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If semen analysis is normal according to WHO criteria, a single test is sufficient. If the results are abnormal on
at least two tests, further andrological investigation is indicated. It is important to differentiate between the
following [1463]:
• oligozoospermia: < 15 million spermatozoa/mL;
• asthenozoospermia: < 32% progressive motile spermatozoa;
• teratozoospermia: < 4% normal forms.
• None of the individual sperm parameters (e.g., concentration, morphology and motility), are diagnostic
per se of infertility.

Often, all three anomalies occur simultaneously, which is defined as oligo-astheno-terato-zoospermia (OAT)
syndrome. As in azoospermia (namely, the complete absence of spermatozoa in semen), in severe cases of
oligozoospermia (spermatozoa < 5 million/mL) [1466], there is an increased incidence of obstruction of the male
genital tract and genetic abnormalities. In those cases, a more comprehensive assessment of the hormonal profile
may be helpful to further and more accurately differentially diagnose among pathological conditions.

In azoospermia, the semen analysis may present with normal ejaculate volume and azoospermia after
centrifugation. A recommended method is semen centrifugation at 3,000 g for 15 minutes and a thorough
microscopic examination by phase contrast optics at ×200 magnification of the pellet. All samples can be stained
and re-examined microscopically [1463]. This is to ensure that small quantities of sperm are detected, which may
be potentially used for intra-cytoplasmic sperm injection (ICSI) and obviate the need for surgical intervention.

10.3.3 Measurement of sperm DNA Fragmentation Index (DFI)
Semen analysis is a descriptive evaluation, and may be unable to discriminate between the sperm of fertile
and infertile men. Therefore, it is now apparent that sperm DNA damage may occur in men with infertility. DNA
fragmentation, or the accumulation of single- and double-strand DNA breaks, is a common property of sperm,
and an increase in the level of sperm DNA fragmentation has been shown to reduce the chances of natural
conception. Although no studies have unequivocally and directly tested the impact of sperm DNA damage on
clinical management of infertile couples, sperm DNA damage is more common in infertile men and has been
identified as a major contributor to male infertility, as well as poorer outcomes following ART [1467, 1468],
including impaired embryo development [1467], miscarriage, recurrent pregnancy loss [1464, 1465, 1469], and
birth defects [1467]. Sperm DNA damage can be increased by several factors including hormonal anomalies,
varicocele, chronic infection and lifestyle factors (e.g., smoking) [1468].

Several assays have been described to measure sperm DNA damage. It has been suggested that current
methods for assessing sperm DNA integrity still do not reliably predict treatment outcomes from ART and
there is controversy whether to recommend them routinely for clinical use [1468, 1470]. Of those, terminal
deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labelling (TUNEL) and the alkaline
comet test (COMET) directly measure DNA damage. Conversely, sperm chromatin structure assay (SCSA)
and sperm chromatic dispersion test (SCD) are indirect tools for DNA fragmentation assessment. Sperm
chromatin structure assay is still the most widely studied and one of the most commonly used techniques to
detect DNA damage [1471, 1472]. In SCSA, the number of cells with DNA damage is indicated by the DNA
fragmentation index (DFI) [1473], whereas the proportion of immature sperm with defects in the histone-to-
protamine transition is indicated by high DNA stainability [1474]. It is suggested that a threshold DFI of 30%
as measured with SCSA, is associated with reduced pregnancy rates via natural conception or Intra-uterine
insemination (IUI) [1472]. Furthermore, DFI values > 50% on SCSA are associated with poorer outcomes from
in vitro fertilisation (IVF). More recently, the mean COMET score and scores for proportions of sperm with high
or low DNA damage have been shown to be of value in diagnosing male infertility and providing additional
discriminatory information for the prediction of both IVF and ICSI live births [1468].

Testicular sperm is reported to have lower levels of sperm DFI when compared to ejaculated sperm [1475].
Couples with elevated DNA fragmentation may benefit from combination of testicular sperm extraction (TESE)
and ICSI, an approach called TESE-ICSI, which may not overcome infertility when applied to an unselected
population of infertile men with untested DFI values [1472, 1475]. However, further evidence is needed to
support this practice in the routine clinical setting [1475].

10.3.4 Hormonal determinations
In men with testicular deficiency, hypergonadotropic hypogonadism (also called primary hypogonadism)
is usually present, with high levels of FSH and LH, with or without low levels of testosterone. Generally,
the levels of FSH negatively correlate with the number of spermatogonia [1476]. When spermatogonia are
absent or markedly diminished, FSH level is usually elevated; when the number of spermatogonia is normal,

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