Postnatal dysregulation of androgens in extremely preterm male infants

Abstract

Abstract Context Neurodevelopmental impairments are common among survivors of extremely preterm birth, particularly in males. Hyperactivation of the hypothalamic-pituitary-gonadal (HPG) axis has been suggested as an underlying cause, but this has been poorly investigated. Objective Establish levels and temporal changes in circulating androgens in extremely preterm infant males. Design and Participants Observational cohort study analyzing cord blood serum (n=25) and postnatal plasma (n=13) collected from day 0 until week 11 from infant males born at 22.8-27.9 weeks gestational age. Main outcome measures Testosterone and dihydrotestosterone (DHT) were determined using gas-chromatography mass-spectrometry, sex hormone-binding globulin (SHBG) with ELISA, and follicle-stimulating hormone (FSH) and luteinizing hormone (LH) with Luminex xMAP multiplex assay. Results Testosterone and DHT levels were higher on day 0 (median 4.27 and 0.30 ng/ml) than in cord blood (0.15 and 0.01 ng/ml), p<0.001 for both. Levels of the hormones then declined rapidly until day 5 (median 0.16 and 0.12 ng/ml), then remained relatively constant throughout the study period. Median levels of testosterone and DHT across the whole study period were approximately 6-fold higher compared to reported in utero levels. FSH and LH showed similar postnatal patterns as the androgens. SHBG steadily increased over time, and as a result, the fraction of bioavailable testosterone declined with infant postnatal age. Conclusions The HPG axis is activated immediately after birth in extremely preterm infant males resulting in an androgen pulse occurring several months earlier than during a normal pregnancy. The long-term implications of high androgen exposure during a sensitive neurodevelopmental period warrant further studies.