Spermatogenesis is a complex process by which primitive, totipotent stem cells divide to either renew themselves or produce daughter cells that become spermatozoa. These processes occur within the seminiferous tubules of the testis. In fact, 90% of testis volume is determined by the seminiferous tubules and germ cells at various developmental stages.

Spermatogenesis
The spermatogonia, the primitive germ cells next to the basal lamina of the seminiferous tubules, mature into primary spermatocytes. This process begins during adolescence. The primary spermatocytes undergo meiotic division, reducing the number of chromosomes. In this two-stage process, they divide into secondary spermatocytes and then into spermatids, which contain the haploid number of 23 chromosomes. The spermatids mature into spermatozoa (sperms).

As a single spermatogonium divides and matures, its descendants remain tied together by cytoplasmic bridges until the late spermatid stage. This apparently ensures synchrony of the differentiation of each clone of germ cells. The estimated number of spermatids formed from a single spermatogonium is 512. In humans, it takes an average of 74 days to form a mature sperm from a primitive germ cell by this orderly process of spermatogenesis.

Each sperm is an intricate motile cell, rich in DNA, with a head that is made up mostly of chromosomal material. Covering the head like a cap is the acrosome, a lysosome-like organelle rich in enzymes involved in sperm penetration of the ovum and other events involved in fertilization. The motile tail of the sperm is wrapped in its proximal portion by a sheath holding numerous mitochondria. The membranes of late spermatids and spermatozoa contain a special small form of angiotensin-converting enzyme called germinal angiotensin-converting enzyme. The function of this enzyme in the sperms is unknown, although male mice in which the function of the angiotensin-converting enzyme gene has been disrupted have reduced fertility.

The spermatids mature into spermatozoa in deep folds of the cytoplasm of the Sertoli cells. Mature spermatozoa are released from the Sertoli cells and become free in the lumens of the tubules. The Sertoli cells secrete androgen-binding protein (ABP), inhibin, and MIS. They do not synthesize androgens, but they contain aromatase (CYP19), the enzyme responsible for conversion of androgens to estrogens, and they can produce estrogens. ABP probably functions to maintain a high, stable supply of androgen in the tubular fluid. Inhibin inhibits FSH secretion (see below). MIS causes regression of the mullerian ducts in males during fetal life.

Further Development of Spermatozoa

Spermatozoa leaving the testes are not fully mobile. They continue their maturation and acquire motility during their passage through the epididymis. Motility is obviously important in vivo, but fertilization occurs in vitro if an immotile spermatozoon from the head of the epididymis is microinjected directly into an ovum. The ability to move forward (progressive motility), which is acquired in the epididymis, involves activation of a unique protein called CatSper, which is localized to the principal piece of the sperm tail. This protein appears to be a Ca²⁺ ion channel that permits cAMP-generalized Ca²⁺ influx. In addition, spermatozoa express olfactory receptors, and ovaries produce odorant-like molecules. Recent evidence indicates that these molecules and their receptors interact, fostering movement of the spermatozoa toward the ovary (chemotaxis; see below).

Ejaculation of the spermatozoon (see below) involves contractions of the vas deferens mediated in part by P2X receptors for ATP, and fertility is reduced in mice in which these receptors are knocked out.

Sertoli Cells

The seminiferous tubules are lined with Sertoli cells that rest on the tubular basement membrane and extend into its lumen with a complex cytoplasm. Sertoli cells are linked by tight junctions, the strongest intercellular barriers in the body. These junctional complexes divide the seminiferous tubule space into basal (basement membrane) and adluminal (lumen) compartments. This anatomic arrangement forms the basis for the blood-testis barrier, allowing spermatogenesis to occur in an immunologically privileged site. The importance of this sanctuary effect becomes clear when we remember that spermatozoa are produced at puberty and are considered foreign to an immune system that develops self-recognition during the first year of life.

Sertoli cells serve as “nurse” cells for spermatogenesis, nourishing germ cells as they develop. These specialized support cells also participate in germ cell phagocytosis. High-affinity FSH receptors exist on Sertoli cells and FSH binding induces the production of androgen-binding protein, which is then secreted into the tubular luminal fluid. By binding testosterone, androgen-binding protein ensures that high levels of androgen (20-50 × that of serum) exist within the seminiferous tubules. Evidence also suggests that inhibin is Sertoli cell-derived. Ligand-receptor complexes, such as c-kit and kit ligand, may also mediate communication between germinal and Sertoli cells.

Germ Cells

Within the tubule, germ cells are arranged in a highly ordered sequence from the basement membrane to the lumen. Spermatogonia lie directly on the basement membrane, followed by primary spermatocytes, secondary spermatocytes, and spermatids toward the tubule lumen. In all, 13 different germ cell stages have been identified in humans. The tight junction barrier supports spermatogonia and early spermatocytes within the basal compartment and all subsequent germ cells within the adluminal compartment. Germ cells are staged by their morphologic appearance; there are dark type A (Ad) and pale type A (Ap) and type B spermatogonia and preleptotene, leptotene, zygotene, and pachytene primary spermatocytes, secondary spermatocytes, and Sa, Sb, Sc, Sd₁, and Sd₂ spermatids.

Cycles & Waves

A cycle of spermatogenesis involves the division of primitive spermatogonial stem cells into subsequent germ cells. Several cycles of spermatogenesis coexist within the germinal epithelium at any one time. The duration of an entire spermatogenic cycle within the human testis is 74 days. During spermatogenesis, cohorts of germ cells at the same point in development are linked by cytoplasmic bridges and pass through the process together. There is also a specific organization of the steps of the spermatogenic cycle within the tubular space, termed spermatogenic waves. In humans, this is likely a spiral cellular arrangement, which probably exists to ensure that sperm production is a continuous and not a pulsatile process.