Estradiol action in the female hypothalamo–pituitary–gonadal axis

It has now been about a century since a flurry of discoveries identified first the pituitary, then more specifically the anterior pituitary and soon thereafter the central nervous system as components regulating gonadal and downstream reproductive functions. This was an era of ablation/replacement designs using at first rudimentary and then increasingly pure preparations of gonadal and pituitary “activities” or transplanting actual glands, whole or homogenized, among subjects. There was, of course, controversy as is typical of lively and productive scientific debates to this day. The goals of this commentary are to briefly review the history of this work and how the terms referring to interactions among the components of the hypothalamo (as the central neural component was soon associated with)–pituitary–gonadal (HPG) axis evolved, and then to question if the current terms used have kept up with our understanding of the system. The focus in this review will be the actions of estradiol primarily upon the hypothalamus. Important actions of progesterone on the hypothalamus as well as both steroids on the pituitary response to hypothalamic factors are both acknowledged and largely ignored in this document, as are any sex differences as we focus on females.