Keywords:
Hepatocellular carcinoma - Anabolic androgen steroids - Testosterone congeners
Descritores:
Carcinoma hepatocellular - Esteroides andrógenos anabólicos - Congêneres da testosterona
INTRODUCTION
Hepatocellular carcinoma (HCC) corresponds to 90% of primary malignant liver cell
carcinomas and is a leading cause of cancer-related death worldwide. The prevalence
of HCC is higher in males than in females (2.4:1), as well the incidence in Eastern
and Southern Asia, Middle and Western Africa, Melanesia and Mi-cronesia/Polynesia.([1], [2])
Many different etiological factors are involved in the development of HCC as chronic
hepatitis B/C, chronic alcohol consumption, nonalcoholic steatohepati-tis (NASH) and
aflatoxin exposure.([1]–[3]) Less common factors are long-term use of oral contraceptives and high-dose anabolic
androgenic steroids.([1], [3])
The association between androgen exposure and the development of HCC was first reported
by Recant and Lacy in 1965 in a male patient with Fanconi’s Anemia. Since this publication,
several clinical reports have been published linking long term androgen exposure to
HCC in Fanconi’s and non-Fanconi’s patients.([4], [5])
Anabolic androgen steroids (AAS), synthetically produced hormones analogs to male
testosterone, are commonly misused and self-administrated by healthy subjects to enhance
physical performance. This independent practice raises concerns because the majority
of users are not aware of their potential life threatening risks.([6], [7])
This compilation of published case reports aims to identify evidence linking anabolic-androgen
steroids abuse for physical performance improvement in healthy subjects and hepatocellular
carcinoma.
METHODS
We performed a literature review searching in Pub-Med, Embase, Scopus and Lilacs databases
using the following key words: ‘liver cell carcinoma’/exp OR ‘carcinoma, hepatic cell’
OR ‘carcinoma, hepatocel-lular’ OR ‘carcinoma, liver’ OR ‘carcinoma, liver cell’ OR
‘hepatic carcinoma’ OR ‘hepatic cell carcinoma’ OR ‘hepatocarcinoma’ OR ‘hepatocellular
carcinoma’ OR ‘hepatoma’ OR ‘liver carcinoma’ OR ‘liver carcinoma rupture’ OR ‘liver
cell carcinoma’ OR ‘malignant hepatoma’ OR ‘primary liver carcinoma’ AND (‘anabolic
agent’/exp OR ‘anabolic agent’ OR ‘anabolic agents’ OR ‘anabolic drug’ OR ‘anabolic
hormone’ OR ‘anabolic steroid’ OR ‘anabolic steroid agent’ OR ‘anabolic steroids’
OR ‘anabolizing agent’ OR ‘anabo-lizing cream’ OR ‘anabolizing drug’ OR ‘anabolizing
treatment’ OR ‘steroid, anabolic’ OR ‘androgen’/exp OR ‘androgen’ OR ‘androgen sulfate’
OR ‘androgen sulphate’ OR ‘androgenic agent’ OR ‘androgenic hormone’ OR ‘androgenic
steroid’ OR ‘androgens’ OR ‘androgens, synthetic’).
We have identified 935, 1148, 12 and 3 articles in Pubmed, Embase, Scopus and Lilacs,
respectively. Last literature research was performed on 27th December, 2017. The three
authors searched independently in databases. Only studies, reviews and case reports
evaluating the association between andro-gens and hepatocarcinoma were included with
no restrictions in time span or language. Further on, we excluded studies and case
reports which patients were receiving therapeutic androgens and collected data only
of those reporting androgen intake to improve physical performance.
Six articles fulfilled these inclusion criteria, excluding the duplicates. For general
purposes, we included conceptual studies evaluating the link between an-drogens and
HCC.
RESULTS
The review of literature identified 6 case reports linking anabolic androgen steroids
uses for enhancing physical performance and hepatocellular carcinoma.
([Table 1]) No clinical trials or retrospective studies regarding the subject were found.
Table 1
Case reports of hepatocellular carcinoma after long term anabolic androgen steroids
use for performance enhancement in healthy subjects
|
Age
|
Sex
|
Androgen, Duration
|
Patient characteristics
|
Alfa-fetoprotein
|
Pathology and management
|
Outcomes
|
References
|
|
26y
|
M
|
Four years taking one or more androgens: methandrosteno-lone, oxandrolone, stanozolol,
nandrolonedecanoate, and methenolone.
|
Bodybuilder This patient also had a cholangio carcinoma
|
375ng/mL
|
Pleural and liver biopsies were performed. Patient refused treatment.
|
Near total liver replacement by tumor and pleural, pulmonary and intraabdominal metastases.
Died 4 months after diagnosis.
|
Overly et al, 1984.([8])
|
|
37y
|
M
|
Five years taking, firstly, methandrostenolone and, after, oxymetholone.
|
Athlete
|
NA
|
Liver biopsy followed by tumor resection. Tumor with 1.8 Kg.
|
NA
|
Goldman B, 1985.([9])
|
|
35y
|
M
|
Two years taking one or more androgens: testosterone, stano-zolol, nandrolonedeconat
|
Bodybuilder
|
Normal
|
Right hemi-hepatec-tomy for a tumor with 70 × 90 mm.
|
NA
|
Gorayski et al, 2008.([10])
|
|
37y
|
M
|
Five years taking one or more androgens: Testosterone propionate, testosterone phenylpropiona-te,
testosteroneisocaproate, testosteronedecanoate,-trenboloneacetate, 5alpha--androstanediol,
boldenone and methandrioldipropionate, 17α-Methyl-5α-androstano[3, -2-c]pyrazole-17β-ol,
17β-hy-droxy-17α-methyl-2-oxa-5α-an-drostane-3-one, oxymetholonor methandienone.
|
Bodybuilder
|
Normal
|
Partial hepatectomy for a tumor with 60 × 60 × 50 mm.
|
After a follow-up period of 27 months there were no recurrence signs.
|
Hardt et al, 2012.([11])
|
|
24y
|
M
|
Seven years of testosterone 200mg/week.
|
Bodybuilder
|
366 ng/mL
|
Liver biopsy was performed. The two biggest lesions had 111 × 105 mm (right lobe)
and 79 × 72 mm (left lobe).
|
NA
|
Kesler et al, 2014([12])
|
|
29y
|
M
|
Six years taking one or more androgens: nandrolone decanoate, sustanon, methandienone,
stanozolol.
|
Bodybuilder
|
NA
|
Liver biopsy followed by liver transplantation.
|
27 months after liver transplantation he is in excellent condition without any signs
of metastasis or local recurrence.
|
Solbach et al, 2015.([13])
|
NA: not available
DISCUSSION
Historically, the use of anabolic steroids dates back to World War II when they were
provided to German soldiers in order to enhance their aggressiveness. Since then,
anabolic steroids have become increasingly popular amongst athletes, so much so, that
steroid use in both professional and amateur athletics has reached epidemic proportions.
In the late 1950s, Ciba Pharmaceuticals introduced methandrosteno-lone.([14]
[15]
[16]
[17]) which would become the most popular anabolic drug for athletes. By this time, the
era of the steroid athletes was well underway and world records were being shattered
and re-shattered with remarkable regularity.([15]) Nowadays, this practice is controlled by specialized agencies, but despite the
increased surveillance, it is still a concern in sports.
Estimates of the extent of steroid use among intercollegiate male athletes range from
2% to 20%.([17]
[18]
[19]
[20]) Two-thirds of AAS abusers start by the age of 16 years([18]) and the main reasons for using steroids are to increase strength and size, improve
physical appearance, enhance athletic and sexual performance.([21]) In Brazil, the unsupervised use of AAS is a reality and a risk not only for HCC
and hepatic adenoma (HCA), but also for fatty liver disease.([22])
The scarcity of data in the literature linking HCC and AAS in healthy patients for
performance improvement might be due to the abnormal development of HCC after AAS
usage, underdiagnosis and/or under-reported cases.
Hepatocarcinoma onset after AAS abuse seems to occur at earlier ages than HCC triggered
by chronic hepatitis B/C, chronic alcohol consumption and nonalcoholic steatohepatitis
(NASH).([8]
[9]
[10]
[11]
[12]
[13]) HCC outbreak is also time-dependent and long term usage appears to be required
for HCC development and timeframe for onset ranged from two to seven years in the
cases reported in this literature review. However, it is important to stress that
despite HCC being probably a late complication of continuous AAS use, much other life
threatening complications can occur earlier on, so unsupervised AAS usage is a high
risk strategy and not recommended to any healthy subjects.([7]) [Table 2] describe the main complications of AAS continuous exposure.
Table 2
Adverse events related to anabolic androgen steroids.([7],[22])
|
Adverse events
|
|
Cardiovascular
|
Neuropsychiatry
|
|
Coronary heart disease
|
Reduced inhibitory control
|
|
Cardiomyopathy
|
Anxiety
|
|
Erythrocytosis
|
Aggression, violence, impulsive behavior
|
|
Hemostasis/coagulation abnormalities
|
Depression
|
|
Dyslipidemia
|
Hypomania and, occasionally, frank mania
|
|
Hypertension
|
Dependence
|
|
Atherosclerosis
|
Men
|
|
Arrhythmia
|
Hypogonadism
|
|
Anatomic remodeling
|
Testicular atrophy
|
|
Infection
|
Gynecomastia
|
|
HIV, hepatitis B and C, MRSA (unsafe needle practices and contaminated products)
|
Suppression of spermatogenesis
|
|
Musculoskeletal
|
Impaired fertility
|
|
Tendon rupture
|
Acne
|
|
Amyotrophic lateral sclerosis
|
Premature epiphyseal closure
|
|
Women
|
Potential increased risk for prostate cancer
|
|
Acne
|
Renal
|
|
Virilization (hirsutism, deepening of voice, clitoromegaly)
|
Renal insufficiency
|
|
Irregular menses
|
Proteinuria
|
|
Hepatic
|
Nephrotic syndrome
|
|
Fatty liver disease
|
|
|
Cholestasis
|
|
|
Peliosis hepatis
|
|
|
Hepatic adenoma
|
|
|
Hepatocarcinoma
|
|
Hepatocellular carcinoma is more prevalent in men than in women and one of the reasons
for this difference could be related to testosterone and androgen receptor (AR) activities.([2], [23], [24]) Human epidemiological studies have shown that elevated testosterone levels and
the presence of genetic polymorphisms linked to increased androgen activity were significantly
associated with a higher risk of HCC in male HBsAg carriers.([24]
[25]
[26]) In rodent HCC models, castration, treatment with anti-androgen agents and modulation
of AR can protect male rodents from tumor development.([27], [28]) This evidence suggest that up-regulation of the androgen pathway signaling in male
patients is able to accelerate the carcinogenic process in he-patocytes([24], [27], [28])
AAS subtypes seem to induce distinct liver damage; e.g.17a-alkylated AAS appear to
be hepatotox-ic whereas non-alkylated AAS is not. The 17a-alkyl substitution delays
hepatic metabolism of the AAS, rendering it orally bioavailable. The main mechanism
responsible for the hepatotoxicity induced by 17a-alkylated AAS is probably induction
of oxida-tive stress, because it has repeatedly been shown to be associated with this
biochemical pathway.([29]) However, not only oral androgens may induce hepatic neoplasms but also parenteral
ones.([5], [8]
[9]
[10]
[11]
[12]
[13]) As several AAS subtypes were used by subjects in case reports, it is difficult
to conclude or estimate if a particular AAS is safer than the other.
Since 1965, when the first case report correlating HCC and AAS was published, HCC
became a significant concern for patients undergoing long term treatment with androgens,
especially those afflicted by hematological diseases as Fanconi’s Anemia (FA).([5]) These patients have a strict follow up to their physicians, which include liver
imaging to detect any lesions at early stages, allowing effective interventions when
needed. Blood markers efficacy is questionable, since alpha-fetoprotein rarely deviates
from baseline in early stage disease and liver enzymes may not raise to pathologic
levels until death is imminent and unpreventable.([6], [30]) The alpha-fetoprotein levels were shown to be high only in two case reports described
in this review; the first patient had metastat-ic disease and the second locally advanced
disease. Therefore, these findings are in line with literature([6], [30]) and they suggest that this biomarker could be an indicator of disease burden and,
for this reason, absent in early stage disease.
When a suspect hepatic focal lesion is identified in a patient undergoing long lasting
AAS treatment, its further characterization is mandatory. The differential diagnosis
may be difficult since HCC and hepatic adenoma (HCA), a benign liver tumor, can present
similar clinical, radiological, and histological features. One way to differentiate
the etiology is that benign lesions can reduce the size or even disappear upon AAS
treatment cessation.([6], [30], [31]) If the nature of the hepatic focal lesion etiology cannot be determined, it is
advisable to perform the surgical resection. A major concern is that HCA can undergo
malignant transformation, presenting rapid or progressive tumor growth and/or tumor
obstruction of the intra-hepatic portal veins. Therefore, close monitoring of HCA
lesions is mandatory.([16]) Gorayski et al. and Solbach et al. found foci in hepatic lesions devoid of CD34-positive
immunostaining, raising the possibility of malignant transformation within a pre-existing
adenoma (HCA).([10], [13]) The best evidence available in the literature reports a frequency of malignant
transformation in about 4.5–9 % of HCA cases.([32], [33]) However, if these statistics also hold true for HCC induced by AAS abuse is not
known.
Routine abdominal imaging screening in healthy AAS users for performance improvement
could be an alternative to detect early stage liver diseases, however, because the
abnormal development of such lesions, a better strategy would be focusing on orientation
to such population and warning them about the need of medical supervision.
Despite the limited data in the literature and the limitation of a study compiling
a small number of cases, we would like to put forth the idea that unsupervised AAS
usage is an emerging public health concern, as the population exposed to this practice
is usually young, healthy and unaware of the potentially severe adverse events. Furthermore,
evidence suggest an association between long term anabolic androgenic steroids abuse
for physical performance improvement and hepatocarcinoma.
CONCLUSIONS
Despite the limited evidence, there is some suggestion that hepatocarcinoma may be
associated with anabolic-androgenic steroids abuse for performance improvement. AAS
must be taken only under specialized supervision and public policies to make high
risk populations aware of the risks of AAS misuse and self-administration should be
pursued.
Bibliographical Record
Rafael Corrêa Coelho, Gustavo dos Santos Fernandes, Cinthya Sternberg. Exploring the
link between anabolic-androgenic steroids abuse for performance improvement and hepatocellular
carcinoma: a literature review. Brazilian Journal of Oncology 2018; 14: e-BJO20181447A175.
DOI: 10.26790/BJO20181447A175
