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Integrative Physiology Ch. 7 - Introduction to the Endocrine System

Endocrinology The study of hormones
Chemical hormones A chemical secreted by a cell or group of cells into the blood for transport to a distant target, where it exerts its effect at very low concentrations
Processes that usually fall under hormonal control include: Growth/development, metabolism, regulation of the internal environment (temp., water balance, ions), and reproduction
Hormones act on their targets in one of three basic ways (1) by controlling the rates of enzymatic reactions; (2) by controlling the transport of ions or molecules across cell membranes; or (3) by controlling gene expression and the synthesis of proteins
The first documented association between endocrine structure and function was probably… …castration which illustrated the link between the testes and male sexuality. It was a common practice in both Eastern and Western cultures because it decreased male sexuality and made them infertile
Classic hormones Hormones of the pancreas, thyroid, adrenal glands, pituitary, and gonads – discrete endocrine glands that can be easily identified and surgically removed
Hormones may be secreted by… …Isolated (diffuse) endocrine cells; by neurons (neurohormones); and by cells of the immune system (cytokines)
Key for gland/hormone summary: [P], [A], [S] [P] = peptide, [A] = amino acid-derived, [S] = steroid
Posterior pituitary: hormones Oxytocin [P]; vasopressin (ADH)
Posterior pituitary: Primary targets Oxytocin: breast and uterus; vasopressin: kidney
Posterior pituitary: Main effects Oxytocin: milk ejection, labor and delivery, behavior; vasopressin: water reabsorption
Anterior pituitary: hormones (Note: All [P]) Prolactin; GH; ACTH; TSH; FSH; LH
Anterior pituitary: primary targets Prolactin: breast; GH: liver and many tissues; ACTH: adrenal cortex; TSH: thyroid gland; FSH: gonads; LH: gonads
Anterior pituitary: main effects for prolactin, GH, ACTH, TSH Prolactin: milk production; GH: growth factor secretion, growth, and metabolism; ACTH: cortisol release; TSH: thyroid hormone synthesis
Anterior pituitary: main effects for FSH, LH FSH: egg or sperm production, sex hormone production; LH: sex hormone production, egg or sperm production
Thyroid gland: hormones Triiodothyronine and thyroxine [A]; calcitonin [P]
Thyroid gland: primary targets Triiodothyronine and thyroxine: many tissues; calcitonin: bone
Thyroid gland: main effects Triiodothyronine and thyroxine: metabolism, growth, and development; calcitonin: plasma calcium levels (minimal effect in humans)
Heart: hormones Atrial natriuretic peptide [P]
Heart: primary targets Atrial natriuretic peptide: kidneys
Heart: main effects Atrial natriuretic peptide: increases Na+ excretion
Liver: hormones Angiotensinogen [P]; insulin-like growth factors [P]
Liver: primary targets Angiotensinogen: adrenal cortex, blood vessels; insulin-like growth factors: many tissues
Liver: main effects Angiotensinogen: aldosterone secretion, increases blood pressure; insulin-like growth factors: growth
Pancreas: hormones Insulin, glucagon, somatostatin, pancreatic polypeptide [all P]
Pancreas: primary target Insulin, glucagon, somatostatin, pancreatic polypeptide: many tissues
Pancreas: main effects Insulin, glucagon, somatostatin, pancreatic polypeptide: metabolism of glucose and other nutrients
Adrenal cortex: hormones [All S:] aldosterone; cortisol; androgens
Adrenal cortex: primary targets Aldosterone: kidney; cortisol: many tissues; androgens: many tissues
Adrenal cortex: main effects Aldosterone: Na+ and K+ homeostasis; cortisol: stress response; androgens: sex drive in females
Adrenal medulla: hormones Epinephrine, norepinephrine [A]
Adrenal medulla: primary target Epinephrine, norepinephrine: many tissues
Adrenal medulla: main effects Epinephrine, norepinephrine: Fight or flight response
Secretion The movement of a substance from the intracellular compartment either to the extracellular compartment or to the external environment
Ectohormone The term given to hormones that are secreted into the external environment
Pheromones Specialized ectohormones that act on other organisms of the same species to elicit a physiological or behavioral response. E.g. ants release pheromones to attract fellow workers to food sources
Sex pheromones Pheromones that are used to attract members of the opposite sex for mating purposes. They can be found throughout the animal kingdom, in animals from fruit flies to dogs
Do humans have pheromones? The question is still a matter of debate. Some studies hint that axillary (armpit) sweat glands secrete hormones that might serve as sex pheromones. A study showed females preferred the smell of more genetically diverse men
Candidate hormones Molecules suspected of being hormones but not fully accepted as such (e.g. not sufficiently that it travels long distances to target cells) are called candidate hormones
How to identify candidate hormones by their names They’re usually identified by the word “factor”, e.g. growth factor
Growth factors A large group of substances that influence cell growth and division. Many have been proven to act as paracrine or autocrines, but they haven’t been proven yet as hormones.
Another example of a candidate hormone The lipid-derived signal molecules, eicosanoids
What complicates the classification of signal molecules A molecule may act like a hormone when secreted from one location but as a paracrine or autocrine signal when secreted from another location
The concentration range at which hormones are able to act In the nanomolar (10^-9 M) to picomolar (10^-12) range (very small concentrations)
Are all chemical signals transported in the blood to distant targets considered hormones? No, some don’t meet the low concentration requirement: that is, they need to be too high in concentration to act to be considered a hormone. E.g., histamine isn’t a hormone for this reason
All hormones bind to target cells and initiate biological responses. These responses are known as the _____ of the hormone Cellular mechanism of action
What happens to hormones that are circulating in the blood if they’re taken up by a cell? They’re degraded into inactive metabolites by enzymes primarily found in the liver and kidneys, and then excreted in either the bile or the urine
Half-life of a hormone in circulation Indicates the rate of hormone breakdown in circulation; it is defined as the amount of time required to reduced the concentration of the hormone by one half
How do cells terminate the action of hormones already bounded to receptors? Enzymes that are always present in the plasma can degrade peptide hormones bound to cell membrane receptors. Also, some cells bring in the hormone-receptor complex into the cell via endocytosis and then digested
How do cells terminate the actions of hormones that have made it into the cell’s ICF? Intracellular enzymes metabolize them
Three main chemical classes of hormones and brief descriptions Peptide/protein hormones: composed of linked amino acids; steroid hormones: derived from cholesterol; and amino-acid derived hormones: modifications of single amino acids, either tryptophan or tyrosine
Most hormones are of which chemical class of hormones? Peptide/protein hormones
Peptide hormones Huge size variability: ranging from three amino acids to larger proteins and glycoproteins. How to identify them? By exclusion: if they’re not steroid hormones nor amino acid derivatives, they’re peptide hormones
Preprohormones The initial, inactive peptide that comes off the ribosome at the beginning of hormone production.
What happens to the preprohormone immediately upon being produced by the ribosome? A signal sequence directs the protein into the lumen of the rough ER
What happens to the preprohormone as it moves through the ER and Golgi? In the ER, the signal sequence is removed creating a smaller, still inactive *prohormone*. In the Golgi, the prohormone is packaged into secretory vesicles along with proteolytic enzymes
What do the proteolytic enzymes in the secretory vesicles do to the prohormone? Post-translational modification
Post-translational modification The proteolytic enzymes chop the prohormone into active hormone and other fragments
What happens to the secretory vesicles that are filled with the hormone? They are stored in the cytoplasm of the endocrine cell until the cell receives a signal for secretion. At that time they’ll move to the cell membrane to be released via calcium-dependent exocytosis
Co-secretion All of the peptide fragments created from the prohormone are released together into the ECF, in a process known as co-secretion
Interesting discovery relating to the prohormone for thyrotropin-releasing hormone (TRH) It contains multiple copies of its hormone
Interesting discovery relating to proopiomelanocortin It splits into three active peptides plus an inactive fragment
Can the inactive fragments of proteolyzed prohormones be clinically useful? Yes, for example proinsulin is cleaved into active insulin and an inactive fragment known as C-peptide. Clinicians measure the levels of C-peptide in the blood of diabetics to monitor how much insulin the patient is producing
Solubility of peptide hormones in water and the significance? Peptide hormones are water soluble and therefore generally dissolve easily in the ECF for transport throughout the body
Half life of a peptide hormone and the significance? Relatively short: in the range of several minutes. Thus if the organism wants to sustain the effect of the hormone for a while it must be secreted continually
Are peptide hormones able to enter their target cell? They’re lipophobic so they’re usually unable to enter the target cell.
How do peptide hormones create a response in a cell? They bind to surface receptors to activate a signal transduction system. Many peptide hormones work through cAMP messenger systems. A few peptide hormones have tyrosine kinase activity or other pathways
What kind of changes to peptide hormones create? The response is usually rapid because second messenger systems usually modify existing proteins. Changes include opening or closing membrane channels and modulating metabolic enzymes or transport proteins
Which second messenger systems have longer-lasting effects? If the second-messenger system activates genes and directs synthesis of new proteins then the effects are longer-lasting. Some peptide hormones do this, most don’t.
Note: endothelium vs. epithelium Endothelium is just simple squamos epithelium that lines organs and blood vessels INSIDE the body. Just remember that the thin lining of tissues INSIDE the body is usually endothelial
Where are steroid hormones made (as opposed to peptide hormones)? Unlike peptide hormones, which are made in tissues all over the body, steroid hormones are made only in a few organs: three types are made in the adrenal cortex, sex steroids are produced in the gonads; and placenta in pregnancy
Where is the adrenal cortex It makes up the outer portion of the adrenal glands, which are each located atop each kidney
Unique characteristics of cells that produce steroid hormones They have unusually large amounts of smooth ER, the organelle where the steroid hormones are produced.
Are steroid hormones stored in advance in secretory vesicles like peptide hormones? Since steroids are lipophilic and diffuse easily across cell membranes, they can’t be trapped in secretory vesicles. Instead, the cells secrete steroid hormones as it is needed.
How are steroid hormones secreted by the cell? When a stimulus activates the endocrine cell, precursors in the cytoplasm are rapidly converted to active hormone. The hormone concentration in the cytoplasm rises, and the hormones move out of the cell via diffusion
How do steroid hormones reach their targets? They must bind to carrier proteins to travel through the ECF and reach their target? Why? Because unlike peptide hormones, steroid hormones are not soluble in the ECF.
What proteins are used as carriers? Some steroid hormones have specific carriers, such as corticosteroid-binding globulin. Others simply bind to plasma proteins, such as albumin.
Describe the half-life of steroid hormones The binding of a steroid to a carrier protein protects the hormone from enzymatic degradation and results in an extended half-life. E.g. cortisol’s half-life is 60-90 minutes while epinephrine’s is measured in seconds
Can steroid hormones diffuse into their target cells? Yes, but only UNBOUND steroids can be diffused through membranes, so the steroids must release from their carriers first. (Carriers—since they’re soluble in water and can diffuse through the plasma—are lipophobic)
Where are steroid receptors found? Inside the cytoplasm or nucleus of the target cells.
Where is the ultimate destination of steroid receptor-hormone complexes? Once they reach their destination, what do they do? The nucleus, where the complex acts as a transcription factor, binding to DNA and either activating or repressing (turning off) one or more genes.
Any hormone that alters gene activity is said to have a _____ effect on the target cell Genomic effect
Response time for the biological effects to occur for released steroid hormones that have genomic effects There is usually a large lag-time between hormone-receptor binding and the first measurable effects. The lag can be as much as 90 minutes. Thus, steroids with genomic effects do not mediate reflex pathways requiring rapid responses
Steroids with nongenomic responses Several hormones including estrogens and aldosterone have cell membrane receptors linked to signal transduction pathways on cell membranes, just as peptide hormones do. These responses are very rapid.
Review: what is the parent compound for all steroid hormones? Cholesterol – it’s modified by enzymes to make various steroid hormones
Example of three steroid hormones and where they’re derived from Aldosterone: adrenal cortex. Cortisol: adrenal cortex. Estradiol (an estrogen): ovary
Amino acid-derived hormones Small molecules created from either tryptophan or tyrosine, both notable for the ring structures in their R-groups. Only melatonin (made by pineal gland) is derived from tryptophan, all others are derived from tyrosine
Structural differences between catecholamines and thyroid hormones Catecholamines have one tyrosine molecule; thyroid hormones have two AND iodine atoms
Catecholamines Epinephrine, norepinephrine, and dopamine – they’re neurohormones that bind to cell membrane receptors the way peptide hormones do.
Thyroid hormones Produced by the thyroid gland in the neck, behave more like steroid hormones, with intracellular receptors that activate genes
Review: all reflex pathways have the same components: Stimulus, input signal, integration of the signal, output signal, and response
The output signal in endocrine and neuroendocrine reflexes. Example of output signal and related integrating center A hormone or neurohormone. E.g., insulin is the output signal and the pancreatic cells constitute the integrating center (they have to integrate various reflexes from the nervous system and blood to “decide” output)
The simplex reflex control pathways Pathways in which an endocrine cell directly senses a stimulus and responds by secreting its hormone. In this type of pathway, the endocrine cell acts as both sensor (receptor) and integrating center
Examples of hormones that operates via the simple endocrine reflex Parathyroid hormone (PTH – secreted by the parathyroid glands), insulin, glucagon, as well as some hormones of the diffuse endocrine system
Parathyroid endocrine cells: where are they and what do they do? Clustered in four small glands that lie behind the thyroid gland. They monitor and control plasma (via their hormone, PTH) Ca^2+ concentration with the aid of G protein-coupled Ca^2+ receptors on their cell membrane.
Parathyroid endocrine cells: how do they do it? When a lot of Ca^2+ receptors are bound to Ca^2+, PTH secretion is inhibited. If Ca^2+ is low, PTH is secreted. PTH travels through the blood to act on bone/kidney/intestine, initiating Ca^2+ absorption responses in cells
How does the nervous system lead to the secretion of hormones? Either via efferent neurons (e.g. from the brain to the pancreas to secrete insulin) or via specialized groups of neurons that secrete neurohormones (e.g. in the brain or adrenal medulla, etc)
Two endocrine structures incorporated into the anatomy of the brain Pituitary gland and pineal gland
Example of efferent neurons leading to hormone secretion Stretch receptor in the digestive tract causes afferent neuron to send signal to brain which then sends signal to pancreas via efferent neuron to secrete more insulin. Note: now pancreas has two different pathways to integrate
The human nervous system produces three major groups of neurohormones: (1) Catecholamines, made by modified neurons in the adrenal medulla; (2) hypothalamic neurohormones secreted from posterior pituitary; (3) hypothalamic neurohormones secreted from anterior pituitary
Note: another (non-major, I guess) endocrine gland located in the brain and its related neurohormone The pineal gland which produces and secretes melatonin
Pituitary gland A lima-bean sized structure extending downward from the brain, connected to it by a thin stalk and cradled in a protective pocket of bone
Anatomy of pituitary gland: infundibulum The stalk that connects the pituitary to the brain
Anatomy of pituitary gland: sphenoid bone The type of bone that’s surrounding and protecting the pituitary gland
Composition of pituitary gland It’s comprised of two different tissue types that merged during embryonic development: the anterior pituitary (located closer to the front of head) and the posterior pituitary (located closer to the back of head)
Anterior pituitary A true endocrine gland of epithelial origin, derived from embryonic tissue that formed the roof of the mouth. The anterior pituitary is AKA the adenohypophysis and its hormones are adenohypophyseal secretions
Posterior pituitary An extension of the neural tissue of the brain. It secretes neurohormones made in the hypothalamus. It is AKA the neurohypophysis.
The two neurohormones stored and released in the posterior pituitary: Oxytocin and vasopressin – both of which are small peptide hormones
Where are the two neurohormones which are stored/secreted in the posterior pituitary initially synthesized? In the cell bodies of neurons in the hypothalamus, a region of the brain that controls many homeostatic functions. Each of the two hormones are made in a different cell type
After oxytocin and vasopressin are synthesized in the hypothalamus, how do they make their way down into the posterior pituitary? Hypothalamic neurohormones are synthesized in the same manner as any other peptide hormone. But after synthesis, the secretory vesicles are transported down long neuronal extensions into the posterior pituitary
How are hypothalamic neurohormones released into circulation? When a stimulus reaches the hypothalamus, and electrical signal passes from the neuron cell body to the distal (distant) end of the cell in the posterior pituitary, and the vesicle contents are released into the circulation
How many amino acids is each of the posterior pituitary neurohormones comprised of? Nine amino acids
Vasopressin AKA antidiuretic hormone, or ADH, regulates water balance in the body.
Oxytocin In women, oxytocin released from the posterior pituitary controls the ejection of milk during breast-feeding and contractions of the uterus during labor and delivery
Another, more general, role of oxytocin in the body Some neurons release oxytocin as a neurotransmitter or neuromodulator onto neurons in other parts of the brain. Some postulate that autism may be related to defects in the normal oxytocin-modulated pathways of the brain
Hormones secreted by the anterior pituitary prolactin (PRL), thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), growth hormone (GH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH)
What controls secretion of all hormones of the anterior pituitary? Hypothalamic neurohormones
Trophic hormone; which hypothalamic and anterior pituitary hormones are trophic? A hormone that controls the secretion of another hormone. Trophic hormones in the body: all hypothalamic hormones, all except one of the anterior pituitary hormones
Naming scheme of hypothalamic hormones Even though they’re all trophic hormones, for historical reasons they’re given the names “releasing” (-RH) and “inhibiting” (-IH) hormones. E.g. “growth hormone-inhibiting hormone”.
Which anterior pituitary hormone is not a trophic hormone? Prolactin, which directly targets the breast
How do the pathways containing the trophic anterior pituitary hormones work? Note: these are regarded as “complex” pathways The hypothalamus secretes a hypothalamic hormone “releasing” or “inhibiting” hormone whose target is endocrine cells of the anterior pituitary; the anterior pituitary then secretes a hormone that targets an endocrine gland
Once the anterior pituitary hormone reaches the endocrine gland in the body… …the endocrine gland will secrete a hormone that will eventually reach a non-endocrine target. E.g. upon being stimulated by ACTH, the adrenal cortex will secrete cortisol which will target many non-endocrine tissues
How does negative feedback occur in the hypothalamic-anterior pituitary pathway? Instead of the response acting as the negative feedback signal, the hormones themselves are the feedback signal. Each hormone feeds back to suppress hormone secretion by integration centers earlier in the reflex pathway
Long-loop negative feedback When secretion of one hormone in a complex pathway increases or decreases, the secretion of other hormones also changes because of feedback loops that link the hormones in the same pathway
Short-loop negative feedback Pituitary hormones feed back to decrease hormone secretion by the hypothalamus. E.g., ACTH exerts short-loop negative feedback on the secretion of CRH
Portal system A specialized region of the circulation consisting of two sets of capillaries directly connect by a set of larger blood vessels
Three portal systems in the body: One in the kidneys, one in the digestive system, and one in the brain
Hypothalamic-hypophyseal portal system The portal system though which hypothalamic trophic hormones are transported directly to the pituitary.
The advantage of having hypothalamic hormones secreted into the portal system? A much smaller amount of hormone can be secreted to elicit a given level of response because the blood volume flowing through is so small. The same amount of hormone in a normal blood vessel would be too dilute
Why is it advantageous to have a smaller volume of blood flowing through the hypothalamic-hypophyseal pituitary portal system? Higher concentration. A small number of neurosecretory neurons in the hypothalamus can control the anterior pituitary
Overall processes the pituitary gland controls in the body Metabolism, growth, and reproduction
Prolactin (PRL) One anterior pituitary hormone. It controls milk production in the female breast, along with other effects. In both genders it seems to play a role in the regulation of the immune system.
Growth hormone (GH), AKA somatotropin Effects metabolism of many tissues in addition to stimulating hormone production by the liver which are then sent to tissues like the bone and soft tissue to promote growth
Gonadotropins Includes the follicle-stimulating hormone and luteinizing hormone. They have effects on the testes and ovaries
Thyroid-stimulating hormone (TSH) Controls hormone synthesis and secretion in the thyroid gland
Adrenocorticotropic hormone (ACTH) Acts on certain cells of the adrenal cortex to control synthesis and release of the steroid hormone cortisol
Three types of hormone interaction Synergism, permissiveness, and antagonism
Synergism When two or more hormones interact at their targets so that the combination yields a result that is greater than additive. E.g. epi = 5mg glucose /100 ml blood; glucagon = 10mg/100ml; epi + glucagon = 22mg/100. Note: chart pg 234
Synergism is AKA… …potentiation, as in “epinephrine potentiates glucagon’s effect on blood glucose”
Mechanism behind synergism Not always clear, but often linked to overlapping effects on second messenger systems
Permissiveness One hormone cannot fully exert its effects unless a second hormone is present.
Example of permissiveness Maturation of the reproductive system is controlled by gonadotropin-releasing hormones, gonadotropins, and steroid hormones. If thyroid hormone isn’t present, maturation is delayed. Thyroid hormone has a permissive effect
Mechanism behind permissiveness Not well understood
Antagonism When two molecules are working against each other, with one diminishing the effectiveness of the other.
Example of antagonism Competitive inhibitors, where two molecules compete for the same receptor. Used in pharmacology; e.g. the estrogen receptor antagonist tamoxifen, which is used to treat breast cancers that are stimulated by estrogen
Functional antagonists Two hormones that have opposing physiological actions. E.g. glucagon and growth hormone both raise glucose levels whereas insulin decreases it, thus they’re antagonistic to each other
Do hormones that are antagonistic toward each other compete for the same receptors? Not necessarily. They may act through different metabolic pathways, or one may decrease the number of receptors for the opposing hormone.
Three basic patterns of endocrine pathology: (1) hormone excess, (2) hormone deficiency, and (3) abnormal responsiveness of target tissues to a hormone
Hypersecretion If a hormone has been secreted too much and now exists in excessive amounts. As a result the effect of the hormone will be exaggerated
Causes of hypersecretion Numerous causes including benign tumors (adenomas) and cancerous tumors of the endocrine glands. Occasionally nonendocrine tumors secrete hormones
Exogenous Coming from the outside of the body.
Endogenous Coming from inside the body
A condition that is iatrogenic means… It means the condition has been physician caused. E.g. if an exogenous hormone (from a medical treatment) resulted in a state of hormonal excess in the patient, the cause is regarded as iatrogenic
What happens if a patient is given too much exogenous cortisol? The cortisol will feedback negatively to the hypothalamus and stop the production of CRH. As a result cortisol production would shut down. If the adrenal cortex is starved of cortisol long enough, the glands will atrophy
Atrophy Loss of cell mass; in the previous example with excess endogenous cortisol, the endocrine cells of the adrenal glands shrink and lose their ability to manufacture ACTH, i.e. the adrenal gland atrophies
Can atrophied glands regain function after the administration of exogenous sources of a hormone? They may be very slowly or even totally unable to gain back function. Therefore patients on hormone therapy must be tapered off the treatment very slowly to give their glands time to recover
Hyposecretion Too little hormone is secreted, causing symptoms of hormone deficiency.
Example of Hyposecretion Insufficient diet in iodine will make the thyroid unable to manufacture the iodinated thyroid hormone
Most common cause of hyposecretion Atrophy of the gland due to some disease process
How is negative feedback pathways affected in hyposecretion? The opposite to that of hypersecretion. The absence of negative feedback causes more trophic hormones to be produced.
Example of the negative feedback affect in hyposecretion The adrenal cortex atrophies in tuberculosis and cortisol production decreases. The hypothalamus and anterior pituitary will then secrete more CRH and ACTH in an attempt to stimulate the adrenal gland into making more cortisol
Abnormal tissue responsiveness When the hormones exist in normal concentrations but the tissue isn’t responsive. This can be due to receptor or second messenger problems
Down regulation If hormones secretion is abnormally high for a long time, target cells may down-regulate (decrease the number of) their receptors in an effort to diminish their responsiveness to excess hormone
Hyperinsulinemia Classic example of down-regulation. Sustained high levels of insulin cause target cells to remove insulin receptors from their cell membrane. Signs of diabetes, even though insulin levels may be high, will result
Receptor abnormalities Abnormal tissue responsiveness can result when there are mutations in the receptors that cause them to be absent or nonfunctional
Testicular feminizing syndrome Androgen receptors are nonfunctional in the male fetus because of a genetic mutation. As a result the androgens produced by the developing fetus are unable to influence development of the genitalia.
Signal transduction pathway abnormalities Abnormal tissue responsiveness can also result when there are problems in the signal transduction pathway, e.g. defects in the G protein
Pseudohypoparathyroidism Low parathyroid hormone results even though blood levels of the hormone are normal or elevated. This is due to a defect in the G protein that links the hormone receptor to the cAMP amplifier, adenylyl cyclase
Primary pathology If a pathology (deficiency or excess) arises in the last endocrine gland in a reflex, the problem is considered to be a primary pathology
Example of primary pathology If a tumor in the adrenal cortex begins to produce excessive amounts of cortisol, the resulting condition is called primary hypersecretion
Secondary pathology If a dysfunction occurs in one of the tissues producing trophic hormones, the problem is secondary pathology.
Example of secondary pathology The pituitary is damaged because of head trauma and ACTH secretion diminishes. The resulting cortisol deficiency is considered to be secondary hyposecretion of cortisol
Etiology of a disease The cause of a disease
How common are hypothalamic pathologies? How common are pathologies in the anterior pituitary? Hypothalamic: rare. Anterior pituitary: about 2/3 of all cortisol hypersecretion syndromes.
Two possible explanations in a primary disorder Endogenous hypersecretion of the hormone or exogenous administration of the hormone
What happens if there is an adrenal tumor that is secreting a hormone, e.g. cortisol, in an unregulated fashion The normal control pathways are totally unaffected. The excess cortisol shuts off hypothalamic and anterior pituitary cortisol production via negative feedback, but the tumor is not reliant upon their signals
Evolutionary conservation of hormone function As scientists sequence the genomes of diverse species, they are discovering that in many cases hormone structure and function have changed amazingly little from primitive vertebrates through the mammals
How is modern insulin produced Genetic engineering: the human gene for insulin is inserted into a bacterium which then synthesizes the hormone, providing us with a plentiful source of human insulin
E.g. of a hormone that we don’t use any more and is evolutionarily “on its way out” Calcitonin which is found in fish and plays a major role in their metabolism, is also in humans and apparently has no role
Some endocrine structures that are important in lower vertebrates are vestigial in humans, meaning… …that in humans these structures are present as minimally functional glands.
Example of vestigial structure in humans E.g. melanocyte-stimulating hormone (MSH) from the intermediate lobe of the pituitary controls pigmentation in reptiles and amphibians. Adult humans only have a vestigial intermediate lobe with no measurable MSH
Comparative endocrinology The study of endocrinology in nonhuman organisms. E.g. melatonin was discovered via research in tadpoles.
Melatonin The “darkness hormone” secreted at night as we sleep. It is the chemical messenger that transmits information about light-dark cycles to the brain center that governs the body’s biological clock
Grave’s disease Autoimmune disorder in which the body produced antibodies that mimic TSH and bind to the receptor in the thyroid. The thyroid gland then is fooled into overproducing the hormone.
Graves’ disease effect on relevant hormone levels in the blood TRH and TSH are both low and thyroid hormones (thyroxine) are elevated because it’s a primary hypersecretion pathology
Hypothalamic-anterior pituitary pathway, target: breast PRFs (prolactin releasing factors) AND dopamine (inhibits) -> prolactin (non-trophic) -> [[breast tissue]]
Hypothalamic-anterior pituitary pathway, target: thyroid gland TRH (thyroid releasing hormone) -> TSH (thyroid stimulating hormone) -> [thyroid gland] -> thyroid hormones -> [[many tissues]]
Hypothalamic-anterior pituitary pathway, target: adrenal cortex CRH (corticotropin-releasing hormone) -> ACTH (adrenocorticotropin) -> [adrenal cortex] -> cortisol -> [[many tissues]]
Hypothalamic-anterior pituitary pathway, target: Liver Somatostatin (inhibits) AND GHRH (stimulates) -> GH (growth-hormone) -> [liver] -> IGFs (insulin-like growth factors) -> [[many tissues]]
Hypothalamic-anterior pituitary pathway, target: endocrine cells of the gonads GnRH (gonadotropin-releasing hormone) -> FSH (follicle stimulating hormone) OR LH (luteinizing hormone) -> [gonads] -> Androgens OR estrogens/progesterone -> [[germ cells of gonads]] and [[many tissues]]
Insulin release requires phosphorylation by: PKC and PKA in addition to the calcium influx in order to exocytose the secretory vesicles filled with insulin
Translocation The process of moving the protein throughout the ER. Hence “cotranslational translocation” which occurs in the ER
Summary of synthesis/secretion of peptide hormones RER: cotranslational translocation -> Golgi: prohormone processing -> cytosol: storage in immature secretory granules (hydrophilic so can be stored); exocytosis via mature granules (way after synthesis, stored long term)
Proinsulin -> insulin + c-peptide (note: proinsulin cannot function, only insulin can. This process is therefore required) Pro-insulin is a single “curly-Q”-looking unit. During post-translational modification a large portion called “C-peptide” is snipped off and all that remains are two strands linked by multiple disulfide bonds (cysteines) = insulin
What enzymes are involved in snipping proinsulin to insulin? Prohormone convertases that live in the secretory pathway. They recognize pairs of bases of amino acids and cleave them, *especially Lys-Arg*
Prohormone for ACTH Pro-opiomelanocortin which is snipped to: ACTH, gamma-lipotropin, beta-endorphin, and an inactive fragment
Preprohormone for TRH Snipped to *6 copies* of TRH as well as some other peptides and a signal sequence
Parent of steroids Cholesterol
Where are steroids made Adrenal cortex and testes/ovaries
Glucocorticoid is important for Mobilizing glucose stores in the body during fasting
Aldosterone does what? Controls sodium reabsorption – too much reabsorption will result in too much in the blood, more fluid being retained and ultimately increased pressure
Summary of the synthesis/secretion of steroids Cholesterol is shuttled first to the mitochondria where it’s converted to an intermediate. The intermediate is sent to the ER where it’s modified. Then sent back to mitochondria. Then immediately synthesized, diffuses through membrane
A cell that makes steroids is called a… …steroidogenic cell.
Difference between steroidogenic and peptide-synthesizing cells Peptide cell has lots of rough ER, golgi, and dark secretory granules. Steroidogenic cells = more smooth ER, lots of lipid droplets (cholesterol), and no secretory granules.
How are steroids transported through circulatory system? Carriers since they’re lipophilic
How can steroid hormones affect its target? Bind straight to DNA; bind to receptor in nucleus; bind to receptor in cytosol; or bind to cell surface receptor
How does steroid hormone glucocorticoid bind to its target? Binds directly to receptor located ON DNA!
From where are catecholamines and thyroid hormones derived? Tyrosine
Compare half life of peptide hormones to steroids Peptide: short, steroid: long (especially when it directly affects gene expression)
Three catecholamines Dopamine, norepinephrine, epinephrine
Two thyroid hormones Thyroxine, triiodothyronine
Overall structural difference between thyroid hormones and catecholamines Thyroid hormones have two ring structures
Conversion of tyrosine to dopamine Hydroxylation of benzene ring (add another hydroxyl group) by enzyme *TYROSINE HYDROXYLASE* and de-carboxylation of carbon next to amine
Conversion of dopamine to norepinephrine Convert H on C next to benzene to OH by the enzyme DOPAMINE BETA-HYDROXYLASE
Conversion of norepinephrine to epinephrine Convert primary amine to secondary amine by turning one of the H’s into a methyl group
Why the name “catecholamine”? A benzene with two hydroxyls next to each other is the basis for the molecule “catechol”. And of course there’s an amino on the opposite side of the molecule.
What do you call a cell that can produce catecholamines? Catecholaminergic cells
What do you call pathways that are dominated by catecholamines? Catecholaminergic pathways
Recap: what do you call cell that can produce peptide hormones? Peptinergic cells
What happens if a neuron continuously secretes norepinephrine? After it runs out it will response by producing more tyrosine hydroxylase thus creating more dopamine thus creating more norepinephrine. A form of up regulation if you will
The most stored catecholamine in neurons Norepinephrine
Unique part about thyroid hormones The multiple iodines – it’s the only place in the body where you use iodine
Summary of the synthesis of neurotransmitters (e.g. in adrenal medullary cell or any other catecholaminergic cell) Tyrosine -> dopamine -> stored in hydrophilic granules -> secreted long after creation via exocytosis
Compare catecholamines and thyroid hormones to peptide and steroid hormones Catecholamines are like peptide hormones; thyroid hormones are like steroid hormones
One of the peptide hormones stored in the adrenal medulla Enkephalin – opiate peptide that mimics opium. Mood modulator and pain reducer. Narcotic analgesic. It’s secreted along with epinephrine every time you have a fight/flight response. They’re coordinately secreted from same vesicles
Difference between catecholamine and peptide hormone Dopamine is pumped INTO vesicles from cytosol – there’s no golgi or ER involved. VERY IMPORTANT.
For thyroid hormones, what is stored in the secretory vesicles? Add note Precursors. The fact that these are stored in secretory vesicles is the only difference between that of steroid hormones
Transcriptome The population of all mRNAs
Is the anterior/posterior pituitary part of the brain? Anterior = no, it’s not made of neurons. The posterior = yes.
Somatotrophs Cells that release growth hormones
Effects of glucocorticoids from chronic stress Increased blood sugar and proteins/fats broken down for energy
Effects of mineralcorticoids (e.g. cortisol) from chronic stress Retention of sodium and water, increased blood pressure and blood volume
Effects of catecholamines from short term stress response Increased heart rate, increased bp, convert glycogen to blood glucose, dilation of bronchioles, decreased digestion, decreased urine, increased alertness
HPA axis Hypothalamic-pituitary-adrenal axis
All hypothalamic hormones are _____ hormones Peptide
How many peptides make up TRH and what are they? 3: Glutamic acid – histidine – proline
Why is the small size of TRH significant It makes it resistant to changes in pH and temperature
Unique aspect of peptide hormones in the brain such as TRH Their C-terminus is not a carboxylic acid, it’s an amide; the OH is replaced by NH2
Enzyme discovered by professor PAM, it requires O2 and Cu as cofactors
High levels of cortisol do a good thing and a bad thing Decrease inflammation and suppress immune system
Cells that CRH binds to in anterior pituitary Corticotrophs
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