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CBD Oil and Testosterone

 

Does CBD impact testosterone levels, and if so, how?

Testosterone is the dominant sex hormone in males. Besides helping maintain a healthy mood, testosterone plays several essential roles. 

These roles include the development of the penis and testes, muscle size, strength, sperm production, and sex drive or libido (1).

Testosterone is also one of several androgens (male sex hormones) in females, and they are produced in the adrenal gland and ovaries. 

Androgens have significant effects on ovarian function, bone strength, and sexual behavior, including healthy libido. 

The proper balance between testosterone (including androgens) and estrogen is vital for the ovaries to work healthily. 

While the specifics are uncertain, it is possible that androgens also play a critical role in normal brain function, including mood, sex drive, and cognitive function.

A testosterone levels test measures the levels of testosterone in the blood. Testosterone levels that are either too high or too low can cause health problems in both men and women (3).

CBD and Testosterone: The Role of the ECS Explained

The endocannabinoid system (ECS) is a system of the human body which includes the naturally-produced cannabinoids. 

Among its many critical bodily functions is its vital role in reproduction, which is essential to consider when discussing CBD (cannabidiol) and testosterone (4).

The ECS is also one of the primary regulatory feedback mechanisms in the hypothalamic-pituitary-gonadal (HPG) axis. When CB1 and CB2 receptors are triggered, the reproductive hormones are also signaled and activated (5).

However, unlike THC (tetrahydrocannabinol), CBD does not directly bind to the CB1 and CB2 receptors. Instead, it indirectly impacts the ECS through other neurotransmitter systems present. 

The binding of cannabinoids to either receptor can have adverse effects on the male reproductive system during its presence in the bloodstream.

Evidence suggests that CBD could play a role in balancing testosterone levels. 

In one of the earliest research on CBD and testosterone, researchers found that male sexual and reproductive function in animal models could be affected not only by THC but also by CBD (6). 

In a study published in Molecular and Cellular Endocrinology, the researchers noted that while CBD is present in the human body, it might reduce the generation of testosterone (7). 

The results also indicated that CBD could stifle the decline or oxidation of testosterone in the liver. 

CBD, however, cannot lower the already-circulating serum testosterone levels in the blood, as shown in a study published in Drug Metabolism and Disposition (8).

Ultimately, testosterone production reverts to its natural state when CBD is no longer present. 

CBD’s Impact on Testosterone Levels

According to the American Psychological Association, ongoing stress over an extended period can affect testosterone production, resulting in a decline in sex drive or libido. It can even cause erectile dysfunction or impotence (9). 

Meanwhile, studies have shown CBD’s therapeutic benefits that might impact testosterone levels by helping the body produce more of the hormones.

A study published in the Journal of Psychopharmacology demonstrated CBD’s anti-anxiety characteristics (10). 

The authors noted that CBD could be a useful addition to treatment plans for both social and general anxiety disorders. 

By limiting the amount of emotional stress individuals feel, they can help their body produce testosterone.

When stress affects the immune system, the body can become vulnerable to infection. In the male anatomy, infections to the urethra, testes, and prostate gland can impact male reproductive functioning (11).

Meanwhile, research has demonstrated that cannabinoids, like cannabidiol, can interfere with the release of cytokines (12). Cytokines are proteins involved in acute and chronic inflammation (13).

 Also, the essential fatty acids found in hemp extracts, like CBD oil, have been shown to help increase testosterone production.

A year-long study published in the Asian Journal of Andrology examined the link between fat intake and reproductive hormone levels among healthy human subjects (14). 

The study found a positive correlation between the ingestion of polyunsaturated fats, like omega-3 and 6, and hormone concentrations. 

Ultimately, results showed that subjects who increased their intake of essential fatty acids experienced improved testicular function, which likely helped improve their levels of production of testosterone.

Conclusion

Most experts recommend that individuals looking to improve their testosterone levels naturally should focus on prioritizing sleep, eating a healthy and balanced diet, maintaining a healthy weight, exercising regularly, and finding ways to reduce stress.

CBD can be utilized in all of these measures, as the potent cannabinoid has been shown to possess several therapeutic benefits that may help manage and improve testosterone levels. 

Still, before embarking on a CBD regimen or including it as an adjunct therapy, consult with a doctor experienced in cannabis use for advice. 

 

References

  1. Harvard Health Publishing. (2019, Aug 29). Testosterone — What It Does And Doesn't Do. Retrieved from https://www.health.harvard.edu/drugs-and-medications/testosterone--what-it-does-and-doesnt-do.
  2. Harvard Health Publishing. (2019, Aug 29). Testosterone — What It Does And Doesn't Do. Retrieved from https://www.health.harvard.edu/drugs-and-medications/testosterone--what-it-does-and-doesnt-do.
  3. MedlinePlus. (2020, Feb 26). Testosterone Levels Test. Retrieved from https://medlineplus.gov/lab-tests/testosterone-levels-test/.
  4. Habayeb OM, Bell SC, Konje JC. Endogenous cannabinoids: metabolism and their role in reproduction. Life Sci. 2002;70(17):1963–1977. DOI:10.1016/s0024-3205(01)01539-9.
  5. Hillard CJ. Endocannabinoids and the Endocrine System in Health and Disease. Handb Exp Pharmacol. 2015;231:317–339. DOI:10.1007/978-3-319-20825-1_11.
  6. Dalterio S, Bartke A, Burstein S. Cannabinoids inhibit testosterone secretion by mouse testes in vitro. Science. 1977;196(4297):1472–1473. DOI:10.1126/science.867048. 
  7. Jakubovic A, McGeer EG, McGeer PL. Effects of cannabinoids on testosterone and protein synthesis in rat testis Leydig cells in vitro. Mol Cell Endocrinol. 1979;15(1):41–50. DOI:10.1016/0303-7207(79)90069-8.
  8. Narimatsu S, Watanabe K, Yamamoto I, Yoshimura H. Mechanism for inhibitory effect of cannabidiol on microsomal testosterone oxidation in male rat liver. Drug Metab Dispos. 1988;16(6):880–889.
  9. APA. Stress Effects on the Body. Retrieved from https://www.apa.org/helpcenter/stress/effects-male-reproductive.
  10. Crippa JA, Derenusson GN, Ferrari TB, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011;25(1):121–130. DOI:10.1177/0269881110379283.
  11. APA. Stress Effects on the Body. Retrieved from https://www.apa.org/helpcenter/stress/effects-male-reproductive.
  12. Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M. Cannabinoids as novel anti-inflammatory drugs. Future Med Chem. 2009;1(7):1333–1349. DOI:10.4155/fmc.09.93.
  13. Feghali CA, Wright TM. Cytokines in acute and chronic inflammation. Front Biosci. 1997 Jan 1;2:d12-26. DOI: 10.2741/a171.
  14. MInguez-Alarcón L, Chavarro JE, Mendiola J, et al. Fatty acid intake in relation to reproductive hormones and testicular volume among young healthy men. Asian J Androl. 2017;19(2):184–190. DOI:10.4103/1008-682X.190323.

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.
    
        Su T-P, Pagliaro M, Schmidt PJ, Pickar D, Wolkowitz O, & Rubinow
        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.
    
        Wilson J D. (1992). Androgens. In: Goodman Gilman A., Rall T W,
        Nies A S, & Taylor P. (eds) Goodman and Gilman's Pharmacological
        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:
        Testosterone (IARC Summary & Evaluation, Volume 6, 1974)

INTOX Home Page

 

    Summary for UKPID





    PROGESTOGENS





    Helen Seymour, BPharm (Hons)

 

    National Poisons Information Service (Newcastle Centre)

    Regional Drug & Therapeutics Centre

    Wolfson Building

    Claremont Place

    Newcastle upon Tyne

    NE1 4LP

    UK



    This monograph has been produced by staff of a National Poisons

    Information Service Centre in the United Kingdom.  The work was

    commissioned and funded by the UK Departments of Health, and was

    designed as a source of detailed information for use by poisons

    information centres.

 

    Peer review group: Directors of the UK National Poisons Information

    Service.



    SUMMARY

 

    Type of product

 

         Used for a number of purposes, including treatment of amenorrhea,

         abnormal uterine bleeding, contraception, malignant disease and

         menopausal symptoms.

 

    Ingredients

 

         A progestogen.

 

    Toxicity

 

         Very low.

 

    Features

 

         May cause nausea and vomiting.

         Rarely, withdrawal bleeding may occur in pre-pubertal girls.

 

    Treatment

 

         None required.

 

    SUBSTANCE

 

         Progestogen

 

    ORIGIN OF SUBSTANCE

 

         Synthetic

 

    NAME

 

    Brand Name/Generic Name

         Cyclogest/ Progesterone

         Depo-Provera/Medroxyprogesterone

         Depostat/ Gestronol hexanoate

         Duphaston/ Dydrogesterone

         Duphaston HRT/Dydrogesterone

         Farlutal/ Medroxyprogesterone

         Femulen/ Ethynodiol diacetate

         Gestone/ Progesterone

         Megace/ Megesterol Acetate

         Menzol/ Norethisterone

         Micronor HRT/ Norethisterone

         Micronor/ Norethisterone

         Microval/ Levonorgestrel

         Mirena/Levonorgestrel

         Neogest/ Norgestrel

         Norgeston/ Levonorgestrel

 

         Noriday/ Norethisterone

         Noristat/ Norethisterone

         Norplant/ Levonorgestrel

         Primolut N/ Norethisterone

         Proluten Depot/ Hydroxyprogesterone Hexanoate

         Provera/ Medroxyprogesterone Acetate

         Utovlan/ Norethisterone

 

    CHEMICAL GROUP

 

         Progestogens

         BNF 6.4.1.2

         Progestogen-Only contraceptives

         BNF 7.3.2

         Progestogens

         BNF 8.3.2

 

    SUBSTANCE IDENTITY

 

    REFERENCE NUMBER

 

    CAS

 

    Product licence number

         Cyclogest Pessaries 200mg      2343/0001

         Cyclogest Pessaries 400mg      2343/0002

         Depo-Provera 150mg/ml          0032/0082

         Depostat 200mg in 2ml          0053/0190

         Duphaston/Duphaston HRT        0512/5004R

         Farlutal 100mg tablets         3433/0056

         Farlutal 250mg tablets         3433/0058

         Farlutal 500mg tablets         3433/0080

         Farlutal 200mg/ml, 2.5ml       3433/0045

         Farlutal 200mg/ml, 5ml         3433/0045

         Femulen 500mcg                 08821/0015

         Gestone 25mg                   3194/0061

         Gestone 50mg                   3194/0062

         Gestone 100mg                  3194/0063

         Megace 40mg tablets            0125/0144

         Megace 160mg tablets           0125/0173

         Menzol 5mg tablets

         Micronor Oral Contraceptives   0242/0234

         Micronor HRT                   0242/0241

         Microval                       0011/0040

         Mirena                         0484/0025

         Neogest                        0053/0062

         Norgeston                      0053/0068

         Noriday                        088210036

         Noristerat                     0053/0095

         Norplant                       0109/0249

         Primolut N                     0053/5033R

         Provera 2.5mg                  0032/0168

         Provera 5mg                    0032/5035R

 

         Provera 10mg                   0032/0151

         Provera 100mg                  0032/0111

         Provera 200mg                  0032/0112

         Provera 400mg                  0032/0131

         Proluten Depot 250mg           0053/5031R

         Proluten Depot 500mg           0053/5032R

 

    MANUFACTURER

 

         Bristol-Myers Squibb

         Pharmaceuticals Ltd

         141-149 Staines Rd

         Hounslow

         Middlesex

         TW3 3JA

         0181 5727422

 

         Ferring Pharmaceuticals Ltd

         Greville House

         Hatton Road

         Feltham

         Middlesex

         TW14 9PX

         0181 8931543

 

         Hoechst Rousell Ltd

         Broadwater Park

         Denham

         Uxbridge

         Middlesex

         UB9 5HP

         01895 834343

 

         Janssen-Cilag Ltd

         PO Box 79,

         Saunderton,

         High Wycombe,

         Bucks

         HP14 4HJ

         01494 567567

 

         Organon Laboratories Ltd

         Cambridge Science Park,

         Milton Road,

         Cambridge

         CB4 4FL

         01223 423445

 

         Ortho

         see Janssen-Cilag

 

         P-D

         Parke-Davis Medical,

         Lambert Court,

         Chestnut Avenue,

         Eastleigh,

         Hants

         SO53 3ZQ

         01703 620500

 

         Pharmacia-Leiras Ltd

         Pharmacia & Upjohn

         Davy Avenue

         Knowlhill

         Milton Keynes

         MK5 8PH

         01908 661101

 

         Roussell

         see Hoechst-Roussell

 

         Schering Health Care Ltd

         The Brow,

         Burgess Hill,

         West Sussex

         RH15 9NE

         01444 232323

 

         Schwarz Pharma Ltd

         Schwarz House

         East Street

         Chesham

         Bucks

         HP5 1DG

         01494 772071

 

         Searle Pharmaceuticals

         PO Box 53,

         Lane End Road,

         High Wycombe,

         Bucks

         HP12 4HL

         01494 521124

 

         Solvay Healthcare Ltd

         Hamilton House

         Gaters Hill

         West End

         Southampton

         SO18 3JD

         01703 472281

 

         Upjohn Ltd

         See Pharmacia-Upjohn

 

         Wyeth Laboratories

         Huntercombe Lane South,

         Taplow,

         Maidenhead,

         Berks

         SL6 0PH

         01628 604377

 

    PRESENTATION

 

    Form

 

         Cyclogest Pessaries 200mg          pessaries

         Cyclogest Pessaries 400mg          pessaries

         Depo-Provera 150mg/1ml, 3.3ml      injection

         Depostat100mg/ml, 2ml              injection

         Duphaston/Duphaston HRT 10mg       tablets

         Farlutal 100mg,250mg, 500mg        tablets

         Farlutal 200mg/ml, 2.5ml & 5ml     injection

         Femulen 5mg                        tablets

         Gestone 25mg                       injection

         Gestone 50mg                       injection

         Gestone 100mg                      injection

         Megace 40mg, 160mg                 tablets

         Menzol 5mg                         tablets

         Micronor Oral Contraceptives       tablets

         Micronor HRT                       tablets

         Microval 30mcg                     tablets

         Mirena 20mcg/24hours               intra-uterine system

         Neogest 75mcg                      tablets

         Norgeston 30 mcg                   tablets

         Noriday 350mcg                     tablets

         Noristerat 200mg/ml                injection

         Norplant 38mg                      implant capsule

         Primolut N 5mg                     tablets

         Provera 2.5mg                      tablets

         Provera 5mg                        tablets

         Provera 10mg                       tablets

         Provera 100mg                      tablets

         Provera 200mg                      tablets

         Provera 400mg                      tablets

         Proluten Depot 250mg               injection

         Proluten Depot 500mg               injection

         Utovlan 5mg                        tablets

 

    Pack sizes

 

         Cyclogest Pessaries 200mg          - 15

         Cyclogest Pessaries 400mg          - 15

         Depostat                           - 1

         Depo-Provera 150mg, 3.3ml          - 1

         Depostat                           - 1

         Duphaston                          - 60

         Duphaston HRT                      - 42

         Farlutal 100mg tablets             - 20; 50

         Farlutal 500mg tablets             - 56

         Farlutal 200mg/ml, 2.5ml           - 1

         Farlutal 200mg/ml, 5ml             - 1

         Femulen                            - 28

         Gestone 25mg                       - 1

         Gestone 50mg                       - 1

         Gestone 100mg                      - 1

         Megace 40mg                        - 20

         Megace 160mg                       - 30

         Menzol                             - 3 x 24; 3 x60

         Micronor Oral Contraceptives       - 3 x 28

         Micronor HRT                       - 3 x 12

         Microval                           - 35

         Mirena                             - 1

         Neogest                            - 35

         Norgeston                          - 35

         Noriday                            - 3 x 28

         Noristerat                         - 1

         Norplant                           - 6 implants

         Primolut N                         - 30

         Provera 2.5mg                      - 30

         Provera 5mg                        - 10

         Provera 10mg                       - 10; 90

         Provera 100mg                      - 60

         Provera 200mg                      - 30

         Provera 400mg                      - 30

         Proluten Depot 250mg               - 1

         Proluten Depot 500mg               - 1

 

    PHYSIOCHEMICAL PROPERTIES

 

    Chemical structure

 

         Dydrogesterone - 6-Dehydro-9ß,10alpha-progesterone

 

         Ethynodiol acetate - 19-Nor-17alpha-pregn-4-en-20-yne-3ß

 

         Gestronol - NIF

 

         Hydroxyprogesterone hexanoate - 17alpha-Hydroxypregn-4-ene-3,20-

         dione hexanoate

 

         Levonorgestrel - 13-Ethyl-17ß-hydroxy-18,19-dinor-17alpha-pregn-

         4-en-20-yn-3-one

 

         Medroxyprogesterone acetate - 17alpha-Hydroxy-6alpha-methylpregn-

         4-ene-3,20-dione acetate

 

         Megestrol Acetate - 6-Methyl-3,20-dioxopregna-4,6-dien-17alpha-yl

         acetate

 

         Norgestrel - (±)-13-Ethyl-17ß-hydroxy-18,19-dinor-17alpha-pregn-

         4-en-20-yn-3-one

 

         Norethisterone - 17alpha-Ethinyl-19-nortestosterone, 17ß-hydroxy-

         19-nor-17alpha-pregn-4-en-20-yn-3-one, 17alpha-ethinyl-17ß-

         hydroxy-19-nor-androst-4-en-3-one

 

         Progesterone - Pregn-4-ene-3,20-dione

 

    Physical structure at room temperature

 

         All are solid

 

    Colour

 

         Dydrogesterone - white to pale yellow

 

         Ethynodiol acetate - white or almost white

 

         Gestronol - NIF

 

         Hydroxyprogesterone hexanoate - white or creamy white

 

         Levonorgestrel - white or almost white

 

         Megestrol Acetate - white or creamy-white

 

         Medroxyprogesterone acetate - white or off-white

 

         Norgestrel - white or almost white

 

         Norethisterone - white or yellowish-white

 

         Progesterone - white or slightly yellowish-white

 

    Odour

 

         Dydrogesterone - odourless or almost odourless

 

         Ethynodiol acetate - odourless or almost odourless

 

         Gestronol - NIF

 

         Hydroxyprogesterone hexanoate - odourless or almost odourless

 

         Levonorgestrel - odourless

 

         Megestrol Acetate - odourless or almost odourless

 

         Medroxyprogesterone acetate - odourless

 

         Norgestrel - almost odourless

 

         Norethisterone - odourless

 

         Progesterone - odourless

 

    Viscosity

 

         NA

 

    pH

 

         NA

 

    Solubility

 

    Dydrogesterone - Practically insoluble in water; soluble 1 in 40 of

    alcohol, 1 in 2 of chloroform, and 1 in 200 of ether; soluble in

    acetone; sparingly soluble in methyl alcohol; slightly soluble in

    fixed oils

 

    Ethynodiol acetate - very slightly soluble to practically insoluble in

    water; soluble in alcohol; freely to very soluble in chloroform;

    freely soluble in ether; sparingly soluble in fixed oils

 

    Gestronol - NIF

 

    Hydroxyprogesterone hexanoate - practically insoluble in water; freely

    soluble in alcohol and ether; very soluble in chloroform; dissolves in

    fixed oils and esters

 

    Levonorgestrel - practically insoluble in water; slightly soluble in

    alcohol, in acetone and in ether; soluble in chloroform; sparingly

    soluble in methylene chloride.

 

    Megestrol Acetate - practically insoluble in water; sparingly soluble

    in alcohol; very soluble in chloroform; soluble in acetone; slightly

    soluble in ether and in fixed oils.

 

    Medroxyprogesterone acetate - practically insoluble in water;

    sparingly soluble in alcohol and in methylalcohol; slightly soluble in

    ether; freely soluble in chloroform; soluble in acetone and dioxan

 

    Norgestrel - practically insoluble in water; the BP states that it is

    slightly, and the USP that it is sparingly soluble in alcohol;

    sparingly soluble in methylene chloride; freely soluble in chloroform

 

    Norethisterone - practically insoluble in water; slight to sparingly

    soluble in alcohol; soluble in chloroform and in dioxan; slightly

    soluble in ether.

 

    Progesterone - BP solublities are: practically insoluble in water;

    freely soluble in dehydrated alcohol; very soluble in chloroform;

    sparingly soluble in acetone, in ether and in fixed oils. USP

    solubilities are: practically insoluble in water; soluble in alcohol,

    in acetone and in dioxan; sparingly soluble in vegetable oils

 

    USES

 

    Indications

 

    To prevent conception; as part of hormone replacement regimes; as a

    hormone antagonist in malignant disease.

 

    Therapeutic Dose

 

    Contraceptive: 1 tablet (of whichever preparation prescribed) daily at

    the same time each day, starting on 1st day of cycle then

    continuously.

 

    Dydrogesterone - Endometriosis, 10mg 2-3 times daily from 5th to 25th

    day of cycle or continuously; Infertility, irregular cycles, 10mg

    twice daily from 11th to 25th day for at least 6 cycles (but not

    recommended); Habitual abortion, 10mg twice daily from day 11 to day

    25 of cycle until conception, then continuously until 20th week of

    pregnancy and gradually reduced; Dysfunctional uterine bleeding, 10mg

    twice daily (together with an oestrogen) for 5-7 days to arrest

    bleeding; 10mg twice daily (together with an oestrogen) from 11th to

    25th day of cycle to prevent bleeding; Dysmenorrhoea, 10mg twice daily

    from 5th to 25th day of cycle; Amenorrhoea, 10mg twice daily form 11th

    to 25th day of cycle with oestrogen therapy from 1st to 25th day of

    cycle; Pre-menstrual syndrome, 10mg twice daily from 12th to 26th day

    of cycle, increased if necessary (but not recommended); HRT, 10mg

    daily on days 15-28 of each 28-day oestrogen HRT cycle, increased to

    10mg twice daily if withdrawal bleed is early or endometrial biopsy

    shows inadequate progestational response.

 

    Hydroxyprogesterone hexanoate - Habitual abortion, 250-500mg weekly by

    slow intra-muscular injection during first half of pregnancy.

 

    Medroxyprogesterone acetate - Dysfunctional uterine bleeding, 2.5-10mg

    daily for 5-10 days beginning on 16th-21st day of cycle, repeated for

    2 cycles, for secondary amenorrhoea repeat for 3 cycles; Mild to

    moderate endometriosis, 10mg 3 times daily for 90 consecutive days,

    beginning on 1st day of cycle; Endometrial, prostate and renal cancer,

    100-500mg daily; Breast cancer, various doses in range 0.4-1.5g daily;

 

    by deep intramuscular injection for malignant disease, various doses

    in range 1g daily down to 250mg weekly.

 

    Megestrol Acetate - Breast cancer, 160mg daily in single or divided

    doses; endometrial cancer, 40-320mg daily in divided doses.

 

    Norethisterone - Endometriosis, 10mg daily starting on 5th day of

    cycle (increased if spotting occurs to 20-25mg daily, reduced once

    bleeding has stopped); Menorrhagia, 5mg 3 times daily for 10 days to

    arrest bleeding; to prevent bleeding 5mg twice daily from 19th to 26th

    day; Dysmenorrhoea, 5mg 3 times daily from 5th to 24th day for 3-4

    cycles; Pre-menstrual syndrome, 5mg 2-3 times daily from 19th to 26th

    day for several cycles (but not recommended); Postponement of

    menstruation, 5mg three times daily starting 3 days before anticipated

    onset (menstruation occurs 2-3 days after stopping); HRT 1mg daily on

    days 15-26 of each 28-day oestrogen HRT cycle; Breast cancer, 40mg

    daily, increased to 60mg daily if required.

 

    Progesterone - Pre-menstrual syndrome, pessaries - 200mg daily to

    400mg twice daily starting on day 12-14 and continued until onset of

    menstruation (but not recommended); rectally if barrier methods of

    contraception are used, or if vaginal infection; Embryo transfer, deep

    intramuscular injection as per data sheet.

 

    Contraindications

 

    Pregnancy (except where licensed);a history during pregnancy of

    idiopathic jaundice or severe pruritis. Acute or severe chronic liver

    diseases including liver tumours. Dubin-Johnson or Rotor syndrome.

    Undiagnosed abnormal vaginal bleeding. Thrombo-embolic disorders,

    thrombophlebitis, cerebrovascular disorders, coronary artery disease,

    myocardial infarction, angina, hyperlipidaemia or a history of these

    conditions.

 

    Abuses

 

         NIF

 

    HAZARD/RISK CLASSIFICATION

 

         NIF

 

    PHARMACOKINETICS

 

    Absorption

 

    Dydrogesterone

         NIF

 

    Ethynodiol acetate

         almost 100%

 

    Gestronol

         NIF

 

    Hydroxyprogesterone hexanoate

         90%

 

    Megestrol Acetate

         about 100%

 

    Medroxyprogesterone acetate

         <100%

 

    Norgestrel

         NIF

 

    Norethisterone

         100%

 

    Progesterone - extensive

 

    Distribution

 

    Dydrogesterone

         NIF

 

    Ethynodiol acetate

         33l - extensively bound to albumin and more specifically to sex

         hormone binding globulin

 

    Gestronol

         NIF

 

    Hydroxyprogesterone hexanoate

         5l

 

    Levonorgestrel

         93-95% plasma bound

 

    Megestrol Acetate

         NIF

 

    Medroxyprogesterone acetate

         >20l, 94% is protein bound

 

    Norethisterone

         95% plasma bound

 

    Norgestimate

         NIF

 

    Norgestrel

         NIF

 

    Progesterone

         17-29l, 95-98% plasma protein bound

 

    Metabolism

 

    Dydrogesterone

         Metabolised to glucuronide conjugates

 

    Ethynodiol acetate

         Metabolised in liver or gut wall to norethisterone and then to

         sulphate and glucuronide conjugates.

 

    Gestronol

         NIF

 

    Hydroxyprogesterone hexanoate

         metabolised in liver

 

    Levonorgestrel

         Extensively metabolised by the liver

 

    Megestrol Acetate

         metabolised by liver to glucuronide conjugates

 

    Medroxyprogesterone acetate

         extensively metabolised in the liver

 

    Norgestimate

         NIF

 

    Norgestrel

         NIF

 

    Norethisterone

         Metabolised in the intestinal wall and liver

 

    Progesterone

         About 75% is metabolised presystemically to glucuronide

         conjugates by the liver

 

    Elimination

 

    Dydrogesterone

         60% is excreted via the urine within 72 hours. Only small amounts

         are excreted via the faeces

 

    Ethynodiol acetate

         via urine and faeces

 

    Gestronol

         NIF

 

    Hydroxyprogesterone hexanoate

         NIF

 

    Levonorgestrel

         20-30% eliminated via the faeces and the rest via the urine

 

    Megestrol Acetate

         excreted as metabolites via the urine and faeces

 

    Medroxyprogesterone acetate

         mainly as conjugated metabolites in the faeces

 

    Norethisterone

         60% as metabolites in urine and faeces

 

    Norgestrel

         NIF

 

    Progesterone

         mainly as conjugates in the urine

 

    Half-life

 

    Dydrogesterone

         about 6h

 

    Ethynodiol acetate

         about 25h

 

    Gestronol

         NIF

 

    Hydroxyprogesterone hexanoate

         2-11h, mean 4h

 

    Levonorgestrel

         10.26h

 

    Megestrol Acetate

         15-20h

 

    Medroxyprogesterone acetate

         about 30h

 

    Norgestrel

         NIF

 

    Norethisterone

         5 -12h

 

    Progesterone

         distribution - 3-6min; elimination - 19-95min

 

    Breast Milk

 

    Dydrogesterone

         small quantities are have been measured in breast milk, but this

         is unlikely to present any risk to the infant

 

    Ethynodiol acetate

         norethisterone concentration appears to reach a peak at about

         4-8h after ingestion of ethynodiol acetate, small amounts of

         norethisterone are excreted into breast milk, the concentration

         being 10-20% of that in plasma

 

    Gestronol

         NIF, contraindicated in lactation

 

    Hydroxyprogesterone hexanoate

         contraindicated in lactation

 

    Levonorgestrel

         Approximately 0.1% of the daily dose passes into breast milk

 

    Megestrol Acetate

         Disease states being treated would usually contraindicate

         breast-feeding

 

    Medroxyprogesterone acetate

         excreted into breast milk in concentrations similar to those in

         plasma. No special precautions are advised.

 

    Norgestrel

         NIF

 

    Norethisterone

         daily oral dose of 350micrograms for contraception were reported

         in one study to reduce milk volume somewhat but do not usually

         affect volume or composition. Intramuscular injections of 200mg

         each 8 weeks do not interfere with lactation. The plasma/milk

         ratio of the heptanoate is about 10 and only 0.1% of the dose,

         estimated as a maximum of 1.5micrograms daily, reaches the baby.

         this is unlikely to affect the bay and is undetectable in the

         baby's plasma at the time of the peak maternal plasma level.

         There is a theoretical risk of all steroids interfering with

         bilirubin conjugation, and maternal use of norethisterone should

         probably be avoided whilst a baby has neonatal jaundice.

 

    Progesterone

         excreted in low concentrations, which are unlikely to have any

         effect on the infant

 

    TOXICOKINETICS

 

         NIF

 

    EPIDEMIOLOGY OF POISONING

 

    In 1994, 2007 calls were made to UK NPIS centres about hormonal

    contraceptive poisoning.

 

    ADVERSE EFFECTS

 

    General - Headaches/migraine, nausea, vomiting, breast changes, change

    in weight, changes in libido, chloasma, breakthrough bleeding and

    spotting, rash, depression, irregular cycle length, ocular changes,

    increase in size uterine myofibromata and changes in carbohydrate,

    lipid or vitamin metabolism. Rarely dizziness, hirsutism, haemorrhagic

    eruption and colitis have been reported in users of progestogen-only

    oral contraceptives

 

    Megesterol - as above, rare reports of dyspnoea, heart failure,

    hypertension, hot flushes, mood changes, cushingoid faces, tumour

    flare (with or without hypercalcaemia), hyperglycaemia, alopecia and

    carpel tunnel syndrome. Prolonged administration may cause  urticaria.

    Clinical and laboratory evidence of mild adrenal suppression

 

    INTERACTIONS

 

    Metabolism accelerated by rifamycins; increased plasma-cyclosporin

    levels (inhibition of metabolism); aminoglutethimide reduces plasma

    concentration of medroxyprogesterone

 

    MECHANISM OF ACTION

 

    Progestogens are synthetic compounds with actions similar to that of

    progesterone. Progesterone is the main hormone secreted by the corpus

    luteum. Large quantities are produced by the placenta during

    pregnancy. It acts on the endometrium by converting the proliferative

    phase induced by oestrogen to a secretory phase and preparing the

    uterus to receive the fertilised ovum.

 

    FEATURES OF POISONING

 

    Acute

 

    Ingestion

 

    Toxicity is unlikely following an acute overdose. Occasionally there

    may be nausea and vomiting. Withdrawal bleding may occur in females

    even in pre-pubertal girls.

 

    Chronic

 

    Ingestion/Injection

 

    Chronic or high dose therapy can result in jaundice, headache,

    dizziness, oligomenorrhea or amenorrhea, congestion of the breasts and

    decreased libido. Chronic toxicity may produce a thromboembolic state.

 

    Pregnancy

 

    During the pre-embryonic phase, which lasts until 17 days

    post-conception, the 'all or nothing' concept is thought to apply.

    During this period, cells damaged by a toxic insult, such as a drug

    exposure, will be replaced by extra divisions of the remaining cells

    which will then develop normally. If extensive damage occurs, failure

    of implantation and spontaneous abortion may occur. Thus, if the

    pregnancy is maintained, the risks to the fetus are likely to be no

    greater than those for the general population.

 

    The maternal administration of norethisterone to several species of

    animals, including non-human primates, caused masculinisation of the

    external female genitalia of the offspring but did not increase the

    incidence of non-genital adverse fetal effects.1

 

    There is no conclusive evidence of an association between progestogen

    exposure in early pregnancy and non-genital malformations. Androgenic

    hormones in human pregnancy have been associated with a small risk of

    genital abnormalities when exposure occurs around about 6-7 weeks of

    gestational age when the genitalia are beginning to develop.1-4

    Approximately 1% of female fetuses exposed at this critical period of

    development develop genital anomalies e.g. enlarged clitoris and

    labial folds1,4. Internal genitalia and subsequent pubertal

    development are not affected by norethisterone taken during pregnancy.

    Male infants have an even smaller risk of genital anomalies, usually

    hypospadias which can be treated surgically.

 

    However, a recent meta-analysis of 14 studies involving 65,567 women

    concluded that there was no association between 1st trimester exposure

    to sex hormones generally, or to oral contraceptives specifically, and

    external genital malformations.5

 

    The use of norethisterone during any stage of pregnancy is

    contra-indicated.

 

    A number of congenital malformations, including cardiovascular,

    central nervous system, multiple organ and limb defects, have been

    reported in infants exposed to the drug  in utero.1,2,3,4 However, the

    role of norethisterone in the development of these anomalies has not

    been established due to the influence of other factors such as alcohol

    ingestion, cigarette smoking, concomitant drug therapy and maternal

    obstetric history.1,3

 

    There are three prospective follow-up reports from the European

    Network of Teratology Information Services (ENTIS) following exposure

    to progestogens during pregnancy. One patient had Norplant removed

    after conception (details of timing of exposure not available), a

    normal full term infant was born; there were two reports of exposure

    to Depo-Provera, one woman had a dose at 1 week and 12 weeks of

    gestation, a normal fullterm infant was born, the second woman was

    exposed at 5 weeks of gestation and had an elective termination.

 

    References

 

  1. Gilstrap III LC, Little BB. Drugs and Pregnancy. Amsterdam:

    Elsevier Science Publishing, 1992: 242-244

 

  1. Folb PI, Dukes MNG (Eds). Drug Safety in Pregnancy. Amsterdam:

    Elsevier Science Publishing, 1990: 273-281

 

  1. Briggs CG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation.

    4th ed. Baltimore: Williams and Wilkins, 1994

 

  1. Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York:

    Marcel Dekker, 1993

 

  1. Raman-Wilms L et al. Obs Gyn 1995; 85: 141-9

 

    MANAGEMENT

 

    Symptomatic treatment only is required.

    Parents of prepubertal girls should be warned of the possibility of a

    withdrawal bleed several days after ingestion.

 

    ANALYSIS

 

         NIF

 

    PREVENTION OF POISONING

 

         NIF

 

    OTHER TOXICOLOGICAL DATA

 

    Carcinogenicity

 

    In a retrospective study of 5000 black women who received depot

    medroxyprogesterone for contraception, no increased incidence in

    breast, ovarian, or uterine corpus cancer was seen up to 13 years

    later. (Liang et al 1993).

    There is considerable evidence suggesting that after induction by

    chemical carcinogens, sex hormones act as promoters of

    heptocarcinogenesis.

 

    Teratogenicity

 

    There is no conclusive evidence of an association between progestogen

    exposure in early pregnancy and non-genital malformations. Exposed

    female infant have a small risk (approximately 1%) of clitoral

    hypertrophy and fusion of the labioscrotal folds, when exposure occurs

    during the critical period of genital development. These anomalies can

    be corrected surgically. Male infants have an even smaller risk of

    genital anomalies, usually hypospadias which can be treated

    surgically.

 

    Author

 

    Helen Seymour, BPharm (Hons)

 

    National Poisons Information Service (Newcastle Centre)

    Regional Drug & Therapeutics Centre

    Wolfson Building

    Claremont Place

    Newcastle upon Tyne

    NE1 4LP

    UK

 

    This monograph was produced by the staff of the Newcastle Centre of

    the National Poisons Information Service in the United Kingdom. The

    work was commissioned and funded by the UK Departments of Health, and

    was designed as a source of detailed information for use by poisons

    information centres.

 

    Peer review was undertaken by the Directors of the UK National Poisons

    Information Service.

 

    Last updated January 1997

 

    REFERENCES

 

  1. Martindale: The Extra Pharmacopoeia. 31st Edition. Reynolds JEF

    (Ed.). Pharmaceutical Press 1996.

 

  1. Therapeutic Drugs. Dollery C. (Ed.). Churchill Livingstone 1991.

 

  1. ABPI Compendium of Data Sheets and Summaries of Product

    Characteristics. Datapharm Publications Ltd. 1996-97.

 

  1. British National Formulary. Number 32 (September 1996). British

    Medical Association and Royal Pharmaceutical Society.

 

  1. Poisindex Systemœ, Micromedex, Inc., Denver Colorado, Edition

    Expires 31.12.96.

 

  1. National Teratology Information Service.

 

  1. European Commission; Poison centres: Collection of the annual

    reports 1994, Analysis and synthesis, Final Report 31.8.96.

    

 

See Also:

        Combined oral contraceptives (UK PID)





INTOX Home Page

Stanolone

  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

  1. 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

  1. 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

  1. 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

  1. ROUTES OF EXPOSURE

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. 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

  1. 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

  1. 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

  1. 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

      9.4.12 Other clinical effects

      9.4.13 Special risks

   9.5 Other

   9.6 Summary

  1. 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

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

  1. Additional information

   12.1 Specific preventive measures

   12.2 Other

  1. REFERENCES
  2. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)




    Stanolone

 

    International Programme on Chemical Safety

    Poisons Information Monograph 917

    Pharmaceutical

 

    This monograph does not contain all of the sections completed. This

    mongraph is harmonised with the Group monograph on Anabolic Steroids

    (PIM G007).

 

  1. NAME

 

        1.1  Substance

 

             Stanolone

 

        1.2  Group

 

             ATC Classification:

             A14 (Anabolic Agents for Systemic Use)

             A14A (Anabolic steroids)

 

        1.3  Synonyms

 

             Androstanolone; Dihydrotestosterone.

 

        1.4  Identification numbers

 

             1.4.1  CAS number

 

                    521-18-6

 

             1.4.2  Other numbers

 

        1.5  Main brand names, main trade names

 

             Andractim; Gelovit; Ophtovitol (multi-ingredient

             preparations)

 

        1.6  Main manufacturers, main importers

 

  1. 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.

 

  1. 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-Hydroxy-5alpha-androstan-3-one

    

             Molecular Formula: C19H30O2

    

             Molecular Weight: 290.4

 

        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

 

                    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.

 

  1. USES

 

        4.1  Indications

 

             4.1.1  Indications

 

                    Anabolic agent; systemic

                    Anabolic steroid

                             Androstan derivative; anabolic steroid

                             Estren derivative; anabolic steroid

                             Other anabolic agent

                    Anabolic agent for systemic use; veterinary

                             Anabolic steroid; veterinary

                             Estren derivative; veterinary

 

             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

 

             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.

 

  1. 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

 

  1. 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.

 

        6.2  Distribution by route of exposure

 

             The anabolic steroids are highly protein bound, and is

             carried in plasma by a specific protein called sex-hormone

             binding globulin.

 

        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 (Wilson, 1992).

 

        6.5  Elimination by route of exposure

 

             After administration of radiolabelled testosterone,

             about 90% of the radioactivity appears in the urine, and 6%

             in the faeces; there is some enterohepatic recirculation

             (Wilson, 1992).

 

  1. 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

 

        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

 

             No data available.

 

        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.

 

  1. 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:

    

             Toxicological analysis

             -urinary analysis for anabolic steroids and their

             metabolites

    

             Other investigations

             -electrocardiogram

 

        8.6  References

 

  1. 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

 

             9.4.12 Other clinical effects

 

                    No data available

 

             9.4.13 Special risks

 

                    Risk of abuse

 

        9.5  Other

 

             No data available

 

        9.6  Summary

 

  1. 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

 

  1. 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).

 

  1. 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.

 

  1. 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.

    

        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.

    

        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.

    

        Su T-P, Pagliaro M, Schmidt PJ, Pickar D, Wolkowitz O, & Rubinow

  1. (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.

    

        Wilson J D. (1992). Androgens. In: Goodman Gilman A., Rall T W,

        Nies A S, & Taylor P. Goodman and Gilman's Pharmacological Basis

        of Therapeutics. McGraw-Hill, Toronto. Pages 1413-1430.

 

  1. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE

        ADDRESS(ES)

 

        Author:       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

    



    



International Agency for Research on Cancer (IARC) - Summaries & Evaluations

OXYMETHOLONE

VOL.: 13 (1977) (p. 131)

 

  1. Summary of Data Reported and Evaluation

5.1 Animal data

No data were available to the Working Group.

5.2 Human data

Although ten cases of liver-cell tumours have been reported in patients with aplastic anaemia, Fanconi's anaemia or paroxysmal nocturnal haemoglobinuria treated for long periods with oxymetholone alone or in combination with other androgenic drugs, a causal relationship cannot be established.

The increased risk of developing liver-cell tumours could be related to hepatic damage known to be caused by oxymetholone. On the other hand, patients with congenital anaemias many have an intrinsically higher risk of developing tumours; this risk many become manifest during the extended survival resulting from administration of the drug.

 

Subsequent evaluation: Suppl. 7 (1987) (Androgenic (Anabolic) Steroids)

 

Last updated: 25 March 1998

See Also:

        Oxymetholone (PIM 915)






INTOX Home Page

Oxymetholone

  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

  1. 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

  1. 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

  1. 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

  1. ROUTES OF EXPOSURE

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. 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

  1. 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

  1. 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

  1. 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

  1. 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

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

  1. Additional information

   12.1 Specific preventive measures

   12.2 Other

  1. REFERENCES
  2. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)




    Oxymetholone

 

    International Programme on Chemical Safety

    Poisons Information Monograph 915

    Pharmaceutical

 

    This monograph does not contain all of the sections completed. This

    mongraph is harmonised with the Group monograph on Anabolic Steroids

    (PIM G007).

 

  1. NAME

 

        1.1  Substance

 

             Oxymetholone

 

        1.2  Group

 

             ATC Classification:

             A14 (Anabolic Agents for Systemic Use)

             A14A (Anabolic steroids)

 

        1.3  Synonyms

 

             CI-406; HMD

 

        1.4  Identification numbers

 

             1.4.1  CAS number

 

                    434-07-1

 

             1.4.2  Other numbers

 

        1.5  Main brand names, main trade names

 

        1.6  Main manufacturers, main importers

 

  1. 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.

 

  1. 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-Hydroxy-2-hydroxymethylene-17alpha-methyl-

             -5alpha-androstan-3-one.

    

 

             Molecular Formula: C21H32O3

    

             Molecular Weight: 332.5

 

        3.3  Physical properties

 

             3.3.1  Colour

 

                    White to creamy-white

 

             3.3.2  State/form

 

                    Solid-crystals

 

             3.3.3  Description

 

                    Odourless or almost odourless.

                    British Pharmacopoeia solubilities are: practically

                    insoluble in water; soluble in alcohol and freely

                    soluble in chloroform; slightly soluble in ether.

                    US Pharmacopoeia solubilities are: practically

                    insoluble in water; soluble 1 in 40 of alcohol, 1 in 5

                    of chloroform, 1 in 82 of ether, and 1 in 14 of

                    dioxan.

                    Avoid contact with ferrous metals.

 

        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.

 

  1. USES

 

        4.1  Indications

 

             4.1.1  Indications

 

                    Anabolic agent; systemic

                    Anabolic steroid

                             Androstan derivative; anabolic steroid

                             Estren derivative; anabolic steroid

                             Other anabolic agent

                    Anabolic agent for systemic use; veterinary

                             Anabolic steroid; veterinary

                             Estren derivative; veterinary

 

             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

 

             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.

 

  1. 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

 

  1. 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.

 

        6.2  Distribution by route of exposure

 

             The anabolic steroids are highly protein bound, and is

             carried in plasma by a specific protein called sex-hormone

             binding globulin.

 

        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 (Wilson, 1992).

 

        6.5  Elimination by route of exposure

 

             After administration of radiolabelled testosterone,

             about 90% of the radioactivity appears in the urine, and 6%

             in the faeces; there is some enterohepatic recirculation

             (Wilson, 1992).

 

  1. 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

 

        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

 

             No data available.

 

        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.

 

  1. 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:

    

             Toxicological analysis

             -urinary analysis for anabolic steroids and their

             metabolites

    

             Other investigations

             -electrocardiogram

 

        8.6  References

 

  1. 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

 

  1. 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

 

  1. 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).

 

  1. 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.

 

  1. 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.

    

        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.

    

        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.

    

        Su T-P, Pagliaro M, Schmidt PJ, Pickar D, Wolkowitz O, & Rubinow

  1. (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.

    

        Wilson J D. (1992). Androgens. In: Goodman Gilman A., Rall T W,

        Nies A S, & Taylor P. Goodman and Gilman's Pharmacological Basis

        of Therapeutics. McGraw-Hill, Toronto. Pages 1413-1430.

 

  1. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE

        ADDRESS(ES)

 

        Author:       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:

        Oxymetholone (IARC Summary & Evaluation, Volume 13, 1977)






INTOX Home Page

Stanozolol

  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

  1. 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

  1. 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

  1. 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

  1. ROUTES OF EXPOSURE

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. 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

  1. 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

  1. 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

  1. 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

      9.4.12 Other clinical effects

      9.4.13 Special risks

   9.5 Other

   9.6 Summary

  1. 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

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

  1. Additional information

   12.1 Specific preventive measures

   12.2 Other

  1. REFERENCES
  2. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)




    Stanozolol

 

    International Programme on Chemical Safety

    Poisons Information Monograph 918

    Pharmaceutical

 

    This monograph does not contain all of the sections completed. This

    mongraph is harmonised with the Group monograph on Anabolic Steroids

    (PIM G007).

 

  1. NAME

 

        1.1  Substance

 

             Stanozolol

 

        1.2  Group

 

             ATC Classification:

             A14 (Anabolic Agents for Systemic Use)

             A14A (Anabolic steroids)

 

        1.3  Synonyms

 

             Androstanazole; Methylstanazole; NSC-43193; Win-14833

 

        1.4  Identification numbers

 

             1.4.1  CAS number

 

                    10418-03-8

 

             1.4.2  Other numbers

 

        1.5  Main brand names, main trade names

 

        1.6  Main manufacturers, main importers

 

  1. 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.

 

  1. 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:

             17alpha-Methyl-2'H-5alpha-androst-2- -eno(3,2-c)pyrazol-

             17beta-ol

    

 

             Molecular Formula: C21H32N2O

    

             Molecular Weight: 328.5

 

        3.3  Physical properties

 

             3.3.1  Colour

 

                    White or almost white

 

             3.3.2  State/form

 

                    Solid-crystals

 

             3.3.3  Description

 

                    Odourless.

                    There are 2 forms; needles melt at about 155 degrees

                    and prisms at about 235 degrees. Practically insoluble

                    in water; soluble 1 in 41 of alcohol, 1 in 74 of

                    chloroform, and 1 in 370 of ether; soluble in

                    dimethylformamide; slightly soluble in acetone and

                    ethyl acetate.

 

        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.

 

  1. USES

 

        4.1  Indications

 

             4.1.1  Indications

 

                    Anabolic agent; systemic

                    Anabolic steroid

                             Androstan derivative; anabolic steroid

                             Estren derivative; anabolic steroid

                             Other anabolic agent

                    Anabolic agent for systemic use; veterinary

                             Anabolic steroid; veterinary

                             Estren derivative; veterinary

 

             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

 

             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.

 

  1. 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

 

  1. 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.

 

        6.2  Distribution by route of exposure

 

             The anabolic steroids are highly protein bound, and is

             carried in plasma by a specific protein called sex-hormone

             binding globulin.

 

        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 (Wilson, 1992).

 

        6.5  Elimination by route of exposure

 

             After administration of radiolabelled testosterone,

             about 90% of the radioactivity appears in the urine, and 6%

             in the faeces; there is some enterohepatic recirculation

             (Wilson, 1992).

 

  1. 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

 

        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

 

             No data available.

 

        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.

 

  1. 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: