Page 137 - Remedial Andrology

10.3.5.6 Outcomes from assisted reproductive technology and long-term health implications to the male and
offspring
It is estimated that > 4 million babies have been born with ART since the first baby was conceived by IVF in
1978 [1572]. As the number of couples undergoing ART has increased [1573, 1574], safety concerns related to
ART have been raised. Assisted reproductive technology-conceived offspring have poorer prenatal outcomes,
such as lower birth weight, lower gestational age, premature delivery, and higher hospital admissions compared
with naturally conceived offspring [1575, 1576]. However, the exact mechanisms resulting in these complications
remain obscure. Birth defects have also been associated with children conceived via ART [1577-1579]. Meta-
analyses have shown a 30-40% increase in major malformations linked with ART [1580-1582]. However, debate
continues as to whether the increased risk of birth defects are related to parental age, ART or the intrinsic
defects in spermatogenesis in infertile men [1583-1588].

As for the long-term outcomes, post-natal growth patterns are mostly not associated with ART [1577, 1589,
1590]. However, a number of studies have shown that ART children are taller [1591, 1592]. This may be
important as there is evidence showing that rapid weight gain during early childhood is linked with higher blood
pressure levels in children conceived via ART [1593]. It is also suggested that ART-conceived children have
similar childhood illnesses and hospital services rates as compared with naturally conceived children [1594-
1596]. Some studies have shown an increased risk of retinoblastoma [1597] and hepatoblastoma in children
after ART. However, these studies have been challenged with other studies that have not supported these
findings [1598]. The current evidence for cancer risk in children conceived with ART is inadequate and further
studies are warranted [1599, 1600]. Finally, several epigenetic alterations seem to be caused by ART, which
might be the molecular basis to a some complex traits and diseases [1601].

10.3.6 Imaging in the infertile men
In addition to physical examination, a scrotal US may be helpful in: (i) measuring testicular volume;
(ii) assessing testicular anatomy and structure in terms of US patterns, thus detecting signs of testicular
dysgenesis often related to impaired spermatogenesis (e.g., non-homogeneous testicular architecture and
microcalcifications) and testicular tumours; and, (iii) finding indirect signs of obstruction (e.g., dilatation of rete
testis, enlarged epididymis with cystic lesions, or absent vas deferens) [1458]. In clinical practice, Prader’s
orchidometer-derived testicular volume is considered a reliable surrogate of US-measured testicular volume,
easier to perform and cost-effective [1457]. Nevertheless, scrotal US has a relevant role in testicular volume
assessment when Prader’s orchidometer is unreliable (e.g., large hydrocele, inguinal testis, epididymal
enlargement/fibrosis, thickened scrotal skin; small testis, where the epididymis is large in comparison to the
total testicular volume [1457, 1458]). Ultrasound-patterns of testicular inhomogeneity [1602, 1603] is usually
associated with ageing, although it has also been reported in association with testicular atrophy and fibrosis
[1458]. At present, a diagnostic testicular biopsy is not recommended when testicular inhomogeneity is
detected [1602, 1603].

10.3.6.1 Scrotal US
Scrotal US is widely used in everyday clinical practice in patients with oligo-zoospermia or azoospermia, as
infertility has been found to be an additional risk factor for testicular cancer [1604, 1605]. It can be used in the
diagnosis of several diseases causing infertility including testicular neoplasms and varicocele.

10.3.6.1.1 Testicular neoplasms
In one study, men with infertility had an increased risk of testicular cancer (hazard ratio [HR] 3.3). When
infertility was refined according to individual semen parameters, oligo-zoospermic men had an increased risk of
cancer compared with fertile control subjects (HR 11.9) [1606]. In a recent systematic review infertile men with
testicular microcalcification (TM) were found to have an ~18-fold higher prevalence of testicular cancer [1607].
However, the utility of US as a routine screening tool in men with infertility to detect testicular cancer remains a
matter of debate [1604, 1605].

One issue in undertaking routine screening for testicular neoplasms in this cohort of patients is the risk of
overdiagnosis and the increased detection of indeterminate lesions of the testis. These testicular lesions are
often detected during the diagnostic work-up of infertile men and are difficult to characterise as benign or
malignant based only upon US criteria, including size, vascularity and echogenicity.

A dichotomous cut-off of certainty in terms of lesion size that may definitely distinguish benign from malignant
testicular masses is currently not available. However, in a study with 81 patients with a lesion size < 10 mm,
on histology showed that 56 (69%) were benign lesions, although one-third were malignant. All lesions < 5
mm in diameter were benign [1608]. Available data suggest that the smaller the nodule, the less likely that it is
malignant [1609], and lesions < 5 mm could be monitored, as they have a low probability of malignancy.

136 SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021