Testosterone Replacement Therapy and Methylation Issues
Methylation issues are not a recognized contraindication to testosterone replacement therapy in established medical guidelines or FDA labeling. The established contraindications to TRT focus on breast cancer, prostate cancer, fertility concerns, and certain cardiovascular conditions—not metabolic pathways like methylation 1, 2.
Recognized Contraindications to TRT
The actual contraindications you should be concerned about include:
Absolute Contraindications
- Active or treated male breast cancer is an absolute contraindication 1
- Known or suspected prostate cancer (particularly advanced disease) 2
- Desire for fertility in the near future, as TRT suppresses spermatogenesis 1, 3
- Pregnancy in female partners (testosterone can cause fetal harm if transferred) 2
Relative Contraindications Requiring Caution
- Severe lower urinary tract symptoms (LUTS), though recent evidence suggests this may not worsen with TRT 4, 1
- Uncontrolled congestive heart failure, though stable CHF may not be problematic 4
- Cardiovascular disease requires individual risk assessment 4, 1
- Untreated obstructive sleep apnea, though newer data questions this restriction 4, 2
Why Methylation Is Not Relevant
The medical literature and guidelines make no mention of methylation pathways as a consideration for TRT safety or efficacy. The concerns about "methylation issues" likely stem from:
- Confusion with methyltestosterone, an oral 17-alpha-alkylated testosterone formulation that is hepatotoxic and rarely used 5
- Misunderstanding of metabolic pathways, as testosterone metabolism does not depend on methylation cycles involving folate, B12, or MTHFR polymorphisms
Appropriate Pre-Treatment Assessment
Before initiating TRT, focus on the clinically relevant evaluations 1:
- Morning total testosterone levels (drawn 8-10 AM on two separate occasions, with levels <300-350 ng/dL indicating hypogonadism) 1
- LH and FSH measurements to confirm secondary hypogonadism 1
- Baseline hematocrit and PSA testing 4
- Assessment for pituitary disorders, comorbidities, and medications affecting the hypothalamic-pituitary-gonadal axis 1
- Cardiovascular risk stratification in men over 30 with erectile dysfunction 4
Monitoring During TRT
Required monitoring parameters do not include methylation status 1, 2:
- Testosterone levels at 2-3 months after initiation 1
- Hematocrit monitoring with phlebotomy if >54% 1
- PSA monitoring 1
- Clinical response assessment at 3 months 1
Common Pitfalls to Avoid
- Do not test testosterone during acute illness, as levels may be falsely low 1
- Do not use TRT in eugonadal men or for weight loss as a primary goal 1
- Do not overlook fertility concerns in men of reproductive age, as TRT will suppress spermatogenesis 1, 3
- Ensure proper application technique to avoid secondary exposure to women and children 2