**1. Introduction**

96 Steroids – Basic Science

Trisnar B, Res Muravec. (2009). Fertility potential after unilateral and bilateral orchidopexy

Sasagawa I, Suzuki Y, Tateno T, Nakada T, Murowa K, Ogata T. (2000). CAG repeat length

Sultan C, Paris F, Terouanne B, Balaguer P, Georget V, Poujol N, Jeandel C, Lumbroso S,

Suomi AM, Main Km, Kaleva M, Schmidt IM, Chellakooty M, Virtanen HE. (2006).

Tsuji Y, Misuto M, Yasunami R, Sakata K, Shibahara H, Koyama K. (2000). HLA-DR and

Urry RL, Carrell DT, Starr NT, Snow BW, Middleton RG. (1994). The incidence of antisperm

Wenzler DL, Bloom DA, Park JM. (2004). What is the rate of spontaneous testicular descent

Vidaeff A, Sever LE. (2005). In utero exposure to environmental estrogens and male

Yoshida R, Fukami M, Sasagawa I, Hasegawa T, Kamatani N, Ogata T. (2005). Association of

in infants with cryptorchidism? *Journal of Urology*, 171, 849-851.

*Journal of Clinical Endocrinology & Metabolism*, 90, 4716-4721

Scorer CG. (1964). The descent of the testis. *Archives of Disease in Childhood*, 39, 605-609. Sharpe RM, Skakkebaek NE. (1993). Are oestrogens involved in falling sperm counts and

disorders of the male reproductive tract? *Lancet,* 341, 1392-1396.

of the androgen receptor gene in Japanese males with cryptorchidism. *Molecular* 

Nikolas J. (2001). Disorders linked to insufficient androgen action in male children.

Hormonal changes in 3-month-old cryptorchid boys. *Journal of Clinical* 

HLA-DQ gene typing of infertile women possessing sperm-immobilising antibody.

antibodies in infertility patients with a history of cryptorchidism. *Journal of Urology*,

reproductive health: a systematic review of biological and epidemiologic evidence.

cryptorchidism with a specific haplotype of the estrogen receptor α gene: implication for the susceptibility to estrogenic environmental endocrine disruptors.

for cryptorchidism. *World Journal of Urology*, 27, 513-519.

*Human Reproduction*, 6, 973-975.

*Human Reproduction Update*, 7: 314-322.

*Endocrinology & Metabolism*, 91, 953-958.

*Reproductive Toxicology*, 20, 5-20.

151, 381-383.

*Journal of Reproductive Immunology*, 46, 31-38.

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.

<sup>\*</sup> Kyoko Sakai1, Tomoyuki Ohno1, Kazuyuki Kanemasa1, Yutaka Inada2, Naohisa Yoshida2, Kohichiroh Yasui2, Yoshito Itoh2, Yuji Naito2, Toshikazu Yoshikawa2

*<sup>1</sup>Center for Digestive and Liver Diseases, Nara City Hospital, Japan* 

*<sup>2</sup>Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan* 

Dehydroepiandrosterone in Nonalcoholic Fatty Liver Disease 99

hormones, including androstenedione, testosterone, and estrogen. DHEA and DHEA-S levels peak at approximately age 25 years and decrease progressively thereafter, falling to 5% of peak levels by the ninth decade. DHEA is a potential mediator of ROS synthesis (Bednarek-Tupikowska et al., 2000) and has also been reported to augment insulin sensitivity (Lasco et al., 2001, Jakubowicz et al., 1995, Kawano, 2000, Dhatariya et al., 2005) and peroxisome proliferator activation. (Poynter & Daynes, 1998, Peters et al., 1996), a transcription factor that regulates lipid metabolism, and procollagen type I, collagen precursor that has been associated with hepatic fibrosis of NASH. Both cross-sectional and longitudinal data have clearly indicated that serum concentrations of DHES-S decrease with

age. Advocates of DHEA recommend it to prevent the effects of aging.

Fig. 2. DHEA and DHEA-S

Fig. 3. Synthesis pathway of DHEA and DHEA-S

Endocrine hormones control cell metabolism and the distribution of body fat and, therefore, may contribute to the development of NAFLD/ NASH. Dehydroepiandrosterone (DHEA), and its interchangeable sulfated form, DHEA sulfate (DHEA-S), is the most abundant circulating steroid hormone and is produced primarily by the zona reticularis of the adrenal cortex in response to adrenocorticotropic hormone. DHEA has been known to have a variety of functions, including anti-oxidative stress, decreasing insulin resistance, antiatherosclerosis, and anti-osteoporosis (Baulieu et al. 2000). DHEA-S concentration is independently and inversely related to death from any cause and death from cardiovascular disease in men over age 50. It has been postulated that DHEA and DHEA-S may be discriminators of life expectancy and aging (Phillips et al. 2010). In this chapter, we describe here the role of DHEA or DHEA-S in the pathogenesis or treatment of NAFLD.
