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).
|
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 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). |
|
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). |
|
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). |
|
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.
|
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.) |
|
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.
|
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.) |
|
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).
|