Increased fetal glucocorticoid exposure delays puberty onset in postnatal life

The fetal environment is now recognized as a key determinant of the adult p henotype, being linked to development of diseases, including hypertension, as well as the timing of puberty. Such links may be related, in part, to th e level of fetal exposure to maternal glucocorticoids in utero, which is no rmally regulated by placental expression of the enzyme 11 beta-hydroxystero id dehydrogenase (11 beta-HSD). The present study examined whether manipula tion of fetal glucocorticoid exposure, either directly or indirectly via 11 beta-HSD inhibition, influences the subsequent timing of puberty. Administ ration of dexamethasone acetate at low (LDEX, 0.25 mu g/ml drinking water) or high doses (HDEX, 1 mu g/ml) or carbenoxolone (CBX, 2 x 10 mg/day, sc; a n inhibitor of 11 beta-HSD) to pregnant rats from day 13 to term (day 23) r educed offspring birthweight (LDEX: 9%; HDEX: 27%; CBX: 8%) and resulted in a subsequent delay in the onset of puberty in females (control: 41.4 +/- 0 .5; LDEX: 44.8 +/- 0.7; HDEX: 48.5 +/- 0.4; CBX: 43.6 +/- 0.5 days). Import antly, the effects of CBX were not observed in the absence of maternal adre nals, indicating that they were mediated by increased fetal exposure to end ogenous maternal glucocorticoids. In contrast, maternal treatment with mety rapone (MET; an inhibitor of glucocorticoid synthesis; 500 mu g/ml drinking water from day 13) increased birthweight by 5% and advanced puberty onset in male offspring (control: 48.8 +/- 1.0; MET: 45.7 +/- 0.8 days). Changes in the timing of puberty onset were not attributable to changes in either b odyweight at puberty or peripubertal plasma leptin concentrations. Peripube rtal plasma LH was also unaffected in animals with delayed puberty but was elevated in male offspring of MET-treated mothers. Collectively, these resu lts demonstrate that fetal glucocorticoid exposure is an important determin ant of the timing of puberty onset in postnatal life, and that this effect is operable within the normal physiological range of glucocorticoid concent rations.