Hypothalamus & Anterior Pituitary PDF

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Hypothalamus & Anterior Pituitary Hypothalamus – Pituitary Axis (work tog) = Neuroendocrine Paradigm 

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Connection b/w brain & endocrine system o (Only have to know where the portal hypophysial vessel is, recognize the rest; notice the nuclei that are bundles of neurons in the hypothalamus that secrete hormones into pituitaries) Hypothalamus integrates many signals o E.g. temperature, light, thirst/food, cytokines responding to infection

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Hypothalamus integrates signals from env’t (optic chiasm)

Secretion of Hypothalamic Hormones   

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Specialized regions around hypothalamus lack blood-brain barrier so brain can interact directly with hormones in the blood (e.g. GH negative feedback) Hypophysis = Pituitary Anterior pituitary = Adenohypophysis Posterior pituitary = Neurohypophysis

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ARC = arcuate nucleus SO = supraoptic nucleus PV = paraventricular nucleus AL = Anterior Lobe PL = Posterior Lobe Anterior Pituitary: hypothalamic hormones secreted by neurons through portal hypophysial vessel o Then anterior pituitary releases hormones into the blood (or gets inhibited) Both hypothalamic & pituitary hormones are released in pulses (pulsatile) Posterior Pituitary: neurons originate in hypothalamus & project into posterior pituitary o Neurons deliver hormones

Intermediate Lobe – mostly melanotrophs that produce melanocyte-stimulating hormone (MSH)

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Then released from posterior pituitary into blood

Diagram shows pituitary lobes o 3 main parts – anterior, posterior, intermediate o Hormones come from above (hypothalamus)  Secreted by neurons o Regulatory controls

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Hypothalamus 

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Connects nervous system to endocrine system: o Stimulates many endocrine glands – thyroid, adrenals, gonads etc.  Mostly through pituitary Controls: o Temperature o Appetite o Thirst o Fatigue o Behaviour o Defense Reactions o Circadian Cycle o Blood pressure Inputs (external & internal): o Light o Smell o Autonomic (neural) inputs o Hormones (steroids & thyroid H, blood borne peptides) o Blood borne inputs o Stress o Immune stimuli … Outputs: 1. Direct innervations to adrenal medulla, kidney, parathyroid gland, pancreatic islets (fast) 2. Neurosecretion = H secreted by hypothalamic nuclei  Hypothalamic hormones are mostly small peptides & act via GPCR surface receptors  The hormones act on anterior or posterior pituitary causing the pituitary to release hormones in turn

(may be fast or slower acting depending on pathway activated) Timing & Type of Hormone Response Highly Variable: o Some things must be fast (e.g. fight or flight, adrenaline, cortisol) o Some things must be slow (e.g. brain development via thyroid hormone or bone growth via GH/IGF-1)

Hypothalamic Hormones 

Hypophysiotropic H – regulate release of anterior pituitary hormones o Pulsatile Hormones aka Main Functions Thyrotropin-releasing TRF Regulation of TSH hormone (TRH) Gonadotropin-releasing hormone (GnRH)

LHRH

Regulation pituitary gonadotropins LH & FSH

Somatostatin

GHIH, SRIF

Inhibition of GH, TSH, insulin, glucagon, & others

Growth hormonereleasing hormone (GHRH)

GRF, GHRF, GRH, Somatocrinin

Stimulation of GH (GHRH tropic effect on GH) Also GHRH is trophic for somatotrophs (helps them grow/thrive)

Prolactin-inhibiting hormone (PIH, exactly the same as dopamine) Corticotropin-releasing hormone (CRH)

Inhibits PRL

CRF

*Tropic vs. Trophic

Hormones of the Anterior Pituitary

Regulation of adrenocortical function, ACTH release, regulate appetite, sympathetic nervous system & adrenal medulla

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Different cell types of anterior pituitary secrete different hormones controlled by the upstream hypothalamic hormones for each axis Somatotrophs = GH (growth hormone) Lactotrophs = PRL (prolactin) Thyrotrophs = TSH (thyroid-stimulating hormone) Corticotrophs = ACTH (Adrenocorticotropic hormone) Gonadotrophs = LH (luteinizing hormone) & FSH (follicular stimulating hormone)

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Receptor: GPCR Gαq – stimulate PLC (R found in pituitary, brain, placenta, ovary, testis) o Notes:  You need to know that Gαq stimulates PLC, but don’t need to remember that GnRH uses a Gαq just that it uses a GPCR  Receptors found in reproductive tissues, but main effect is in pituitary release of LH & FSH Main functions: 1. Stimulate release & synthesis of pituitary hormones – LH (luteinizing hormone) & FSH (follicle stimulating hormone) from gonadotroph cells 2. Some axons branch to other parts of brain, limbic system (emotions) neuromodulator 3. Placenta & ovaries make GnRH – acts locally (R found there)  pGnRH releases human chorionic gonadotropin

Gonadotrophs  

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The Hypothalamic-Pituitary-Gonadal Axis 

Cell types need to know o Each responsible for major hormone pathway

GnRH (Gonadotropin-Releasing Hormone) Regulates Reproduction via Anterior Pituitary LH & FSH

10-15% of anterior pituitary cells Release Luteinizing Hormone (LH) & Follicular Stimulating Hormone (FSH) o Both heterodimeric glycoproteins  Consists of a shared α-subunit & a specific β-subunit o The effects of FSH & LH are sex-specific o In general, they:

Bind to receptors in the ovary & testis Regulate gonadal function by promoting sex steroid production & gametogenesis Stimulated by GnRH (Gonadotropin-Releasing Hormone)  

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The hypothalamus must integrate many signals & produce an appropriate response including stimulating or inhibiting endocrine glands Note: hormones downregulate themselves using negative feedback loops Note: GnRH must be pulsatile otherwise LH & FSH become desensitized Right amount of hormone at right time

Corticotropin-Releasing Hormone (CRH) Regulates Stress via ACTH 

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Receptors: o CRHR1 & CRHR2 o GPCR GαS – activates AC which then produces cAMP Main function: o CRH is secreted in response to stress o Stimulates secretion of products derived from Proopiomelanocortin (POMC) like adrenocorticotropic hormone (ACTH) from corticotroph cells of anterior pituitary

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Vasopressin (VP) & angiotensin act synergistically with CRH to mediate ACTH release (so VP positive regulator of ACTH) Oxytocin (OT) inhibits the CRH mediated release of ACTH (so OT negative regulator of ACTH) CRH is also secreted from the placenta

SP = signal peptide CP = cryptic peptide

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Preprohormone 196 aa

GPCR again Know GαS stimulates in general CRH cleaved in proper ways to work

Long – Cortisol can act on the pituitary or hypothalamus to decrease ACTH synthesis o & Can be:  Fast (nonnuclear) – depends on the rate of change of cortisol levels  Slow (nuclear) – depends on the absolute levels cortisol & involves transcription o A negative feedback loop of ACTH on the secretion of corticotropin-releasing hormone (CRH) also exists ACTH followed by cortisol peak before waking & declines as the day progresses o Stress may stimulate ACTH – mediated by VP (vasopressin) & CRH o Low while sleeping o Plasma half-life of ACTH is ~10 min, cortisol ~75 min o

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Corticotrophs  

~ 15-20% of anterior pituitary cells Release of derivatives of Pro-opiomelanocortin (POMC) o POMC – a glycosylated polypeptide of 124 aa o Tissue-specific processing, biologically active peptides ACTH & MSH (other products, e.g. β-LPH, β-endorphin) o Stimulated by Corticotropin-Releasing Hormone (CRH)

Hypothalamus

Regulation of ACTH (& Cortisol): The Hypothalamus-PituitaryAdrenal Axis 

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Cortisol helps the body respond to stress (restore homeostasis) by: o Maintaining blood pressure & cardiovascular function o Reduce immune responses o Maintain blood glucose levels o Regulate metabolism of proteins, carbohydrates & fats Regulated mainly by: o Circadian rhythm (ACTH release) o Stress o Feedback inhibition by cortisol + ACTH Negative feedback: o Short – ACTH inhibits own secretion

Circadian rhythm

for individual Pituitary

F = cortisol  

Feedback loops to try & shut down the system again Adrenal Gland Generally want low cortisol when sleeping (otherwise restless, bad dreams, rapid heartbeat) o Can affect sleep quite a bit if don’t have lower levels

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Cortisol is normally released in response to events & circumstances such as waking up in the morning, exercising, & acute stress Cortisol also plays important role in human nutrition It regulates energy by selecting the right type & amount of substrate (carbohydrate, fat, or protein) the body needs to need the physiological demands placed on it When chronically elevated, cortisol can have deleterious effects on weight, immune function, & chronic disease risk Cortisol (along with its partner epinephrine) is best known for its involvement in the “fight-or-flight” response & temporary increase in energy production, at the expense of processes that aren’t required for immediate survival o The resulting & hormonal imbalances (ideally) resolve due to a hormonally driven negative feedback loop Example – How the stress response operates as its intended survival mechanism: 1. An individual is faced with a stressor 2. A complex hormonal cascade ensues & the adrenals secrete cortisol 3. Cortisol prepares the body for a fight-or-flight response by flooding it with glucose, supplying an immediate energy source to large muscles 4. Cortisol inhibits insulin production in an attempt to prevent glucose from being stored, favouring its immediate use 5. Cortisol narrows the arteries while the epinephrine increase heart rate, both of which force blood to pump harder & faster 6. The individual addresses & resolves the situation 7. Hormone levels return to normal

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Lactotrophs

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~ 10-25% of anterior pituitary cells Release Prolactin (PRL) o A 198 aa protein, mainly non-glycosylated o During pregnancy it helps in the preparation of the mammary glands for future milk production o Following birth, stimulates the production of milk products (protein & lactose synthesis, water excretion & sodium retention) o Dopamine aka PIH (prolactin inhibiting hormone) inhibits PRL, so main regulatory hypothalamic hormone is inhibitory o Stimulated by sleep & stress, but mainly suckling stimulation by baby nursing at breast o Important in men & women for sexual gratification o In women who aren’t pregnant, prolactin helps regulate the menstrual cycle o In men, prolactin affects sperm production

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Prolactin axis Anterior pituitary cells release the hormone prolactin One of the main things you do when developing as a fetus If pregnant = one of the main things that changes things in your body as an adult Following birth need to continue to stimulate milk production Dopamine = negative regulator o Positive stimulus of the baby will overcome this o Sleep + little stress (not too much) can help stimulate this pathway There are other functions of this hormone system – not just milk production

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Dopamine (aka Prolactin Inhibitory Hormone) Regulates Milk Production via Inhibiting PRL 

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Receptors: o 5 Dopamine R subtypes o D2 receptor, Gαi – inhibits AC,  cAMP levels Main function: o Role is inhibitory of prolactin by binding receptor on lactotrophs  So disruption or inhibition of dopamine leads to an increase in prolactin (for milk) Dopamine = an amino acid derivative

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Dopamine also has important role as a neurotransmitter in rewarddriven learning o Every type of “reward” that has been studied increases the level of dopamine transmission in the brain o A variety of highly addictive drugs (incl. stimulants such as cocaine & methamphetamine) act directly on the dopamine system

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Negative regulation of prolactin* Prevents lactotrophs from being active If baby comes along – it stops inhibiting so that milk production can occur

Prolactin Axis

Positive regulation by breast feeding infant stimulates nipple mechanoreceptors that tell hypothalamus to increase PRL

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PRL: o o

Stimulates breast development & milk production Inhibits GnRH synthesis thus inhibiting ovulation in females & spermatogenesis in males (decreases FSH/LH as a response) o Increases dopamine secretion (negative feedback) DA = dopamine o Also called Prolactin Inhibitory Factor Baby will tell hypothalamus to stop producing so much dopamine If pregnant needs to slow the other stuff down bc need to focus on the baby Repression needs to be taken away Baby stimulates mechanoreceptors on breast to regulate pos

Thyrotropin-Releasing Hormone (TRH) Regulates Thyroid Axis via TSH  

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Receptor: o GPCR Gαq – stimulates PLC which then generates IP 3 Main function: o Stimulates release of thyroid stimulation hormone (TSH) from thyrotroph cells of anterior pituitary o Regulates by stimulating TSH Also found in GI tract (gut) & pancreas Tripeptide processed from a large (242 aa) precursor that contains 6 copies of TRH

Also inhibited by thyroid hormone (TH, T3 & T4) negative feedback loop Notes on the subunits: o The glycoproteins (TSH, FSH & LH, as well as hCG – human chorionic gonadotropin) have 2 subunits o They share an identical α-subunit o Their β-subunits confer the biological activity o These subunits are synthesized separately & unite through non-covalent bonding before carbohydrates are added o They are secreted from the cell together o

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Tropic vs. Trophic Effect o Tropic effect – hormone causing release of another hormone o Trophic effect – hormone affecting the cells

TH Axis/Regulation

(Pyro)Glu-His-Pro-NH2

Thyrotrophs  

Less than 10% of anterior pituitary cells Release of Thyroid Stimulating Hormone (TSH) o Glycoprotein  Consists of a shared α-subunit & a TSH-specific βsubunit o Stimulates all aspects of thyroid gland function – including thyroid hormone synthesis & release  TSH also causes an increase in thyroid gland size & vascularization o Stimulated by thyrotropin-releasing hormone (TRH), inhibited by somatostatin (both from hypothalamus)

1. Neurons from hypothalamus secrete thyrotropin-releasing hormone (TRH) into portal veins that provide a direct route for TRH to the anterior lobe cells 2. Thyrotrophs in anterior pituitary are stimulated by TRH & secrete TSH (thyroid-stimulating hormone) into the pituitary venous system (inhibited by somatostatin from hypothalamus) 3. Cells in thyroid are stimulated by TSH & secrete TH (uses iodide – critical to structure) into the capillaries for transport to target tissues or via blood stream back to hypothalamus & pituitary 4. TH transported into cells of target tissue 5. a) Negative Feedback – serum T3 & T4 levels regulate TRH & TSH o b) Negative Feedback – excess iodide inhibits (iodide required for TH, is also a regulator)

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Receptor: GPCR Gαi – inhibits AC,  cAMP levels,  GH secretion Main functions: Inhibits secretion of GH & TSH from pituitary, also made in pancreas, gut, & thyroid o In pancreas inhibits glucagon, insulin & PP release Two forms: 1. SS14 in hypothalamus 2. SS28 (N-term extended) in gut o Differential processing in different tissues allows different function of SS

2 5b SP = signal peptide CP = cryptic peptide 4

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3 Note: Somatostatin inhibits secretion of TSH from pituitary (not shown) Thyroid gland looks like a butterfly shaped thing in back of throat/behind throat T1, T2, T3, etc. shows how many iodines are on them T4 is the most iodated possible Taking iodine off iodated T3 is the main active nuclear TF Genomic & nuclear effects Too much iodine stops, negative feedback loop Negative feedback with T3 & T4 with other thyroid hormones

Somatostatin Regulates the Growth, Thyroid & Insulin Axes by Inhibiting Them

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Preprohormone 116 aa

In the gut – different form of the same molecule Larger one has major role in insulin regulation Smaller in hypothalamus

Growth Hormone-Releasing Hormone (GHRH) Regulates Growth Axis via GH  

Receptor: GPCR GαS – activates AC which then produces cAMP,  GH secretion GHRH Characteristics: o Released in pulses (like the other hypothalamic hormones)  This leads to pulsatile increases of GH in circulation when stimulates somatotrophs cells of anterior pituitary

SP = signal peptide CP = cryptic peptide 

Preprohormone 108 aa

Have to cut off SP & CP to get functional hormone

Somatotrophs 

~ 40% of anterior pituitary cells

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Release Growth Hormone (GH) o A 191 aa protein, mainly non-glycosylated o Stimulates the production of IGF-1 (mediator of the indirect growth promoting effects of GH) o Also exerts direct effects on Lipolysis, aa uptake in various tissues, protein synthesis in the liver, & opposes insulin actions o Stimulated by growth hormone-releasing hormone (GHRH) from hypothalamus, inhibited by somatostatin o Negative feedback on somatotrophs to regulate self = autocrine

Supposed to show 7 transmembrane receptor

GHRH & Somatostatin are Reciprocal Hormones  

Growth Hormone Releasing Hormone (GHRH) stimulates synthesis & secretion of GH by increasing cAMP Somatostatin (SS) inhibits GH release by decreasing cAMP

Somatotrophs

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IGF-1 has negative feedback on pituitary & positive effect on SS Should be able to explain which is positive & negative regulator & which cells/hormones are affecting what if shown diagram like this

Summary GH Regulation 

Note: receptor is 7tm type so spans membrane really

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Both Growth Hormone Releasing Hormone (GHRH) & Somatostatin (SS): o Act on same somatotrophs cells via adenylyl cyclase enzyme (AC) o Stimulate or inhibit synthesis & secretion of GH by increasing or decreasing cAMP

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Shows that in the same cell have different receptors & different hormones Shows cAMP & competing factors More GH releasing hormone, more cAMP, more GH Somatostatin decrease cAMP & decrease GH...