Anabolic-Androgenic Steroids
(AAS)
www.epi.burnet.edu.au/ recentprojects/steroids
www.bigfrog.net/ archives/2003/05/
Mickey Kivitz
CHEM 5398
3/30/06
What are Steroids?
• Endocrine hormones: chemical signals released into the
bloodstream which act upon target receptors far away
from their site of release.
• Produced by body and made synthetically in the lab.
• Classes of Steroids
– Naturally occurring
•
•
•
•
Androgens
Corticoids
Estrogens
Progestogens
– Synthetic
• Anabolic-Androgenic
• Medicinal versus performance enhancing
Definitions
• Androgen: Any hormone with
testosterone-like actions
• Anabolism: Cellular synthesis of organic
molecules (including proteins).
History of AAS
• Testosterone discovered in 1935 by independent
European researchers (1).
– All AAS are synthetic derivatives of testosterone.
• Anabolic steroids initially used in medicine to treat
hypogonadism – a condition in which testes produce
abnormally low testosterone levels (2).
• Bodybuilders and weightlifters first used anabolic
steroids in 1930s to increase skeletal muscle mass (2).
• Current uses:
– Serving medicinal purposes (treating delayed puberty, impotence
and muscle deterioration brought upon by HIV infection) (2).
– Athletic manipulation and taboo.
Hypogonadism
• Hypogonadism in adult males may alter
certain masculine physical characteristics
and impair normal reproductive function.
Signs and symptoms may include:･
Erectile dysfunction･Infertility･Decrease in
beard and body hair growth･Increase in
body fat･Decrease in size or firmness of
testicles･Decrease in muscle mass･
Development of breast tissue･Loss of
bone mass (osteoporosis )
Natural Steroid Derivatives:
Cholesterol and Testosterone
17 carbon atoms in a 4-ringed structure.
cyclopentanoperhydrophenanthrene
www.people.vcu.edu/ ~urdesai/intro.htm (3)
Cholesterol (4)
Testosterone (4)
Steroids as Hormones
• The body uses hormones to maintain a
stable internal environment as well as
perform long-lasting communication.
• Because AAS are cholesterol derivates,
they are nonpolar and readily cross the
plasma membrane.
– However, they are insoluble in aqueous
environments and require plasma protein cotransporters when circulating through blood
(5).
Common Steroid Hormones
Cortisol (4)
Aldosterone
www.icgeb.org/~p450srv/ ligand/aldosterone.html (6)
(4)
Progesterone (4)
Physiological Synthesis of
Androgens
• Manufacture by testis (initiated by luteinizing
hormone) and adrenal cortex, and to a lesser
degree by the ovaries.
• Androgen Receptor (AR) exists in reproductive
as well as non-reproductive tissue (i.e. skeletal
muscle, etc).
– Specificity of action varies based on testosterone
derivative structure.
– Action at tissue or organ also depends on AR
quantity. For example, prostate has 25X more AR
than skeletal muscle (7).
AAS as Drugs
• Medicinal:
Therapeutic effects of
testosterone
replacement
– Restore muscle mass
in degenerative states,
such as
hypogonadism, HIVrelated muscle wasting
conditions, sarcopenia
(age-related muscle
loss) (8).
• Performance
Enhancing Effects
– Commonly selfadministered,
therefore little
empirical evidence.
– Increased strength
and body weight due
to heightened skeletal
muscle mass (8)
– Numerous side
effects.
Common Anabolic Adrogenic
Steroids
Lacks methyl group
Ester as prodrug
OH
CH3
OR
OH
H
H
H
HO
H
H
H
O
O
O
Nandrolone Ester
(R = CH3(CH2)8CO)
Testosterone
Methandrostenolone
(dianabol)
OH
CH3
H
H
H
O
Oxymetholone (androle)
O
OH
H
H
O
H
H
O
O
Androstenedione
(Andro)
Oxandrolone
Androgen Receptor Binding
• AR exists in multiple
tissue types (4).
• Binds ligand in cytoplasm
and translocates into
nucleus (8)
• Functional domains: DNA
binding domain, hinge
domain and hormone
binding domain.
• Androgens are AR
agonists and facilitate
appropriate gene
activation.
www.molfunction.com/ tutorial.htm (9)
AR-Agonist Binding Interactions
• AR activity is contingent upon ligand
binding, AR homodimerization and
subsequent nuclear localization to activate
transcription of target genes (10).
– Local effects such as increased skeletal
muscle mass and strength occur due to
heightened ability to fixate nitrogen, facilitating
protein synthesis (1), as well as erythropoiesis
(production of red blood cells) (11).
AR Competition: Anti-androgens
• Androgen antagonists
• Method of action
– Suppresses testosterone
activity by competing for
AR binding site.
• Therapeutic uses include
prostate cancer, benign
prostatic hyperplasia,
hypersexuality and
others; counteracts
androgen-caused
diseases (4).
Cyproterone (4)
Methods of AAS Use
• Administration of AAS may occur through multiple routes
and often in combination (stacking) (12).
– Intramuscular injection, orally, and in gels or creams that are
rubbed on the skin.
• Self-administration is common and often occurs in a
regimented pattern. (8)
– User cycles may last between 4 and 12 weeks, with “off-cycles”
occuring between using periods.
– Athletes using AAS (doping) cycle during training and compete in
the off-cycle in hopes of circumventing drug tests.
• AAS may be used in combination with accessory drugs
and dietary supplements to maximize results (8)
Why Abuse AAS?
• Most common reason: improve athletic performance.
• Also, to gain rapid and substantial muscle size and/or
reduce body fat in an effort to attain a desired physical
appearance (12)
– Reinforcement issues: in addition to initial physical gains,
androgen receptors in the brain stimulate feelings of euphoria
and increased aggressiveness. Additional use is perpetuated as
one becomes less receptive to outside opinion and resorts to
aggressive behavior to continue the cycle (1).
• AAS reduce recovery time between periods of strenuous
metabolic activity (8), but evidence remains minimal (13).
• No proven effect on endurance or stamina (13).
Side Effects of AAS
• Mild – increased sexual drive, acne, increased
body hair and baldness, aggressive behavior
(13).
• Prolonged use interferes with ability to naturally
produce testosterone in the face of withdrawl
(13).
• Common problems of AAS due to chronic abuse
also include hypertension, atherosclerosis, blood
clotting, jaundice, hepatic carcinoma, tendon
damage, and reduced fertility in males (11).
• Severe life threatening side effects include heart
attacks and liver cancer (12).
Prevalence of Drug Usage
• International Olympic Committee placed
anabolic steroids on their list of banned
substances in 1975 (11).
• AAS put on list of Schedule III Controlled
Substances in 1990, making it available only by
prescription. However, recent studies indicate
that use may be on the rise (8).
• 1999 survey amongst middle school and high
school students showed an increase in lifetime
use by 10th graders, alongside a decrease in risk
of perceived harm among high school seniors
(2).
Conclusion and Future
• Enhancing/ understanding medical treatments
– Fracture healing, soft tissue healing, postoperative
rehabilitation. (8)
• Efforts must be made to eradicate athletic use
through education.
• Long-term effects are currently under
investigation, and adverse effects of AAS on
cardiovascular, hepatic, endocrine/reproductive,
behavioral, dermatologic systems are being
studied (8).
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Shahidi, Nasrollah. A Review of the Chemistry, Biological Action, and Clinical Applications of
Anabolic-Androgenic Steroids. Clinical Therapeutics. 2001; 23: 1355-1390.
Research Report Series – Anabolic Steroid Abuse: What are anabolic steroids? National
Institute on Drug Abuse website.
www.people.vcu.edu/ ~urdesai/intro.htm
http://en.wikipedia.org/wiki/Main_Page
Norris, David O. Vertebrate Endocrinology. Philadelphia; Lea and Febiger, 1980: 284-299.
www.icgeb.org/~p450srv/ ligand/aldosterone.html
http://muscle.ucsd.edu/musintro/steroids.shtml
Evans, Nick A. Current Concepts in Anabolic-Androgenic Steroids. The American Journal of
Sports Medicine. 2004; 32 (2) 534-542.
www.molfunction.com/ tutorial.htm
Chen, Yen, Zajac, Jeffrey D, Maclean, Helen E. Androgen regulation of satellite cell function.
Journal of Endocrinology. 2005; 186: 21-31.
Mottram, DR, George, AJ. Anabolic Steroids. Bailleres Best Pract Res Clin Endocrinol Metab.
2000 Mar; 14 (1) 55-69.
Research Report Series – Anabolic Steroid Abuse: Why do people abuse anabolic steroids?
National Institute on Drug Abuse website.
Hartgens, Fred, Kuipers, Harm. Effects of Androgenic-Anabolic Steroids in Athletes. Sports
Medicine. 2004; 34 (8): 513-554.