Gonadal steroid neuromodulation of developing and mature hypothalamic neuronal networks

•Perinatal estradiol utilizes multiple mechanisms to organize the sexually differentiated brain.•Multiple developmental windows of estradiol sensitivity exist for sexual differentiation of the brain.•Fluctuating estradiol levels in adult females drive coordinated fluctuations in kisspeptin gene expression and neural excitability.•Estradiol modulates ventromedial hypothalamic circuitry to regulate metabolism and body weight.

This review highlights recent findings regarding the diverse mechanisms through which gonadal steroid hormones modulate neuronal structure and function. In males, estradiol aromatized from testosterone in the perinatal period permanently masculinizes several components of mammalian brain circuitry. There is growing appreciation, however, that these ‘organizational’ actions also occur outside the perinatal period and may exist in females as well. In the mature brain, fluctuating levels of plasma estradiol modulate the activity of many neuronal circuits. It is clear that estradiol modulates hypothalamic kisspeptin neurons to drive cyclical changes in their gene expression and excitability to modulate brain control of fertility. Neuronal circuits controlling metabolism and body weight are another network modulated by fluctuating estradiol levels, with studies now beginning to delineate the estradiol-sensitive components of this circuitry.