Effects of Testosterone Undecanoate as Add-On Therapy in Obese Hypogonadal Men That Are Late Responders to Tirzepatide: A Pilot Study

Adding TRT to tirzepatide in 5 non-responding men preserved lean mass and doubled physical activity at 6 months

Journal: Minerva Endocrinology | Published: 2026-03-09 | Type: Pilot RCT | PMID: 41801155 Authors: Seminara G, Leuzzi M, Meduri L, Greco EA, Aversa A (Magna Græcia University of Catanzaro; Niccolò Cusano University) Funding/COI: Not listed for either

Summary

This pilot study asked whether adding intramuscular testosterone undecanoate (1000 mg) to tirzepatide improves outcomes in obese hypogonadal men who failed to lose ≥5% of body weight after three months on the GLP-1/GIP agonist alone. In 10 men split into two groups of 5, the combination arm showed better fat loss, preservation of lean mass, improved insulin sensitivity, and higher IIEF-5 scores at 6 months. The results are directionally interesting but statistically meaningless at this sample size.

Claims

• Group B (TRT add-on) achieved significantly greater body weight and fat mass reduction vs. Group A monotherapy (P<0.05)
• Group A lost lean body mass progressively; Group B gained it — 66.1±3.1 kg vs. 63.4±3.0 kg at 6 months (P<0.01)
• Insulin sensitivity improved more in Group B: HOMA-IR 2.9±0.6 vs. 3.8±0.7 (P<0.01)
• Sexual function scores higher in Group B: IIEF-5 23.2±2.1 vs. 18.0±1.5 (P<0.001)
• Physical activity nearly doubled in Group B vs. Group A (P<0.001, measured by Global Physical Activity Questionnaire)
• Age range 35–44, baseline BMI 35.8±2.1 kg/m² across both groups

Study Quality

Five subjects per arm is not a trial — it is a case series with a comparison group. The reported P-values (some as low as P<0.001) are statistical theater at n=5; with this much variance and this few subjects, small baseline differences between the two groups would produce virtually identical numbers. The study design does not describe randomization procedure, blinding, or how the two groups were "allocated" — whether this was truly randomized or clinician-assigned is unclear from the abstract. No placebo injection was given to Group A, so subjective outcomes (IIEF-5, physical activity questionnaire) are unblinded and therefore uninterpretable.

Outcomes are measured after 6 months without interim data, and there is no description of adherence monitoring for the tirzepatide dose titration, which matters enormously for weight loss response. The "late responder" threshold (<5% weight loss in ≥3 months) is a reasonable clinical construct but is not validated or standardized.

Red Flags

• N=10 total, N=5 per arm — any P-value from this dataset is noise dressed as signal
• No blinding — subjective outcomes (IIEF-5, GPAQ) in an open-label study are confounded by expectation effects; men who got testosterone knew they got testosterone
• Funding and COI not disclosed — tirzepatide is manufactured by Eli Lilly; testosterone undecanoate (Aveed/Nebido) is a commercial product; industry adjacency cannot be assessed
• No randomization details — "allocated" is vague; without block randomization and a CONSORT diagram, group balance is assumed, not verified
• Pilot label does not justify the conclusions — the conclusion section claims this "represents a promising precision medicine strategy," which oversells what 5-person arms can demonstrate
• No safety reporting — testosterone in obese men raises hematocrit, affects lipids, and has cardiovascular implications; none of this is mentioned
• No washout or control for tirzepatide dose escalation — whether the groups had equivalent dose trajectories is unreported

Strengths

• Uses DXA for body composition — more rigorous than BMI or waist circumference
• Addresses a real and underappreciated phenotype: GLP-1-induced lean mass loss in hypogonadal men
• 6-month follow-up is reasonable for body composition endpoints
• IIEF-5 and HOMA-IR are validated, objective-ish instruments
• The research question itself is clinically relevant — muscle preservation during GLP-1 therapy is an active area of concern

Verdict

This is a hypothesis-generating case series wearing the clothes of a clinical trial. The research question is genuinely important — GLP-1 agonists cause lean mass loss, and functional hypogonadism is both common in obese men and potentially addressable — but 10 subjects cannot answer it. The P<0.001 on physical activity questionnaire from an unblinded 5-person arm should be ignored. What this paper does usefully is define a patient phenotype ("tirzepatide late responders with functional secondary hypogonadism") and sketch a testable protocol. A properly powered, blinded RCT of perhaps 80–100 subjects would be needed to take these findings seriously. File under: interesting premise, premature publication.