How does testosterone replacement therapy (TRT) affect male fertility?

Testosterone Replacement Therapy Severely Impairs Male Fertility and Should Not Be Prescribed to Men Desiring Current or Future Paternity

Clinicians should not prescribe exogenous testosterone therapy to males interested in current or future fertility. 1 Exogenous testosterone administration provides negative feedback to the hypothalamus and pituitary gland, resulting in inhibition of gonadotropin secretion, which decreases or completely suppresses spermatogenesis, causing oligospermia or azoospermia. 1

Mechanism of Fertility Impairment

TRT suppresses spermatogenesis through feedback inhibition of the hypothalamic-pituitary-testicular axis. 2 The mechanism is straightforward:

• Exogenous testosterone inhibits gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus 1
• This suppresses follicle-stimulating hormone (FSH) and luteinizing hormone (LH) production from the pituitary 1, 3
• Reduced LH decreases intratesticular testosterone production, which is essential for spermatogenesis 1
• The result is decreased sperm production ranging from oligospermia to complete azoospermia in approximately 40% of patients 4

Recovery Timeline and Prognosis

Recovery of spermatogenesis after TRT cessation is unpredictable and often prolonged. 1 Key considerations include:

• Most azoospermic males will eventually recover sperm in the ejaculate after stopping testosterone 1
• Recovery time is highly variable, ranging from months to rarely years 1
• The impact on fertility may be irreversible in some cases 2
• Testicular atrophy, subfertility, and permanent infertility have been reported, particularly with abuse of anabolic androgenic steroids 2

Clinical Decision Algorithm

For Men Currently Desiring Fertility:

Absolute contraindication to TRT. 1 Instead:

• First-line treatment for hypogonadotropic hypogonadism: human chorionic gonadotropin (hCG) 500-2500 IU, 2-3 times weekly 1
• Add FSH injections if needed after testosterone levels normalize on hCG 1
• The degree of response correlates with baseline testicular size 1

For Men Planning Future Fertility (>1 Year):

TRT may be offered with mandatory counseling about:

• Testosterone's inhibitory effects on spermatogenesis 1
• The prolonged and unpredictable time course required for recovery 1
• The possibility of irreversible infertility 2
• Exogenous testosterone therapy should be avoided in males pursuing or planning to pursue family building in the near future 1

For Men Already on TRT Who Desire Fertility:

Immediate cessation of TRT and transition to fertility-preserving alternatives:

• Stop exogenous testosterone immediately 1
• Initiate hCG therapy (500 IU every other day or 500-2500 IU 2-3 times weekly) 1, 4
• Consider adding FSH if response is inadequate 1
• Monitor semen parameters during recovery 4

Fertility-Preserving Alternatives to TRT

For men requiring testosterone optimization while preserving fertility, alternatives to exogenous testosterone exist:

Human Chorionic Gonadotropin (hCG):

• First-line therapy for hypogonadotropic hypogonadism when fertility is desired 1
• Stimulates intratesticular testosterone production while maintaining spermatogenesis 4
• Can be used concomitantly with TRT to preserve fertility (500 IU every other day) 4
• In one study, no patient became azoospermic during concomitant TRT and hCG therapy, and 9 of 26 men achieved pregnancy 4

Selective Estrogen Receptor Modulators (SERMs):

• Block estrogen receptors at the hypothalamus, stimulating GnRH and gonadotropin release 1
• Meta-analysis of 16 studies showed SERMs significantly increased pregnancy rates and sperm parameters 1
• Off-label use for idiopathic infertility, though evidence quality is limited 1

Aromatase Inhibitors:

• Inhibit conversion of testosterone to estrogen, reducing negative feedback on the hypothalamus 1
• Increase endogenous testosterone production while preserving spermatogenesis 1
• Safe tolerability profile, though prospective RCTs are needed 1

Critical Pitfalls to Avoid

Common clinical errors that compromise male fertility:

1. Prescribing TRT without assessing fertility desires: Always ask about current and future fertility plans before initiating TRT 1

2. Failing to counsel about irreversibility risk: Patients must understand that fertility may not return, even after stopping TRT 2

3. Not offering sperm banking: Men should be encouraged to bank sperm before starting TRT if future fertility is a consideration 1

4. Assuming young age protects against infertility: This is a common issue among pubertal males with hypogonadotropic hypogonadism who are started on exogenous testosterone for pubertal induction and remain on therapy into reproductive years 1

5. Using TRT in men with idiopathic hypogonadism desiring fertility: These patients should receive hCG as first-line therapy, not exogenous testosterone 1

FDA-Labeled Warnings

The FDA label explicitly warns about fertility impairment: 2

• "During treatment with large doses of exogenous androgens, including testosterone gel, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis" 2
• "Reduced fertility is observed in some men taking testosterone replacement therapy" 2
• "Testicular atrophy, subfertility, and infertility have also been reported in men who abuse anabolic androgenic steroids" 2
• "With either type of use, the impact on fertility may be irreversible" 2

Monitoring Requirements

For men who must remain on TRT despite fertility concerns:

• Baseline semen analysis before initiating therapy 4
• Testicular size and consistency assessment (often diminish on TRT) 1
• Serial semen analyses every 3-6 months if fertility preservation is attempted 4
• Consider concomitant hCG therapy (500 IU every other day) to maintain spermatogenesis 4