Synergistic Induction of Aromatase Activity in the Rat Brain by Estradiol and 5α-Dihydrotestosterone

Abstract

Estrogens are produced locally from androgen precursors by cells within the hypothalamus and preoptic area (POA). The activity of the aromatase enzyme complex responsible for this intracellular conversion is controlled by gonadal steroids. The purpose of this study was to determine: whether estrogen acts together with androgen to regulate aromatase activity (AA) and whether nuclear androgen receptor levels are increased after exposure to combined treatment with estradiol benzoate (EB) and dihydrotestosterone (DHT). Thus, adult male rats were castrated and treated for 1 week with either vehicle (0.1 ml sesame oil, s.c), EB (2 µg/day), testosterone (3-cm Silastic implant), DHT (3-cm Silastic implant) or EB + DHT. These treatments produced hormone levels in the physiologic range. We found that both testosterone and DHT significantly stimulated AA (p < 0.05 vs. castrated rats). However, testosterone induced AA significantly more than DHT in the POA (p < 0.05; castrated + testosterone vs. castrated + DHT). EB alone did not affect AA but synergized with DHT to stimulate AA in the POA to levels equivalent with the testosterone-treated group. By comparison, EB alone did not enhance the induction of AA by DHT in the hypothalamus. Combined treatment with EB and DHT had no effect on the concentrations of nuclear androgen receptors in either tissue suggesting that the effect of EB was not mediated through an androgen receptor mechanism. These results suggest that both androgens and estrogens play a physiologic role in the control of estrogen formation in the rat brain. Furthermore, the anatomical specificity that we observed indicates that critical differences in enzyme responsiveness are present in different areas of the brain.

Involvement of Granulin in Estrogen-Induced Neurogenesis in the Adult Rat Hippocampus

“…Proliferation of neural progenitor cells separated from the hippocampi of 3-month old rats was also enhanced by estrogen in vitro in a dose-dependent manner, although the significant effect of estrogen was observed at a relatively high concentration (10 -5 M). Since aromatase, an estradiol-synthesizing enzyme, is expressed in the cell of the dentate gyrus [ 45 ] a n d e s t r o g e n c a n i n c r e a s e a r o m at a s e expression [46], it is possible that systemicallyadministered estrogen increases hippocampal aromatase and that locally-produced estrogen in the hippocampus in turn participates in enhancing progenitor cell proliferation. Observation that the antibody against granulin precursor effectively blocked the stimulatory effect of estrogen on proliferation of progenitors further supports the above-mentioned notion that granulin is involved in estrogenic action on cell proliferation.…”

Androgen Receptors and Estrogen Receptors Are Colocalized in Male Rat Hypothalamic and Limbic Neurons that Express Fos Immunoreactivity Induced by Mating

“…Testosterone facilitates aromatase activity through a receptor mechanism [16] in preoptic, hypothalamic as well as limbic regions. E 2 in combination with DHT also activates aromatase activity in the preoptic area [17]. This suggests the existence of a single cell type, one that contains AR, ER and the aromatase, which would be activated during mating.…”

“…Depending on the tissue, androgenic and estrogenic interactions may be either antagonistic or synergistic [14, 15]. Levels of aromatase activity are directly proportional to levels of testosterone [16, 17], and treatment of castrated males with DHT combined with E 2 at doses which have little or no effect alone, restores aromatase activity to levels equivalent to those achieved by treatment with testosterone [17]. …”

Androgen and Estrogen Receptors Coexist within Individual Neurons in the Brain of the Syrian Hamster

“…When steroids are reduced by exposure to short-dav photoperiod or eliminated via cas- only estrogens stimulate the preovulatory LH surge [5]. In contrast, both DHT and estradiol can facilitate sexual behavior and suppress gonadotropin secretion [6][7][8][9][10][11], and the combination of DHT and estradiol is often supe rior to either hormone alone [10,12], To understand how androgens and estrogens regulate neural function, indi vidually and in combination, it is necessary to determine sites of steroid action in the brain. In particular, the over lapping functions of androgens and estrogens to influence neuroendocrine control and sexual behavior suggest that the receptors for these two steroids overlap.…”