Comparative review of the pharmacokinetics and pharmacodynamics of testosterone therapies in type 2 diabetes

The objective of this review is to evaluate how formulation-dependent PK characteristics of oral, transdermal, intramuscular (IM), and subcutaneous testosterone therapies translate to metabolic effects in hypogonadal men with T2D. A narrative review of clinical trials, PK studies, and endocrinology guidelines indexed in PubMed and Scopus up to October 2025. Evidence was synthesized comparing absorption pathways, kinetic variability, androgen receptor (AR) engagement patterns, and downstream metabolic endpoints including insulin sensitivity and glycemic control. Transdermal formulations provide relatively stable, circadian-like testosterone concentrations supporting gradual anabolic effects, whereas oral TU produces short-lived peaks with larger fluctuations that limit sustained anabolic and metabolic signaling. Oral TU utilizes lymphatic transport to reduce first-pass hepatic metabolism, increases free testosterone via hepatic SHBG suppression, yet yields lower total serum testosterone concentrations relative to injectables. Transdermal absorption is highly anatomical site-dependent, with scrotal application significantly enhancing systemic levels and DHT conversion. Short-acting IM esters generate supraphysiological peaks and deep troughs, destabilizing glucose regulation and enhancing aromatase/5α-reductase activity. In contrast, long-acting esters demonstrate flip-flop kinetics with prolonged, stable serum testosterone exposure, enabling continuous AR activation and sustained improvements in insulin sensitivity and glycemic control. Formulation-specific PK dictate hormonal stability and metabolic benefit in hypogonadal men with T2D. Long-acting injectable therapies provide the most favorable and durable endocrine-metabolic profile by maintaining continuous physiologic AR stimulation. In comparison, the more oscillatory exposure produced by transdermal gels, oral TU, and short-acting esters may deliver anabolic benefits yet insufficient hormonal stability for consistent improvements in glycaemic control. These findings reinforce the need to prioritise sustained-release formulations when targeting metabolic endpoints in men with T2D receiving TRT.