7.1. The hypothalamus-pituitary gland system. Growth hormone and somatomedins.

Question 1

I. PITUITARY GLAND
1. What are the features and position of pituitary gland?

Answer 1

• Master gland in endocrinology -> produces many hormones and controls the function of the periphery endocrine glands
• Located in the base of the skull (sella turcica)
• The pituitary is connected to the hypothalamus via the pituitary stalk (close to optic chiasm)

Question 2

I. PITUITARY GLAND
2. What is the position of pituitary gland?

Answer 2

Located in the base of the skull (sella turcica)

Question 3

I. Basics
3. What is the Approximal weight of pituitary gland?

Answer 3

0,6g in the adult

Question 4

I. Basics
4. What are the characteristics of Posterior lobe of pituitary (neurohypophysis)?

Answer 4

• Contain axon terminals
• The paraventricular + supraoptic nuclei in the HT contain
  magnocellular secretory neurons
• These neurons send their axons to the posterior lobe
  through the pituitary stalk
• These neurons will produce peptide hormones (ADH + oxytocin), which can be released from the axon terminals into the blood circulation -> neurocrine secretion
  => When there is an AP on the neuron, it will run along the fiber and this will be the stimulus which releases the hormone in the circulation (controlled by CNS)

Question 5

I. Basics
5. Which are the nuclei contained in neurohypophysis?

Answer 5

• The paraventricular + supraoptic nuclei in the HT contain magnocellular secretory neurons

Question 6

I. Basics
6. What are the 2 hormones produced by neurohypophysis?

Answer 6

1. Vasopressin (ADH/AVP)
2. Oxytocin

Question 7

I. Basics
7. What are the characteristics of vasopressin (neurohypophysis)?

Answer 7

• Role in kidney (absorption in collecting duct)
• Regulates water balance of the body
• If ↑concentration in the circulation = vasoconstriction

Question 8

I. Basics
8. What are the characteristics of oxytocin (neurohypophysis)?

Answer 8

• Stimulates the contraction of the pregnant uterus (contributes to delivery of baby)
• [oxytocin]↑ -> uterine contraction↑ -> cervix stretch↑ (aids in delivery)

Question 9

I. PITUITARY GLAND - Anterior lobe of pituitary (adenohypophysis)
9A. What are the characteristics of adenohypophysis?

Answer 9

• Derivative of Rathke’s pouch
• Highly vascular glands
• Parvocellular nuclei of the HT produces a variety of hormones
• Hormone producing cells = acidophilic, basophilic,
  chromophobic cells

Question 10

I. PITUITARY GLAND - Anterior lobe of pituitary (adenohypophysis)
9B. What are the hormone producing cells of adenohypophysis?

Answer 10

• Hormone producing cells = acidophilic, basophilic,
  chromophobic cells

Question 11

I. PITUITARY GLAND - Anterior lobe of pituitary (adenohypophysis)
9C. What are the nuclei included in adenohypophysis?

Answer 11

• Parvocellular nuclei of the HT produces a variety of hormones

Question 12

I. PITUITARY GLAND
10A. What are the 3 hormone families of the pituitary?

Answer 12

1. Growth hormone / prolactin family
2. Glycoprotein family
3. Pro-opio-melano-cortin (POMC) family

Question 13

I. PITUITARY GLAND
10B1. What are the 3 hormones of Growth hormone / prolactin family? Which cells produce them?

Answer 13

1. Growth hormone (GH)
2. prolactin (PRL)
3. human chorionic somatomammotropin (hCS)

Question 14

I. PITUITARY GLAND
10B2. What are the characteristics of growth hormone (GH)?

Answer 14

Somatotropic cell -> growth hormone (GH)
- Placenta secretes placental GH, which may suppress GH secretion of the maternal pituitary gland (negative feedback)

Question 15

I. PITUITARY GLAND
10B3. What are the characteristics of prolactin (PRL)?

Answer 15

Mammotropic (lactotrope) cell -> prolactin (PRL)
- Milk production (breast feeding)
- Growth and development of breast
- Most frequent hormone producing pituitary tumor: prolactinoma
+) Causes overproduction of prolactin
+) Gynecomastia: enlargement of breast tissue in males
+) Galactorrhea: spontaneous milk leakage in females

Question 16

I. PITUITARY GLAND
10B4. What are the characteristics of human chorionic somatomammotropin (hCS)?

Answer 16

Placenta secretes human chorionic somatomammotropin (hCS)
- Hormone of highest secreted amount in the human body
- May contribute to ↑ in [glucose] + [AA], but normal pregnancy in its absence

Question 17

I. PITUITARY GLAND
10C1. What are the main features of hormones in Glycoprotein family?

Answer 17

Hormones in this family are composed of 2 subunits:
- α-subunit: identical in every hormone
- β-subunit: is different in every hormone (provides specificity)

Question 18

I. PITUITARY GLAND
10C2. What are the 3 main hormones of glycoprotein family?

Answer 18

1. thyroid stimulating hormone (TSH)
2. Follicle stimulating hormone (FSH)
3. Luteinizing hormone (LH)

Question 19

I. PITUITARY GLAND
10C3. Which cell produces thyroid stimulating hormone (TSH)?

Answer 19

Thyrotropic cell

Question 20

I. PITUITARY GLAND
10C4. Which hormones are produced by gonadotropic cell? What are the characteristics of these hormones?

Answer 20

• Follicle stimulating hormone (FSH):
  +) Ovary (granulosa cells): stimulates development of follicles
  +) Testis (Sertoli cells): regulates spermatogenesis
• Luteinizing hormone (LH):
  +) Ovary (theca cells)
  +) Testis (Leydig cells)

Question 21

I. PITUITARY GLAND
10D1. What are the characteristics of hormones Pro-opio-melano-cortin (POMC) family?

Answer 21

• POMC a precursor polypeptide (prohormone) with 241 AA residues
• POMC is cleaved at different sites to give rise to multiple peptide hormones

POMC: -pro = has to be cleaved, -opio (β-endorphin) = opiate, -melano (α-MSH) = melanocyte-stimulating hormone, -cortin (ACTH) = cortex of adrenal gland / adrenocorticotropic hormone

Question 22

I. PITUITARY GLAND
10D2. What are the 2 main hormones of Pro-opio-melano-cortin (POMC) family?

Answer 22

1. adrenocorticotropic hormone (ACTH)
2. α-melanocyte stimulating hormone (α-MSH)

Question 23

I. PITUITARY GLAND
10D3. What are the characteristics of adrenocorticotropic hormone (ACTH)?

Answer 23

Corticotropic cell -> adrenocorticotropic hormone (ACTH)
- Major effect is on the adrenal cortex, especially the fasciculate layer
- Fasciculate layer produces glucocorticoids (most important: cortisol)
- β-endorphin: neurotransmitter + hormone associated with hunger, sexual behavior etc.

Question 24

I. PITUITARY GLAND
10D4. What are the characteristics of α-melanocyte stimulating hormone (α-MSH)?

Answer 24

• responsible for pigmentation of the skin + production/release of melanin in hair
• equivalent to the first 13 AAs of the ACTH -> related closely
• serious ACTH overproduction -> skin pigmentation (Addison’s disease) LIFE THREATHENING!
  => Destruction of the adrenal gland -> no cortisol produced = ↑ACTH (person cannot survive)

Question 25

I. PITUITARY GLAND - Regulation of pituitary hormone secretion 11A. What are the 2 most important regulators of pituitary hormone secretion?

Answer 25

1. Hypothalamus 2. Negative feedback from the periphery

Question 26

I. PITUITARY GLAND - Regulation of pituitary hormone secretion 11B. Why is hypothalamus the most important regulators of pituitary hormone secretion?

Answer 26

1. Releasing hormones (RH) 2. Release-inhibiting hormones (RIH) (through the special portal circulation of the pituitary)

Question 27

I. PITUITARY GLAND - Regulation of pituitary hormone secretion 11C. Why is Negative feedback from the periphery the most important regulators of pituitary hormone secretion?

Answer 27

By a hormone produced in the target glands (tissues)

Question 28

I. PITUITARY GLAND 12. How is portal circulation of the pituitary occur?

Answer 28

- The HT contains cell bodies of neurons which produce RH + RIH - These cell bodies send their axons to the median eminence, where we have a capillary bed - Here, the neurons secrete their products into the circulation - There is a 2nd capillarization in the adenohypophysis -> connected in series -> portal circulation

Question 29

I. PITUITARY GLAND - Hormones from the HT affecting the adenohypophysis 13A. What are the hormones from the HT that affect the adenohypophysis?

Answer 29

1. Growth hormone releasing hormone (GHRH) 2. Somatostatin (SST) 3. Thyrotropin releasing hormone (TRH) 4. Gonadotropin releasing hormone (GnRH) 5. Corticotropin releasing hormone (CRH) 6. Dopamine

Question 30

I. PITUITARY GLAND - Hormones from the HT affecting the adenohypophysis 13B. How is Growth hormone releasing hormone (GHRH) affecting the adenohypophysis?

Answer 30

Growth hormone releasing hormone (GHRH) uses a Gs GPCR to stimulate release of growth hormone (GH). - Somatostatin (SST) uses a Gi GPCR to decrease the production of GH

Question 31

I. PITUITARY GLAND - Hormones from the HT affecting the adenohypophysis 13C. How is Somatostatin (SST) affecting the adenohypophysis?

Answer 31

Somatostatin (SST) uses a Gi GPCR to decrease the production of GH

Question 32

I. PITUITARY GLAND - Hormones from the HT affecting the adenohypophysis 13D. How is Thyrotropin releasing hormone (TRH) affecting the adenohypophysis?

Answer 32

Thyrotropin releasing hormone (TRH) uses a Gq receptor to activate thyroid stimulating hormone (TSH).

Question 33

I. PITUITARY GLAND - Hormones from the HT affecting the adenohypophysis 13E. How is Gonadotropin releasing hormone (GnRH) affecting the adenohypophysis?

Answer 33

Gonadotropin releasing hormone (GnRH) mostly uses a Gq receptor (and less-so a Gi) to stimulate the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) - After puberty, this release must be pulsatile to function correctly without desensitization

Question 34

I. PITUITARY GLAND - Hormones from the HT affecting the adenohypophysis 13F. How is Corticotropin releasing hormone (CRH) affecting the adenohypophysis?

Answer 34

Corticotropin releasing hormone (CRH) uses a Gs receptor to stimulate adrenocorticotropic hormone (ACTH), which is the major stimulator for cortisol production in the adrenal gland,

Question 35

I. PITUITARY GLAND - Hormones from the HT affecting the adenohypophysis 13G. How is Dopamine affecting the adenohypophysis?

Answer 35

Dopamine inhibits the anterior lobe secretion of prolactin. - Prolactin is normally secreted constitutively from the anterior lobe (does not require any stimulus), but then prolactin is downregulated by dopamine via a D2 (Gi) receptor -> TRH, VIP and a newborn baby suckling all stimulate the release of prolactin.

Question 36

II. HYPOTHALAMUS-PITUITARY GLAND SYSTEM - Growth hormone (GH) 1A. How is the regulation of GH occur?

Answer 36

- GH has a pulsatile secretion pattern about every 2 hours and has its highest concentration during sleep (lowest during day). GH is also more heavily secreted in childhood/puberty - GH is secreted in response to: GHRH, hypoglycemia (↓[glucose]), fasting (ghrelin), sleep, stress, physical exercise, basic amino acids and α2 adrenergic agonist (clonidine) - Secretion of GH is inhibited by: somatostatin, hyperglycemia (↑[glucose]), increased [FFA] in blood

Question 37

II. HYPOTHALAMUS-PITUITARY GLAND SYSTEM - Growth hormone (GH) 1B. GH is secreted in response to ....

Answer 37

- GH is secreted in response to: GHRH, hypoglycemia (↓[glucose]), fasting (ghrelin), sleep, stress, physical exercise, basic amino acids and α2 adrenergic agonist (clonidine)

Question 38

II. HYPOTHALAMUS-PITUITARY GLAND SYSTEM - Growth hormone (GH) 1C. Secretion of GH is inhibited by ....

Answer 38

Secretion of GH is inhibited by: somatostatin, hyperglycemia (↑[glucose]), increased [FFA] in blood

Question 39

II. HYPOTHALAMUS-PITUITARY GLAND SYSTEM - Growth hormone (GH) 2. The negative feedback control of GH is due to... (3 REASONS)

Answer 39

1. GHRH inhibiting its own secretion from the hypothalamus 2. The somatomedin IGF-1 (insulin-like growth factor 1, produced in the liver as a result of GH) that comes back to inhibit the release of GH from the adenohypophysis 3. GH and IGF-1 activating the release of somatostatin, thus, inhibiting GH from being released

Question 40

II. HYPOTHALAMUS-PITUITARY GLAND SYSTEM - Growth hormone (GH) 3. How does GH receptor (cytokine receptor) signaling occur?

Answer 40

- When GH binds to a receptor, it activates the JAK2 kinase and/or Grb2-SOS-Ras ( -> causes MAP kinase cascade -> gene expression) - JAK2 pathway is more important, and these are cytokine signaling pathways using the tyrosine kinase mechanism - When the JAK2 is activated, the major substrate to be phosphorylated is STAT5, which then dimerize, translocates to the nucleus, and this causes increased gene expression of certain genes (production of somatomedins such as IGF-1 and IGF-2, GH etc.)

Question 41

II. HYPOTHALAMUS-PITUITARY GLAND SYSTEM - Growth hormone (GH) 4A. What are the 2 main effects of GH

Answer 41

1. Acute (metabolic) 2. Chronic – GH

Question 42

II. HYPOTHALAMUS-PITUITARY GLAND SYSTEM - Growth hormone (GH) 4B. What does Acute (metabolic) – GH do?

Answer 42

Acute (metabolic) – GH will directly cause an increase of: - ↑glucagon secretion and ↓glucose tissue uptake -> ↑[glucose]plasma - Lipolysis (by targeting adipocytes) -> ↑[FFA]plasma - Amino acid uptake of tissues↑, protein synthesis↑

Question 43

II. HYPOTHALAMUS-PITUITARY GLAND SYSTEM - Growth hormone (GH) 4C. What does Chronic – GH do?

Answer 43

Chronic – GH indirectly causes growth (through somatomedins) via: - Bone length growth (diameter, calcification↑) - Chondrocyte differentiation↑ - Collagen synthesis↑ - Mucopolysaccharide synthesis↑ - Growth of organs↑

Question 44

II. HYPOTHALAMUS-PITUITARY GLAND SYSTEM - Growth hormone (GH) 5. What are other things the growth require except GH?

Answer 44

Question 45

II. HYPOTHALAMUS-PITUITARY GLAND SYSTEM - Growth hormone (GH) 6. What happen if there is GH deficiency in childhood?

Answer 45

GH deficiency in childhood => pituitary dwarfism (nanosomia) - Average height >120cm - All the physical parts of the body develop inappropriate portion to one another - Maybe: child-like facial features (e.g. small chin)

Question 46

II. HYPOTHALAMUS-PITUITARY GLAND SYSTEM - Growth hormone (GH) 7. What happen if there is GH overproduction in childhood?

Answer 46

GH overproduction in childhood => gigantism: - GH-producing pituitary adenoma (benign tumor) - Rapid growth (before closure of the epiphyseal plates) - Average height < 220-230cm - Large organs, high performance - Bitemporal hemianopia may occur (loss of vision in outer half of both visual field) -> compression of optic chiasm by tumors => Without treatment: low life expectancy

Question 47

II. HYPOTHALAMUS-PITUITARY GLAND SYSTEM - Growth hormone (GH) 8. What happen if there is GH overproduction in adult?

Answer 47

- GH overproduction in adulthood -> acromegaly - Exaggerated GH effect after closure of the epiphyseal plates - ‘’endings’’ grow: +) ‘’coarse’’ features (chin, nose, pronounced brow protrusion) +) Fingers, foot grow + thicken (larger shoes needed, ring does not fit) +) Mandible grows, but teeth do not = teeth gapping +) Macroglossia - Organs enlarge: +) Heart (cardiac failure at the age of 50-60) +) Liver +) Kidney (large nephron, GFR↑, glucose reabsorption↑) - Metabolic disturbances: glucose tolerance↓, diabetes mellitus - Without treatment: low life expectancy

Question 48

II. HYPOTHALAMUS-PITUITARY GLAND SYSTEM - Somatomedins 9. What are the main features of Somatomedins?

Answer 48

- Somatomedins are a group of hormones that are stimulated by GH and (mostly) promote cell growth and division. - These are local growth factors and are responsible for indirect effects of GH - Produced by the target tissue

Question 49

II. HYPOTHALAMUS-PITUITARY GLAND SYSTEM - Somatomedins 10. Explain a special case in liver related to Somatomedins

Answer 49

- A special case in the liver: GH -> IGF-1 enters circulation (hormone) +) Negative feedback: [somatostatin]↑ = inhibits GH release +) Has a binding protein in blood plasma +) GH -> IGF-1 (also known as somatomedin C) -> growth

Question 50

II. HYPOTHALAMUS-PITUITARY GLAND SYSTEM 11. Explain the Relation of acute and chronic effects of GH

Answer 50

- GH and somatomedins have a complicated relationship with fasting, which stimulates GH and at the same time inhibits production of somatomedins. - This means that even though growing children who are not eating enough food may have higher amounts of GH, they still have lower amounts of somatomedins -> means that they will not grow as much as if they were well-fed.

Question 51

II. HYPOTHALAMUS-PITUITARY GLAND SYSTEM 12. Make a schematic diagram explain major pathways of growth regulation by the GH system

Answer 51