The hypothalamus is an integral part of the
substance of the brain. A small cone-shaped
structure, it projects downward, ending in the pituitary (infundibular)
stalk, a tubular connection to the
pituitary gland. The round
bony cavity containing the pituitary gland is called the sella turcica. The
posterior portion of the hypothalamus, called the median eminence, contains
many neurosecretory cells. Important adjacent structures include the
mammillary bodies, the third ventricle, and the optic chiasm, the last being
of particular concern to physicians because pressure from expanding tumours
or inflammations in the hypothalamus or pituitary gland may result in severe
visual defects or total blindness. Above the hypothalamus is the thalamus.
(For discussion of the function of these surrounding structures, see
the nervous system.)
The hypothalamus regulates
homeostasis. It has regulatory areas for thirst, hunger, body
temperature, water balance, and blood pressure, and links the
nervous system to the
endocrine system.
The hypothalamus, like the rest of the brain, consists of interconnecting
nerve cells ( neurons) with a rich blood
supply. To understand hypothalamic function it is necessary to define the
various forms of neurosecretion. First, there is neurotransmission, which
occurs throughout the brain and is the process by which one nerve cell
communicates with another at an intimate intermingling of projections from
the two cells (a synapse). This transmission of an electrical impulse from
one cell to another requires the secretion of a chemical substance from a
long projection from one nerve cell body (the axon) into the synaptic space.
The chemical substance that is secreted is called a
neurotransmitter. The process of synthesis and secretion of
neurotransmitters is similar to that shown in Figure 1
with the exception that neurosecretory granules migrate through lengths of
the axon before being discharged into the synaptic space.
Figure 1: Intracellular
structure of a typical endocrine cell.
Neurologists have long been aware of four classical
neurotransmitters:
epinephrine,
norepinephrine,
serotonin, and
acetylcholine, but recently there have emerged a large number of
additional neurotransmitters, of which an important group is the
neuropeptides. While bioamines and neuropeptides function as
neurotransmitters, some of them also perform the role of
neuromodulators; they do not act directly as neurotransmitters but
rather as inhibitors or stimulators of neurotransmission. Well-known
examples are the opioids (for example, enkephalins), so named because they
are the naturally occurring peptides with a strong affinity to the receptors
that bind opiate drugs such as morphine and heroin. In effect, they are the
body's opiates.
Thus the brain, and indeed the entire central nervous system, consists of an
extraordinary network of neurons interconnected by
neurotransmitters. The secretion of specific neurotransmitters, modified
by neuromodulators, lends an organized, directed function to the overall
system. These neural connections extend upward from the hypothalamus into
other key areas, including the cerebral cortex. The result is that
intellectual and functional activities as well as external influences,
including stresses, can be funneled into the hypothalamus and thence to the
endocrine system, from which they may exert effects on the body.
In addition to secreting neurotransmitters and neuromodulators, the
hypothalamus synthesizes and secretes a number of
neurohormones. The neurons secreting neurohormones are true endocrine
(neurohemal) cells in the classical sense since secretory granules
containing neurohormones travel from the cell body through the axon to be
extruded, where they enter directly a capillary network, thence to be
transported through the hypophyseal-portal circulation to the anterior
pituitary gland.
Finally, the neurohypophysis, or
posterior lobe of the
pituitary gland, provides the classical example of neurohormonal
activity. The secretory products, mainly vasopressin and oxytocin, are
extruded into a capillary network, which feeds directly into the general
circulation.
The existence of hormones of the hypothalamus was predicted well before they
were detected and chemically characterized, and they have been studied
intensively by many investigators. Two groups of American investigators, led
by Andrew Schally and Roger Guillemin, respectively, shared the Nobel Prize
for Physiology or Medicine for 1977 for their research on pituitary
hormones.
These neurohormones are known as releasing hormones because the major
function generally is to stimulate the secretion of hormones originating in
the anterior pituitary gland. They consist of simple peptides (chains of
amino acids) ranging in size from only three amino acids
(thyrotropin-releasing hormone) to 44 amino acids (growth hormone-releasing
hormone).
Thyrotropin-releasing hormone (TRH), a neurohormone,
is the simplest of the hypothalamic neuropeptides. It consists essentially
of three amino acids in the sequence glutamic acid–histidine–proline. The
simplicity of this structure is deceiving for TRH is involved in an
extraordinary array of functions. Not only is it a neurohormone that
stimulates the secretion of thyroid-stimulating hormone from the pituitary,
and, quite independently, the secretion of another pituitary hormone called
prolactin, but it also subserves other central nervous system activities
because it is a widespread neurotransmitter or neuromodulator within the
brain and spinal cord. There is evidence that TRH is involved in the control
of body temperature and that it has psychological and behavioral effects, at
least in animals. It may also have therapeutic value. There are studies
suggesting that it mitigates the damage induced by spinal cord injury and
that it leads to some improvement in the nervous disease known as
amyotrophic lateral sclerosis (Lou Gehrig's disease).
These multiple effects are less surprising when it is considered that TRH
appeared very early in the evolutionary scale of vertebrates and that, while
the concentration of TRH is greatest in the hypothalamus, the total amount
of TRH in the remainder of the brain far exceeds that of the hypothalamus.
The TRH-secreting cells are subject to stimulatory and inhibitory influences
from higher centres in the brain and they also are inhibited by circulating
thyroid hormone. In this way TRH forms the topmost segment of the
hypothalamic-pituitary-thyroid axis.
Gonadotropin-releasing hormone (GnRH), a
neurohormone also known as luteinizing hormone-releasing hormone (LHRH), is
a peptide chain of 10 amino acids. It stimulates the synthesis and release
of the two pituitary gonadotropins, luteinizing hormone (LH) and
follicle-stimulating hormone (FSH). While some investigators hold that there
are two types of GnRH, most evidence supports the conclusion that only one
type of neuropeptide stimulates the release of the two gonadotropins and
that the variations in levels of both gonadotropins in the circulation are
due to other modulating factors.
Characteristic of all releasing hormones and most striking in the case of
GnRH is the phenomenon of pulsatile secretion. In normal individuals, GnRH
is released in spurts at intervals of about 80 minutes. The pulsatile
administration of GnRH in large doses results in an ever-increasing
concentration of gonadotropins in the blood. In striking contrast, the
constant infusion of GnRH suppresses gonadotropin secretion. This phenomenon
is advantageous for persons for whom suppression is important. Such persons
include children with precocious puberty, and elderly men with cancer of the
prostate. On the other hand, pulsatile administration of GnRH is efficacious
in men or women in whom deficiency of gonadal function is due to impaired
secretion of GnRH. A potential application of this phenomenon is the
synthetic modifications of GnRH as a male as well as a female contraceptive.
Neurons
that secrete GnRH have connections to an area of the brain known as the
limbic system, which is heavily involved in the control of emotions and
sexual activity. Studies in rats deprived of pituitary glands and ovaries
but maintained on physiological amounts of female hormone (estrogen) have
demonstrated that the injection of GnRH results in complex and striking
changes in posture characteristic of the receptive female stance for sexual
intercourse.
Some individuals have hypogonadism (in which the functional activity of the
gonads is decreased and sexual development is inhibited) due to a congenital
deficiency of GnRH, which responds to treatment with GnRH. Most of these
people also suffer from hypothalamic disease and are deficient in other
releasing hormones as well, but there are also individuals in whom GnRH
deficiency is isolated and associated with a loss of the sense of smell
(anosmia). Abnormalities in the pulses of GnRH secretion result in subnormal
fertility, abnormal or absent menstruation, and possibly cystic disease of
the ovary or even ovarian cancer
Corticotropin-releasing hormone (CRH), a
neurohormone, is a large peptide consisting of a single chain of 41 amino
acids. It stimulates not only secretion of corticotropin in the pituitary
gland but also the synthesis of corticotropin in the corticotropin-producing
cells (corticotrophs) of the anterior lobe of the pituitary gland. Many
factors, both neurogenic and hormonal, regulate the secretion of CRH, since
CRH is the final common element directing the body's response to all forms
of stress, whether physical or emotional, external or internal. (This key
role of CRH in the hypothalamic-pituitary-adrenal axis is discussed below in
connection with the adrenal gland.) Among the hormones that play an
important role in modulating the influence of CRH is cortisol, the major
hormone secreted by the adrenal cortex, which, as part of the negative
feedback servomechanism (exerting control over another system through
negative feedback), blocks the secretion of CRH. Vasopressin, the major
regulator of the body's excretion of water, has an additional ancillary role
in stimulating the secretion of CRH.
Excessive secretion of CRH leads to an increase in the size and number of
corticotrophs in the pituitary gland, often resulting in a pituitary tumour.
This, in turn, leads to excessive stimulation of the adrenal cortex,
resulting in high circulating levels of adrenocortical hormones, the
clinical manifestations of which are known as Cushing's syndrome.
Conversely, a deficiency of CRH-producing cells can, by a lack of
stimulation of the pituitary and adrenal cortical cells, result in
adrenocortical deficiency. (These conditions are discussed below.
Like CRH, growth hormone-releasing hormone (GHRH) is
a large peptide. A number of forms have been described that differ from one
another only in minor detail and in the number of amino acids (varying from
37 to 44). Unlike the other neurohormones, GHRH is not widely distributed in
other parts of the brain. It is stimulated by stresses, including physical
exercise, and secretion is blocked by a powerful inhibitor called
somatostatin (see below Somatostatin). Negative feedback control of GHRH
secretion is mediated largely through compounds called somatomedins,
growth-promoting hormones that are generated when tissues are exposed to
growth hormone itself.
An excess of circulating growth hormone in adults leads to a condition
called acromegaly. Rarely, a benign tumour, called a hamartoma, located in
the hypothalamus may produce excessive amounts of GHRH, leading to
acromegaly. Equally rare are tumours arising in the islets of Langerhans of
the pancreas that may secrete excessive quantities of GHRH. Indeed, GHRH was
first successfully isolated and analyzed from such an ectopic (abnormally
positioned) hormone-producing tumour. Isolated deficiency of GHRH (in which
there is normal functioning of the hypothalamus except for this deficiency)
may be the cause of one form of dwarfism, a general term applied to all
individuals with abnormally small stature.
Somatostatin refers to a number of polypeptides
consisting of chains of 14 to 28 amino acids. The name was coined when its
discoverers found that an extract of the hypothalamus strongly inhibited the
release of growth hormone from the pituitary gland. Somatostatin is also a
powerful inhibitor of pituitary TSH secretion. Somatostatin, like TRH, is
widely distributed in the central nervous system and in other tissues. It
serves an important paracrine function in the islets of Langerhans, by
blocking the secretion of both insulin and glucagon from adjacent cells.
Somatostatin has emerged not only as a powerful blocker of the secretion of
GH, insulin, glucagon, and other hormones but also as a potent inhibitor of
many functions of the gastrointestinal tract, including the secretion of
stomach acid, the secretion of pancreatic enzymes, and the process of
intestinal absorption. Despite these multiple, widespread actions, the term
somatostatin has persisted because of its major role as a regulator of GH
secretion, and impaired somatostatin secretion may cause some forms of
hypersecretion of growth hormone.
No examples of somatostatin deficiency have been found, but a tumour called
a somatostatinoma has been well characterized in a number of patients.
Persons with a somatostatinoma have cramping abdominal pain, persistent
diarrhea, a mild elevation of blood glucose levels, and sudden flushing of
the skin.
The hypothalamic regulation of prolactin secretion
from the pituitary is different from the hypothalamic regulation of other
pituitary hormones in two respects. First, the hypothalamus primarily
inhibits rather than stimulates the release of prolactin from the pituitary
(the hypothalamus stimulates the release of all other pituitary hormones).
Thus, if pituitary cells are removed from the influence of the hypothalamus,
few or none of the pituitary hormones are secreted, except for prolactin,
which continues to be secreted by the prolactin-secreting cells
(lactotrophs). Second, this major inhibiting factor is not a neuropeptide,
but rather the neurotransmitter dopamine, a fact exploited in afflicted
persons by physicians who are able to reduce abnormally high concentrations
of prolactin by using drugs that mimic the prolactin-inhibiting effects of
dopamine. Another prolactin-inhibiting factor (PRF) comes into play
primarily during pregnancy and lactation. Prolactin-stimulating factors also
exist, among them TRH.
Prolactin deficiency is known to occur, but only rarely. Excessive prolactin
production (hyperprolactinemia) is a common endocrine abnormality, and the
prolactinoma is the most frequently encountered pituitary tumour.
Although modern endocrinology began with the
discovery that a substance, secretin, secreted into the blood from the cells
lining the gastrointestinal
tract stimulates the secretion of pancreatic juices, little attention
was subsequently paid to gastrointestinal hormones. When investigators began
to examine the distribution of neuropeptides within the body, however, there
emerged a bewildering variety of these hormones, not only within the brain
but also in the lining of the gastrointestinal tract and in other organs.
The list includes glucagon, the enkephalins, secretin, cholecystokinin,
gastrin, calcitonin, angiotensin, substance P, pancreatic polypeptide,
neuropeptide Y (a human variant of a peptide called bombesin),
delta-sleep-inducing peptide, and vasoactive intestinal peptide. The actions
and interactions of these hormones both in the intestinal tract and in the
brain are complex and are the subject of continuing investigations. Briefly,
these peptides play important roles in the transmission and inhibition of
pain stimuli, in eating and drinking behaviour, in memory and learning, in
the regulation of body temperature, in the induction of sleep, and in sexual
behaviour.
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