Low Free Testosterone Does Not Cause Testicular Atrophy—Exogenous Testosterone Replacement Does
Low free testosterone itself does not cause testicular atrophy; rather, exogenous testosterone replacement therapy causes testicular atrophy by suppressing the hypothalamic-pituitary-gonadal axis, leading to reduced intratesticular testosterone and diminished testicular size. 1
Understanding the Mechanism
The critical distinction here is between endogenous low free testosterone (your body's natural low production) versus exogenous testosterone administration:
- Endogenous low free testosterone (whether from primary testicular failure or secondary hypogonadism) does not directly cause the testes to shrink 2
- Exogenous testosterone therapy suppresses luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion from the pituitary, which then causes reduced intratesticular testosterone concentrations and subsequent testicular atrophy 1, 3
- Testicular atrophy from testosterone replacement is "common, especially in young men" and is "usually reversible with cessation of treatment" 1
Clinical Evidence Supporting This Distinction
In men with naturally low testosterone:
- Men with low free testosterone (even with normal total testosterone) show hypogonadal symptoms including sexual dysfunction, reduced bone density, and lower hemoglobin, but testicular atrophy is not a characteristic feature of the low testosterone state itself 2
- A study of 508 men with sexual dysfunction found that testicular atrophy on physical examination could not predict hypogonadism, indicating these are independent findings rather than cause-and-effect 4
In men receiving testosterone replacement:
- Testosterone therapy causes testicular atrophy through suppression of gonadotropins (LH/FSH), which are necessary to maintain testicular size and spermatogenesis 1, 3
- This effect is particularly pronounced in younger men and can lead to azoospermia (complete absence of sperm) 3
- Animal studies demonstrate that intratesticular testosterone administration actually causes testicular atrophy, while control animals with ischemic injury showed testicular recovery without testosterone intervention 5
Age-Related Testicular Changes
In aging men, testicular size reduction occurs as part of the natural aging process, independent of testosterone levels:
- Age-related changes include reduced testicular parenchymal weight, reduced seminiferous epithelium volume, impaired spermatogenesis, and increased tubular boundary tissue thickness 6
- These changes occur alongside declining testosterone levels but are not caused by the low testosterone itself—both are consequences of aging 6
Critical Clinical Implications
For fertility preservation:
- Testosterone replacement therapy is absolutely contraindicated in men seeking to maintain fertility, as it causes testicular atrophy and suppresses spermatogenesis 7, 3
- Alternative treatments like clomiphene citrate or gonadotropin therapy (hCG plus FSH) should be used instead, as these stimulate the testes directly and maintain testicular size while improving testosterone levels 7, 8
- Clomiphene citrate treatment in young hypogonadal men (mean age 29 years) showed significant increases in testosterone without causing testicular atrophy, with 64% of patients seeking treatment specifically for infertility concerns 8
Common Pitfall to Avoid
Do not confuse the presence of small testes in a hypogonadal man with testosterone-induced atrophy:
- Small testes may indicate primary testicular failure (Klinefelter syndrome, prior orchitis, cryptorchidism), which is the cause of low testosterone, not the result 7
- Measuring LH and FSH distinguishes primary hypogonadism (elevated gonadotropins with small testes from baseline pathology) from secondary hypogonadism (low-normal gonadotropins) 7, 3
- Only after starting exogenous testosterone will previously normal-sized testes shrink due to gonadotropin suppression 1