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to placebo among infertile men with male factor infertility. Moreover, cumulative live-birth rate did not differ at
6 months between the antioxidant and placebo groups (15% vs. 24%) [1797]. However, all the aforementioned
studies also recognised important limitations: data were derived from low-quality RCTs with serious risk of bias
due to poor methods of reporting randomisation; failure to report on the clinical outcomes including live-birth
and clinical pregnancy rates; high attrition rates; and imprecision due to often low event rates and small overall
sample sizes [1796]. No clear conclusions were possible regarding the specific antioxidants to use or and/or
therapeutic regimes for improving sperm parameters and pregnancy rate [1796].

10.5.2.3 Selective oestrogen receptor modulators
Selective oestrogen receptor modulators (SERMs) have been advocated as a possible empirical treatment in
male idiopathic infertility. The proposed mechanism of action is based on the activity of these compounds to
block oestrogen receptors at the level of the hypothalamus, which results in stimulation of GnRH secretion
leading to an increase in pituitary gonadotropin release. The latter effect, by stimulating spermatogenesis,
represents the rational basis for SERM administration to patients with reduced sperm count [1798]. In an initial
meta-analysis including 11 RCTs, in which only 5 were placebo-controlled, it was concluded that SERMs
were not associated with an increased pregnancy rate in the 459 patients analysed [1799]. In a subsequent
Cochrane review published 1 year later, these findings were confirmed in a larger number of studies (n = 10
and 738 men), although positive effects on hormonal parameters were documented. More recently, Chua
et al. meta-analysed data derived from 11 RCTs and showed that SERMs were associated with a significantly
increased pregnancy rate [1800]. Additionally, a significant improvement in sperm and hormonal parameters
was detected. Similar results were confirmed in the latest updated meta-analysis of 16 studies [1798].
However, it should be recognised that the quality of the papers included was low and only a few studies were
placebo-controlled. In conclusion, although some positive results relating to the use of SERMs in men with
idiopathic infertility have been reported, no conclusive recommendations can be drawn due to poor quality of
the available evidence. Furthermore, complications from the use of SERMs were under-reported.

10.5.2.4 Aromatase inhibitors
Aromatase, a cytochrome p450 enzyme, is present in the testes, prostate, brain, bone, and adipose tissue
of men; it converts testosterone and androstenedione to oestradiol and oestrone, respectively. Oestradiol
negatively feeds back on the hypothalamus and pituitary to reduce gonadotropic secretions, ultimately
affecting spermatogenesis. In this context, aromatase inhibitors (AIs) may decrease oestrogen production
by reversibly inhibiting cytochrome p450 isoenzymes 2A6 and 2C19 of the aromatase enzyme complex
inhibiting the negative feedback of oestrogen on the hypothalamus resulting in stronger GnRH pulses that
stimulate the pituitary to increase production of FSH [1801-1804]. Aromatase activity has been associated
with male infertility characterised by testicular dysfunction with low serum testosterone and/or testosterone to
oestradiol ratio. In this context, AIs have been reported to increase endogenous testosterone production and
improve spermatogenesis in the setting of infertility as an off-label option for treatment [1805]. Either steroidal
(testolactone) and non-steroidal (anastrozole and letrozole) AIs significantly improve hormonal and semen
parameters in infertile men, with a safe tolerability profile, although prospective RCTs are necessary to better
define the efficacy of these medications in this clinical setting [1803, 1805].

Recommendations Strength rating
In men with idiopathic oligo-astheno-teratozoospermia, life-style changes including weight Weak
loss and increased physical activity, smoking cessation and alcohol intake reduction can
improve sperm quality and the chances of conception.
No clear recommendation can be made for treatment of patients with idiopathic infertility Weak
using antioxidants, although anti-oxidant use may improve semen parameters.
No conclusive recommendations on the use of selective oestrogen receptor modulators in Weak
men with idiopathic infertility can be drawn.
No conclusive recommendations on the use of either steroidal (testolactone) or nonsteroidal Weak
(anastrozole and letrozole) aromatase inhibitors in men with idiopathic infertility can be
drawn, even before testis surgery.

10.5.3 Hormonal therapy
10.5.3.1 Gonadotrophins
Follicle Stimulating Hormone is primarily involved in the initiation of spermatogenesis and testicular growth
during puberty. The role of FSH post puberty has not been clearly defined. Luteinising hormone stimulates
testosterone production in the testes, but due to its short half-life, it is not suitable for clinical use. Human
Chorionic Gonadotrophin acts in a similar manner to LH and can be used pharmacologically to stimulate

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