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(e.g., striated, smooth and cardiac muscle). Any elevation above the normal range for haematocrit usually
becomes evident between 3 and 12 months after testosterone therapy initiation. However, polycythaemia
can also occur after any subsequent increase in testosterone dose, switching from topical to parenteral
administration and, development of co-morbidity, which can be linked to an increase in haematocrit (e.g.,
respiratory or haematological diseases).
There is no evidence that an increase of haematocrit up to and including 54% causes any adverse
effects. If the haematocrit exceeds 54% there is a testosterone independent, but weak associated rise in CV
events and mortality [77, 157-159]. Any relationship is complex as these studies were based on patients with
any cause of secondary polycythaemia, which included smoking and respiratory diseases. There have been no
specific studies in men with only testosterone-induced erythrocytosis.

Three large studies have not shown any evidence that testosterone therapy is associated with an increased risk
of venous thromboembolism [160, 161]. However, one study showed that an increased risk peaked at 6 months
after initiation of testosterone therapy, then declined over the subsequent period [162]. No study reported
whether there was monitoring of haematocrit, testosterone and/or E2 levels. High endogenous testosterone
or E2 levels are not associated with a greater risk of venous thromboembolism [163]. In one study venous
thromboembolism was reported in 42 cases and 40 of these had diagnosis of an underlying thrombophilia
(including factor V Leiden deficiency, prothrombin mutations and homocysteinuria) [164]. In a RCT of
testosterone therapy in men with chronic stable angina there were no adverse effects on coagulation, by
assessment of tissue plasminogen activator or plasminogen activator inhibitor-1 enzyme activity or fibrinogen
levels [165]. A meta-analysis of RCTs of testosterone therapy reported that venous thromboembolism was
frequently related to underlying undiagnosed thrombophilia-hypofibrinolysis disorders [76].

With testosterone therapy an elevated haematocrit is more likely to occur if the baseline level is toward the
upper limit of normal prior to initiation. Added risks for raised haematocrit on testosterone therapy include
smoking or respiratory conditions at baseline. Higher haematocrit is more common with parenteral rather
than topical formulations. In men with pre-existing CVD extra caution is advised with a definitive diagnosis of
hypogonadism before initiating testosterone therapy and monitoring of testosterone as well as haematocrit
during treatment.
Elevated haematocrit in the absence of co-morbidity or acute CV or venous thromboembolism
can be managed by a reduction in testosterone dose, change in formulation or if the elevated haematocrit is
very high by venesection (500 mL), even repeated if necessary, with usually no need to stop the testosterone
therapy.

3.7.7 Obstructive Sleep Apnoea
There is also no evidence that testosterone therapy can result in onset or worsening of sleep apnoea.
Combined therapy with Continuous Positive Airway Pressure (CPAP) and testosterone gel was more effective
than CPAP alone in the treatment of obstructive sleep apnoea [166]. In one RCT, testosterone therapy in men
with severe sleep apnoea reported a reduction in oxygen saturation index and nocturnal hypoxaemia after 7
weeks of therapy compared to placebo, but this change was not evident after 18 weeks’ treatment and there
was no association with baseline testosterone levels [167].

3.7.8 Follow up
Testosterone therapy alleviates symptoms and signs of hypogonadism in men in a specific time-dependent
manner. The TTrials clearly showed that testosterone therapy improved sexual symptoms as early as 3 months
after initiation [86]. Similar results have been derived from meta-analyses [53, 76]. Hence, the first evaluation
should be planned after 3 months of treatment. Further evaluation may be scheduled at 6 months or 12
months, according to patient characteristics, as well as results of biochemical testing (see below). Table 6
summarises the clinical and biochemical parameters that should be monitored during testosterone therapy.

Trials were designed to maintain the serum testosterone concentration within the normal range for young men
(280–873 ng/dL or 9.6-30 nmol/L) [86]. This approach resulted in a good benefit/risk ratio. A similar approach
could be considered during follow-up. The correct timing for evaluation of testosterone levels varies according
to the type of preparation used (Table 5). Testosterone is involved in the regulation of erythropoiesis [108]
and prostate growth [75], hence evaluation of PSA and haematocrit should be mandatory before and during
testosterone therapy. However, it is important to recognise that the risk of PCa in men aged < 40 years is low.
Similarly, the mortality risk for PCa in men aged > 70 years is not been considered high enough to warrant
monitoring in the general population [168]. Hence, any screening for PCa through determination of PSA and
DRE in men aged < 40 or > 70 years during testosterone therapy should be discussed with the patients.
Baseline and, at least, annually glyco-metabolic profile evaluation may be a reasonable

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