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Introduction
Cryptorchidism is the failure of one or both testicles to descend into the scrotum during in utero development of the male fetus (Barteczko and Jacob 2000). This is one of the most common (1.8–9%) urogenital abnormalities observed in normal term male newborns (Virtanen and Toppari 2008). In brief, two stages are involved in testis migration (Barthold 2008). The first occurs between gestational weeks 8 and 15, when the testicles travel from an intra-abdominal perirenal position to the top of the inguinal ring. Late in the third trimester, they then migrate through the inguinal ring and into the scrotal sac. In certain cases, the testes do not undergo the final migration until after birth but by 3 months the majority will have descended, spontaneously reducing the number of cases that require surgery (orchidopexy) to reposition the testes within the scrotum (Kollin and Ritzén 2014). Orchidopexy is recommended between ages of 6 and 12 months to decrease the risk of testicular torsion or trauma, improve fertility and decrease the risk of testicular neoplasm in adulthood.
Animal and clinical studies have demonstrated that normal migration of the testes is dependent on both genetic factors and the in utero hormonal environment (Barthold 2008; Barthold et al. 2015; Huang et al. 2012; Jensen et al. 2010; Virtanen and Toppari 2008). The trans-abdominal phase is linked to expression of two genes: one for the insulin-like peptide-3 (INSL-3) hormone produced by Leydig cells and a second for the INSL-3 receptor, relaxin-family peptide receptor 2 (RXFP2). The second inguinal–scrotal phase is thought to be primarily dependent on androgens produced by the fetal Leydig cells and normal expression of the androgen receptor. Clinical reports have linked cryptorchidism with mutations in the INSL-3, RXFP2, or Androgen Receptor (AR) genes but only in a small number of cases (Bay et al. 2011; Feng et al. 2009; Ferlin et al. 2009). Thus, the etiology of most cases remains unknown. In a study that evaluated the risk contribution from genetic versus intrauterine environmental factors, Jensen et al. (Jensen et al. 2010) found a similar concordance rate in monozygotic and dizygotic twins, providing strong support for an important role of the intrauterine environment.
There is increasing evidence that maternal exposure to certain environmental chemicals may have endocrine disrupting...