Sperm Production Depends on Intratesticular Testosterone, Not Blood Testosterone
Sperm production primarily depends on high levels of intratesticular testosterone rather than blood (free) testosterone levels. 1, 2
Mechanism of Testosterone's Role in Spermatogenesis
- Intratesticular testosterone is vital for spermatogenesis and male fertility, with levels approximately 40 times higher than serum testosterone in normal men 1, 2
- Within the testes, testosterone binds to androgen receptors in Sertoli cells, which initiates and maintains the spermatogenic process and inhibits germ cell apoptosis 2
- High concentrations of intratesticular testosterone are necessary for normal sperm production, and these levels cannot be achieved through oral or parenteral administration of testosterone 2
Evidence from Clinical Observations
- Exogenous testosterone therapy suppresses natural intratesticular testosterone production through negative feedback on the hypothalamic-pituitary axis, resulting in decreased spermatogenesis 3
- This suppression can lead to oligospermia or azoospermia in men taking exogenous testosterone, despite having normal or elevated blood testosterone levels 3
- Recovery of sperm production after cessation of exogenous testosterone therapy can take months or even years, demonstrating the importance of natural intratesticular testosterone production 3
Treatment Approaches That Support This Concept
- For men with hypogonadotropic hypogonadism who desire fertility, human chorionic gonadotropin (hCG) is the first-line treatment rather than testosterone replacement therapy 3
- hCG stimulates testicular Leydig cells to produce intratesticular testosterone, bypassing the suppressed hypothalamic-pituitary axis 4
- The American Urological Association specifically recommends avoiding exogenous testosterone in men interested in current or future fertility 3
Research Findings
- Studies have shown that when intratesticular testosterone is suppressed to levels comparable to serum testosterone (about 98% reduction), spermatogenesis is severely impaired despite normal blood testosterone levels 5
- Even low levels of intratesticular testosterone (approximately 2% of normal) can support qualitative spermatogenesis up to elongated spermatids, though optimal sperm production requires higher levels 6
- Intratesticular androgenic bioactivity is crucial, and during testosterone suppression, it remains higher than measured intratesticular testosterone, suggesting other androgens may play a role 5
Clinical Implications
- For men desiring fertility, clinicians should not prescribe exogenous testosterone therapy as it inhibits intratesticular testosterone production and suppresses spermatogenesis 3
- Alternative treatments that preserve or enhance intratesticular testosterone (hCG, SERMs, aromatase inhibitors) should be considered for hypogonadal men who wish to maintain fertility 3
- Currently, the only direct method to assess intratesticular testosterone is through testicular biopsy, which is invasive and rarely performed clinically 1
Common Pitfalls
- A common mistake is assuming that normal or high serum testosterone levels will support normal spermatogenesis, when in fact exogenous testosterone can severely impair fertility 3
- Men with hypogonadotropic hypogonadism who were started on testosterone therapy for pubertal induction may remain on this therapy into adulthood, unknowingly compromising their fertility 3
- Physicians may incorrectly assume that testosterone therapy will improve sperm counts in infertile men, when it typically has the opposite effect 2