Spermatogenesis and Male Reproductive Physiology — Sertoli, Leydig, Hormones and Timeline

Spermatogenesis is the process by which diploid germ cells give rise to haploid, motile spermatozoa. It takes place inside the seminiferous tubules of the testis and begins at puberty. The testis therefore does two jobs at once: it makes sperm (tubular compartment) and it makes testosterone (interstitial compartment, from Leydig cells).

StatPearls describes three integrated steps: mitotic division of spermatogonia so the stem-cell pool is renewed and expanded, meiosis to halve the chromosome number, and spermiogenesis, the transformation of round spermatids into mature, motile sperm. After release from the tubule, sperm pass through the rete testis to the epididymis, where they mature and are stored until ejaculation.

For every diploid primary spermatocyte, the two meiotic divisions yield four haploid spermatids. This is the key difference from oogenesis, where one egg and polar bodies result. Note the vocabulary: spermatocytogenesis is the stage up to the formation of spermatids (mitosis plus meiosis), and spermiogenesis is the morphological change from spermatid to spermatozoon with no further cell division.

Sertoli cells are the large, columnar 'nurse' or sustentacular cells of the seminiferous epithelium. They rest on the basement membrane and reach the lumen, with pale nuclei and prominent nucleoli that distinguish them from the darker germ-cell nuclei. They respond to FSH (and to testosterone) and are the only somatic cells inside the tubule.

• Blood-testis barrier: tight junctions between adjacent Sertoli cells separate developing germ cells from the circulation, give an ion-regulated, immune-privileged environment and allow a high local testosterone concentration. Cells beyond the junction (spermatocytes, spermatids) are protected from the immune system.
• Nutrition and support: supply germ cells with nutrients, regulate ions and amino acids, and secrete fluid that helps move sperm along the tubule.
• Androgen-binding protein (ABP): secreted under the influence of FSH and testosterone; keeps intratubular testosterone high and maintains the efferent ductal epithelium.
• Inhibin B: negative feedback on FSH at the anterior pituitary. Activin is another Sertoli product.
• Müllerian-inhibiting substance (MIS / AMH): made by fetal Sertoli cells; causes regression of the Müllerian ducts, preventing female internal genitalia.
• Phagocytosis: engulf apoptotic germ cells and the residual cytoplasm shed by spermatids during spermiogenesis.
• Development: differentiation depends on SRY, SOX9 and steroidogenic factor 1 (NR5A1).

Leydig cells (interstitial cells) lie in the connective tissue between the tubules, in clusters around capillaries. They have an eosinophilic cytoplasm, abundant lipid and well-developed smooth endoplasmic reticulum — the structure of a steroid-producing cell — and may contain Reinke crystals. They are the main source of testosterone, which is under the control of LH.

1. LH binds its G protein-coupled receptor on the Leydig cell and raises cyclic AMP.
2. Cholesterol is converted to pregnenolone by cholesterol desmolase (side-chain cleavage) — the rate-limiting step.
3. Weak androgens dehydroepiandrosterone and androstenedione follow.
4. 17β-hydroxysteroid dehydrogenase converts androstenedione to testosterone.
5. In target tissues testosterone is converted by 5α-reductase to dihydrotestosterone (DHT), which has a higher receptor-binding affinity; peripheral aromatase converts testosterone to estradiol.

Testosterone production does not simply track Leydig cell number: immunohistochemistry shows that only a few Leydig cells produce testosterone even when cell number is increased, as in hyperplasia or tumours.

The hypothalamus releases GnRH in pulses, at puberty roughly every 1 to 2 hours. GnRH acts on pituitary gonadotrophs to release LH and FSH. Both are glycoproteins that share an identical α subunit and differ in the β subunit. They act through G protein-coupled receptors, stimulating adenylyl cyclase and cyclic AMP in Leydig and Sertoli cells respectively.

Before puberty gonadotropin and androgen levels remain low and stable. After puberty, FSH, LH and testosterone are sustained by the pulsatile GnRH drive, and testosterone levels begin a gradual decline from about the third decade of life.

In adult men one complete wave of spermatogenesis lasts about 74 days, and a new wave is initiated roughly every two weeks (reported figures range from about 13 to 16 days), so sperm output is continuous even though individual tubules are not synchronised. Meiosis alone — from preleptotene spermatocytes to round spermatids — takes about 24 days in humans. After leaving the testis, sperm spend about 12 days maturing and gaining motility in the epididymis.

Normal spermatogenesis needs the testis to be about 2 to 4 °C below core body temperature. The scrotum, the pampiniform plexus (counter-current heat exchange around the testicular artery), the dartos muscle and the cremaster muscle all contribute to this thermoregulation. Failure of descent — cryptorchidism — is the classic example of heat damage to the germinal epithelium, and raised testicular temperature reduces the number of mature spermatids or produces malformed ones.

Spermatogenesis is also wasteful: StatPearls estimates that about 75% of developing germ cells are lost to apoptosis, and even among ejaculated cells a large fraction are malformed, so the usable output is a small fraction of the cells that start.

During spermiogenesis a round spermatid is remodelled without dividing: the nucleus condenses, an acrosome forms over the head, a single flagellum develops for motility, and most of the cytoplasm is shed. Sertoli cells degrade the discarded residual cytoplasm. The release of the elongated spermatid into the lumen is called spermiation.

• Head: condensed haploid nucleus plus acrosome (enzyme-containing cap needed to establish contact with the oocyte).
• Tail: the single flagellum — the source of motility.

Freshly released spermatozoa are immotile; they travel along the tubules by peristalsis of the peritubular myofibroblasts to the rete testis and then the efferent ductules and epididymis. Sperm gain motility during their roughly 12 days in the epididymis, where they are then stored until ejaculation.

When the Sertoli cells are present but germ cells are lost, tubules look empty — 'shadows' of tubules — and sperm are absent while testosterone production is often maintained. This histology (Sertoli cells only) is what separates it from germ-cell arrest, where spermatogenesis halts at the primary spermatocyte stage.

• Spermatogenesis vs spermiogenesis: spermiogenesis is only the final remodelling of a spermatid; it involves no cell division.
• Which cell makes testosterone: Leydig, not Sertoli. Which cell makes inhibin: Sertoli, not Leydig.
• Chromosome number: halves at meiosis I; the secondary spermatocyte is the first haploid cell.
• Duration: ~74 days for spermatogenesis; ~12 days epididymal transit; the commonly asked number is 74.
• Temperature: testes are about 2 to 4 degrees Celsius below body temperature; cryptorchidism and any rise in testicular temperature impair spermatogenesis.
• Blood-testis barrier: formed by Sertoli-Sertoli tight junctions, not by Leydig cells or myoid cells; it protects meiotic and post-meiotic cells from immune attack.

More physiology and anatomy questions of this type are collected in NEET PG Physiology PYQs and NEET PG Anatomy PYQs; recurring patterns across subjects are listed on most repeated topics.