Body Composition by DXA in Patients with Klinefelter and Kallmann Syndrome: The Kama Study

Men with Klinefelter syndrome had significantly less lean mass than Kallmann men (ALMI 7.28 vs 8.37 kg/m²), implicating FSH

Journal: The Journal of Clinical Endocrinology & Metabolism | Published: 2026-03-17 | Type: Retrospective Observational Study | PMID: 41073368 Authors: Buoso C et al. — Department of Clinical and Experimental Sciences, University of Brescia, Italy; Ferlin A — Unit of Andrology and Reproductive Medicine, University of Padova Funding/COI: Not listed for either

Summary

Two genetic hypogonadism syndromes — Klinefelter (high FSH/LH) and Kallmann (low FSH/LH) — produce similar testosterone deficiency but apparently different muscle outcomes. This study found Kallmann patients had significantly more lean mass despite comparable testosterone levels on replacement therapy, suggesting FSH itself may suppress muscle mass. The finding is preliminary but points at a mechanism most testosterone research ignores entirely.

Claims

• Kallmann patients had higher appendicular lean mass index than Klinefelter patients (8.37 ± 1.15 vs 7.28 ± 1.20 kg/m²; P < .001)
• FSH levels were inversely associated with ALMI after multivariate adjustment (B = −0.030; P = .0022)
• 14% of patients met criteria for radiologic sarcopenic obesity — 6/29 Klinefelter vs 1/21 Kallmann
• Osteosarcopenic obesity found in 4% overall, both cases in Klinefelter patients
• 26% had reduced bone mineral density (31% Klinefelter, 19% Kallmann) — difference not statistically significant
• No significant difference in BMD between groups, even on multivariable analysis
• ALMI, not FSH or testosterone, was the only variable independently associated with BMD at lumbar spine and total hip

Study Quality

This is a small (n=50), single-center, retrospective observational study from one Italian endocrinology unit. The core comparison is reasonable — both syndromes share testosterone deficiency but differ systematically in gonadotropin levels, making them a natural quasi-experiment for isolating FSH effects. DXA is an appropriate and validated tool for body composition assessment.

The main statistical concern is the difference in TRT duration between groups: Kallmann patients had been on testosterone significantly longer (median 17 vs 6 years; P = .023), which is a meaningful confounder for both lean mass and bone outcomes. The authors adjusted for TRT duration in multivariable models, but retrospective adjustment has limits. Different TRT formulations (79% of Klinefelter on gel vs 82% of Kallmann on undecanoate) add another layer of potential confounding that's difficult to fully disentangle.

Red Flags

• n=50 total — 29 Klinefelter, 21 Kallmann; underpowered for most secondary analyses
• No healthy control group — all comparisons are between two diseased populations
• Funding and COI not disclosed — cannot assess independence
• All White male patients from one Italian center — results may not generalize
• TRT duration differed by 11 years between groups, a major potential confounder for lean mass and bone outcomes
• Different TRT formulations across groups, not fully accounted for
• Retrospective chart review — data quality depends on clinical documentation
• No dietary or physical activity data collected, both relevant to lean mass

Strengths

• First direct head-to-head body composition comparison between Klinefelter and Kallmann syndromes
• Clean natural experiment: gonadotropin levels differ systematically while testosterone levels on replacement are comparable (P = .138)
• DXA performed on all patients with standardized equipment (Hologic Discover A)
• Ethics approval obtained; written informed consent documented
• Multivariate analysis adjusted for age, TRT duration, smoking, vitamin D, and calcium

Verdict

A genuinely interesting hypothesis — that FSH independently suppresses lean mass — dressed in a study too small to prove it. The Klinefelter-vs-Kallmann framework is clever and the ALMI difference is striking, but 50 patients, no controls, a confounded TRT duration gap, and undisclosed funding mean this paper can only be read as hypothesis-generating. The FSH-muscle axis finding is worth watching in larger prospective studies; it changes nothing about current practice.