Spermatogenesis and Cryptorchidism

Cryptorchidism is a very common anomaly of the male genitalia, affecting 2%-4% of male infants and is more common in premature infants. There are two separate stages of testicular descent. The first stage occurs at 8-15 weeks' gestation in the human fetus and is characterized by enlargement of the genito-inguinal ligament, or gubernaculum, and regression of the cranial suspensory ligament. The testis remains close to the future inguinal region as the fetal abdomen grows. Leydig cells in the testis produce insulin-like hormone 3, which stimulates the caudal gubernaculum to grow and become thicker. Mullerian inhibiting substance may have a role in the first phase of descent by stimulating the swelling reaction in the gubernaculum. The second phase of testicular descent requires migration of the gubernaculum and testis from the inguinal region to the scrotum, between 25 and 35 weeks' gestation. The genitofemoral nerve releases calcitonin gene-related peptide, a neurotransmitter that provides a chemotactic gradient to guide migration. The exact cause of cyrptorchidism remains elusive. Information is mainly derived from animal studies (especially in rodents), which may not extrapolate to the human setting. These findings, however, do have some similarities among mammalian species. The current recommended timing for orchidopexy is between 6 and 12 months of life in an effort to preserve the spermatogonia--the stem cells for subsequent spermatogenesis. Despite surgical treatment by orchidopexy, the long-term outcome still remains problematic and controversial. Impaired fertility (33% in unilateral cases and 66% in bilateral undescended testes) and a cancer risk 5-10 times greater than normal is observed over time. Further research into the cause and management of undescended testes is necessary. Copyright 2010 Elsevier Inc. All rights reserved.

The failure of testicular descent or cryptorchidism is the most common defect in newborn boys. The descent of the testes during development is controlled by insulin-like 3 peptide and steroid hormones produced in testicular Leydig cells, as well as by various genetic and developmental factors. While in some cases the association with genetic abnormalities and environmental causes has been shown, the etiology of cryptorchidism remains uncertain. Cryptorchidism is an established risk factor for infertility and testicular germ cell tumors (TGCT). Experimental animal models suggest a causative role for an abnormal testicular position on the disruption of spermatogenesis however the link between cryptorchidism and TGCT is less clear. The most common type of TGCT in cryptorchid testes is seminoma, believed to be derived from pluripotent prenatal germ cells. Recent studies have shown that seminoma cells and their precursor carcinoma in situ cells express a number of spermatogonial stem cell (SSC) markers suggesting that TGCTs might originate from adult stem cells. We review here the data on changes in the SSC somatic cell niche observed in cryptorchid testes of mouse models and in human patients. We propose that the misregulation of growth factors’ expression may alter the balance between SSC self-renewal and differentiation and shift stem cells toward neoplastic transformation.

Current indications for orchiopexy are to decrease the risk of infertility and to facilitate testicular self-examination. Although the increased risk of germ cell cancer in cryptorchid testes is undisputed, it is unclear whether orchiopexy affects the natural history of testis cancer development. We hypothesize that early orchiopexy is protective against subsequent development of testicular germ cell cancer. We conducted a systematic review and meta-analysis of the literature. Studies pertaining to cryptorchidism and testicular cancer risk were retrieved by searching MEDLINE, BIOSIS and the Cochrane Library, using cryptorchidism as a keyword, combined with treatment, orchiopexy, testis and cancer. For data extraction exposure was dichotomized to orchiopexy before or after age 10 to 11 years, while outcome was defined as the development of testicular germ cell cancer. Summary risk measures were calculated using the random effects model. Four studies met our criteria. Review of all studies revealed an increased risk of testicular cancer if orchiopexy was delayed until after age 10 to 11 years or was never performed. Odds ratios ranged from 2.9 to 32.0. Meta-analysis showed that testicular cancer was nearly 6 times more likely (OR 5.8 [1.8, 19.3]) to develop in men in whom orchiopexy was delayed or was not performed, compared to those in whom it was performed early. Prepubertal orchiopexy may decrease the risk of testicular cancer. Thus, early surgical intervention is indicated in children with cryptorchidism. These findings suggest that the testicular environment, as well as underlying genetics, may have a role in testicular carcinogenesis.