Pituitary Network Connectivity as a Mechanism for the Luteinising Hormone Surge

Abstract

Ovulation in vertebrates is caused by a surge of luteinising hormone (LH) from the pituitary. The LH surge is initiated by rising oestradiol concentration, although the precise mechanism of oestradiol action in humans and primates is not yet understood. Recent advances in labelling and three-dimensional imaging have revealed a rich pituitary structure of interwoven networks of different cell types. In the present study, we develop a mathematical model to test the hypothesis that oestradiol modulation of connectivity between pituitary cells can underlie the LH surge. In the model, gonadotrophin-releasing hormone (GnRH) pulses stimulate LH secretion by two independent mechanisms. The first mechanism corresponds to the well known direct action of GnRH on gonadotrophs, which is inhibited by the rising oestradiol concentration. The second mechanism of GnRH action is to stimulate a recurrent network of pituitary cells; in this case, the folliculostellate cells, which in turn stimulate LH secretion from the gonadotrophs. The network activity is modelled by a one-dimensional ordinary differential equation. The key to the LH surge in the model lies in the assumption that oestradiol modulates network connectivity. When the circulating oestradiol concentration is low, the network is barely connected, and cannot maintain a recurrent signal. When the oestradiol concentration is high, the network is highly connected, and maintains a high level of activity even after GnRH stimulation, thereby leading to a surge of LH secretion.