Background:
Pituitary gland (hypophysis)-The pituitary gland lies in the hypophyseal fossa of the sphenoid and (in the bony sella turcica) is connected to the hypothalamus by the infundibulum, or pituitary stalk. The dura covering the superior aspect of the gland forms the diaphragma sella. The gland is about 12mm transversely and 8mm in anteroposterior diameter. Pituitary weighs 0.5-1.0 g. The pituitary gland lies posterior/superior to the sphenoidal sinus. The major divisions of the gland are the anterior lobe, or adenohypophysis, and the posterior lobe, the neurohypophysis. Each of these major subdivisions, which have different embryological origins, is further subdivided: Adenohypophysis: pars distalis MSH, ACTH created here, pars intermedia-MSH also found here, pars tuberalis Neurohypophysis: pars nervosa, pituitary stalk, median emminence.
The pituitary gland is derived from two sources. The anterior lobe is an upgrowth of ectoderm from the roof of the stodeum, while the posterior lobe is a down growth of neurectoderm from the diencephalon. In the middle of the fourth week, a diverticulum, Rathke's pouch, grows upwards from the roof of what will become the mouth towards the developing brain. As the upgrowth contacts a downgrowth from the brain, the infundibulum, it begins to pinch off from its connection with the stomodeum. By the sixth week the connection between Rathke's pouch and the oral cavity degenerates. The cells of Rathke's pouch proliferate to form the pars distalis, and extend up the anterior aspect of the infundibulum as the pars tuberallis. The posterior surface of Rathke's pouch does not proliferate but forms the poorly developed pars intermedia. The infundibulum having grown down from the floor of the diencephalon, expands as the axons of cells in the diencephalon grow down into it.
Control of the hormone producing cells of the pars distalis is through secretion by cells of the hypothalamus.
The pars intermedia is not well developed and it is thought that its cells produce pre-pro-opiomelanocortic peptides. The pars tuberalis is formed mainly of gonadotrophs.
The posterior lobe or neurohypophysis is a continuation from the hypothalamus. The hormone producing cells are located in the supraoptic and paraventricular nuclei of the hypothalamus. The axons of these neurons run down the pituitary stalk to terminate on the capillary bed of the posterior lobe. The terminals are separated and grouped by glial cells, the pituicytes. The axons of the hormone producing cells can be seen to contain numerous small clear vesicles, and larger dense core vesicles.
Upward growth of pituitary tumors may press on the optic chiasma. Typical visual field defects would be bitemporal hemianopia, and upper quadrantopia. Tumors can grow up into the third ventricle causing hydrocephalus. Rapid lateral expansion, perhaps due to haemorrhage may compress the third, fourth or sixth cranial nerves. Headache may be present from stretch of the meninges. Surgery to remove pituitary tumors is usually performed through the sphenoidal sinus.
Adrenocorticotropic hormone (ACTH)
Adrenocorticotropic hormone (ACTH) - Another name for adrenocorticotropic hormone is corticotrophin. ACTH is a 39 chain-amino acid peptide (polypeptide) (protein) tropic hormone secreted by the anterior pituitary to regulate the release and production of steroid hormones by the adrenal cortex. ACTH secretion from the anterior pituitary is controlled by both a classical negative feedback control mechanism and CNS-stress mediated control system.
ACTH tropic hormone secretion more specifically stimulates secretion of glucocorticoids from the zona fasiculata, the thick middle and largest of the three zones of the adrenal cortex. Cells in the fasiculata zone are polyhedral and usually have a foamy appearance due to abundant lipid droplets (very similar looking to adipocyte cells) . The main glucocorticoid hormone released by ACTH through interaction with ACTH receptors of the adrenal cortex being cortisol- a steroid hormone produced by the zona fasiculata (middle) with interaction of the zona reticularis (inner layer) of the adrenal cortex that participates in control of blood glucose concentration, and the bodies water balance, as well as several other processes.
Cortisol's principle physiological actions include: Increase hepatic gluconeogenesis, increase hepatic glycogenolysis, increase protein catabolism, increase lipolysis, help resist stress, anti-inflammatory, inhibit ACTH secretion (negative feedback mechanism), maintenance of blood pressure by sensitizing arterioles to the action of noradrenaline, renal excretion. 90% of the secreted cortisol in circulation is bound to protein. Serum cortisol concentration show diurnal variation, with its highest concentration being after waking then declining throughout the day. The synthetic form of this steroid is hydrocortisone used to treat inflammation in injuries, arthritis or dermatitis, and as adjunction therapy for conditions such as autoimmune diseases.
Peptide hormones such as ACTH are synthesized in endoplasmic reticulum, transferred to the Golgi and packaged into secretory vesicles for export. Most peptide hormones circulate unbound to other proteins, but exceptions exist; for example, ACTH, and insulin-like growth factor-1 binds to one of several binding proteins. In general, the halflife of circulating peptide hormones is only a few minutes.
ACTH is produced by Corticotrophs, endocrine cells that are found mainly in the centre of the lobe of the pars distalis of the anterior pituitary. Biologically active ACTH results from enzymatic cleavage (glycosylation) of a large precursor molecule, pro-opiomelanocortin (POMC) nicknamed Big Momma a 260 amino acid protein. This prohormone molecule contains within its structure the amino acid sequences of ACTH, Pro-ACTH, ß-melanocyte stimulating hormone, lipotropin, as well as endorphin and the enkephalins. Corticotrophs are also responsible for the production of, beta-lipotrophin, alpha-melanocyte stimulating hormone and beta-endorphin.
Control of the ACTH hormone produced by Corticotroph cells of the pars distalis is through neurosecretory release of another hormone Corticotropin releasing hormone (CRH), another peptide hormone released from cells of the anterior part of the paraventricular nuclei of the hypothalamus. CRH neurosecretion begins with low levels of cortisol in the bloodstream thus stimulating release of ACTH from the anterior pituitary gland. This negative feedback of cortisol in blood level or various types of stress or pain perceived in higher levels of the brain modulate release of the hypothalamic neurosecretory hormone, corticotropin releasing hormone (CRH), a 41-amino acid peptide. A secondary peptide hormone that modulates ACTH secretion is vasopressin (AVP). AVP secretion is also stimulated by stress and acts synergistically with CRH to increase ACTH secretion in the pituitary portal circulation. ACTH increases the synthesis and release of all adrenal sterioids, aldosterone, cortisol and adrenal androgens. It is the principal modulator of cortisol, the most important glucocorticoid in man. As the cortisol level in blood increases, release of ACTH is inhibited directly at the pituitary level. Through this same mechanism, decreasing cortisol levels lead to elevated ACTH levels.
ACTH and Learning?
Removal of the pituitary decreases active avoidance learning in rats which injection of ACTH reinstates-- ACTH doesn't affect learning in intact individuals. DeWied tested whether the pituitary removal detrimentally affected learning through the loss of ACTH or some other pituitary hormone. He replaced all hormones except ACTH and still found the deficit. Learning was not restored until ACTH was administered. ACTH can't pass across the blood brain barrier. So, does it work via the adrenals or via the CNS? The answer is that it must work through the CNS because it restores performance in animals that have had both their pituitary and their adrenal glands removed. ACTH can be divided into fragments. Some of these fragments (ACTH4-8 for example) have no active effect on the adrenals but can probably cross the blood brain barrier. ACTH4-8 produces a very potent restorative effect on memory ACTH receptors are abundant in much of the brain, especially the limbic system (classically associated with learning and emotion). One exception is the hippocampus which does not contain ACTH receptors. But that doesn't mean that ACTH cannot influence hippocampal activity. The septum which projects to the hippocampus has ACTH receptors. The septum is known to pace or modulate hippocampal theta rhythm (activity (EEG) in the 2-8 Hz range). Elevated levels of theta rhythm have been
assocaited with faster learning. So, ACTH could alter learning rate by affecting septal modulation of hippocampal theta waves.
ACTH Clinical
Disease and syndrome disorders – Cushing’s Disease or Syndrome (hyperadrenalism) is either usually caused by an adrenal gland tumor that causes the secretion of too much cortisol, or related to the excess release of ACTH by the anterior pituitary gland. Cause is often a tumor on the pituitary gland. This syndrome can also occur when large doses of steroid drugs are given over several weeks. The condition is characterized by the breakdown of muscle proteins and redistribution of body fats. Symptoms include fat pads on chest, face and upper back, water buildup, high blood sugar, round “moon” face, muscle weakness, purplish streaks on skin. Children with this disorder may stop growing. Both ACTH and MSH associated with pigmentation change in Cushing's syndrome.
Addison’s Disease- Low levels of ACTH is a secondary cause of this adrenal insufficiency disease. Either the production of ACTH is too low, or an autoimmune disorder in which antibodies block the binding of ACTH on receptors of the adrenal cortex, or the antibodies cause adrenal cortex destruction. The symptoms of adrenal insufficiency usually begin gradually and sometimes do not appear until 90% of the adrenal cortex has been destroyed. Chronic, worsening fatigue and muscle weakness, loss of appetite, and weight loss are characteristic of the disease. Addisonian crisis include sudden penetrating pain in the lower back, abdomen, or legs; severe vomiting and diarrhea, followed by dehydration; low blood pressure; and loss of consciousness. Left untreated, an addisonian crisis can be fatal. Frequency: In the US: The reported incidence of Addison disease is 5 or 6 cases per 1,000,000 populations per year, with a prevalence of 60-110 cases per 1,000,000 populations. Mortality/Morbidity: The mortality rate for Addison disease is 1.4 deaths per 1,000,000 cases per year. Sex: The male-to-female ratio is 1:1.5-3.5. Age: Addison disease can occur in persons of any age; however, it is most common in people aged 30-50 years.
Plasma ACTH concentrations are also useful in the differential diagnosis of Congenital adrenal hyperplasia. A rare disease caused by mutations in the steroidogenic acute regulatory (StAR) gene. The steroidogenic acute regulatory (StAR) protein regulates the rate limiting step in steroidogenesis, the transport of cholesterol from the outer to the inner mitochondrial membrane. Subsequent loss of steroidogenesis that is independent of STAR due to cellular damage from accumulated cholesterol esters. The adrenal cortex becomes engorged with cholesterol and cholesterol esters; consequent deficient adrenal steroidogenesis leads to salt wasting, hyponatremia, hypovolemia, hyperkalemia, acidosis, and death in infancy, although patients can survive to adulthood with appropriate mineralocorticoid- and glucocorticoid-replacement therapy.
Melanocyte-stimulating hormone is another peptide hormone created and released from the intermediate lobe of the anterior pituitary which causes dispersion of melanin (pigment) by melanophores, resulting in darkening of the skin, presumably by promoting melanin synthesis. MSH gets its name because of its effect on melanocytes: skin cells that contain the black pigment, melanin. In humans, melanocytes are responsible for moles, freckles, and suntan.
Inhibitory factors produced by the hypothalamus are Melanocyte-stimulating hormone inhibitory factor (MIF) inhibits MSH release.
In most vertebrates, MSH is produced by an intermediate lobe of the pituitary gland. Its secretion causes a dramatic darkening of the skin of fishes, amphibians, and reptiles. The darkening occurs as granules of melanin spread through the branches of specialized melanocytes called melanophores.
The photomicrograph on the right shows melanophores in the skin of a frog with the melanin dispersed throughout the branches of the cells. This effect is produced by MSH. When the pigment retreats to the center of the cells, the skin lightens.
The response to MSH does not occur during mitosis; presumably the microtubules with their dyneins and kinesins are needed for operation of the mitotic spindle.
Proopiomelanocortin (POMC), the same precursor molecule from which the adrenocorticotropic hormone (ACTH) is synthesized also produces two forms of MSH. In fact, alpha-MSH is identical to the first 13 amino acids at the amino terminal end (or N-terminal, has a free amino group) of ACTH.
Researchers at the University of Arizona have shown that alpha-MSH can cause darkening of human skin. With FDA approval, they injected male volunteers with a synthetic version of alpha-MSH - which they called Melanotan I - to see if their skin darkened. It did, raising the possibility of using melanotan to get a suntan without the risks of exposure to ultraviolet light.
A second synthetic version of MSH - dubbed Melanotan II, also darkened the skin of male volunteers. Unexpectedly, it also caused many of them to develop penile erections. This has raised the possibility of using MSH to cure impotence.
One of the most obvious phenotypes in humans and other animals is coat color. In humans, this is manifest in the pigmentation of skin and hair. Eumelanin is the black pigment that gives one's hair a blond, brown, or black phenotype and whose amount produces skin pigmentation. It is thought to give protection against ultraviolet radiation. Phaeomelanin, the red pigment, produces "red" hair. Individuals having a predominance of phaeomelanin in their hair and skin also have an impaired ability to tan, that is to produce more eumelanin in response to sunlight. In many mammals, the relative proportions of eumelanin and phaeomelanin are controlled by melanocyte stimulating hormone (MSH) by binding to its receptor, MC1R on melanocytes. Red fur in cattle, guinea pigs, and foxeshas been correlated with changes in this MSH-receptor, so it seemed like a good idea to see if certain alleles of MC1R correlated with red hair. Valverde and colleagues (1995) found that in their British and Irish population, more than two-thirds of the individuals with red hair and poor tanning response had at least one variant of the MSH-receptor. These variants were even more abundant in those individuals with fair skin types.
MSH Clinical
ACTH and melanocyte-stimulating hormone (MSH) are both components of the same progenitor hormone. When ACTH is cleaved from the prohormone, MSH is concurrently released. The increased MSH level results in a characteristic bronze hyperpigmentation. Hyperpigmentation is generally noted in primary adrenal insufficiency associated with increased levels of ACTH and MSH. e.g. Addison Disease characteristics.
"Two glands in one" is an apt description of the adrenal gland. Sectioning through this endocrine gland reveals a pale medulla surrounded by a darker cortex, and each of these two regions produces a distinctly different group of hormones. Some species such as fish and amphibians have these glands in two separate organs.
II) Medulla: Secretes catecholamines (epinephrine (adrenaline) and norepinephrine (noradrenaline)).
III) Cortex: Secretes several classes of steroid hormones (glucocorticoids e.g. cortisol, mineralocorticoids e.g. aldosterone, and androgens e.g. DHEA, plus a few others).
Histologic examination of the cortex reveals three concentric zones of cells that differ in the major steroid hormones they secrete.
A) zona glomerulosa - thin, outermost zone-hormone- mineralocorticoids (aldosterone). Cells within this zone tend to be columnar in shape and are arranged in irregular cords.
B) zona fasiculata - thick, middle zone-hormone- glucocorticoids (cortisol). The middle and largest of the three zones in the cortex. Cells in the fasiculata are polyhedral and usually have a foamy appearance due to abundant lipid droplets (very similar looking to adipocyte cells) .
C) zona reticularis - thin, inner zone - sex steroids (androgens). Cells within this zone are arranged in cords that project in many different directions and anastomose with one another.
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13. Pro-opiomelanocortin processing in the hypothalamus: impact on melanocortin signalling and obesity
14. http://www.niddk.nih.gov/health/endo/pubs/addison/addison.htm
15. http://www.pituitarysupport.com/id48.htm
16. MSH Antibody http://www.biogenex.com/pdf/932-060p.pdf
17. Dewied http://salmon.psy.plym.ac.uk/year1/stressho.htm#avoidance_learning