterations could lead to an
increased thrombosis risk or atherosclerotic effects on vessels [42,69].
Medicina 2020, 56, 606 10 of 24

Many studies have tried to identify a direct relationship with heart disorders by performing
animal experiments and identifying autonomic dysfunction [70,71], fibrosis, hypertrophy,
and myopathy [56,72,73], affecting ionic balance across the organ with a probable synergistic effect
with other drugs [74].
Almaiman and colleagues showed an increase in creatine kinase (CKL) and creatine kinase muscle
and brain subunits (CK-MB) [30]. In a case reported by Huie and coworkers, an acute myocardial
infarction in an anabolic steroid user, raised questions about any link between them [75].
Most AAS abusers tend to use multiple substances at once, causing synergic effects and systemic
disorders whose causes cannot be quickly identified by physicians. In a study by Clark and colleagues,
the authors reported a case of a subject using several drugs, thus causing dilated cardiomyopathy [76].
Several molecular pathways are implied in androgen-induced cardiac damage, where nuclear and
cytoplasmatic factors play a role [77]. ND abnormally affects ionic balance in several ways, including
altered Ca2+ mobilization [74] downregulated K+ channel-interacting proteins causing longer QT
repolarization time [78], along with increased oxidative stress and pro-apoptotic effects [79].
Although previous studies verified the association between AAS exposure and high blood
pressure, the molecular mechanisms involved in blood pressure increase due to AASs are not
fully understood. Some studies, however, have suggested that mechanisms such as changes in
sodium balance, degenerative vascular lesions, cardiac hypertrophy, and an unfavorable lipid profile
exist [80,81]. Franquni M. and colleagues showed that myocyte hypertrophy and cardiac remodeling
(ND related) are related to augmentation of ACE activity and the development of a pro-inflammatory
state, and consequent cardiac changes result in the development of hypertension in animals treated
with ND [62].

4.3. Skin Disorders

In our data, the most reported skin lesions were colored patches, acne, and itch disorders.
Almaiman and colleagues, in a study conducted on a group of gym athletes who were using a mix of
several AASs, reported itching and the emergence of skin patches among other adverse reactions [30].
Similar skin characteristics were highlighted in another case report by Tripathi and colleagues, of
a 55-year-old woman [82]. Self-injection of ND in external genitalia was reported as the cause of
a paraffinoma and an above skin ulceration by Balighia and colleagues, in a 56-year-old man [83].
Such findings are in line with previous literature findings [19].

4.4. Psychiatric and Neurological Disorders

Evidence indicates the potential role of AASs in modifying behavior with symptoms such as
anxiety [84], concentration defects, irritability, and even violence during a long-term administration.
In contrast, when the administration was stopped, the reported side effects were melancholy and
depression [82,85,86].
Aggressiveness is a common finding in AAS abusers, among other psychiatric disorders [87],
and this has been confirmed by several studies on animals [88–93].
Several studies on animals confirmed neurotoxic effects of AASs in the brain. Turillazzi and
colleagues demonstrated the role played by oxidative stress, thus causing an apoptotic response in
the rat brain after chronic treatment with nandrolone decanoate [94]. Chronic exposure permanently
influences the expression of serotonergic and noradrenergic neurotransmission [95].
Both human and animal studies have shown dysfunction of visual-spatial memory after AAS use.
Magnusson and colleagues propose that administration of nandrolone to male rats may affect memory
function via dynorphinergic actions [96,97].
Seitz and colleagues highlighted an increased amygdala volume and reduced resting-state
functional magnetic resonance imaging (MRI) coupling of the amygdala with cognitive control
and memory regions in AAS abusers. The authors concluded that long-term AAS use might alter
amygdala-related functional and structural brain networks [85,98].
Medicina 2020, 56, 606 11 of 24

Moreover, Selakovic and colleagues suggested the possibility that alterations in hippocampal
parvalbumin interneurons (i.e., GABAergic system) may be involved in anxiousness induced by ND
abuse [99].
Chronic treatment with ND has been associated with impact on both opioid concentrations and
tachykinin levels in brain areas connected with the control of emotional behavior such as depression,
aggression, and reward.
The androgen action is related to its ability to bind and activate AR. The immunoreactivity of
substance P (SP), which is a peptidergic factor associated with enhanced aggression in several brain
regions, namely the amygdala, hypothalamus, periaqueductal gray area, and striatum [100], has been
shown to increase after ND administration. ND has also been shown to react on the Substance
P system at several levels, including receptor densities, peptide concentrations, and enzymatic
processing [101,102].
ND may induce its effect directly through AR, causing oxidative stress and different effects
across the brain [103]. Moreover, serotonin, glutamate, and dopamine systems, activation of
gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors as well as the
activation of steroid receptors, such as estrogen, mineralocorticoid, progesterone, and glucocorticoid
receptors, could all contribute to the altered behaviors described. Increased aggressive behavior
has been shown in many studies but there is no univocal opinion of authors because of different
methodological approaches [90]. While several studies correlate severity and duration of symptoms
with chronic ND administration, it is already known that a single injection of ND is enough to alter
brain activity: a hyper-adrenergic state with an increased amount of 5-hydroxytryptamine (5-HT)
metabolites in the hypothalamus, after a single dose [17], altered the reward system by affecting
dopamine metabolism [104], and altered monoamine metabolism [105].

4.5. Musculoskeletal Disorders

In our collected data, we identified only two studies that reported adverse effects of ND, both
concerning abusers.
Liow and colleagues reported a case of a 29-year-old male who abused a mix of several AASs and
got a bilateral rupture of the quadriceps tendons [106], while Stennard and colleagues presented a case
of isolated rupture of the triceps tendon in an athlete who was lifting weights [107]. Both cases suggest
that oral steroid abuse may cause negative effects on the mechanical properties of connective tissue,
confirming the experimental study of Marqueti and colleagues [108]. In animal experiments, anabolic
steroids produced a stiffer tendon that absorbs less energy and fails with less elongation [109].
The molecular mechanism underlying this altered tendon activity may be related to collagen
synthesis [60,110]. Hassager and colleagues concluded that anabolic steroids stimulate type III collagen
synthesis, which affects muscular tissues as well as bone tissues [111].

4.6. Excretory and Liver Disorders

Hepatotoxicity is one of the most frequent side effects of AAS abuse [112,113]. AAS-induced
hepatotoxicity has been hypothesized to be related to oxidative stress in hepatic cells. Indeed, because of
AR activation an increase in reactive oxygen species can be observed due to the increase in mitochondrial
b-oxidation. Moreover, antioxidant substances have a protective role against hepatotoxicity mediated
by AASs. It has also been demonstrated that androgenic potency and metabolic resistance are positively
linked to the degree of liver damage.
Medicina 2020, 56, 606 12 of 24

AAS-induced hepatotoxicity is influenced by genetic factors and is related to the infiltration of

inflammatory cells in liver tissue, such as lymphocytes, neutrophils, and eosinophils. Oxidative stress
could play a role in determining liver damage consequently to AAS abuse by activating androgen
receptors that lead to mitochondrial degeneration of hepatic cells. A recent study evaluated the liver
effects of five weeks of ND administration in rats. The results highlighted an increase of plasma
levels of liver necrosis markers, an increase in collagen deposition in liver parenchyma, portal space,
and centro lobular vein [113,114]. The mechanism involved in collagen deposition could be the increase
in the number and in the activity of Kuppfer cells. In this regard, Kuppfer cell activation leads to
the production of many inflammatory cytokines, such as transforming growth factor beta 1 (TGF-b1),
nuclear factor kappa-light-chain-enhancer of activated B cells (NF-Kb), and interleukin 1 beta (IL-1 β),
related to the liver fibrosis process [115,116].
Many AASs can be administrated in parenteral or oral ways, causing different metabolism altering
androgenic or anabolic effects. ND is injected intramuscularly with an oil that delays absorption and is
not hepatotoxic [16,117].
Several studies highlighted that prolonged androgen exposure has a direct toxic effect on kidneys,
especially glomerular cells, causing the accumulation of mesangial matrix, podocyte depletion and
structural adaptations [118,119]. In this regard, kidney tissues are characterized by the expression of
ARs. AR activation leads to cell growth and hypertrophy in the kidney. A recent report suggested that
ND exposure promotes hypertrophy in proximal and distal convoluted tubules of mice kidneys [120].
Moreover, both testosterone activity and ND direct action to AR may play a role in the genesis of
kidney fibrosis after long-term ND exposure [121].
Prolonged ND administration in mice has been shown to cause dose-dependent oxidative kidney
stress and damage. Indeed, mice kidneys treated with ND exhibited increased lipid peroxidation and
decreased antioxidant enzymes activity, such as glutathione reductase and glutathione peroxidase.
A recent study suggested a dose related oxidative stress in mice kidneys treated with prolonged doses
of ND [118]. The authors observed an increase in markers of lipid peroxidation and an increase of
pro-inflammatory and pro-apoptotic markers, such as IL-1 β, heat shock protein 90 (Hsp90), and tumor
necrosis factor (TNF) associated with a decrease of antioxidant enzymes, which could lead to secondary
focal segmental glomeruloscelerosis [118].
Bagchus and colleagues, studied healthy men after injecting ND: urinary metabolites were
detectable for at least 33 days after injection and the serum concentration of ND showed a half-life of
7–12 days [38].
Increasing bilirubin, alkaline phosphatase, and transaminases are the most frequent evidence in
blood. Several studies evidence the role of ND in functional and morphological liver and kidney changes,
thus developing an increase of creatinine, urea, alanine transaminase and aspartate transaminase blood
levels [30,122].
Kidney and liver histological changes in ND users are usually fibrosis and cell proliferation.
The causes of this degenerative process are multifactorial, but much evidence shows that oxidative
stress is involved [19,60,110,111,118]. During ultrasound examination, kidneys usually show increased
volume and cortical thickness in bodybuilders who regularly take anabolic steroids. These findings
are in line with the theory of a multifactorial association of steroid, hyperproteic diets and intensive
sport training being involved in renal damage [94,123] along with hypertension and fluid retention
that could probably be associated with a decreased level of kidney α1B-adrenoceptors [124,125].
Long administration could cause hepatic peliosis, fibrosis and hepatic cancer [126], and related
alteration of cellular redox balance [111,115]. Wen-Lung and colleagues studied the role of AR on
different liver diseases, but univocal results have not yet been obtained. Moreover, the underlying
molecular mechanism is not well defined [127].
Medicina 2020, 56, 606 13 of 24

4.7. Immune Disorders

In our collected data, we identified only one case concerning adverse effects of ND on abusers,
reported by Singh and colleagues, namely a 21-year-old man who started with a mix of anabolic steroids,
with the emergence of a rare serious adverse effect of suspected tubercular reactivation [46,128].
Supra-physiologic doses of common AASs alter immune function by influencing the production
of certain cytokines. In fact, the users of AASs have abnormal immunoglobulin (Ig) concentrations; the
lowest levels of immunoglobulin G (IgG), immunoglobulin M (IgM) and immunoglobulin A (IgA),
“significantly lower” than controls for IgA and IgM [129]. Kanda and coauthors [130] showed that
spontaneous IgM and IgG production in humans was inhibited by exposure to 1 nM testosterone,
which is nearly a physiological dose, suggesting that high doses would potentially adversely affect the
immune system. Some studies suggest that AASs are immune suppressive and depend on the type of
AAS used and the dose and timing of administration.
AASs increase serum hemoglobin concentrations, improving the aerobic capacity in athletes: two
studies recorded an AAS-induced alteration of hematology in athletes [131,132]. Alen demonstrated
an increase in serum hemoglobin concentration and hematocrit, platelets, and white blood cell count
after six months of high dose AASs. Similarly, Hartgens and coworkers found an increase in platelet
count after short-term dosing (eight weeks) of AASs. The significance of these studies is that they
indicate that AAS abuse can potentially affect erythropoiesis and other hematological parameters.
Hughes and associates [133] determined that supraphysiologic doses of nandrolone decanoate
and oxymethenelone enhanced the production of the inflammatory cytokines IL-1β and TNF-α in
human peripheral blood lymphocyte cultures in vitro.
On this basis, it can be hypothesized that the chronic administration of nandrolone, favoring the
persistence and viability of stem cells in different tissues, could represent a preconditioning that, in
addition to multiple hits, could enhance the risk of carcinogenesis onset especially in stem-cell-rich
tissues such as liver [40]. The side effects on the natural synthesis of anabolic steroids play a
potential role on hormonal changes/regulation and they could be suspected to be at the base of
certain carcinogenic mechanisms [134,135]. Furthermore, easily accessible and commonly diffused
AASs, such as nandrolone and stanozolol, playa potential role in the pathogenesis of cancer, such
as Leydig cell tumor, through multiple process pathways [134]. Nandrolone magnified cyclin D1
concentration, inducing breast cell proliferation. These processes, individually or in combination, can
induce micronuclei formation that are strictly related to several mutagenic stresses and are formed
following chromosomal damage eliciting profound modifications in genetic sequences by means of
alterations in telomerase activity [136].
Nandrolone is an androgen receptor agonist. On binding to the AR, it may induce the release of
the AR receptor from Hsp90 and its translocation to the nucleus; higher nandrolone concentrations
induced a more pronounced increase in Hsp90 levels of expression and phosphorylation. This result is
an indirect demonstration that nandrolone binds to AR and induces its activation. Hsp 90 was found
to be overexpressed in multiple cancers, including prostate cancer [137].

5. Conclusions
The anabolic-androgenic steroids are a family of hormones abused by athletes because of their
well-known properties on increasing muscle mass and strength, and among them ND is the most used
one. Historically, it was used for the treatment of anemia of chronic kidney disease, or osteoporosis in
postmenopausal women.
This review evidences that improper usage and abuse of AASs cause several adverse effects in all
body tissues and organs, highlighting the mechanics behind side effects. To sum up, inflammatory
cytokines, oxidative stress, protein synthesis alteration, and apoptosis are common mechanisms
involved in AAS-related damage.
Several studies showed cardiovascular and endocrine system, reproductive system,
musculoskeletal system, as well as kidney and liver are affected by side effects in most cases. To date
Medicina 2020, 56, 606 14 of 24

most experimental studies have been conducted on animal models, because it would be unethical to
administer high doses of AASs over prolonged periods of time. Much remains to be investigated about
the basic mechanisms in humans. Moreover, the habit of polydrug abuse makes it hardly possible to
distinguish the toxic effects of AASs from those caused by other drugs [138]. In addition, a general
limitation of human studies is the fact that data about the modality and doses of AAS use/abuse are
often self-reported. Furthermore, there is a tendency to abuse multiple substances at the same time.
Lastly, the susceptibility of individuals is influenced by genetic factors that are well known as key
factors in developing adverse events [139].
In a systematic review of the literature on online resources, we found a total of 766 articles, but
only 33 studies reported data about subjects abusing ND. Most reported adverse effects were endocrine
(18 studies, 42%), cardiovascular (six studies, 14%), skin (five studies, 12%), and psychiatric (four
studies, 9%) disorders.
Side effects secondary to the use of ND may arise in some cases since the first administration. Some
side effects regress quickly after suspension (for example, side effects on the skin or blood changes).
However, there are some side effects that persist for some time and may not regress completely on
suspension (for example, side effects on the reproductive, hormonal, nervous, and immune systems,
organ damage to the kidney and liver, and cardiovascular or behavioral changes).
The result of this review highlights the need to investigate the consequences of the use of these
substances because, currently, there are discordant results in many studies.

Author Contributions: Conceptualization, A.N.M.M., F.G.P. and A.M.; methodology, F.G.P. and A.M.; software,
F.G.P.; validation, N.D.N., A.L. and G.L.R.; formal analysis, P.M., M.E., G.L.R. and G.C.; resources, F.A., A.M.
and D.C.; data curation, A.N.M.M., F.G.P. and A.M.; writing—original draft preparation, F.G.P. and A.N.M.M.,
writing—review and editing, A.L., P.M. and M.E.; visualization, F.A. and G.C.; supervision, G.L.R., A.M. and
N.D.N.; project administration, A.M., N.D.N. and G.L.R. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Acknowledgments: The authors thank the Scientific Bureau of the University of Catania for language support.
Conflicts of Interest: The authors declare no conflict of interest.
Medicina 2020, 56, 606 15 of 24

Appendix A. General Data Obtained by Analyzing the Studies Included in This Literature Review
Name Authors Publication Date Males Females Age Abuse Adverse Effects
Suspected reactivation of extrapulmonary tuberculosis focus after
Singh V, Batta A. 2019 1 0 21 Yes Immune system disorders
non-medical abuse of anabolic androgenic steroids: a case report
Side effects of anabolic steroids used by athletes at Unaizah Gyms, Saudi
Almaiman AA 2019 12 0 30 Yes Kidney injuries, Skin disorders
Arabia: a pilot study
Evaluation of anabolic steroid induced renal damage with sonography in Kidney injuries, Cardiovascular
Kantarci UH 2018 22 0 25 Yes
bodybuilders disorders
Anabolic steroid abuse: what shall it profit a man to gain muscle and Cardiovascular disorders,
Chowdhury P 2017 1 0 30 Yes
suffer the loss of his brain? Neurological disorders
Impact of single-dose nandrolone decanoate on gonadotropins, blood Gårevik N, Börjesson A, Choong E,
2016 11 0 37,3 No Endocrine disorders
lipids and HMG CoA reductase in healthy men Ekström L, Lehtihet M.
Iatrogenic dependence of anabolic-androgenic steroid in an Indian Tripathi A, Tekkalaki B, Saxena S, Psychiatric disorders, Endocrine
2014 1 0 55 Yes
non-athletic woman Dandu H. disorders, Skin disorders
Chromosome damage and cytotoxicity in oral mucosa cells after 2
Martins RA, Gomes GA, Aguiar O Jr, Not
months of exposure to anabolic steroids (decadurabolin and winstrol) in 2010 15 0 Yes Genetic disorders
Medalha CC, Ribeiro DA. available
weight lifting
Paraffinoma and ulcer of the external genitalia after self-injection of Balighi K, Farsinejad K, Naraghi ZS,
2008 1 0 56 Yes Skin disorders
nandrolone Tamizifar B.
Acne induced by ‘Sus’ and ‘Deca’ Walker SL, Parry EJ. 2006 1 0 22 Yes Skin disorders
Kidney injuries, Cardiovascular
Dilated cardiomyopathy and acute liver injury associated with combined
Clark BM, Schofield RS. 2005 1 0 40 Yes disorders, Liver injuries, Endocrine
use of ephedra, gamma-hydroxybutyrate, and anabolic steroids
disorders
Hepatocellular adenomas associated with anabolic androgenic steroid Steensland P, Blakely G, Nyberg F,
2005 2 0 29 Yes Liver injuries
abuse in bodybuilders: a report of two cases and a review of the literature Fahlke C, Pohorecky LA.
Androgen-induced cerebral venous sinus thrombosis in a young body Kurling S, Kankaanp A, Ellermaa S,
2004 1 0 22 Yes Cardiovascular disorders
builder: case report Karila T, Sepp T.
Socas L, Zumbado M, Pérez-Luzardo
Effect of Nandrolone Decanoate on serum lipoprotein (a) and its isoforms Cardiovascular disorders,
O, Ramos A, Pérez C, Hernández JR, 2004 47 17 63 No
in hemodialysis patients Endocrine disorders
Boada LD.
Effects of androgenic-anabolic steroids on apolipoproteins and Steensland P, Hallberg M, Kindlundh A,
2004 19 0 31 No Endocrine disorders
lipoprotein (a) Fahlke C, Nyberg F.
Successful treatment of anabolic steroid-induced azoospermia with
Menon DK 2003 1 0 37 Yes Endocrine disorders
human chorionic gonadotropin and human menopausal gonadotropin
Measurement of androgen and estrogen receptors in breast tissue from Calzada L, Torres-Calleja J, Martinez JM,
2001 12 0 28 No Endocrine disorders
subjects with anabolic steroid-dependent gynecomastia Pedron N.
Reversible hypogonadism and azoospermia as a result of
Boyadjiev NP, Georgieva KN, Psychiatric disorders, Endocrine
anabolic-androgenic steroid use in a bodybuilder with personality 2000 1 0 20 Yes
Massaldjieva RI, Gueorguiev SI. disorders
disorder. A case report
Not
Androgens for the treatment of anemia in peritoneal dialysis patients Navarro JF 1998 9 0 No Endocrine disorders
available
Medicina 2020, 56, 606 16 of 24

A report on alterations to the speaking and singing voices of four women

Baker J 1999 0 4 43 No Endocrine disorders
following hormonal therapy with virilizing agents
Nandrolone decanoate is a good alternative for the treatment of anemia Gascón A, Belvis JJ, Berisa F, Iglesias E, Not
1999 14 0 No Endocrine disorders
in elderly male patients on hemodialysis Estopiñán V, Teruel JL. available
Effects of nandrolone decanoate (Decadurabolin) on serum Lp(a), lipids Lippi G, Guidi G, Ruzzenente O, Braga V, Not
1997 0 19 No Endocrine disorders
and lipoproteins in women with postmenopausal osteoporosis Adami S. available
Androgen therapy for anemia of chronic renal failure. Indications in the Not
Teruel JL 1996 67 17 No Endocrine disorders
erythropoietin era available
Exogenous androgens influence body composition and regional body fat
Not Psychiatric disorders, Endocrine
distribution in obese postmenopausal women—a clinical research Lovejoy JC 1996 5 5 No
available disorders, Skin disorders
center study
Bilateral rupture of the quadriceps tendon associated with
Liow RY 1995 1 0 29 Yes Musculoskeletal injuries
anabolic steroids
Assessment of attentional bias and mood in users and non-users of
Bond AJ 1995 32 0 23,2 Yes Psychiatric disorders
anabolic-androgenic steroids
Not
An acute myocardial infarction occurring in an anabolic steroid user Huie MJ 1994 1 0 Yes Cardiovascular disorders
available
Virilization of the voice in post-menopausal women due to the anabolic
Not
steroid nandrolone decanoate (Decadurabolin). The effects of medication GerritsmaEJ 1994 0 0 No Endocrine disorders
available
for one year
Rupture of the triceps tendon associated with steroid injections Stannard JP 1993 1 0 35 Yes Musculoskeletal injuries
Not
Anabolicsteroids in postmenopausalosteoporosis Need AG 1993 0 0 No Endocrine disorders
available
Exuberant local tissue reaction to intramuscular injection of nandrolone
decanoate (Decadurabolin)—a steroid compound in a sesame seed oil Not
Khankhanian NK 1992 1 0 Yes Connective disorders
base—mimicking soft tissue malignant tumors: a case report and review available
of the literature
Not
Anabolic steroid-associated hypogonadism in male hemodialysis patients Maeda Y 1989 66 0 No Endocrine disorders
available
Regeneration of murine megakaryocytopoiesis and the hematopoietic
Endocrine disorders, Sleep
inductive microenvironment after sublethal whole body irradiation by Johnson MW 1984 0 1 54 No
Apnea Syndrome
treatment with an anabolic steroid
Medicina 2020, 56, 606 17 of 24

References
1. Lee, D.M.; Min, T.; Choi, I.; Cheon, Y.P.; Chun, T.; Park, C.S.; Lee, K.H. Feeding effect of an anabolic
steroidnandrolone, on the male rat testis. Asian-Australas J. Anim. Sci. 2010, 23, 1566–1577. [CrossRef]
2. Sessa, F.; Salerno, M.; Di Mizio, G.; Bertozzi, G.; Messina, G.; Tomaiuolo, B.; Pisanelli, D.; Maglietta, F.;
Ricci, P.; Pomara, C. Anabolic Androgenic Steroids: Searching New Molecular Biomarkers. Front. Pharmacol.
2018, 9. [CrossRef] [PubMed]
3. Evans, N.A. Current Concepts in Anabolic-Androgenic Steroids. Am. J. Sports Med. 2004, 32, 534–542.
[CrossRef] [PubMed]
4. Pomara, C.; Neri, M.; Bello, S.; Fiore, C.; Riezzo, I.; Turillazzi, E. Neurotoxicity by Synthetic Androgen
Steroids: Oxidative Stress, Apoptosis, and Neuropathology: A Review. Curr. Neuropharmacol. 2015, 13,
132–145. [CrossRef]
5. Monda, V.; Salerno, M.; Fiorenzo, M.; Villano, I.; Viggiano, A.; Sessa, F.; Triggiani, A.I.; Cibelli, G.;
Valenzano, A.; Marsala, G.; et al. Role of sex hormones in the control of vegetative and metabolicfunctions of
middle-agedwomen. Europe PMC 2017, 8, 773. [CrossRef]
6. Wijnand, H.P.; Bosch, A.M.G.; Donker, C.W. Pharmacokinetic parameters of nandrolone (19-nortestosterone)
after intramuscular administration of nandrolone decanoate (Deca-Durabolin® ) to healthy volunteers.
Eur. J. Endocrinol. 1985, 110, S19–S30. [CrossRef]
7. Pardridge, W.M. 4 Serum bioavailability of sex steroid hormones. Clin. Endocrinol. Metab. 1986, 15, 259–278.
[CrossRef]
8. Llewellyn, W. Anabolics. Mol. Nutr. 2011, 193–194, 402–412.
9. Basaria, S.; Wahlstrom, J.T.; Dobs, A.S. Clinical review 138: Anabolic-androgenic steroid therapy in the
treatment of chronic diseases. J. Clin. Endocrinol. Metab. 2001, 86, 5108–5117. [CrossRef]
10. Bahrke, M.S.; Yesalis, C.E., 3rd; Wright, J.E. Psychological andbehavioural effects of endogenous testosterone
and anabolicandrogenicsteroids. Update Sports Med. 1996, 22, 367–390. [CrossRef]
11. Buckley, W.E.; Yesalis, C.E., 3rd; Friedl, K.E.; Anderson, W.A.; Streit, A.L.; Wright, J.E. Estimated prevalence
of anabolic steroiduse among male high school seniors. JAMA 1988, 260, 3210283. [CrossRef]
12. DuRant, R.H.; Rickert, V.I.; Ashworth, C.S.; Newman, C.; Slavens, G. Use of multiple drugs among adolescents
who useanabolic steroids. NEJM 1993, 328, 922–926. [CrossRef] [PubMed]
13. Kopera, H. The history of anabolic steroids and a review of clinicalexperience with anabolic steroids.
Acta Endocrinol. Suppl. 1985, 271, 11–18. [CrossRef] [PubMed]
14. Kadi, F.; Bonnerud, P.; Eriksson, A.; Thornell, L.-E. The expression of androgen receptors in human neck and
limb muscles: Effects of training and self-administration of androgenic-anabolic steroids. Histochem. Cell
Biol. 2000, 113, 25–29. [CrossRef] [PubMed]
15. Sinha-Hikim, I.; Artaza, J.; Woodhouse, L.; Gonzalez-Cadavid, N.; Singh, A.B.; Lee, M.I.; Storer, T.W.;
Casaburi, R.; Shen, R.; Bhasin, S. Testosterone-induced increase in muscle size in healthy young men is
associated with muscle fiber hypertrophy. Am. J. Physiol. Metab. 2002, 283, E154–E164. [CrossRef]
16. Pan, M.M.; Kovac, J.R. Beyond testosterone cypionate: Evidence behind the use of nandrolone in male health
and wellness. Transl. Androl. Urol. 2016, 5, 213–219. [CrossRef]
17. Tamaki, T.; Shiraishi, T.; Takeda, H.; Matsumiya, T.; Roy, R.R.; Edgerton, V.R. Nandrolone Decanoate Enhances
Hypothalamic Biogenic Amines in Rats. Med. Sci. Sports Exerc. 2003, 35, 32–38. [CrossRef] [PubMed]
18. Shahidi, N.T. A review of the chemistry, biological action, and clinical applications of anabolic-androgenic
steroids. Clin. Ther. 2001, 23, 1355–1390. [CrossRef]
19. Turillazzi, E.; Perilli, G.; Di Paolo, M.; Neri, M.; Riezzo, I.; Fineschi, V. Side effects of AAS abuse: An overview.
Mini-Rev. Med. Chem. 2011, 11, 374–389. [CrossRef]
20. Van Amsterdam, J.; Opperhuizen, A.; Hartgens, F. Adverse health effects of anabolic–androgenic steroids.
Regul. Toxicol. Pharmacol. 2010, 57, 117–123. [CrossRef]
21. Brower, K.J. Anabolic steroid abuse and dependence. Curr. Psychiatry Rep. 2002, 4, 377–387. [CrossRef]
[PubMed]
22. Basaria, S. Androgen Abuse in Athletes: Detection and Consequences. J. Clin. Endocrinol. Metab. 2010, 95,
1533–1543. [CrossRef] [PubMed]
Medicina 2020, 56, 606 18 of 24

23. Frati, P.; Busardò, F.P.; Cipolloni, L.; De Dominicis, E.; Fineschi, V. Anabolic Androgenic Steroid (AAS)
Related Deaths: Autoptic, Histopathological and Toxicological Findings. Curr. Neuropharmacol. 2015, 13,
146–159. [CrossRef] [PubMed]
24. Hall, R.C. Abuse of supraphysiologic doses of anabolic steroids. South Med. J. 2005, 98, 550–555. [CrossRef]
[PubMed]
25. Dotson, J.L.; Brown, R.T. The History of the Development of Anabolic-Androgenic Steroids. Pediatr. Clin.
N. Am. 2007, 54, 761–769. [CrossRef]
26. Stojanovic, M.D.; Ostojic, S.M. Steroids From Physiology to Clinical Medicine; Intech: Rijeka, Croatia, 2012;
pp. 169–186. [CrossRef]
27. De Souza, G.L.; Hallak, J. Anabolic steroids and male infertility: A comprehensive review. BJU Int. 2011, 108,
1860–1865. [CrossRef]
28. Fink, J.; Schoenfeld, B.J.; Hackney, A.C.; Matsumoto, M.; Maekawa, T.; Nakazato, K.; Horie, S.
Anabolic-androgenic steroids: Procurement and administration practices of doping athletes.
Physician Sportsmed. 2018, 47, 10–14. [CrossRef]
29. Pope, H.G.; Kanayama, G.; Ionescu-Pioggia, M.; Hudson, J.I. Anabolic steroidusers’attitudes towards
physicians. Addiction 2004, 99, 1189–1194. [CrossRef]
30. Almaiman, A.A.; Almaiman, S.H.; Elagamy, E.I.; Al Wutayd, O.; Almarzuqi, M.; Alzunaidi, R.; Alhatlani, S.;
Eid, E.E. Side effects of anabolicsteroidsused by athletesatUnaizahGyms, Saudi Arabia: A pilotstudy. J. Sports
MedPhys. Fit. 2019, 59, 489–495. [CrossRef]
31. Sessa, F.; Salerno, M.; Bertozzi, G.; Cipolloni, L.; Messina, G.; Aromatario, M.; Polo, L.; Turillazzi, E.;
Pomara, C. miRNAs as Novel Biomarkers of Chronic Kidney Injury in Anabolic-Androgenic Steroid Users:
An Experimental Study. Front. Pharmacol. 2020, 11. [CrossRef]
32. Albano, G.D.; Sessa, F.; Messina, A.; Monda, V.; Bertozzi, G.; Maglietta, F.; Giugliano, P.; Vacchiano, G.;
Gabriella, M.; Salerno, M. AAS and organs damage: A focus on Nandrolone effects. Oncotarget 2017, 6,
939–946.
33. Andrade, G.; Simão, V.; Souza, B.; Chuffa, L.G.A.; Camargo, I.C.C. Sex steroid receptors profiling is influenced
by nandrolone decanoate in the ampulla of the fallopian tube: Post-treatment and post-recovery analyses.
Tissue Cell 2018, 50, 79–88. [CrossRef] [PubMed]
34. Sessa, F.; Salerno, M.; Cipolloni, L.; Bertozzi, G.; Messina, G.; Di Mizio, G.; Asmundo, A.; Pomara, C.
Anabolic-androgenic steroids and brain injury: miRNA evaluation in users compared to cocaine abusers and
elderly people. Aging 2020, 12, 15314–15327. [CrossRef] [PubMed]
35. Simão, V.A.; Berloffa Belardin, L.; AraújoLeite, G.A.; de AlmeidaChuffa, L.G.; Camargo, I.C. Effects of
different doses of nandrolonedecanoate on estrous cycle and ovarian tissue of rats after treatment and
recovery periods. Int. J. Exp. Pathol. 2015, 96, 338–349. [CrossRef] [PubMed]
36. Bafunno, V.; Santacroce, R.; Chetta, M.; Peyvandi, F.; Sessa, F.; Chinni, E.; Longo, V.; Margaglione, M.
PolymorphicmiRNA-mediated gene contribution to inhibitor development in haemophilia A. Haemophilia
2012, 18, 1003–1007. [CrossRef]
37. Gomes, F.C.; Chuffa, L.G.A.; Scarano, W.R.; Pinheiro, P.F.F.; Fávaro, W.J.; Domeniconi, R.F. Nandrolone
decanoate and resistance exercise training favor the occurrence of lesions and activate the inflammatory
response in the ventral prostate. Andrology 2016, 4, 473–480. [CrossRef]
38. Bagchus, W.M.; Smeets, J.M.W.; Verheul, H.A.M.; Veen, S.M.D.J.-V.D.; Port, A.; Geurts, T.B.P. Pharmacokinetic
Evaluation of Three Different Intramuscular Doses of Nandrolone Decanoate: Analysis of Serum and Urine
Samples in Healthy Men. J. Clin. Endocrinol. Metab. 2005, 90, 2624–2630. [CrossRef]
39. Pany, S.; Panigrahi, S.K.; Rao, E.V.; Patnaik, L.; Sahu, T. Anabolic Androgenic Steroid Abuse and their Health
Impacts: A Cross-sectional Study among Body Builders in a City of Eastern India. Int. J. Prev. Med. 2019, 10,
178. [CrossRef]
40. Agriesti, F.; Tataranni, T.; Pacelli, C.; Scrima, R.; Laurenzana, I.; Ruggieri, V.; Cela, O.; Mazzoccoli, C.;
Salerno, M.; Sessa, F.; et al. Nandrolone induces a stemcell-like phenotype in human hepatocarcinoma-
derivedcell line inhibiting mitochondrial respiratory activity. Sci. Rep. 2020, 10, 2287. [CrossRef]
41. Sessa, F.; Maglietta, F.; Bertozzi, G.; Salerno, M.; Di Mizio, G.; Messina, G.; Montana, A.; Ricci, P.; Pomara, C.
Human Brain Injury and miRNAs: An Experimental Study. Int. J. Mol. Sci. 2019, 20, 1546. [CrossRef]
Medicina 2020, 56, 606 19 of 24

42. Ghorbani-Haghjo, A.; Argani, H.; Rahbaninobar, M.; Rashtchizadeh, N. Effect of Nandrolone Decanoate on
Serum Lipoprotein (a) and its isoforms in hemodialysis patients. Lipids Heal. Dis. 2004, 3, 16. [CrossRef]
[PubMed]
43. Hartgens, F.; Rietjens, G.; Keizer, H.; Kuipers, H.; Wolffenbuttel, B. Effects of androgenic-anabolic steroids on
apolipoproteins and lipoprotein (a). Br. J. Sports Med. 2004, 38, 253–259. [CrossRef] [PubMed]
44. Achar, S.; Rostamian, A.; Narayan, S.M. Cardiac and Metabolic Effects of Anabolic-Androgenic Steroid Abuse
on Lipids, Blood Pressure, Left Ventricular Dimensions, and Rhythm. Am. J. Cardiol. 2010, 106, 893–901.
[CrossRef] [PubMed]
45. Glazer, G.; Suchman, A.L. Lack of demonstrated effect of nandrolone on serum lipids. Metabolism 1994, 43,
204–210. [CrossRef]
46. Pomara, C.; Barone, R.; Gammazza, A.M.; Sangiorgi, C.; Barone, F.; Pitruzzella, A.; Locorotondo, N.; Di
Gaudio, F.; Salerno, M.; Maglietta, F.; et al. Effects of Nandrolone Stimulation on Testosterone Biosynthesis in
Leydig Cells. J. Cell. Physiol. 2016, 231, 1385–1391. [CrossRef]
47. Gårevik, N.; Börjesson, A.; Choong, E.; Ekström, L.; Lehtihet, M. Impact of single-dose nandrolone decanoate
on gonadotropins, blood lipids and HMG CoA reductase in healthy men. Andrologia 2015, 48, 595–600.
[CrossRef]
48. Balgoma, D.; Zelleroth, S.; Grönbladh, A.; Hallberg, M.; Pettersson, C.; Hedeland, M. Anabolic androgenic
steroids exert a selective remodeling of the plasma lipidome that mirrors the decrease of the de novo
lipogenesis in the liver. Metabolomics 2020, 16, 12–13. [CrossRef]
49. Racca, S.; Piccione, F.; Spaccamiglio, A.; Carriero, V.M.; De Francia, S.; Cangemi, L.; Esculapio, P.; Papotti, M.;
Migliaretti, G.; Portaleone, P.; et al. Effects of sub-chronic nandrolone administration on hormonal adaptive
response to acute stress in rats. Psychoneuroendocrinology 2012, 37, 1234–1247. [CrossRef]
50. Clark, A.S.; Henderson, L.P. Behavioral and physiological responses to anabolic-androgenic steroids.
Neurosci. Biobehav. Rev. 2003, 27, 413–436. [CrossRef]
51. Nishizawa, H.; Shimomura, I.; Kishida, K.; Maeda, N.; Kuriyama, H.; Nagaretani, H.; Matsuda, M.;
Kondo, H.; Furuyama, N.; Kihara, S.; et al. Androgens Decrease Plasma Adiponectin, an Insulin-Sensitizing
Adipocyte-Derived Protein. Diabetes 2002, 51, 2734–2741. [CrossRef]
52. Mesbah, F.; Bordbar, H.; Talaei-Khozani, T.; Dehghani, F.; Mirkhani, H.M. The non-preventive effects of
human menopausal gonadotropins on ovarian tissues in Nandrolone decanoate-treated female rats: A
histochemical and ultra-structural study. Int. J. Reprod. Biomed. 2018, 16, 159–174. [CrossRef] [PubMed]
53. Chuffa, L.G.A.; De Souza, R.B.; Frei, F.; Mesquita, S.D.F.P.; Camargo, I.C.C. Nandrolone Decanoate and
Physical Effort: Histological and Morphometrical Assessment in Adult Rat Uterus. Anat. Rec. Adv. Integr.
Anat. Evol. Biol. 2010, 294, 335–341. [CrossRef] [PubMed]
54. Gerritsma, E.J.; Brocaar, M.P.; Hakkesteegt, M.M.; Birkenhäger, J.C. Virilization of the voice in post-menopausal
women due to the anabolic steroid nandrolone decanoate (decadurabolin). the effects of medication for one
year. Clin. Otolaryngol. 1994, 19, 79–84. [CrossRef] [PubMed]
55. Mohammed, E.T.; Radi, A.M.; Aleya, L.; Abdel-Daim, M.M. Cynara scolymus leaves extract alleviates
nandrolone decanoate-induced alterations in testicular function and sperm quality in albino rats. Environ.
Sci. Pollut. Res. 2019, 27, 5009–5017. [CrossRef]
56. Kahal, A.; Allem, R.; Zahzeh, T.; Koriche, S.; Kouri, A.; Douani, A.; Kassoul, H.; Ababou, A. Evolutions
in cardiac and gonadal ultra-structure during a “cycle” of androgenic anabolic abuse in adult male mice.
Steroids 2020, 155, 108571. [CrossRef]
57. Kimura, N.; Mizokami, A.; Oonuma, T.; Sasano, H.; Nagura, H. Immunocy tochemical localization of
androgen receptor with polyclonal antibody in paraffin-embedded human tissues. J. Histochem. Cytochem.
1993, 41, 671–678. [CrossRef]
58. Pomara, C.; D’Errico, S.; Riezzo, I.; De Cillis, G.P.; Fineschi, V. Sudden cardiac death in a child affected by
Prader-Willi syndrome. Int. J. Leg. Med. 2005, 119, 153–157. [CrossRef]
59. Shirpoor, A.; Heshmatian, B.; Tofighi, A.; Eliasabad, S.N.; Kheradmand, F.; Zerehpoosh, M. Nandrolone
administration with or without strenuous exercise increases cardiac fatal genes overexpression,
calcium/calmodulin-dependent protein kinaseiiδ, and monoamine oxidase activities and enhances blood
pressure in adult wistar rats. Gene 2019, 697, 131–137. [CrossRef]
60. Liu, P.Y.; Death, A.K.; Handelsman, D.J. Androgens and Cardiovascular Disease. Endocr. Rev. 2003, 24,
313–340. [CrossRef]
Medicina 2020, 56, 606 20 of 24

61. Melchert, R.B.; Welder, A.A. Cardiovascular effects of androgenic-anabolic steroids. Med. Sci. Sports Exerc.
1995, 27, 1252–1262. [CrossRef]
62. Franquni, J.V.M.; Nascimento, A.M.D.; Lima, E.M.; Brasil, G.A.; Heringer, O.A.; Cassaro, K.O.D.S.; Da
Cunha, T.V.P.; Musso, C.; Santos, M.C.L.S.; Kalil, I.C.; et al. Nandrolone decanoate determines cardiac
remodelling and injury by an imbalance in cardiac inflammatory cytokines and ACE activity, blunting of the
Bezold–Jarisch reflex, resulting in the development of hypertension. Steroids 2013, 78, 379–385. [CrossRef]
63. Wei, P.K.M. Cytokine responses and myocardial injury in coronary artery bypass grafting. Scand. J. Clin. Lab.
Investig. 2001, 61, 161–166. [CrossRef]
64. Carmo, E.C.D.; Fernandes, T.; Koike, D.; Da Silva, N.D.; Mattos, K.C.; Rosa, K.T.; Barretti, D.; Melo, S.F.S.;
Wichi, R.B.; Irigoyen, M.C.C.; et al. Anabolic Steroid Associated to Physical Training Induces Deleterious
Cardiac Effects. Med. Sci. Sports Exerc. 2011, 43, 1836–1848. [CrossRef] [PubMed]
65. Du Toit, E.F.; Rossouw, E.; Van Rooyen, J.; Lochner, A. Proposed mechanisms for theanabolic steroid-induced
increase in myocardial susceptibility to ischaemia/reperfusion injury. Cardiovasc. J. S. Afr. 2005, 16, 21–28.
[PubMed]
66. Tanno, A.P.; Das Neves, V.J.; Rosa, K.T.; Cunha, T.S.; Giordano, F.C.L.; Calil, C.M.; Guzzoni, V.; Fernandes, T.;
Oliveira, E.M.; Novaes, P.D.; et al. Nandrolone and resistance training induce heart remodeling: Role of fetal
genes and implications for cardiac pathophysiology. Life Sci. 2011, 89, 631–637. [CrossRef] [PubMed]
67. Omar, M.; Abdul, R.; Panday, A.; Teelucksingh, S. Anabolic steroid abuse: What shall it profit a man to gain
muscle and suffer the loss of his brain? QJM: Int. J. Med. 2017, 110, 747–748. [CrossRef]
68. Sahraian, M.A.; Mottamedi, M.; Saeen, A.A.; Moghimi, B. Androgen-induced cerebral venous sinus
thrombosis in a young body builder: Case report. BMC Neurol. 2004, 4, 22. [CrossRef] [PubMed]
69. Neri, M.; Riezzo, I.; Pomara, C.; Schiavone, S.; Turillazzi, E. Oxidative-Nitrosative Stress and Myocardial
Dysfunctions in Sepsis: Evidence from the Literature and Postmortem Observations. Mediat. Inflamm. 2016,
2016, 1–12. [CrossRef] [PubMed]
70. Marocolo, M.; Silva-Neto, J.A.; Neto, O.B. Acute interruption of treatment with nandrolone decanoate is
not sufficient to reverse cardiac autonomic dysfunction and ventricular repolarization disturbances in rats.
Steroids 2018, 132, 12–17. [CrossRef] [PubMed]
71. Phillis, B.D.; Abeywardena, M.Y.; Adams, M.J.; Kennedy, J.A.; Irvine, R.J. Nandrolone Potentiates
Arrhythmogenic Effects of Cardiac Ischemia in the Rat. Toxicol. Sci. 2007, 99, 605–611. [CrossRef]
72. Akbari, Z.; Esmailidehaj, M.; Avarand, E.; Shariati, M.; Pourkhalili, K. Ischemic Preconditioning Efficacy
Following Anabolic Steroid Usage: A Clear Difference Between Sedentary and Exercise-Trained Rat Hearts.
Cardiovasc. Toxicol. 2018, 19, 287–296. [CrossRef] [PubMed]
73. Vasilaki, F.; Tsitsimpikou, C.; Tsarouhas, K.; Germanakis, I.; Tzardi, M.; Kavvalakis, M.; Ozcagli, E.;
Kouretas, D.; Tsatsakis, A.M. Cardiotoxicity in rabbits after long-term nandrolone decanoate administration.
Toxicol. Lett. 2016, 241, 143–151. [CrossRef] [PubMed]
74. Seara, F.D.A.C.; Arantes, P.C.; Domingos, A.E.; Barbosa, R.A.; Olivares, E.L.; Sudo, R.T.; De Carvalho, A.C.C.;
Nascimento, J.H. Cardiac electrical and contractile disorders promoted by anabolic steroid overdose are
associated with late autonomic imbalance and impaired Ca2+ handling. Steroids 2019, 148, 1–10. [CrossRef]
[PubMed]
75. Huie, M.J. An acute myocardial infarction occurring in an anabolic steroid user. Med. Sci. Sports Exerc. 1994,
26, 408–413. [CrossRef]
76. Clark, B.M.; Schofield, R.S. Dilated Cardiomyopathy and Acute Liver Injury Associated with Combined Use
of Ephedra, γ-Hydroxybutyrate, and Anabolic Steroids. Pharmacother. J. Hum. Pharmacol. Drug Ther. 2005,
25, 756–761. [CrossRef]
77. Lucas-Herald, A.K.; Alves-Lopes, R.; Montezano, A.C.; Ahmed, S.F.; Touyz, R.M. Genomic and non-genomic
effects of androgens in the cardiovascular system: Clinical implications. Clin. Sci. 2017, 131, 1405–1418.
[CrossRef]
78. Medei, E.; Marocolo, M.; Rodrigues, D.D.C.; Arantes, P.C.; Takiya, C.M.; Silva, J.; Rondinelli, E.;
Goldenberg, R.C.D.S.; De Carvalho, A.C.C.; Nascimento, J.H.M. Chronic treatment with anabolic steroids
induces ventricular repolarization disturbances: Cellular, ionic and molecular mechanism. J. Mol. Cell.
Cardiol. 2010, 49, 165–175. [CrossRef]
Medicina 2020, 56, 606 21 of 24

79. Fanton, L.; Belhani, D.; Vaillant, F.; Tabib, A.; Gomez, L.; Descotes, J.; Dehina, L.; Bui-Xuan, B.; Malicier, D.;
Timour, Q. Heart lesions associated with anabolic steroid abuse: Comparison of post-mortem findings in
athletes and norethandrolone-induced lesions in rabbits. Exp. Toxicol. Pathol. 2009, 61, 317–323. [CrossRef]
80. Guzzoni, V.; Cunha, T.S.; Das Neves, V.J.; Briet, L.; Costa, R.; Moura, M.J.C.S.; Oliveira, V.; Franco, M.;
Novaes, P.D.; Marcondes, F.K. Nandrolone combined with strenuous resistance training reduces vascular
nitric oxide bioavailability and impairs endothelium-dependent vasodilation. Steroids 2018, 131, 7–13.
[CrossRef]
81. Tofighi, A. The effect of nandrolone treatment with and without enforced swimming on histological and
biochemical changes in the heart and coronary artery of male rats. Anatol. J. Cardiol. 2017, 17, 176–183.
[CrossRef]
82. Tripathi, A.; Tekkalaki, B.; Saxena, S.; Himanshu, D. Iatrogenic dependence of anabolic-androgenic steroid in
an Indian non-athletic woman. BMJ Case Rep. 2014, 2014, 2013202472. [CrossRef] [PubMed]
83. Balighi, K.; Farsinejad, K.; Naraghi, Z.S.; Tamizifar, B. Paraffinoma and ulcer of the external genitalia after
self-injection of nandrolone. Int. J. Dermatol. 2008, 47, 1092–1094. [CrossRef] [PubMed]
84. Rosic, G.; Joksimovic, J.; Selakovic, D.; Milovanovic, D.; Jakovljevic, V. Anxiogenic effects of chronic exposure
to nandrolone decanoate (ND) atsupraphysiological dose in rats: A brief report. Neuro EndocrinolLett. 2014,
35, 703–710.
85. Seitz, J.; Lyall, A.E.; Kanayama, G.; Makris, N.; Hudson, J.I.; Kubicki, M.; Kaufman, M.J. White
matterabnormalities in long-term anabolic-androgenic steroidusers: A pilotstudy. Psychiatry Res.
Neuroimaging 2017, 260, 1–5. [CrossRef]
86. Thurelius, A.-M.; Garle, M.; Rane, A. The anti-doping hot-line, a means to capture the abuse of doping agents
in the Swedish society and a new service function in clinical pharmacology. Eur. J. Clin. Pharmacol. 2003, 59,
571–577. [CrossRef]
87. Boyadjiev, N.P.; Georgieva, K.N.; Massaldjieva, R.I.; Gueorguiev, S.I. Reversible hypogonadism and
azoospermia as a result of anabolic-androgenic steroid use in a bodybuilder with personality disorder. A case
report. J. Sports Med. Phys. Fit. 2000, 40, 271.
88. Masonis, A.; McCarthy, M.P. Direct interactions of androgenic/anabolic steroids with the peripheral
benzodiazepine receptor in rat brain: Implications for the psychological and physiological manifestations of
androgenic/anabolic steroid abuse. J. Steroid Biochem. Mol. Biol. 1996, 58, 551–555. [CrossRef]
89. Bertozzi, G.; Salerno, M.; Pomara, C.; Sessa, F. Neuropsychiatric and Behavioral Involvement in AAS Abusers.
A Literature Review. Medicina 2019, 55, 396. [CrossRef]
90. Busardò, F.P.; Frati, P.; Di Sanzo, M.; Napoletano, S.; Pinchi, E.; Zaami, S.; Fineschi, V. The Impact of
Nandrolone Decanoate on the Central Nervous System. Curr. Neuropharmacol. 2015, 13, 122–131. [CrossRef]
91. McGinnis, M.Y.; Lumia, A.R.; Possidente, B.P. Effects of withdrawal from anabolic androgenic steroids on
aggression in adult male rats. Physiol. Behav. 2002, 75, 541–549. [CrossRef]
92. Long, S.F.; Wilson, M.C.; Sufka, K.J.; Davis, W. The effects of cocaine and nandrolone co-administration on
aggression in male rats. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 1996, 20, 839–856. [CrossRef]
93. McGinnis, M.Y. Anabolic Androgenic Steroids and Aggression: Studies Using Animal Models. Ann. N. Y.
Acad. Sci. 2006, 1036, 399–415. [CrossRef] [PubMed]
94. Turillazzi, E.; Neri, M.; Cerretani, D.; Cantatore, S.; Frati, P.; Moltoni, L.; Busardò, F.P.; Pomara, C.; Riezzo, I.;
Fineschi, V. Lipid peroxidation and apoptotic response in rat brain areas induced by long-term administration
of nandrolone: The mutual cross talk between ROS and NF-kB. J. Cell Mol. Med. 2016, 20, 601–612. [CrossRef]
[PubMed]
95. Rainer, Q.; Speziali, S.; Rubino, T.; Dominguez-Lopez, S.; Bambico, F.R.; Gobbi, G.; Parolaro, D. Chronic
nandrolone decanoate exposure during adolescence affects emotional behavior and monoaminergic
neurotransmission in adulthood. Neuropharmacology 2014, 83, 79–88. [CrossRef] [PubMed]
96. Magnusson, K.; Hånell, A.; Bazov, I.; Clausen, F.; Zhou, Q.; Nyberg, F. Nandrolone decanoate administration
elevates hippocampal prodynorphin mRNA expression and impairsMorris water maze performance in male
rats. Neurosci. Lett. 2009, 467, 189–193. [CrossRef]
97. Bertozzi, G.; Sessa, F.; Albano, G.D.; Sani, G.; Maglietta, F.; Roshan, M.H.K.; Volti, G.L.; Bernardini, R.;
Avola, R.; Pomara, C.; et al. The Role of Anabolic Androgenic Steroids in Disruption of the Physiological
Function in Discrete Areas of the Central Nervous System. Mol. Neurobiol. 2018, 55, 5548–5556. [CrossRef]
Medicina 2020, 56, 606 22 of 24

98. Monda, V.; Salerno, M.; Sessa, F.; Bernardini, R.; Valenzano, A.; Marsala, G.; Zammit, C.; Avola, R.;
Carotenuto, M.; Messina, G.; et al. Functional Changes of Orexinergic Reaction to Psychoactive Substances.
Mol. Neurobiol. 2018, 55, 6362–6368. [CrossRef]
99. Selakovic, D.; Joksimovic, J.; Zaletel, I.; Puskas, N.; Matovic, M.; Rosic, G. The opposite effects of nandrolone
decanoate and exercise on anxiety levels in rats may involve alterations in hippocampal parvalbumin–positive
interneurons. PLoS ONE 2017, 12, e0189595. [CrossRef]
100. Hallberg, M.; Johansson, P.; Kindlundh, A.M.; Nyberg, F. Anabolic-androgenic steroids affect the content of
substance P and substance P1–7 in the rat brain. Peptides 2000, 21, 845–852. [CrossRef]
101. Pernow, B. Distribution of Substance P in the Central and Peripheral Nervous System. Nat. Cell Biol. 1953,
171, 746. [CrossRef]
102. Chang, M.M.; Leeman, S.E.; Niall, H.D. Amino-acid Sequence of Substance P. Nat. New Biol. 1971, 232, 86–87.
[CrossRef] [PubMed]
103. Zarei, F.; Moradpour, F.; Moazedi, A.A.; Pourmotabbed, A.; Veisi, M.; Veisi, M. Nandrolone administration
abolishes hippocampal fEPSP-PS potentiation and passive avoidance learning of adolescent male rats. Can. J.
Physiol. Pharmacol. 2019, 97, 130–139. [CrossRef] [PubMed]
104. Kurling, S.; Kankaanpää, A.; Seppälä, T. Sub-chronic nandrolone treatment modifies neurochemical
and behavioral effects of amphetamine and 3,4-methylenedioxymethamphetamine (MDMA) in rats.
Behav. Brain Res. 2008, 189, 191–201. [CrossRef] [PubMed]
105. Birgner, C.; Kindlundh-Högberg, A.M.; Oreland, L.; Alsiö, J.; Lindblom, J.; Schiöth, H.B.; Bergström, L.
Reduced activity of monoamine oxidase in the rat brain following repeated nandrolone decanoate
administration. Brain Res. 2008, 1219, 103–110. [CrossRef] [PubMed]
106. Liow, R.Y.; Tavares, S. Bilateral rupture of the quadriceps tendon associated with anabolic steroids. Br. J.
Sports Med. 1995, 29, 77–79. [CrossRef] [PubMed]
107. Stannard, J.P.; Bucknell, A.L. Rupture of the triceps tendon associated with steroid injections. Am. J. Sports
Med. 1993, 21, 482–485. [CrossRef] [PubMed]
108. Marqueti, R.D.C.; Prestes, J.; Wang, C.C.; Ramos, O.H.P.; Perez, S.E.A.; Nakagaki, W.R.; Carvalho, H.F.;
Selistre-De-Araujo, H.S. Biomechanical responses of different rat tendons to nandrolone decanoate and load
exercise. Scand. J. Med. Sci. Sports 2010, 21, e91–e99. [CrossRef]
109. Miles, J.W.; A Grana, W.; Egle, D.; Min, K.W.; Chitwood, J. The effect of anabolic steroids on the biomechanical
and histological properties of rat tendon. J. Bone Jt. Surg. Am. Vol. 1992, 74, 411–422. [CrossRef]
110. Tsitsimpikou, C.; Vasilaki, F.; Tsarouhas, K.; Fragkiadaki, P.; Tzardi, M.; Goutzourelas, N.; Nepka, C.;
Kalogeraki, A.; Heretis, I.; Epitropaki, Z.; et al. Nephrotoxicity in rabbits after long-term nandrolone
decanoate administration. Toxicol. Lett. 2016, 259, 21–27. [CrossRef]
111. Frankenfeld, S.P.; Oliveira, L.P.; Ortenzi, V.H.; Rego-Monteiro, I.C.; Chaves, E.A.; Ferreira, A.C.; Leitão, A.C.;
Carvalho, D.P.; Fortunato, R.S. The Anabolic Androgenic Steroid Nandrolone Decanoate Disrupts Redox
Homeostasis in Liver, Heart and Kidney of Male Wistar Rats. PLoS ONE 2014, 9, e102699. [CrossRef]
112. Bond, P.; Llewellyn, W.; Van Mol, P. Anabolic androgenic steroid-induced hepatotoxicity. Med. Hypotheses
2016, 93, 150–153. [CrossRef] [PubMed]
113. Neri, M.; Bello, S.; Bonsignore, A.; Cantatore, S.; Riezzo, I.; Turillazzi, E.; Fineschi, V. Anabolic 759 androgenic
steroidsabuse and liver toxicity. Mini Rev. Med. Chem. 2011, 11, 430–437. [CrossRef] [PubMed]
114. Solimini, R.; Rotolo, M.C.; Mastrobattista, L.; Mortali, C.; Minutillo, A.; Pichini, S.; Pacifici, I.; Palmi, I.
Hepatotoxicity associated with illicit use of anabolican drogenic steroids in doping. Eur. Rev. Med.
Pharmacol. Sci. 2017, 21 (Suppl. 1), 7–16. [PubMed]
115. Vieira, R.P.; França, R.F.; Damaceno-Rodrigues, N.R.; Dolhnikoff, M.; Caldini, E.G.; Carvalho-Pinto, R.M.;
Ribeiro, W. Dose-Dependent Hepatic Response to Subchronic Administration of Nandrolone Decanoate.
Med. Sci. Sports Exerc. 2008, 40, 842–847. [CrossRef]
116. Schwingel, P.A.; Cotrim, H.P.; Salles, B.R.; Almeida, C.E.; dos Santos, C.R., Jr.; Nachef, B.; Andrade, A.R.;
Zoppi, C.C. Anabolic-androgenic steroids: A possible new risk factor of toxicant-associated fatty liver disease.
Liver Int. 2011, 31, 348–353. [CrossRef]
117. Kalicharan, R.; Bout, M.; Oussoren, C.; Vromans, H. Where does hydrolysis of nandrolone decanoate occur
in the human body after release from an oil depot? Int. J. Pharm. 2016, 515, 721–728. [CrossRef]
Medicina 2020, 56, 606 23 of 24

118. Riezzo, I.; Turillazzi, E.; Bello, S.; Cantatore, S.; Cerretani, D.; Di Paolo, M.; Fiaschi, A.I.; Frati, P.;
Neri, M.; Pedretti, M.; et al. Chronic nandrolone administration promotes oxidative stress, induction
of pro-inflammatory cytokine and TNF-α mediated apoptosis in the kidneys of CD1 treated mice. Toxicol.
Appl. Pharmacol. 2014, 280, 97–106. [CrossRef]
119. Kahal, A.; Allem, R. Reversible effects of anabolic steroid abuse on cyto-architectures of the heart, kidneys
and testis in adult male mice. Biomed. Pharmacother. 2018, 106, 917–922. [CrossRef]
120. Hossein, L.; Roozbeh, J.; Sagheb, M.; Karbalay-Doust, S.; Noorafshan, A. Nandrolone decanoate increases
the volume but not the length of the proximal and distal convoluted tubules of the mouse kidney. Micron
2009, 40, 226–230. [CrossRef]
121. Brasil, G.A.; Lima, E.M.; Nascimento, A.M.D.; Caliman, I.F.; De Medeiros, A.R.S.; Silva, M.S.B.; De Abreu, G.R.;
Dos Reis, A.M.; Andrade, T.U.; Bissoli, N.S. Nandrolone decanoate induces cardiac and renal remodeling in
female rats, without modification in physiological parameters: The role of ANP system. Life Sci. 2015, 137,
65–73. [CrossRef]
122. Bertozzi, G.; Sessa, F.; Maglietta, F.; Cipolloni, L.; Salerno, M.; Fiore, C.; Fortarezza, P.; Ricci, P.; Turillazzi, E.;
Pomara, C. Immunodeficiency as a side effect of anabolic androgenic steroid abuse: A case of necrotizing
myofasciitis. Forensic. Sci. Med. Pathol. 2019, 15, 616–621. [CrossRef] [PubMed]
123. Kantarci, U.H.; Punduk, Z.; Senarslan, O.; Dirik, A. Evaluation of anabolic steroid induced renal damage
with sonography in bodybuilders. J. Sports Med. Phys. Fit. 2018, 58, s0022–s4707. [CrossRef] [PubMed]
124. Uhlén, S.; Lindblom, J.; Kindlundh, A.; Mugisha, P.; Nyberg, F. Nandrolone treatment decreases the level of
rat kidney alpha(1B)-adrenoceptors. Naunyn. Schmiedebergs Arch. Pharmacol. 2003, 368, 91–98. [CrossRef]
[PubMed]
125. Fineschi, V.; Neri, M.; Di Donato, S.; Pomara, C.; Riezzo, I.; Turillazzi, E. An immunohistochemical study in a
fatality due to ovarian hyper stimulation syndrome. Int. J. Leg. Med. 2006, 120, 293–299. [CrossRef]
126. Socas, L.; Zumbado, M.; Pérez-Luzardo, O.; Ramos, A.; Pérez, C.; Hernández, J.R.; Boada, L.D. Hepatocellular
adenomas associated with anabolic androgenic steroid abuse in bodybuilders: A report of two cases and a
review of the literature. Br. J. Sports Med. 2005, 39, e27. [CrossRef]
127. Ma, W.-L.; Lai, H.-C.; Yeh, S.; Cai, X.; Chang, C. Androgen receptor roles in hepatocellular carcinoma, fatty
liver, cirrhosis and hepatitis. Endocr.-Relat. Cancer 2014, 21, R165–R182. [CrossRef]
128. Singh, V.; Batta, A. Suspected reactivation of extra pulmonary tuberculosis focus after non-medical abuse of
anabolic androgenic steroids: A case report. J. Basic Clin. Physiol. Pharmacol. 2019, 31, 20190167. [CrossRef]
129. Calabrese, L.H.; Kleiner, S.M.; Barna, B.P.; Skibinski, C.I.; Kirkendall, D.T.; Lahita, R.G.; Lombardo, J.A.
The effects of anabolic steroids and strength training on the human immune response. Med. Sci. Sports Exerc.
1989, 21, 386–392. [CrossRef]
130. Kanda, N.; Tsuchida, T.; Tamaki, K. Testosterone inhibits immunoglobulin production by human peripheral
blood mononuclear cells. Clin. Exp. Immunol. 1996, 106, 410–415. [CrossRef]
131. Alén, M.; Reinilä, M.; Vihko, R. Response of serum hormones to and rogen administration in power athletes.
Med. Sci. Sports Exerc. 1985, 17, 354–359.
132. Hartgens, F.; Hamulyak, K.; Pernot, C.; Willems, S.M. Effects of high dosesandrogenic-anabolicsteroids
on haematoglicparameters in bodybuilders. In Proceedings of the 8th FIMS European Sports Medicine
Congress, Granada, Spain, 23–27 October 1995.
133. Hughes, T.K.; Fulep, E.; Juelich, T.; Smith, E.M.; Stanton, G. Modulation of immune responses by anabolic
androgenic steroids. Int. J. Immunopharmacol. 1995, 17, 857–863. [CrossRef]
134. Salerno, M.; Cascio, O.; Bertozzi, G.; Sessa, F.; Messina, A.; Monda, V.; Cipolloni, L.; Biondi, A.; Daniele, A.;
Pomara, C. Anaboli candrogenic steroids and carcinogenicity focusing on Leydigcell: A literature review.
Oncotarget 2018, 9, 19415. [CrossRef] [PubMed]
135. Tentori, L.; Graziani, G. Doping with growth hormone/IGF-1, anabolic steroids or erythropoietin: Is there a
cancer risk? Pharmacol. Res. 2007, 55, 359–369. [CrossRef]
136. Kara, M.; Ozcagli, E.; Fragkiadaki, P.; Kotil, T.; Stivaktakis, P.D.; Spandidos, D.A.; Tsatsakis, A.M.;
Alpertunga, B. Determination of DNA damage and telomerase activity in stanozolol-treated rats.
Exp. Ther. Med. 2016, 13, 614–618. [CrossRef] [PubMed]
137. Trepel, J.B.; Mollapour, M.; Giaccone, G.; Neckers, L. Targeting the dynamic HSP90 complex in cancer.
Nat. Rev. Cancer 2010, 10, 537–549. [CrossRef]
Medicina 2020, 56, 606 24 of 24

138. Dodge, T.; Hoagland, M.F. The Use of Anabolic Androgenic Steroidsand Polypharmacy: A Review of the
Literature. Drug Alcohol. Depend 2011, 114, 100–109. [CrossRef]
139. Schulze, J.J.; Rane, A.; Ekström, L. Genetic variation in androgen disposition: Implications in clinical medicine
including testosterone abuse. Expert Opin. Drug Metab. Toxicol. 2009, 5, 731–744. [CrossRef]

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional
affiliations.

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).