Regulation of sex-specific formation of oestrogen in brain development: endogenous inhibitors of aromatase.

ABSTRACT

Brain sexual differentiation occurs during the steroid-sensitive phases in early development, and is affected particularly by exposure to oestrogens formed in the brain by aromatisation of androgen. The organisational effects of oestrogen result in male-specific neuronal morphology, control of reproductive behaviour, and patterns of gonadotrophin secretion. A question which still has to be resolved is what determines changes in aromatase activity effective for the differentiation of sexually dimorphic brain development during sensitive periods of growth. In the mouse, a sex difference exists at early stages of embryonic development in aromatase-containing neurones of the hypothalamus. The embryonic aromatase system is regulated later in foetal development by androgens. Testosterone treatment increases the numbers of aromatase-immunoreactive hypothalamic neuronal cell bodies. Kinetic evidence from studies on the avian brain suggest that endogenous steroid inhibitors of aromatase, probably formed within neuroglia, also have a role in the control of oestrogen production. Inhibitory kinetic constant determination of endogenous androgenic metabolites formed in the brain showed that preoptic aromatase is potently inhibited by 5 alpha-androstanedione(K(i)=6nM) and less strongly by 5 beta-dihydrotestosterone (K(i)=350nM). Regulation by steroidal and possibly non-steroidal inhibitors may contribute to the special characteristics and plasticity in aromatase activity which develops at certain stages in ontogeny.