Basic and Clinical Neurosciences | Transcripts | Functional Anatomy of the Hypothalamus and Pituitary

Overview of the Hypothalamus
Afferent and Efferent Connections
Structures of Neuroendocrine Control
Functions of the Hypothalamus
Temperature Control and Its Dysfunction
Water and Osmotic Balance
Circadian Rhythms
Fear, Rage, and Pleasure
Research on Hypothalamic Therapy
Pituitary Function

Chapter 1: Overview of the Hypothalamus

Peter Carmel: Thank you. It is a pleasure to return. I am surprised at how many of you are loyal and come back either year after year or every couple of years for an update. And this is, as Sander mentioned, really home.

I'm going to talk about the functional anatomy of the hypothalamus and pituitary. As you see before you, the New Jersey Medical School in bucolic downtown Newark, New Jersey, and that's who I am. The hypothalamus has been part of our cultural heritage for centuries. We have, as a species, always thought of the base of the brain, or at least for the past two millennia, thought of the area of the base of the brain as controlling many of our senses and our emotions. And this is a 14th-century woodcut that says basically everything I'm going to say here today, so thank you.

The hypothalamus is phylogenetically very ancient. Almost from the time that we were teleost fishes our hypothalamus has had its important position. It's linked to the oldest portions of the brainstem, the cortex, and the limbic system. Most of all the hypothalamus, shown here outlined, is surprisingly small. It is less than an inch in any of its dimensions. We have, artificially somewhat, parcellated the hypothalamus into a number of cell groups, which we call nuclei, and there are far more subdivisions than are shown in the cartoon. This is Macaca mulatta, and it shows the division of the hypothalamus; this is rostral, this is caudal; this is a sagittal plane, a sagittal view; this is the optic chiasm, and from the lamina terminalis to the posterior border of the mammillary bodies, we tend to divide the hypothalamus into an anterior, medial, and posterior group of nuclei, based largely on their function. We have major nuclei in the anterior, a lot more nuclei in the medial, and a very simple structure in the posterior hypothalamus. I should warn you that there is one proposal that subdivides the mammillary nuclei into 11 different nuclei.

Then if you look at the coronal view from the front, we see another organization. And this organization is paraventricular, alongside the third ventricle, medial, and lateral. This organization is based largely on the fiber bundles which traverse the hypothalamus roughly in a rostral-caudal direction. And here we see them. This is the paraventricular band. The medial portion are the nuclei, as represented here by the ventral medial hypothalamic nucleus. The lateral part of the hypothalamus is this enormously big, busy, broad band of fibers called the median forebrain bundle. There you have the paraventricular, medial, and lateral parts of the hypothalamus, based on fiber bundles. You can see here the ventromedial nucleus is there in between these two broad fiber systems that bring information to it and take it away.

Chapter 2: Afferent and Efferent Connections

The afferent connections, the information coming into the hypothalamus, has multiple short-chain pathways, and it is bilaterally represented. Both on the afferent and on the efferent side there is bilateral representation, so that for hypothalamic damage to take effect virtually requires that bilateral hypothalamic nuclei are damaged. There's a strong input from the brainstem, and these are monoamine fibers from the median raphe nuclei. There is a cortical input from the old brain, the paleocortex, which is largely our old smell brain. And finally a strong input from the limbic system. These are the four major bundles that bring information to the hypothalamus: the medial forebrain bundle we've talked about from both the forebrain and the brainstem, the fornix from the hippocampus, the stria terminalis from the amygdala, and the mammillary peduncle, misspelled, from the midbrain tegmentum. And here's the cartoon represents that, and you see here the mammilotegmental tract, strong input from the brainstem; and from the median forebrain bundle, a strong input from a cortex of the midline nuclei of the septa, septal region, and from the supraorbital region of the frontal cortex.

The effect of the hypothalamus is carried out again by multiple short-chain pathways. What that means is that the effect doesn't come on rapidly the way a knee jerk does or a simple monosynaptic reflex, but in fact builds over a period of time, requiring multiple synapses to be involved, and allowing for bilateral representation. The hypothalamus has been called the head ganglion of the autonomic nervous system because of the profound sympathetic and parasympathetic effects that it has.

There are frequent feedback loops, and that allows for set-point mechanisms or oscillators. And Barry Levin at our medical school, who is one of the leading researchers in experimental obesity, says if you talk about the hypothalamus you have to talk about set-points and oscillators, and that is what the hypothalamus is designed to do. And in addition, we have a portion of a hypothalamus that has neurosecretory cells. So think of the neurosecretory portion of the hypothalamus as somewhat apart from the anterior and posterior hypothalamus, which are really involved in our autonomic nervous system. The hypothalamus sends fibers to all of the structures from which it receives fibers, a primary requisite for feedback regulation.

Now, here are the efferent connections, and again four major efferent bundles: the medial forebrain bundle, going to the forebrain and the brainstem; the posterior longitudinal fasciculus, which goes all the way down to the spinal cord, but hits portions of the spinal cord that are important for autonomic responses; the mammillothalamic tract to the anterior nucleus of the thalamus—I have a doctorate from neuroanatomy from this institution and I did the doctorate for reasons that seemed important at the time on the ventroanterior nucleus of the thalamus, but its chief claim to fame is that it is the recipient of this tract, which is very distinctive in gross dissections, and has the wonderful name of the tract of [inaudible]—and then the hypothalamic-hypophyseal tract, perhaps the most important functional portion of the hypothalamus.

And here you see them. This is the hypothalamic-hypophyseal portion, and this important efferent connection that goes down all the way to the brainstem, as we'll see on the next cartoon, and down to the spinal cord. The four pathways, the autonomic control within the spinal cord, posterior lobe of the pituitary, regulation of the primary portal plexus to control the anterior lobe of the pituitary, and important connections involved in osmoreceptors in the ventricle.

The structure of the hypothalamus when you look at it under the microscope when you stain it, is incredibly, incredibly dense. It is filled with receptor sites, neurosecretory cells, very rich in neural transmitters, and the hypothalamic releasing and inhibiting hormones, and a strange cell called the tanycyte. This is from Sue Calchalk's work in our lab; this is cat, but it is stained for monoamine fiber endings, and you can see how densely monoamine terminals are found in the hypothalamus. This next is the sagittal view of a cat pituitary and hypothalamus; and particularly the primary plexus, the upper portion of the stalk, is incredibly rich in monoamine fiber terminals. The influences of monoamines on the releasing hormones of the hypothalamus is their major way of being regulated.

Chapter 3: Structures of Neuroendocrine Control

There are two portions for neuroendocrine control in the hypothalamus, and they are divided into the large cells and the small cells; seems pretty straightforward. The magnocellular neurons are in the supraoptic and paraventricular nuclei, and they stimulate water uptake by releasing ADH [antidiuretic hormone]. Loss of that hormone causes diabetes insipidus, and oversecretion causes water intoxication or the syndrome of inappropriate ADH secretion. Oxytocin is used in the milk ejection reflex, and it makes the myoepithelium of the lactiferous ducts contract. Both vasopresin and oxytocin are polypeptides, but are always linked to a protein precursor called neurophysin, which is wonderful beautiful, neurophysin stains beautifully, and you can always tell where the magnocellular neurons are if you stain for neurophysin. The neurophysin is this rich brown color, and these are in fact the magnocellular neurons.

This is a dark field illustration of the supraoptic nucleus. And you see there's a band of fibers that comes down from the paraventricular nuclei, picks up more fibers from the supraoptic nuclei, and sweep on down to the pituitary. This is shown in this cartoon, the paraventricular nucleus, the supraoptic nucleus, this broad band of fibers which principally goes to the posterior lobe of the pituitary for the release of ADH. Zimmerman, Ferin, and I some years ago found that in fact a good portion of these fibers also terminate on the primary portal plexus, so that there is an ADH and oxytocin influence on the release of hormones from the anterior pituitary. This is from our Science article in 1984. This actually was the cover of Science. It shows a magnocellular neuron stained with neurophysin, and then it's counter-stained to show the monoamine terminals. And the monoamine influence on the release of hypothalamic releasing hormones is extensive.

The small cell neurosecretory neurons, the parvocellular neurons, produce the nine hypothalamic releasing factors. These neurons end on the primary portal plexus. The primary portal plexus is interesting because it's the only place around the brain where there is a fenestrated epithelium. How those fenestrations work is still a matter of some debate.

From your knowledge of the portal circulation in the liver in which a capillary bed drains into a vein, which then breaks up into a secondary capillary bed, you know the analogy of the primary and secondary pituitary portal system. The primary capillary bed is in the median eminence. That blood drains into long portal veins, which are the surface of the stalk, and then that breaks up into another capillary-like bed, really a sinusoidal bed, of venous blood in the distal portion of the anterior pituitary. And the receptors for these releasing hormones are found on the pituitary cells.

This cartoon shows the influence of monoamines, dopamine and norepinephrine, and 5-hydroxytryptophan, serotonin, on the parvicellular neuron, influencing the rate at which the parvicellular neuron produces and releases its releasing hormone, and then the releasing hormone or releasing factors are discharged into the capillary of the primary portal plexus.

Here's an illustration of what we've just talked about. The blood supply for both the median eminence and much of the pituitary comes from the superior hypophyseal artery, and then breaks up into a capillary bed in the upper portion of the stalk, or the median eminence, the primary portal plexus. That blood gathers into the long portal veins, and then breaks up again into a secondary capillary bed within the pituitary.

This is a nice view we happened to get during an operation on a cranial pharyngioma. This is the tumor capsule here being lifted off the pituitary stalk. The pituitary stalk has a unique striate appearance which is caused by the long portal veins on its surface. And with Drs Zimmerman and Ferin, we were able to cannulate the individual long portal veins and stimulate and record from pituitary cells in Macaca mulatta.

Here are the hypothalamic releasing factors. One is missing from this list. Growth hormone releasing factor, somatomedin, and then in here should be growth hormone inhibiting factor, or somatostatin. But three of the pituitary hormones are under dual control—that is, growth hormone, prolactin and melanin, are both stimulated and inhibited by separate releasing factors from the hypothalamus. The other hormones—thyroid, cortisone, the sexual hormones—are released by a single factor. Here the cartoon showing the releasing factors here and the target cells in the pituitary with TSH [thyroid stimulating hormone (thyrotropin)], ACTH [adrenocorticotropic hormone (corticotropin)], LH [luteinizing hormone], and FSH [follicle-stimulating hormone], having just stimulatory releasing factors, and growth hormone, prolactin, and melanin having both releasing and inhibiting hormones.

I wish I knew what I was talking about here. This is the tanycyte. We know he's there. It's a cell that has a border on the base of the third ventricle. The whole third ventricle is lined by ependyma, and much of that ependyma is ciliated ependyma. Wherever you have ependyma you have a barrier of glia just beneath it. But the base of the third ventricle is very specialized in that it has very flat, nonciliated ependymal cells and no glial barrier. The good Lord didn't design it this way without purpose, as we know from our creationism friends, but he has not yet revealed that to us, but He will. But the tanycyte lies in that strange area of the base of the third ventricle, and it connects directly to the primary portal plexus of the portal system. We can see under electromicrographs and experimentally that the tanycyte imbibes CSF [cerebrospinal fluid], just gulps it up, and that this CSF goes down the tanycyte and is released into the primary portal plexus. We know it's there, we know what it's doing, we don't know why. But it is among many things we don't know why. And here is another cartoon showing the tanycyte at the base of the third ventricle, and ending multiplied on the primary portal plexus of the median eminence.

Chapter 4: Functions of the Hypothalamus

The hypothalamus coordinates drive-related activities. I don't know who initiated that use of the phrase but it is widespread in the literature now, and drive-regulated activities, I think, is a perfect description of hypothalamic activity. With our connection to the limbic system, the hypothalamus regulates our emotional drives, with outputs to both lobes of the pituitary; it regulates and coordinates our hormonal drives; and with connections to visceral and somatic nuclei of the brainstem and of the spinal cord, it controls our autonomic drives. The hypothalamus is our homeostasis watchdog. It regulates all of the basic things of our life: temperature, food and water, sleep and wakefulness, defense or stress, circulatory volume and blood pressure, circadian rhythms, sexual behavior, and affective behavior. And it doesn't charge $180 an hour like most psychiatrists.

Now in the early part of the 20th century Karplus and Kreidel gave phoretic stimulation to the hypothalamus first of rats and then of cats and dogs. They found that basically there were two sets of responses that they could elicit. If they stimulated the anterior hypothalamus, they got a series of responses that we now know are controlled by the parasympathetic autonomic system—and those would be bradycardia, pupillary constrictions, salivation, peristalsis, and vasodilatation; whereas if they stimulated the posterior hypothalamus, they got responses which were largely sympathetic—tachycardia, hypertension, pupillary dilatation, intestinal stasis, and vasoconstriction. A more sophisticated look at stimulation of the hypothalamus was carried out in Zurich by W. R. Hess, nominated but never elected for the Nobel Prize; and this was his publication in '42, and he could observe all sorts of responses to hypothalamic stimulation. Pupillary dilatation is easy to do—rage, sleep, all of the affective behaviors could be elicited by hypothalamic stimulation.

One of the other ways that we can examine hypothalamic function is to see what happens with tumors in the region of the hypothalamus. The most vulnerable part of the hypothalamus when we have tumors is the area of the hypothalamus, the medial portion of the hypothalamus, that controls the pituitary stalk functions. So the endocrine effects of tumors are often very prominent, and those would be short stature, sexual abnormalities, hypogonadism or precocious puberty, and diabetes insipidus. Less often we see effects that are related to hypothalamic damage—not really part of the stalk—and those include obesity and hyperphasia, psychiatric disturbances, somnolence, emaciation and anorexia, and thermodisregulation.

Hypothalamic damage disrupts our basic homeostasis. The hypothalamus protects our homeostatic mechanisms. These are the hypothalamic syndromes, if you will, and they are disorders of endocrine, caloric, osmolar function, thermal regulation, state of alertness, affective disorders, disorders of autonomic balance, and memory and learning disorders.

Chapter 5: Temperature Control and Its Dysfunction

Let's look first at temperature control. The temperature control mechanisms of the hypothalamus have been worked out in surprising detail. We know that in the anterior hypothalamus there are cold-sensitive cells and there are heat-sensitive cells. We know that the cold-sensitive cells are mediated by serotonin, and we know that the heat-sensitive cells use norepinephrine as their mediator. And we know that the heat-sensitive cells are more numerous. So when the anterior hypothalamus—where these temperature receptors are—are stimulated, we feel warm. The response elicited is vasodilatation, sweating, and heat loss. When the posterior hypothalamus is stimulated, we feel cold, and vasoconstrict, have shivering and try to produce heat.

Here is a cartoon showing what we've just talked about, the sensory portion of the temperature system in the anterior hypothalamus with hot- and cold-sensitive cells; they give off fibers that run in the median forebrain bundle to the posterior hypothalamus, and with their appropriate stimulation, the posterior hypothalamus either tries to produce heat or tries to lose heat. This leads to some interesting things. This is the handiwork of Dr Housepian. Dr Housepian was at one time one of the leading people, and certainly the leading New York person, on doing lesions to cure Parkinsonism. Those of you who know the saga of this know that there have been numerous sites where you can influence the extrapyramidal system to try to modulate either the tremor of Parkinsonism or its rigidity. For a while that target was very much here at the base of the thalamus. But in fact other targets were used. Now what we noticed is that for some of the lesions right in here there were sympathetic deficits following thalomotomy. So clearly these were interrupting a pathway that was involved in the sympathetic discharge system. We now know that it was fibers from the posterior hypothalamus running just here under the thalamus on their way down to the brainstem and spinal cord.

This is one of our patients. This is a sweat test. To do a sweat test, the face is first coated with an organic iodide and we let that dry; and then the iodide is touched with a puff of cornstarch; and then you give the patient some aspirin, you put him in a warm room and you try to make him sweat. If he sweats, the iodine mixes with the starch and produces a black color. If there's no sweating then the starch remains white. This patient has ptosis of his right eye, he has anhydrosis of the right side of his face, and in fact the upper portion of his trunk, and there was a degree of myosis. This is from a pupillary test on that same patient. So a sympathetic deficit, and Horner's syndrome, if you wish, could be induced by interrupting the efferent fibers coming from the posterior hypothalamus.

Chapter 6: Water and Osmotic Balance

Moving onto water and osmotic balance, there are both peripheral and central volume and osmoreceptors. Volume is separate from osmolarity—the same cells do not do both. And the effect, the way we control our water and osmotic balance, is by the release or the inhibition of antidiuretic hormone [ADH]. The osmoreceptors, and some of the volume receptors, are in specialized organs that are clustered around the surface of the third ventricle. This is the anterior wall of the third ventricle here, the lamina terminalis, and the subfornical organ and the organum vasculosum lamina terminalis are both prominent osmoreceptor sites. In addition, the subcommissural organs also have that effect. These organs have a lot of input into the magnocellular portion of the hypothalamus, and control or inhibit the release of ADH from the neurohypothesis. Here is a cartoon representing that, showing that the supraoptic and paraventricular nuclei, which release ADH, have this input from osmoreceptors. Notice also that there is prominent input from the bloodstream with angiotensin II levels, and there is telencephalic input into these osmo and volume receptors.

Chapter 7: Circadian Rhythms

The hypothalamus is also our clock. And there's been a lot of popular press over the last decade or so on circadian rhythms and how we keep our clock going. Circadian means circa dia, about 12 hours, and in fact that clock is really not a very good clock because some of us run on a 23-hour clock, some of us run on a 25-hour clock. I've always been a night person locked in a deadly day-person profession, and I know that it's the fault of my hypothalamus. This is just one of our circadian rhythms, and there are hundreds of them. This is the release of serotonin during a 24-hour cycle, and this is one of the typical ways in which our body works for 24 hours. Circadian rhythms are in our species, but not in all species, largely driven by input from the retina. We sense the light, and we react to the light. Interesting, blind people who have no light perception still can have their circadian rhythms changed by coming out of daylight. A blind person locked in a cave will have very much the same reaction as a sighted person locked in a cave. So we sense the light in ways more than our retina. But the strongest input is from the retina, and the oscillator, the guardian of our 24-hour clock is the suprachiasmatic nucleus. The suprachiasmatic nucleus, lying appropriate[ly] enough just above the optic chiasm, is rich in inputs and a lot of neuromediators. It exercises its effects via the brainstem; and the median raphe nuclei and the dorsal raphe nuclei are the source of the feedback to the suprachiasmatic nucleus. The cartoon tells us this. Here is the retina. The retina has direct inputs to the suprachiasmatic nucleus, but most of our sight goes through the geniculate bodies in the thalamus, and the geniculate bodies of the thalamus in turn control some of the input from the dorsal and medial raphe nuclei. They in turn affect our oscillator in the suprachiasmatic nucleus, another one of the feedback loops in which many levels of the brain are integrated by the hypothalamus.

Chapter 8: Fear, Rage, and Pleasure

We have pleasure responses. And a prurient interest at one time led me to put a lot of illustrations into this portion of the talk, which I no longer do. I have matured beyond that. Stimulation of the rostral anterior hypothalamus near the septal nuclei, just actually rostral to the anterior hypothalamic nucleus, will cause animals to self-stimulate, and monkeys will bar-press hundreds of times to get a single buzz near their septal nuclei. And if the electrode is in exactly the right place, the animal will bar-press continuously in preference to both sleeping and eating. And they will die of pleasure. We don't know, but it is likely that this is mediated by the release of endorphin from this area.

Fear and rage responses are common with both hypothalamic stimulation and hypothalamic lesions. If the ventromedial nucleus of the hypothalamus is destroyed, episodic rage is common. With that episodic hyperenergy raise is hyperphasia, overeating. Stimulation of the lateral nuclei may cause rage response, and both of these responses are mediated by the limbic system. Both can be abolished by bilateral removal of the amygdala.

Here are some affective reactions. Here a lesion of VM bilaterally would cause episodic rage. The Japanese often are trying to influence affective behavior by brain stimulation, and stimulation of the posterior hypothalamus will cause fear and horror, and a lesion in that same area bilaterally will cause apathy and inactivity.

We have come to see that there is a new number one public health menace in the United States. For years it was smoking. You will be pleased to know that the incidence of lung cancer is down in 2005 as compared to 2004, as well as the incidence of colon cancer, so that some of the effects of smoking are being reduced. I think the huge amount of publicity and the well-circulated programs against smoking are having an effect. Now we are moving to an era where more people in the United States will die from the effects of obesity than the effects of smoking. Obesity has gotten to be a huge public health problem in the last 40 years. There are studies that have been done by the CDC of weight and body mass for 50 years in this country, and the change over the last 40 years, particularly in the last 20 years, is startling. Not only among adults, but the greatest rate of new obesity is in children and in adolescents. It is our number one health problem today in the United States, and its effects on diabetes, hypertension, and heart disease are well known. It is the leading indicator of health disparities. Obesity, not overweight but obesity, in adults in the Pima Indian nation is 78%. Body mass index above 30, 78% of adult Pima Indians. But in Hispanic communities and in black communities in this country, the rate of obesity is becoming startling. And I ask you could hypothalamic therapy be the answer?

Chapter 9: Research on Hypothalamic Therapy

Here is some early work that was done at Yale by Anand and Brobeck and unfortunately published in the Yale Quarterly Journal of Biology, which is hard to get. What Anand and Brobeck did is they made lesions that involved VM in the first operation. Those rats became enormously hyperphagic and obese. They then made a second lesion in the lateral hypothalamus and these same animals became aphagic and wasted away. This brought about the concept of a satiety center, our VM nucleus, which tells us, or is supposed to tell us, when we're full. Feedback loop through the lateral hypothalamus, and important inputs from the telencephalon, "I think I'm hungry," from our prostaglandin receptors in our fat, "My fat feels I'm hungry," and important elements of leptin and ghrelin, proteins which we'll talk about in a second. So this is the cartoon, the satiety center, stimulation and feedback from the lateral hypothalamus, and throughout the body.

We can describe a medial hypothalamic syndrome: hyperphasia, obesity, stria, rage attacks, and longer periods of sleep. This is a 28-year-old woman described by Reeves and Plumm. She has been gaining weight steadily for the last 15 years and becoming more and more aggressive. She beat up both of her parents and was at this point hospitalized in a psychiatric institution. She eventually died in a rage attack, and at autopsy she had a hamartoma replacing the ventral medial nuclei of both sides of the hypothalamus. There was also a lateral hypothalamic lesion, with aphagia, lethargy, and severe emaciation. And this is a lateral hypothalamic syndrome patient described by Cushing.

What I've just told you was a good simplistic way of thinking about satiety in the hypothalamus, but now we have a new functional anatomy based on the receptors for anorexins and orexins, orexins in the lateral hypothalamus, anorexins in the medial hypothalamus. We have now recognized a group of anorexogenic neuropeptides and orexigenic neuropeptides, and most importantly leptin, which was only discovered in 1994, which comes in from our adipose tissue; leptin tells us we're full, and ghrelin, which comes from stomach and intestines, and which tells us we're hungry. It is possible to put a leptin infusion into the third ventricle to inhibit food intake and increase energy expenditure. There are various others, I'm going to rush through this because I see we're running out of time, but it may not be that the bolus infusion actually reflects the way the physiology work[s], that has to be worked out. But the drug companies are working night and day on these areas. They want something that will block the neuropeptide Y receptor. They want something that will activate the melanocortin receptor, the MC4 receptor. They want something that will activate leptin receptors, and something that will be antagonistic to ghrelin. CART [cocaine- and amphetamine-regulated transcript] is another problem, probably not going to be a useful path to look at for obesity because it has such big effects throughout the body.

This is a hypothalamic syndrome described by Russell called the diencephalic syndrome of infancy. And what Russell described is a loss of subcutaneous fat, small stature, happy personality, and a hypothalamic lesion.

Here's a patient of mine, this is my patient here, seen with her twin brother in infancy. Here they are at their second birthday party. My patient is small, almost no subcutaneous fat, and you can see how big her brother is relative to her. But she's a really happy child. Unfortunately she has a tumor in her hypothalamus. The next picture shows the same little girl five months later. I must say that this is during her radiation therapy, so she looks terrible and emaciated, but in fact she was terrible and emaciated. I biopsied the tumor, in those days we didn't remove tumors like this, and we gave her the accepted therapy at that time, which was irradiation of the tumor in the supracellular region. This is her tumor. It's an astrocytoma grade II, and it was treated with irradiation via two ports, which was what was common in those days. Here she is at her sixth birthday. She's huge, she's obese, she's much bigger than her brother. And by the time she was nine she was actively beating him, virtually on a daily basis. She attacked both of her parents. She was put in a psychiatric institute and died there at the age of 24.

So, endocrine function is the most vulnerable with tumors, but the time course of damage is pivotal. Trivial damage at surgery or with trauma can be fatal, but massive displacement over years can leave normal function, which raised the question of, is this due to regeneration? And here is a patient with a cystic cranial pharyngioma, and Cushing remarked about this case that in fact there was virtually no evidence of hypothalamic damage.

Changes within the hypothalamus can bring about precocious puberty or panhypopituitarism. These are tumor types. This is an infant at eight months that I'm operating on, and what you can see is that he has full penile and scrotal development and pubic hairs, at the age of eight months. And what we see here is a very large chiasmatic hypothalamic glioma. And the chiasm should occupy no more than about a third of this space, and now you see the whole thing is a tumor.

Chapter 10: Pituitary Function

Let's quickly move on to some pituitary function. The pituicytes have the ability to secrete hormones, and many of the pituitary cells on electronmicrograph will have these secretory granules which they release into the bloodstream. There are cells in the pituitary that have no secretory granules. The first of the functional pituitary tumors described by Pierre Marie more than a century ago was acromegaly. He called this acromegaly because of the enlargement of the extremities. Here you see a young man at 25 and here he is at 38, overgrowth of the chin, the lips, the nose, the brow, and the skull, also the ears. And so all of the ends of bones and the face were enlarged.

Babinski, he of the reflex, was startled therefore to find a patient in 1900 who had no acromegaly but still had a pituitary tumor. Here is Babinski's young woman's pituitary tumor, and Babinski's patient had—this is a 24-year-old woman—she has very poor secondary sexual development, and a strange distribution of fat around the midportion of her body. Perhaps the most famous of these patients is Froelich's patient. This is Froelich's patient at the age of 14 in 1906. No secondary sexual development, and an abnormal distribution of fat around the midportion of the body. This has become known as adiposogenital dystrophy, hypogonadism—lack of secondary sexual characteristics and a deposition of fat on the lower abdomen, thighs, and hips. Froelich's patient was operated by von Eiselsberg using Schloffer's approach through the nose, and Brook in 1938 published the picture of Froelich's patient at the age of 44, and you can see the indent here from his operation (he was working as a postal clerk), neurologically and intellectually intact, but with his same syndrome. I believe from the description of von Eiselsberg that this was a cranial pharyngioma. This young man almost certainly perished in a Nazi concentration camp.

Finally here's the father of American pituitary studies, Harvey Cushing, and this is a famous patient, Dr Turney's patient, a young woman seen at the age of 20, and at 25, and she has Cushing's syndrome, associated with the buffalo hump, the obesity, stria on the abdomen, from the oversecretion of ACTH from a pituitary tumor.

So I have tried to cover for you some of the basic physiology of both the hypothalamus and a little bit of pituitary function. And again, Harvey Cushing probably summed up the hypothalamus best when he said, "Here in this well-concealed spot almost to be covered by a thumbnail lies the very mainspring of primitive existence, vegetative, emotional, and reproductive."

Thank you.

Functional Anatomy of the Hypothalamus and Pituitary Peter W. Carmel, MD, DMSc — February 25, 2006