Gland: Hypothalamus

THE HYPOTHALAMUS

The hypothalamus is located right above the pituitary gland that sits in the sella turcica of the sphenoid bone. The hypothalamus is attached to the pituitary gland by the pituitary infundibulum. The hypothalamus is the “major player” in the function of the endocrine system, where neurological energy is transposed into chemical energy (HORMONE RELEASING HORMONES.)
The hypophyseal vein transports these releasing hormones to the anterior pituitary. In other words, all neurological transmission and communication that is directed toward the hypothalamus help determine what hormones are to be released.
In fact, the pons varoli, medulla oblongata and the hypothalamus, form a network of visceral trophic sensors that receive information from many hormones (estrogen, testosterone, thyroid, etc.) and all sensory tropic nerves, including but not limited to all the cranial nerve nuclei, located in the medulla oblongata. Therefore, all cranial nerve activity, such as sight, smell, taste, hearing, and balance, influences hypothalamic secretions.
The hypothalamus also receives all sensory trophic information through the thalamus via the spinal cord and brain stem. Neurological control over the hypothalamus comes from many other sources such as:
1. The limbic system and brain stem which connect to the periventricular and arcuate nuclei which stimulate GHRH
2. Emotional stress triggers thru the red nucleus, stria terminalis, and amygdale complex
3. Circadian rhythms are regulated via the supra chiasmatic nucleus
4. GH and sleep are regulated by the cortex and sub cortical nuclei
5. Dopa minergic and histaminergic in the arcuate and mammilla nuclei, respectively
6. Catechol minergic ascend and arise from the ventral lateral medulla and the tractus solitarius
7. Serotoninergic fibers from the raphae nucleus
There are also peripheral hormones, metabolic signals, and cytokines that affect hypothalamic secretions, via the medial basal hypothalamus and the pituitary gland (acetyl choline stimulates GH secretion.) The hypothalamus also produces anti-diuretic hormone and oxytocin, which are made up of small peptides that are attached to large proteins found along the neural tracts from the hypothalamus to the posterior pituitary.

Let us not forget the vagus nerve that affects all parasympathetic outflow to all organs from the heart to the descending colon. The hypothalamus also receives communications from the external environment, such as light, pain, temperature, and odorants. As you can see, there is a multitude of information directed toward the hypothalamus. The hypothalamus then serves as the link between the endocrine and nervous systems. In fact, the hypothalamus is composed of both nervous and endocrine tissue. The hormones that the hypothalamus produces are peptides, except for dopamine, which is a biogenic amine. The neurological tissue stimulates the endocrine tissue to produce the following hormones:

1. GONADOTROPHIN RELEASING HORMONE GnRH (FOLLICLE STIMULATING HORMONE RELEASING HORMONE)
GnRH is a ten amino acid protein that stimulates the pituitary to produce follicle-stimulating hormone. There are 2 genes encoding GnRH, and they are:
• GnRH 1-stimulates the release of the pituitary hormone
• GnRH 2- serves as a neurotransmitter in the forebrain
GnRH binds to a membrane receptor on the pituitrophes (G-protein-coupled receptor), which stimulates LH and FSH synthesis and secretion. GnRH receptors on the hypothalamus are affected and suppressed by steroids, estrogens, progesterones, and gonadotrophins.
GnRH receptors are stimulated by calcium and protein C kinase. Calcium is important in GnRH stimulation and the release of gonadotrophins. GnRH receptors can increase or decrease uptake regulation or self-priming based on seasonal periods, malnutrition, and lactation or by GnRH downgrade due to high levels of GnRH.
GnRH from the hypothalamus sends neurons to the portal circulation in the median eminence in coordinated, repetitive and spasmodic pulses into the portal blood. Neurological control is via neurotransmitter systems in the brain stem and limbic system, which includes norepinephrine and glutamate, which drive the reproductive axis, dopamine, GABA and opioids, which then inhibit GnRH neurons and serotonin.

2. ADRENOCORTICO-TROPHIC HORMONE RELEASING HORMONE
(CORTICOTROPHIN RELEASING HORMONE) (CRH)
CRH stimulates the pituitary to produce the adrenocorticotrophic hormone. CRH neurons are located in the parvi-cellular division of the hypothalamus. They send projections into the median eminence. Glucocorticoids inhibit the release of CRH and AVP. CRH neurons, which contain AVP, arise from the periventricular nucleus, SC nucleus, amygdala, and raphae nucleus in the brain stem. Inhibition of CRH is from the hippocampus and locus ceruleus of the midbrain. Neurotransmitters that are cholinergic and serotoninergic excite CRH release and noradrenergic inhibit CRH release.
The HPA axis ‘s primary job is to maintain homeostasis in the body, as internal and external stressors affect it. The system is comprised of neurological control causing the release of catacholamines from the adrenal medulla, as well as hypothalamic-pituitary control over ACTH. This axis also controls behavioral response to stress via CRH-like peptides called urocortin 1, 2 and 3. CRH binds to a specific receptor and stimulates hormonal release only in the presence of Ca++ increasing
cAMP and enhances the transcription rate of ACTH and its pro hormone POMC (pro-opiomelanocortin). CRH is also found in the limbic system and is used in the processing of sensory information and in the regulation of ANS function. CRH is also located in the amygdale, substantia nigra, solitary tract nucleus, cerebral cortex, pineal, spinal cord, lungs, and liver. GI tract and is also found in the human placenta.
CRH increases sympathetic activity, blood pressure, heart -rate, cardiac output and suppresses GH and hunger. CRH and AVP play important roles in regulating inflammatory responses in the body via cytokines due to their extinguishing effects on inflammation.
CRH also acts as a vasodilator on the uterine lining, regulating decidulization or implantation of the fertilized egg. The human placenta has the largest concentration of CRH outside the hypothalamus. The CRH system is also regulated by a CRH-binding hormone, which inhibits CRH action.
Glucocorticoids are lipid soluble, inhibit CRH and can enter thru the blood brain barrier and bind to two receptors which are the:
1. Mineral corticoid receptors for aldosterone and glucocorticoids
2. Gluco corticoid receptors which have low affinity for mineral corticoids

It has been said that the type mineral corticoid receptors regulate basal activity, and the glucocorticoid receptors are responsible for stress reactions. CRH runs on a circadian rhythm, which peaks in the early morning and falls during the day until midnight, then starts to increase at 1:00 pm. Glucocorticoids inhibit the release of CRH and AVP.

3. THYROID STIMULATING HORMONE RELEASING HORMONE (THYROTROPHIN RELEASING HORMONE (TRH)
TRH is a tripeptide that stimulates the pituitary to produce thyroid-stimulating hormone (thyrotropin) via glycosylation of thyrotrophin. This happens with a maximum circadian rhythm between 9pm-5am, and a minimum circadian rhythm between 4 pm and 7 pm, accompanied by an ultradian rhythm of 90-180 minutes. TRH is also a potent releaser of prolactin and may in some cases cause the release of growth hormone and corticotropin. The binding sites are on the plasma membrane of the pituitary cells where TRH hydrolyzing phosphatidylinositol and phosphorylation via protein kinases, stimulate mRNA coding for thyrotrophin.
TRH is also found in all parts of the brain, cerebral cortex, circum ventricular structures, posterior pituitary, pineal, spinal cord, islets of Langerhan, myocardium, prostate/testes and various parts of the GI tract. The TSH of these tissues far exceeds that in the hypothalamus. TRH receives nerve supply from catecholamines, neuropeptide Y and somatostatin-containing axons, and is released thru peptidergic neurons into the portal hypothalamic pituitary circulation.

TSH has many affects on the CNS such as:
• Increasing and improving motor function and activity, good for ALS patients (amyotrophic lateral sclerosis).
• Altering sleep
• Increasing blood pressure
• Producing anoxia
• Releasing norepinephrine and dopamine
• Ameliorating human behavior disorders
• Protecting against spinal shock

4. MELANOTROPHIC STIMULATING HORMONE RELEASING HORMONE
Which stimulates the pituitary to produce the melanocyte-stimulating hormone.

5. LUTENIZING HORMONE RELEASING HORMONE (LHRH)
LHRH is a deca peptide, which is derived from a precursor molecule called pre-pro LHRH (92 aa’s long), which stimulates the pituitary. LHRH neurons from the hypothalamus more specifically the arcuate nucleus, medial basilar hypothalamus and the pre-optic nuclei from the anterior hypothalamus, project into the median eminence (about 1-3000 neurons) and terminate in capillaries of the portal vein descending into the pituitary stalk to produce the lutenizing hormone in the anterior pituitary.
LHRH is also found in the limbic system (hippocampus, cingulated cortex and olfactory bulb) and has been implicated in sexual drive, mating behavior, and emotional expression. Pituitary receptors are found on the plasma membrane, which then increases calcium concentration, hydrolysis of inositol phosphates and phosphorylation of protein C kinase. LHRH binds to the receptor, which initiates transcription of subunit genes, translated to subunit mRNA. This is followed by post-transitional modification of the precursor subunits and subunit folding and combination, followed by mature hormone packaging and secretion. LHRH also stimulates gonadotrophin synthesis.
Dopamine, norepinephrine, serotonin, opioids, estrogen and progesterone produced by the brain regulate LHRH secretion. LHRH secretion by the hypothalamus causes the pituitary to produce FSH and LH. It appears that pulse frequency of LHRH influences LH and FSH secretion, whereby fast pulses favors LH secretion and slow pulses favor FSH secretion.
Pulse frequencies affect the receptor concentration on the cell membranes of the pituitary gland, which increases receptor concentration with pulsations of 30 minutes and decreases the number of receptors when pulsations (every two hours) decrease.
The half-life of LHRH is 2-4 minutes, which depends on a number of carbohydrate residues making up the glycoprotein and sialic acid content of the gonadotrophin. Ovarian steroids and peptides modify the secretions of FSH and LH.
LH stimulates androstenedione production of the theca cells where FSH regulates estradiol production in the granulose cells, as well as follicular growth. The release of the egg from the follicle is due to sudden bursts of LH during mid-cycle.
After ovulation, the follicle becomes a corpus luteum that secretes both estradiol and progesterone, which is also under the control of FSH and LH. The endometrium of the uterus has many receptors for estrogen, which increases endometrial growth Progesterone limits the estrogenic effect on the endometrium, but increases cell differentiation. Both a withdrawal of either estrogen or progesterone causes a sloughing off of the functional portion of the endometrium called the functionalist layer and the deeper remaining layer, the basal layer is regenerated due to estrogen.
The entire reproductive function (no more oocytes), and most of the endocrine function is lost after menopause. Menses occurs approximately every 24-35 days.

6. LUTEOTROPHIC HORMONE RELEASING HORMONE
Unlike other hypothalamic hormones that stimulate the pituitary to release hormones, this hormone inhibits prolactin (PRL) secretion by the pituitary. Prolactin inhibiting factor (PIF) with dopamine is the most important. PIF is a secretory product of the tuber infundibular dopaminergic pathways. Y-amino butyric acid (GABA) and prolactin releasing factors such as TRH, AVP, VIP, oxytocin, PHI-27 (peptide-histodine-isoleucine-27), EGF (epidermal growth factor), angiotensin 2, substance P and interleukin 6 stimulate the pituitary to produce the leutotrophic hormone.
Prolactin secretion is also affected by autocrine/paracrine factors in the anterior and neuro intermediate lobe, whereby these factors gain access thru the sinusoids via short portal vessels. PRL is reduced by acetylcholine and calcitonin. PRL is also affected by estrogens, pregnancy, lactation, menstrual cycle, light, olfactory cues, and stress. Neurological control comes from serotoninergic neurons from the dorsal raphae nucleus, which activate PRL neurons in the paraventricular nucleus.

7. SOMATOTROPHIC HORMONE RELEASING HORMONE (GHRH)
GHRH stimulates the pituitary via a circadian rhythm that is reactive to stress, and the pituitary stalk can block its action. Negative feedback control of GHRH is mediated by GH and IGF-1, which is synthesized by the liver under the control of GH. IGF-1 is a critical growth factor that is responsible for the growth promoting activities of GH. IGF-1 now via negative feedback stops production of GH by directly influencing the pituitary receptors.
The GHRH receptor is a G-protein coupled receptor. GHRH stimulates GH secretion via calcium channels, which activate adenyl cyclase and the phosphatidylinositol cycle, thereby stimulating transcription of GH mRNA.
Somatostatin (growth hormone-release inhibiting factor) blocks the effect of GHRH and inhibits TSH secretion, as well. On the other hand, glucocorticoids enhance GHRH secretion.
Somatostatin also acts as a neurotransmitter and neuromodulator in the CNS and PNS. In the gut, somatostatin is found in the myenteric plexus where it acts as a neurotransmitter on the epithelial cells, which influence adjacent cells (paracrine function such as the islet pancreas cells). Somatostatin also acts in an autocrine fashion, where it can stimulate surrounding cells to produce it.
A gut exocrine secretion, which is modulated by the intraluminal action called a lumone.. Somatostatin-14 is found in the brain (cortex, lateral septum, amygdale, brain stem nuclei, thalamus, and hippocampus) and inhibits GH and somatostatin. There is a wealth of data linking decreased levels of somatostatin in the CSF of the forebrain with Alzheimer’s, major depression and neuro psychiatric disorders.
Somatostatin 28 is found in the GI tract (especially in the duodenum and jejunum) and inhibits the secretion of the salivary glands, parathyroid glands, calcitonin via the thyroid, PRL and ACTH. It also inhibits all pancreatic and gall bladder endocrine and exocrine gland function such as gastrin, secretin, motilin, insulin, glucagon, VIP, rennin, and glucentin (enteroglucagon). Somatostatin 28 also inhibits gastric acid and jejuna fluid secretion and emptying, pancreatic bicarbonate and enzyme secretion, intestinal absorption, bile flow and GI blood flow. Somatostatin can inhibit immune cell function and also inhibits the growth of tumor cells.
Please note that these releasing hormones are peptides, with the exception of dopamine, which is the principle PRL (release inhibiting factor.) These do not, by themselves, act as sole controllers of each pituitary secretion, but are performed by a combination of releasing hormones that either inhibit or stimulate hormone release from the anterior pituitary. For example, TRH can release PRL, TSH, ACTH, GH, and LHRH. PRL inhibits TSH and GH.

FAT STORAGE, THE BRAIN GUT ADIPOSE AXIS LEPTINS

Long term energy and fat storage is controlled by the hypothalamic axis. Energy homeostasis is regulated via the triune of behavior, autonomic and hormonal inputs.
Lepton, which is 167 AA’s long, is secreted by adipocytes with minor levels secreted by the skeletal muscle, placenta, and stomach. A decrease in fat deposits due to starvation and anorexia nervosa decreases lepton levels. Lepton also triggers puberty and fertility. Lepton is actively taken up by the capillary endothelial and microvascular system of the choroids plexus of the brain. Once it passes the blood-brain barrier, there are specific receptors (which are cytokine) found in the arcuate, ventromedial, and dorsal medial nuclei of the hypothalamus. Lepton also appears to inhibit feeding and increases metabolism.
As far as the neurological circuitry is concerned, below is a brief description from Guyton’s physiology as to the hypothalamus’s far-reaching effects. Not only does it affect the body chemically, and physically, but mentally and emotionally, as well. As you will note, the hypothalamus is considered to be part of a system known as the limbic system.

THE LIMBIC SYSTEM

The limbic system refers to all the neuronal circuitry necessary to control emotional behavior and motivational drives. A major part of the limbic system is the hypothalamus but it also consists of the:
1. SEPTUM
2. PARAOLFACTORY AREA
3. EPITHALAMUS
4. ANTERIOR NUCLEUS OF THE THALAMUS
5. PORTIONS OF THE BASAL GANGLIA
6. HIPPOCAMPUS
7. AMYGDALA
The purpose of this system is to affect behavioral control, body temperature, body weight, appetite and osmolality of body fluids. The portion of the cerebral cortex that lies directly above the limbic system is known as the limbic cortex.
The purpose of this cortex is to form a two-way communication system between the limbic system and the cerebral cortex. Also, note that the reticular nuclei, and their associated nuclei in the brainstem (cranial nerve nuclei), mediate control over the limbic system, which elicit many behavioral functions and patterns such as rage, anger, grief, pain, etc. They also exert influence over the autonomic nervous system, via the hypothalamus.
*PITUITARY
*PINEAL
*I have included the pituitary and pineal, which are involved in the endocrine axis that is affected/or affects the hypothalamus.

The hypothalamus, through hormonal release, causes the pituitary to release/store hormones that can affect our emotions, as well as maintaining biochemical balance throughout the body. The pineal, through sensory feedback from the eye (light), acts as an environmental sensor or third eye and produces a hormone called melatonin, which inhibits the release of sex hormones affecting sexual drive and behavior.

The hypothalamus is made up of an anterior, posterior and lateral portion with each portion consisting of the following:

THE ANTERIOR HYPOTHALAMUS

The anterior hypothalamus is divided into the:

1. PARAVENTRICULAR NUCLEUS (PVN)-which is composed of neurons from the:
a. Magnicellular nucleus, which contain oxytocin and vasopressin neurons that extend into the posterior pituitary and regulate fluid balance, blood pressure, lactation, and parturition. The magnocellular division also releases the following hormones peptides and neurotransmitters:
• Angiotension 2
• Cholecystokinin
• Glucagon
• Oxytocin
• Peptide 782
• Pro encephalin B (dynorphin, rimorphin, alpha-neo-endorphin)
• Vasopressin
b. Neurons projecting into the brain stem and spinal cord regulating a variety of ANS responses
c. Parvicellular nucleus (PVN), which is composed of CRH neurons that project into the median eminence regulating ACTH synthesis and release. Visceral sensory output to the PVN occurs thru the nucleus of the solitary tract via the thoracic abdominal viscera, which send dense catecholaminergic projections to the PVH thru the ventro lateral medulla.

The parvicellular division releases the following hormones/peptides and neurotransmitters
• Y-amino butyric acid
• Angiotension 2 stimulates drinking thirst reflex.
• Atrial natriuretic factor
• Cholecystokinin
• CRH
• Dopamine
• FSHRH
• Glucagon
• Neuropeptide Y
• Neurotensin
• Peptide 782
• Pro encephalin A (met and leu-enkephalins, BAM 22P, metorphamide)
• Somatostatin
• TRH
• Vasopressin
• Vasoactive intestinal peptide/peptide-histidine-isoleucine (PHI)

2. MEDIAL PREOPTIC AREA-decreases heart rate, blood pressure and bladder contraction.

3. SUPRAOPTIC NUCLEI-for release of vasopressin

4. OPTIC CHIASMA

5. INFUNDIBULUM

6. POSTERIOR PREOPTIC AND ANTERIOR HYPOTHALAMIC AREA-for the regulation of body temperature through panting, sweating and thyrotropin inhibition.

THE POSTERIOR HYPOTHALAMUS

The posterior hypothalamus controls shivering, increases blood pressure and pupil dilation. The posterior hypothalamus is composed of the:

1. DORSOMEDIAL NUCLEI-for gastrointestinal stimulation

2. PERIFORNICAL NUCLEUS-for hunger, rage and increased blood pressure

3. VENTROMEDIAL NUCLEUS-for neuro-endocrine control and satiety

4. MAMILLARY BODY-for the feeding reflex.

5. ARCUATE NUCLEI AND PERIVENTRICULAR ZONE-Dopamine fibers from this nucleus project into the median eminence and releases the following hormones/ peptides and neurotransmitters:
• Acetylcholine
• Y-amino butyric acid
• Dopamine
• GHRH
• Neuropeptide Y
• Neurotensin
• Pancreatic polypeptide
• Pro encephalin A
• Prolactin
• Pro-opiomelanocortin (ACTH, beta-lipotropin, Y-melanocyte stimulating hormone, beta-endorphins)
• Somatostatin
• Substance P
•

THE LATERAL HYPOTHALAMUS

The lateral hypothalamic area is for thirst and hunger.

THE BLOOD BRAIN BARRIER
THE ROLE OF THE CIRCUMVENTRICULAR ORGANS

The role of the circum ventricular organs (CVOs) is to act as doormen, so to speak, about what vital information crosses into the brain and what does not. More specifically, vital sensory chemical information (hormones, metabolites, toxins, bacteria, etc) to maintain homeostasis needs to be allowed to pass thru into these CVOs, which have a rich blood supply and can give vital information to the glial cells and neurons that reside in these blood vessels This is done thru key junctures (CVOs) that lie in the midline of the brain in the third and fourth ventricles, and include the:
• Median eminence that gives sensory input to adjacent nuclei such as the arcuate, ventro medial, dorsal medial and para ventricular nuclei. The para ventricular nucleus then sends magnicellular neuron projections to the posterior pituitary to release arginine, vasopressin or oxytocin
• Area post rema lies in the fourth ventricle and sends efferent projections into the nucleus of the solitary and ventral lateral medulla. It receives sensory input from the vagus and gloss pharyngeal nerves and the carotid sinus nerve. The area post rema can induce vomiting in response to foreign substances and control of blood pressure.
• Posterior pituitary (see posterior pituitary)
• Sub commissural organ located at the junction of the 3rd ventricle and cerebral aqueduct below the pineal that is composed of ependymal cells that secrete glycosylated protein. These extrude thru the aqueduct of the 4th ventricle, down the spinal cord lumen, and terminate in the caudal equine.
• Subfornical organ located in the third ventricle having receptors for angiotensin 2 and atrial natriuretic peptide that project into sites of the hypothalamus, producing oxytocin and AVP. The SFO is also a blood pressure fluid regulator. The SFO innervates the parvicellular neurons of the para ventricular nucleus, which project into the median eminence releasing CRH and regulating neuroendocrine and autonomic control.
• Organium vasculosum of the lamina terminalis is located in the third ventricle and is innervated by neurons that secrete many neurotransmitters and peptides such as LHRH, somatostatin, dopamine, serotonin, acetylcholine, oxytocin, vasopressin and TRH. The organium vasculosum has a dramatic effect on fluid regulation (osmolality), electrolyte balance, reproduction, and thermoregulation.

So the CVOs act as a critical link between the chemical cues from the body, transposing them into neurological cues (communications) to regulate hormonal, autonomic and behavioral responses. This is where the vascular endothelial cells of the brain prevent passage of polarized macromolecules (hormones, peptides.) Perimicroglial cells, neurons and glial cells that arise in the CVOs contribute neurological intelligence to the integrity of this complex by transposing this chemical information into neurological information, stimulating key neuronal cell groups of the median eminence, posterior pituitary, and the hypothalamus, maintaining homeostasis.

Blood chemistry tests that determine the function of the hypothalamus:

1. CALCIUM is the largest and most abundant mineral in the body.
The purpose of calcium is to attach to all lipoproteins, fatty acids, and triglycerides within the digestive tract. All minerals that are involved in biochemical reactions within the body are in an ionic state. They will have a positive or negative charge.
The purpose of these electrically charged ions is to act as magnets, repelling and attracting biochemical substances through the body. The purpose of hormones and releasing factors is to direct these mineral magnets and their biochemical substances throughout the body to specific sites, at specific times, creating growth/repair, energy and all the chemicals necessary for your survival.
The mineral calcium (which is a cation) is the substance that pushes proteins, fatty acids, and triglycerides through the intestinal wall. When the calcium to magnesium ratio is greater than two-part calcium to one-part magnesium, there is movement of food substances through the intestinal wall. This calcium to magnesium phenomenon creates an electrical osmotic gradient that draws the calcium/lipoprotein across the cell membrane.
The hypothalamus, through its releasing factors, creates growth, reproduction, digestion, assimilation, metabolism and protein deposition in cells. You can see why calcium would be dramatically affected by hypothalamic malfunctions. The releasing factors are all geared for protein deposition in cells, as well as controlling triglycerides, cholesterol, and fatty acid distribution throughout the body. These releasing factors also influence the production of energy and the creation of hormones, enzymes, and antibodies. It’s rather obvious that other blood tests such as protein, cholesterol and triglycerides can all be used and are affected by hypothalamic malfunctions.

2. POTASSIUM AND SODIUM
The purpose of potassium is to create an action potential with sodium across a neurological membrane. When a neurological impulse passes through a cell membrane, there is a large influx of potassium out of the cell, and a large inflow of sodium into the cell, allowing the propagation of the neurological impulse, which then must be repolarized (sodium pumped out of the cell and potassium pumped in.) Since the hypothalamus is neurologically controlled via a vast network of sensory trophic nerves, sodium and potassium, levels must be observed as indicators of hypothalamic function, since they literally control neurological activity on a chemical level. This then would have a dramatic effect on communication between the body and hypothalamus, creating improper hormonal release to the pituitary.