Why do women have similar erythropoietin levels to men but lower hemoglobin levels?

To the editor:

Mean red cell mass and hematocrit levels are higher in men than women. How or why this is the case has never been explained. If decreased erythropoiesis due to iron loss or blood loss in females or increased erythropoiesis due to androgens in males were causative, there would be a feedback effect on erythropoietin production, resulting in lower erythropoietin levels in males. However, reference ranges for erythropoietin are not different between the sexes. This indicates that females have higher levels of tissue oxygenation for a given red cell mass. This, in turn, suggests that females must have more efficient tissue red cell delivery.

In a comparison of more than 36 000 paired venous and capillary blood samples in blood donors where the capillary hemoglobin (Hb) level was < 12.4 g/dL in females (n = 25 762), and < 13.4 g/dL in males (n = 10 496), the capillary level was generally lower than the venous level, by a mean of 1.07 g/dL in males, and .67 g/dL in females.¹  Subsequently we have observed that the gap between the capillary and venous hemoglobin levels decreased both in males and in females as the hemoglobin level increased. In addition, the curves for males and females were parallel: they did not overlap (Figure 1A). When analyzed by age cohort, the mean capillary-venous hemoglobin gap in females increased after the age range of 45 to 50 years. In males there was gradual decline with age (Figure 1B).

That a gap exists between the capillary and venous hematocrit is well described. The total body hematocrit is approximately 0.91 times the venous hematocrit.²  This is due to the Fåhraeus effect, a relative dilution of red cells in capillaries caused by the difference in flow speeds between the faster-flowing, centrally concentrated cells and the slower-flowing, peripherally displaced plasma.³  We have now shown that the gap is under physiologic control and is dependent on sex, age, and red cell count. The gap is higher on average in males and increases as capillary red cell content declines. Above the age range of 45 to 50 years in women, the gap increases toward the level found in men.

Further studies are required to determine how this modulation of the Fåhraeus effect is achieved. Possible causative or contributory mechanisms include rheologic effects, including sex differences in blood flow speeds, and changes in blood viscosity with red cell concentration. In addition, eNOS up-regulation by estrogen in premenopausal females could modulate the Fåhraeus effect by increasing local NO production leading to vasodilation,⁴  and the nitrite reductase effect of deoxyhemoglobin⁵  could produce a similar effect through increased vasodilation as the red cell content in the capillary blood rises.

Physiologic modulation of the Fåhraeus effect, leading to more efficient delivery of red cells to the capillary circulation, may underlie the lower requirement for red cells in women. It may also contribute to lower rates of cardiovascular disease in premenopausal women, and may have important consequences for the treatment of cardiovascular diseases and anemias, and for blood transfusion.