**8. References**

92 Steroids – Basic Science

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

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

antibodies seems to be only weakly associated with HLA class II genes.

spermatogenesis that was to be triggered at the onset of puberty.

Cryptorchidism is one of the most common urogenital disorders found in postnatal boys. Main predisposing factor are: preterm birth, dysfunctional endocrine regulations, gene

**7. Final remarks** 


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1737.


**5** 

*Japan* 

**Dehydroepiandrosterone in** 

Yoshio Sumida1 et al.\*

 **Nonalcoholic Fatty Liver Disease** 

*1Center for Digestive and Liver Diseases, Nara City Hospital,* 

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease (CLD) in many developed countries and results in a serious public health problem worldwide. NAFLD includes a wide spectrum of liver diseases, ranging from simple fatty liver, which is usually a benign and nonprogressive condition, to nonalcoholic steatohepatitis (NASH) which may progress to liver cirrhosis (LC), hepatic failure and hepatocellular carcinoma (HCC) in the absence of significant alcohol consumption (Ludwig et al., 1980, Matteoni et al. 1999). About a third of people with NAFLD will develop NASH, and about 20% of people with NASH will go on to liver fibrosis and cirrhosis, with its accompanying risk of liver failure and even HCC (Yasui et al. 2011). In Japan, current best estimates make the prevalence of NAFLD approximately 20% and of NASH 2% to 3% in the general population. Pathophysiology of primary NASH still hasn't been completely clarified. According to the "two-hits" model of NASH pathogenesis proposed by Day and James (Day & James. 1999), excessive triglyceride accumulation is the most likely first step. The second step may relate to an increase in oxidative stress (Sumida et al. 2011a), which, in turn, triggers liver cell necrosis and activation of hepatic stellate cells, both leading to fibrosis and ultimately to the development of LC. Although the number of NASH cases in women is known to be higher than in men over 50 years of age, the mechanisms remain unknown (Hashimoto & Tokushige, 2011). According to our study produced by Japan Study Group of NAFLD (JSG-NAFLD) including nine hepatology centers in Japan (Sumida et al., 2011b), NASH patients with significant or advanced fibrosis (Brunt stage 2-4) was more prevalent in females than in males (Fig.1). Although plausible mechanisms have been proposed, including estrogen deficiency after menopause, iron accumulation generating hydroxylradicals via Fenton reaction (Sumida et al., 2009), and so on, precise mechanisms have not been clarified. Although several factors have been associated with more advanced NAFLD, the biological basis of the histological diversity of severity of NAFLD [i.e., why some patients develop simple fatty liver and others develop NASH with advanced fibrosis] remains unknown. More advanced NAFLD is characterized by

insulin resistance, oxidative stress, and advanced fibrosis.

Kohichiroh Yasui2, Yoshito Itoh2, Yuji Naito2, Toshikazu Yoshikawa2 *1Center for Digestive and Liver Diseases, Nara City Hospital, Japan* 

Kyoko Sakai1, Tomoyuki Ohno1, Kazuyuki Kanemasa1, Yutaka Inada2, Naohisa Yoshida2,

*2Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan* 

**1. Introduction** 

 \*

