Circulating Markers of Cardiovascular Health in Hypogonadism Before and After Testosterone Therapy: Molecular Aspects and Formulation Comparison

Low testosterone tracks with worse blood vessel markers, and TRT improves most of them, but gel vs. injection safety claims are still unproven

Journal: International Journal of Molecular Sciences | Published: 2026-07-05 | Type: Journal Article, Review | PMID: 42450305 Authors: La Vignera Sandro, Condorelli Rosita A (Department of Clinical and Experimental Medicine, University of Catania, Italy) Funding/COI: No funding listed; authors declare no conflicts of interest

Summary

This is a narrative review, not a new study. Two authors from the University of Catania pull together existing literature on how hypogonadism affects circulating markers of vascular health, and how testosterone replacement therapy (TRT) changes those markers. The paper also wades into a live debate: whether transdermal (gel/patch) testosterone is cardiovascularly safer than intramuscular injections. Their answer is that it might be, but nobody has actually tested it head-to-head with real cardiovascular outcomes.

Claims

• Men with hypogonadism show reduced circulating endothelial progenitor cells (EPCs), elevated endothelial microparticles (EMPs), and increased platelet reactivity compared to eugonadal men
• Hypogonadal men have higher levels of endothelial activators (ICAM-1, VCAM-1, E-selectin, von Willebrand factor, endothelin-1, ADMA) and inflammatory markers (hsCRP, IL-6, TNF-α)
• TRT improves most of these biomarkers through androgen receptor-dependent PI3K/Akt/eNOS signaling, VEGF upregulation, CXCL12/CXCR4-mediated EPC mobilization, and NF-κB suppression
• Transdermal formulations produce more stable, physiological testosterone levels and are associated with lower rates of erythrocytosis than intramuscular injections, which produce supraphysiological peaks
• The authors state explicitly that no randomized controlled trial has directly compared transdermal versus intramuscular TRT using hard cardiovascular endpoints (myocardial infarction, stroke, cardiovascular death)

Study Quality

This is a narrative review with no stated search strategy, no PRISMA-style methodology, no inclusion/exclusion criteria, and no quality scoring of the underlying studies it synthesizes. That's not automatically disqualifying for a review article, but it means the paper's conclusions are only as strong as the individual biomarker studies it cites, and readers have no way to judge how selectively those studies were chosen.

The formulation-comparison section is the weakest part. The evidence supporting a transdermal safety advantage is pharmacokinetic (steadier testosterone levels) and hematological (less erythrocytosis), not outcomes-based. The authors are upfront about this gap in the conclusion, which is to their credit, but the framing throughout the abstract and body leans toward transdermal being the safer choice before that caveat lands.

Red Flags

• No systematic search methodology or PRISMA framework, despite covering a clinically consequential comparison (formulation choice)
• No quantitative synthesis (no meta-analytic pooling of effect sizes) — biomarker changes are described qualitatively, not with pooled numbers
• Two-author, single-institution review; independent replication of the interpretation isn't possible from this paper alone
• The transdermal-vs-intramuscular safety claim is repeated multiple times in the abstract and conclusion despite being explicitly acknowledged as unsupported by hard-endpoint trials

Strengths

• No funding and no declared conflicts of interest
• Explicit, repeated acknowledgment that head-to-head RCTs with hard cardiovascular endpoints don't exist for the formulation question
• Detailed mechanistic coverage of specific signaling pathways (PI3K/Akt/eNOS, CXCL12/CXCR4, NF-κB) rather than vague hand-waving about "vascular health"
• Lays out concrete future research directions, including standardizing EPC/EMP measurement protocols, which is a real methodological gap in this subfield

Verdict

This is a useful mechanistic roundup of a real, understudied biomarker literature, but it's not evidence of anything new, and the formulation-safety conclusion that will likely get quoted out of context ("transdermal is safer") is built on pharmacokinetic reasoning and hematology, not on any trial that actually measured heart attacks or strokes. Treat the biomarker synthesis as a legitimate summary of prior work and the formulation-safety claim as an open question the authors themselves say remains open.