**3. Hormonal regulation of testicular descent**

Testicular descent is hormonally regulated. Regulation of testicular descent is not yet completely understood. There are various forms of cryptorchidism (congenital with or without spontaneous descent, mild versus severe, acquired). These forms may reflect distinct hormonal patterns which differ in each situation (Suomi 2006). Apart from anatomical configuration and hormonal stimulation, genetic control of testis descent is very important. Major regulators of testicular descent are insulin-like factor 3 and testosterone. Testes migrate from initial intraabdominal position into the scrotal sac in two distinct hormonally regulated phases. During the first transabdominal phase (androgen independent) (10-23th week gestation) the CLS (cranial suspensory ligament) regresses while the gubernaculum shortens and develops caudal segment into the gubernaculum bulge. The second inguinoscrotal phase (depends on androgens) is normally completed by the 35th week – the gubernaculum extends caudally into the scrotum and involutes, following the passage of the testis through the inguinal canal.

The first phase of testis descent (transabdominal) is regulated essentially by insulin-like factor 3 (INSL3), a peptide, product of the pre- and postnatal Leydig cells. INSL3 controls the passage through its receptor Lgr8 (leucine-rich-containing repeats G protein-coupled receptor). Genetic disruption of the Insl3 gene or its receptor (Lgr8) in mice has led to high intraabdominal cryptorchidism (Adham 2004). In the second phase (inguinoscrotal) androgens (testosterone) are the major mediators of testis descent (Foresta 2008). The inguinoscrotal phase is at least partly dependent on fetal testicular testosterone secretion, which in turn is initiated and maintained by human chorionic gonadotropin produced by

The contalateral testis in men with unilateral testis cancer (Berthelsen 1983) or unilateral cryptorchidism (Kaki 1999) can be often damaged as well. There is also clear confirmation of testicular dysgenesis syndrome. Fetal exposure to endocrine disruptors (EDs) with estrogenlike or antiandrogen-like activity has been suggested as a cause for TDS (Sharpe 1993). Environmental or genetic defects can influence Leydig cell function and result in androgen

Uterine exposure to environmental endocrine disruptors can have also deleterious effects on male reproductive system development in embryos. Environmental endocrine disruptors (EEDs) are defined as exogenous substances witch can disrupt endocrine homeostasis and reproduction. EEDs include xenoestrogens, synthetic hormones, natural hormones or

Chemicals have been found to possess either weak estrogenic, anti-androgenic or other hormonal activities, which are often referred to as endocrine disrupters. Fetal or perinatal exposure to endocrine disrupters results in disturbed sexual differentiation, urogenital

The significantly increased risk of bilateral cryptorchidism in boys whose mothers smoked heavily during pregnancy may indicate that heavy maternal smoking can be included in the pathogenesis of cryptorchidism (Throup 2005). Altered hormonal levels in smokers may have a casual role in cryptorchidism. Paternal pesticide exposure may be also associated with cryptorchidism. The investigation of circulating androgens bioactivity in 3-month-old boys suggests that infant boys are exposed to biological effects of androgens during the postnatal activation of the hypothalamic-pituitary-testicular axis, and the degree of the

Testicular descent is hormonally regulated. Regulation of testicular descent is not yet completely understood. There are various forms of cryptorchidism (congenital with or without spontaneous descent, mild versus severe, acquired). These forms may reflect distinct hormonal patterns which differ in each situation (Suomi 2006). Apart from anatomical configuration and hormonal stimulation, genetic control of testis descent is very important. Major regulators of testicular descent are insulin-like factor 3 and testosterone. Testes migrate from initial intraabdominal position into the scrotal sac in two distinct hormonally regulated phases. During the first transabdominal phase (androgen independent) (10-23th week gestation) the CLS (cranial suspensory ligament) regresses while the gubernaculum shortens and develops caudal segment into the gubernaculum bulge. The second inguinoscrotal phase (depends on androgens) is normally completed by the 35th week – the gubernaculum extends caudally into the scrotum and involutes, following the

The first phase of testis descent (transabdominal) is regulated essentially by insulin-like factor 3 (INSL3), a peptide, product of the pre- and postnatal Leydig cells. INSL3 controls the passage through its receptor Lgr8 (leucine-rich-containing repeats G protein-coupled receptor). Genetic disruption of the Insl3 gene or its receptor (Lgr8) in mice has led to high intraabdominal cryptorchidism (Adham 2004). In the second phase (inguinoscrotal) androgens (testosterone) are the major mediators of testis descent (Foresta 2008). The inguinoscrotal phase is at least partly dependent on fetal testicular testosterone secretion, which in turn is initiated and maintained by human chorionic gonadotropin produced by

insufficiency which may cause testicular maldescent (Skakkebaek 2001).

malformations and decreased reproductive health in adult life (Sharpe 1993).

exposure may result in testis location superior to the scrotum (Raivio 2003)

substances affecting endocrine signaling (Vidaeff 2005).

**3. Hormonal regulation of testicular descent** 

passage of the testis through the inguinal canal.

placenta. In mutation analysis of the human homologs of INSL3, LGR8 or HOXA10 genes in patients with cryptorchidism there were rarely found mutations or polymorphisms (Bogatcheva 2005, Bertini 2004).

For a normal descent and testicular development of the testes, a normal hypothalamopituitary-gonadal axis is essential. Certain androgens:estrogens ratio is required for physiological function of the testis. Steroid hormones act through specific receptors: ARs, ERα, ERβ.

Insl-3 is under estrogenic control. Mutations in ins-3 gene showed a low incidence at 1.3% in patients with cryptorchidism. Estrogens may affect insl-3 expression and may have a role in regulation of testicular descent (Tomboc, 2000).

**Androgen receptors (ARs)** mediate the biological effects of both T and 5αdihydrotestosterone. AR mutations are not a frequent cause of isolated cryptorchidism (Ashim 2004, Ferlin 2006, Ferlin 2008). AR mutations in men with history of cryptorchidism are connected rather with infertility. The AR is highly polymorphic due to a glutamine repeat (CAG) and a glycine repeat (GGN). Polymorphic CAG and GGN segments regulate AR function. A clear associations were observed between shorter CAG repeats and disorders dependent on enhanced androgen action. Longer CAG repeats have been associated with undescended testes, idiopathic hypospadias and decreased sperm counts. In result of combined analysis of CAG and GGC repeat lengths the stronger association with cryptorchidism was found (Ferlin 2005). The CAG repeat length has been also assessed in males with cryptorchidism, but no association between CAG repeat length and undescended testes was found in Japanese population (Sasagawa 2000) or Caucasian population (Aschim 2004). It was indicated rather association between GGN length and cryptorchidism or hypospadias (Aschim 2004). Median GGN lengths were significantly higher (24 vs. 23) among subjects with cryptorchidism, compared with controls and subjects with hypospadias. GGN length 23 is the most prevalent in males from general population. A majority of individuals with cryptorchidism demonstrated GGN numbers of 24 or more (Aschim 2004).
