Guideline summary

Endocrine Society of Australia position
statement on male hypogonadism (part 2):
treatment and therapeutic considerations
Bu B Yeap1, Mathis Grossmann2, Robert I McLachlan3, David J Handelsman4, Gary A Wittert5,6, Ann J Conway4,
Bronwyn GA Stuckey1,7, Douglas W Lording8, Carolyn A Allan3, Jeffrey D Zajac2, Henry G Burger3

T

he Endocrine Society of Australia commissioned this position statement to update its 2000 guidelines for testosterone prescribing1 and to inform the recommended
management of men with androgen deﬁciency in light of recent
regulatory changes to the Pharmaceutical Beneﬁts Scheme.2 Part 1of this position statement dealt with the assessment of male
hypogonadism, including the indications for testosterone therapy.3 This article, Part 2, focuses on treatment and therapeutic
considerations for male hypogonadism, particularly considering
the ongoing debate about the risk of cardiovascular events related
to testosterone treatment.4 The methods used to develop the position statement are detailed in Part 1.3

Recommendations

Main recommendations: Key points and recommendations are:
 Excess cardiovascular events have been reported in some
but not all studies of older men without pathologicalhypogonadism who were given testosterone treatment.
Additional studies are needed to clarify whether testosterone
therapy inﬂuences cardiovascular risk.
 Testosterone is the native hormone that should be replacedin men being treated for pathological hypogonadism.
Convenient and cost-effective treatment modalities include
depot intramuscular injection and transdermal administration(gel, cream or liquid formulations).
 Monitoring of testosterone therapy is recommended for
efﬁcacy and safety, focusing on ameliorating symptoms,
restoring virilisation, avoiding polycythaemia and maintaining
or improving bone mineral density.
 Treatment aims to relieve an individual’s symptoms andsigns of androgen deﬁciency by administering standard doses
and maintaining circulating testosterone levels within thereference interval for eugonadal men.
 Evaluation for cardiovascular disease and prostate cancer
risks should be undertaken as appropriate for eugonadal menof similar age. Nevertheless, when there is a reasonable
possibility of substantive pre-existing prostate disease, digital
rectal examination and prostate-speciﬁc antigen testingshould be performed before commencing testosterone
treatment.
Changes in management as result of the position
statement: Treatment aims to relieve symptoms and signs ofandrogen deﬁciency, using convenient and effective
formulations of testosterone. Therapy should be monitored for
efﬁcacy and safety.

1
School of Medicine and Pharmacology, University of Western Australia, Perth, WA. 2 Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC. 3 Hudson
Institute of Medical Research, Melbourne, VIC. 4 ANZAC Research Institute, University of Sydney, Sydney, NSW. 5 Discipline of Medicine, University of Adelaide, Adelaide, SA.
6
Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA. 7 Keogh Institute for Medical Research, Sir Charles Gairdner Hospital, Perth, WA. 8 Endocrinology, Cabrinibu.yeap@uwa.edu.au j doi: 10.5694/mja16.00448 j Online ﬁrst 29/08/16
Hospital, Melbourne, VIC.

5 September 2016

levels or did not receive treatment.12 Comparable Australianstudies are lacking. However, no ﬁrm conclusion can be drawn
from these non-randomised retrospective studies — which did notaccount for the reasons some men were treated and others not, andoften used prescription or insurance databases with limited population coverage and clinical information — due to the potential for
multiple sources of bias and confounding. A review of the existingdata commissioned by the US Food and Drug Administration(FDA) found no convincing increase of major adverse cardiac
events in men treated with testosterone and highlighted the deﬁciencies of available retrospective studies.13 Nevertheless, thejSome observational studies in older men have shown increased
risk, and some decreased risk, of cardiovascular events, or
improved survival with testosterone treatment.4 A recent retrospective observational study of US veterans (whose indications for
testosterone treatment were not made clear) suggested that men
with low baseline testosterone levels who achieved normalisationof circulating testosterone levels after treatment had better outcomes compared with men who did not normalise testosterone

Introduction: Part 1 of this position statement dealt with theassessment of male hypogonadism, including the indications for
testosterone therapy. This article, Part 2, focuses on treatment
and therapeutic considerations for male hypogonadism andidentiﬁes key questions for future research.

MJA 205 (5)Cardiovascular events
The current evidence regarding testosterone treatment and cardiovascular outcomes is contradictory and inconclusive.4 There
have been no adequately powered randomised controlled trials(RCTs) of testosterone treatment with cardiovascular events as apre-speciﬁed outcome. One RCT has shown an increase in cardiovascular events with testosterone treatment in older men withmobility limitations, many of whom had diabetes or pre-existing
cardiovascular disease.5 However, event numbers were small
and may have been due to chance. Another RCT in a similar population of frail or intermediate-frail older men has not conﬁrmed
this ﬁnding.6 In the United States, the Testosterone Trials reported
no difference in cardiovascular events between treatment andplacebo arms of the study over 1 year.7 A recently published RCT
showed no effect of testosterone treatment over 3 years on two
measures of pre-clinical atherosclerosis (carotid intima media
thickness and coronary calciﬁcation).8 One meta-analysis showed
an increased risk of broadly deﬁned vascular-related events withtestosterone therapy but, due to methodological limitations, thesedata are not deﬁnitive.9 Another meta-analysis showed no evidence of any increase in major cardiovascular events relating totestosterone therapy.10 A recent meta-analysis showed no signiﬁcant increase in cardiovascular events related to testosterone
treatment when all administration routes were grouped.11

Abstract1Guideline summary
FDA mandated labelling of US testosterone products to warn
about a possible increased risk of venous thromboembolism, heart
attack and stroke, and recommended a new prospective study of
sufﬁcient power to evaluate safety.14 Overall, until better evidence
is available, it seems prudent to use testosterone treatment with adegree of caution in older men with known cardiovascular disease,especially in men without pathological hypogonadism.
Testosterone formulations and side effects
The effects of testosterone in different tissues vary as a result of themetabolism of testosterone into its active metabolites by the enzymes 5a-reductase (an ampliﬁcation pathway that converts
testosterone to 5a-dihydrotestosterone [DHT], an androgen withenhanced potency acting on the androgen receptor) and aromatase(a diversiﬁcation pathway that converts testosterone to oestradiol,which acts on the oestrogen receptor).15 Each of these hormones isincreasingly recognised as being critical for male health. DHT
drives genital differentiation in the male fetus (acting on the urogenital sinus derivatives that form the prostate and external genitalia), while oestradiol is a major determinant of male bone density
and has additional roles in the brain, metabolism and possibly
sexual function.16,17 In many ways, testosterone is “three hormonesin one” — an important physiological consideration when using
testosterone rather than other androgens for replacement therapy
regimens.
Testosterone preparations available in Australia, with their routeof administration, dosing and side effects, are shown in Box 1. The
more common adverse effects include polycythaemia, elevation of

1 Testosterone formulations currently available in Australia
Preparation

Advantages

Disadvantages and adverse effects

Testosterone level monitoring

Testosterone gel 1%(Testogel, Besins Healthcare)Can be self-administered

Pump applicator option
available

Chance for inadvertent transfer
to close contacts (spouse,children, nurses)

Morning, before application,
after use for 7 daysMust cover application siteVariation in blood
testosterone levels

Slow to reach steady-state
blood testosterone levels

Morning, before fourth injection;
aim for trough level of 10e15 nmol/LAllow a further 2e3 injections
after dose adjustment before
recheckingAfter 2 weeks, trough level taken
2e8 hours after applicationMorning, before application,on the 15th day after starting
treatmentBaseline and at intervals
during treatment

Morning, after evening application

After 2 weeks

50 mg sachets (or pump pack)
Daily

Testosterone undecanoate(Reandron 1000, Bayer)ConvenienceCompliance

1 g intramuscular injection

Cannot be self-administered

3-monthlyInjection site painPost-injection cough due topulmonary oil microembolism

Deep intramuscular injection
unsuitable for men withcoagulopathies or thrombocytopenia

Chance for inadvertent transfer
to close contacts (spouse,children, nurses)



Pump applicator requiredMust be administered in
the axilla and cover application siteMay not wash, shower orswim within 2 hours of applicationChance for inadvertent transfer
to close contacts (spouse, children,nurses)Must cover application siteVariation in blood testosterone
levelsTestosterone transdermal solution (Axiron, Eli Lilly)

60 mg (2  30 mg applications)



Daily

Testosterone cream 5%(Androforte, Lawley)

5 September 2016j

MJA 205 (5)Can be self-administered

2 mL
Daily

Testosterone esters (Sustanon,
Aspen; or Primoteston, Bayer)2Can be self-administered

250 mg intramuscular injection

Fortnightly

Testosterone patch(Androderm, Allergan)

2.5 mg or 5.0 mg



Daily

Testosterone undecanoate oral
(Andriol, Merck Sharp & Dohme)

40 mg capsule

2e3 times per day







Fewer treatment episodes 
may improve compliance Can be self-administered

Can be self-administered

Frequency of injections
Fluctuation in blood
testosterone levels

Injection site painFluctuation in mood or libido



Excessive erythrocytosisSkin irritation



Limited scope fordose variation

Frequent dosing required(2e3/day)Marked variation in blood
testosterone levels



Gastrointestinal intoleranceGuideline summary
prostate-speciﬁc antigen (PSA) levels (which includes an expected effect of testosterone replacement at the start of treatment,
but may also detect subclinical or latent prostate cancer), acne andoily skin, reduced sperm production and impaired fertility. Less
common adverse effects include gynaecomastia, male patternbalding (which can be familial) and weight gain, as well as ﬂuctuations in mood, libido or hot ﬂushes, which reﬂect stopestart
treatment or excessive ﬂuctuations in serum testosterone
levels. Other reported side effects include difﬁculty passing urine,
muscle pain, priapism and increased blood pressure. Refer toprescribing information for further details of formulation-speciﬁcside effects.
Monitoring of testosterone therapy
Efﬁcacy. The best clinical measure of adequate restoration ofandrogen status is identiﬁcation and monitoring of the man’s
leading symptom. These clinical features are highly variable between men but highly reproducible within any man and distinctive
to that individual.18 Timing of hormone sampling relative to themost recent dose is important in monitoring the adequacy of
testosterone replacement therapy, with the goal being to evaluate
steady-state blood levels. This is feasible with injectable andtransdermal products, using the trough (ie, pre-next dose sampling), but not with oral testosterone, due to its capricious pharmacokinetics. Random blood sampling without regard to thetiming of the most recent dose is uninformative and not recommended. In patients using injectable or transdermal testosterone
products, trough testosterone levels should be within the lower
part of the reference interval for eugonadal men. In patients withtesticular failure (primary or hypergonadotropic hypogonadism),
persistent elevation of serum luteinising hormone levels during
treatment may indicate inadequate testosterone dosage, frequency
or compliance. Periodic monitoring of bone density (at intervals of
1e2 years) may assist in evaluating extent and chronicity of pretreatment androgen deﬁciency, as well as adequacy of replacement therapy.19

All transdermal preparations remain on the skin for some hours
after application. These should be applied after morning showering, then covered with clothing to avoid direct skin transfer andrisk of virilisation among children or women in intimate contact
with the patient.

Conclusions
Different formulations of testosterone are available for replacement
therapy to relieve symptoms and signs of androgen deﬁciency inmen with pathological hypogonadism, and can be personalised toindividual men. There is no evidence that appropriate use of

2 Key research questions for well controlled clinical trials
Does testosterone therapy provide meaningful health beneﬁts
in older men without pathological hypogonadism?

Does testosterone treatment improve weight loss, in addition tolifestyle measures?

Is testosterone an effective and safe treatment for preventing
progression of pre-diabetes to type 2 diabetes in men?



Does testosterone therapy among men without pathologicalhypogonadism inﬂuence the risk of heart attacks or strokes?

What is the role of testosterone therapy in men with
suppression of the hypothalamicepituitaryetesticular (HPT)
axis from opioids?

What is the optimal management of men with prolonged
suppression of the HPT axis as a result of recreational misuseof androgens?

What is the effect of depression and treatment of depression
on function of the HPT axis?

Is there a therapeutic role for partial oestrogen blockade (eg, using
clomiphene) and aromatase inhibition (eg, using anastrozole,
letrozole) to improve suppressed HPT axis function in men?

5 September 2016

Is there a role for pharmacological androgen therapy with
5a-dihydrotestosterone in men with speciﬁc diseases, to increase
muscle or bone mass, aid wound healing or treat othersystemic illness? u3jElevation of haemoglobin (or haematocrit [packed cell volume])levels above the normal reference interval may occur with testosterone treatment, particularly in smokers. Haematology proﬁleProduct-speciﬁc safety issues (Box 1). Injectable testosterone
preparations are relatively contraindicated in patients who have
bleeding disorders or who are taking anticoagulants, where deep
intramuscular injection carries a risk (although low) of haematoma
formation.29 Transdermal preparations are preferable in thissetting. In all patients, injectable preparations carry a risk of pain,
bruising and pulmonary oil microembolism, which results incough at the time of injection.29,30

MJA 205 (5)Safety. There is no convincing evidence that men with pathological hypogonadism treated with testosterone have any increased
risk of benign or malignant prostate disease, although men withlifelong androgen deﬁciency due to Klinefelter syndrome are
relatively protected against prostate cancer.20 A recent metaanalysis of 22 RCTs involving 2351 participants treated for up to
36 months found no association of testosterone treatment withprostate cancer.21 Similarly, an analysis from a population-based
linked cancer registry did not ﬁnd any association of testosterone
therapy with high-grade prostate cancer.22 Given that population
screening for prostate cancer by measuring serum PSA levels is notrecommended, as it is not sufﬁciently safe and cost-effective,23monitoring for prostate disease during testosterone treatment
should be undertaken as appropriate for eugonadal men of similarage (ie, based on individualised clinical assessment and judgement). However, when there is a reasonable possibility of substantive pre-existing prostate disease, digital rectal examination
and PSA testing are required before testosterone treatment iscommenced, so that pre-existing prostate cancer is not missed.
Although PSA monitoring during testosterone therapy has become
widely used,24 it is possible that routine PSA testing could essentially constitute PSA screening for prostate cancer and may lead to
overdiagnosis and harm from interventions for clinically insignificant organ-conﬁned prostate cancers.

should be assessed 3 months after initiation of testosterone
treatment and then monitored on an annual basis. Secondary
polycythaemia induced by testosterone treatment should
prompt evaluation of other aggravating hypoxic conditions, suchas smoking, sleep apnoea and respiratory failure. It can usually
be managed by reduction of the testosterone dose (and/or
frequency), but may rarely require venesection. In men with
obstructive sleep apnoea, low testosterone levels are related
primarily to obesity and will improve with weight loss. Treatment with continuous positive airway pressure improved
testosterone levels in one study, but not in another study or ameta-analysis.25-27 Testosterone treatment only transiently
worsens the severity of obstructive sleep apnoea,28 which, unlesssevere and untreated, need not be considered an absolutecontraindication to its use (see Part 1, Box 4).3

Guideline summary
testosterone therapy increases the risk of prostate cancer. Testosterone replacement may be safely used among men with pathological hypogonadism at any age. A cautious approach totestosterone replacement is warranted in older, frail men, particularly in those with a history of cardiovascular disease. In complex
cases, evaluation by an endocrinologist is recommended.
The recommendations given in this position statement are based ondata from a limited number of RCTs, as well as non-randomised

1

Conway AJ, Handelsman DJ, Lording DW, et al. Use,misuse and abuse of androgens. The Endocrine Societyof Australia consensus guidelines for androgenprescribing. Med J Aust 2000; 172: 220-224. Erratum in:
Med J Aust 2000; 172: 334. https://www.mja.com.au/journal/2000/172/5/use-misuse-and-abuse-androgens

2 Australian Government Department of Health.
Pharmaceutical Beneﬁts Scheme. Testosterone
undecanoate. http://www.pbs.gov.au/medicine/item/1
0205D (accessed Nov 2015).
3 Yeap BB, Grossmann M, McLachlan RI, et al. Endocrine
Society of Australia position statement on male
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4 Yeap BB. Testosterone and cardiovascular disease risk.
Curr Opin Endocrinol Diabetes Obes 2015; 22: 193-202.
5 Basaria S, Coviello AD, Travison TG, et al. Adverse events
associated with testosterone administration. N Engl J
Med 2010; 363: 109-122.
6 Srinivas-Shankar U, Roberts SA, Connolly MJ, et al.
Effects of testosterone on muscle strength, physicalfunction, body composition, and quality of life inintermediate-frail and frail elderly men: a randomized,
double-blind, placebo-controlled study. J Clin Endocrinol
Metab 2010; 95: 639-650.
7 Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of
testosterone treatment in older men. N Engl J Med 2016;374: 611-624.
8 Basaria S, Harman SM, Travison TG, et al. Effects of
testosterone administration for 3 years on subclinicalatherosclerosis progression in older men with low or
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9 Xu L, Freeman G, Cowling BJ, Schooling CM.
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10 Corona G, Maseroli E, Rastrelli G, et al. Cardiovascularrisk associated with testosterone-boosting medications:a systematic review and meta-analysis. Expert Opin DrugSaf 2014; 13: 1327-1351.

MJA 205 (5)j

5 September 2016114

Borst SE, Shuster JJ, Zou B, et al. Cardiovascular risks
and elevation of serum DHT vary by route ofclinical studies and observational studies. As such, further
research is warranted, which may have an impact on the recommendations. Key research questions for future well controlled
clinical trials are presented in Box 2.
Competing interests: Author disclosures are listed in the Appendix.
Provenance: Not commissioned; externally peer reviewed. nª 2016 AMPCo Pty Ltd. Produced with Elsevier B.V. All rights reserved.

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13 US Food and Drug Administration. FDA Drug Safety
Communication: FDA cautions about using testosterone
products for low testosterone due to aging; requires
labeling change to inform of possible increased risk ofheart attack and stroke with use. 3 Mar 2015. http://
www.fda.gov/Drugs/DrugSafety/ucm436259.htm(accessed Mar 2015).
14 US Food and Drug Administration. Summary minutes of
the Joint Meeting of the Bone, Reproductive and
Urologic Drugs Advisory Committee and the Drug Safety
and Risk Management Advisory Committee. September
17, 2014. http://www.fda.gov/downloads/
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17

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19 Aminorroaya A, Kelleher S, Conway AJ, et al. Adequacyof androgen replacement inﬂuences bone density
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22 Baillargeon J, Kuo Y-F, Fang X, Shahinian VB. Long-term
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23 Ilic D, Neuberger MM, Djulbegovic M, Dahm P. Screening
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24 Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone
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26 Knapp A, Myhill PC, Davis WA, et al. Effect of continuous
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30 Sartorius G, Fennell C, Spasevska S, et al. Factors
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