Neurobiological mechanisms underlying oestradiol negative and positive feedback regulation of gonadotrophin-releasing hormone neurones

Abstract

The feedback actions of ovarian oestradiol during the female reproductive cycle are among the most unique in physiology. During most of the cycle, oestradiol exerts homeostatic, negative feedback upon the release of gonadotrophin-releasing hormone (GnRH). Upon exposure to sustained elevated oestradiol levels, however, there is a switch in the feedback effects of this hormone to positive, resulting in induction of a surge in the release of GnRH that serves as a neuroendocrine signal to initiate the ovulatory cascade. We review recent developments stemming from studies in an animal model exhibiting daily switches between positive and negative feedback that have probed the neurobiological mechanisms, including changes in neural networks and intrinsic properties of GnRH neurones, underlying this switch in oestradiol action.

Figure 1

Model depicting possible feedback actions of estradiol upon the GnRH neuronal network. Oestradiol interacts with the circadian clock to produce diurnal changes in the regulatory network afferent of GnRH neurons, including changes in GABA and glutamate transmission and neuromodulation of GnRH neurons, resulting in a net negative afferent signal during negative feedback in the AM and positive feedback as the time of lights-out approaches in the PM. This produces an alteration between a strictly episodic GnRH signal and one that is elevated in surge mode for several hours. Oestradiol may also act directly on GnRH neurons in a positive manner that is independent of the circadian clock to modulate the output of these cells.