**6. Steroid hormones, male immune system and reproductive system**

Steroid hormones especially testosterone, progesteron and estradiol can modulate the immune system. The relationship between the immune system and reproduction is very strict. The immune response may be involved in reproductive processes what may interfere with fertility. A role of estrogens and testosterone in (auto)antibody production was proved. Estrogens increase, while testosterone decreases antibody production. Immune disorders have been formulated to take part in etiology of cryptorchidism.

The significant associations of cryptorchidism with HLA class I antigens were found. Some associations of HLA class I alleles (HLA-A11, A23, A29) with cryptorchidism were explained by their crossreactivity with receptors for LH and hCG present on fetal Leydig cells and/or interference with the hormone-binding sites through a mechanism of "molecular mimicry" (Martinetti 1992). Most likely the "molecular mimicry" between hormonal receptors and HLA surface antigens may also play a role in etiopathogenesis of cryptorchidism. The human major histocompatibility complex class II HLA molecules, by presenting antigens to helper T cells, play a decisive role in induction of antibody production (Chen 2008). Antisperm antibodies (AsA) in serum samples from prepubertal boys with testicular failure were substantially reported (Lenzi 1991, Kurpisz 1996, Sinisi 1998). We have investigated the frequency of HLA class II alleles to recognize possible genetic predisposition for antisperm antibodies development in prepubertal boys with diagnosed cryptorchidism. We have found, a strong correlation between the presence of some HLA-antigens in patients with unilateral and bilateral cryptorchidism, and a formation of antisperm antibodies. We have observed that boys suffering from bilateral cryptorchidism differed from controls in their HLA-DRB1\*11 frequency. Associations of cryptorchidism with some HLA-DRB1 and HLA-DQB1 alleles, very rare in Caucasians, were described only for a Japanese population (Tsuji 2000). No correlation with HLA class II polymorphism, however, was observed in a study of Italian population. We have observed strong difference between

Cryptorchidism and Steroid Hormones 93

defects and environmental factors (endocrine disruptions). It is believed that testicular descent is hormonally regulated and although genetic, contribution is observed, the number of genes/mutations responsible for testis descent is relatively rare. Changed environment in testis located in abdomen may induce pathological reactions mainly resulted in immune response induction. This, however, seems to be a secondary phenomenon. Despite this, once triggered immune response may persist and underlie future infertility in adulthood. Early

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cryptorchidism with history of infertility within these families and healthy controls, showing a high risk for HLA-DRB1\*11 bearers. This result may suggest that sporadic and familial cryptorchidism may have different genetic background. HLA-DRB1\*11 was also, albeit weakly, associated with bilateral cryptorchidism. Predisposition to produce anti-sperm antibodies seems to be only weakly associated with HLA class II genes.

Autoimmune reactions, particular directed to testicular elements and/or spermatozoa have been found to be often associated with cryptorchidism. Antisperm immunization has been proposed as possible additional factor associated with late surgery in prepubertal boys with cryptorchidism. Cryptorchidism in young boys can induce immune reactions against spermspecific antigens. Future fertility status thus may be endangered, because antisperm antibodies can impair fertility at different levels. The relationship between the presence of antisperm antibodies and male infertility has been documented in large number of earlier studies (Krause 2009). There are some reports on high frequency of antisperm antibodies (AsA) in infertility patients who have suffered in the past from cryptorchidism. In healthy men seminiferous epithelium is anatomically sequestered from the systemic immunity. There exist multiple elements of active tolerance. An increased ability for induction of antisperm antibodies in men has been observed in various testicular pathologies: varicocele, testicular torsion, vasectomy and genital tract infections. An induction of antisperm antibodies in adult males may take place because of a break in the anatomical "blood-testis" barrier or because of the failure of an immunosuppressive mechanism providing tolerance to sperm. Sometimes, such antibodies can arise without a known reason. Pathologic conditions within the urogenital tract may predispose to antisperm antibody formation. In prepubertal boys, testicular failures may cause an activation of destructive to testes humoral immune response, because the anatomical testicular barrier is then not completely formed and immunosupression not fully activated due to the absence of male germ cells. Diminished levels of testosterone observed in prepubertal boys may be an additional reason for inefficient immunosupresion at young age and may contribute to the rise of autoantibody development (Jones 1994). It is difficult to argue whether it is mainly anatomical sequestration or rather active immunosuppresion playing a dominant role in preserving intact spermatogenic differentiation. It was earlier reported that 20-60% of individuals with a history of maldescended testis have circulating antisperm antibodies and most of them demonstrates oligoasthenozoospermia (Urry 1994). Evaluating the immune status of prepubertal boys with testicular failures, we have previously found detectable levels of AsA predominantly in boys with pathology of both gonads (Kurpisz 1996). One possible explanation for the induction of immune response to spermatozoa (testis) may be an increase of testicular temperature in boys with cryptorchidism, which may initiate the degenerative changes in spermatogenesis and alter testicular functions. A unique exposure of membrane antigens on testicular cells can be thus noted. Changes in the Leydig cells function may provoke the disturbances in the levels of locally secreted hormones, e.g. diminished levels of testosterone. Altogether, this multifactorial machinery may create a "vicious circle" that will perpetuate intratesticular inflammation leading to the inhibition of spermatogenesis that was to be triggered at the onset of puberty.
