Ancient views on the hypothalamic-pituitary-thyroid axis: an historical and epistemological perspective.

The modern views on the anatomical and physiological interactions between the hypothalamus, pituitary and thyroid gland have emerged only in the last fifty years, although their historical roots may be found in a number of ancient and still not widely known ideas and observations. The regulation of energy body stores and temperature by the hypothalamic-pituitary-thyroid axis, for example, is a classical case of "fixitè du mileu interieur" in the sense originally suggested by Claude Bernard in the late 1800s, i.e. a homeostatic mechanism, but already 2100 year previously Aristotle had stated that the brain was necessary for the maintenance of body integrity by regulating food intake and behavior in relation to body temperature, the latter primarily determined by the heat of the blood. Five hundred years later Galen of Pergamon reported fundamental discoveries in the anatomy of the third ventricle region, including the location of the pituitary gland inside the sella turcica embodied in a vascular network, the rete mirabilis, and observed nerves adjoining the "soft flesh" in the neck, i.e. the thyroid gland. He first proposed that the energy of the body (the vital spirit) was carried through the arteries at the level of the rete mirabilis, where it was transformed into nerve impulse (the animal spirit), eventually transferred by the nerves to the periphery of the body, "glands" included, raising implicitly the possibility for a nervous influence over the thyroid activity. The Galenic model remained virtually unaltered up to the beginning of the 14th century, when the mediaeval anatomist Mondino de' Liuzzi put forth the idea that the thyroid gland interacted with the heat of the blood present in the internal carotid arteries due to their anatomical relation with the thyroid. This interaction enriched the vital spirit, i.e. the energy of the body, prior to its transformation into animal spirit, i.e. to nerve impulse directed to the periphery of the body. In addition, Mondino envisaged the possibility that the third ventricle was implicated in the regulation of the animal behavior by processing sensory, cognitive and emotional informations. No trace of these Mondino's ideas can be found throughout the Renaissance, despite the leading anatomical work of the period, the Fabrica by Andreas Vesalius, remained apparently inclined to the Galenic dogma of the rete mirabilis. After Vesalius, the Galenic anatomy and physiology of the infundibular region survived for at least two more centuries, and we owe Luigi Galvani, the discoverer of animal electricity, the first detailed anatomical observation that in humans the nasal secretions were not a "drainage" waste of the brain ventricles, as postulated by Galen, but the product of nasal mucous glands. From an epistemological standpoint, Aristotle anticipated the possibility that the "set point" for energy intake and behavioral adaptation was determined by the interplay between the brain activity and a thermogenic principle present in the blood, in a manner very close to a circuitry devoted to maintain the energetic and thermic steady state of the living organism (homeostasis). The Galenic modelling of brain-thyroid interaction is an evolution of the Aristotelian one, since it postulates an anatomical and functional loop linking the transport of body energy to the brain through the arteries, and the transformation of this energy into neural output directed to the peripheral glands, "thyroid" included, by the mediation of the pituitary gland. Finally, the proposal by Mondino de' Liuzzi provides a scheme of brain-thyroid interaction that merges together the "homeostatic" Aristotelian with the "pituitary/autonomic" Galenic models, suggesting that the thyroid plays a "thermoregulatory" role linked to the control of body energy. This remarkable set of ideas has never been credited to Mondino by the modern historical critique, possibly due to the impact that the methodological reform of anatomy by Vesalius, resulting in the denial of much Galenic tradition, had on the way to interpret Mondino's work from the late Renaissance up to the 20th century. The current concepts of the regulation by peripheral nerves of the thyroid blood flow and/or secretion seems to have been anticipated by anecdotal observations in the Egyptian and Roman times. In the second half of the 18th century the belief by Luigi Galvani that the peripheral nerves were carrying electrical impulses can be considered the first theoretical statement derived from an empirical evidence, i.e. the animal electricity, supporting the Galenic idea that autonomic fibers might influence the secretion of "humors" from peripheral glands, thyroid included. (ABSTRACT TRUNCATED)