The most common cause of male infertility is testicular dysfunction. This dysfunction can be of congenital origin or acquired later in life. Maldevelopment of the testes (dysgenesis) during early pregnancy can result in cryptorchidism, primary hypogonadism and impaired spermatogenesis later in life. These men also have an increased risk for testicular malignancies. Severe forms of testicular dysgenesis syndrome (TDS, Skakkebaek et al. 2001) may also be accompanied by other genital malformations, such as hypospadias and anogenital malformations. The cause of TDS is unknown: both genetic factors and environmental influences are suggested, especially elevated levels of (pseudo-) estrogens and antiandrogens in early pregnancy. Many genes are involved in gonadal development, including the sex region of the Y chromosome (SRY gene, Rey and Grinspon 2011). Polymorphisms of these genes may increase the chance of testicular dysgenesis.

Men with TDS present with small size testes, elevated FSH and LH, low testosterone and abnormal semen quality. On scrotal ultrasound examination testicular microcalcifications can be found and an inhomogeneous parenchyma of the testes. Severe forms of TDS are associated with testicular atrophy and non-obstructive azoospermia.

Acquired forms of testicular insufficiency are less common and can be the result of testicular torsion, testicular trauma, urogenital infections (epididymo-orchitis) and cancer treatment (chemotherapy and irradiation). Chronic diseases may influence spermatogenesis, either directly or by influencing the production of reproductive hormones.

Male infertility can be the result of chromosomal defects, DNA mutations and deletions in genes involved in spermatogenesis. Cytogenetic abnormalities are present in 2–4 % of men with oligozoospermia and in 15 % of men with non-obstructive azoospermia. The most common example of a cytogenetic abnormality that causes male infertility is Klinefelter’s syndrome (47, XXY karyotype, Rey and Grinspon 2011). This occurs in about 1:500 men. Klinefelter patients have atrophic testis and usually present with male infertility due to azoospermia. Mosaic Klinefelter patients (46, XY/47, XXY) may have severe oligozoospermia. It is suggested that the disturbance in spermatogenesis in men with Klinefelter’s syndrome is progressive from puberty on. During adolescence spermatozoa may still be found in the testes; in older Klinefelter patients spermatogenesis is usually absent. Some Klinefelter patients have a typical eunuchoid body composition as a consequence of primary hypogonadism, including gynaecomastia and a tall stature. Klinefelter patients may need testosterone supplementation later in life.

Deletions of the azoospermic factor gene (AZF gene Reijo et al. 1995, Krausz 2009) on the long arm of the Y chromosome are associated with severe oligozoospermia and azoospermia. These are de novo deletion which will be passed on to the sons of these men, if a pregnancy can be obtained through intracytoplasmic sperm injection (ICSI). They are present in 2–4 % of men with less than five million spermatozoa per ml and in 13–15 % of men with non-obstructive azoospermia.

Mutations of the gene involved in cystic fibrosis (CFTR gene, De Braekeleer and Ferec 1996) can result in maldevelopment of the epididymis, vas deferens and the seminal vesicles, resulting in obstructive azoospermia. These men present with bilateral absence of the vas deferens and have azoospermia with a low seminal volume (<1 ml) and a low seminal Ph (<7.0), due to the absence of fluid from the seminal vesicles. The gene defect can be passed on to the children of these men and may result in a child with some form of cystic fibrosis.

A less common cause of male infertility is endocrine dysfunction. This also can be congenital and acquired. A congenital form of hypogonadotropic hypogonadism is Kallmann’s syndrome with a prevalence of 1:10,000 men, characterised by the absence of gonadotropins (LH and FSH) (Behre et al. 2010). The testes of the men will not develop properly from puberty on (hypogonadism) due to the absence of LH and FSH. Spermatogenesis is absent. Delayed puberty and hypogonadism can be treated in these boys by weekly injections of gonadotropins (HCG/HMG or rFSH).

Acquired hypogonadotropic hypogonadism can be the result of pituitary dysfunction (adenoma, infection, haemochromatosis, drugs). Tumours of the pituitary (prolactinoma’s, Bolyakov and Paduch 2011) should be ruled out in men with unexplained hypogonadotropic hypogonadism: a CT-scan or MRI of the pituitary (sella) region is recommended.

A suppression of reproductive hormones can occur in men taking testosterone, especially in a supraphysiological dose (anabolic steroids, Turek et al. 1995). This temporarily affects spermatogenesis and can result in infertility. It may take several months to more than 1 year before the hypothalamus and the pituitary resume their normal production of gonadotropins in these men, depending on the amount and duration of the testosterone abuse.

Obesity can also influence male infertility: the enzyme aromatase, abundantly present in fatty tissue, converts testosterone into estradiol. Estrogens suppress the production of LH and FSH. Normalisation of body weight next to eating healthy food is an important lifestyle advise for these men that can help them in improving their semen quality (Teerds et al. 2011).