Germ cell development in the postnatal testis: the key to prevent malignancy in cryptorchidism?

Abstract

To permit normal postnatal germ cell development, the mammalian testis undergoes a complex, multi-staged process of descent to the scrotum. Failure of any part of this process leads to congenital cryptorchidism, wherein the malpositioned testis finds itself at the wrong temperature after birth, which leads to secondary germ cell loss and later infertility and risk of cancer. Recent studies suggest that neonatal gonocytes transform into the putative spermatogenic stem cells between 3 and 9 months, and this initial postnatal step is deranged in cryptorchid testes. In addition, it is thought the abnormality high temperature may also impair apoptosis of remaining gonocytes, allowing some to persist to become the possible source of carcinoma in situ and malignancy after puberty. The biology of postnatal germ cell development is of intense interest, as it is likely to be the key to the optimal timing for orchidopexy.

Keywords: cryptorchidism; germ cell; gonocyte; orchidopexy; spermatogium; testis.

FIGURE 1

Testicular descent. (A) Cranial suspensory ligament (CSL) and gubernaculum (G) hold the testis. Testosterone (T) and MIS/AMH act on Wolffian duct (WD) and Müllerian duct (MD). (B) Insulin 3 (Insl3) causes the gubernacular swelling reaction that holds the testis near the groin during midgestational growth (8–15 weeks). (C) Calcitonin gene-related peptide (CGRP) released by the genitofemoral nerve, and under the control of testosterone, steers the migrating gubernaculum to the scrotum.

FIGURE 2

“Mini-puberty,” with testosterone (T) and MIS/AMH secreted after birth. Neonatal gonocytes mature into adult dark spermatogonia between 3 and 9 months of age, and primary spermatocytes form about 3–4 years. After a period of quiescence, spermatids form about 10 years of age, with the onset on spermatogenesis. Undescended testis (UDT) interferes with the first step.

FIGURE 3

The age at which orchidopexy has been advocated since the 1950s. Reproduced with modifications from Hutson and Beasley (1992).

FIGURE 4

Postnatal germ cell development in humans. (A) Gonocytes migrate from the center of the cords to the basement membrane around 6 months, and become type-A spermatogonia. By 3–4 years of age the center of the cords becomes recolonized with primary spermatocytes. (B) Numbers of germ cells/tubule in a normal testis and undescended testis (UDT) relative to age in years. Note the normal fall in total numbers between birth and 2 years, but failure of this to recover in UDT. The shaded area shows the normal range and the dotted lines show the average numbers.

FIGURE 5

Germ cell development in the first week postnatally in the rat, showing the germ cells labeled with MVH (mouse homolog of Drosophila Vasa), and the Sertoli cells labeled with MIS/AMH (bar = 10 μm). (A) Day 0, (B) Day 4, (C) Day 6, (D) Day 10.

FIGURE 6

Abnormal persistence of gonocytes beyond 6 months of age in a boy with cryptorchidism. The germ cells are labeled with MVH (mouse homolog of Drosophila Vasa), and the Sertoli cells are labeled with MIS/AMH (bar = 10 μm).

FIGURE 7

Testicular tissue from a 12-month-old boy with bilateral cryptorchidism. Carcinoma in situ (CIS) is suspected. (A) H&E staining: Sertoli cells are normal and the germ cell number is at the upper range for age. Some germ cells have two nuclei, and some nuclei have irregular morphology and some nucleolus. A microlith is clearly seen within a tubule. (B) Strong PLAP expression seen in all germ cells. (C) OCT4 expression in germ cells also in the periphery of tubules, which is not often seen so impressively in most cryptorchid testes at a similar age.

FIGURE 8

Testicular temperature in humans and rodents. (A) Human gonocytes mature in the first year when the testicular temperature is 33°C. Congenital UDT have abnormal temperature early, which interferes with gonocyte development. By contrast, acquired UDT only interferes with subsequent survival of stem cells. (B) In rodents, gonocytes mature before a change in temperature occurs, so that gonocyte development is unaffected, similar to acquired UDT in humans.