Nelson Vergel
Founder, ExcelMale.com
The attached study is a narrative, mechanistic review that compares how different testosterone replacement therapies (TRT) behave pharmacokinetically and pharmacodynamically, and how those differences translate into metabolic outcomes in hypogonadal men with type 2 diabetes (T2D).PK-and-PD-of-TRT-options-pdf.pdf
Purpose and methods
- The authors aim to link formulation‑dependent pharmacokinetics (PK) of oral, transdermal, intramuscular (IM), and subcutaneous (SC) testosterone with pharmacodynamic (PD) effects on insulin sensitivity, glycemic control, and body composition in men with T2D and hypogonadism.PK-and-PD-of-TRT-options-pdf.pdf
- They perform a targeted narrative review of human PK/PD studies, clinical trials, and guidelines in PubMed/Scopus up to October 2025, focusing on Quartile 1 journals and classifying studies by formulation and relevance to PK/PD and T2D outcomes.PK-and-PD-of-TRT-options-pdf.pdf
Key background points
- T2D is highly prevalent and rising worldwide; low testosterone is common in men with T2D and is usually hypogonadotropic (secondary) hypogonadism, not just obesity‑related.PK-and-PD-of-TRT-options-pdf.pdf
- Testosterone acts as a metabolic regulator via androgen receptors in muscle, liver, adipose tissue and β‑cells: it increases AMPK and GLUT4 in muscle, reduces hepatic gluconeogenesis, limits visceral adiposity and inflammation, and supports β‑cell function.PK-and-PD-of-TRT-options-pdf.pdf
- The metabolic benefits of TRT emerge in phases: early improvements in insulin sensitivity and inflammatory markers within weeks, followed by slower changes in HbA1c, lipids, and body composition over 6–12 months or longer.PK-and-PD-of-TRT-options-pdf.pdf
PK/PD of major TRT formulations
Transdermal gels/creams
- Absorption is rate‑limited by passage through the stratum corneum; the skin acts as a reservoir, producing flip‑flop kinetics and relatively smooth, diurnal‑like serum profiles when dosed daily.PK-and-PD-of-TRT-options-pdf.pdf
- Site matters: shoulders/upper arms have ~30–40% higher bioavailability than abdomen; scrotal application gives much higher systemic levels and markedly raises DHT due to high local 5α‑reductase and thin, vascular skin.PK-and-PD-of-TRT-options-pdf.pdf
- Transdermal therapy bypasses first‑pass liver metabolism, minimally lowers SHBG (~9%), and therefore does not substantially change free testosterone fraction.PK-and-PD-of-TRT-options-pdf.pdf
- PK: Androgel 1% 50 mg yields Cmax≈29 nmol/L at ~4 h, Cavg≈19 nmol/L, t½ ~15 h, with moderate apparent clearance and relatively low peak–trough variability versus injections.PK-and-PD-of-TRT-options-pdf.pdf
- PD in T2D: in the 12‑month TIMES2 trial, 2% gel produced modest but significant improvements in HOMA‑IR and small benefits in lipids and waist circumference, with only transient, small HbA1c reduction; effects are sensitive to adherence and exposure stability.PK-and-PD-of-TRT-options-pdf.pdf
Oral testosterone undecanoate (TU)
- TU is a lipophilic ester absorbed via intestinal lymphatics, largely bypassing initial hepatic first pass, then hydrolyzed to testosterone in systemic circulation.PK-and-PD-of-TRT-options-pdf.pdf
- Older oil‑based TU (e.g., Andriol) had strong fat‑dependence; newer SEDDS formulations (Jatenzo, Kyzatrex) form microemulsions and show more consistent absorption with reduced food effect.PK-and-PD-of-TRT-options-pdf.pdf
- PK: oral TU (e.g., Jatenzo 158–396 mg BID) achieves Cavg24 ~14–17 nmol/L with Cmax often in the 35–45 nmol/L range and Tmax 2–6 h, then returns to baseline within ~12 h, creating short‑lived peaks and relatively low troughs.PK-and-PD-of-TRT-options-pdf.pdf
- Oral TU exposes the liver to higher androgen levels, suppressing SHBG synthesis by ~30–45%, which significantly increases calculated free testosterone despite lower total T than injectables.PK-and-PD-of-TRT-options-pdf.pdf
- Oral TU does not disproportionately raise DHT relative to T (unlike scrotal topical), and produces a more physiologic DHT:T and E2 profile.PK-and-PD-of-TRT-options-pdf.pdf
- PD in T2D: clinical data specific to T2D are limited; the authors suggest that the pulsatile PK might be adequate for sexual/energy symptoms but may provide insufficient sustained exposure for robust insulin‑sensitizing or glycemic effects compared with long‑acting injections, although direct head‑to‑head data are lacking.PK-and-PD-of-TRT-options-pdf.pdf
Short‑acting injectable esters (IM/SC TE and TC)
- IM TE and TC form oily depots with flip‑flop kinetics; systemic profile is dominated by slow depot release, not intrinsic metabolic clearance.PK-and-PD-of-TRT-options-pdf.pdf
- IM TC 200 mg q2wk: Cmax ≈ 38.6 nmol/L at 4–5 days; IM TE 100 mg weekly: Cmax≈30 nmol/L at ~24–48 h; both show large peak–trough swings over each dosing interval.PK-and-PD-of-TRT-options-pdf.pdf
- Peaks are often supraphysiologic within 24–48 h, driving increased aromatase and 5α‑reductase activity, higher transient E2 and DHT, and more fluctuation in metabolic signaling.PK-and-PD-of-TRT-options-pdf.pdf
- SC TE at 100 mg weekly produces similar exposure to IM but with a longer Tmax and flatter curve; Vd appears larger with SC due to slower absorption.PK-and-PD-of-TRT-options-pdf.pdf
- PD in T2D: in a 24‑week trial with TE 250 mg q2wk, insulin sensitivity by clamp improved ~32%, lean mass increased and subcutaneous fat decreased, inflammatory markers fell, but visceral/hepatic fat and HbA1c did not change over 6 months.PK-and-PD-of-TRT-options-pdf.pdf
- Authors interpret this as evidence that intermittent, high‑amplitude exposure can improve tissue‑level insulin signaling and body composition but may not be long enough or stable enough to translate into HbA1c change in the short term; they argue that extending duration or smoothing exposure might yield better glycemic outcomes.PK-and-PD-of-TRT-options-pdf.pdf
Long‑acting injectable TU (IM/SC)
- IM TU 1000 mg in castor oil (e.g., Reandron) forms a large, viscous depot with very slow ester hydrolysis; this yields a flat, prolonged profile over 10–14 weeks (flip‑flop kinetics).PK-and-PD-of-TRT-options-pdf.pdf
- PK: IM TU Cmax ~42 nmol/L with Tmax 7–14 days, terminal t½ ~53 days, relatively low peak–trough variability; SC TU 1000 mg gives delayed Tmax (~8 days) but similar overall exposure.PK-and-PD-of-TRT-options-pdf.pdf
- Depot geometry, injection volume, and tissue vascularity strongly impact ka; SC tends to be slower than IM but produces similar AUC at steady state.PK-and-PD-of-TRT-options-pdf.pdf
- PD in T2D and prediabetes:
- T4DM RCT: in high‑risk men, IM TU q3mo plus lifestyle reduced progression to T2D by ~40% vs lifestyle plus placebo (12% vs 21% incidence) and lowered 2‑h OGTT glucose more than placebo.PK-and-PD-of-TRT-options-pdf.pdf
- Haider/Saad registry: in hypogonadal men with established T2D followed up to 11 years on TU q12wk, HbA1c fell from ~9.0% to ~5.9%, HOMA‑IR improved, and many achieved diabetes remission or normoglycemia; untreated controls worsened.PK-and-PD-of-TRT-options-pdf.pdf
- Authors attribute these outcomes to continuous AR activation from stable long‑acting TU exposure, supporting sustained AMPK–GLUT4 signaling, reduced hepatic gluconeogenesis, and long‑term reductions in visceral adiposity and inflammation.PK-and-PD-of-TRT-options-pdf.pdf
Distribution, metabolism, and excretion nuances
- Distribution: testosterone is highly protein‑bound; ~43–45% to SHBG, 33–54% to albumin, <2% free; bioavailable testosterone is free plus non‑SHBG‑bound fraction.PK-and-PD-of-TRT-options-pdf.pdf
- Oral TU reduces SHBG substantially, raising the free fraction; transdermal and injectable routes have only small or transient effects on SHBG, so free fraction is more stable.PK-and-PD-of-TRT-options-pdf.pdf
- Metabolism:
- Phase I: 5α‑reductase (DHT), aromatase (E2), and CYP3A4 (6β‑ and 16β‑hydroxy metabolites) predominate; scrotal transdermal use accentuates DHT formation, whereas long‑acting TU minimizes excessive aromatization by avoiding sharp peaks.PK-and-PD-of-TRT-options-pdf.pdf
- Phase II: UGT2B17 glucuronidation and SULT2A1 sulfation generate water‑soluble conjugates (TG, TS) that are actively secreted in the kidney and excreted in urine; UGT2B17 polymorphisms and MRP2/3 transport influence variability and anti‑doping detectability.PK-and-PD-of-TRT-options-pdf.pdf
- Excretion: <2% is excreted as unchanged T; >90% appears in urine as glucuronide/sulfate conjugates, with 6–10% via bile/feces; route of administration affects the pattern and timing but not the basic pathway.PK-and-PD-of-TRT-options-pdf.pdf
Overall conclusions and clinical implications
- The central thesis is that PK profile—especially stability versus oscillation—largely determines the metabolic impact of TRT in men with T2D.PK-and-PD-of-TRT-options-pdf.pdf
- Long‑acting injectable TU, with its flat, absorption‑limited profile and continuous receptor engagement, shows the strongest and most durable improvements in insulin sensitivity, glycemic control, and even diabetes remission in available data.PK-and-PD-of-TRT-options-pdf.pdf
- Short‑acting injections, transdermal gels, and oral TU can restore eugonadal levels and clearly improve symptoms, body composition, and some insulin‑resistance markers, but their more oscillatory exposure seems less reliable for consistent HbA1c and glycemic benefits, especially in the short term.PK-and-PD-of-TRT-options-pdf.pdf
- The authors argue that when the therapeutic goal includes metabolic endpoints (insulin sensitivity, HbA1c, diabetes prevention/remission), clinicians should preferentially consider sustained‑release, long‑acting regimens that minimize peak–trough variability while maintaining physiologic concentrations.PK-and-PD-of-TRT-options-pdf.pdf
- They also highlight limitations: heterogeneity between trials, lack of direct head‑to‑head PK/PD comparisons across formulations in T2D populations, and unresolved questions around SHBG, enterohepatic recycling, and interindividual variability; they call for standardized comparative trials and advanced PK/PD modeling.PK-and-PD-of-TRT-options-pdf.pdf
