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

Abstract

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.