What is the current evidence for the use of exogenous testosterone (testosterone) as a male contraceptive?

Exogenous Testosterone as Male Contraception: Current Evidence and Ongoing Trials

Exogenous testosterone should NOT be used as a contraceptive method in clinical practice, as it lacks FDA approval for this indication, demonstrates inconsistent efficacy (achieving azoospermia in only 50-70% of Caucasian men), and carries significant risks including incomplete reversibility and adverse effects. 1

Mechanism and Efficacy Evidence

How Testosterone Functions as a Contraceptive

• Exogenous testosterone suppresses pituitary gonadotropins (LH and FSH) through negative feedback to the hypothalamus and pituitary gland 1, 2
• This suppression decreases endogenous testosterone production from the testes and deprives developing sperm of signals required for normal maturation 3
• At large doses, spermatogenesis may be suppressed, potentially leading to oligospermia or azoospermia 2
• The degree of testosterone-induced suppression determines whether spermatogenesis decreases or ceases altogether 1

Clinical Trial Results

The most recent high-quality trial (2016) demonstrated modest contraceptive efficacy but was terminated early due to safety concerns: 4

• In a prospective multicenter study of 320 men receiving intramuscular norethisterone enanthate (200 mg) combined with testosterone undecanoate (1000 mg) every 8 weeks, 95.9% of continuing users achieved sperm concentration ≤1 million/mL within 24 weeks 4
• During the efficacy phase (up to 56 weeks), the pregnancy rate was 1.57 per 100 continuing users (95% CI, 0.59-4.14) 4
• Critical limitation: The study was terminated early following recommendations from an external safety review committee due to relatively high frequencies of mild to moderate mood disorders, acne, injection site pain, and increased libido 4

Racial and Ethnic Disparities in Response

• Only 50-70% of Caucasian men achieve complete azoospermia with testosterone-based regimens, compared to higher rates in East Asian men 5, 6
• The remaining men maintain oligospermia (low but not absent sperm production), making the contraceptive unreliable 6
• This polymorphism in response appears related to differences in 5-alpha-reductase activity, with oligozoospermic responders showing higher conversion of testosterone to dihydrotestosterone 6

Current Guideline Recommendations

Explicit Contraindications

Multiple professional societies explicitly warn against using testosterone as contraception: 1

• The AUA (American Urological Association) states that exogenous testosterone therapy "should not be used in men trying to conceive" and "can put patients in severely oligospermic or azoospermic states" 1
• The AUA/ASRM (American Society for Reproductive Medicine) guidelines emphasize that exogenous testosterone "provides negative feedback to the hypothalamus and pituitary gland that can result in inhibition of gonadotropin secretion" leading to decreased or absent spermatogenesis 1

Special Population Warnings

The AAP (American Academy of Pediatrics) specifically addresses transgender and gender-diverse adolescents: 1

• Clinicians should "discuss the lack of evidence and poor efficacy of exogenous testosterone (or exogenous estrogen in a sperm-producing partner) as a contraceptive method" 1
• This is particularly important given the vulnerability of this population and the need for reliable contraception

Risks and Adverse Effects

Fertility-Related Risks

• Testicular atrophy and potential infertility or azoospermia are recognized complications 1
• While reversibility was demonstrated in 94.8% of users after 52 weeks of recovery in one trial, this still leaves approximately 5% with persistent suppression 4
• The FDA specifically lists "infertility or azoospermia" as a potential risk of testosterone therapy 1

Other Significant Adverse Effects

The FDA drug label and clinical guidelines identify multiple concerning adverse effects: 1, 2

• Polycythemia (increased red blood cell production) 1
• Elevated prostate-specific antigen levels and potential prostatic hypertrophy 1, 2
• Increased blood pressure 1
• Gynecomastia 1
• Fluid retention 1
• Sleep apnea (worsening or development) 1
• Mood disorders (relatively high frequency in contraceptive trials) 4
• Risk of transfer to women or children with transdermal preparations, causing virilization 1

Cardiovascular Concerns

• The FDA has required manufacturers to conduct the TRAVERSE trial (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy ResponSE in Hypogonadal Men), which began enrollment in May 2018 and will follow participants for up to 5 years for cardiovascular safety 1
• This ongoing trial reflects inadequate data regarding cardiovascular harms, particularly in older men 1

Ongoing Research and Future Directions

Combination Approaches

Research has focused on combining testosterone with other agents to improve efficacy: 5, 7

• Testosterone combined with progestins (depot medroxyprogesterone acetate, norethisterone enanthate, desogestrel, or etonogestrel) has shown promising efficacy 5
• Testosterone combined with GnRH (gonadotropin-releasing hormone) analogues has been studied 3, 7
• Long-acting testosterone preparations (implants or injectable testosterone undecanoate) are being investigated to improve convenience 5

Current Trial Status

• The 2016 multicenter trial was the most recent large-scale study, but it was terminated early due to safety concerns 4
• The TRAVERSE trial (ongoing since 2018) is evaluating cardiovascular safety of testosterone therapy in hypogonadal men, not contraceptive efficacy 1
• No FDA-approved testosterone-based contraceptive exists for men, and no imminent approval is evident from the available evidence 1

Clinical Bottom Line

In real-world practice, testosterone should never be recommended or prescribed as a contraceptive method because: 1

• It lacks FDA approval for contraceptive use
• Efficacy is inconsistent, with 30-50% of Caucasian men failing to achieve azoospermia
• Even with azoospermia, breakthrough pregnancies can occur
• Reversibility is not guaranteed in all men
• Adverse effects are common and can be serious
• Superior contraceptive options exist (barrier methods, vasectomy)

For men desiring fertility preservation while on testosterone therapy for hypogonadism, alternative approaches include aromatase inhibitors, hCG, or selective estrogen receptor modulators to maintain endogenous testosterone production and spermatogenesis. 1