This tab covers the male reproductive axis and the biology that underlies fertility: the hypothalamic–pituitary–testis axis, testosterone metabolism, spermatogenesis, the role of the epididymis, vas, and seminal vesicles, sperm structure, and the effects of aging.
Hypothalamic–Pituitary–Testis Axis
- GnRH (from the hypothalamus) stimulates LH and FSH release from the anterior pituitary. Its secretion is seasonal (peaks in spring), circadian (testosterone highest in the morning), and pulsatile (every 90–120 min); pulsatility begins at puberty (~age 12).
- The anterior pituitary produces LH, FSH, GH, TSH, ACTH, and prolactin — only LH and FSH act on the gonads.
- LH stimulates Leydig-cell steroidogenesis and is the most important regulator of testosterone production (so LH-deficient infertility is treated with hCG, an LH analogue). It is suppressed by negative feedback from estrogens (primary) and androgens — estradiol acting mainly at the pituitary, testosterone mainly at the hypothalamus — so exogenous testosterone lowers both LH and FSH.
- FSH stimulates Sertoli cells and seminiferous-tubule growth. It is essential to initiate spermatogenesis at puberty but not for spermatogenesis in acquired (post-pubertal) infertility — so hCG monotherapy can suffice without recombinant FSH. FSH is stimulated by estrogen and activin (a Leydig-cell product) and inhibited by inhibin-B (a Sertoli-cell product, stimulated by FSH, acting by negative feedback at the pituitary).
- Prolactin at normal levels supports Leydig-cell LH receptors and intratesticular testosterone, but hyperprolactinemia abolishes GnRH pulsatility and causes infertility.
- In the testis, Leydig cells make testosterone (drives the internal genitalia — seminal vesicles, epididymis, vas, ejaculatory ducts), DHT (drives the external genitalia and prostate), insulin-like growth factor-3 (transabdominal testicular descent), and activin; Sertoli cells make inhibin, Müllerian-inhibiting substance (regresses the Müllerian ducts), and androgen-binding protein (maintains high intratubular androgen). The SRY gene is critical for sex determination.
Testosterone and Androgens
Testosterone peaks at three life stages: ~13 weeks' gestation, ~2 months of age, and puberty. It is the most important circulating androgen — 90% from the testes, 10% from the adrenals, with normal production of ~5 mg/day.
- Circulation — testosterone is 98% bound (albumin ~50%, loosely; SHBG ~44%, tightly; corticosteroid-binding globulin ~4%, loosely) and 2% free. The free plus loosely-bound fractions are bioavailable testosterone — the only fraction that enters cells. Equilibrium dialysis is the most accurate assay. Total testosterone <300 ng/dL and calculated free testosterone <6.5 ng/dL are considered low; intratesticular testosterone is 50–100× serum levels and is required for spermatogenesis.
| ↓ SHBG (→ more bioavailable T) | ↑ SHBG (→ less bioavailable T) |
|---|---|
| Obesity, nephrotic syndrome, hypothyroidism, glucocorticoids/progestins/androgens, acromegaly, diabetes | Aging, cirrhosis/hepatitis, hyperthyroidism, anticonvulsants, estrogens, HIV |
- Metabolism (mainly hepatic) — aromatase converts testosterone to estradiol (the most potent regulator of the male HPG axis; inhibits LH; supports bone and libido), and 5α-reductase converts it to DHT in target organs. Testosterone and DHT are of similar potency, but if 5α-reductase is blocked, ~13× more testosterone is needed for the same effect; DHT is concentrated in the prostate and hair follicles. The plasma half-life of testosterone is ~12 minutes.
| 5α-reductase | Location | Inhibited by |
|---|---|---|
| Type 1 | Non-genital skin, liver, brain | Dutasteride |
| Type 2 | Androgen-dependent tissue (epididymis, genitalia, seminal vesicle, prostate), hair follicles | Finasteride and dutasteride |
- Adrenal androgens (androstenedione — more potent than DHEA) are ACTH-driven, albumin-bound, weak, and remain normal after orchiectomy (but cannot maintain prostatic epithelium).
- Cardiovascular — androgen-deprivation therapy raises CV risk, and testosterone deficiency correlates inversely with CAD severity, but a 3-year RCT of testosterone gel in older men (TEAAM, 2015) found no benefit on carotid intima-media thickness, coronary calcium, or sexual function (with greater rises in hematocrit and PSA). Guidelines do not recommend testosterone screening or supplementation to improve cardiovascular outcomes.
Spermatogenesis
There are 13 recognisable germ-cell types, from dark/pale type A and type B spermatogonia → primary spermatocytes (preleptotene → leptotene → zygotene → pachytene) → secondary spermatocytes → spermatids (Sa–Sd2). Only type A spermatogonia are true stem cells (self-renew or differentiate). Producing an ejaculated sperm takes 42–76 days — ~45–60 days in the testis and 2–12 days in the epididymis (seconds in the ducts during ejaculation).
The three phases are proliferative (spermatogonial division), meiotic (crossing-over and halving of chromosomes — mature primary spermatocytes are the first to undergo meiosis; faulty recombination causes azoospermia), and spermiogenesis (remodelling and nuclear compaction of spermatids into spermatozoa). The sequence runs spermatOGONIA → spermatOCYTE → spermatID → spermatOZOA.
Sperm Transport and Accessory Glands
- Epididymis — provides sperm transport (rhythmic contractions), storage (in the cauda/tail), and maturation (improved membrane integrity, fertilising ability, motility, and glycolysis). Maturation completes at the distal corpus/proximal cauda, so in CAVD or post-vasectomy obstruction, sperm retrieval targets the cauda for better motility.
- Vas deferens — has absorptive and secretory functions, converts testosterone to DHT, and does not store sperm; sympathetic stimulation propels sperm to the ejaculatory duct before emission.
- Seminal vesicles — secrete 70–80% of the ejaculate and provide fructose; functions include coagulating semen, promoting motility, stabilising chromatin, immune suppression, and antioxidant protection. Their alkaline secretions make semen mildly alkaline, so an acidic ejaculate (pH <7.2) suggests seminal-vesicle obstruction or absence.
Spermatozoa
The spermatozoon has a head (nucleus and acrosome — needed for capacitation/fertilisation; its absence gives infertile round-headed sperm), a neck, and a tail (the midpiece holds the mitochondria, with a 9+2 axoneme for motility, using glucose and fructose for energy). Fertilisation requires four steps: motility, the acrosome reaction, capacitation, and zona pellucida binding.
Aging
Testosterone falls with age (fewer Leydig cells, more SHBG, loss of diurnal variation, blunted HPG feedback, irregular GnRH pulses), while FSH rises. Sperm production declines (from reduced germ-cell proliferation), and paternal age increases the fraction of sperm with sex-chromosomal aneuploidies (though evidence for aneuploid births is limited, except possibly trisomy 21).
Self-Test
1. What hormones are secreted by the anterior pituitary? LH, FSH, growth hormone, TSH, ACTH, and prolactin.