Introduction to Human Physiology - 6 Endocrine System

Source: My personal notes from Introduction to Human Physiology | Coursera

Hypothalamus Pituitary (H-P) Axis

Dominant axis for entire body

Regulates Homeostasis

• The pituitary sits outside the blood-brain barrier and can receive signals from blood.

Embryonic Development and Pituitary Anatomy

Look at development to understand different parts of the brain.

• During development, brain has a “down growth” towards mouth area and expands.

• Brain grows downwards. The Rathke’s pouch grows from the roof of the mouth upwards.

• Brain forms infundibulum and pars nervosa which both form the posterior pituitary. Eventually pouch is severed and forms pars tuberalis and pars distalis which forms the anterior pituitary (glandular tissue)

• There are 2 lobes of the pituitary - anterior and posterior.

• 8 hormones from the pituitary

  • 6 from anterior
  • 2 from posterior

Hypothalamus-Pituitary Portal System and Anatomy

• Called portal system as blood enters from superior hypophyseal artery to upper region of pituitary.
• Numbered areas in diagram are capillary beds. They are connected by veins -> called a venous portal system.
• Hypothalamus has neurons with axons extending into the #1 capillary bed. These neurons secrete neural peptides to #1. #1 blood moves to #2.
  • Pars distalis interprets peptides and regulates secretions of hormones into the vein resulting in delivery to circulatory system.
  • Things to keep in mind:
    • Neural peptide release has a pulse to prevent downregulation since they are released at high concentrations. Normally at high concentrations, cell surface receptors of the peptides would down regulate.
    • Secretions from hypothalamus is episodic, like circadian rhythms and female monthly reproductive cycle.
    • Target receptor cells have low affinity due to large concentrations.

H-P Axis Target Cells

• 6 different hormones

• Releasing factors come from hypothalamus.

• Each factor targets pituitary cells.

• Target secretes hormones called tropic factors that act on target organ in periphery

• e.g. Thyroid releasing hormone (TRH) acts on pituitary to release Thyroid Stimulating Hormone (TSH) into the system, that acts on the thyroid gland and gland secretes T3, T4.

• Most releasing factors are positive except for Somatostatin and Dopamine which are negative.

  • The combination of negative and positive factors in the pituitary determines the secretion of the trophic hormone.

Regulation of H-P Axis

• Hypothalamus with positive factor > pituitary > hormone secretion > some hormone > short/long negative feedback loops.

• There is also an ultra short loop at XRH via paracrine (Neighbouring cells regulate).

• Feedback loop also present for negative factor.

Application to Growth Hormone (GH)

• Secretion is pulsatile and follows 24 hour rhythm.

• For older people, GH secretion patterns are the same, just less than younger people. Young people will have higher amplitudes.

Increases due to stress, sleep

Decreases due to increased blood glucose. In early hours there is a drop in blood glucoses due to rise in cortisol.

H-P-GH Axis

• IGF = insulin growth factor 1

• Note the short, long, and ultra short loops and their locations.

• Somatostatin is negative factor and has a feedback loop.

• Research shows GH is important for mice (mice who had GH receptors knocked out) growth after birth; however, fetal development occurs normally without GH. Research also showed IGF-1 is required for fetal development and GH is required after birth.

GH Biological Role

What do growth hormones do?

• Grows muscles, depletes fat

• IGF1 role:

  • Affects long bones growth (i.e. growth vertically)

  • Size and function of all organs grow accordingly to body size

GH essentially develops a strong, muscular lean body.

GH Excess

What happens when GH is too high?

Gigantism = people grow very tall, like > 8ft

So what are the downsides of having too much GH even though it provides a lean muscular body which is ideal for athletes?

• Organs inside body grow as well. Enlarged heart, liver, etc. which causes early death in 20s-30s.

GH Insufficiency

What happens if there is insufficient GH? In these cases, GH is present, but insufficient IGF-1.

Pygmies are the result. They have normal body proportions, but reduced size.

General Concepts

Hypothalamus - Pituitary Axis Posterior

Posterior Pituitary

• There is a capillary bed in the posterior lobe.

• Hypothalamus extends axons into posterior

Two peptides are secreted as below.

Neuropeptides

• Oxytocin is present in males and females. Helps females during breast feeding and female delivery of baby through contraction and relaxation of birth canal.

  • As a “bonding hormone” it is created during high intimacy with love partners or when a parent takes care of a child (feeding, taking care, cuddling). A “love potion” if you will.

  • If one has low oxytocin levels (pathological situation, there is weak/no bonding occurring). Case: mother rejects her own baby. These individuals have no interest in caring for child.

• Vasopressin attempts to retain water for the body due to [Na] or reduced blood volume. Water is going back into the plasma to reduce [Na] and increase blood volume.

Pathology of Vasopressin

Diagnosis of diabetes insipidus in ancient Greeks for people drinking a lot and peeing a lot (polyuria):

• Taste urine of patient and if:

  • Sweet: diabetes mellitus, people urinating glucose from the body.

  • No taste: diabetes insipidus (“no taste”), problem with vasopressin or antidiuretics.

    • CNS Lesion: Secretion is inhibited or blocked, person isn’t able to concentrate their urine and they end up urinating 18 L /day

    • Nephrogenic (kidney) lesion:

      • Vasopressin receptors can’t recognize vasopressin.

      • Aquaporin 2 channels (channels that allow water to transfer kidney to plasma). If channels are disturbed, exchange cannot occur, so water is restricted to kidney.

  • Diabetes comes from the Greek word means “siphon” as people with diabetes passed water like a siphon.

Causes

General Concepts

Feedback is via changes in [Na] or blood volume for vasopressin and of a mechanical nature for breast/birth canal for oxytocin.

Specific Hypothalamus-Anterior Pituitary Axes

 

Hypothalamus-Pituitary Adrenal Axis

• Axis the governs response to (psychological/physical) stress.

• Flight or fight response and parasympathetic and sympathetic connections.

• Immune system dampener

Adrenal Gland

• 2 adrenal glands, one on top of each of the 2 kidneys in body.

• No ducts as it is an endocrine gland.

• 3 hormones come from cortex and are steroids - they travel through plasma. They are synthesized on demand since they can pass through membranes. Target cells have receptors for the steroids. Transcription occurs with RNA and creation of proteins.

  • Process: synthesized steroids > plasma transport > pulled off their carriers > transcription of gene > protein synthesis.

  • All in all 30 minutes from synthesis in adrenal gland to protein generation.

  • 3 hormones:

    • Aldosterone - salt

    • Cortisol - sugar

    • DHEA - sex, secondary

• Medulla secretes Epinephrine and norepinephrine.

Mineralocorticoid Aldosterone

Governs salt level

• Cause and effect #1: [K+] rise in blood, Aldosterone Moves [Na] to plasma and [K+] to kidney. Increased K+ in urine, reducing [K+] in blood.

• Cause and effect #2: low blood volume/pressure, angiotensin II ( a vasoconstrictor) occur. End effect as cause #1. Increased blood volume and pressure.

Glucocorticoid Cortisol

Governs sugar level

• Triggers are circadian rhythm. Has pulsatility.

• During stressful times, circadian rhythm pattern is preserved, but levels may be higher.

H-P Axis Regulation

Stressor = low plasma glucose is root cause of cortisol.

Cortisol is delivered to target tissues.

• Long feedback loop from cortisol to anterior pituitary to govern level of ACTH and to hypothalamus for levels of CRH.

• Short feedback loop anterior pituitary to hypothalamus.

• Axis can be suppressed by giving cortisol as a drug. Suppression takes 4-6 weeks to come back to normal. So for pharmacological application considers gradual return and patients are gradually weaned off cortisol.

• With high ACTH, DHEA is also high. However, DHEA doesn’t have negative feedback loops to ACTH and CRH. In certain cases of low cortisol, if ACTH is stimulated, DHEA will rise.

  • Since DHEA is a weak androgen, male effect on higher DHEA is small. However, for females it will increase male (Secondary sex) characteristics

Metabolic effects of Cortisol

Fat in peripheral stores are reduced, though beer belly fat will be increased. Fuel sources are moved to easily altered (labile) sources.

Pharmacologic effects of Cortisol

Suppress immune response

Catabolic by degrading certain types of fat.

 

Adrenal Pathology

• Addison’s disease: adrenal cortex is being degraded due to autoimmune disease.

  • Note if [K+] is too high, it effects resting membrane potentials of neurons, heart, skeletal muscle and moves them towards threshold (depolarization). They are easily excitable.

  • High [K+] can cause death (hyperkalemia)

  • Reaction to stress is low.

  • ACTH is high, since negative feedback of cortisol to pituitary is disturbed.

• Cushing’s disease:

Dexamethasone can be used to test if ACTH is the problem.

Medulla Regulation

• Sympathetic nervous system (SNS) stimulates adrenal medulla.

• EPI (epinephrine) can feedback to change perception of stress.

Metabolism in Stress

• Cortisol releases fat energy stores, causing plasma glucose levels to rise.

• EPI causes breakdown of fat, free fatty acids and glycerol are delivered to blood.

• SNS also acts on pancreas to inhibit insulin and stimulates glucagon.

Glucagon + EPI + Cortisol produces synergy of three hormones to increase blood glucose when person is in stress.

General Concepts

Comprised of two glands that are regulated separately and produce different hormones.

Hypothalamus-Pituitary Thyroid Axis

• Regulate basal metabolic rate, impacts all cells of body.

• Expression of other endocrine hormones (growth, reproduction, etc. impacts).

• Required for fetal development, w/o thyroid hormones will result in mental retardation.

Thyroid Gland

• Like a bowtie in front your throat.

• Two lobes connected by isthmus

• Gland has follicles (balls of cells)

• Cells secrete hormones into capillary beds which surround follicles.

• No ducts, since it is an endocrine gland.

• Hormones can be stored as thyroid globulin. Body usually has 3 month supply.

• Outside follicles are “C” cells = clear cells.

• Gland can grow in size under stimulation. Cells elongate = hyperthyroid

• Gland can also shrink where colloid (black stuff) is the dominant volume = hypothyroid

Thyroid Hormones

• Gland makes 2 hormones.

• 4 iodines in thyroxine (hence T4)

• Reverse T3 = inactive species. (T3, 3 iodines)

• Carrier proteins carry hormones to target tissues. Since proteins have low affinity and tissues have high affinity, hormones are bound to tissues. Tissue cell receptors will activate transcription.

Folicular Cell Activity

First diagram

• Apical side of cell faces colloid

• Basal side of cell faces blood capillaries

• Cells actively take iodide from blood.

• Iodine is stored in colloid. Colloid is Preprohormone (https://en.wikipedia.org/wiki/preprohormone

A preprohormone is the precursor protein to one or more prohormones, which are in turn precursors to peptide hormones.)

Second diagram

• Thyroglobulin is fused with lysosome and T4 (thyroxine) and T3 (Triiodothyronine) is released. More T4 is released than T3 (11:1 ratio). T4,T3 will be picked up by carriers in blood.

• Cells are regulated from thyroid stimulating hormone (TSH) - a peptide hormone, secreted by pituitary. Hence H-P axis regulates. TSH receptor is on basal (facing blood) side of cell.

• There is a large amount of TSH stored and circulating in plasma (as much as 7 days). TSH can be measured to monitor activity of gland.

H-P-Thyroid Axis

• Negative feedback loops are in place to anterior pituitary and hypothalamus (long, short, ultra short).

• When body is cold, TRH will go up.

• High leptin levels from fat also drives TRH. The body understands there are energy stores. Opposite is true, so when energy levels are low, TRH is stopped.

• TRH = Thyrotropin-releasing hormone

Tissue Conversion by Deiodinases

• Enzyme = end in -ases; Enzymes are molecules that accelerate, or catalyze, chemical reactions.

• Deiodinases convert T4 to T3.

• Some T4 is converted to inactive reverse T3 and some to T3.

• Deiodinase I is regulated by energy levels. During starvation it is less active.

• Deiodinase II is not regulated. It is on nuclear envelope. Converts T4 to T3.

Changes in Thyroid Hormones during Fasting

• Mild fasting (e.g. 1500 calories per day, down from 2000 calories / day for a week) = lowered metabolic rate. Deiodinase is down regulated in all body cells.

• Severe fasting (e.g. 1000 calories per day, down from 2000 calories / day for a week) = much lower metabolic rate. All amounts of thyroid hormones decreased.

  • Leptin levels decreased explains why negative feedback does not elevate TRH levels.

  • Fuel is conserved for CNS and heart (basic needs). Low body heat.

Pathology with H-P-Thyroid axis

• Development of goiter (large growth of thyroid gland and colloid).
• Historically, many people in the world had goiters until iodine was added to salt which decreased goiters dramatically.

Hypo secretion

• Congenital hypothyroidism = too little T4 in fetal development which causes poor DNS development and mental retardation
• Hashimoto disease (hypothyroidism)
• Cold, foggy thoughts, low energy levels.
• Can be treated with T4/T3. Usually T4.

Hypersecretion

• Grave’s disease - autoimmune disease, antibody IgG activates TSH receptor, increases secretion of T3 and T4, but TSH is lowered. Negative feedback loop is disrupted due to antibodies. Most common endocrine disease

• Thyroid storm - tachycardia, high fever/body temperature. Heart can’t be filled due to high heart rate. Treatment: Beta blockers and Deiodinase blockers.

Key Concepts

T4 is the prohoromone. T3 is the used hormone.

Fed State and Insulin

Fed state = well fed body vs. hungry state

Fuel Homeostasis

• Mass balance (weight gain and loss) is related to energy intake and output.

• Feeding axis governed by insulin.

Fed and fasting states

• Anabolic = building tissues.

  • Fuel delivered to liver from GI tract

  • Liver stores fuel as glycogen, fat, or in muscle.

• Catabolic = break down of molecules.

  • Fat/glycogen is used

  • Muscle can be degraded for energy

  • Ketones can be consumed by brain.

Metabolic States

• Insulin and glucagon comes from pancreas inslets.

Opposing Reflex Loops

• When glucose plasma levels rise > 100 mg / decilitre, insulin is secreted by beta cells of pancreas to target liver and skeletal muscle/adipose tissue. Target glucose plasma level is 80 mg / decilitre
  • Insulin promotes glucose storage.
  • In muscle and adipose tissue, glucose transporters incept glucose and allow entry into cells.
  • Inhibit glucagon secretion
• Negative feedback loop to pancreas from plasma glucose level.
• Glucagon can mobilize fuel and raise plasma glucose levels.

Glucose Stimulated Insulin Secretion (beta cell in pancreas)

• Beta cell counts glucose (like a bean counter).

• Insulin (a peptide hormone) is secreted.

• Sulfonylurea can be given to diabetes mellitus type 2 patients to close the K+ channels to increase insulin secretion by beta cells.

Beta Cell Regulation

• Depends on positive factors:

  • Plasma amino acids

  • Plasma glucose

  • Feed forward anticipates raised glucose levels as food enters GI tract (potentiation). Can also occur when smelling, thinking, tasting food.

• Negative factors:

  • Stress / High sympathetic drive / high SNS activity. Inhibits insulin secretion which removes glucagon inhibition.

Insulin Receptor and Target Cells

• Receptor signals inside of cell to recruit a glucose transporter to allow glucose to enter cell rapidly.

• Glucose removed quickly from plasma.

• In liver: energy storage.

Overnight Fasting and Oral Glucose Tolerance Test (OGTT)

• Overnight fasting glucose tests for diabetic onset (mg/dL = micrograms per decilitre).

• Diagram on right: Oral glucose tolerance test - patient is asked to drink high concentration glucose syrup, checks resting glucose and ability of body to deal with glucose spike. Glucose will eventually be expelled through kidneys and urine.

Diabetes Mellitus

• Fuel cannot be absorbed into cells despite intake. Lots of urine (polyuria) is a symptom.

• Type 1 can occur during a person’s lifetime (young children or early adulthood).

• Type 2 = receptor resistance.

  • GLUT 4 transporters not activated, glucose not cleared effectively from blood.

  • Could mean high glucose and insulin levels in blood (insulin cannot be received).

Fasted State and Glucagon

• Body fuel management, feedback, target sites,

Review of Anabolic and Catabolic Metabolism

aa = amino acids

Brain can use ketones and other fuels

Glucagon Target Cells

• Glucagon in liver breaks down energy sources = glycogen (catabolic).

• Rise in plasma [glucose], negative feedback to alpha cells. Keep in mind, insulin inhibits glucagon as well.

Intense Exercise and Glucagon

When do we see a change in glucagon?

• During day (around meals). When insulin rises, glucagon lowers; however fluctuation is not large.

• Exercise

Hypo - gylc - emia

Emia = in blood

Gylc = glucose

Hypo = low

But, how does glucose move into the muscle without insulin for use since glucagon is being secreted?

• Skeletal muscle’s own working moves GLUT 4 transporters up to cell surface to allow glucose to be moved into muscle.

Metabolism in Stress

• EPI and cortisol acts to degrade fat, free fatty acids are released.

• Three hormones in all: EPI, Cortisol, Glucagon - creates synergy.

• Insulin secretion inhibited, alpha cell is activated.

• Drop in plasma [glucose] < 80 mg / dL also activates glucagon release.

• Liver metabolism is affected to raise plasma [glucose]

Acute IDDM Pathology

• Insulin deficiency diabetes mellitus (IDDM) type 1

• Osmotic pressure of increased glucose in blood, increases glucose in urine.

• End result can be coma and life threatening.