ANABOLIC STEROIDS

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Steroids
• Fat soluble molecule which contains a system of 4 rings made up of 17 carbon atoms �
E.g. cholesterol, estrogen, testosterone, progesterone, cortisol, etc.

Testosterone

 Produced by Leydig’s cells in testes

 Responsible for secondary sex characteristics in men - Sex glands, libido, reduced
body fat percentage, increased body hair

• Over the years, Testosterone has also been given for many other conditions and purposes
besides replacement, with variable success but higher rates of side effects or problems.
• Examples include infertility, lack of libido or erectile dysfunction, osteoporosis, penile
enlargement, height growth, bone marrow stimulation and reversal of anemia, and even
appetite stimulation. By the late 1940s testosterone was being touted as an anti-aging
wonder
• Decline of testosterone production with age has led to a demand for Androgen
Replacement Therapy.
• Testosterone analogs are made to achieve increased oral activity, prolonged action, and
selectivity for either anabolic or androgenic activity, but not both.
• Testosterone analogs are used in the treatment of hypogonadism, delayed onset of male
puberty, and estrogen-dependent breast cancer in females.
• Testosterone is necessary for a sense of well being and sex drive in both men and
women. In women, removal of the ovaries, such as from a total hysterectomy, usually
results in a need for testosterone as well as estrogen replacement. Estragen replacement
therapies now use a separate dosing of testosterone as needed. Testosterone cream, using
testosterone propionate, is a generic only preparation for topical application. Testosterone
from the cream is absorbed through mucosal skin to achieve desired effects

History of Performance Drug Abuse

 Greeks reported using certain mushrooms and plant seed to increase performance.
 Romans used drugs to increase performance of horses and gladiators to increase
crowd response.
 Steroids first developed in the 1930’s
 Used by the Germans on their soldiers and animals during WW2 to make up for a lack
of nutrition.
 1950’s first used for athletic purposes in Russia and Europe Primarily for
weightlifting.
 Mid 1950’s it was discovered that testosterone was the driving force behind increased
athletic performance.
 Used in all levels of sports, in the 1972 Olympics 68% of athletes reported using
anabolic steroids.
 1991 the Federal Anabolic Control Act classified steroids as a schedule 3 drug.
 Men that abuse steroids have a high incidence of some form of opioid abuse.
  90% of athletes reported have used some form of performance enhancing drugs during
there career.
 During the 1970's demand for anabolic-androgenic steroids grew as athletes in speed-
dependent sports discovered some of the potential benefits to using anabolic-
androgenic steroids. For one thing, the drugs allowed athletes to train harder because
muscle strains and tears repair themselves faster.
 In 1988 the sale of anabolic-androgenic steroids for non-medical purposes was illegal
under the Anti-Drug Abuse Act of 1988. In 1990, possession of anabolic-androgenic
steroids without a prescription was made illegal in the U.S
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Anabolic steroid

– Any hormonal substance, chemically and pharmacologically, related to testosterone that

promotes muscle growth
– Anabolic-androgenic steroids are usually called simply "anabolic steroids." They are
synthetic substances related to the male sex hormones (androgens.) The anabolic effects
of the drugs promote the growth of skeletal muscle, and the androgenic effects promote
the development of male sexual characteristics.

Anabolic/Androgenic

 Anabolic – “building”, increased skeletal muscle mass, bone density,

hemoglobin, nitrogen retention and protein synthesis
 Androgenic – androgens are sex hormones that can induce male traits (e.g.
growth of sex organs, increased body hair, libido, skin oil, and change in voice)

Anabolic/Androgenic steroids (AAS) seek to maximize the anabolic effects

while minimizing the androgenic effects The ratio of these anabolic/androgenic effects is
called the therapeutic index. Testosterone is the baseline at 1.
Therapeutic index of common AAS: Methenolone 7-16, Stanazolol 5-20, Nandrolone
Decanoate 11-12, Testosterone

CommonAAS- Testosterone cypionate, Nandrolone decanoate,

Nandrolone phenylpropionate, Fluoxyymesterone, Stanozolol,
Testosterone enanthate, methandienone, Methandrostenolone,
Oxandrolone, Oxymesterone, Boldenone undecyclate, Trenobolone
acetate

Administration
� Oral preparations – 17 methyl alklayted to survive acidic gastric ecretions, short half
life (e.g. dianabol, winstrol)
� Injectable solutions – prepared in water or oil. Longerrelease times for oil. (e.g.
Nandrolone Decanoate)
� Patch and gel – provides steady and constant testosterone delivery (e.g. Trenbolone)
� Aerosol propellant – rapid effects, very hard to detect in drug tests
� Sublingual preparations – absorbed directly into bloodstream so avoid digestive
system, rapid effects
Mechanism
• Steroids are carried through the bloodstream bound to a protein to keep them
soluble. Since they are lipophyllic, they can traverse cell membranes. Once
inside a cell they may bind to a receptor and the complex may then interact with
DNA to modulate transcription, turning genes off or on. This will effect protein
synthesis

Major effects:
• Activation of rRNAresulting in protein synthesis
• Anticatabolic effect – block action of natural cortisone
• Increase free testosterone levels
• Appetite stimulants
• Stimulates activity of IGF-1 (Insulin-like growth factor)
• Positive side effects of AAS
 Enhanced muscle mass/strength , increased nitrogen retention, retention of
minerals- Na, K, Ca, P
 Enhanced blood volume and hemoglobin concentration
 Enhanced bone density and strength
 Hastened healing of muscular injuries
 Decreased body fat
 Increased immune response
 Elevated mood

Clinical Applications/Indications of AAS

• Debilitating, wasting diseases, catabolic states, in major acute illness,

immunosuppressive state sand diseases, severe trauma, - all conditions where there is
negative nitrogen balance
• Bone metabolism conditions – osteoporosis in elderly, to remove tissue depleting
processes in young ones , in diseases like CD, heavy parasitism, hypoproteinaemia etc
• To hasten the tissue repair after major surgery and to promote the healing and reunion
in fracterous conditions.
• To counteract glucocorticoid induced catabolism and negative effects
• To stimulate erythropoiesis in conditions of hypolplastic, hemolytic anemia and
malignancy conditions
• Testosterone deficiency conditions – male hypogonadism, andropause
• Cardiovascular conditions – reduces angina pectoris, hypertension, coronary artery
disease
• To increase the body weight for which, it has been used illegally.
• To enhance the physical ability , by increasing muscle strength, in suboptimal growth
in childen
• In renal insufficviency, they decrease urea production , transciently as in CRF
•
Nandrolone decanoate
 Long acting ester, Most widely used
 Side effects: Water retention, endogenous test suppression, other mild
Effects , Detectable for over 1 year in drug screenings
Methandrostenolone
 Easy to use, very effective
 C17 alpha alkylated , Can show extreme side effects due to its tendency
to break down into 17alpha methylestradiol, a form of estrogen that is much more
active in the body
 Short half life (3-5 hrs.)

Stanozolol

• Used illegally in bodybuilding, typically "stacked" with other testosterone-based

anabolic steroids, Stanozolol is liked by many due to the fact it causes strength increases
without excess weight-gain, promotes increases in vascularity, and will not convert to
estrogen. It also does not cause excess water retention, and even sometimes is thought to
have a diuretic effect on the body.
• It has ben used as appetite stimulant

 both oral and injectable forms

 Side Effects- Hypertension, acne, fluid retention, hypogonadism, gynecomastia,

sleep disturbances, increased aggression, epistaxis
withdrawal depression, prostate enlargement, heart enlargement, virilization, abnormal blood
clotting, libido reduction, appetite stimulation, benign
prostate enlargement Acne and hair loss
Acne: Sebaceous glands (responsible for oilsecretion) arestimulated by androgens
Bad acne may develop on the shoulders, back, and face
Hair loss - Highly androgenic steroids that convert to DHT will aggravate balding. DHT
chokes the hair follicle, eventually killing it

Trenbolone is a steroid used by veterinarians on livestock to increase muscle growth and

appetite. To increase its effective half-life, trenbolone is not used in an unrefined form, but is
rather administered as trenbolone acetate

General drawbacks of AAS include- sterility , reproductive failure, oedema, hypertension and
increased chance of coronary heart disease due to retention of sodium and water.

The major side effects from abusing anabolic steroids can include liver tumors and cancer,
jaundice (yellowish pigmentation of skin, tissues, and body fluids), fluid retention, high
blood pressure, increases in LDL (bad cholesterol), and decreases in HDL (good cholesterol).
Other side effects include kidney tumors, severe acne, and trembling. In addition, there are
some gender-specific side effects:

• For males : shrinking of the testicles, reduced sperm count, infertility, baldness,
development of breasts, increased risk for prostate cancer.

• For females : growth of facial hair, male-pattern baldness, changes in or cessation of the
menstrual cycle, enlargement of the clitoris, deepened voice.
 • For adolescents: growth halted prematurely through premature skeletal maturation and
accelerated puberty changes. This means that adolescents risk remaining short for the
remainder of their lives if they take anabolic steroids before the typical adolescent growth
spurt.

Other anabolics

hCG - used clinically to treat hypo-gonadism. Used postcycle to stimulate endogenous test.
By mimicking LH
Insulin
• Regulates glucose levels in the blood , its role in the body is to control the uptake,
utilization, and storage of amino acids, carbohydrates, and fatty acids in the body.
• Insulin is both anti-catabolic and anabolic because itstimulates the use and retention
of nutrients in muscle cells (specifically glycogen)
• Cannot be detected in drugs tests
• Hypoglycemia one possible outcome of use. Can also result in immediate death,
coma, or insulin dependent diabetes.
Clenbuterol
• Beta-2 sypathomimetic,used as a bronchodilator
• Animal studies indicate anabolic properties, but used primarily as a thermogenic
compound by directly stimulating fat cells and breaking down
triglycerides. Effects are temporary due to down regulation
Thyroid hormone
• Used to treat thyroid deficiency, obesity, and other metabolic disorders
• Synthetic version of T3 which stimulates thyroid gland resulting in; acceleration of
cellular reactions, increase in metabolism & cardiovascular functions.
• Rebound effect
Steroid Precursors/Prohormones
Androstenedione, androstenediol and Dehydroepiandrosterone (DHEA)
Androstenedione
• Produced by the adrenal glands
• Androstenedione is converted into testosterone by 17beta-hydroxysteroid
dehydrogenase, which is activated by luteinizing hormone secreted by the
hypothalamus and pituitary gland
• Androstenedione may also be converted to the estrogen, by the enzyme aromatase.
Androstenediol
• Similar to Androstenedione
• Lacks a 3-keto group that enables the conversion into estrogen
• A much more androgenic compound (produces much more male based effects)
• Has higher conversion rates to testosterone. Doesn’t convert into estrogen., Does
not convert into DHT (cause of balding).
DHEA
• A precursor to testosterone that is produced in the adrenal glands.
• Aids in producing Androstenedione which produces testosterone and estrogen
Estrogen/Aromatase
• Estradiol (estrogen) – primary female sex hormone, controls fertility
cycle
• Estradiol is beneficial to muscle growth
 • Aromatase – any enzyme which removes the 19 methyl from AAS and
forms 3 double bonds on the A ring.
DHT
• Through 5-alpha reductase, testosterone is converted to a hormone
4X as potent, dihydrotestosterone
• DHT binds to receptors much more avidly than testosterone
• 5-alpha reductase is present in high amounts in tissues of the
prostate, skin, scalp, liver, and central nervous system
Aromatase inhibitors/Estrogen Blockers

� Aromatase Inhibitors - Blocks the aromatase enzyme, preventing test.

From converting to estrogen Slows muscle growth, suppresses HDL
cholesterol, prevents water retention e.g. anastrozole

� Estrogen Blockers- Binds to free floating estrogen molecules, preventing

estrogen from attaching toandrogen receptors May also stimulate FSH
and LH Production e.g. Tamoxifen citrate

GROWTH HORMONE(hGH; SOMATOTROPIN)

- A naturally occurring hormone in the body. , Signaled release from the hypothalamus.
- Single chain , 191 amino acids, 2 intramolecular disulfide bonds
- Similar to: prolactin, placental lactogen hGH-V
- Release from the pituitary gland regulated by two hormones.
• Somatostatin (SS) – decreases GH output.
• Growth Hormone-Releasing Hormone (GHRH) – Increase GH output.
- Can also be regulated by the amount of GH and Insulin
- Like Growth Factor 1 (ILGF-1) that is circulated back through the body.
Other Factors that Increase GH
� Decreased blood glucose during exercise and sleep trigger the release of GH.
� High protein increase small amounts GH release.
� Some amino acids such as L-arginine can increase GH by decreasing the release SS
from the hypothalamus.
� Niacin has been shown to increase exercise induced GH release by 300- 600%

Effects stimulate protein synthesis,stimulate growth,increase muscle mass , increase

synthesis of chondroitin and collagen, increase skeletal growth, soft tissue growth
• Urinary retention of nitrogen, potassium, phosphate, increase strength of muscles,
tendons
Somatomedin hypothesis - . GH is released from the pituitary gland., . Travels to the liver
where it is converted into ILGF. . ILGF enters the blood stream and stimulates muscle growth.
Once converted into ILGF, ILGF stimulates the production of, and the conversion of satellite
cells into muscle cells.
Satellite cells – Cells that lie dormant around muscle tissue until stimulated
by ILGF.
Have the ability to replicate the genetic makeup of muscle cells.
Mechanism of action:
 Specific membrane receptors - members of the cytokine receptor superfamily
Mitogenic and antiapoptotic effects: IGF-I expression in liver - systemic release
IGF-I in other tissues - paracrine activity
Metabolic effects (primarily direct):
Stimulation of triglyceride hydrolysis
Stimulation of protein synthesis
Insulin resistance (counterregulatory hormone)
Adverse effects
• acromegaly - large hands & feet
• abnormal shaped head
• increase size of heart, liver, kidneys
• increase cholesterol
Alternative to steroids in being misused ; as they are cheaper and harder to detect

Growth Hormone Enhancers

• Amino acids (Aa) have been used to increase circulating growth hormone (GH)
concentrations.
• Strength training increases GH serum concentrations so looking for synergistic
effect.
• Most common Aa used are arginine, lysine & ornithine
• Many studies confirm increased GH concentrations after ingestion of arginine &
lysine.
• Effects are modified by training level, sex, diet and age.
• High levels produce stomach cramps & diarrhea
• Ingestion right before exercise blunts absorption
Peptide Secretagogues-Being developed and studied as compounds that stimulate secretion of
endogenous GH., on GH deficient patients.
Other GH Releasing Agents
• Clonidine, L-dopa & methylphenidate have been shown to induce GH release.
• L-dopa most commonly used by athletes but no studies have been done on
effectiveness but does induce nausea & vomiting.
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RECOMBINANT GH PREPARATIONS USED CURRENTLY:
Somatropin
Recombinant human GH (rhGH)
Somatrem
Recombinant methionyl GH (met-rhGH)
N-terminal Met start signal for transcription
More antigenic
Nearly equal in effectiveness to rhGH
Sustained-release rhGH- 1 to 2 doses/month;
Increases compliance
Hypersecretion; Gigantism in children, Acromegaly in adults
progressive enlargement of head, face, hands, feet, thorax; heat intolerance, sweating,
fatigue, lethargy
Deficiency : Postnatal growth retardation, Congenital/Acquired
Adult GH deficiency ; Adult-onset pituitary/hypothalamic disease, surgery, radiation
therapy, or trauma
 Age-associated (up to 1/3 of the elderly)
Recombinant hGH analog : Pegvisomant- Most effective treatment for acromegaly
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GROWTH HORMONE-RELEASING HORMONE (GRH OR GHRH)

Chemistry: 37-, 40- and 44-amino acid single polypeptide chains
Related to GI peptides- secretin, gastrin, VIP, GIP
Preparation used clinically: sermorelin acetate- first 29 (N-terminal) amino acids ,
Activity is equivalent to full length forms

Clinical uses:
Diagnostic: To determine GH secretory reserve:
For treating growth hormone deficiency:
Sermorelin acetate is used in . hypothalamic GRH deficiency

SOMATOSTATIN (SOMATOTROPIN RELEASE-INHIBITING FACTOR, SRIF)

• Secreted by hypothalamic anterior periventricular region and by d cells of the pancreatic
islets
• Secretion increased by GH, IGF-I, thyroid hormones
• A single peptide of 14 amino acids; A 28-amino acid form is found in the gut
Actions:
• Inhibits GH secretion but not its synthesis
• Inhibits basal and TRH-stimulated TSH secretion
• Inhibits secretion of GI peptide hormones:insulin, glucagon, VIP, gastrin
Mechanism of action:
• Gi protein-coupled receptors with tissue-specific expression
• Reduces cAMP production and Ca2+

Octreotide: Synthetic octapeptide analog used clinically

• More potent at inhibiting GH secretion than native SRIF
• Less potent at inhibiting insulin secretion
• Increased half-life: 1.7 hours (SRIF: 1 to 3 minutes), Resistant to enzymatic
degradation-
• Rebound hypersecretion lower than for SRIF
• Sustained-release form recently approved for use

Clinical uses of octreotide Acromegaly; For excess GH secretion by somatrope adenomas hat
remains or recurs after irradiation or surgery , Does not induce hyperglycemia
• Carcinoid tumors Intestinal tumors, may secrete physiologically active
substances (5-HT, prostaglandins, etc.) Have somatostatin receptors
• Pancreatic cell tumors