A role for ovarian hormones in sexual differentiation of the brain

Abstract

Historically, studies of the role of endogenous hormones in developmental differentiation of the sexes have suggested that mammalian sexual differentiation is mediated primarily by testicular androgens, and that exposure to androgens in early life leads to a male brain as defined by neuroanatomy and behavior. The female brain has been assumed to develop via a hormonal default mechanism, in the absence of androgen or other hormones. Ovarian hormones have significant effects on the development of a sexually dimorphic cortical structure, the corpus callosum, which is larger in male than in female rats. In the females, removal of the ovaries as late as Day 16 increases the cross-sectional area of the adult corpus callosum. Treatment with low-dose estradiol starting on Day 25 inhibits this effect. Female callosa are also enlarged by a combination of daily postnatal handling and exogenous testosterone administered prior to Day 8. The effects of androgen treatment are expressed early in development, with males and testosterone-treated females having larger callosa than control females as early as Day 30. The effects of ovariectomy do not appear until after Day 55. These findings are more consistent with other evidence of a later sensitive period for ovarian feminization as compared to androgenic masculinization.

Sex differences and effects of neonatal aromatase inhibition on masculine and feminine copulatory potentials in prairie voles

“…These results are consistent with the suggestion that perinatal exposure to estrogens is necessary for femaletypical brains and reproductive behaviors Fitch and Denenberg, 1998;Gerall et al, 1973). It is possible that neonatal ATD altered females' behavior to make them less attractive to males, but similar to Gray and Dewsbury (1973), we did not detect any proceptive behaviors that could have been affected.…”

Mechanisms of Stress-induced Visceral Pain

“…Estrogen has been shown to be an important modulator of brain development, specifically influencing the plasticity of nociceptive circuits. 97,98 In one study, direct administration of female hormones into the brain induced visceral hypersensitivity in adult female rats. 99 Visceral hyperalgesia can also be induced in male rats by estrogen administration, 100 further demonstrating that estrogen can be a pivotal modulator of visceral pain processing.…”

Prenatal sex hormone effects on child and adult sex-typed behavior: methods and findings

“…Fetuses of both sexes are exposed to high levels of estrogens from the placenta, perhaps explaining why estrogen does not play a large role in prenatal development. Very little is known about the human behavioral effects of ovarian estrogens during early development (organizational effects) [21] It has been suggested that estrogen's organizational effects occur during early postnatal rather than prenatal development [36,37], but there is no relevant evidence. Progestins from the ovary are thought to have anti-androgenic effects, but there are also reports that they act as androgens [21], and it may be important to consider that effects vary by dose [38].…”

“…In rodents, these processes are largely dependent on estradiol as it is converted from testosterone in the brain via the action of the aromatase enzyme ('aromatization'). Female rodents are protected from the masculinizing effects of estrogen by a protein which binds circulating estrogen and prevents it from entering the brain [for reviews, see 8,37]. It is unclear whether aromatization is important for human behavior, although the limited evidence suggests that it is not, with masculinization and defeminization resulting directly from the effects of testosterone or other metabolites (see the discussions of Complete Androgen Insensitivity and exposure to diethylstilbestrol, below).…”