Developmental Changes in the Uptake of Testosterone by the Primate Brain

Abstract

During the neonatal period in male macaques, the testis produces adult-like levels of plasma testosterone (T), but the function of this in development is not understood. To investigate the interaction of T with the neonatal brain, 4 male and 5 female cynomolgus monkeys were gonadectomized 2-5 days after birth, and were injected subcutaneously 3 days later with 500 µCi [³H]-testosterone ([³H]-T). 60 min later, brains and other tissue samples were removed. Purified nuclear pellets were prepared by centrifugation through 2 M sucrose, extracted into ether and analyzed by high-performance liquid chromatography. The aromatized metabolite, [³H]-estradiol ([³H]-E2), was found only in the hypothalamus (HYP) and amygdala (AMG). In HYP, [³H]-E2 represented 55 ± 3% of the radioactivity in males and 53 ± 3% in females. In AMG, [³H]-E2 represented 40 ± 9% of the radioactivity in males and 47 ± 3% in females. Concentrations of unchanged [³H]-T were higher than those of [³H]-dihydrotestosterone ([³H]-DHT). Both androgens were present in nuclear pellets from all 8 brain regions studied, and concentrations were significantly higher in females than in males (p < 0.005). [³H]-T was also the main form of radioactivity in nuclear pellets from pituitary gland, adrenal gland, uterus and liver, but very high levels of [³H]-DHT were found in seminal vesicles, prostate and penis. Comparisons were made with previous results from orchidectomized fetuses at 122 days gestation and from fully adult male castrates, and the largest developmental changes occured in the AMG where concentrations of [³H]-E2 were 20-fold higher in adults than in fetuses, and most of this increase took place after the neonatal stage. Nuclear concentrations of [³H]-T also increased markedly during development in most brain regions except the cerebellar cortex where they declined.

Preterm infant circulating sex steroid levels are not altered by transfusion with adult male plasma: a retrospective multicentre cohort study

“…In contrast to steroids found in central and peripheral organs, low sex steroid radioactivity was detected in blood 60 min after administering [ 3 H]-testosterone. Similar experiments in fetal macaques also support brain uptake of exogenously administered [ 3 H]-testosterone 28 29. In neonatal rats, both non-selective and selective uptake of oestradiol into specific brain regions after intravenous administration of [ 3 H]-oestradiol have been described 30.…”

“…Unconjugated steroids, as measured in this study, are hydrophobic molecules that readily diffuse across cellular membranes 24. Animal data support tissue uptake of intravenously supplied free steroids and a longer half-life in the tissues compared with blood 25–29. For example, Bonsall and Michael29 administered [ 3 H]-testosterone to gonadectomised macaques 1 week after birth and examined sex steroid radioactivity in brain regions and peripheral tissues after 60 min.…”

“…24 Animal data support tissue uptake of intravenously supplied free steroids and a longer half-life in the tissues compared with blood. [25][26][27][28][29] For example, Bonsall and Michael 29 administered [ 3 H]-testosterone to gonadectomised macaques 1 week after…”

“… 24 Animal data support tissue uptake of intravenously supplied free steroids and a longer half-life in the tissues compared with blood. 25–29 For example, Bonsall and Michael 29 administered [ 3 H]-testosterone to gonadectomised macaques 1 week after birth and examined sex steroid radioactivity in brain regions and peripheral tissues after 60 min. Both [ 3 H]-labelled oestradiol and testosterone were detected in different brain regions.…”

Non‐human primate models of childhood psychopathology: the promise and the limitations

“…For example, male fetuses have similar levels of aromatase (an enzyme that converts testosterone into estradiol within tissues) in the amygdala as adult males (Clark, MacLusky, & Goldman‐Rakic, 1988; Abdelgadir, Roselli, Choate, & Resko, 1997), although these levels were significantly higher than female fetuses (Roselli & Resko, 1986). Both pre‐ and post‐natally, the amygdala displays higher estradiol and testosterone levels than other neural areas, except for the hypothalamus, and these levels remain stable throughout further development (Sholl, Goy, & Kim, 1989; Sholl & Kim, 1989; Bonsall & Michael, 1992; Michael, Zumpe, & Bonsall, 1992; Abdelgadir et al, 1997).…”