Steroids 155 (2020) 108574

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Steroids
journal homepage: www.elsevier.com/locate/steroids

Abuse of androgenic anabolic drugs with “Cycling” induces hepatic steatosis T

in adult male mice
⁎
Aida Kahala, , Rachida Allema, Touria Zahzehb, Saida Oulmanec, Zahra Tafroukhted
a
Laboratory of Natural Bioresources, Faculty of Science, Department of Biology, University of Hassiba Ben Bouali, BP 151, 02000 Chlef, Algeria
b
Laboratory of Molecular Microbiology, Proteomics and Health, Department of Biology, University of Djillali Liabes Sidi Bel Abbès, Algeria
c
Sadat Laboratory of Pathological Anatomy and Cytology, Chlef, Algeria
d
Faculty of Science, Department of Biology, University of Hassiba Ben Bouali, Chlef, Algeria

A R T I C LE I N FO A B S T R A C T

Keywords: Background: The importance of the present study comes from the lack of sufficient information about the re-
Androgenic drugs versibility of the potential hepatic histopathological alterations which may result from anabolic androgenic
Doping drugs abuse by “Cycling” protocol. So, the aim of this study is to explore the negative effects of Deca-Durabolin
Cycling abuse in hepatic function and structure during an administration cycle.
Liver
Methods: For our purpose, study was performed on 40 male adult mices. Animals were divided into five groups
Cyto-architecture
of 8 animals each treated weekly by Deca-Durabolin (nandrolone decanoate) at 30 g/kg of BW during one month
(GI); during two months (GII); during three months (GIII); during three months followed by six weeks of
treatment discontinuation (GIV) and Control (C). Plasma assay of liver enzymes (ALT and AST) and cytohisto-
logical examination to determine the histopathological damage properties of the liver were performed.
Results: Our results showed that the animals supported very well the administrated substance. Our study showed
an increase in plasma levels of liver enzymes (ALT and AST) with the duration of treatment accompanied by
important degenerative changes in hepatic tissue with peliosis evolution after two months of treatment. These
damages worsen again 6 weeks after stopping treatment and ended by the development of hepatic steatosis with
increases hepatic distress.
Conclusion: These results ported that the use of AAS with “Cycling” may lead to the development of hepatic
steatosis before progressing to more serious pathological liver situations in AAS abusers.

1. Introduction even fatal. Reported cases include suicides, acute myocardial infarction,
end-stage renal disease, peliosis hepatis, hepatic coma, hepatocellular
Anabolic-androgenic steroid (AAS) compounds were developed as adenoma and lymphoma related to athletes taking AAS [1,3,5,22–28].
synthetic analogs of testosterone produced to minimize androgenic ef- Therefore, anabolic steroids are known as multifaceted substance with
fects and maximize the anabolic ones [1–3]. They are prescribed for the both beneficial and harmful properties, and listed as reference sub-
treatment of primary or secondary hypogonadism, short stature [1,3], stances in terms of endocrine disruption for the reason that they largely
HIV wasting syndrome, severe burns [3], refractory anemia, hereditary remain the most bioactive compounds that exert their actions by dif-
angioedema, breast cancer, starvation states and osteoporosis [1]. On ferent general mechanisms [16].
the other hand, AAS ranks among the most widely abused drugs used by The “Cycling” is a widely used method by athletes in the AAS
athletes to improve athletic ability or muscle mass compounds [1,2,4]. consumption, it consists of using those drugs for a specified period,
For this purpose, the doses of these compounds used by athletes are in usually between 6 and 12 weeks, stop the administration during the
excess 10- to 100-fold of therapeutic doses [4–7]. same period, then repeat the cycle [1,29]. This model of administration
Abuse of AAS can cause various pathological changes related to is based on the idea that the adverse effects of AAS abuse are revertible
dose, frequency and use patterns. These alterations affect the hepatic, during this period, although this is not proven. Studies conducted in
cardiovascular, reproductive, musculoskeletal, endocrine, renal, im- this direction are few and prove absolutely the opposite of this idea,
munological, hematological and nervous systems [6–21], and can be noting here the irreversibility of adverse effects such as the cardiac

Abbreviations: AAS, anabolic androgenic steroid; IM, intra-muscular injection; BW, body weight
⁎
Corresponding author at: Mohamed Sella City, Jdiouia, 48360 Relizan, Algeria.
E-mail address: [email protected] (A. Kahal).

https://doi.org/10.1016/j.steroids.2019.108574
Received 10 September 2019; Accepted 27 December 2019
Available online 31 December 2019
0039-128X/ © 2019 Published by Elsevier Inc.
A. Kahal, et al. Steroids 155 (2020) 108574

disorders [30–32], sperm quality deterioration [4] and histological 2.2. Androgens administration
damage of heart and kidney [21]. The reversibility of hepatic altera-
tions due to AAS has only two recent studies available to our knowl- The commercial 19-nortestosterone ester used in experiment was
edge. The first is conducted on male albinos rats treated orally with nandrolone decanoate (Deca-Durabolin), purchased from Organon
anabol (supra-therapeutic daily dose of 18 mg/kg of body weight) for pharmaceutical company (N.V. Organon, Kloosterstraat 6, Oss – Pays-
3 months, and report that functional alterations and histopathological Bas). Androgen doses administration begun at the mice’s age of two
damage of liver are not completely reversible after one month of re- months. The animals were injected weekly at 30 mg per 1 kg of animal
covery [33]. However, Shalaby AM and Bahey NG (2018) ported that body weight. For our purpose, animals were divided into five groups as
hepatotoxic effects including hepatic damage induced by the supra- follows: treated by nandrolone decanoate during one month (GI,
physiological dose of nandrolone decanoate (10 mg/kg/IM/weekly, N = 8); during two months (GII, N = 8); during three months (GIII,
taken for four weeks) are reversible four weeks after its withdrawal in N = 8); during three months followed by six weeks of stop treatment
the adult male rat [34]. (GIV, N = 8) and Control (C, N = 8).
It should be noted that the protocols of animal experiments con-
ducted on the adverse effects of SAA, as well as those conducted on 2.3. Sampling
their reversibility, do not always resemble the way in which these drugs
are taken by athletes; the doses administered to the animal are often At the end of the treatment periods, the animals in each group were
under the dose of doping, and the frequency is sometimes far from real weighed then sacrificed (seven days after the last administration in GI,
in human practice. This remark is even mentioned by some authors [1]. GII, and GIII groups) by decapitation. Blood samples obtained were
In relation, the effect of AAS on the liver has attracted attention centrifuged. Plasma was separated and stored at (−20 °C) for bio-
given its importance. Studies in human and in animals report that he- chemical examination. The target organs for histopathological ex-
patic structure and function are severely altered by AAS abuse amination were obtained. After sampling and fresh wet organ weight
[9,16,25,33,35–37]. Socas L et al., (2005) report two very different registration the histological sections were accomplished.
cases of adult male bodybuilders who developed hepatocellular ade-
nomas following AAS abuse. The first had two large liver lesions. The 2.4. Biochemical assays
second had acute renal failure and mild hepatomegaly with several very
close hyperechogenic nodules in liver concordant with adenomas. In Plasma levels of Aspartate and Alanine transaminases (AST and
both cases, oral and parenteral SAA were taken by cycling at very high ALT) were determined by commercial spectrophotometric kids (SPIN-
doses [25]. Authors report that hepatic toxicity and alterations are in- REACT, Espagne).
duced by oral SAA, and almost exclusively by 17a-alkylated AAS
[25,33]. But it seems that SAA taken orally are not the only in- 2.5. Cytohistological exam
criminated. AAS taken by parenterally are also involved in these al-
terations as nandrolone decanoate [9,16,20,36] which is the major For cytohistological investigations, hepatic samples were fixed in
androgen administered for doping purposes [6,7,16,20,34,38]. formaldehyde 4%, after which they were washed, dehydrated and in-
To have targeted effects and minimize undesirable ones among cluded in paraffin. Paraffin blocks containing tissue fragments were
athletes, ways of taking these products are very complicated and not sectioned on microtome, resulting in 5-μm thick sections, after which
studied. Knowing that the dose and frequency of taking AAS largely they were mounted on glass slides. Sections were stained using the
influences the development of their undesirable effects, as well as the Hematoxylin–Eosin method. Microscopy was performed to determine
reversibility of these effects, the purpose of this study is to apply the and monitor histopathological damage in liver tissue.
manner of taking these products by the abusers in the most simple
administration: deca-dorabolin (nandrolone decanoate) taken in dose 2.6. Statistical analysis
estimated to be 10 times supra-medical (30 mg / kg of BW /IM per
week, for 3 months) well stopped treatment for 6 weeks; what con- To estimate the differences in quantitative variables, the compar-
stitutes a cycle of use frequently used by the abuser (president de- ison of the averages is done using the “Student” t test carried out on
scribed in this document) and follow the evolution of hepatotoxicity excel. All data were expressed as mean ± S.D. at P value < 0.05
and hepatic cyto-architecture under these conditions. significant

3. Results
2. Materials and methods
3.1. Biochemical results
2.1. Lab animals
The treated animals supported very well the administrated sub-
40 healthy adult male mices (Mus musculus) reported from the stance and the increase in muscle strength is the most noticeable trait in
Institut Pasteur of Alger, (Algeria) having 45 days with body weight longer-term treated groups. In Table 1 and Fig. 1 is presented the
between 25 and 40 g, were housed in groups of four mices in poly- average rate of ALT and AST plasmatic evolution in the studied groups
ethylene cages with 430 × 270 × 150 mm (L × w × h) dimensions, as before and after each administration.
bedding wood shaving being used. The environmental temperature was
maintained at 20 ± 20C and relative humidity of 25 ± 10%. They 3.2. Macroscopic and cytohistological observations
were fed ad libitum with a standard laboratory diet and had free access
to water. Animals were left for two weeks before commencement of the Important histological changes identified by us were present in li-
study to be acclimatized to lab conditions. Compliance with the legal vers from C, GI, GII, GIII groups in Fig. 2, and from GIV group in Fig. 4,
and ethical requirements for the humane treatment of animals de- accompanied by the modification macroscopic of liver from GIV group
scribed in this study is well confirmed and approved by the Department as presented in Fig. 3.
of Biology, Faculty of Nature and Life Sciences, Hassiba Benbouali Our results shown in Table 1 and Figs. 1 and 2 demonstrate dete-
University of Chlef. rioration in liver function and structure since the first month of nan-
drolone decanoate administration. these deteriorations worsen towards
the second and third months of treatment with the increase in mean

2
A. Kahal, et al. Steroids 155 (2020) 108574

Table 1
Average rate of plasmatic ALT and AST in mices from experimental and control group (U/L).
Group Mean ± standard deviation of ALT rate (U/L) Difference [%] Mean ± standard deviation of AST rate (U/L) Difference [%]

C 11,89 ± 5,71 – 32,08 ± 8,00 –

GI 71,00 ± 26,89 +497,37 41,56 ± 13,25 +29,55
GII 76,31 ± 20,13 +7,48 67,33 ± 22,26 +61,99
GIII 126,84 ± 20,81 +66,22 65,44 ± 21,16 −2,80
GIV 16,41 ± 2,93 −87,07 22,06 ± 8,39 −66,30

plasma levels of liver transaminases (ALT and AST) accompanied by be noted here that our animals, from the beginning of the experiment to
signs of peliosis, inflammation, hemorrhage, hypertrophy and cellular the end (5 months for the GIV group) behave very well; no sign of
degeneration in the liver tissue. discomfort, full of energy and motivation with remarkable strength
Remarkably, stopping treatment for 6 weeks is accompanied by a despite their pathological state, and it is perhaps the same situation
spotted liver appearance (Fig. 3). This appearance is clearly visible in among the abusers.
all the animals of the GIV group. Although the plasma ALT and AST Our findings regarding the deleterious effects of anabolic androgen
assay show a decrease in levels that are similar to the control values administration on liver function and structure are in agreement with
(Table 1 and Fig. 1), liver histology reveals well-distinguished peri- those of the other studies. Mohammed AR et al. (2017) ported that male
portal microvesicular steatosis (Fig. 4). Steatosis is associated with a albino rats treated by nandrolone decanoate at a dose of 7.93 mg/kg
total loss of structure in different areas accompanied by a frequent and 11.9 mg/kg for 8 weeks show an increase in body weight, hepatic
vascular hyalinization and fibrous structures in the lumen of vessels; and renal weights, liver enzymes (ALT and AST), plasma bilirubin, urea
which reflects a thrombosis with a fibro-hyaline organization (“hyali- and creatinine, depending on the dose of treatment, in addition to
nization” by fibrous organization of platelets), cellular hypertrophy, histopathological changes in the liver and kidneys. In rats treated with
degeneration zones and inflammations. This result shows that the 6- low dose, histological changes in the liver were congestion in central
week rest did not serve liver recovery. For against, the liver is in a vein and hepatic sinusoids, and cholangitis with appearance of newly
suffering state. formed bile ductuoles. The high dose induced thickening of hepatic
capsule and necrosis of subcapsular hepatocytes, cholangitis, severe
4. Discussion congestion of central vein and hepatic sinusoids, hydropic degeneration
of hepatocytes and hepatic périportal fibrosis [20]. In another study,
In the current study, supra-therapeutic doses of AAS were experi- nandrolone decanoate administration at three different doses; clinical,
mentally used to evaluate functional and different histological changes intermediate, and suprapharmacological dose (0.7, 5.3 and 7.5 mg/kg
in liver of adult male mices. So, the structural changes in liver of ani- of body weight, respectively) for 5 weeks, showed an increase in serum
mals that regularly use supraphysiological doses of AAS are char- levels of liver enzymes (ALT, AST and ALP), a decrease in total proteins,
acterized by the development of peliosis with an inflammatory aspect in bilirubin, total cholesterol and triglycerides. The number of Kupffer
the second and third months of treatment. In our study, these changes cells was increased in the liver parenchyma, and the content of collagen
worsen again 6 weeks after stopping treatment with a distinguished was increased in the central lobular vein wall, the hepatic parenchyma,
periportal microvesicular steatosis and loss of liver structure. So, our and the portal space, suggesting that subchronic administration of
results demonstrate liver damage induced by nandrolone decanoate, nandrolone decanoate lead to incipient fibrosis [9]. The inducing effect
which is a parenterally administered product and is considered less of AAS on the peliosis development in the liver is reported in humans
toxic to the liver compared to androgenic anabolic taken orally [25,33]. [22] and animals [33]. Notably, Cristina RT et al., (2014) ported that
These damages are not repairable and explain the hepatic alterations in the cytohistological images in livers of adults male rats injected by
the subjects who take the androgenic anabolic with “Cycling” described nandrolon decanoate (at 7.5 mg/kg BW, daily for 10 consecutive days)
in some case reports [25]. Indeed, in common practice, liver damage revealed the liver’s granular dystrophy; hydroprotidic dystrophy and
may be more serious because the dose used in our experimentation is steatosis characterized by the entry and storage of serum proteins in
the minimum used for doping. In addition, nandrolone decanoate is mitochondria, causing the mitochondria swelling (mega-mitochondria).
administered alone for one cycle, while the abusers take a mixture of Hepatocytes presented a pale cytoplasm and larger than normal (re-
anabolic androgenic products (and other complementary products) vealing the hypertrophy) due to micro- and macrovesicular steatosis as
a following of the endocrine disruptor activity. Also, was observed the
with much higher doses; modifiable during repeated cycles, which
means that the risk is higher. thickened of the intimae tunic of the central vein [16].
However, in our study, discontinuation of treatment induced the
The work done by this study comes to supplement the results re-
ported previously [21] on the reversible effects of androgen abuse on development of hepatic microvesicular steatosis in male adult mices. By
reviewing the literature, Hepatic steatosis is characterized by massive
cardiac, kidney and gonadal histopathology by the same experimental
protocol, and shows the gravity of the abuse of these products. It should fat accumulation in the liver and thus is strongly related to several

Fig. 1. Average rate of plasmatic ALT and AST in mices from experimental and control group (U/L). The difference is not significant at p > 0,05; significant (s) at
p ≤ 0,05; very significant (vs) at p < 0,01; highly significant (hs) at p < 0,001; very highly significant (vhs) at p < 0,0001.

3
A. Kahal, et al. Steroids 155 (2020) 108574

Fig. 2. Hepatic histological sections in male mices from C, GI, GII and GIII groups (H&E stain, ×100, ×400 and ×1000). A photomicrograph of a transversal section
of liver in C group showing a preserved hepatic parenchyma structure; slightly dilated sinusoids and normal-sized portal spaces with venous lumen, arterial lumen,
and biliary canal (1, ×400). A photomicrograph of a transversal section of liver in GI group 1 month after intramuscular injection of androgen showing a dilation of
the sinusoids, expanded portal space with dilation of the portal vein without inflammatory aspect (2, ×100), a dilated central vein, hepatocytes are outsized and
their cytoplasm is heterogeneous seems to have distinct intracellular organelles (3, ×400). A photomicrograph of a transversal section of liver in GII group 2 months
after intramuscular injection of androgen showing a dilation of the sinusoids, expanded portal space with dilation of the portal vein and biliary canal (4, ×100), a
congested central vein too dilated with extravasation of red blood cells and edema (5, ×400) vasocongestion, blood lakes, hyalinization and pyknotic nuclei (6,
×400); more clearly visible (7 and 8, ×400). A photomicrograph of a transversal section of liver in GIII group 3 month after intramuscular injection of androgen
showing a congested central vein too dilated and pyknotic nuclei (9, ×400), a dilated portal vein and portal artery, inflammatory infiltrate and edema (10, ×1000),
vasocongestion and blood lake, hypertrophy of hepatocytes with a heterogeneous cytoplasm including remarkable intracellular organelles (11, ×400).

features of metabolic syndrome, including hyperlipidemi and insulin storage in the liver [39]. In accordance, Foletto MP et al. (2015) ported
resistance. It’s associated with imbalance between glucose production that intramuscular injections of nandrolone decanoate (0.5 mg/kg/
and catabolism, lipid formation and breakdown, and cholesterol week) during four weeks caused a decrease on diameter of adipocytes
synthesis and secretion. In males, testosterone works via androgen re- and in the amount of adipose tissue stored, as well as decreased the
ceptors to decrease glucose uptake and lipogenesis, increase insulin plasma levels of glucose and total cholesterol in adult male rats [38]. It
receptor expression and glycogen synthesis, and promote cholesterol is important to note here that hepatic steatosis is one of the risk factors

4
A. Kahal, et al. Steroids 155 (2020) 108574

androgen treatment may lead to an increase of the adipose tissue stores

[38].
On the other hand, it’s demonstrated that supraphysiological doses
of nandrolone decanoate induces genetic damage in multiple organs
[13,15], and are able to disrupt redox balance in organs that can lead to
many diseases linked to oxidative stress [7,14,43]. So, the study of do
Carmo CA et al. (2012) showed dose-related increase in the frequency
of DNA damage in liver cells and other organs at three single tested
doses (1.0, 2.5 and 5.0 mg/kg BW) of nandrolone decanoate in adult
male Swiss albino mice [13]. Frankenfeld SP et al. (2014) indicate that
oxidative stress is linked to the pathophysiology of most of these al-
terations, being involved in fibrosis, cellular proliferation, tumorigen-
esis, amongst others. The same authors demonstrated that chronically
administered nandrolone decanoate (10 mg/kg of body weight once a
week for 8 weeks) is able to disrupt the cellular redox balance in liver,
heart and kidney, leading to an oxidative stress stat in Wistar adult male
rats [7].

Fig. 3. Photomacrograph of liver in male mices from GVI group. All the animals 5. Conclusion
treated with androgens for 3 months, and then stopped the treatment for
6 weeks, have a visibly spotted liver. Our results reports that the use of AAS for a period of 3 months by
only a 10 times supra-therapeutic dose is associated with a lot of de-
leading to the development of liver cancer [40–42]. leterious effects on liver with peliosis and hepatic inflammations in
In addition, it’s admitted that the AAS administration with high male which cannot be reversible. Moreover, these effects worsen again
dose inhibits gonadal function by the negative retro-control exerts on 6 weeks after stopping treatment. Therefore, the periodical cessation of
the hypothalamic-pituitary-gonadal axis by these products [12,17,18]. treatment which constitutes a “Cycling” protocol for abusers leads to
The gonadal function is not restored immediately after the treatment the development of hepatic steatosis and increases hepatic distress. It
cessation [4,21], which signifies that the testosterone production re- can be concluded from the present histopathological results that
mains low at this time. We think that, until the testes recover and begin abusing AAS by “Cycling” for long periods by athletes can induce ser-
to manufacture testosterone in an amount sufficient for metabolic ious histological damages in liver which may lead to the development
functions, the plasma level of androgens decreases and the liver is de- of hepatic steatosis before progressing to more serious pathological
prived of androgenic signal, which results in the increase of the lipo- liver situations such as hepatic carcinoma. So, physicians should take
genesis and fat accumulation in this organ. According to our proposal, these damages in mind seriously as a predictable and potential com-
some authors mention the possibility that the interruption of the plication in liver resulting from abusing these drugs. At the same time,
the control and restrictions on these drugs should be increased to

Fig. 4. Hepatic histological sections in male mices from GVI group (H&E stain, ×100, ×400 and ×1000). A photomicrograph of a transversal section of liver in GIV
group 3 months after intramuscular injection of androgen followed by six weeks of treatment discontinuation showing deteriorated liver parenchyma architecture (1,
×100), microvesicular steatosis (lipid overload) periportal (in the peripheral of the portal space) (2, ×400), a dilated biliary canal and inflammatory infiltrate (3,
×1000), loss of structure, vasocongestion and vascular hyalinization (4, ×400), fibrous appearance of vascular lumens, edema and inflammatory infiltrate (5,
×400), hyalinization, pyknotic nuclei and areas of cellular degeneration (6, ×400).

5
A. Kahal, et al. Steroids 155 (2020) 108574

prevent the abusers from obtaining these drugs. All these findings are target tissues after testosterone administration compared to nandrolone decanoate
confirming the important deleterious activity as endocrine disruptor on in castrated rats in the aim of Hershberger bio test, Rom. J. Morphol. Embryol. 55
(3) (2014) 1143–1148.
liver for over dose of androgens administration. [17] M.A.E. Ahmed, Amelioration of nandrolone decanoate-induced testicular and sperm
toxicity in rats by taurine: effects on steroidogenesis, redox and inflammatory
Acknowledgements cascades, and intrinsic apoptotic pathway, Toxicol. Appl. Pharmacol. 282 (3)
(2015) 285–296.
[18] R. Jannatifar, S. Shokri, A. Farrokhi, R. Nejatbakhsh, Effect of supraphysiological
We would like to acknowledge the technical assistance of all stu- dose of Nandrolone Decanoate on the testis and testosterone concentration in ma-
dents on the animal work presented in this study. ture and immature male rats: a time course study, Int J Reprod BioMed 13 (12)
(2015) 779–786.
[19] A.E. Rosca, I. Stoian, C. Badiu, et al., Impact of chronic administration of anabolic
Conflict of interest statement androgenic steroids and taurine on blood pressure in rats, Braz. J. Med. Biol. Res. 49
(6) (2016) e5116.
[20] A.R. Mohammed, G.M. Al-Galad, A.A. Abd-Elgayd, M.A. Mwaheb, H.M. Elhanbuli,
The authors declare that they have no competing interests.
Effect of nandrolone decanoate (anabolic steroid) on the liver and kidney of male
albino rats and the role of antioxidant (antox-silymarin) as adjuvant therapy, J.
Role of the funding source Drug Metab. Toxicol. 8 (1) (2017) 224.
[21] A. Kahal, R. Allem, Reversible effects of anabolic steroid abuse on cyto-archi-
tectures of the heat, kidneys and testis in adult male mice, Biomed. Pharmacother.
This work has not been financed; the only funding is that of the 106 (2018) 917–922.
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steroid therapy: a severe form of hepatic injury, Ann. Intern. Med. 81 (5) (1974)
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Nature and Life Sciences, Hassiba Benbouali University of Chlef. bodybuilder: a multifactorial process or simply doping? Nephrol. Dial. Transplant.
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