Y It Matters-Sex Differences in Fetal Lung Development

Abstract

Within this review, sex-specific differences in alveolar epithelial functions are discussed with special focus on preterm infants and the respiratory disorders associated with premature birth. First, a short overview about fetal lung development, the challenges the lung faces during perinatal lung transition to air breathing and respiratory distress in preterm infants is given. Next, clinical observations concerning sex-specific differences in pulmonary morbidity of human preterm infants are noted. The second part discusses potential sex-specific causes of pulmonary complications, including pulmonary steroid receptors and local lung steroid metabolism. With regard to pulmonary steroid metabolism, it is important to highlight which steroidogenic enzymes are expressed at which stage during fetal lung development. Thereafter, we review the knowledge concerning sex-specific aspects of lung growth and maturation. Special focus is given to alveolar epithelial Na⁺ transport as a driver of perinatal lung transition and the sex differences that were noted in this process.

Keywords: epithelial Na+ transport; fetal lung development; preterm infants; respiratory distress; sex differences.

Figure 1

Alveolar epithelial Na⁺ transport. Na⁺ ion are passively taken up by the ENaC in the apical membrane of alveolar epithelial cells and actively extruded by the Na,K-ATPase in the basolateral membrane compartment. Fluid follows this vectorial Na⁺ transport and is absorbed into the circulation.

Figure 2

Male disadvantage. The male sex represents an important risk factor for pulmonary complications associated with preterm birth. ↑ represents an increased need or risk, while ↓ describes a reduction.

Figure 3

Local lung androgen metabolism. 17βHSD5 results in T production, whereas 17βHSD2 inactivates T. The 5αR reduces e.g., T to DHT, which 3αHSD rapidly inactivates. Production and inactivation of androgens take place in different lung cell types during development.

Figure 4

Sex differences in fetal lungs. Studies showed that the fetal sex has multiple effects on the developing alveolar structures, surfactant synthesis and Na⁺ transport, among others.

Figure 5

Impact of female and male sex steroids during fetal lung development. A relationship between male and female sex steroids and the developing alveolar structure as well as surfactant synthesis has been reported. In contrast, Na⁺ transport was affected only by female sex steroids.