60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-pituitary-gonadal axis.

In the fourth chapter of Geoffrey Harris’ widely acclaimed 1955 monograph (Harris 1955), which now 60 years later provides the corner stone of this special issue of the journal, he succinctly and systematically presented his views, and the evidence upon which they were based, on the neural mechanisms controlling the pituitary-gonadal axis. That gonadal function was under control by the central nervous system was well established at the time of Harris’ monograph, as was the recognition of the gonad-stimulating properties of pituitary gonadotropin, the relative insignificance of gonadal nerves to gonadal function and the concept of neurosecretion. The problem for Harris and his fellow neuroendocrinologists was how did the hypothalamus regulate the secretion of the anterior pituitary hormones, specifically gonadotropin in the context of this review, and what was the role of the hypopophysial portal system in this regard. After elegantly interpreting and summarizing the extant data, Harris proposed that of the hypotheses that were being debated at the time “the most likely seems to be that nerve fibres from the hypothalmus liberate some humoral substance(s) into the capillaries of the primary plexus in the median eminence and that this substance is carried by the portal vessels to excite or inhibit the cells of the pars distalis.” It is to be recalled, that this idea had been proposed by Harris and Green and Harris on several occasions prior to publication of the monograph (see Harris, 1955). It is also worth noting that the evidence upon which Harris’ hypothesis was based had been obtained primarily from studies of the female, most likely because ovulation was a discrete and readily detected event and, at the time, the only reliable surrogate marker of acute hypothalamic activation. The main purpose of the present chapter is to describe the essential refinements and additional complexities that have been added to the fundamental model Harris put forward in 1955 for the neuroendocrine control of gonadal function (Figure 1). The major additions to the neuroendocrinologist’s armamentarium that have facilitated the development of the ideas of Harris are, according to an historical timeline, the introduction of radioimmunoassay to measure concentrations of pituitary and gonadal hormones in the peripheral circulation and GnRH in portal blood, the development of immunohistochemical techniques to localize neuropeptides and neurotransmitters in the hypothalamus, the application of techniques in molecular endocrinology to the study of gene expression in the hypothalamus and pituitary, the introduction of transgenic models, the advances in molecular genetics, and the arrival of the “omics” era. After discussing refinements to the Harris model resulting from the application of the foregoing technologies, the review will close with a brief outline of ways in which knowledge of the operation of this neuroendocrine axis has been applied to clinical practice, and a personal glimpse into the future of this field. Open in a separate window Figure 1 Model proposed by Harris in his 1955 monograph to illustrate the relationship between the external environment and the reproductive organs (reprinted from Harris, 1955).