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Male Hypogonadism: EAU Guidelines On
Male Hypogonadism: EAU Guidelines On
Male
Hypogonadism
G.R. Dohle (Chair), S. Arver, C. Bettocchi,
T.H. Jones, S. Kliesch
2. METHODS 4
2.1 Introduction 4
2.2 Review 5
2.3 Future goals 5
4. DIAGNOSTIC EVALUATION 10
4.1 Clinical symptoms and laboratory testing 10
4.2 History-taking and questionnaires 12
4.3 Physical examination 12
4.4 Summary of evidence and recommendations for the diagnostic evaluation 12
4.5 Clinical consequences of hypogonadism 12
4.5.1 Prenatal androgen deficiency 12
4.5.2 Prepubertal onset of androgen deficiency 13
4.5.3 Adult-onset hypogonadism 13
4.5.4 Hypogonadism in Type 2 Diabetes 14
4.5.4.1 Recommendations for screening men with
adult-onset hypogonadism 14
5. DISEASE MANAGEMENT 14
5.1 Indications and contraindications for treatment 14
5.2 Benefits of treatment 15
5.3 Choice of treatment 16
5.3.1 Preparations 16
5.3.1.1 Testosterone undecanoate 16
5.3.1.2 Testosterone cypionate and enanthate 16
5.3.1.3 Transdermal testosterone 17
5.3.1.4 Future perspectives 17
5.4 Hypogonadism and fertility issues 17
5.5 Recommendations for testosterone replacement therapy 18
5.6 Risk factors in testosterone treatment 18
5.6.1 Male breast cancer 18
5.6.2 Risk for prostate cancer 18
5.6.3 Cardiovascular diseases 19
5.6.4 Cardiac Failure 20
5.6.5 Obstructive sleep apnoea 21
5.6.6 Anabolic steroid–induced hypogonadism 21
5.7 Summary of evidence and recommendations on risk factors in testosterone
replacement treatment 21
7. REFERENCES 23
8. CONFLICT OF INTEREST 33
9. CITATION INFORMATION 34
It must be emphasised that clinical guidelines present the best evidence available to the experts. However
following guideline recommendations will not necessarily result in the best outcome. Guidelines can never
replace clinical expertise when making treatment decisions for individual patients, but rather help to focus
decisions - also taking personal values and preferences/individual circumstances of patients into account.
Guidelines are not mandates and do not purport to be a legal standard of care.
2. METHODS
2.1 Introduction
For the 2018 edition of the EAU Guidelines, the Guidelines Office have transitioned to a modified GRADE
methodology across all 20 guidelines [2, 3]. For each recommendation within the guidelines there is an
accompanying online strength rating form which addresses a number of key elements namely:
1. t he overall quality of the evidence which exists for the recommendation, references used in
this text are graded according to a classification system modified from the Oxford Centre for
Evidence-Based Medicine Levels of Evidence [4];
2. the magnitude of the effect (individual or combined effects);
3. the certainty of the results (precision, consistency, heterogeneity and other statistical or
study related factors);
4. the balance between desirable and undesirable outcomes;
5. the impact of patient values and preferences on the intervention;
6. the certainty of those patient values and preferences.
A list of Associations endorsing the EAU Guidelines can also be viewed online at the above address.
The recommendations provided in these guidelines are based on a systematic literature search and review
performed by the panel members in 2016. For the 2018 update, a scoping search was performed, covering all
areas of the guideline and the search terms ‘hypogonadism’, ‘eugonadal or hypogonadism or hypogonadal or
gonadal’, and ‘low or lower testosterone’, starting from April 2016 with a cut-off date of July 2017. Embase,
Medline and the Cochrane Central Register of Controlled Trials databases were searched, with a limitation to
reviews or meta-analysis of randomised controlled trials (RCTs). A total of 542 unique records were identified,
retrieved and screened for relevance. A detail search strategy is available online: http://www.uroweb.org/
guideline/male-hypogonadism/.
2.2 Review
This document was subject to peer review prior to publication in 2015.
Androgen deficiency increases slightly with age also in healthy men [10, 11]. In middle-aged men, the incidence
of biochemical hypogonadism varies from 2.1-12.8% [12]. The incidence of low testosterone and symptoms
of hypogonadism in men aged 40-79 varies form 2.1-5.7% [11, 12]. Hypogonadism is more prevalent in older
men, in men with obesity, those with comorbidities, and in men with poor health status.
3.2 Physiology
Male sexual development starts between the seventh and twelfth week of gestation. The undifferentiated
gonads develop into a foetal testis through expression of multiple genes, including the sex-determining region
of the Y chromosome (SRY gene complex) and the SOX genes [14]. The foetal testis produces three hormones:
testosterone, insulin-like peptide 3 (INSL3) and anti-Müllerian hormone (AMH). Testosterone is needed for the
stabilisation of the Wolffian ducts, resulting in formation of the epididymis, vas deferens and seminal vesicle.
Anti-Müllerian hormone activity results in regression of the Müllerian ducts (Figure 1). Insulin-like peptide 3,
AMH and testosterone regulate testicular descent.
During puberty, intratesticular testosterone is needed to initiate and then maintain the spermatogenic process
and to inhibit germ cell apoptosis [17]. The seminiferous tubules of the testes are exposed to concentrations of
testosterone 25-100 times greater than circulating levels. Suppression of gonadotropins (e.g. through excessive
testosterone abuse) results in a reduced number of spermatozoa in the ejaculate and hypospermatogenesis
[18]. Complete inhibition of intratesticular testosterone results in full cessation of meiosis up to the level of
round spermatids [19, 20].
Testosterone does not appear to act directly on the germ cells, but functions through the Sertoli cells by
expression of the androgen receptor (AR) and by influencing the seminiferous tubular microenvironment [19].
Testosterone can also be metabolised into oestradiol by aromatase, present in fat tissue, the prostate, the
testes and bone. Oestradiol is also essential for bone mineralisation in men [21]. The production of testosterone
is controlled in the foetus by placental chorion gonadotropin (hCG) and after birth by luteinising hormone (LH)
from the pituitary gland. Immediately after birth, serum testosterone levels reach adult concentrations over
several months (mini puberty). Thereafter and until puberty, testosterone levels are low, thus preventing male
virilisation. Puberty starts with the production of gonadotropins, initiated by gonadotropin-releasing hormone
(GnRH) secretion from the hypothalamus and results in testosterone production, male sexual characteristics
and spermatogenesis [22]. Figure 1 shows the development of the male reproductive system.
Summary of evidence
Testosterone is essential for normal male development.
Foetal pituitary
SRY gene complex
SOX genes
LH FSH
Anti-Müllerian
Testosterone INSL3
hormone (AMH)
Regression of the
5α-reductase
Müllerian ducts
Dihydrotestosterone
(DHT)
Differentiation of the
Testicular descent
Wolffian ducts
Differentiation of the
genital tubercle and
the urogenital sinus
Epididymis
External genitalia Vasdeferens
Prostate
FSH = follicle-stimulating hormone; LH = luteinising hormone; SRY = sex determining region of the Y
chromosome; INSL3= insulin-like peptide 3.
3.3 Aetiology
Hypogonadism results from testicular failure, or is due to the disruption of one or several levels of the
hypothalamic-pituitary-gonadal axis (Figure 2).
Male hypogonadism can be classified in accordance with disturbances at the level of:
• the testes (primary hypogonadism);
• the hypothalamus and pituitary (secondary hypogonadism);
• the hypothalamus/pituitary and gonads (common in adult-onset hypogonadism);
• androgen target organs (androgen insensitivity/resistance).
3.4 Classification
3.4.1 Male hypogonadism of testicular origin (primary hypogonadism)
Primary testicular failure is the most frequent cause of hypogonadism and results in low testosterone levels,
impairment of spermatogenesis and elevated gonadotropins (high LH and FSH). Male infertility is accompanied
by hypogonadism in up to 32% of patients and and is an associated risk factor for hypogonadism, depending
on the severity of the underlying causes [26, 27]. The most common clinical forms of primary hypogonadism
are Klinefelter syndrome and testicular tumours.
• Klinefelter syndrome affects 0.2% of the male population. It is the most frequent form of male
hypogonadism and the most common numerical chromosomal aberration, with 47,XXY in 90% of cases
[28]. It arises due to non-disjunction during paternal or maternal meiotic division of germ cells [29].
• Testicular germ cell tumours are the most frequent type of cancer in young males after puberty. Risk
factors are contralateral germ cell cancer, maldescended testes, gonadal dysgenesis, infertility, testicular
atrophy and familial germ cell cancer. Twenty-five per cent of men with testicular tumours develop
testosterone deficiency after treatment [30-32].
These disorders are characterised by disturbed hypothalamic secretion (low levels of gonadatropin-releasing
hormone, followed by low levels of the gonadotropins LH and FSH). An inborn error of migration and homing
of GnRH-secreting neurons results in Kallmann’s syndrome [34, 35]. The most important symptom is the
constitutional delay of puberty: it is the most common cause of delayed puberty (pubertas tarda) [36]. Other
rare forms of secondary hypogonadism are listed in Table 2.
The classification of hypogonadism has therapeutic implications. In patients with secondary hypogonadism,
hormonal stimulation with hCG and FSH or alternatively pulsatile GnRH treatment can restore fertility in most
cases [41, 42]. Detailed evaluation may, for example, detect pituitary tumours, systemic disease, or testicular
tumours (see table 2). Combined forms of primary and secondary hypogonadism can be observed in ageing,
mostly obese men, with a concomitant age-related decline in testosterone levels resulting from defects in
testicular as well as hypothalamic-pituitary function.
Testosterone
Hypothalamus
(-)
(+) GnRH
Inhibin B Testosterone
FSH (+) LH
Testosterone
Leydig
Sertolicells
cells
Germ cells
Testes
Spermatozoa
4. DIAGNOSTIC EVALUATION
Hypogonadism is diagnosed on the basis of persistent signs and symptoms related to androgen deficiency
and assessment of consistently low testosterone levels (on at least two occasions) with a reliable method
[12, 46-49]. It should be noted that over time, there is a substantial portion of men who recover from secondary
hypogonadism, prompting the importance of re-evaluation if testosterone therapy has been instituted in men
without defined hypothalamic or pituitary disease [50].
The most prevalent symptoms of male hypogonadism in ageing men are reduced sexual desire and sexual
activity, erectile dysfunction, loss of vigour and changes in mood [12, 52]. Other factors found associated
with low testosterone are obesity and a poor general health status [12]. Signs and symptoms of androgen
deficiency vary depending on age of onset, duration and the severity of the deficiency. Reference ranges for
the lower normal level of testosterone (2.5%) have been compiled from three large community-based samples,
suggesting a cut-off of 12.1 nmol/L for total serum testosterone and 243 pmol/L for free testosterone, to
distinguish between normal levels and levels possibly associated with deficiency [53]. Symptoms suggesting
the presence of hypogonadism [12, 52] are summarised in Table 3. It should, however, be noted that these
symptoms are also found in men with normal testosterone levels and may have causes other than androgen
deficiency.
In men aged 40-79 years, the threshold for total testosterone was 8 nmol/L for decreased frequency of sexual
thoughts, 8.5 nmol/L for erectile dysfunction, 11 nmol/L for decreased frequency of morning erections and
13 nmol/L for diminished vigour [54, 55]. The strongest predictor for hypogonadism in this age group was three
sexual symptoms (decreased sexual thoughts, weakened morning erections, erectile dysfunction) and either a
total testosterone level of < 8 nmol/L or serum testosterone in the range of 8-11 nmol/L and free testosterone
< 220 pmol/L. These data are based on serum samples taken in the morning, when mean levels are highest
and most reproducible in younger men [56].
Laboratory testing of testosterone should reflect on the diurnal variation of testosterone. In most cases two
morning (7.00 a.m. to 11.00 a.m.) samples are sufficient, but should trigger further evaluation if the difference
is > 20% [57]. Both immuno-assay and mass spectrometry based assays can produce reliable results, as long
as they are well-validated. Evaluation should be based on reference ranges for normal men provided by the
laboratory measuring the samples.
In cases with discrepancy between testosterone levels and symptoms, free testosterone (FT) levels should
be analysed. For determination of FT levels, the calculation of FT with the help of the sex hormone binding
globulin (SHBG) is recommended.
Hypogonadism may be more subtle and not always evident by low testosterone levels. For
example, men with primary testicular damage often have normal testosterone levels but high LH. This could
be considered a subclinical or compensated form of hypogonadism. The clinical consequences of an isolated
elevation of LH are not clear yet, but potentially, these men may become hypogonadal in the future.
To differentiate between primary and secondary forms of hypogonadism and to clarify
hypogonadism in adult men, determination of LH serum levels is required. Both LH and testosterone serum
levels should be analysed twice within 30 days, preferably in a fasting state [58].
Summary of evidence
The diagnosis of male hypogonadism is based on signs and symptoms of androgen deficiency, together with
consistently low serum testosterone levels.
In addition, testosterone has explicit psychosexual effects, including increased libido. Delayed puberty is
defined as an absence of testicular enlargement at the age of fourteen [65]. As this is a ‘statistical’ definition,
based on reference ranges for the onset of puberty in the normal population, delayed puberty does not
necessarily indicate the presence of a disease. In cases of severe androgen deficiency, the clinical picture of
prepubertal-onset hypogonadism is evident (Table 4) and diagnosis and treatment are fairly straightforward.
The major challenge in younger individuals with presumed isolated (congenital) hypogonadotrophic
hypogonadism is to differentiate the condition from a constitutional delay in puberty and to determine when to
start androgen treatment. In milder cases of androgen deficiency, as seen in patients with Klinefelter syndrome,
pubertal development can be normal, incomplete or delayed, resulting in a more subtle phenotypic picture. In
these patients, several clues may lead to a diagnosis of hypogonadism. These include: small testes, (a history
of) cryptorchidism, gynaecomastia, sparse body hair, eunuchoid habitus, low bone mass and sub-fertility [66].
Delayed puberty
Small testes
Cryptorchidism
Gynaecomastia
High-pitched voice
Unclosed epiphyses
Linear growth into adulthood
Eunuchoid habitus
Sparse body hair/facial hair
Infertility
Low bone mass
Sarcopenia
Reduced sexual desire/activity
Depending on the underlying cause of hypogonadism, the decline in gonadal function may be gradual and
partial. The resulting clinical picture may be variable and the signs and symptoms may be obscured by the
physiological phenotypic variation. Symptoms that have been associated with adult-onset hypogonadism are
summarised in Table 3. Most of these symptoms have a multi-factorial aetiology, are reminiscent of normal
ageing and can also be found in men with completely normal testosterone levels [10]. As a result, signs
and symptoms of adult-onset hypogonadism may be non-specific, and confirmation of a clinical suspicion
by hormonal testing is mandatory. For many of the symptoms mentioned above, the probability of their
presence increases with lower plasma testosterone levels. Most studies indicate a threshold level below
which the prevalence of symptoms starts to increase [52, 67]. This threshold level is near the lower level of the
normal range for plasma testosterone levels in young men, but there appears to be a wide variation between
individuals and, even within one individual, the threshold level may be different for different target organs.
Androgen receptor activity may also contribute to this variance [68, 69].
5. DISEASE MANAGEMENT
5.1 Indications and contraindications for treatment
Testosterone treatment aims to restore testosterone levels to the physiological range in men with consistently
low levels of serum testosterone and associated symptoms of androgen deficiency. The aim of testosterone
treatment is to restore physiological androgen dependent functions and to improve QoL, e.g. sense of well-
being, sexual function, muscle strength and bone mineral density. Table 5 highlights the main indications for
testosterone treatment. Table 6 lists the main contraindications against testosterone treatment.
In adult-onset hypogonadism testosterone treatment may improve symptoms, but many hypogonadal men are
obese and have comorbidities: weight reduction, lifestyle modification and good treatment of comorbidities are
more important than just testosterone treatment [84, 85]. Reduction of BMI in obese patients, for example, is
associated with significant increase of serum testosterone levels [86].
Testosterone treatment may present several benefits regarding body composition, metabolic control,
psychological and sexual parameters, although the effects are usually modest. Observational trials show
a correlation between restored physiological testosterone levels, muscle mass and strength measured
as leg press strength and quadriceps muscle volume [51, 87-89]. Low testosterone levels are common in
men with chronic renal failure on haemodialysis and there is also a worsening of prognosis associated with
lower testosterone levels. There, is however, a lack of interventional studies evaluating eventual benefits of
testosterone therapy in this group of men [90]. Similar positive results are shown in meta-analysis designed
to address the value of the role of exogenous testosterone in bone mineral density: it is evident how
testosterone therapy improves mineral density at the lumbar spine producing a reduction in bone resorption
markers. Available trials failed to demonstrate a similar effect at the femoral neck. At present though,
bone mineral density seems to remain a surrogate marker of bone health and there are no RCTs detailing
actual bone fracture risk [88, 91-93]. Improvement in bone mineral density and bone structure in men with
Klinefelter syndrome has also been reported [94]. Body composition is influenced by testosterone therapy in
hypogonadal men, with a consequent decrease of fat mass and an increase in lean body mass [88, 95]. Men
with hypogonadism are at an increased risk of having osteoporosis and osteopenia. Young men with testicular
dysfunction and men older than 50 years of age with low testosterone should additionally be screened for
osteoporosis [96].
A strong correlation between decreased testosterone levels and increased cardiovascular mortality has been
reported in meta-analyses and retrospective studies showing that total-testosterone and FT in the normal range
are related to reduced all-cause mortality [100-106]. It is suggested that low testosterone is a biomarker for a
poor health condition and as such is a marker for increased risk of cardiovascular disease [107]. Also of interest
is the observation that testosterone treatment (transdermal) over a three year period compared to placebo did
not cause any change in dynamics of atherosclerotic plaque development in the intima media of the carotids
[108]. Normalisation of testosterone levels after testosterone replacement therapy also seems to be associated
with decreased incidence of atrial fibrillation [109].
A recent double-blinded, placebo-controlled study on men 65 years or older suggests that among men with
low testosterone levels, testosterone replacement therapy significantly increases haemoglobin levels thus
correcting anaemia from known or unknown causes [110].
In a small RCT, testosterone therapy did not improve cognitive functions but had a positive effect on
verbal memory and depressive symptoms [120]. However, a recent, large, placebo-controlled study showed
no significant improvement on memory and other cognitive functions in older men with symptomatic
hypogonadism after one year of testosterone treatment [121]. Significant improvement of depressive symptoms
in men treated with testosterone undecanoate was reported in a recent randomised trial [74]. Meta-analysis
of data from randomised placebo-controlled trials has shown a significant positive impact of testosterone on
mood [122].
Summary of evidence LE
Testosterone treatment may improve symptoms, but many hypogonadal men have a chronic illness 2
and are obese. Weight reduction, lifestyle modification and good treatment of comorbidities can
increase testosterone and reduce associated risks for diabetes and cardiovascular diseases.
Testosterone treatment can improve body composition, bone mineralisation, signs of the metabolic 3
syndrome, male sexual problems, diabetes regulations, memory and depressive symptoms.
A reduction in BMI and waist size, improved glycaemic control and lipid profile are observed in 2a
hypogonadal men receiving testosterone treatment.
5.3.1 Preparations
5.3.1.1 Testosterone undecanoate
Testosterone undecanoate (TU) is the most widely used and safest oral delivery system. It rarely causes a rise
in testosterone levels above the mid-range and it is therefore infrequently associated with side-effects [123].
In oral administration, resorption depends on simultaneous intake of fatty food. Testosterone undecanoate is
also available as a long-acting intramuscular injection (with intervals of up to three months). This long period of
action ensures a normal testosterone serum concentration for the entire period, but the relatively long wash-out
period may cause problems if complications appear [126]. In the recent IPASS study, a total worldwide sample
of 1,438 men was evaluated during nine to twelve months of treatment with injectable TU: TU was effective and
well-tolerated, with marked improvements in several psychosexual functions and waist circumference. Adverse
events and adverse drug reactions (more common: increase in haematocrit, increase in Prostate-Specific
Antigen (PSA), and injection site pain) were 12% and 6% respectively, mostly mild to moderate, and with
no increase in prostate cancer observed [99]. A recent RCT shows that sexual function benefits are evident
principally in patients with severe hypogonadism (< 8nmol/L): improvements in intercourse satisfaction and
sexual desire appear by the sixth week of treatment while erectile function improvements appear after at least
30 weeks of treatment [75].
Human chorionic gonadotropin treatment has higher costs than testosterone treatment. There is insufficient
information about the therapeutic and adverse effects of long-term hCG treatment. This type of treatment
can therefore not be recommended for long-term treatment of male hypogonadism, except in patients in
whom fertility treatment is indicated. Previous testosterone treatment does not seem to affect the efficacy of
gonadotropin therapy [82, 83]. Anti-oestrogens and aromatase inhibitors are further options for hypogonadal
patients with an active child wish, though evidence is limited [141].
Testosterone treatment is clearly contraindicated in men with advanced prostate cancer. A topic under debate
is the use of testosterone treatment in hypogonadal men with a history of prostate cancer and no evidence of
active disease. So far only studies with a limited number of patients and a relatively short period of follow-up
are available and indicate no increased risk for prostate cancer recurrence [153, 154]. According to a recent
retrospective study on hypogonadal men with previous history of prostate cancer receiving testosterone
following cancer diagnosis, treatment was not associated with increased overall or cancer-specific mortality, but
testosterone treatment was more likely to be prescribed in patients undergoing radical prostatectomy for well-
differentiated tumours [155]. No randomised placebo-controlled trials are available yet to document its long-term
safety in these patients [123]. Symptomatic hypogonadal men who have been surgically treated for localised
prostate cancer and who are currently without evidence of active disease (i.e. measurable PSA, abnormal rectal
examination, evidence of bone/visceral metastasis) can be cautiously considered for testosterone treatment [156].
Patients who underwent brachytherapy or external beam radiation (EBRT) for low-risk prostate cancer can
also be cautiously considered for testosterone treatment in case of symptomatic hypogonadism with a close
monitoring of prostate cancer recurrence [155, 157, 158], although no long-term safety data are available in
these patients.
Two studies have reported that men with testosterone levels in the upper quartile of the normal range have a
reduced number of cardiovascular events when compared to the combined data from the lower three quartiles
[160, 161]. The knowledge that hypogonadism and erectile dysfunction are biomarkers of cardiovascular
disease demonstrates that patients should be assessed for cardiovascular risk factors and where appropriate
referred to cardiology. Individual cardiovascular risk factors (e.g. lifestyle, diet, exercise, smoking, hypertension,
diabetes, dyslipidaemia) should be treated in men with pre-existing cardiovascular disease. Their secondary
prevention should be optimised as best possible.
Testosterone treatment has also demonstrated in some studies beneficial effects on certain cardiovascular
risk factors [162]. In men with angiographically proven coronary disease those with low testosterone are at
greater risk of mortality [163, 164]. Over the many years since testosterone treatment has been available up
until recently, there have been no clinical studies in the medical literature, which have shown concern in regard
to an increased risk of major cardiovascular events (MACE) apart from heart failure [165]. A major adverse
cardiac event is defined as the composite of cardiovascular death, non-fatal acute myocardial infarction, acute
coronary syndromes, stroke and cardiac failure. However, three recent studies (one placebo-controlled trial
[166] and two observational studies [167, 168]) have suggested that testosterone treatment may be associated
with an increased risk of cardiovascular events. These studies have recently been reviewed by the FDA who
concluded that, ‘each of the studies had major limitations, precluding the ability to draw definitive conclusions’
[169]. These findings are supported by letters in response to the paper by Vigen et al. [170]. The controversy
was fuelled also by a meta-analysis by Xu et al. [171] of 27 small studies involving 2,994 predominantly older
men that demonstrated that testosterone therapy increased the risk for cardiovascular-related events and that
the effect of testosterone therapy was more dependent on the source of funding of the reported trials than
on underlying baseline testosterone levels [172, 173]. However, other studies demonstrated that testosterone
treatment is at least not proatherogenic over a wide range of doses [174]. In order to overcome some of the
limitations of the analysis of Xu et al., Corona et al. performed an updated systematic review and meta-analysis
of RCTs on testosterone treatment, using a more conventional definition of cardiovascular events similar to that
used by regulatory authorities to verify the safety of newly registered drugs (including MACE). The results do
not support a causal role between testosterone treatment and adverse cardiovascular events [101].
Recent studies have provided some clarification in regard to the effect of testosterone treatment on
cardiovascular events. A large (n=83,010, mean follow up > 4.7 years) retrospective study of men with low
testosterone that had testosterone replaced to the normal range was associated with a reduction in myocardial
infarction, whereas men treated with testosterone which did not achieve normalisation had no benefit [175]. A
second retrospective analysis of MACE at three years (n=4,736) in men again treated to normalise testosterone
compared groups with low, normal and high testosterone. The result was that normal testosterone reduced
MACE and death [176]. A third large study (population-based matched cohort 10,311 TRT vs. 28,029 controls)
followed up for five years, reported that men with the highest tertile of testosterone treatment exposure
decreased mortality and cardiovascular events, whereas men in the lowest tertile of testosterone treatment
exposure had decreased mortality and cardiovascular events [105]. These studies demonstrate that when
testosterone is used, adequate replacement should be administered in order to normalise testosterone levels
and that patients must be compliant.
The European Medicines Agency (EMA) has stated ‘The Co-ordination Group for Mutual Recognition and
Decentralised Procedures - Human (CMDh), a regulatory body representing EU Member States, has agreed
by consensus that there is no consistent evidence of an increased risk of heart problems with testosterone
A large retrospective analysis of 76,639 men has demonstrated that testosterone therapy that achieves
normalisation of levels results in a significant reduction in the incidence of atrial fibrillation, the commonest
cardiac arrhythmia which is associated with an increased risk of stroke, cardiac complications and death [109].
Caution should, however, be used in men with pre-existing cardiovascular disease. Firstly, hypogonadism must
be carefully diagnosed beyond reasonable doubt. Secondly, if testosterone is prescribed then testosterone
levels should not exceed the mid-normal range and the haematocrit should not exceed 0.54% [181].
Testosterone dose adjustment may be required and/or venesection (500 mL) should be considered and
repeated if necessary, if the haematocrit is greater than 0.54%. The haematocrit value of > 54% is based on
the increased risk of cardiovascular mortality from the Framingham Heart Study [182], which was recently
confirmed in another study [183]. This value is also supported by the known increased risk of thrombosis in the
congenital condition of idiopathic erythropoiesis [184]. The majority of patients with cardiovascular disease will
be receiving anti-platelet therapy. An electrocardiogram prior to testosterone treatment in the assessment of
hypogonadism could be considered.
Adding to the controversy, a recent double-blind, placebo-controlled trial at nine academic medical
centres in the United States shows that treatment with testosterone gel for one year is associated
with a significantly greater increase in coronary artery non-calcified plaque volume, as measured
by coronary computed tomographic angiography. However, the clinical significance remains to
be determined [185]. Two large retrospective studies have not shown any evidence that testosterone
treatment is associated with an increased incidence of venous thromboembolism [186, 187]. Venous
thromboembolism in one study of men on testosterone treatment reported 42 (38 men) cases, 40 of
which had evidence of underlying thrombophilia (which included Factor V Leiden deficiency, prothrombin
mutations, homocysteinuria) of which 39 had their condition diagnosed after an event [188]. The risk
of venous thromboembolism is suggested to increase soon after the start of testosterone use and
peak in the first six months of treatment [189]. In addition, high endogenous levels of testosterone
and/or oestradiol are not associated with an increased risk of venous thromboembolism [186, 187, 190].
A recent meta-analysis of previous RCTs does not support an increased cardiovascular risk related to
testosterone replacement therapy. It also draws similar conclusions for the relationship between testosterone
treatment and venous thromboembolism risk, while stating that reported cases of venous thromboembolism
are frequently related to an undiagnosed thrombophilia-hypofibrinolysis status [191].
Summary of evidence LE
Case reports and small cohort studies point to a possible correlation between testosterone treatment 3
and the onset of breast cancer, but there is as yet a lack of strong evidence for this relationship.
Randomised controlled trials support the hypothesis that testosterone treatment does not result in 1b
changes in prostatic histology.
Recent studies indicate that testosterone treatment does not increase the risk of prostate cancer, but 3
long-term follow-up data are not yet available.
There is no evidence for a relationship between testosterone treatment and obstructive sleep apnoea. 3
There is no substantive evidence that testosterone treatment, when replaced to the normal 1a
physiological range, is related to the development of major adverse cardiovascular events.
In hypogonadal men testosterone treatment has been demonstrated to have a positive impact on 1b
cardiovascular risks.
6.4 Haematocrit
It is important to use only minimal or no venous occlusion when taking a blood sample for haematocrit
measurements [184]. Elevated haematocrit is the most frequent side-effect of testosterone treatment. The
clinical significance of a high haematocrit level is unclear, but it may be associated with hyperviscosity and
thrombosis [190]. The effect of erythropoiesis may become evident at three months and peaks at twelve
months [88].
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8. CONFLICT OF INTEREST
All members of the EAU Male Hypogonadism Guidelines Panel have provided disclosure statements on all
relationships that they have that might be perceived to be a potential source of a conflict of interest. This
information is publically accessible through the European Association of Urology website: http://www.uroweb.
org/guideline/. This guidelines document was developed with the financial support of the European Association
of Urology. No external sources of funding and support have been involved. The EAU is a non-profit
organisation, and funding is limited to administrative assistance and travel and meeting expenses. No honoraria
or other reimbursements have been provided.