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western countries [1653, 1654]. In almost all countries with reliable cancer registries, the incidence of testicular
cancer has increased [1540, 1655]. This has been postulated to be related to TDS, which is a developmental
disorder of the testes caused by environmental and/or genetic influences in pregnancy. As detailed above,
the adverse sequelae of TDS include cryptorchidism hypospadias, infertility and an increased risk of testicular
cancer [1624]. Endocrine disrupting chemicals have also been associated with sexual dysfunction [1656]
and abnormal semen parameters [1657]. These cancers arise from premalignant gonocytes or GCNIS [1658].
Testicular microcalcification, seen on US, can be associated with TGCT and GCNIS of the testes [1607, 1659,
1660].

10.4.2.1 Testicular germ cell cancer and reproductive function
Sperm cryopreservation is considered standard practice in patients with cancer overall, and not only in those
with testicular cancer [1661, 1662]. As such, it is important to stress that all men with cancer must be offered
sperm cryopreservation prior to the therapeutic use of gonadotoxic agents or ablative surgery that may impair
spermatogenesis or ejaculation (i.e., chemotherapy; radiotherapy or retroperitoneal surgery).

Men with TGCT have decreased semen quality, even before cancer treatment. Azoospermia has been observed
in 5–8% of men with TGCT [1663] and oligospermia in 50% [1664]. Given that the average 10-year survival rate
for testicular cancer is 98% and it is the most common cancer in men of reproductive potential, it is mandatory
to include counselling regarding fertility preservation prior to any gonadotoxic treatment [1664, 1665]. Semen
analysis and cryopreservation was therefore recommended prior to any gonadotoxic cancer treatment and all
patients should be offered cryopreservation of ejaculated sperm or sperm extracted surgically (e.g., c/mTESE)
if shown to be azoospermic or severely oligozoospermic. Given that a significant number of men with testicular
cancer at the time of first presentation have severe semen abnormalities (i.e., severe oligozoospermia/
azoospermia) even prior to (any) treatment [1658], it is recommended that men should undergo sperm
cryopreservation prior to orchidectomy. As mentioned above, in those who are either azoospermic or severely
oligo-zoospermic this will allow an opportunity to perform TESE prior to further potential gonadotoxic/ablative
surgery [1664]. The use of cryopreservation has been demonstrated to be the most cost effective strategy
for fertility preservation in patients undergoing potential gonadotoxic treatments [1666, 1667]. In cases of
azoospermia, testicular sperm may be recovered to safeguard patient’s fertility (onco-TESE) potential. The
surgical principles in onco-TESE do not differ from the technique of mTESE for men with infertility (e.g., NOA)
[1668, 1669]. In this context, referral to a urologist adept in microsurgery is desirable with facilities for sperm
cryopreservation.

Rates of under-utilisation of semen analysis and sperm cryopreservation have been reported to be high;
resulting in the failure to identify azoospermic or severely oligozoospermic patients at diagnosis who may
eventually benefit from fertility-preserving procedures (e.g., onco-mTESE at the time of orchidectomy).
Therefore, counselling about fertility preservation is a priority and needs to be broached earlier in men
with testicular cancer [1664]. There are controversial arguments that performing cryopreservation prior to
orchidectomy may delay subsequent treatment and have an adverse impact on survival. In this context,
orchidectomy should not be unduly delayed if there are no facilities for cryopreservation or there is a potential
delay in treatment.

Treatment of TGCT can result in additional impairment of semen quality [1670] and increased sperm aneuploidy
up to two years following gonadotoxic therapy [1671]. Chemotherapy is also associated with DNA damage and
an increased DNA fragmentation rate [1672]. However, sperm aneuploidy levels often decline to pre-treatment
levels 18-24 months after treatment [1671]. Several studies reviewing the offspring of cancer survivors have not
shown a significant increased risk of genetic abnormalities in the context of chemotherapy and radiotherapy
[1673].

In addition to spermatogenic failure, patients with TGCT have Leydig cell dysfunction, even in the contralateral
testis [1674]. The risk of hypogonadism may therefore be increased in men treated for TGCT. The measurement
of pre-treatment levels of testosterone, SHBG, LH and oestradiol may help to stratify those patients at
increased risk of hypogonadism and provide a baseline for post-treatment hypogonadism. Men who have had
TGCT and have low normal androgen levels should be advised that they may be at increased risk of developing
hypogonadism, as a result of an age-related decrease in testosterone production and could potentially develop
MetS; there are no current long-term data supporting this. The risk of hypogonadism is increased in the
survivors of testicular cancer and serum testosterone levels should be evaluated during the management of
these patients [1675]. However, this risk is greatest at 6-12 months post-treatment and suggests that there
may be some improvement in Leydig cell function after treatment. Therefore it is reasonable to delay initiation
of testosterone therapy, until the patient shows continuous signs or symptoms of testosterone deficiency

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