ANDROGEN SIGNALLING DURING EARLY POSTNATAL LIFE PROGRAMS SEXUALLY DIMORPHIC VMH DEVELOPMENT IN RATS

The early developmental stages are critical for the programming of the circuits that regulate food intake. This programming can be modulated by gonadal hormones since neonatal inhibition of androgen signalling produces long-term alterations in metabolic parameters, and hypothalamic neuropeptide and hormone receptor expression. The aim of this study was to investigate the effects of early androgen activity inhibition on the volume, number of neurons and apoptosis in a key structure in the regulation of metabolism and food intake, the ventromedial hypothalamic nucleus (VMH), at postnatal day 11 (P11) or P21. Male and female Wistar rats were treated from postnatal day 1 (P1) to P5 with a daily sc injection of: (A) sesame oil (control vehicle), (B) flutamide (a competitive androgen receptor antagonist), (C) letrozole (an aromatase inhibitor), and (D) finasteride, (a 5α-reductase inhibitor). At P11 or P21, animals were euthanised by transcardiac perfusion. In one in every seven cresyl violet–stained coronal sections all divisions and subdivisions of the VMH were analysed using ImageJ software. At P11, control rats exhibited sexual dimorphism in the dorsomedial subdivision (VMHdm; males > females) for both volume and neuron number, and all three treatments abolished this dimorphism. At P21, flutamide-exposed males showed reduced VMHdm and medial division volumes, and fewer Nissl-positive neurons in VMHdm, central subdivision (VMHc), the medial division, and the total VMH compared with control males. These findings indicate that neonatal androgen signalling and testosterone metabolic pathways organize sex-specific VMH development, with potential implications for later metabolic vulnerability. Supported by PID2020-115829GB-I00 MICINN.