Use, misuse and abuse of androgens
The Endocrine Society of Australia consensus guidelines for
Ann J Conway, David J Handelsman, Douglas W Lording, Bronwyn Stuckey, Jeffrey D Zajac
on behalf of the
Endocrine Society of Australia
MJA 2000; 172: 220-224
Use of androgens -
Misuse of androgens -
Abuse of androgens -
Key references -
More articles on Endocrinology
- Androgen replacement therapy (ART) is usually life-long, and
should only be started after androgen deficiency has been proven by
hormone assays. The therapeutic goal is to maintain physiological
- Testosterone rather than synthetic androgens should be used.
- Oral 17α-alkylated androgens are hepatotoxic and should not be used
- There is no indication for androgen therapy in male infertility.
Although androgen deficiency is an uncommon cause of erectile
dysfunction, all men presenting with erectile dysfunction should be
evaluated for androgen deficiency. If androgen deficiency is
confirmed, investigation for the underlying pathological cause is
- Contraindications to androgen therapy are prostate and breast
cancer. Precautions include using lower starting doses for older men
and induction of puberty. Intramuscular injections should be
avoided in men with bleeding disorders. Androgen-sensitive
epilepsy, migraine, sleep apnoea, polycythaemia or fluid overload
need to be considered. Competitive athletes should be warned about
the risks of disqualification.
- ART should be initiated with intramuscular injections of testosterone esters, 250 mg every two weeks. Maintenance requires
tailoring treatment modality to the patient's convenience.
Modalities currently available include testosterone injections,
implants, or capsules. Choice depends on convenience, cost,
availability and familiarity.
- There is no convincing evidence that, in the absence of proven
androgen deficiency, androgen therapy is effective and safe for
older men per se, in men with chronic non-gonadal disease, or
for treatment of non-specific symptoms. Until further evidence is
available, such treatment cannot be recommended.
Androgens are hormones that are based on the structure of
testosterone, the major male sex hormone, and are capable of
developing and maintaining masculine sexual characteristics
(including the genital tract, secondary sexual characteristics,
and fertility) and the anabolic status of somatic tissues. All
androgens have similar biological effects because they all act
through the single androgen receptor. Their effects in different
tissues are diversified by metabolism of testosterone to its active
metabolites by the enzymes 5α reductase (which converts
testosterone to 5α-dihydrotestosterone, an androgen with enhanced
potency acting on the androgen receptor) and aromatase (which
converts testosterone to oestradiol, which acts on the oestrogen
Use of androgens
The main medical use of androgens (Box 1) is as androgen replacement
therapy (ART) for established androgen deficiency.1-3 Classical
androgen deficiency occurs in about 1 in 200 men, due to testicular
disorders that directly reduce testosterone output, or
hypothalamic-pituitary disorders that reduce pituitary
luteinising hormone (LH) secretion, which is the main drive to
testosterone production by the interstitial (Leydig) cells of the
testes. Although classical androgen deficiency is relatively easy
to recognise, diagnosis of less severe androgen deficiency can be
more difficult. Owing to its subtle and variable clinical features,
the diagnosis may easily be missed, denying patients simple and
effective medical treatment with often striking subjective
Potential extensions of classical indications to partial androgen
deficiency remain to be fully evaluated for clinical safety and
efficacy. These indications include age, androgen deficiency
secondary to a chronic medical condition or its treatment, hormonal
male contraception, and postmenopausal symptoms.4-6 Until more
definitive objective evidence is available regarding the safety and
efficacy of prescribing androgens for these indications, they
remain suitable for carefully monitored, controlled clinical
research trials, but not for routine medical treatment.
Pharmacological applications of androgens (Box 1) usually
represent second-line therapy where more specific treatments are
not yet available or have failed.
Androgen treatment can evoke a strong placebo response. In men
without genuine androgen deficiency, this placebo effect
invariably wanes with time, leading to confusion and
dissatisfaction with treatment. In addition, once androgen therapy
has commenced, the biochemical changes can cloud further
interpretation of results for months. Therefore, androgen
replacement therapy should be commenced only after androgen
deficiency is clearly established.2,3
Diagnosis of androgen deficiency1-3|
Diagnosis of androgen deficiency involves the recognition of
appropriate clinical features, with confirmation by biochemical
testing. Important clinical features required to evaluate
testicular function include reproductive history (including
pubertal development), fertility status, changes in sexual
function and body hair growth, known testicular pathology, drug use,
and occupation. Physical examination should record
androgenisation (secondary sexual characteristics, especially
body hair distribution, musculature and gynaecomastia) and testis
volumes (by orchidometry).
Serum LH, follicle-stimulating hormone and testosterone levels
should be measured, on at least two separate days and preferably in the
morning, to minimise the effects of random and laboratory
fluctuations and diurnal rhythms. Direct measurements of free
testosterone, if available, may help establish the diagnosis of
androgen deficiency, but require extensive validation. Indirect
measurements of free testosterone, such as the free androgen index
(testosterone/sex hormone binding globulin [SHBG] ratio),
correspond poorly with direct measurements and lack empirical
validation as a diagnostic test.
Additional tests that may be required to identify underlying
disorders include karyotyping, pituitary radiology and
measurement of prolactin levels, serum ferritin levels, iron
saturation and, increasingly, genetic diagnosis.
Androgen deficiency is unlikely in men with mean testis volume >
20 mL without atrophy, with a plasma testosterone level consistently
above 20 nmol/L, or presenting with erectile dysfunction and a plasma
testosterone level consistently above 8 nmol/L (Box 2). Where the
diagnosis is not clear, referral to a clinical endocrinologist with
experience in this area is recommended.1
Androgen replacement therapy1-3|
ART is indicated to rectify androgen deficiency of any cause
sufficient to cause clinical consequences. After puberty, there is
no age limit to ART. Androgen-deficiency effects may manifest as
changes in one or more androgen-sensitive functions; for example,
psychosexual function, or loss of anabolic effects on bone, muscle,
blood-forming marrow and other androgen-responsive tissues. Apart
from decreased spermatogenesis, ART can rectify all clinical
features of androgen deficiency, which usually respond within 1-2
months of starting therapy, although the full effect may take longer.
Dosage: Standard ART is either testosterone
enanthate (Primoteston in castor oil; Schering) or mixed
testosterone esters (Sustanon in arachis oil; Organon) as 250 mg in 1
mL oil at 14-day intervals. Deep intramuscular injections are
usually given into the upper and outer quadrant of the buttock,
although some patients prefer the deltoid or lateral thigh muscle
sites. Few men can manage self-injection with the viscous oil
For all ART, testosterone and its esters should be used in preference
to synthetic androgens, because of their established safety and
efficacy, as well as ease of dose-titration and assay monitoring.
Lower starting doses may occasionally be needed, especially in
previously untreated elderly men and during first induction of
puberty. Less frequent dosing intervals (eg, every three weeks) are
occasionally necessary for those unable or unwilling to have
standard dosage, but are accompanied by more extreme peaks and
troughs in blood testosterone levels, which may exaggerate symptom
An inadequate clinical response raises doubt about androgen
deficiency as the cause of recalcitrant symptoms. Rarely, an
inadequate clinical response may require increased dosage. If
suboptimal symptomatic benefit is supported by biochemical
evidence of inadequate maintenance of androgen levels (low trough
testosterone levels with or without persistently supranormal LH
levels in primary hypogonadism), the same dose may be injected at
10-day intervals. Persistently inadequate responses indicate that
unresponsive symptoms are not due to androgen deficiency; further
escalation in dose or frequency is not warranted. Men with mild or
partial androgen resistance due to androgen-receptor mutations may
benefit from high-dose androgen therapy.
As the underlying disorders are almost always permanent, life-long
ART after the age of puberty is usually necessary. Long term
therapeutic compliance depends on an acceptable regimen. Crossover
studies indicate that patients strongly prefer the stable
testosterone levels and smoother clinical effects provided by
implants or transdermal formulations, compared with the wide
fluctuations in testosterone levels and symptoms during
intramuscular testosterone ester injections. Thus, although ART
should commence with injections, alternative modalities (Box 3) may
improve compliance. Factors to consider include cost, convenience,
availability, familiarity with alternatives, and tolerance for
Monitoring: Monitoring of ART is mainly to ensure
effective androgen replacement by a regimen tailored to the
patient's needs, aiming to maintain adequate therapeutic
compliance by continuation of treatment. Serial clinical
observation of clinical well-being and major symptoms of androgen
deficiency, together with limited numbers of hormonal assays, is
usually adequate. Restoration of sexual function has a low threshold
for androgen action, so adequate libido and potency is a necessary,
but not sufficient, indication of clinically adequate androgen
Blood hormone assays have limited utility in optimising an ART
regimen at the start of treatment and in evaluating androgen
replacement. Trough blood testosterone levels (ie, before the next
scheduled dose) within the eugonadal reference range can be a
valuable guide to the adequacy of parenteral androgen replacement,
but random blood testosterone levels are not useful for monitoring
with either oral or injectable testosterone. In men with
hypergonadotropic hypogonadism, suppression of blood LH levels
into the eugonadal reference range indicates adequate ART, whereas
persistent non-suppression of LH after 3-6 months of regular
treatment indicates inadequate dosage or compliance. In
hypogonadotropic hypogonadism, blood gonadotropin levels are
uninterpretable. Serial evaluation of bone density (especially
vertebral trabecular bone) by dual-photon absorptiometry at
1-2-year intervals may be useful in evaluating the adequacy of
long-term androgen effects on bone. Other biochemical indices of
androgen action, such as haemoglobin, SHBG, and high density
lipoprotein cholesterol levels, reflect only supraphysiological
effects and are too insensitive for routine monitoring of ART.
Androgen deficiency is protective against prostate disease, and ART
may restore the risks to those equivalent to, but no more than,
eugonadal men of similar age. Screening of men receiving ART for
cardiovascular and prostate disease need be no more intensive than
for men of similar age not on ART.
Precautions and side effects14-17|
Adverse effects of androgen treatment are uncommon. Virilisation
may occur with androgen therapy in women or children; androgen
therapy in these settings requires expert management. Truncal acne
and hair growth, weight gain, gynaecomastia and male-pattern hair
loss may be observed, and should be managed symptomatically. Certain
side effects are characteristic of specific therapeutic modalities
(eg, discomfort from intramuscular injections, extrusion of
subdermal implants, gastrointestinal disturbance from oral
testosterone undecanoate). Polycythaemia may occur
disproportionately often in older men treated with testosterone
ester injections. In addition, certain testosterone formulations
have distinctive effects due to their pharmacokinetic features (eg,
reduced levels of SHBG, high density lipoprotein cholesterol and
other hepatic proteins due to supraphysiological hepatic
testosterone exposure). This may be due to injectable testosterone
esters (via high peak blood testosterone concentrations) or oral
testosterone undecanoate (via high first-pass portal testosterone
concentrations), whereas more steady formulations (transdermal,
implants) exhibit fewer or no such effects.
Oral synthetic androgens that have a 17α-alkyl substituent
(oxandrolone, fluoxymesterone, danazol) are inherently
hepatotoxic, causing cholestatic hepatitis, peliosis hepatis and
hepatic tumours. Other classes of synthetic androgen, such as
19-nortestosterone derivatives (nandrolone, MENT) and the
1-methyl androgens (mesterolone, methenolone), are not
Absolute contraindications to androgen therapy are prostate or
breast cancer in men. Androgen therapy should be started in men over
the age of 40 only after exclusion of undiagnosed prostate disease.
Precautions are required for:
- older men starting
androgen treatment, where it may precipitate urinary obstruction or
unfamiliar increases in libido;
- pubertal boys, in whom excessive dosage may accelerate epiphyseal
closure, leading to shortened final stature;
- parenteral androgen therapy in men with bleeding disorders;
- competitive athletes, who may be disqualified;
- androgen-sensitive epilepsy, migraine, sleep apnoea or
- cardiac or renal failure or severe hypertension susceptible to
fluid overload from sodium and fluid retention.
Misuse of androgens
Medical misuse of androgens involves prescription with no
acceptable medical indication. Some common examples of misguided
prescribing of androgens in the absence of established androgen
Male infertility: There
is no indication for androgen therapy in male infertility. The only
likely consequence is an adverse effect of suppressing
Male sexual dysfunction or impotence: Androgen
deficiency (with or without hyperprolactinaemia) is an uncommon
(< 5%) cause of men presenting with erectile dysfunction. In such
men, excluding androgen deficiency as a readily treatable
underlying cause is essential. In the unusual event of severe
androgen deficiency presenting with erectile dysfunction, the
underlying cause needs to be identified, and plans for life-long ART
need to be established.
"Male menopause" or "andropause": There is still no
evidence that the modest decreases in circulating blood
testosterone levels which commence during mid-life have any
clinical importance. The risks and benefits of androgen
supplementation for partially androgen-deficient older men
require further evaluation by placebo-controlled studies.
Androgen treatment may be inappropriate, wasteful, and involve
placebo effects. Terms such as "male menopause" and "andropause" are
misleading; they have little place in meaningful medical or
Elderly men (> 65 years):18 There is no basis
for androgen therapy based on age per se. Further controlled
clinical trials are needed to evaluate the potential role of androgen
supplementation in ageing. While some preliminary
placebo-controlled studies suggest short-term benefits for
muscle, bone and quality of life, findings are not yet consistent and
the identification of appropriate treatment objectives and target
subgroups, as well as overall analyses of risks, benefits and costs,
are lacking. Specifically, it remains to be determined whether
androgen supplementation has significant and sustained clinical
benefits in older men with low-normal plasma total testosterone and
normal LH levels. At present, there is no basis for androgen treatment
outside properly designed clinical trials.
Treatment of non-specific symptoms: There is no
basis for androgen therapy based on symptoms in the absence of
established androgen deficiency. In addition to the unproven safety
and efficacy, the placebo effect of androgen injections may be
confusing to both doctor and patient. When placebo effects wane,
further confusion and dissatisfaction with treatment may be
Abuse of androgens
Illicit use of androgens19-24 ("anabolic
steroids") depends largely on obtaining androgens without legal
prescription to be used in the absence of any medical indication.
Illicit androgen use became epidemic over the past four decades,
since androgens were reportedly first used in elite competitive
power sports. A recent placebo-controlled study has shown that
high-dose androgen administration does improve muscle size and
strength in healthy eugonadal men. Whether these changes enhance
athletic performance, whether they are sustained, and whether they
apply to older men remains to be clarified.
Medical prescription appears to support only a small proportion of
illicit androgen use, but such activity has been formally ruled as a
breach of professional standards by medical boards in most States and
by the Royal Australasian College of Physicians. Highly motivated
young men can be very sophisticated in manipulating and pressuring
general practitioners while attempting to obtain prescriptions for
androgens. The doctor is often led to believe that other
practitioners are prescribing androgens for young men, and that he or
she is being uncaring or negligent by not acceding to the patient's
wishes. We recommend that general practitioners resist these
Fortunately, most people appear ultimately to lose interest in this
form of drug abuse.
Background and evidence basis of recommendations|
The Endocrine Society of Australia (ESA) Consensus Guidelines for Androgen Prescribing were written on behalf of the Endocrine Society of Australia. The ad hoc Writing Committee commissioned by the ESA's Council was Dr A J Conway, Professor D J Handelsman (Chair), Associate Professor D W Lording, Dr B Stuckey, and Associate Professor J D Zajac. The draft guidelines were extensively circulated for comment to active members of the ESA with clinical expertise or interests in male reproductive endocrinology. Comments were incorporated into the final document, which was ratified by the ESA's Council.
Androgen therapy, in regular clinical use for over 60 years, is one of the oldest hormonal regimens in modern therapeutics. As a long established standard and effective form of hormone replacement for many decades, placebo-controlled studies are unavailable and now unacceptable. Consequently, the NHMRC Quality of Evidence Ratings for these recommendations are those appropriate to an expert committee reviewing all available evidence from controlled experimental and observational studies as well as clinical experience.
Diagnosis and management of androgen deficiency
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Endocrine Society of Australia, Sydney, NSW.
Ann J Conway, MB BS, FRACP;
David J Handelsman, MB BS,
Douglas W Lording, MB BS, FRACP;
Stuckey, MB BS, FRACP;
Jeffrey D Zajac, PhD,
Reprints will not be available from the authors.
Associate Professor J D Zajac, Department of Medicine, University of
Melbourne, Royal Melbourne Hospital, Parkville, VIC 3050.
1: Use, misuse and abuse of androgens|
Physiological (androgen deficiency)
Pharmacological (non-androgen deficiency)4-6
Classical androgen deficiency ("hypogonadism")
- Age-related partial androgen deficiency
- Micropenis (neonatal)
- Delayed puberty
- Aged men*
- Androgen deficiency secondary to chronic disease*
- Induced androgen deficiency
- Hormonal male contraception*
- Anaemia due to marrow or renal failure
- Advanced breast cancer
- Excessively tall stature in boys
- In absence of proven androgen deficiency:
- Male infertility
- Sexual dysfunction/impotence
- "Male menopause", "andropause"
- Older men (>65 years)
- Non-specific symptoms
Absence of medical indication
||Competitive power sports (athletics,
weightlifting, football, swimming, rowing,
|"Body beautiful" subculture|
|Security, police, armed forces, professional sports|
* These indications remain to be fully evaluated for safety and efficacy in
controlled clinical trials.
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2: Biochemical evaluation of the diagnosis of androgen deficiency in men with clinical features consistent with hypogonadism*|
|Testosterone level||Luteinising hormone level||Diagnosis|
|<8 nM||High||Androgen deficiency (hypergonadotropic hypogonadism§)|
|<8 nM||Not high||Androgen deficiency (hypogonadotropic hypogonadism§)|
|8-15 nM||High||Androgen deficiency (Leydig cell failure)|
|8-15 nM||Not high||Androgen deficiency not confirmed: unproven therapeutic benefit of androgen replacement therapy|
|>20 nM||Any||Excludes androgen deficiency|
|>30 nM**||High||Androgen resistance|
|*There is necessarily an arbitrary component to this type of table. It is based on current experience and should be subject to changes according to further
clinical evidence. Blood sample classification based on at least two separate morning blood samples. "High" luteinising hormone level is defined as >
1.5 times the upper limit of the eugonadal reference range for young men. §Hypergonadotropic and hypogonadotropic hypogonadism are also referred to as
primary and secondary hypogonadism, respectively. Compensated Leydig cell failure is a form of partial androgen deficiency in which androgen replacement
is often beneficial. **Elevated testosterone is defined as above the upper limit of the eugonadal reference range for young men.
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3: Androgen treatment modalities7-13|
- Fused cylindrical pellets of pure crystalline testosterone that form a subdermal depot
- Provide stable, physiological levels of testosterone for 4-6 months following a single implantation of four 200 mg (800 mg) implants
- Implantation uses a trochar and cannula technique under office sterile conditions, and requires local anaesthesia
- Main adverse effect is extrusion of implants via the insertion site 1-2 months after implantation
- Extrusion rate (about 10%) depends on operator experience and patient's physical activity
- Minor adverse effects related to the minor office surgery (bleeding, infection) are infrequent (<5%)
- Should only be used for patients who have demonstrated satisfactory tolerance of androgen effects with shorter-acting preparations
Other depot testosterone formulations
- Administered daily via androgen-impregnated adhesive skin patches or hydroalcoholic gels (not yet available in Australia)
Oral testosterone undecanoate
- Newer injectable esters (testosterone undecanoate, testosterone buciclate)
- Testosterone-laden biodegradable microspheres
- Both these formulations deliver stable, physiological testosterone levels for 2-3 months following injection
- Useful where parenteral testosterone is undesirable (eg, bleeding disorders or anticoagulation) or poorly tolerated
- Administered as 160-240 mg (four to six 40 mg capsules), divided into 2-4 doses per day
- Second-line formulation for routine ART, because of frequency of administration, high hepatic load, gastrointestinal intolerance, and higher cost
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