What causes normal descent of the testis in a fetus, and what goes wrong with this complex process to cause undescended testes (UDT), or cryptorchidism? Over the last 2 decades, most authors searching for the cause(s) of UDT have looked at the 2 main hormones involved, insulin-like hormone 3 (Insl3) and testosterone (T)/ dihydrotestosterone (DHT), and their known upstream (hypothalamic-pituitary axis) and intracellular ‘downstream' pathways. Despite these detailed searches, the genetic causes of UDT remain elusive, which suggest the aetiology is multifactorial, and/or we are looking in the wrong place.
In this review we highlight the intricate morphological steps involved in testicular descent, which we propose may contain the currently ‘idiopathic' causes of UDT. By integrating decades of research, we have underlined many areas that have been overlooked in the search for causes of UDT.
It is quite likely that the common causes of UDT are still hidden in these areas, and we suggest examining these processes is worthwhile in the hope of finding the common genetic anomalies that lead to cryptorchidism. Given the fact that a fibrous barrier preventing descent is often described at orchidopexy, examination of the extracellular matrix enzymes needed to allow gubernacular migration may be a fruitful place to start.
This review of the complex anatomical steps and hormonal regulation of testicular descent highlights many areas of morphology and signalling pathways that have been overlooked in the search for causes of UDT.
