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"Ironically, a hormone that has received great attention as a potential means to optimise the health of older women may be a beneficial treatment for humans during the earliest stages of life," said Dr. Philip Shaul, professor of pediatrics at UT Southwestern and the study's senior author.
The study, conducted in preterm primates, appears in the March issue of the American Journal of Respiratory and Critical Care Medicine. The study was performed at the Southwest Foundation for Biomedical Research Primate Center in San Antonio as part of a National Institutes of Health-funded consortium investigating causes and treatments for bronchopulmonary dysplasia (BPD), a devastating primary complication of premature birth that develops in the preterm lung following ventilation and oxygen support.
Sufficient production of nitric oxide in foetal and newborn lungs is necessary for the lungs to develop and function properly. During the latter part of pregnancy the placenta produces large amounts of oestrogen that enters the fetal circulation. Another spike of oestrogen occurs during labour. In prior studies in cultured cells the investigators found that oestrogen activates the genes in lung cells encoding nitric oxide synthases, enzymes that produce nitric oxide. That research suggested treatment with the hormone may achieve the same results in the intact lung. Premature infants - nearly 50,000 are born in the U.S. each year - miss out on this exposure to oestrogen in the womb and, as a consequence, may experience respiratory problems because they lack nitric oxide.
Dr. Shaul and his colleagues found that administering oestrogen to premature primates accomplished several things.
First, the treated animals had greater abundance of nitric oxide synthases in their lungs, resulting in markedly enhanced lung function and a significantly reduced need for ventilation support. This represents an important step in lessening the lung injury that causes BPD in humans, Dr. Shaul said. It also prevented low blood pressure, which is a common problem in preterm infants.
Oestrogen also caused the closure of the ductus arteriosus, a shunt that connects the pulmonary artery to the aorta during the primates' foetal development to allow blood flow to bypass the foetus' fluid-filled lungs. In the case of full-term infants, the ductus arteriosus normally closes at the time of birth once breathing is established. In premature infants, however, it frequently fails to close resulting in further impairment in lung and heart function.
"With just one therapeutic intervention multiple benefits occurred in the lungs and the circulation," Dr. Shaul said. "Estrogen-based therapies to prevent BPD and other complications of prematurity should be further developed, and it is our hope to begin clinical trials in the near future."
Dr. Shaul said that future studies also would need to evaluate other potential targets of oestrogen in the lung in addition to nitric oxide synthases and possible effects of postnatal oestrogen treatment on nonpulmonary development, including those related to the later reproductive health of the child.