TESTICULAR DEVELOPMENT AND SPERMATOGENESIS
Histologically, newborn testes appear as “testis cords” that harbor mainly Sertoli cells and rarer early germ cells, called gonocytes, in layers without tubular lumina. Consistent with a brief surge in androgen levels during the ﬁrst few months of life that is thought to hormonally imprint later androgen-dependent organs, large prominent interstitial Leydig cells occupy the spaces among the testis cords. In early childhood, little change occurs in the testis cords except for linear growth. At 5 to 7 years of age, lumina begin to appear in the cords and they gradually increase in diameter to become seminiferous tubules, characterized by primitive spermatogonial stem cells and marking the ﬁrst stage of spermatogenesis. Mitotic activity of early spermatogonia begins at about 11 years of age; however, the age at which the germ cells begin to differentiate varies greatly, as does the onset of puberty. Primary spermatocytes appear soon thereafter, indicating the beginning of meiosis in the testis, and spermatids are noted at about 12 years of age. Once this germ cell maturation sequence (termed spermarche) begins, the testes enlarge rapidly and constitute one of the ﬁrst signs of puberty (Tanner stage I).
The interstitial Leydig cells mature concurrently with germ cells during early puberty, but androgen production lags slightly behind spermatogenesis. The pubertal surge in testosterone from mature Leydig cells is responsible for the remainder of pubertal development (Tanner stages II to V). Spermatogenesis remains active throughout adult life but decreases during the seventh or eighth decade with the onset of andropause, as a response to decreased androgen production by Leydig cells.
Spermatogenesis is a continuous process in vertebrates (only seasonal in some moose species) and, in males, involves germ cell progression though 13 cell types over a period of 64 days. It consists of (1) a proliferative phase as spermatogonia divide to replace their number (self-renewal) or differentiate into daughter cells that become mature gametes; (2) a meiotic phase when germ cells undergo a reduction division, resulting in haploid (half the normal DNA complement) spermatids; and (3) a spermiogenesis phase in which spermatids undergo a profound metamorphosis to become mature sperm.
Spermatogenesis begins with type B spermatogonia dividing mitotically to form primary spermatocytes within the adluminal compartment. Primary spermatocytes are the ﬁrst germ cells to undergo meiosis. As they move from the adluminal or basal to luminal or apical compartment of the Sertoli cell (as deﬁned by intercellular tight junctions), they divide into secondary spermatocytes. The latter cleave immediately into spermatids, which metamorphose into mature sperm.
A cycle of spermatogenesis involves the division of spermatogonial stem cells into sperm. Several cycles of spermatogenesis coexist within the germinal epithelium at any one time and are described morphologically as stages. When viewed from a ﬁxed point within a seminiferous tubule, six recognizable stages exist in humans. Superimposed on this, there is also a speciﬁc organization of spermatogenic cycles within the seminiferous tubule space, termed spermatogenic waves. It is likely that human spermatogenesis occurs in a spiral or helical wave pattern that ensures constant and not pulsatile sperm production at 1200 sperms/heartbeat.
There are two important differences between mitosis and meiosis. During the phase of DNA synthesis in both mitosis and meiosis, reproducing cells have double the normal content of DNA (4n). In mitosis, DNA content is reduced to diploid (2n) after a single reduction division. However in meiosis, a second reduction division (secondary spermatocytes to spermatids) occurs to generate daughter cells with haploid (n) DNA content consisting of 22 autosomes and either an X or a Y chromosome. The other difference is that mitosis produces identical daughter cells, whereas genetically different daughter cells result from meiosis. This occurs as a consequence of chromosomal synapse and recombination during meiosis, in which DNA is exchanged between sister chromatids and is the basis for genetic diversity in our species.