Chapter 3B – Functional Anatomy of the Hypothalamus and Pituitary

Ronald M. Lechan, M.D., Ph.D – Professor of Medicine
Division of Endocrinology, Diabetes and Metabolism and Department of Neuroscience, Tufts Medical Center, Tupper Reasearch Institute and Tufts University School of Medicine, Box #268, 750 Washington Street, Boston, MA, 02111, USA

Roberto Toni, M.D., Ph.D. – Professor of Human Anatomy
Department of Human Anatomy, Pharmacology and Forensic Medicine, University of Parma School of Medicine, Parma, Italy, Adjunct Professor of Medicine, Division of Endocrinology, Diabetes and Metabolism, Tufts Medical Center and Tufts University School of Medicine, Boston, MA, 02111, USA

Updated 22 March 2013

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I. Historical Overview

As suggested by its Greek derivation, the hypothalamus (hypo = below, thalamus = bed) is that portion of the diencephalon in all vertebrates that lies inferior to the thalamus (1). The hypothalamus and pituitary gland has attracted the interest of scientists and artists for centuries since the first description by Galen of Pergamon in the 2nd century AD. Galen described the hypothalamic infundibulum and the pituitary gland in De Usu Partium as the draining route and receptacle, respectively, for mucus passing from the brain ventricular structures to the nasopharynx, and named the capillary network surrounding the pituitary gland the rete mirabilis (2). The Galenic concepts dominated scientific thought about the hypothalamus and pituitary for approximately 1200 years until the 14^th century when the Italian anatomist, Mondino de’ Liuzzi, in his Anothomia, proposed that the third ventricle serves as an “integrator” of body functions (Fig. 1) (3). Some of these ideas were extended by Andreas Vesalius in the 16th century in De Humani Corporis Fabrica, the first anatomical depiction of the infudibular-pituitary stalk (Fig. 2). Attention to the importance of the hypothalamic-pituitary region influenced the work of some of the most famous Renaissance artists including Leonardo da Vinci, whose drawings of the third ventricle and rete mirabilis are shown in Fig. 3, and Michelangelo Buonarroti, whose painting on the ceiling of the Sistine Chapel in the Vatican uses the brain including the hypothalamic-pituitary region as a backdrop to his depiction of the creation of man (Fig. 4) (4).

Fig. 1. Description of the functional role exerted by the cerebral third ventricle, as reported by Mondino de’ Liuzzi in Anothomia. (A) Original front page of Anothomia in a XIV century edition; (B) Original text (in brackets) in medieval Latin (from the 1316 A.D. manuscript kept at the Società Medica Chirurgica in Bologna, Italy); (C) a portion of the Latin fragment shown in (B) containing the most important concepts; (D) English translation shown in (B). (From Toni R., Ancient views on the hypothalamic-pituitary-thyroid axis: an historical and epistemological perspective, Pituitary 3: 83-95, 2000).

Fig. 2. Plates from the seventh book of the first edition (1543) of the Fabrica by Andreas Vesalius, showing what is believed to be the oldest anatomical images in Western literature of the hypothalamic-pituitary unit. (Courtesy of the Library of the Department of Human Anatomy of the University of Bologna, Italy, with permission.) 1) Enlarged view of the pituitary gland (A), hypothalamic infundibulum (B) and ducts comprising the foramen lacerum and superior orbital fissure (C, D, E, F) believed to drain brain mucus or phlegm (in Latin pituita) from the pituitary gland to the nasopharynx; 2) anatomical relationships between the infundibulum (D), the dural diaphragma sellae (F), the internal carotid arteries (C, D) and occulomotor nerves (G); 3) composite image including a) an enlarged view of the rete mirabilis formed as a reticular plexus by the carotid arteries entering (A, B) and emerging (C, D) around the pituitary gland (E); b) detailed view of the reticular plexus arising from the carotids (B, C) on each side of the pituitary (A). (From Toni R., Ancient views on the hypothalamic-pituitary-thyroid axis: an historical and epistemological perspective, Pituitary 3: 83-95, 2000).

Fig. 3. Drawings by Leonardo da Vinci (1508-1509) taken from the Codici di Anatomia of the Windsor’s Collection (Courtesy of the Library of the Department of Human Anatomy of the University of Parma, Italy). (A) Inferior surface of the brain, showing the rete mirabilis (arrow) that surrounds the pituitary gland; (B) three-dimensional representation of the cerebral ventricles. The third ventricle (3v) was believed to be the site of afference and elaboration of the “sensus communis” (Latin for peripheral physical sensations). (From Toni R, Malaguti A, Benfenati F, Martini L: The human hypothalamus: a morphofunctional perspective. J Endocrinol Invest 27 (supp to n.6), 73-94, 2004.)

Fig. 4. Detail from the fresco, “Creation of Adam,” by Michelangelo Buonarroti, visible on the ceiling of the Sistine Chapel in the Vatican at Rome, Italy, painted between 1508-1512. (A) Photograph of the fresco showing God giving spiritual life and intellect to Adam through his touch; (B) The contour of the same image is reminiscent of a midline saggital section of the brain and includes the hypothalamus, pituitary and brainstem. (From Toni R, Malaguti A, Benfenati F, Martini L: The human hypothalamus: a morphofunctional perspective. J Endocrinol Invest 27 (supp to n.6), 73-94, 2004.)

The current term “hypothalamus", however, was not actually introduced until 1893 by the Swiss anatomist, Wilhelm His. On the basis of his studies on the ontogenesis of the human, fetal brain, His named the first anatomical subdivision of the hypothalamus the “pars optica hypothalami” (5), which is now recognized to include the preoptic region, tuber cinerium and infundibulum. Discovery of the connection between the hypothalamus and posterior pituitary (supraoptic-hypophysial tract) by Ramon Cajal in 1894, and subsequent work on neurosecretion in fish hypothalamus by the Sharrers in 1928, set the groundwork for rapid advancement in the understanding of the hypothalamus that unraveled throughout the 20^th century and continues into the 21^st century. Table 1 summarizes the major historical advances in the elucidation of the anatomy of the mammalian hypothalamic-pituitary unit (6).

Table 1. Timeline of Major Breakthroughs in Elucidation of Anatomy of the Mammalian Hypothalamic-Pituitary Unit
II century A.D.	Galen in Anatomicae Administrationes describes the association of the third ventricle with the rete mirabilis around the pituitary gland. In De Usum Partium considers the hypothalamic infundibulum and pituitary gland as draining route and receptacle for brain mucous passing down to the nasopharynx	1928	E. Scharrer describes “glandular cells” in the fish hypothalamus (concept of “neurosecretion”)
1316	Mondino dei Liuzzi da Bologna in his “Anothomia” refers to the third cerebral ventricle as “integrator” of body functions	1930	Popa and Fielding describe in the human pituitary stalk a portal vascular system interpreted as a route of the blood upward the hypothalamus
1522	Berangario da Carpi in his “Isagogue Breves” denies the existence of the Galenic “rete mirabilis” in the human brain	1940-1955	Harris and Green establish the basis for the neural control of the pituitary gland secretion and demonstrate its vascular link with the hypothalamus
1543	Vesalius includes in the “Fabrica” the first anatomical drawings of the hypothalamic infundibulum and pituitary	1954	WH Hess shows that both pituitary and autonomic responses are regulated by the anterior (trophotropic area) and posterior (ergotropic area) hypothalamus
1561-1627	Fallopius in the “Observationes Anatomicae” and Casserio in the “Tabulae Anatomicae” mention the arterial polygon at the base of the brain then described by Willis	1950-1958	Nauta and Kuypers describe the connections of the mammalian hypothalamus with the rest of the brain and propose that the limbic system influences pituitary function, introducing the concept of “hypothalamic integration”
1664	Willis in his “Cerebri Anatome” argues that humors out of the third ventricle may be carried to the pituitary gland	1960	Martinez describes the structure of the median eminence
1655-1672	Schneider and Lower reject the Galenic idea that the pituitary gland filters brain secretions to the nose	1962	Halaz put forth the concept of “hypophysiotrophic area” of the hypothalamus”
1742	Lieutand discovers vessels in the pituitary stalk	1964	Szentagothi defines the tuberoinfundibular tract
1767	Luigi Galvani in Disquisitiones Anatomicae circa Membranam Pituitariam discovers that mucus passing through the nostrils originates from small mucous glands of the human nasal mucosa and not from the pituitary	1968	Guillemin and Schally isolate the first hypothalamic releasing factor
1778	Sommering introduces the term “hypophysis”	1970	Nakane provides the first ultrastructural evidence for paracrine interactions in the pituitary gland
1860	Von Luska describes the primary (or hypothalamic) capillary plexus of the portal vessels	1971	L. Martini shows that circulating hypothalamic releasing-factors may regulate their own secretion, introducing the concept of “ultrashort feedback regulation”
1872-1877	Meynert and Forel define the anatomical borders of what they call “the neural portion extending forward the region of the subthalamus” (i.e. the hypothalamus)	1984	T. Hokfelt demonstrates the presence of two different neurotrasmitters in the same hypothalamic neuron, introducing the concept of “neuroendocrine regulation by multiple neuronal messengers”
1893	His introduces the term “hypothalamus” and provides the first anatomical subdivision based on ontogenesis of the human brain	1986	K. Fuxe and L. F. Agnati show that the median eminence is organized in modules, introducing the concept of “medianosome”, and hypothalamic neurons are regulated by both autocrine/paracrine and synaptic mechanisms, better known as “volume and wiring transmissions”
1894	Ramon Y Cajal discovers in rats the connection between the hypothalamus and posterior pituitary (supraoptico-hypophysial tract)

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