ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Endocrinol Metab. 2020; 105(3): dgz145. PMID: 31665349.

Prenatal treatment with glucocorticoids (GC) is used in several clinical indications. However, the long-term outcome on offspring metabolic, somatic and cognitive health has raised significant concern. In rodents, high glucocorticoid levels inhibit development of beta cells during fetal life and lead to insulin deficiency in adulthood. To investigate whether similar phenomena occur in humans, Jean-Pierre Riveline and colleagues compared the beta-cell function of adults exposed to glucocorticoids during the first part of fetal life with that of nonexposed subjects. The authors assessed beta cell function using the oral glucose tolerance test (OGTT) and the graded intravenous glucose and arginine tests in adults (n =16) treated with dexamethasone (DEX) during the first trimester of fetal life. They were compared to untreated healthy participants (n =16) with normal glucose tolerance, who were matched for age, sex, and body mass index. Subjects exposed to glucocorticoids were born to mothers who had been treated with DEX 1 – 1.5 mg/day from the sixth gestational week (GW) to prevent genital virilization in children at risk of 21-hydroxylase deficiency (1), but stopped DEX before the 18th GW following negative genotyping of the fetus. Insulin sensitivity was determined by the hyperinsulinemic-euglycemic-clamp.

Although there was no evidence of altered insulin sensitivity, DEX exposed participants showed significantly lower insulin secretion both on OGTT and arginine tests, indicating lower beta cell function. These findings confirm that GC exposure during the first part of fetal life is associated with a decrease in insulin secretion in response to IV glucose and arginine at adult age. The present human model of GC exposure is unique, since exposure was limited to the first part of gestation, a period corresponding to the differentiation of beta cells with low risk of confounding factors, such as gestational diabetes and hypertension. DEX, a fluorinated synthetic GC used in this model, evades inactivation by placental 11-beta-hydroxysteroid dehydrogenase type 2, which oxidizes cortisol to the inactive form cortisone (2). Therefore, when given to pregnant women, DEX enters directly into fetal circulation in its active form. This study provides the first evidence that prenatal treatment with DEX during the first part of fetal life is associated with decreased beta-cell function at adult age and may lead to glucose intolerance later in life. This new evidence adds to other existing concerns regarding the long-term safety of prenatal DEX treatment in CAH.

References:

1. David M, Forest MG. Prenatal treatment of congenital adrenal hyperplasia resulting from 21-hydroxylase de ciency. J Pediatr. 1984;105(5):799–803.

2. Brown RW, Diaz R, Robson AC, et al. The ontogeny of 11 beta- hydroxysteroid dehydrogenase type 2 and mineralocorticoid re- ceptor gene expression reveal intricate control of glucocorticoid action in development. Endocrinology. 1996;137(2):794–797.