**5. Estrogen receptor α, ERs**

The association of cryptorchidism with a specific haplotype of the estrogen receptor 1 gene was reported (Yoshida 2005). The specific haplotype AGATA located within the 3' end of

axis is fundamental for testicular descent. Gonadotropin-releasing hormone (GnRH) regulates the production of pituitary gonadotropins FSH and LH. Gonadotropins FSH and LH are the main regulators of postnatal testicular activity. LH stimulates Leydig cells to produce testosterone while FSH regulates Sertoli cell functions (Toppari 2006). Human fetal testis binds hCG and physiological levels hCG stimulate testosterone production at least from 14 weeks of gestation (Huhtaniemi 1977). LH becomes more important regulator of fetal testosterone synthesis in the late pregnancy (Quinton 2001). The high percentage of cryptorchidism cases resolves spontaneously during the period of high serum gonadotropin

**Testosterone** is one of the main regulators of testiculat descent. It is the main androgen in the circulation, mainly protein-bound, either strongly to sex hormone binding globulin (SHGB), or loosely to albumin. Only about 2% of this hormone is unbound; this is called free testosterone and is considered to be the most biologically active form of testosterone. In the target tissue testosterone can either bind directly to the androgen receptor (AR) or, if the tissue expresses the enzyme 5a-reductase, can be converted to dihydrotestosterone (DHT). Testosterone is produced by Leydig cells and low testosterone level is a consequence of a

Impaired testosterone biosynthesis or distinct increase in testosterone metabolism is observed in cryptorchidism. Aromatase may convert androgens into estradiol. Testosterone is converted by aromatase CYP 19 to estradiol in many tissues of healthy men. The development of internal male genitalia is testosterone dependent, and 5αdihydrotestosterone (synthesized from T by the enzyme 5α-reductase 2) is essential for normal external masculinization. DHT is produced from circulating testosterone, which is

**Estrogens** Estrogens are necessary for maintaining functional integrity of the male reproductive tract. Estrogens and ERα are important for fertility. Excess of estrogens can affect function of the cells of male reproductive system. The excess of estrogens was reported to be associated with cryptorchidism, epididymal defects, impaired fertility. Estradiol however is an essential hormone for male reproduction. The maternal and placental estradiol is elevated in children with cryptorchidism. The increased expression of estradiol in the syncytiotrophoblast may have an impact on testicular descent (Hadziselmovic 2000). Low estrogen levels in mothers may mean that a placental defect increases the risk of cryptorchidism (Mc Glynn 2005). Estrogens are synthesized in the male reproductive system by at least four different cell types: Leydig cells, Sertoli cells, germ cells and epithelial cells of the epididymis. Estrogens are synthesized in a cortex of the adrenal

In horse and mouse *in vivo* cryptorchidism is associated with the increase in conversion of androgens to estrogens in the testis (Hejmej 2008), epididymal duct and the prostate. Increase in testosterone metabolism rather than an impairment of testosterone production is proposed to explain incidence of cryptorchidism. Testicular descent is significantly inhibited by estradiol. The estrogen effect might be mediated through suppression of fetal Leydig cell

The association of cryptorchidism with a specific haplotype of the estrogen receptor 1 gene was reported (Yoshida 2005). The specific haplotype AGATA located within the 3' end of

gland, too. In the immature testis, the main source of estrogens are Sertoli cells.

development, with resulting decrease of androgens and INSL3 production.

**5. Estrogen receptor α, ERs** 

and steroid hormone levels at the age of 1-3 months (Anderson 1998).

reduced ability of the Leydig cells to synthesize T.

manufactured by the fetal testis under stimulation of hCG.

human ESRI1 is associated with cryptorchidism in the Japanese population. The AGATA haplotype was frequently found to be significant in cryptorchid children. Homozygosity for the AGATA haplotype was found only among cryptorchid boys (Yoshida 2005). ERα and PR (progesterone receptor) expressed in paratesticular tissues are important for normal testicular descent. ERα was overexpressed in boys with undescended testis previously treated with human chronic gonadotropin (Przewratil 2004).

The analysis of the whole AGATA haplotype is possible by testing only the SNP12 (the tag SNP for the AGATA haplotype). Results obtained by Galan indicated that SNP 12 is the tag SNP for the AGATA haplotype also in Caucasians, but is not connected with cryptorchodism and infertility. Surprisingly ESR1 SNP12 may have a protective effect on cryptorchidism in the Italian populations, since it was found more frequently among healthy populations (Galan 2007).

**Progesterone** influences spermiogenesis, sperm capacitation/acrosome reaction and testosterone biosynthesis in the Leydig cells. The detection of progesterone receptor (PR) isoforms have a diagnostic value in prostate cancer (Oettel 2004). The position of the undescended testis did not appear to influence progesterone metabolism (Läckgren 2008). PRs density was higher in paratesticular tissues (cremaster muscle and processus vaginalis) obtained from boys with undescended testis compared to the control group (Przewratil 2005)
