FSH May Suppress Muscle Mass Independent of Testosterone in Men

Low testosterone is well-established as a driver of reduced muscle mass, increased body fat, and weakened bones. But testosterone is not the only hormone at play. This study from the University of Brescia, Italy, used the natural contrast between two rare male genetic conditions — Klinefelter syndrome (hypergonadotropic hypogonadism, high FSH) and Kallmann syndrome (hypogonadotropic hypogonadism, near-zero FSH) — to isolate the potential independent effect of FSH on body composition. By comparing men on testosterone replacement therapy with similar serum testosterone levels, the researchers created a quasi-natural experiment to test whether FSH itself influences muscle and fat independently of androgen status.

The study enrolled 50 White men (29 Klinefelter, 21 Kallmann) attending an outpatient endocrinology clinic between 2020 and 2025. All participants were on testosterone replacement therapy and had comparable total serum testosterone levels (median 2.9 vs 3.7 mcg/L, P=.138). The groups were matched on age, BMI, body weight, and waist circumference. As expected by diagnosis, FSH levels diverged dramatically: median 40.8 IU/L in Klinefelter versus 0.5 IU/L in Kallmann patients (P<0.001). Whole-body DXA provided measurements of appendicular lean mass (ALM), total body fat percentage, visceral adipose tissue (VAT), and the key metric appendicular lean mass index (ALMI, kg/m²).

The headline finding was a striking difference in lean mass: Kallmann men had a mean ALMI of 8.37 ± 1.15 kg/m² versus 7.28 ± 1.20 kg/m² in Klinefelter men (P<0.001). This 15% gap in lean mass index persisted despite equivalent testosterone. Reduced muscle mass by any DXA criterion was more prevalent in Klinefelter patients. Sarcopenic obesity was identified in 7 patients overall (14%), with 6 of those being Klinefelter. Osteosarcopenic obesity — the dangerous co-occurrence of obesity, low muscle mass, and low bone mineral density — was found in 2 patients, both Klinefelter. Total body fat percentage and VAT did not differ significantly between groups.

Linear regression confirmed that FSH levels were inversely associated with ALMI in univariable analysis (B = −0.026, P=.002). Critically, this association remained statistically significant after multivariable adjustment for age, testosterone, TRT duration, BMI, and other confounders (B = −0.030, P=.0022). This strongly suggests FSH exerts a direct suppressive effect on skeletal muscle mass, not merely an indirect one through testosterone deficiency. The proposed mechanism involves FSH receptors expressed on muscle and adipose tissue, with elevated FSH potentially promoting catabolism or inhibiting anabolic signaling in muscle.

For bone health, low BMD was found in 62% of Klinefelter and 52% of Kallmann patients, with no statistically significant difference between groups — though Klinefelter patients had numerically lower BMD at lumbar spine and femoral neck. Vertebral fractures were detected in 4 Klinefelter patients and 1 Kallmann patient. The authors note that Kallmann syndrome's longer TRT duration (median 17 vs 6 years) may partially protect bone in that group. Overall, the data support a model in which FSH — beyond its classical reproductive role — acts as a systemic regulator of body composition, with implications for any clinical condition featuring elevated FSH, including natural male aging.