Anabolic androgenic steroids and aggression: studies using animal models.

Ann N Y Acad Sci. 2004 Dec;1036:399-415.

Anabolic androgenic steroids and aggression: studies using animal models.

McGinnis MY.

Department of Biology, University of Texas at San Antonio, 6900 North Loop 1604
West, San Antonio, Texas 78249, USA. mmcginnis@utsa.edu

The use of anabolic androgenic steroids (AASs) has escalated in teenagers and is
associated with increased violence. Adolescent exposure to chronic high levels of
AASs is of particular concern because puberty is a hormonally sensitive period
during which neural circuitry for adult male patterns of behavior develop. Thus,
teenage AAS use may have long-term repercussions on the potential for displaying
aggression and violence. Animal models have contributed valuable information on
the effects of AAS use. For example, studies in rodents confirmed that exposure
to the AASs testosterone and nandrolone, but not stanozolol, does indeed increase
aggression. A side effect of AAS use reported in humans is "'roid rage,"
characterized by indiscriminate and unprovoked aggression. Results of animal
studies demonstrated that pubertal rats receiving AASs respond appropriately to
social cues as they are more aggressive toward intact males than are castrates.
Also, testosterone-treated males recognize appropriate environmental cues as they
are most aggressive in their home cage. Thus, adolescent AAS exposure increases
aggressive behaviors, but does not induce indiscriminate aggression. To assess
whether AAS exposure increases aggression after provocation, rats were tested
following a mild tail-pinch. In adolescent males, provocation increased
aggression after withdrawal from testosterone, nandrolone, and stanozolol, an
effect which persisted for many weeks. The data suggest that AASs sensitize
animals to their surroundings and lower the threshold to respond to provocation
with aggression. Thus, in humans, pubertal AAS exposure may not cause violent
behaviors, but may increase the likelihood that aggressive acts will result in
violence. This may persist into adulthood.

Multiple hepatic adenomas caused by long-term administration of androgenic steroids for aplastic anemia in association with familial adenomatous polyposis

J Gastroenterol. 2000;35(7):557-62.

Multiple hepatic adenomas caused by long-term administration of androgenic
steroids for aplastic anemia in association with familial adenomatous polyposis.

Nakao A, Sakagami K, Nakata Y, Komazawa K, Amimoto T, Nakashima K, Isozaki H,
Takakura N, Tanaka N.

Department of Surgery, Shobara Red Cross Hospital, Japan.

We report a rare case of hepatic adenomas (HA), in a 20-year-old Japanese girl
treated for 6 years with anabolic androgens for aplastic anemia. In a review of
the world literature using computer MEDLINE search, we found only 17 cases of
androgen-induced HA published between 1975 and 1998 in the English-language
literature. The patient was referred to us because of liver lesions detected
during a follow-up examination for familial adenomatous polyposis. After being
diagnosed with aplastic anemia at 14 years of age, she had been treated with
oxymetholone (30 mg/day) for 6 years. Laboratory evaluation revealed normal liver
function. Ultrasonography (US) and computed tomography (CT) demonstrated multiple
liver lesions. Histopathological examinations of biopsied specimens from the
liver tumor showed HA. After the patient was diagnosed with HA, oxymetholone was
tapered off. Patients taking androgenic-anabolic steroids should be carefully
monitored with US and CT and tumor markers should be measured. This report may be
helpful in identifying the population who is at risk of developing hepatic sex
hormone-related tumors.

Use of growth hormone and other anabolic agents in AIDS wasting

JPEN J Parenter Enteral Nutr. 1999 Nov-Dec;23(6 Suppl):S202-9.

Use of growth hormone and other anabolic agents in AIDS wasting.

Mulligan K, Tai VW, Schambelan M.

Division of Endocrinology, San Francisco General Hospital, CA 94110, USA.

Body wasting and loss of lean body mass (LBM) have been associated with increased
mortality and disease progression, and reduced quality of life, in patients with
human immunodeficiency virus (HIV) infection. The failure of nutritional
therapies and, more recently, of effective viral suppression, to consistently
restore LBM has prompted investigation of the pharmacologic use of a number of
specific protein anabolic agents, including recombinant human growth hormone
(rhGH), insulin-like growth factor I (rhIGF-I), and synthetic testosterone
derivatives, such as nandrolone decanoate, oxandrolone, and oxymetholone. In a
placebo-controlled trial, treatment with rhGH resulted in a significant and
sustained increase in weight that was accompanied by an even greater increase in
LBM and a decrease in fat, and improvement in treadmill work output. Preliminary
data suggest that short-term rhGH treatment may be effective in mitigating weight
loss in patients with secondary infections. Open-label studies of nandrolone
decanoate suggest that this injectable agent also can increase weight and LBM.
Two oral agents, oxandrolone and oxymetholone, can increase weight, but their
effects on LBM in placebo-controlled trials have not been reported. Taken
together, these studies demonstrate that HIV-infected individuals can regain
weight and LBM under the proper therapeutic circumstances. The effects of
reversal of wasting on survival and disease progression, long-term safety, and
the potential value of these therapies in the treatment of fat redistribution
remain to be determined.

Oxymetholone: I. Evaluation in a comprehensive battery of genetic toxicology and in vitro transformation assays

Toxicol Pathol. 1999 Sep-Oct;27(5):501-6.

Comment on:
    Toxicol Pathol. 1999 Sep-Oct;27(5):507-12.

Oxymetholone: I. Evaluation in a comprehensive battery of genetic toxicology and
in vitro transformation assays.

Holden HE, Studwell D, Majeska JB.

Department of Toxicology and Safety Assessment, Boehringer Ingelheim
Pharmaceuticals, Ridgefield, Connecticut 06877, USA. heholden@midcoast.com

Oxymetholone is generally assumed to be a nongenotoxic carcinogen. This
assumption is based primarily on the results of an Ames test, existing data in
repeat-dose toxicology studies, and the predicted results of a 2-yr National
Toxicology Program (NTP) rat carcinogenicity bioassay. To provide a comprehensive
assessment of its genotoxicity in a standard battery of mutagenicity assays,
oxymetholone was tested in microbial and mammalian cell gene mutation assays, in
an in vitro cytogenetics assay (human lymphocytes), and in an in vivo
micronucleus assay. Oxymetholone was also tested in an in vitro morphologic
transformation model using Syrian hamster embryo (SHE) cells. These studies were
initiated and completed prior to the disclosure of the results of the NTP
bioassay. Oxymetholone was tested at doses up to 5,000 microg/plate in the
bacterial plate incorporation assay using 4 Salmonella strains and the WP2 uvrA
(pKM101) strain of Escherichia coil. There was no induction of revertants up to
the highest dose levels, which were insoluble as well as toxic. In the L5178Y
tk+/- mouse lymphoma assay, doses up to 30 microg/ml reduced relative survival to
approximately 30% with no increase in mutants. Male or female human lymphocytes
were exposed in vitro to oxymetholone for 24 hr without S9 or 3 hr with S9 and
evaluated for the induction of chromosomal aberrations. There was no increase in
aberration frequency over control levels and no difference between male and
female cells. Peripheral blood from Tg.AC transgenic mice treated dermally for 20
wk with 0, 1.2, 6.0, or 12.0 mg/day of oxymetholone and from p53 transgenic mice
treated orally by gavage for 26 wk with 125, 625, or 1,250 mg/kg/day of
oxymetholone was evaluated for micronuclei in polychromatic and normochromatic
erythrocytes. There was no difference in micronuclei frequency between control
and treated animals. These results confirm that oxymetholone is not genotoxic in
a comprehensive battery of mutagenicity assays. In the SHE assay, oxymetholone
produced a significant increase in morphologically transformed colonies at dose
levels of 13-18 microg/ml. The lack of genotoxicity of oxymetholone, the positive
response in the in vitro transformation assay, and the results of transgenic
mouse carcinogenicity assays will provide an interesting perspective on the
results of an on-going NTP rat carcinogenicity bioassay.

Poststeroid balance disorder--a case report in a body builder

Int J Sports Med. 1999 Aug;20(6):407-9.

Poststeroid balance disorder--a case report in a body builder.

Bochnia M, Medraś M, Pośpiech L, Jaworska M.

Clinic of Otolaryngology, Medical University in Wroclaw, Poland.

The authors describe a case of poststeroid balance disorder in a 20-year-old
athlete. Previous information of such a doping pathology among sportsmen taking
anabolics was not found. That anabolic steroids had a harm to central activities
and could be suspected especially on the basis of reported psychiatric sequels
and cerebrovascular disorders. The case described is of a patient who had been
given metandienone, oxymetholone, and nandrolone phenyloproprionate in two
courses. Vertigo appeared twice just after introducing doping and persisted in
spite of a 1.5 year break in taking anabolics. In the electronystagmography a
positional nystagmus was detected, the eye-tracking test was distempered, and
abnormal responses in the caloric tests were obtained. In the computed dynamic
posturography the number and length of body sway were increased and,
consequently, the field of the outspread area was enlarged. The moment of
appearance and long-lasting vertigo as well as the results of laboratory
examinations indicate a poststeroid permanent disorder of the central part of the
equilibrium organ. Such a diagnosis seems to be most probable here.

Analysis of 65 Turkish patients with congenital aplastic anemia (Fanconi anemia and non-Fanconi anemia): Hacettepe experience

Clin Genet. 1997 May;51(5):296-302.

Analysis of 65 Turkish patients with congenital aplastic anemia (Fanconi anemia
and non-Fanconi anemia): Hacettepe experience.

Altay C, Alikaşifoglu M, Kara A, Tunçbilek E, Ozbek N, Schroeder-Kurth TM.

Department of Pediatrics, Pediatric Hematology Unit, Ihsan Dogramaci Children's
Hospital, Hacettepe University, Ankara, Turkey.

During the last 14 years, 65 unrelated patients were diagnosed as having
constitutional aplastic anemia (CAA). In 52 of 65 patients the diepoxybutane
(DEB) test was positive. Comparison of several hematological and clinical
parameters in Fanconi anemia (FA) (DEB+) and non-Fanconi anemia (non-FA)(DEB )
patients disclosed no statistically significant differences. The study indicated
that in Turkey there were no peculiarities in associated congenital abnormalities
in FA and non-FA. The rate of consanguinity was 78% in FA and 46% in non-FA,
suggesting that also among the non-FA group recessively inherited disorders are
hidden. The mean age at diagnosis in FA was 7.7+/-4.4 (1.8-12) and in non-FA
7.8+/-3.8 (2-15) years. Nine out of 52 FA and five out of 13 non-FA patients died
during the follow-up period. Five of the 52 FA patients developed malignancies,
three of them had acute myeloblastic leukemia (AML), one a squamous cell
carcinoma of the gingiva, and another a hepatocellular carcinoma. Peliosis
hepatica occurred in three of the FA and one of the non-FA patients. A total of
seven patients stayed in remission without any medication. The remaining 58
patients were given 2-5 mg/kg of oxymetholone and 5 mg prednisolone treatment.
Because of sustained remission, oxymetholone therapy was terminated in four of
the 45 FA and two of the 13 non-FA patients. Detailed examination of the
pedigrees of all of patients indicated the presence of multiple congenital
anomalies. In seven of 52 FA and one of 13 non-FA patients there was increased
risk for AML and/or other cancers among family members.

Treatment results of 23 cases of severe aplastic anemia with lymphocytapheresis

Arch Med Res. 1997 Spring;28(1):85-90.

Treatment results of 23 cases of severe aplastic anemia with lymphocytapheresis.

Morales-Polanco MR, Sánchez-Valle E, Guerrero-Rivera S, Gutiérrez-Alamillo L,
Delgado-Márquez B.

Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F.

We report the results of 23 patients with aplastic anemia (AA) treated with a
program of 14 lymphocytapheresis (LC). Treatments were performed with apheresis
machines, models Haemonetics 30-S and Baxter CS3000, using the standard program.
This procedure was done because AA in many cases appears as a result of the
action of a T cell population that inhibits hematopoiesis. Theoretically, removal
of this clonal population would produce hematopoietic recovery. Of the total of
23 patients, 9 were excluded for final evaluation of treatment results because 7
died during or shortly after treatment (0.7-3 months); one patient abandoned
treatment after three LC and another died 7 months later because of
transformation to acute leukemia. The remaining 14 patients were included in the
final evaluation of treatment; seven females and seven males, average age 46.1
years (range 22-69); 13 with severe, and one with moderate AA; 11 with recently
diagnosed, and 3 with chronic AA; 12 without previous treatment and two treated
before with antilymphocyte globulin + oxymetholone (OXM) + cyclosporine A (CsA)
with transient partial remission (PR). Besides lymphocytapheresis, 13 patients
received OXM; 4 of them GM-CSF and one low dose CsA. Four patients had complete
remission lasting > 59.5 months (range 42-78); eight PR (average duration of >
38.6 months), and two minimal remission (> 37 and 29 months). Platelet,
reticulocyte and granulocyte counts increased on average at 48.7, 73.3 and 91.4
days, respectively. In conclusion, 14 (60.8%) of 23 patients with AA showed an
improvement related to LC treatment, with a survival probability of 63% from the
fourth month, the latter with an added beneficial effect of the other therapies
used. Larger numbers of patients have to be treated with LC to determine its real
usefulness, mechanism of action and the best conditions for its use.