Dihydrotestosterone Inhibits Fetal Rabbit Pulmonary Surfactant Production

Abstract

A B S T R A C T Males have a higher morbidity and mortality for neonatal respiratory distress syndrome (RDS) than females, and respond less well to hormone therapy designed to prevent RDS by stimulating fetal pulmonary surfactant production. We have shown that male fetuses exhibit delayed production of pulmonary surfactant. We tested the hypothesis that the sex difference in fetal pulmonary surfactant production is under hormonal control. Pulmonary surfactant was measured as the saturated phosphatidylcholine/sphingomyelin ratio (SPC/S) in the lung lavage of fetal rabbits at 26 d gestation. There was an association between the sex of neighboring fetuses and the SPC/S ratio of the female fetuses, such that with one or two male neighbors, respectively, females had decreasing SPC/ S ratios (P < 0.05). We injected dihydrotestosterone (DHT) into pregnant does from day 12 through day 26 of gestation in doses of 0.1, 1.0, 10, and 25 mg/d, and measured the SPC/S ratio in fetal lung lavage on day 26. In groups with the normal sex difference in fetal serum androgen levels (controls, 0.1 mg DHT/d) the normal sex difference in the SPC/S ratio was also present (females> males, P = 0.03). In the 1-mg/d group there was no sex difference in androgen levels and the sex difference in the SPC/S ratio was also eliminated as the female values were lowered to the male level. Higher doses of DHT (10, 25 mg/d) further reduced the SPC/S ratios. We injected the anti-androgen Flutamide (25 mg/d) from day 12 through day 26 of gestation. This treatment eliminated the normal sex difference in the lung lavage SPC/S ratio by increasing the male ratios to that of the females. We conclude that androgens inhibit fetal pulmonary surfactant production. An understanding of the mechanism of the sex difference in surfactant production

Apolipoprotein A-I, A-II, C-II, and H expression in the developing lung and sex difference in surfactant lipids

“…Fetal lung maturation leading to the surge of surfactant synthesis was delayed by androgens, both in vitro (Torday 1990) and in vivo (Nielsen et al 1982, Nielsen 1985. Moreover, the sex difference in surfactant production was eliminated by administration of the antiandrogen flutamide, which resulted in an increase in male surfactant levels up to that of the females (Nielsen et al 1982).…”

“…Male fetuses present a transient delay in lung maturation compared with female fetuses (Nielsen & Torday 1981, Torday & Dow 1984, Nielsen 1985 in such a way that preterm delivery leads to a higher incidence of respiratory distress syndrome (RDS or hyaline membrane disease) in males (Farrell & Avery 1975, Papageorgiou et al 1981, Nielsen et al 1982, Perelman et al 1986a. Surfactant deficiency is one major cause of RDS and the surge of surfactant synthesis is normally delayed in the developing male lung when compared with the female (Nielsen & Torday 1981, Torday & Dow 1984, Nielsen 1985.…”

“…Surfactant deficiency is one major cause of RDS and the surge of surfactant synthesis is normally delayed in the developing male lung when compared with the female (Nielsen & Torday 1981, Torday & Dow 1984, Nielsen 1985. In fact, the sex difference in surfactant production pertains to its lipid moiety (Nielsen et al 1982, Nielsen 1985, Ballard 1989.…”

Age, Sexual Dimorphism, and Disease Associations in the Developing Human Fetal Lung Transcriptome

“…Response to in utero exposure, such as maternal cigarette smoking, differs in the male and female lung (10). Androgens have been shown to enhance branching morphogenesis (11) and inhibit surfactant production (12) in the developing fetal lung. Male lung development lags behind female lung development in the alveolar phase of development in late gestation, based on the assessment of amniotic fluid indices (13,14).…”

Expression du gène 17β-HSD2 dans le poumon fœtal et le placenta : contrôle de l’action des stéroïdes sexuels

“…La maturation des cellules PTII conduisant à la production de surfactant s'effectue dans le dernier tiers de la grossesse et est stimulée par des facteurs paracrines sécrétés par les fibroblastes [13,14]. Des études in vitro ont montré que les androgènes inhibaient, via le récepteur des androgènes [15], la sécré-tion par les fibroblastes de ces facteurs paracrines essentiels à la maturation des cellules PTII. Nous avons montré que les cellules A-549, une lignée épithéliale productrice de surfactant et issue de cellules PTII d'origine mâle, ont une très forte activité de conversion de l'androstènedione en testostérone catalysée par la 17β-HSD5.…”