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Route-dependent oestrogen effects on SHBG and free testosterone: what the supplied evidence supports

A direct multi-route comparison (oral vs transdermal vs IV) across human trials cannot be completed from the supplied evidence records. No transdermal oestrogen trial reporting SHBG or free testosterone outcomes is present in the supplied claim-level data. The closest route-relevant human experimental evidence is:

• Short-term oral ethinyl oestradiol (0.05 mg twice daily, 4 days) in normal men decreased testosterone metabolic clearance rate by 32%, plasma concentration by 49%, production rate by 65%, and free index by ~75% via increased protein binding; IV stilboestrol produced negligible acute changes, pointing to oral first-pass hepatic effects on binding proteins as the key route-dependent mechanism Oral vs IV oestrogen effects on testosterone metabolism
• Baseline SHBG varies substantially with age (mean 51 nmol/L at 45-54y rising to 89 nmol/L at ≥85y in 2,085 men), a major confounder any cross-trial route comparison must control for Age-dependent SHBG and free testosterone reference data
• SHBG genetic polymorphisms ((TAAAA)n repeat, Asp327Asn) independently explain interindividual SHBG variation (regression B = -1.7 to -3.6 nmol/L per allele), another mandatory covariate SHBG gene polymorphisms predict SHBG levels

What is missing: no transdermal oestrogen trial with SHBG/free testosterone outcomes is supplied; no head-to-head route-comparison RCT with those endpoints is available in these records. A rigorous cross-trial route comparison would additionally require assay harmonisation (SHBG binding capacity measurements vary up to ~52% depending on assay buffer conditions Assay buffer effects on SHBG measurement) and BMI control, since BMI inversely predicts SHBG (B = -0.463, P<0.001) BMI predicts SHBG inversely.