Page 31 - Remedial Andrology

and chronic inflammatory state [133]. Atherosclerosis is a chronic inflammatory disease, that releases pro-
inflammatory cytokines into the circulation, which are known to suppress testosterone release from the HPG
axis. Evidence from RCTs of testosterone therapy in men with MetS and/or T2DM demonstrates some benefit
in CV risk, including reduced central adiposity, insulin resistance, total cholesterol and LDL-cholesterol and
suppression of circulating cytokines [14, 23-25, 29, 133]. However, due to the equivocal nature of these
studies, testosterone therapy cannot be recommended for indications outside the specific symptoms.

Published data show that LOH is associated with an increase in all-cause and CVD-related mortality [12, 134-
137]. These studies are supported by a meta-analysis that concluded that hypogonadism is a risk factor for
cardiovascular morbidity [123] and mortality [138]. Importantly, men with low testosterone when compared
to eugonadal men with angiographically proven coronary disease have twice the risk of earlier death [133].
Longitudinal population studies have reported that men with testosterone in the upper quartile of the normal
range have a reduced number of CV events compared to men with testosterone in the lower three quartiles
[134]. Androgen deprivation therapy for PCa is linked to an increased risk of CVD and sudden death [139].
Conversely, two long-term epidemiological studies have reported reduced CV events in men with high normal
serum testosterone levels [140, 141]. Erectile dysfunction is independently associated with CVD and may be
the first clinical presentation in men with atherosclerosis.

The knowledge that men with hypogonadism and/or ED may have underlying CVD should prompt individual
assessment of their CV risk profile. Individual risk factors (e.g., lifestyle, diet, exercise, smoking, hypertension,
diabetes and dyslipidaemia) should be assessed and treated in men with pre-existing CVD and in patients
receiving androgen deprivation therapy. Cardiovascular risk reduction can be managed by primary care
clinicians, but patients should be appropriately counselled by clinicians active in prescribing testosterone
therapy [80]. If appropriate, they could be referred to cardiologists for risk stratification and treatment of
co-morbidity.

No RCTs have provided a clear answer on whether testosterone therapy affects CV outcomes. The TTrial
(n=790) in older men [142], the TIMES2 (n=220) [24] and the BLAST studies in men with MetS and T2DM
and the pre-frail and frail study in elderly men - all of 1-year duration - did not reveal any increase in Major
Adverse Cardiovascular Events (MACE) [24, 27, 142, 143]. In this context, MACE is defined as the composite
of CV death, non-fatal acute myocardial infarction, acute coronary syndromes, stroke and cardiac failure.
Randomised controlled trials between 3 and 12 months in men with known heart disease treated with
testosterone have not found an increase in MACE, but have reported improvement in cardiac ischaemia,
angina and functional exercise capacity [144-146]. The European Medicines Agency has stated that ‘The
Co-ordination Group for Mutual recognition and Decentralisation 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 in men who lack the hormone (a condition known as
hypogonadism). However, the product information is to be updated in line with the most current available
evidence on safety, and with warnings that the lack of testosterone should be confirmed by signs and
symptoms and laboratory tests before treating men with these drugs [147].

As a whole, as for MACE, current available data from interventional studies suggest that there is no increased
risk with up to 3 years of testosterone therapy [148-151]. The weight of the currently published evidence has
reported that testosterone therapy in men with diagnosed hypogonadism has neutral or beneficial actions on
MACE in patients with normalised testosterone levels. The findings could be considered sufficiently reliable
for a 3-year course of testosterone therapy, after which no available study can exclude further or long-term CV
events [152, 153].

3.7.5.1 Cardiac Failure
Testosterone treatment is contraindicated in men with severe chronic cardiac failure because fluid retention
may lead to exacerbation of the condition. Some studies including one of 12 months’ duration have shown
that men with moderate chronic cardiac failure may benefit from low doses of testosterone, which achieve
mid-normal range testosterone levels [145, 154, 155]. If a decision is made to treat hypogonadism in men with
chronic cardiac failure, it is essential that the patient is followed up carefully with clinical assessment and both
testosterone and haematocrit measurements on a regular basis. An interesting observation is that untreated
hypogonadism increased the re-admission and mortality rate in men with heart failure [156].

3.7.6 Erythrocytosis
An elevated haematocrit is the most common adverse effect of testosterone therapy. Stimulation of
erythropoiesis is a normal biological action that enhances delivery of oxygen to testosterone-sensitive tissues

30 SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021