Endocrine Lecture 2

Question 1

Hypothalamus regions receive unique inputs from all areas in the body and then the hypothalamus has to integrate those signals into a singular output:

either to the anterior or posterior pituitary

What hormones are released from anterior vs posterior pituitary?

Answer 1

Anterior Pituitary: ACTH, GH. TSH, LH, FSH, Prl (metabolism, growth and development, reproduction, lactation and response to stress)

Posterior Pituitary: OT and AVP (water balance, parturition and lactation)

Question 2

The hypothalamus is an example of a _____ endocrine gland.

It is ______ and dumps its hormones _____

Answer 2

Hypothalamus is a classic endocrine gland

It is ductless, dumps its hormones into the blood stream at the medial geniculate

Question 3

Explain the functions of these hypothalamuc nuclei:

PVN

POA

SO

AR

Answer 3

Hypothalamic Nuclei Functions:

PVN (avp neurons, regulates thirst, blood pressure, also mood/emotion/stress)

POA: reproductive function and body temp

SO (lots of avp neurons regulating osmolarity)

ARC (regulates stress and feeding behavior)

Question 4

What is the median eminence?

Answer 4

The median eminence is the floor of the hypothalamus, convergence point for axons

“Important to point out that cell bodies of neurons are located in the hypothalamic nuclei, BUT their axons are extended down to the median eminence, where hormones are dumped directly into the blood”

Question 5

Explain the following hypothalamic releasing factor hormones (which brain nucleui do they originate from, what is their pituitary target, function)

1. GnRH and GnIH
2. CRH
3. TRH

Answer 5

1. GnRH (IH is inhibitor) comes from neurons scattered all over brain, but majority in POA, targets gonadotrope cells in the pituitary to release FSH and LH for reproductive function
2. CRH comes from the PVN to target corticotropes in the pituitary to release ACTH for many functions (glucocorticoids)
3. TRH comes from the PVN, and targets thyrotropes in the pituitary to release TSH for function of thyroid hormone (also has many functions)

Question 6

Explain the following hypothalamic releasing factors (which nuclei they originate from, what their pituitary targets are and what their function is)

1. GHRH
2. Somatostatin
3. Dopamine

Answer 6

1. GHRH comes from the Arcuate nucleus to target somatotropes in the pituitary to release GH, function of growth and development
2. Somatostatin (GHRH inhibitor) comes from the PeVN to target somatotropes in the pituitary to inhibit GH as its function
3. Dopamine: comes from arcuate nucleus, targets lactotropes in the pituitary to release prolactin for milk production

Question 7

GnRH:

Cell bodies are _________

Very long axons extend toward the _______

If you do not have these neurons you will be _____

GnRH is a _______ hormone, meaning that it binds to a ____-

Answer 7

GnRH:

Cell bodies are scattered throughout forebrain, with the largest concentration in the POA (Pre-optic area)

Very long axons extend toward the median eminance

If you don’t have these neurons you will be sterile

GnRH is a decapeptide, meaning its a peptide hormone and therefore binds to a cell surface receptor

Question 8

Kallman Syndrome:

What is kallman syndrome?

Answer 8

Kallman Syndrome:

Rare genetic disease where the GnRH neurons fail to enter the CNS during embryonic development (these neurons originate in the nose and travel to the brain during early development)

Kallman disease is characterized by reproductive failure and anosmia

It is heritable: X linked (Kal 1) and Autosomal (Kal 2)

Question 9

GnRH:
GnRH is released via the ___________ system and binds to cell surface receptors on ________ (pituitary cells).

It then through different secondary messenger systems causes the pituitary to release two hormones: ____, ___

Explain how one hormone can regulate the synthesis of two different hormones

Answer 9

GnRH:

GnRH is released via the hypophysial portal system and binds to cell surface receptors on gonadotroph cells in the pituitary. It then causes through different pathways those gonadotroph cells to release LH or FSH

It regulates two totally different hormones from the same cell type by regulating the frequency by which GnRH itself is released / “pulsitility” (LH is fast pulsitility, FSH is slow pulses), and also by two different signaling pathways.

Question 10

Explain the hypophysial portal system

Can you measure hypothalamuc releasing hormones via a blood test?

Answer 10

The hypophysial portal system is a vascular connection between the hypothalamus and the pituitary gland.

The cell bodies of the hypothalamic releasing and inhibiting hormones are within the hypothalamus, and the axons of them end right at the median eminence, where the hormones travel through portal vein to get to anterior pituitary.

NOTE: you CANNOT measure these hypothalamic releasing portal veins in systemic blood, only in portal vein so they are never looked at

Question 11

GnRH Pulsitility:
Explain the relationship between GnRH pulsing and the pituitary hormone pulses of LH and FSH

Also explain the significance of GnRH pulsing and why it is important that it is pulsitle

Answer 11

GnRH Pulsitility:

• GnRH pulse is right before the pituitary hormone pulse
• Pulse frequency determines which pituitary hormone is released:
  
  • Slow: FSH
  • Fast: LH

For GnRH pulsitility is important to recycle receptors back to the surface AND important for distinguishing which pituitary hormone gets released

Question 12

Explain the difference for pituitary hormones between the Beta subunit and the alpha subunit in all the hormones

Answer 12

All pituitary hormones contain ghe same alpha subunit (a-GSU)

But they all differ in which Beta subunit they have

Question 13

Explain the tuberoinfundibular system vs the neurohypophysial tract

Answer 13

Two Major Pathways for Hypothalamic-Pituitary Connection:

1. Tuberoinfundibular system: comprises all neurons that send axonal projections to the median eminence. Hormones target the anterior pituitary through the portal vein
2. Neurohypophysial Tract: comprises neurons whose axons terminate in the posterior pituitary

Question 14

Pituitary Gross Anatomy:

The Anterior Pituitary main part is called the _____

The posterior pituitary consists of ______ and ____

Answer 14

Pituitary Gross Anatomy:

Anterior Pituitary: pars distalis

Posterior Pituitary: pars nervosa and infundibulum (stalk)

Question 15

Explain the different tissue types that make up the anterior and posterior pituitary:

Anterior pituitary: _______ tissue

Posterior pituitary: ______ tissue

Answer 15

Anterior pituitary: glandular tissue: cords of epithelial cells

anterior pituitary: adenohypophysis

Posterior Pituitary: neurohypophysis, neural tissue

Question 16

Label these stains: which part is anterior pituitary which part is posterior pituitary

Answer 16

Darker stain: anterior pituitary (pars distalis)

Lighter stain on the bottom: posterior pituitary (pars nervosa)

Question 17

Posterior Pituitary - Neurohypophysis:

Axons from ______ neurons terminate in the neurohyphophysis

Blood supply is seperate, and is from the ____ artery

Major hormones released from posterior pituitary:

• *

Answer 17

Posterior Pituitary: Neurohypophysis:

Axons from magnocellular neurons terminate in neurhypophysis (neurohypophysial tract)

Blood supply from inferior hypophysial artery- has its own capillary bed

Major Hormones: Argininge Vasopressin (AVP) and oxytocin (OXY)

Question 18

Posterior Pituitary:

Pars Nervosa Histology:

Axons terminate near the _________

Answer 18

Posterior Pituitary:

Axons terminate near fenestrated capillaries that way they can go right into the blood stream

Question 19

Posterior Pituitary: Pars Nervosa and Herring Bodies;

What are herring bodies?

Answer 19

Pars Nervosa:

Herring bodies are dilations of unmyelinated axons near their terminals

Contain vesicles of either AVP or oxytocin plus a binding protein called neurophysin (the copeptide)

Question 20

Anterior Pituitary- Adenohypophysis:;

The median eminence (ME) is the interface for all hypophysial hormones

ME lies _____ the BBB and forms the floor of the third ventricle (explain what that means)

Answer 20

Anterior Pituitary - Adenohypohysis:

The median eminence (ME) is the interface for all hypophysial hormones

ME lies outside the BBB and forms the floor of the third ventricle

This means that hormones can also be regulated from things outside of the blood stream

Question 21

**Explain which cells within the anterior pituitary are responsible for producing the following hormones:

LH/FSH

TSH

ACTH

GH

Prolactin

Answer 21

LH and FSH : gonadotrophs

TSH: thyrotrophs

ACTH: corticotrophs

GH: somatotrophs

Prolactin: lactotrophs

Question 22

Anterior Pituitary Cell Types and Hormones:
_______ are the most abundant hormone producing cell type (include which two types of cells)

Basophils - dark stain (which three types of anterior pituitary cells are basophils)

What are chromophobes?

Answer 22

Anterior Pituitary Cell Types and Hormones:

Acidophils - most abundant hormone producing cell type (light stain)

• somatotrophs : GH
• lactotrophs: prolactin

Basophils: dark stain

• corticotrophs: ACTH
• gonadotrophs: LH and FSH
• Thyrotrophs: TSH

Chromophobes have clear appearnace, paracrine actions, often pituitary tumors are in these and show no symptoms

Question 23

Explain the regional distribution of anterior pituitary cell types:

Are are the kind of cells that are located on the outside?

Inside

Answer 23

Look at the diagram:

Most somtotrophs and lactotrophs are located outside

Question 24

KEY CONCEPT:
Draw out the differences between the hypothalamus to anterior pituitary general axis vs the hypothalamus to posterior pituitary axis

Answer 24

Question 25

AVP: (posterior pituitary tract) AVP is made in the _____ neurons within the hypothalamus, travels down the ________ tract to the posterior pituitary, where it goes into systemic circulation and targets _____ and \_\_\_\_\_ AVP: is processed as a _____ peptide What does it look like as a preprohormone and a prohormone? (which copeptide does AVP vs OXY have)

Answer 25

AVP is made in the magnocellular neurons within the hypothalamus, travels down the axons (neurohypophysial tract) to the posterior pituitary where it goes into systemic circulation and targets the vasculature and the kidneys. AVP is a nonapeptide (9 AA) Transcribed as a preprohormone (means signal peptide still attached) Prohormones: AVP and neurophysin II, and OXY is neurophysin I

Question 26

AVP is made in cell bodies within the ___ and \_\_\_ The PVN has two types of cells: magnocellular and parvocellular Only _______ neurons project to the posterior pituitary Parvocellular neurons that contain AVP project to ___ and are important for \_\_\_\_\_ AVP in magnocellular SON and PVN is important for maintaining \_\_\_\_\_\_\_

Answer 26

AVP is made in cell bodies in the PVN and SON PVN has two types of cells: magnocellular and parvocellular Only magnocellular neurons project to the posterior pituitary Parvocellular PVN neurons that contain AVP project to median eminence and are important for regulating mood/anxiety/stress AVP in magnocellular SON and PVN is important for maintaining fluid balance

Question 27

\*\*\*AVP Release Posterior Pituitary: Explain the signaling pathways that trigger AVP release from the posterior pituitary and how sensitive they are relative to one another 1. Plasma osmolarity 2, Significant blood loss

Answer 27

1. Plasma Osmolarity (VERY sensitive) When plasma osmolarity increases, the osmoreceptors in the brain shrink. The shrinkage of those osmoreceptors decreases the inhibition that is normally on magnocellular neurons, allowing them to release AVP and target vasculature (constrict to increase BP) and kidneys (increase water reabsorption) 2. Significant blood loss (less sensitive, have to lose 5-10% of blood volume): A decrease in mean arterial BP causes a decrease in baroreceptor stretch and thus a decrease in baroreceptor firing, the brain then increases sympathetic tone. Also, the osmoreceptors now respond to lower osmolarity (shifts curve to left)

Question 28

AVP Targets: The first target of AVP is the vasculature AVP as a peptide hormone will bind to ______ receptors to cause \_\_\_\_\_\_\_ What does this do to vascular resistance?

Answer 28

AVP Targets: First target of AVP is the vasculature AVP as a peptide hormone will bind to a surface receptor, and for vascular smooth muscle the receptor is called the **V1 receptor** to cause **vasoconstriction** AVP causes vasoconstriction- increases vascular resistance

Question 29

AVP: AVP targets the vasculature and the ____ (which organ) On the _____ it binds to the ___ receptor AVP causes ____ insertion on the cell membrane facing the lumen, thus causing water \_\_\_\_\_

Answer 29

AVP: second target is the KIDNEY On the kidney it binds to the **V2 receptor** AVP causes AQP2 insertion in cell membrane facing the lumen, **increases water reabsorption**

Question 30

SUMMARY of AVP affects: In the vasculature, AVP binds to the __ receptor, causing _____ and an ____ in vascular resistance In the kidney, AVP binds to the ___ receptor, causing _______ and thus \_\_\_\_\_\_

Answer 30

In the vasculature, AVP binds to the V1 receptor, causing vasoconstriction and an increase in vascular resistance In the kidney, AVP binds to V2 receptor, causing AQP2 insertion in cell membrane facing the lumen, increasing water reabsorption

Question 31

OXYTOCIN: Oxytocin causes smooth muscle \_\_\_\_\_ Where does it have its effects, and what does that cause? Example of _____ feedback loops

Answer 31

Oxytocin: Oxytocin causes _smooth muscle contraction_ 1. Breast: contracts myoepithelial cells and causes **milk ejection** 2. **Uterine contraction**: giving birth (note: "PITOCIN" is synthetic oxytocin used to induce labor) POSITIVE FEEDBACK

Question 32

HPL Axis: What are the three parts of the HPL Axis Explain the axis briefly

Answer 32

HPL Axis: (regulation of growth overall) Hypothalamus : arcuate nucleus makes GHRH P: anterior pituitary somatotrope releases GH Liver: releases IGF-1 GHRH is made by the arcuate nucleus and is released into portal vein, targets pituitary somatotrope to activate PKA and release GH. The three major targets of GH are muscle, adipose tissue, and the liver (and the liver is what makes IGF-1)

Question 33

Somatostain is the ______ of GHRH \_\_\_\_\_\_ is made in the hypothalamus and pancreatic delta cells (\_\_\_\_\_) Most of the somatostatin in the body is made where?

Answer 33

Somatostatin is the inhibitor of GHRH (it does this two ways, explained on another card) SS14 is made in the hypothalamus and pancreatic delta cells PC1/PC2 SS14 is the inhibitor of GHRH Most of the somatostatin in the body is SS28 and that is made by D cells in the stomach and cleaved by the enzyme furin

Question 34

GHRH and somatostatin: Somatostatin inhibits GHRH in two ways: 1. 2. Also, explain what graphs would look like that compare the relationship between somatostatin, GHRH, and GH levels (somatostatin and GHRH/GH have an ____ relationship\_

Answer 34

GHRH and somatostatin: Somatostatin inhibits GHRH at two levels: 1. Somatostatin modulates GHRH pulsatility in the hypothalamus (decreasing its pulsatile frequency) 2. Somatostatin inhibits PKA in the pituitary thereby inhibiting GH release There is an inverse relationship between somatostatin levels and levels of both GHRH and GH

Question 35

Key Concept: GH Intermediates Many downstream target organ effects of GH are mediated through \_\_\_\_\_\_ GH stimulates ____ production in the \_\_\_\_

Answer 35

Key Concept: GH Intermediates: Many downstream target organs effects of GH are mediated through IGF-1 GH stimulates IGF-1 production in the liver (and this stimulation is insulin dependent)

Question 36

HPL Axis: GHRH is released from hypothalamus and travels to the anterior pituitary where it stimulates PKA to release GH. GH has three major targets: \_\_\_\_\_, \_\_\_\_, \_\_\_\_\_ GH stimulates IGF1 in the liver (\_\_\_\_ dependent) Explain the feedback loop of IGF-1 in the HPL axis

Answer 36

HPL Axis: GHRH is released from hypothalamus, travels to anterior pituitary and activates PKA to create and release GH GH has three targets: adipose tissue, muscle, and the liver In the liver, GH stimulates IGF-1 production as long as there is insulin (IGF-1 stimulation is insulin dependent) IGF-1 acts as negative feedback: in a long loop, IGF-1 inhibits GH release at the pituitary gland AND IGF-1 stimulates somatostatin in the hypothalamus (both of these cause negative feedback)

Question 37

Explain the negative feedback loop that IGF-1 has on the HPL axis

Answer 37

IGF-1 is stimulated by GH in the presence of insulin IGF-1 asserts negative feedback on the HPL axis via: inhibiting GH release at the pituitary somatotropes ``` AND stimulating somatosatin (so that somatostatin can inhibit the pathway as well) ```

Question 38

Explain the Physiological Effects of GH (and IGF-1) in the fed vs fasted state

Answer 38

Fed State: * GH stimulates liver to increase RNA and protein synthesis, and to increase IGFBPs and IGFs * GH stimulates muscle to increase AA uptake and increase protein synthesis GH goal in fed state is to increase lean body mass * also in fed state, IGF-1 will increase organ size and bone size Fasted State: * in fasted state, GH will cause adipose tissue to decrease glucose uptake and increase lipolysis * Liver: increase gluconeogenesis * Muscle: decrease glucose uptake

Question 39

Explain what happens in the following scenarios within the HPL axis: 1. eating only protein 2. eating a donut 3. fasted state

Answer 39

1. eating only protein: amino acids stimulate GHFH, increase GH levels, increase IGF-1 levels, increase protein synthesis and growth 2. donut: low AA, high glucose will inhibit GHRH 3. fasting state: low glucose stimulates GHRH but no IGF-1, GH will then increase (without IGF-1 increase), and that GH will ause caloric mobilization in lipids

Question 40

IGF-1 peaks are critical during _____ periods IGF-1 levels are at the highest during _____ (life stage)

Answer 40

IGF-1 peaks during critical growth periods - highest during puberty

Question 41

What are the main stimulators and inhibitors of GH? GH is increased by \_\_\_, \_\_\_\_, \_\_\_ GH is decreased by \_\_\_\_, \_\_\_\_, \_\_\_\_

Answer 41

Stimulators and Inhibitors of GH: Main stimulator of GH is GHRH, other stimulators include dopamine, NE/Epi (exercise/stress), Amino Acids (protein building), and thyroid hormone Main inhibitor of GH is somatostatin, other inhibtors of GH are IGF-1 (negative feedback loop), glucose (hyperglycemia), and free fatty acids (obesity) GH is increased by stress, exercise, starvation GH is decreased by aging, high blood glucose, and obesity

Question 42

GH Excess- somatotrope tumor (20%) Explain the differences between gigantism and acromegaly: Gigantism: extremely \_\_\_\_, occurs before \_\_\_\_\_ Acromegaly: usually diagnosed in \_\_\_\_ * gradual enlargement of ____ and \_\_\_\_ * changes in facial features * possible increased organ size * most often caused by \_\_\_

Answer 42

GH Excess - somatotrope tumor (20%) Gigantism - extremely rare, occurs before the closing of the epiphyseal plate during childhood Acromegaly: usually diagnosed in middle age * gradual enlargement of hands and feet * changes in facial features * possible increased organ size * most often caused by pituitary adenoma

Question 43

GH Deficiency: _Dwarfism (children): related to GH_ * Laron Syndrome: genetic defect in \_\_\_\_\_, causing ______ of IGF-1. Plasma GH levels are\_\_\_\_\_ * African Pygymy (explain) Adult GH Deficiency: * caused by \_\_\_\_\_ * increased ___ deposition, muscle wasting * risk of fractures, reduced bone density

Answer 43

GH Deficiency: Dwarfism (children): related to GH * **Laron Syndrome**: genetic defect in GH receptor - NO production of IGF-1. Plasma GH levels are normal to high (lack of negative feedback) * treatment for laron syndrome is giving the pt IGF-1 * African Pgymy: partial defect in GH receptor, some IGF-1 response * plasma levels of Gh normal Adult GH Deficiency: * caused by pituitary tumor/surgery * increased fat deposition and muscle wasting

Question 44

Explain what you would expect to see in terms of GH levels for: Laron Syndrome African Pgymy

Answer 44

Laron Syndrome: genetic defect in GH receptor, causing no production of IGF-1. Due to that lack of negative feedback, GH levels are normal to high African Pgymy: partial defect in GH receptor, some IGF-1 response, plasma GH levels are normal

Question 45

Prolactin: Prolactin is made in pituitary \_\_\_\_\_\_ Prolactin is tonically inhibited by \_\_\_\_\_\_ Early antihypertensive drugs inhibited \_\_\_, thereby causing what? Prolactin is released in response to \_\_\_\_

Answer 45

Prolactin: Prolactin is made in pituitary somatotropes Under normal conditions, dopamine tonically inhibits prolactin early antihypertensive drugs inhibited dopamine, caused prolactin release and caused galactorrhea (milk production in breasts) Prolactin is released in response to suckling (positive feedback loop) Prolactin is important in milk production

Question 46

\_\_\_\_\_ inhibits prolactin Prolactin inhibits \_\_\_\_\_\_\_ (so in instances where prolactin is abnornally high, then what?)

Answer 46

Dopamine inhibits prolactin Prolactin inhibits GnRH At times where prolactin is high, you will have diminished FSH and decreased menstral cycles

Question 47

Prolactin: Prolactin hormone is in the same family as ___ hormone This means that ___ can bind the prolactin receptor, and prolactin can bind the ___ receptor Explain what they means for acromegaly patients

Answer 47

Prolactin Prolactin is in the same family as GH hormone This means that prolactin can bind the GH receptor. and GH can bind the prolactin receptor In patients with acrogemaly (high GH levels), the extra GH can bind to prolactin receptors and cause galactorrhea (milk production)

Question 48

Prolactin Excess: * prolactinomas are common pituitary adenomas * cause _____ prolactin levels * causing ______ (increased milk production) * reproductive \_\_\_\_\_\_\_\_ Prolactin Deficiency: * Sheehan's syndrome (explain what this is.... it was in small group)

Answer 48

Prolactin Excess: * prolactinomas are common pituitary adenomas * cause increased prolactin levels * causing galactorrhea (milk discharge from breast) * reproductive dysfunction (prolactin inhibits GnRH release) Prolactin Deficiency: * Sheehan's Syndrome: * occurs as a result of hemorrhage during childbirth * causes pituitary cell death * affects lactotrophs, causing an inability to produce milk, and also causes loss of pubic hair

Question 49

Predict the GH level for the following scenarios: 1. Insulin induced hypoglycemia should cause an ___ in GH levels 2. Administration of IGF-1 should cause an __ in GH levels

Answer 49

1. Insulin induced hypoglycemia should cause an increase in GH levels (low blood sugar stimulates GHRH release, thereby increasing GH levels) 2. Administration of IGF-1 causes a decrease in GH levels (due to negative feedback)