Early androgen activity after birth determines the hypothalamic expression of androgen and estrogen receptors in adulthood in female but not in male rats

Abstract

Gonadal steroids are involved in the organization and programming of several neural systems. The main objective of this study was to determine whether androgen activity in the early postnatal stage influenced the long-term expression of androgen and estrogen receptors in the hypothalamus. Androgen receptors (AR) and the main metabolic pathways of testosterone were inhibited using Flutamide, an AR inhibitor, Letrozole, an aromatase inhibitor, or Finasteride, a 5-alpha-reductase inhibitor, during the first five days of life in male and female Wistar rats. Hypothalamic hormonal receptors AR, and estradiol receptors (ER)α, and ERβ were analyzed by qPCR, and circulating hormone levels (testosterone, DHT, and estradiol) were measured using ELISA assay at P90. The inhibition of AR, 5α-reductase or aromatase did not alter the hypothalamic levels of hormone receptors in males. However, in females, blocking the androgen receptor increased the ERβ, while the inhibition of 5α-reductase decreased the ERα and the inhibition of aromatase increased AR and ERβ hypothalamic mRNA levels. Moreover, testosterone plasma levels decreased significantly in females independent of whether the AR, 5α-reductase, or aromatase were inhibited. However, only the inhibition of aromatase decreased circulating testosterone levels in males. Furthermore, higher plasma testosterone and DHT levels were detected in males compared to females. Our results highlight the influence of androgen activity during the first days of life in females on the long-term expression of androgen and estrogen receptors in the hypothalamus, which reaffirms the importance of studying both sexes to accurately explain the processes that determine the programming of neural systems during development.