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Testosterone

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names, main trade names
   1.6 Main manufacturers, main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    Testosterone

    International Programme on Chemical Safety
    Poisons Information Monograph 519
    Pharmaceutical

    1.  NAME

        1.1  Substance

             Testosterone

        1.2  Group

             ATC Classification:
             A14 (Anabolic Agents for Systemic Use)
             A14A (Anabolic steroids)

        1.3  Synonyms

             Testosteroid; testosteron; testostosterone;
             trans-testosterone

        1.4  Identification numbers

             1.4.1  CAS number

                    58-22-0.

             1.4.2  Other numbers

                    NIOSH/RTECS XA 3030000

                    Testosterone Cypionate (CAS 58-20-8)
                    Testosterone Enanthate (CAS 315-37-7)
                    Testosterone Isocaproate (CAS 15262-86-9)
                    Testosterone Phenylpropionate (CAS 1255-49-8)
                    Testosterone Propioponate (CAS 57-85-2)

        1.5  Main brand names, main trade names

             Androderm; Andropatch; Histerone; Malogen Aqueous (FM);
             Sterile Testosterone Suspension USP 23; Tesamone; Testandro;
             Testoderm; Testopel; Testosterone Implants; Testosterone
             Implants BP 1993; Testotop; Homosten (FM)

        1.6  Main manufacturers, main importers

    2.  SUMMARY

        2.1  Main risks and target organs

             There is no serious risk from acute poisoning, but
             chronic use can cause harm. The main risks are those of
             excessive androgens: menstrual irregularities and
             virilization in women and impotence, premature cardiovascular
             disease and prostatic hypertrophy in men. Both men and women
             can suffer liver damage with oral anabolic steroids
             containing a substituted 17-alpha-carbon. Psychiatric changes
             can occur during use or after cessation of these
             agents.

        2.2  Summary of clinical effects

             Acute overdosage can produce nausea and gastrointestinal
             upset. Chronic usage is thought to cause an increase in
             muscle bulk, and can cause an exageration of male
             characteristics and effects related to male hormones.
             Anabolic steroids can influence sexual function. They can
             also cause cardiovascular and hepatic damage. Acne and male-
             pattern baldness occur in both sexes; irregular menses,
             atrophy of the breasts, and clitoromegaly in women; and
             testicular atrophy and prostatic hypertrophy in men.

        2.3  Diagnosis

             The diagnosis depends on a history of use of oral or
             injected anabolic steroids, together with signs of increased
             muscle bulk, commonly seen in "body-builders". Biochemical
             tests of liver function are often abnormal in patients who
             take excessive doses of oral anabolic steroids.
    
             Laboratory analyses of urinary anabolic steroids and their
             metabolites can be helpful in detecting covert use of these
             drugs.

        2.4  First aid measures and management principles

             Supportive care is the only treatment necessary or
             appropriate for acute intoxication. Chronic (ab)users can be
             very reluctant to cease abuse, and may require professional
             help as with other drug misuse.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Naturally-occuring anabolic steroids are synthesised in
             the testis, ovary and adrenal gland from cholesterol via
             pregnenolone. Synthetic anabolic steroids are based on the
             principal male hormone testosterone, modified in one of three
             ways:
    

             alkylation of the 17-carbon
             esterification of the 17-OH group
             modification of the steroid nucleus
    
             (Murad & Haynes, 1985).

        3.2  Chemical structure

             Chemical name: 17beta-Hydroxyandrost-4-en-3-one
    
             Alternatives:       -17-Hydroxy-androst-4-en-3-one
                                 -(17-beta)-androst-4-en-17(beta)-ol-3-one
                                 -delta (sup 4) -androsten-17 (beta)-ol-3-
                                  one
                                 -17-beta-Hydroxy-androst-4-en-one
                                 -17-beta-Hydroxy-delta (sup 4)-androsten-
                                  3-one
                                 -17-beta-Hydroxy-4-androsten-3-one
                                 -17-beta-Hydroxyandrosten-4-en-3-one
    
             Molecular Formula:  C19H28O2
    
             Molecular Weight:   288.4
    
             The following salts also are available:
    
                    Testosterone Cypionate;
                    Testosterone Enanthate;
                    Testosterone Isocaproate;
                    Testosterone Phenylpropionate;
                    Testosterone Propionate;
                    Testosterone Cyclopentylpropionate;
                    Testosterone Heptanoate;
                    Testosterone Oenanthate;
                    Testosterone Isohexanoate;
                    Testosterone Bucyclate;
                    Testosteron Hydrate;
    
             Molecular formulas:
    
                    Testosterone Cypionate C27H40O3.
                    Testosterone Enanthate C26H40O3.
                    Testosterone Isocaproate C25H3803.
                    Testosterone Phenylpropionate C28H36O3.
                    Testosterone Propionate C22H32O3.
                    Testosteron Undecanoate C29H48O3.

        3.3  Physical properties

             3.3.1  Colour

                    White or slightly creamy-white

             3.3.2  State/form

                    Solid-crystals

             3.3.3  Description

                    Odourless or almost odourless, crystals or
                    crystalline powder. Practically insoluble in water;
                    freely soluble in alcohol; soluble 1 in 6 of
                    dehydrated alcohol, 1 in 2 of chloroform, and 1 in 100
                    of ether; slightly soluble in ethyl oleate; soluble in
                    dioxan and vegetable oils.

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

             3.4.2  Storage conditions

                    Protect from light.
    
                    Vials for parenteral administration should be stored
                    at room temperature (15 to 30°C). Visual inspection
                    for particulate and/or discoloration is
                    advisable.

    4.  USES

        4.1  Indications

             4.1.1  Indications

                    Anabolic agent; systemic
                    Anabolic steroid
                             Androstan derivative; anabolic steroid
                             Estren derivative; anabolic steroid
                             Other anabolic agent

             4.1.2  Description

                    The only legitimate therapeutic indications for
                    anabolic steroids are:
    
                    (a) replacement of male sex steroids in men who have
                    androgen deficiency, for example as a result of loss
                    of both testes
    
                    (b) the treatment of certain rare forms of aplastic
                    anaemia which are or may be responsive to anabolic
                    androgens.
    
                    (ABPI Data Sheet Compendium, 1993)
    

                    (c) the drugs have been used in certain countries to
                    counteract catabolic states, for example after major
                    trauma.

        4.2  Therapeutic dosage

             4.2.1  Adults

                    testosterone undecanoate            up to 160 mg/day
                    testosterone esters                 150 to 300 mg/week
                    (Reynolds, 1992)

             4.2.2  Children

                    Not applicable

        4.3  Contraindications

             Known or suspected cancer of the prostate or (in men) breast.
             Pregnancy or breast-feeding.
             Known cardiovascular disease is a relative contraindication.

    5.  ROUTES OF EXPOSURE

        5.1  Oral

             Anabolic steroids can be absorbed from the
             gastrointestinal tract, but many compounds undergo such
             extensive first-pass metabolism in the liver that they are
             inactive. Those compounds in which substitution of the 17-
             carbon protects the compound from the rapid hepatic
             metabolism are active orally (Murad and Haynes, 1985).
             There are preparations of testosterone that can be taken
             sublingually.

        5.2  Inhalation

             Not relevant

        5.3  Dermal

             No data available

        5.4  Eye

             Not relevant

        5.5  Parenteral

             Intramuscular or deep subcutaneous injection is the
             principal route of administration of all the anabolic
             steroids except the 17-alpha-substituted steroids which are
             active orally.

        5.6  Other

             Not relevant

    6.  KINETICS

        6.1  Absorption by route of exposure

             The absorption after oral dosing is rapid for
             testosterone and probably for other anabolic steroids, but
             there is extensive first-pass hepatic metabolism for all
             anabolic steroids except those that are substituted at the
             17-alpha position.
    
             The rate of absorption from subcutaneous or intramuscular
             depots depends on the product and its formulation. Absorption
             is slow for the lipid-soluble esters such as the cypionate or
             enanthate, and for oily suspensions.
    
             Testosterone esters, prepared for parenteral administration
             are less polar than the free steroids.  Therefore, they are
             absorbed more slowly being effective if given with 1 to 3
             weeks intervals. Some preparations are effective even when
             given at 12 week intervals (Wilson, 1992).

        6.2  Distribution by route of exposure

             The anabolic steroids are highly protein bound, and are
             carried in plasma by a specific protein called sex-hormone
             binding globulin.
             After absorption, only two per cent of testosterone is found
             free in plasma with  98% becoming bound.  The testosterone
             esters are hydrolyzed prior to action.  In the tissues, it is
             transformed by steroid 5-alphareductase to
             dihydrotestosterone, the more active compound (Prod. Info.,
             1994).

        6.3  Biological half-life by route of exposure

             The metabolism of absorbed drug is rapid, and the
             elimination half-life from plasma is very short. The duration
             of the biological effects is therefore determined almost
             entirely by the rate of absorption from subcutaneous or
             intramuscular depots, and on the de-esterification which
             precedes it (Wilson, 1992).

        6.4  Metabolism

             Free (de-esterified) anabolic androgens are metabolized
             by hepatic mixed function oxidases in the liver (Wilson,
             1992). Conversion of testosterone to androstenedione involves

             oxidation of the 17-OH group. Androsterone and
             androstenedione are formed by reducing metabolic
             pathways.

        6.5  Elimination by route of exposure

             After administration of radiolabelled testosterone,
             about 90% of the radioactivity appears in the urine as
             glucuronic or sulfate conjugates, and 6% % of the
             unconjugated testosterone in the faeces; there is some
             enterohepatic recirculation (Wilson, 1992). Small amounts of
             androstenediol and estrogens are excreted in the urine.

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  Toxicodynamics

                    The toxic effects are an exaggeration of the
                    normal pharmacological effects.

             7.1.2  Pharmacodynamics

                    Anabolic steroids bind to specific receptors
                    present especially in reproductive tissue, muscle and
                    fat (Mooradian & Morley, 1987). The anabolic steroids
                    reduce nitrogen excretion from tissue breakdown in
                    androgen deficient men. They are also responsible for
                    normal male sexual differentiation. The ratio of
                    anabolic ("body-building") effects to androgenic
                    (virilizing) effects may differ among the members of
                    the class, but in practice all agents possess both
                    properties to some degree. There is no clear evidence
                    that anabolic steroids enhance overall athletic
                    performance (Elashoff et al, 1991).

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             No data available.

                    7.2.1.2  Children

                             No data available.

             7.2.2  Relevant animal data

                    No data available.

             7.2.3  Relevant in vitro data

                    No data available

        7.3  Carcinogenicity

             Anabolic steroids may be carcinogenic. They can
             stimulate growth of sex-hormone dependent tissue, primarily
             the prostate gland in men. Precocious prostatic cancer has
             been described after long-term anabolic steroid abuse(Roberts
             & Essenhigh, 1986). Cases where hepatic cancers have been
             associated with anabolic steroid abuse have been reported
             (Overly et al, 1984).

        7.4  Teratogenicity

             Androgen ingestion by a pregnant mother can cause
             virilization of a female fetus (Dewhurst & Gordon,
             1984).

        7.5  Mutagenicity

             No data available.

        7.6  Interactions

             The main clinically important drug-drug interactions of
             testosterone are related to the increase in the anticoagulant
             effects of coumarinic drugs.  Therefore, if these drugs are
             used together the anticoagulant response should be carefully
             monitored.  Decreased anticoagulant tolerance has been
             described when oxymetholone is administered together with
             warfarin (Edwards & Curtis, 1971).

        7.7  Main adverse effects

             The adverse effects of anabolic steroids include weight
             gain, fluid retention, and abnormal liver function as
             measured by biochemical tests. Administration to children can
             cause premature closure of the epiphyses. Men can develop
             impotence and azoospermia. Women are at risk of
             virilization.

    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan
             8.1.1  Sampling and specimen collection
                    8.1.1.1  Toxicological analyses
                    8.1.1.2  Biomedical analyses
                    8.1.1.3  Arterial blood gas analysis
                    8.1.1.4  Haematological analyses
                    8.1.1.5  Other (unspecified) analyses

             8.1.2  Storage of laboratory samples and specimens
                    8.1.2.1  Toxicological analyses
                    8.1.2.2  Biomedical analyses
                    8.1.2.3  Arterial blood gas analysis
                    8.1.2.4  Haematological analyses
                    8.1.2.5  Other (unspecified) analyses
             8.1.3  Transport of laboratory samples and specimens
                    8.1.3.1  Toxicological analyses
                    8.1.3.2  Biomedical analyses
                    8.1.3.3  Arterial blood gas analysis
                    8.1.3.4  Haematological analyses
                    8.1.3.5  Other (unspecified) analyses
        8.2  Toxicological Analyses and Their Interpretation
             8.2.1   Tests on toxic ingredient(s) of material
                    8.2.1.1  Simple Qualitative Test(s)
                    8.2.1.2  Advanced Qualitative Confirmation Test(s)
                    8.2.1.3  Simple Quantitative Method(s)
                    8.2.1.4  Advanced Quantitative Method(s)
             8.2.2  Tests for biological specimens
                    8.2.2.1  Simple Qualitative Test(s)
                    8.2.2.2  Advanced Qualitative Confirmation Test(s)
                    8.2.2.3  Simple Quantitative Method(s)
                    8.2.2.4  Advanced Quantitative Method(s)
                    8.2.2.5  Other Dedicated Method(s)
             8.2.3  Interpretation of toxicological analyses
        8.3  Biomedical investigations and their interpretation
             8.3.1  Biochemical analysis
                    8.3.1.1  Blood, plasma or serum
                    8.3.1.2  Urine
                    8.3.1.3  Other fluids
             8.3.2  Arterial blood gas analyses
             8.3.3  Haematological analyses
             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their
             interpretation

        8.5  Overall Interpretation of all toxicological analyses and
             toxicological investigations

             Biomedical analysis
             The following tests can be relevant in the investigation of
             chronic anabolic steroid abuse:
             a) full blood count
             b) electrolytes and renal function tests
             c) hepatic function tests
             d) testosterone
             e) Lutenizing hormone
             f) prostatic acid phosphatase or prostate related antigen
             g) blood glucose concentration
             h) cholesterol concentration
    

             Toxicological analysis
             -urinary analysis for anabolic steroids and their metabolites
    
             Other investigations
             -electrocardiogram

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Nausea and vomiting can occur.

             9.1.2  Inhalation

                    Not relevant

             9.1.3  Skin exposure

                    Not relevant

             9.1.4  Eye contact

                    Not relevant

             9.1.5  Parenteral exposure

                    Patients are expected to recover rapidly after
                    acute overdosage, but there are few data. "Body-
                    builders" use doses many times the standard
                    therapeutic doses for these compounds but do not
                    suffer acute toxic effects.

             9.1.6  Other

                    Not relevant

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Hepatic damage, manifest as derangement of
                    biochemical tests of liver function and sometimes
                    severe enough to cause jaundice; virilization in
                    women; prostatic hypertrophy, impotence and
                    azoospermia in men; acne, abnormal lipids, premature
                    cardiovascular disease (including stroke and
                    myocardial infarction), abnormal glucose tolerance,
                    and muscular hypertrophy in both sexes; psychiatric

                    disturbances can occur during or after prolonged
                    treatment (Ferner & Rawlins, 1988; Kennedy, 1992; Ross
                    & Deutch, 1990; Ryan, 1981; Wagner, 1989).

             9.2.2  Inhalation

                    Not relevant

             9.2.3  Skin exposure

                    Not relevant

             9.2.4  Eye contact

                    Not relevant

             9.2.5  Parenteral exposure

                    Virilization in women; prostatic hypertrophy,
                    impotence and azoospermia in men; acne, abnormal
                    lipids, premature cardiovascular disease  (including
                    stroke and myocardial infarction), abnormal glucose
                    tolerance, and muscular hypertrophy in both sexes.
                    Psychiatric disturbances can occur during or after
                    prolonged treatment. Hepatic damage is not expected
                    from parenteral preparations.

             9.2.6  Other

                    Not relevant

        9.3  Course, prognosis, cause of death

             Patients with symptoms of acute poisoning are expected
             to recover rapidly. Patients who persistently abuse high
             doses of anabolic steroids are at risk of death from
             premature heart disease or cancer, especially prostatic
             cancer. Non-fatal but long-lasting effects include voice
             changes in women and fusion of the epiphyses in children.
             Other effects are reversible over  weeks or months.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Chronic ingestion of high doses of anabolic
                    steroids can cause elevations in blood pressure, left
                    ventricular hypertrophy and premature coronary artery
                    disease (McKillop et al., 1986; Bowman, 1990; McNutt
                    et al., 1988).

             9.4.2  Respiratory

                    Not reported

             9.4.3  Neurological

                    9.4.3.1  Central nervous system

                             Stroke has been described in a young
                             anabolic steroid abuser (Frankle et al., 
                             1988).
    
                             Pope & Katz (1988) described mania and
                             psychotic symptoms of hallucination and
                             delusion in anabolic steroid abusers. They
                             also described depression after withdrawal
                             from anabolic steroids.  There is also
                             considerable debate about the effects of
                             anabolic steroids on aggressive behaviour
                             (Schulte et al., 1993) and on criminal
                             behaviour (Dalby, 1992). Mood swings were
                             significantly more common in normal
                             volunteers during the active phase of a trial
                             comparing methyltestosterone with placebo (Su
                             et al., 1993).

                    9.4.3.2  Peripheral nervous system

                             No data available

                    9.4.3.3  Autonomic nervous system

                             No data available

                    9.4.3.4  Skeletal and smooth muscle

                             No data available

             9.4.4  Gastrointestinal

                    Acute ingestion of large doses can cause nausea
                    and gastrointestinal upset.

             9.4.5  Hepatic

                    Orally active (17-alpha substituted) anabolic
                    steroids can cause abnormalities of hepatic function,
                    manifest as abnormally elevated hepatic enzyme
                    activity in biochemical tests of liver function,and
                    sometimes as overt jaundice.
    

                    The histological abnormality of peliosis hepatis has
                    been associated with anabolic steroid use (Soe et al.,
                    1992).
    
                    Angiosarcoma (Falk et al, 1979) and a case of
                    hepatocellular carcinoma in an anabolic steroid user
                    has been reported (Overly et al., 1984).

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Not reported

                    9.4.6.2  Other

                             Men who take large doses of anabolic
                             steroids can develop prostatic hypertrophy.
                             Prostatic carcinoma has been described in
                             young men who have abused anabolic steroids
                             (Roberts & Essenhigh, 1986).

             9.4.7  Endocrine and reproductive systems

                    Small doses of anabolic steroids are said to
                    increase libido, but larger doses lead to azoospermia
                    and impotence. Testicular atrophy is a common clinical
                    feature of long-term abuse of anabolic steroids, and
                    gynaecomastia can occur (Martikainen et al., 1986;
                    Schurmeyer et al., 1984;  Spano & Ryan, 1984).
    
                    Women develop signs of virilism, with increased facial
                    hair, male pattern baldness, acne, deepening of the
                    voice, irregular menses and clitoral enlargement
                    (Malarkey et al., 1991; Strauss et al., 1984).

             9.4.8  Dermatological

                    Acne occurs in both male and female anabolic
                    steroids abusers.  Women can develop signs of
                    virilism, with increased facial hair and male pattern
                    baldness.

             9.4.9  Eye, ear, nose, throat: local effects

                    Changes in the larynx in women caused by
                    anabolic steroids can result in a hoarse, deep voice.
                    The changes are irreversible.

             9.4.10 Haematological

                    Anabolic androgens stimulate erythropoesis.

             9.4.11 Immunological

                    No data available

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             No data available.

                    9.4.12.2 Fluid and electrolyte disturbances

                             Sodium and water retention can
                             occur, and result in oedema; hypercalcaemia
                             is also reported (Reynolds, 1992).

                    9.4.12.3 Others

                             Insulin resistance with a fall in
                             glucose tolerance (Cohen & Hickman, 1987),
                             and hypercholesterolaemia with a fall in high
                             density lipoprotein cholesterol, have been
                             reported (Cohen et al., 1988; Glazer,
                             1991;Webb et al., 1984).

             9.4.13 Allergic reactions

                    No data available

             9.4.14 Other clinical effects

                    No data available

             9.4.15 Special risks

                    Risk of abuse

        9.5  Other

             No data available

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             The management of acute overdosage consists of
             supportive treatment, with fluid replacement if vomiting is
             severe.  Chronic abuse should be discouraged, and
             psychological support may be needed as in the treatment of

             other drug abuse. The possibility of clinically important
             depression after cessation of usage should be borne in
             mind.

        10.2 Life supportive procedures and symptomatic/specific treatment

             Not relevant

        10.3 Decontamination

             Not usually required.

        10.4 Enhanced elimination

             Not indicated

        10.5 Antidote treatment

             10.5.1 Adults

                    None available

             10.5.2 Children

                    None available

        10.6 Management discussion

             Not relevant

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             A 38-year old man presented with acute urinary
             retention, and was found to have carcinoma of the prostate.
             He had taken anabolic steroids for many years, and worked as
             a "strong-man" (Roberts and Essenhigh, 1986).
    
             A 22-year old male world-class weight lifter developed severe
             chest pain awaking him from sleep, and was shown to have
             myocardial infarction. For six weeks before, he had been
             taking high doses of oral and injected anabolic steroids.
             Total serum cholesterol was 596 mg/dL (HDL 14 mg/dL, LDL 513
             mg/dL) (McNutt et al., 1988). Values of total cholesterol
             concentration above 200 mg/dL are considered undesirable.
    
             A 22-year old body builder took two eight-week courses of
             anabolic steroids. He became severely depressed after the
             second course, and when the depression gradually receded, he
             had prominent paranoid and religious delusions (Pope and
             Katz, 1987).
    

             A 19-year old American college footballer took intramuscular
             testosterone and oral methandrostenolone over 4 months. He
             became increasingly aggressive with his wife and child. After
             he severely injured the child, he ceased using anabolic
             steroids, and his violence and aggression resolved within 2
             months (Schulte et al, 1993).

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             Anabolic steroid abuse amongst athletes, weight
             lifters, body builders and others is now apparently common at
             all levels of these sports. Not all abusers are competitive
             sportsmen.
             There is therefore scope for a public health campaign, for
             example, based on gymnasia, to emphasize the dangers of
             anabolic steroid abuse and to support those who wish to stop
             using the drugs.

        12.2 Other

             No data available.

    13. REFERENCES

        ABPI Data Sheet Compendium (1993) Datapharm Publications,
        London.
    
        Bowman S. (1990) Anabolic steroids and infarction.  Br Med J; 
        300:
    
        Cohen JC &  Hickman R. (1987) Insulin Resistance and diminished
        glucose tolerance in powerlifters ingesting anabolic steroids. J
        Clin Endocrinol Metab  64: 960.
    
        Cohen JC, Noakes TD, & Spinnler Benade AJ. (1988)
        Hypercholesterolemia in male power lifters using Anabolic
        Androgenic Steroids. The Physician and Sports medicine 16: 
        49-56.
    
        Dalby JT. (1992) Brief anabolic steroid use and sustained
        behavioral reaction. Am J Psychiatry 149: 271-272.
    
        Dewhurst J.  & Gordon RR (1984).  Fertility following change of
        sex: a follow-up.  Lancet: ii: 1461-2.
    
        Edwards, MS & Curtis, JR (1971) Decreased anticoagulant tolerance
        with oxymetholone. Lancet; 2: 221.
    
        Elashoff JD, Jacknow AD, Shain SG, & Braunstein GD. (1991) Effects
        of anabolic-androgenic steroids on muscular strength. Annals Inter
        Med 115: 387-393.
    

        Falk H, Thomas LB, Popper H, Ishak KG. (1979). Hepatic
        angiosacroma associated with androgenic-anabolic steroids. Lancet
        2; 1120-1123.
    
        Ferner RE & Rawlins MD (1988) Anabolic steroids: the power and the
        glory? Br Med J 1988; 297: 877-878.
    
        Frankle MA, Eichberg R, & Zacharian SB. (1988) Anabolic Androgenic
        steroids and stroke in an athlete: case report. Arch Phys Med
        Rehabil 1988; 69: 632-633.
    
        Glazer G. (1991) Atherogenic effects of anabolic steroids on serum
        lipid levels. Arch Intern Med 151: 1925-1933.
    
        Kennedy MC. (1992). Anabolic steroid abuse and toxicology. Aust NZ
        J Med 22: 374-381.
    
        Malarkey WB, Strauss RH, Leizman DJ, Liggett M, & Demers LM.
        (1991). Endocrine effects in femal weight lifters who self-
        administer testosterone and anabolic steroids. Am J Obstet 
        Gynecol 165: 1385-1390.
    
        Martikainen H, Alen M, Rahkila P, & Vihko  R. (1986)  Testicular 
        responsiveness to human chorionic gonadotrophin during transient 
        hypogonadotrophic  hypogondasim  induced  by androgenic/anabolic 
        steroids in power athletes.  Biochem 25: 109-112.
    
        McKillop G, Todd IC, Ballantyne D. (1986) Increased left
        ventricular mass in a body builder using anabolic steroids. Brit J
        Sports Med 20: 151-152.
    
        McNutt RA, Ferenchick GS, Kirlin PC, & Hamlin NJ. (1988) Acute
        myocardial infarction in a 22 year old world class weight lifter
        using anabolic steroids.  Am J Cardiol 62: 164.
    
        Mooradian JE, Morley JE, Korenman SG.  (1987) Biological actions
        of androgens.  Endocrine Reviews 8:1-27.
    
        Murad F, & Haynes RC. (1985). Androgens. in.  Ed:  Goodman Gilman
        A, Goodman L S, Roll T W, Murad F. The Pharmacological Basis of
        Therapeutics, 7th edition, Macmillan,  New York:  1440-1458
    
        Overly WL et al. (1984). Androgens and hepatocellular carcinoma in
        an athlete. Ann Int Med 100: 158-159.
    
        Pope GR,, & Katz DL. (1988). Affective and psychotic symptoms
        associated with anabolic steroid use.  Am J Psychiatry 145:
        487-490.
    
        Product Information- Deposteron (R) - Novaquomica,(1994).
    
        Reynolds Ed. (1992) Martindale-The Extra Pharmacopeia. The
        Pharmaceutical Press. London.
    

        Roberts JT, & Essenhigh DM. (1986) Adenocarcinoma of prostate in
        40-year old body builder.  Lancet 2: 742.
    
        Ross RB, & Deutsch S I.(1990)  Hooked on hormones.  JAMA 263:
        2048-2049.
    
        Ryan A J. (1981) Anabolic steroids are fool's gold.  Fed Proc 40:
        2682-2688.
    
        Schurmeyer T, Belkien L, Knuth UA, & Nieschlag E. (1984) 
        Reversible azoospermia induced by the anabolic steroid
        19-nortestosterone.  Lancet i:  417-420.
    
        Soe KL. Soe M. & Gluud C. (1992). Liver pathology associated with
        the use of anabolic-androgenic steroids.  Liver  12: 73-9.
    
        Schulte HM, Hall MJ, & Boyer M. (1993). Domestic violence
        associated with anabolic steroid abuse. Am J Psychiatr 150:
        348.
    
        Spano F, & Ryan W G. (1989) Tamoxifen for gynecomastia induced by
        anabolic steroids?  New Engl J Med 311:  861-862.
    
        Strauss  RH, Liggett MT, & Lanese RR. (1984)  Anabolic steroid use
        and perceived effects in 10 weight-trained women athletes JAMA
        253: 2871-2873.
    
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        DR. (1993) Neuropsychiatric effects of anabolic steroids in male
        normal volunteers. JAMA 269: 2760-2764.
    
        Wagner JC (1989). Abuse of drugs used to enhance athletic
        performance. Am J Hosp Pharm 46: 2059-2067
    
        Webb O L, Laskarzewski P M, & Glueck, CJ. (1984) Severe depression
        of high-density lipo protein cholesterol levels in weight lifters
        and body builders by self-administered exogenous testerone and 
        anabolic-andorgenic steroids.  Metabolism 33: 971-975.
    
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        Basis of Therapeutics. McGraw-Hill, Toronto.

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
        ADDRESS(ES)

        Author:       Staff of the Poison Control Center of Rio de
                      Janeiro:
    
                      Sylvana do Valle Costa , MD
                      Denir Gomes Nogueira, Pharm. D.; MSc.
                      Carlos Alberto Guimarœes Reis; MD.
                      Marcia Matos Silva; Pharm D.
                      Jaderson Socrates Lima; MD, MSc.
    
                      Poison Control Center of Rio de Janeiro
                      University Hospital - Federal University of Rio de
                      Janeiro.
                      Av Brig. Trompovsky,
                      SN - 21940-590-
                      Rio de Janeiro - Brazil
    
        Reviewed:     INTOX 9, Cardif, Wales, September, 1996
    
        This monograph has been harmonised with the Group Monograph (G007)
        on Anabolic Steroids written by Dr R. Ferner:
    
                      Dr R. E. Ferner,
                      West Midlands Centre for Adverse Drug Reaction
                      Reporting,
                      City Hospital Dudley Road,
                      Birmingham B18  7QH
                      England.
                      Tel: +44-121-5074587
                      Fax: +44-121-5236125
                      Email: fernerre@bham.ac.uk
    
        Date:         1994
    
        Peer review:  INTOX Meeting, Sao Paulo, Brazil, September 1994
                      (Drs P.Kulling, R.McKuowen, A.Borges, R.Higa,
                      R.Garnier, Hartigan-Go, E.Wickstrom)
    
        Editor:       Dr M.Ruse, March 1998
    



    See Also:
       Toxicological Abbreviations
       TESTOSTERONE (JECFA Evaluation)
       Testosterone (IARC Summary & Evaluation, Volume 6, 1974)
       Testosterone (IARC Summary & Evaluation, Volume 6, 1974)