Follow-Up Examination at the Age of 15 Months of Extremely Preterm Infants after Postnatal Estradiol and Progesterone Replacement

Trotter, Andreas; Bokelmann, Birgit; Sorgo, W.; Bechinger-Kornhuber, Doris; Heinemann, Hilde; Schmücker, G.; Oesterle, M; Köhntop, B.; Brisch, Karl-Heinz; Pohlandt, Frank

doi:10.1210/jcem.86.2.7176

Cited by 51 publications

(16 citation statements)

References 7 publications

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“…In a recently reported small trial by Trotter and colleagues, intravenous E 2 and progesterone treatment in preterm infants tended to decrease the incidence of BPD. Furthermore, their work to date suggests potential added benefits on bone mineralization, retinopathy of prematurity, and neurologic outcome (49)(50)(51), lending further credence to the concept of postnatal estrogen treatment. In our model there were also favorable impacts on hypotension and patent ductus arteriosus that are also key complications of prematurity.…”

Section: Discussionmentioning

confidence: 93%

Postnatal Estradiol Up-regulates Lung Nitric Oxide Synthases and Improves Lung Function in Bronchopulmonary Dysplasia

McCurnin

Pierce

Willis³

et al. 2009

Am J Respir Crit Care Med

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Rationale: Nitric oxide (NO) plays an important role in lung development and perinatal lung function, and pulmonary NO synthases (NOS) are decreased in bronchopulmonary dysplasia (BPD) following preterm birth. Fetal estradiol levels increase during late gestation and estradiol up-regulates NOS, suggesting that after preterm birth estradiol deprivation causes attenuated lung NOS resulting in impaired pulmonary function. Objective: To test the effects of postnatal estradiol administration in a primate model of BPD over 14 days after delivery at 125 days of gestation (term 5 185 d). Methods: Cardiopulmonary function was assessed by echocardiography and whole body plethysmography. Lung morphometric and histopathologic analyses were performed, and NOS enzymatic activity and abundance were measured. Measurements and Main Results: Estradiol caused an increase in blood pressure and ductus arteriosus closure. Expiratory resistance and lung compliance were also improved, and this occurred before spontaneous ductal closure. Furthermore, both oxygenation and ventilation indices were improved with estradiol, and the changes in lung function and ventilatory support requirements persisted throughout the study period. Whereas estradiol had negligible effect on indicators of lung inflammation and on lung structure assessed after the initial 14 days of ventilatory support, it caused an increase in lung neuronal and endothelial NOS enzymatic activity. Conclusions: In a primate model of BPD, postnatal estradiol treatment had favorable cardiovascular impact, enhanced pulmonary function, and lowered requirements for ventilatory support in association with an up-regulation of lung NOS. Estradiol may be an efficacious postnatal therapy to improve lung function and outcome in preterm infants.The signaling molecule nitric oxide (NO), generated by nitric oxide synthase (NOS), plays a key role in multiple processes in the mature lung (1, 2). In the developing lung, NO participates in pulmonary vascularization, alveolarization, and airway branching, and also counteracts apoptosis in multiple lung cell types (3-6). In the perinatal period, epithelium-derived NO is critically involved in the regulation of lung liquid production and of peripheral contractile elements (7, 8), and it also mediates pulmonary vasomotor tone (9). In studies of lungs from fetal baboons, we showed that all three NOS isoforms, neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS), are principally expressed in proximal respiratory epithelium, and that there are maturational increases in their abundance and in NO production during the early third trimester (10). Thus, pulmonary NOS expression is up-regulated during fetal development in the primate, and this process may be critical to lung structural development and airway, parenchymal, and pulmonary vascular function in the early postnatal period.Bronchopulmonary dysplasia (BPD) is a devastating primary complication of premature birth that develops in the preterm human lung following ventilatory and oxyg...

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Section: Discussionmentioning

confidence: 93%

Postnatal Estradiol Up-regulates Lung Nitric Oxide Synthases and Improves Lung Function in Bronchopulmonary Dysplasia

McCurnin

Pierce

Willis³

et al. 2009

Am J Respir Crit Care Med

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“…PR expression in midbrain and brainstem nuclei during fetal and neonatal development implicates progesterone in the normal development of these structures and in several neurodevelopmental disorders. Elucidating the steroid sensitivity of the developing brain also becomes clinically important as the use of progestins in the treatment of premature infants (Trotter et al, 1999(Trotter et al, , 2001Trotter and Pohlandt, 2000) and of pregnant women for the prevention of premature delivery (Meis et al, 2003;Meis and Aleman, 2004;Dodd et al, 2005;Spong et al, 2005) increases.…”

Section: Discussionmentioning

confidence: 99%

Distribution of progesterone receptor immunoreactivity in the midbrain and hindbrain of postnatal rats

Quadros

Schlueter

Wagner

2008

Developmental Neurobiology

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Nuclear steroid hormone receptors are powerful transcription factors and therefore have the potential to influence and regulate fundamental processes of neural development. The expression of progesterone receptors (PR) has been described in the developing forebrain of rats and mice, and the mammalian brain may be exposed to significant amounts of progesterone, either from maternal sources and/or de novo synthesis of progesterone from cholesterol within the brain. The present study examined the distribution of PR immunoreactive (PRir) cells within the midbrain and hindbrain of postnatal rats. The results demonstrate that PR is transiently expressed within the first 2 weeks of life in specific motor, sensory and reticular core nuclei as well as within midbrain dopaminergic cell groups such as the substantia nigra and the ventral tegmental area. Additionally, robust PRir was observed in cells of the lower rhombic lip, a transient structure giving rise to precerebellar nuclei. These results suggest that progestins and progesterone receptors may play a fundamental role in the postnatal development of numerous midbrain and hindbrain nuclei, including some areas implicated in human disorders. Additionally, these findings contribute to the increasing evidence that steroid hormones and their receptors influence neural development in a wide range of brain areas, including many not typically associated with reproduction or neuroendocrine function.

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“…In a previous study, we found that ER-mediated E 2 plays an important role in normal retinal vascular development and ROP pathogenesis (35). Maternal E 2 levels during pregnancy may increase by ~100-fold (33,(35)(36)(37)(38)(39). Fetal E 2 levels increase with gestational age, with the E 2 concentration peaking between 33 and 36 weeks of pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Estrogen therapy to treat retinopathy in newborn mice

Shi

Zhu

Wang

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to treat retinopathy of prematurity (ROP) with estrogen (E 2 ) so as to elucidate the role of E 2 in the pathogenesis of ROP. A total of 120 postnatal 7-day-old (P7) C57BL/6J mice were selected and raised in a high-oxygen environment (75% oxygen) for 5 days, followed by 5 days in normal room air. Different doses of E 2 or normal saline (NS) were injected intraperitoneally during different time-periods, and the mice were divided into 14 groups according dose of E 2 injection (0.5-1.5 µg/0.05 ml) and dosing time. Blood vessel changes and hyperplasia were evaluated in flat-mounted retina and retinal slices. All mice that were exposed to room air, whether they were administered E 2 or NS, showed good vascular development in the flat-mounted retina at P17. No increase in the number of endothelial cell nuclei in the new blood vessels was observed. In ascending order of E 2 dose the numbers of cell nuclei were as follows: 0.18±0.129, 0.28±0.086 and 0.55±0.110. The number in the NS group was 2.12±0.373. When the results of the room-air groups were compared with those of the hyperoxia groups, a highly significant difference was found in each comparison (P<0.0001). All mice showed varying degrees of neovascularization and vascular obstruction in the flat-mounted retina at P17, and it was difficult to compare the blood vessels morphologically among these groups. The number of endothelial cell nuclei decreased following E 2 injection, and the difference from the NS group exposed to hyperoxia was highly significant (P<0.0001). For all dose levels, the number of cell nuclei was the lowest when the drug was administered during P7-16, and the difference from the other two time-periods was statistically significant (P<0.05). When E 2 was administered during P7-16, the number of cell nuclei was 15.5±1.993 in the 0.5-µg group, 14.23±2.49 in the 1.0-µg group and 18.05±1.62 in the 1.5-µg group. No significant difference was found among these three groups (P>0.05). In conclusion, E 2 treatment during the development of retinopathy can improve symptoms in neonatal mice, suggesting that E 2 plays an important role at the two initial stages in the pathogenesis of ROP. This may indicate new pharmacological measures to prevent and treat ROP.

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Follow-Up Examination at the Age of 15 Months of Extremely Preterm Infants after Postnatal Estradiol and Progesterone Replacement

Cited by 51 publications

References 7 publications

Postnatal Estradiol Up-regulates Lung Nitric Oxide Synthases and Improves Lung Function in Bronchopulmonary Dysplasia

Postnatal Estradiol Up-regulates Lung Nitric Oxide Synthases and Improves Lung Function in Bronchopulmonary Dysplasia

Distribution of progesterone receptor immunoreactivity in the midbrain and hindbrain of postnatal rats

Estrogen therapy to treat retinopathy in newborn mice

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