The effects of flutamide on the neonatal rat hypothalamic–pituitary–adrenal and gonadal axes in response to hypoxia

Hypoxia is common with preterm birth and may lead to long‐term effects on the adult hypothalamic–pituitary–adrenal (HPA) axis that are sexually dimorphic due to neonatal androgens. Although the adult rat adrenal does not express appreciable CYP17 activity, the neonatal rat adrenal may synthesize androgens that could be a critical local factor in the development of adrenal function. We evaluated these phenomena by pretreating the neonatal rats on postnatal days (PD) 1, 6, 13, 20 with flutamide (a nonsteroidal androgen receptor antagonist) at a standard or a high dose (10 mg/kg or 50 mg/kg) compared to vehicle control. One day later, neonatal rats were exposed to acute hypoxia and blood was sampled. We found that (a) in PD2 pups, flutamide augmented corticosterone responses in a sexually dimorphic pattern and without an increase in ACTH, (b) PD7 and PD14 pups had the smallest corticosterone response to hypoxia (c) PD21 pups had an adult‐like corticosterone response to hypoxia that was sexually dimorphic, (d) flutamide attenuated ACTH responses in PD7 hypoxic pups, and (e) high‐dose flutamide suppressed the HPA axis, FSH, and estradiol. Flutamide demonstrated mixed antagonist and agonist effects that changed during the first three weeks of neonatal life. We conclude that the use of flutamide in neonatal rats to evaluate androgen‐induced programming of subsequent adult behavior is not optimal. However, our studies suggest neonatal androgens play a role in regulation of adrenal function that is sexually dimorphic and changes during early development.