THE HYPOTHALAMUS AND PITUITARY
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 the 14th 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 who published the first anatomical depiction of the infudibular-pituitary stalk in De Humani Corporis Fabrica (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 ancient drawing of the third ventricle and rete mirabilis is shown in Fig. 3, and Michelangelo Buonarroti, whose painting on the ceiling of the Sistine Chapel in the Vatican at Rome uses the hypothalamic-pituitary region as a backdrop to his depiction of the creation of man (Fig. 4) (4).
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Figure 1. Description of the functional role exerted by the cerebral third ventricle, as reported by Mondino de' Liuzzi in Anothomia. (A) Original frontpage of Anothomia in a XIV century edition; (B) Original text (in brackets) in meidieval Latin (from the 1316 A.D. manuscript kept at the Societ� 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). |
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Figure 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 oribital fissure (C, D, E, F) believed to drain the brain mucus or phlegm (in Latin pituita) from the pituitary gland to the nasopharynx; 2) anatomical relationships beween 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). |
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Figure 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 sorrunds the pituitary gland; (B) three-dimensional representaion 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., The Human Hypothalamus: clinical anatomy of endocrine, autonomic and behavioral responses, J. Endocrinol. Invest 2003, in press). |
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Figure 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., The human hypothalamus: clinical anatomy of endocrine, autonomic and behavioral responses, J. Endocrinol. Invest 2003, in press). |
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 20th century and continues into the 21st century. Table 1 summarizes the major historical advances in the elucidation of the anatomy of the mammalian hypothalamic-pituitary unit.
Table 1. Timeline of Major Breakthroughs in Elucidation of Anatomy of the Mammalian Hypothalamic-Pituitary Unit |
II century A.D. |
Galen describes in the "De Usum Partium" the hypothalamic infundibulum and pituitary gland as draining route and receptacle for brain mucous, and the existence of the "rete mirabilis" |
1316 |
Mondino dei Liuzzi da Bologna in his "Anothomia" refers to the third cerebral ventricle as "integrator" of body functions |
1522 |
Berangario da Carpi in his "Isagogue Breves" denies the existence of the Galenic "rete mirabilis" in the human brain |
1543 |
Vesalius includes in the "Fabrica" the first anatomical drawings of the hypothalamic infundibulum and pituitary |
1561- 1527 |
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 |
1664 |
Willis in his "Cerebri Anatome" argues that humors out of the third ventricle may be carried to the pituitary gland |
1655- 1672 |
Schneider and Lower reject the Galenic idea that the pituitary gland filters brain secretions to the nose |
1742 |
Lieutand discovers vessels in the pituitary stalk |
1778 |
Sommering introduces the term "hypophysis" |
1860 |
Von Luska describes the primary (or hypothalamic) capillary plexus of the portal vessels |
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) |
1893 |
His introduces the term "hypothalamus" and provides the first anatomical subdivision based on ontogenesis of the human brain |
1894 |
Ramon Y Cajal discovers in rats the connection between the hypothalamus and posterior pituitary (supraoptico-hypophysial tract) |
1928 |
E. Scharrer describes "glandular cells" in the fish hypothalamus (concept of "neurosecretion") |
1930 |
Popa and Fielding describe in the human pituitary stalk a portal vascular system interpreted as a route of the blood upward the hypothalamus |
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 |
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" |
1960 |
Martinez describes the structure of the median eminence |
1962 |
Halaz put forth the concept of "hypophysiotrophic area" of the hypothalamus" |
1964 |
Szentagothi defines the tuberoinfundibular tract |
1968 |
Guillemin and Schally isolate the first hypothalamic releasing factor |
1970 |
Nakane provides the first ultrastructural evidence for paracrine interactions in the pituitary gland |
Anatomy of the Pituitary Gland
Gross and Radiologic Anatomy
The pituitary gland lies within a recess of the median part of the middle cranial fossa in the sphenoid bone (sella turcica) and is composed of two major components, the anterior lobe (adenohypophysis) and the posterior lobe (neurohypophysis) that can be readily distinguished radiologically by magnetic resonance imaging (Fig. 5). The anterior lobe contains three subdivisions including the pars distalis, pars intermedia and pars tuberalis. The pars distalis makes up the bulk of the anterior pituitary and is primarily responsible for the secretion of anterior pituitary hormones into the peripheral circulation. The pars intermedia lies between the pars distalis and the posterior pituitary and is vestigial in man, while the pars tuberalis is well defined in most mammalian species and surrounds the infundibular stem (6). The floor of the sella, or lamina dura, abuts the sphenoid sinus, allowing direct surgical access to the pituitary by the transsphenoidal route. Other important boundaries to the pituitary gland are the cavernous sinus laterally, which contain the internal carotid artery surrounded with sympathetic fibers, and the cranial nerves III, VI, V (ophthalmic and maxillary branches), and VI (Fig. 6). The optic chiasm is located superiorly, separated from the pituitary by the cerebrospinal fluid-filled suprasellar cistern and the dural roof of the pituitary, the diaphragma sella.
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Figure 5. (A) Magnetic resonance image (MRI) and (B) corresponding schematic illustration of the human hypothalamus (H) and pituitary gland seen in saggital orientation. Note the high intensity or "bright spot" of the posterior pituitary by MRI in (A), sharply defining the boundary between the anterior pituitary gland. III = third ventricle (Modified from Lechan RM. Neuroendocrinology of Pituitary Hormone Regulation. Endocrinology and Metabolism Clinics 16:475-501, 1987.) |
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Figure 6. (A) MRI and (B) schematic image of the pituitary fossa and its anatomic relationships seen in coronal orientation. The cavernous sinus contains the internal carotid artery and cranial nerves III, IV, V1, V2, and VI. The optic chiasm resides immediately above the pituitary gland and is separated from it by a cerebrospinal fluid-filled cistern. (Modified from Lechan RM. Neuroendocrinology of Pituitary Hormone Regulation. Endocrinology and Metabolism Clinics 16:475-501, 1987.) |
Embryologic Anatomy
The posterior lobe of the pituitary gland is smaller than the anterior lobe and embryologically derives from the neural primordia as an outpouching from the floor of the third ventricle. As a direct, anatomic extension of the central nervous system, it is not surprising that the posterior pituitary is composed primarily of unmyelinated axons and axon terminals as well as specialized glial cells called pituicytes.
In contrast to the posterior pituitary, the anterior pituitary derives from the oral ectoderm as Rathke's pouch, first seen by the third week of pregnancy in man. There is little if any direct nervous innervation to the pars distalis, but cell to cell contact with the neuroectoderm of the primordium of the ventral hypothalamus is critical for differentiation of the anterior pituitary into the five major cell types. This occurs as a result of the release of specific growth and transcription factors such as bone morphogenic protein (BMP)-4 and fibroblast growth factor (FGF)-8 (7). Transcription factors involved in differentiation of specific cell types in the anterior pituitary are shown schematically in Fig. 8. Once mature, however, the ability of the hypothalamus to communicate with the pars distalis is dependent upon the hypophysial portal system, a vascular link that connects the base of the hypothalamus to the pituitary gland.
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Figure 8. Pituitary-specific transcription factors involved in the development of the anterior pituitary from Rathke's pouch. Thyrotrophs, lactotrophs and somatotrophs derive from a common lineage, determined by Prop-1 and Pit-1. Independent lineages are observed for corticotrophs and gonadotrophs. (From Cohen and Radovick, Endocrine Reviews 23: 431-442, 2002.) |
Microscopic Anatomy
Microscopically, the anterior pituitary is composed of nests or cords of cuboidal cells organized near venous sinusoids lined with a fenestrated epithelium into which secretory products from the anterior pituitary are collected. Class ically, five cell types and six secretory products of the anterior pituitary gland can be identified immunocytochemically including the somatotrophs (growth hormone), lactotrophs (prolactin), corticotrophs (adrenocorticotropic hormone), thyrotropes (thyroid-stimulating hormone), and gonadotrophs (luteinizing hormone and follicle-stimulating hormone) (8). It is now recognized, however, that the anterior pituitary is vastly more complicated. In addition to morphological and physiological evidence for heterogenity among the classical anterior pituitary cell types (9-12) and the presence of clusters of a unique cell type, the folliculostellate cell (13), the anterior pituitary can also synthesize numerous other nonclassical peptides, growth factors, cytokines, binding proteins and neurotransmitters listed in Table 2 that are important for paracrine and/or autocrine control of anterior pituitary secretion and/or cell proliferation under defined physiological conditions (14).
Table 2. Nonclassical Anterior Pituitary Substances and Cell(s) of Origin |
Substances |
Cell Types |
PEPTIDES |
ACTIVIN B, INHIBIN, FOLLISTATIN |
F,G |
ALDOSTERONE STIMULATING FACTOR |
UN |
ANGIOTENSIN II (ANGIOTENSINOGEN, ANGIOTENSIN I CONVERTING ENZYME, CATHEPSIN B, RENIN) |
C,G,L,S |
ATRIAL NATURETIC PEPTIDE |
G |
CORTICOTROPIN-RELEASING HORMONE-BINDING PROTEIN |
C |
DYNORPHIN |
G |
GALANIN |
L,S,T |
GAWK (CHROMOGRANIN B) |
G |
GROWTH HORMONE RELEASING HORMONE |
UN |
HISTIDYL PROLINE DIKETOPIPERAZINE |
UN |
MOTILIN |
S |
NEUROMEDIN B |
T |
NEUROMEDIN U |
C |
NEUROPEPTIDE Y |
T |
NEUROTENSIN |
UN |
PROTEIN 7B2 |
G,T |
SOMATOSTATIN 28 |
UN |
SUBSTANCE P (SUBSTANCE K) |
G,L,T |
THYROTROPIN RELEASING HORMONE |
G,L,S,T |
VASOACTIVE INTESTINAL POLTPEPTIDE |
G,L,T |
GROWTH FACTORS |
BASIC FIBROBLAST GROWTH FACTOR |
C,F |
CHONDROCYTE GROWTH FACTOR |
UN |
EPIDERMAL GROWTH FACTOR |
G,T |
INSULIN-LIKE GROWTH FACTOR I |
S,F |
NERVE GROWTH FACTOR |
UN |
PITUITARY CYTOTROPIC FACTOR |
UN |
TRANSFORMING GROWTH FACTOR ALPHA |
L,S,G |
VASCULAR ENDOTHELIAL GROWTH FACTOR |
F |
CYTOKINES |
INTERLEUKIN-1 BETA |
T |
INTERLEUKIN-6 |
F |
LEUKEMIA INHIBITORY FACTOR |
C,F |
NEUROTRANSMITTERS |
ACETYLCHOLINE |
C,L |
NITRIC OXIDE |
F |
C = corticotroph, F = folliculostellate cell, G = gonadotroph, L = lactotroph, S = somatotroph, T = thyrotroph, UN = unknown
neurosecretion based on the presence of "glandular cells" in the fish hypothalamus |
Blood Supply
The pars distalis of the anterior pituitary gland receives little or no arterial blood supply from branches of the internal carotid artery (15,16), while the posterior pituitary is fed by an anastomotic arterial circle derived from each of the inferior hypophysial arteries as they pierce the cavernous sinus (Fig. 7). Rather, the pars distalis is supplied by venous blood delivered through the long portal veins that descend along the ventral surface of the pituitary stalk and interconnect capillary beds in the pars distalis with specialized capillary beds of the portal capillary system in the base of the hypothalamus called the median eminence (Fig. 7). In turn, the portal capillary plexus in the median eminence receives arterial blood from a separate branch of the internal carotid artery, the superior hypophysial artery, after the internal carotid artery ascends from the cavernous sinus. In addition to venous blood draining from the hypothalamus, the pars distalis also receives venous blood draining from the posterior pituitary through the short portal vessels, giving rise to approximately 30 per cent of the total blood supply to the anterior pituitary (17,18). The perfusion sequence of arterial blood first reaching the posterior pituitary and the median eminence, followed by venous drainage to the anterior pituitary can visualized in man using rapidly enhanced magnetic resonance images (dynamic MRI) (19) (Fig. 9). As a result of the venous blood flow pattern to the pituitary, the pars distalis is in a unique position where it can receive humoral information from both the hypothalamus and the posterior pituitary, as well as substances circulating in the peripheral bloodstream. Due to the location of pars tuberalis cells in the pituitary stalk and ventral surface of the median eminence, adjacent to the portal capillary plexus, it is likely that these cells also contribute to the humoral substances that are carried by a vascular route to the pars distalis (20), although its physiological significance is unknown.
Available soon |
Figure 7. Drawing of the vasculature of the primate anterior and posterior pituitary gland. A portion of the pituitary stalk (I) has been cut away to visualize the infundibular recess (IR) and portal capillaries (PC). CPV = confluent pituitary veins, CS = cavernous sinus, H = hypothalamus, IC = internal carotid artery, IHA = inferior hypophysial artery, IP = infundibular processes or posterior pituitary, LPV = long portal veins, SHA = superior hypophysial artery, SPV = short portal veins. (From Lechan RM, Functional Microanatomy of the Hypophysial-Pituitary Axis, in Melmed, S (Ed), Oncogenesis and Molecular Biology of Pituitary Tumors, Frontiers of Hormone Research, 20: 2-40, 1996.) |
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Figure 9. (A-D) MRI of sequential sequences of the stalk and pituitary gland in saggital orientation following the intravenous administration of gadolineum. (A) Appearance prior to gadolineum. (B) Following gadolineum, the posterior pituitary is the first structure to show contrast enhancement. (C) This is followed by the pituitary stalk (arrow) and then finally (D) the anterior pituitary. (From Yuh et al, AJNR 15: 101-108, 1994.) |
Venous drainage from the anterior pituitary to the systemic circulation is through adenohypophyseal veins located at a sulcus separating the anterior pituitary from the posterior pituitary (15). Other than the short portal vessels, venous drainage from the posterior pituitary collects into neurohypophyseal veins, which together with adenohypophyseal veins, extend as common vessels (confluent pituitary veins) to the cavernous sinus (Fig. 7). |
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