Intermittent exogenous ketosis increases erythropoietin in healthy adults: A randomized, placebo-controlled study with preliminary sex-specific observations

Exogenous ketosis may stimulate erythropoietin (EPO), yet its impact on erythropoiesis, iron metabolism, and potential sex-specific responses in humans remains unknown. We investigated these effects in healthy adults using oral β-hydroxybutyrate ketone monoester (KE) to induce intermittent ketosis. Acute EPO responses to a single dose of KE were assessed in 16 healthy adults (pre-post), followed by a 2-week randomized study (KE twice daily vs. placebo). After 2 weeks, EPO levels with intermittent ketosis were approximately 30% higher (95% CI 6, 60), p = 0.01, an effect more evident in females (9.7 IU/L (95% CI 6.0, 13.5) vs. 6.4 IU/L (95% CI 4.0, 8.8), p = 0.008) than in males (10.7 IU/L (7.2, 14.2) vs. 9.6 IU/L (6.3, 12.9), p = 0.46). Ferritin was elevated in females with KE vs. placebo (42 μg/L vs. 16 μg/L, p < 0.001). Hemoglobin and red blood cell count were unaffected at 2 weeks. Over 2 weeks, intermittent exogenous ketosis was associated with a modest increase in erythropoietin levels, with a stronger signal in females. Although hemoglobin and red blood cell count did not change significantly, females showed higher ferritin levels and a trend toward increased hematocrit, suggesting subtle effects on erythropoietic stimulation and iron handling.