The sex difference in haemoglobin levels in adults — Mechanisms, causes, and consequences

Abstract

Men and women have different mean haemoglobin levels in health in venous blood — women have mean levels approximately 12% lower than men. A similar sex-related difference in haemoglobin levels in adult animals is found in many species of mammals, birds and reptiles, indicating that it is an important physiological phenomenon. It is probably a direct effect of sex hormones, both oestrogen and androgens, on erythropoiesis. However, since there is no difference in erythropoietin levels between the sexes, this effect most likely takes place in the kidney, rather than in the bone marrow. Oestrogens dilate and androgens constrict the renal microvasculature: dilation and vasoconstriction in vessels below 300 μm in diameter respectively increase and decrease the haematocrit in blood in arterioles, capillaries and venules, altering the oxygen delivery per unit red cell mass, and providing a mechanism for varying the red cell mass without compensatory changes in erythropoiesis.

Introduction

The long phylogenetic history of the sex difference in haemoglobin levels in vertebrates indicates that males and females evolved different mean venous haemoglobin levels for different purposes, or under different selection pressures. How and why these differences are maintained, and their relevance in medical practice, have not been fully defined to date, and are the subjects of this review.

Adult men and adult women have different haemoglobin levels in health [1], [2], [3], [4]. This sex difference is independent of iron status — iron replete premenopausal women have mean haemoglobin levels approximately 12% lower than age & race matched men [1], [4]. The mean circulating erythropoietin (Epo) level does not differ between men and women, and in women does not differ between pre and postmenopausal women [5], [6], indicating that the sex difference is constitutive, and that women do not attempt to achieve male levels in health [5], [7]. The sex difference in adult haemoglobin levels is conserved throughout Mammalia — a higher adult male haemoglobin level occurs in almost all mammal species studied to date, including non-menstruating and non-placental species: chimpanzees [8], rhesus macaques [9], vervet [10], cynomolgus [11] & capuchin monkeys [12], baboons [13], rodents [14], dogs [15], marsupials & monotremes [16], and in seals [17]. It also occurs in adults in many bird species [18], and in at least some reptiles at some stages of reproduction [19]. Whether the phenomenon occurs even further back in phylogenetics remains to be determined, but it is an ancient or recurring feature in evolution, which raises profound questions of what its importance may be.

A sex difference in haemoglobin levels has not been reported in juveniles in any species of mammal, bird or reptile: after the onset of adulthood male mammals and birds diverge from the juvenile state, raising their haemoglobin level by several percentage points. Females also increase their haemoglobin levels above the juvenile level, but not to the same extent as males.