Association between testicular dysgenesis syndrome (TDS) and testicular neoplasia: Evidence from 20 adult patients with signs of maldevelopment of the testis

Abstract

Based on a well established association between testicular cancer and undescended testis and more recent publications on epidemiological links between these disorders and male infertility, we proposed the existence of a testicular dysgenesis syndrome (TDS). In most cases TDS presents with impaired spermatogenesis, only in rare cases the full range of its signs, including genital malformations and testicular cancer can be seen in one patient. In order to further corroborate our hypothesis about the presence of testicular dysgenesis in patients with testicular abnormalities, we decided to re-analyse recent testicular biopsies derived from patients with infertility, hypospadias and undescended testis. We searched for histological signs of testicular dysgenesis: microliths, Sertoli-cell-only tubules, immature seminiferous tubules with undifferentiated Sertoli cells, and tubules containing carcinoma in situ (CIS) cells. We identified 20 patients who fulfilled the histological criteria for testicular dysgenesis, 9 of whom were diagnosed with uni- or bilateral testicular germ cell neoplasia, and the remaining ones with subfertility. The presence of CIS was detected in 5 patients (3 of them with overt contralateral germ cell tumours). In all but one of the CIS cases, at least one additional sign of testicular dysgenesis was detected. Clinical records of all patients were subsequently analysed. The majority of cases had oligozoospermia or azoospermia. Their reproductive hormone profiles correlated with the results of semen sampling and testicular histology. In conclusion, our study of 20 patients with various reproductive abnormalities provided evidence that TDS is a real clinical entity. We speculate that most of these abnormalities are caused by adverse environmental effects rather than specific gene mutations.

Molecular analysis of the androgen receptor gene in testicular cancer

“…They provided evidence for a TGCT predisposition locus on chromosome Xq27 (TGCT1); however, this putative gene has yet to be identified and probably other TGCT putative genes exist. Recently, other suggestions of a genetic basis for TC (Chemes et al 2003, Skakkebaek et al 2003 have been made; however, specific genetic alterations including genetic susceptibility to endocrine disruption are still unknown. Although definitive proof is still lacking, it is generally assumed that the development of TC is under endocrine control (Rajpert-De Meyts et al 1993).…”

“…Increasing adverse factors in male reproductive health as reduced sperm quality, TC, undescended testis and hypospadias might be symptoms of one underlying entity named testicular dysgenesis syndrome (TDS) (Møller & Skakkebaek 1999, Skakkebaek et al 2001, Aitken & Sawyer 2003, Bolsen et al 2004. The aetiology of TDS is supposed to be related either to environmental factors, so-called endocrine disrupters (Weir et al 2000, Huyge et al 2004, and chemical toxicants (Toppari & Skakkebaek 1998, Guo et al 2000 or to genetic factors (Rapley et al 2000, Hemminki & Li 2004, including genetic susceptibility to endocrine disruption (Skakkebaek et al 2003). TDS is supposed to arise during early foetal development when male reproductive tract formation, germ cell proliferation and Sertoli and Leydig cell differentiation occur (Yasuda et al 1985, Sharpe & Skakkebaek 1993, Skakkebaek et al 2001.…”

Origins and molecular biology of testicular germ cell tumors

“…[37][38][39][40][41][42] 43 have shown a strong correlation between the presence of the Y chromosome and the severity of the gonadal dysgenesis. Gonadoblastoma acts as an 'in situ' precursor in these patients.…”

“…Gonadoblastoma acts as an 'in situ' precursor in these patients. Recently, Skakkebaek and co-workers 37,42 suggested that many patients with testicular GCT have some evidence of gonadal dysgenesis in the contralateral gonad, be it microlithiasis, Sertoli-cell-only tubules, seminiferous tubules with undifferentiated Sertoli cells or IGCNU. If this is true, it suggests that a specific genetic mutation may not be required to initiate the process of tumor development, but rather environmental factors are sufficient as initiating events.…”

Expressing urine from a gel disposable diaper for biomonitoring using phthalates as an example

“…Subsequent research demonstrated a coordinated, dosedependent reduction in expression of key genes and proteins involved in cholesterol transport and steroidogenesis and a corresponding reduction in testosterone in the fetal testes (Lehmann et al, 2004). In humans, similar dysgenetic changes in the histology of the testis have been found in patients with testicular cancer, subfertility, or cryptorchidism (Sohval, 1954(Sohval, , 1956Berthelsen & Skakkebaek, 1983;Hoei-Hansen et al, 2003;Skakkebaek et al, 2003). Furthermore, men with rare genetic abnormalities that cause testicular dysgenesis (e.g.…”