**1. Introduction**

Two important functions of testis are production of spermatozoa and synthesis of steroids. These functions depend on anatomical, hormonal and constitutional homeostasis and begin during the first stage of gestation. Cryptorchidism can be defined as an abnormal localization of one or both testes. It's the failure of one or both testes descent into the scrotal sac. The third trimester in humans is crucial for the testis descent. When the testis is not found in normal location it may be palpable or nonpalpable. The palpable testis may be cryptorchid, ectopic or retractile. Non-palpable testis may be cryptorchid, atrophic or absent. Cryptorchidism occurs when the testis fails to descend into its normal postnatal location and may be found in the abdomen, in the inguinal canal or just reaching the external ring (prescrotal) (Nguyen 1999). Before sex determination, both female and male embryonic gonads are located in the same high intra-abdominal position. During mammalian development, the cranial suspensory ligament (CLS) and the caudal ligament (or gubernaculum) is responsible for a sexual dimorphic position of the testis and ovary. In males, regression of the CLS, along with the outgrowth of the gubernaculum and its migration to the scrotum, results in the extraabdominal position of the testis (Agoulnik 2005). Androgens induce regression of the cranio-suspensory ligament to release the testis to descent. The inguinoscrotal descent of the normal testicle takes place between 26 and 35 weeks of gestation. In preterm males with cryptorchidism the testes may descent postnatally (Berkowitz 1993, Cortez 2008). Cryptorchidism is one of the most common urogenital disorders in boys. Cryptorchidism can occur as an isolated disorder or may be associated with other congenital anomalies. The intraabdominal temperature is dangerous for germ cells and cryptorchidism may be a risk factor for male infertility and for testicular malignancy in adulthood. The decrement in intratesticular temperature in adult males is 2- 4ºC lower compared with body temperature (Thonneau 1998). This temperature difference is necessary to maintain spermatogenesis. The lower temperature in the scrotum is essential for normal spermatogenesis. Dangerous effects of increased temperature on spermatogenesis are well documented. For undescended testis abnormal spermatogenesis may be related with degenerative changes connected with high temperature (Mieussed 1993). This condition affects both morphology and function of the Sertoli and Leydig cells of the testis (Farrer 1985) The association of cryptorchidism with testicular cancer is also well

Cryptorchidism and Steroid Hormones 87

with birth weight less than 2.5 kg (Scorer 1964). Androgens play a crucial role in the development of male external genital organs and testicular descent. Hormonal dysregulation can be one out of many etiological factors of cryptorchidism (Suomi 2006). Testicular descent is at least partly dependent on fetal testicular testosterone, which in turn is initiated and maintained by human chorionic gonadotropin produced by the placenta (Biggs 2002). An increased risk of cryptorchidism in cases with placental abnormalities is noted (Biggs 2002). The increasing incidence of reproductive abnormalities in human males may be associated with increased estrogen exposure during gestation. The increased expression of estradiol in the syncytiotrophoblast may have impact on testicular descent (Hadziselmovic 2000). Industrial and agricultural chemicals acting as endocrine disrupters might have a deleterious effect on normal male sexual differentiation. These chemicals may occur in our close environments of work and life, drinking water, a food. Humans can also be exposed to natural phytoestrogens through consumption of food products derived from the plants (Toppari 1996, Sultan 2001). Various groups of chemicals, including pesticides and phthalate esters, have been identified as being weakly estrogenic or antiandrogenic (Sharpe 2003). Ferlin has proposed a distinction between intrinsic and extrinsic causes of cryptorchidism. In the first group frequenly displayed bilateral cryptorchidism is associated with progressive testicular damage and icreased risk of infertility or testicular damage. In these cases early orchidopexy may reduce the risk of these consequences but does not eliminate it definitely. Genetic alterations are more frequent in this group (Klinefelter syndrome, RXFP2 gene mutations) (Ferlin 2008). In the group with extrinsic causes of cryptorchidism (low birth weight, prematurity, maternal diabetes or preeclampsia during pregnancy) a spontaneous descent in the first months of age is noted. The early orchidpexy can reduce almost completely risk of testicular damage (Trisnar 2009). The possible genetic background of cryptorchidism still remains unresolved and genetics causes are rarely found

The following genetic abnormalities may be associated with cryptorchidism:

The mutation R102C was detected in a boy with unilateral persistent cryptorchidism (Ferlin 2008). The other mutation (T86M) was detected in a boy with bilateral cryptorchidism and

Seasonal variation in the incidence of cryptorchidism suggest that environmental factors may have the importance in its etiology. Cryptorchidism can be often the consequence of testicular dysgenesis, a developmental disorder of the gonads due to disruption of embryonal programming and gonadal development during fetal life. Testicular dysgenesis syndrome (TSD) can result in maldescent, reduced fertility and an increased risk for malignant development, increased frequency of incomplete descent of a testis into the scrotum and hypospodias (Skakkebaek 2001). TSD can arise due to environmental factors including endocrine disrupters (potential endocrine disruptors in diet, in place of occupation; lifestyle, dietary phytoestrogens, present in food, water, air) or genetic defects.


spontaneous descent in the first months of age (Ferlin 2008).





Familial occurrence – cryptorchidism is heritable susceptibility.

(Ferlin 2008).

INSL3/LGR8,

documented (Giwercman 1989). The prevalence of cryptorchidism among boys is 2-4% in full - term male birth and 2-8.4% among boys with premature births. The incidence of cryptorchidism is significantly increased in premature males (Berkowitz 1993). Presently we observe an increased trend in the incidence of congenital cryptorchidism. Sometimes statistics includes testis in a high scrotal position (as normal descent) or cryptorchid testis may spontaneously descent in the first months after birth, therefore the incidence of cryptorchidism decreases from 1% to 0.5% by age of 1 year due to spontaneous descent (Barthold 2003). In earlier studies it has been speculated that the late spontaneous testicular descent occurs in more than half (Boisen 2004) or 70% of newborns with cryptorchidism. On the contrary the data obtained by Wenzler et al. (Wenzler 2004) showed that in patients with cryptorchidism spontaneous testicular descent occurs infrequently during the first year of life. They found that in patients with cryptorchidism before 12 months only 6.9% of the cryptorchid testicles reached the acceptable scrotal location at age of 1 year or later (Wenzler 2004). There are large regional differences in incidence of cryptorchidism. The study on the prevalence of congenital cryptorchidism in Demmark and Finland was also performed and much higher incidence of congenital cryptorchidism in Denmark was found. In Denmark an increase in reproductive health problems is explained by environmental factors, including endocrine disrupters and a lifestyle (Boisen 2004). In the meantime the incidence of cryptorchidism has increased in many countries. In two comparable British studies the incidence of cryptorchidism delivered at term boys approximately doubled between the 1950s and the 1980s. (Toppari 2001). However the report by Cortes (2008) has shown that the incidence of cryptorchidism in Denmark has not changed and is similar to the previous reports obtained in the 1950s. They have pointed out the general difficulties to compare the frequency of cryptorchidism as reported in different publications, since the definition of cryptorchidism is not yet uniform (Cortes 2008). The International Clearinghouse for Birth Defects Monitoring System has collected data on cryptorchidism, but they are unreliable, because of a discrepancy with the data from cohort studies (Toppari 2001). The present incidence may be even higher than reported one because of under-reporting tendency (Kaleva 2005).

Cryptorchidism is a risk factor for male infertility in adulthood and for the male health (testicular cancer). Cryptorchidism uni- or bilateral is associated with degenerative changes in Sertoli cells and germ cells and is the most common etiologic factor of azoospermia (Hadziselmovic 2001). 89% of untreated cryptorchid patients with bilateral maldescent develop azoospermia and 32% treated medically or 46% boys treated surgically develop azoospermia (Hadziselimovic 2001). Hormonal treatment with human chorionic gonadotropin (HCG) or gonadotropin releasing hormone may be given initially for cryptorchidism. Very often a surgical intervention is needed to protect function of seminiferous tubules and to prevent degenerative changes in Sertoli and germ cells saving the man's future fertility potential.
