6 - Hypothalamus and Pituitary Hormones Flashcards
Describe the pituitary and hypothalamus - overview
- Function together
- Coordinate physiological responses of many different organs
- Form an interface between the central nervous system and the endocrine system
- Act to regulate multiple endocrine glands (thyroid, adrenals, gonads)
- Disruption of normal function has profound physiological consequences
What are the two types of hypothalamus neurons?
- Magnocellular neurons
- Parvivellular neurons
Describe the location and function of magnocellular neurons
- neurosecretory cells
- axons terminate in posterior lobe of pituitary
- secrete large quantities of hormone into the systemic circulation
Describe the location and function of parvicellular neurons
- neurosecretory cells
- axons terminate at the median eminence
- secrete small quantities of hormone into the portal hypophysial system
- these hormones are hypophysiotropic factors which are transported to the anterior pituitary
- they regulate hormone release from the anterior pituitary
What is feedback regulation of hormone secretion?
When the release of a given pituitary hormone is regulated in response to the level of that same hormone in the blood
Describe one of the general themes in hormone receptors
- Most of the hormones we will discuss are hydrophilic ***
- These hormones bind to receptors that are integral membrane proteins
- Many of these receptors are G-protein coupled receptors
What do G-protein coupled receptors do?
- Regulate the activity of adenylate cyclase
- Activate phospholipase C
Describe the way in which G-protein coupled receptors regulate adenylate cyclase
- They either increase or decrease the production of cAMP
- This either increases or decreases the activity of cAMP-dependent protein kinase (protein kinase A - PKA)
Describe the way in which G-protein coupled receptors activate phospholipase C
- They generate IP3 and diacylglycerol
- This increases the intracellular Ca++
- This also activates protein kinase C (PKC)
Quick reminder - What is PKA?
PKA activity is dependent on cAMP. PKA is also known as cAMP-dependent protein kinase.
Protein kinase A has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism.
Quick reminder - what is PKC?
PKCs are a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins
Give a basic overview of how peptide hormones are processed
- Many hormones that we will cover are peptide hormones
- These hormones are synthesized as larger precursor proteins
- Specific proteolysis reactions release peptide fragments
Describe the peptide fragments that are released
- Peptide fragmetns are the functional hormone
- Often several distinct proteolytic fragments are generated
- The fragments may each have distinct biological activities
What are the two hormones secreted by the posterior pituitary?
- Oxytocin
- Vasopressin
Describe the synthesis and secretion of oxytocin and vasopressin
- Oxytocin and arginine vasopressin are peptide hormones that are synthesized in the cell bodies of hypothalamic magnocellular neurons
- The hormones are then secreted into systemic circulation from the posterior pituitary gland
What are oxytocin and vasopressin derived from?
- Derived from proteolytic processing of precursor polypeptide
What is the process of synthesis of oxytocin and vasopressin?
- pre-pro-hormone is synthesized on membrane associated ribosomes
- it is then translocated into the ER, signal sequence cleaved, routed through Golgi to neurosecretory vesicles, processed on route to nerve terminal
What is the function of oxytocin?
Oxytocin stimulates smooth muscle contraction
What does oxytocin target?
- Uterus during pregnancy
- Lactating breast
What does oxytocin do to the uterus during pregnancy?
Smooth muscle contractions which induce labor
What does oxytocin do to the lactating breast during pregnancy?
Promotes milk ejection
What type of receptors are found in the tissues that oxytocin targets?
G-protein coupled receptors
- Signaling for the hormone receptors occurs through the activation of phospholipase C
What stimulates the release of oxytocin?
- Mechanical stimulation of uterine cervix by the fetus
- Suckling of lactating breast
What inhibits the release of oxytocin?
- Severe pain
- Fever
- Loud noises
What is the function of arginine vasopressin?
- Stimulates water reabsorption in the kidney
- Stimulates contraction of vascular smooth muscle
What type of receptors are found in the tissue that vasopressin targets?
G-protein coupled receptors
- When a receptor is stimulated, it activates adenylate cyclase and phospholipase C
- PKA phosphorylates aquaporin 2 transporter proteins
- This leads to increased water permeability of the collecting duct (more resorption)
What does the activation of adenylate cyclase result in?
- PKA phosphorylates aquaporin 2 transporter proteins
- This leads to increased water permeability of the collecting duct (more resorption)
What does the activation of phospholipase C result in?
- There is an increase in Ca++ concentration which activates protein kinase C
- This causes smooth muscle contraction and raises the blood pressure
What stimulates the release of vasopressin?
- Changes in plasma osmolarity such as dehydration which is sensed by hypothalamic neurons
- Changes in blood volume or blood pressure (low BP, low volume)
What inhibits the release of vasopressin?
- Increased blood pressure
- Hydration
- Atrial natiuretic factors
- Alcohol
Describe the presentation of a patient with hypermatremia, polydipsia and polyuria
- Hypernatremia = high sodium
- Polydipsia = high level of thirst
- Polyuria = high urine output
- Symptoms present since birth with other family members showing similar symptoms
- Diagnosis of diabetes insipidus is made
What are the two types of diabetes insipidus?
- Neurogenic diabetes insipidus
- Nephrogenic diabetes insipidus
When the levels of plasma AVP (vasopressin) are checked, they are normal. What does this mean?
- This means that there is a defect in the vasopressin secretion
- If the vasopressin secretion was normal, there would be an elevated level in response to hyperosmolarity
- There is a mutation in the region of vasopressin gene encoding neurophysin II
This is neurogenic diabetes insipidus
What is nephrogenic diabetes insipidus?
A defect in the ability of the kidney to respond to AVP
What is neurogenic diabetes insipidus?
A defect in AVP production
What are hypophysiotropic factors?
Hormones that are released by the parvicellular neurons
What is the function of hypophysiotropic factors?
- Hypophysioropic factors regulate the release of hormones from the anterior pituitary gland
- They serve as a link between the CNS and the endocrine system
What are the three groups of hormones of the anterior pituitary?
They can be divided into three groups based upon chemical structure and origin
- Adrenocorticotropic hormones (ACTH) and related peptides
- Sommatomammotropins which are also peptides
- Glycoproteins
What sommatomammotropins come from the anterior pituitary?
- Growth hormone (GH)
- Prolactin (PRL)
What glycoproteins come from the anterior pituitary?
- Follicle stimulating hormone (FSH)
- Luteinizing hormone (LH)
- Thyrotropin (thyroid stimulating hormone TSH)
What is ACTH (adrenocorticotropin) derived from?
ACTH is derived from the cleavage of pro-opiomelanocorin (POMC)
What is the function of ACTH?
ACTH stimulates the synthesis and release of glucocorticoids from the adrenal cortex
It is less effective in stimulating mineralcorticoid release, but still able to do so
What type of receptor does ACTH bind to?
A G-protein coupled-receptor
It is a PKA activated receptor
Describe growth hormone (secreted from the anterior pituitary)
- GH is apolypeptide hormone, derived from larger precursor
- There have been more than 400 effects described
- Direct effects require binding to growth hormone receptor
- Single hormone molecule binds two receptor molecules
- This activates JAK2
- JAK2 phosphorylates STAT5
- Phosphorylated STAT5 enters the nucleus
Does growth hormone directly induce somatic growth?
No - Somatic growth is NOT actually stimulated by growth hormone – it is indirectly stimulated
What are the direct effects of growth hormone?
- Protein synthesis
- Transport of amino acids into cells
- Gluconeogenesis
- Lipolysis
What are the indirect effects of growth hormone mediate by somatomedins?
Stimulate molecules that are structurally related to insulin
- Insulin like growth factor I (IGF-I)
- Insulin like growth factor II (IGF-II)
What is the difference between IGF-I/IGF-II and insulin?
- C peptide is not removed from IGF-I and IGF-II
- A-chain contains an extension (usually labelled D-chain)
Describe what happens when GH binds to receptors in the liver
- It stimulates the production and release of IGF-I
- The IGF-I receptor has protein tyrosine kinase activity
- Binding of IGF-I activates the kinase, propagating the IGF-I signal within the cell
What is the IGF-I signal which propagates within the cell?
- It triggers somatic growth and cell proliferation
- This is ACTUAL GROWTH
- Note that it is not the growth hormone that initiates this actual growth
- It is the effect that GH has on IGF-1 production that causes actual growth
Describe the function of IGF-II
IGF-II mainly functions during fetal development
- Roles and mode of action less clear
- Some signaling might be via IGF-I receptor, some might be via insulin receptor, specific IGF-II receptor also exists
- We don’t know what IFG-II does, but only actions during fetal development
What signals the release of GH?
Growth hormone releasing hormone (GHRH)
- GH’s release is regulated in response to GHRH (stimulates release)
What inhibits the release of GH?
Somatostatin
- GH’s release is inhibited by somatostatin
- somatic = life, statin = halt
- Somatostatin halts life/growth
How does GHRH stimulate GH release?
GHRH triggers activation of PKA
How does somatostatin inhibit GH release?
Somatostatin triggers a decrease in PKA activity, opposing GHRH action
How does IGF-I play a role in this?
IGF-I inhibits GH secretion and stimulates secretion of somatostatin
What happens when there is hypersecretion of growth hormone?
- Giantism in children (overgrowth of long bones)
- Acromegaly in adults
(overgrowth of soft tissue, jaw, hands, not long bones)
What happens when there is hyposecretion of growth hormone?
- Dwarfism in children
- Increased body fat, decreased muscle and bone mass with reduces strength in adults
What is prolactin?
PRL
- a polypeptide hormone which contains 198 residues
How is prolactin generated?
By the cleavage of a larger protein precursor molecule
Prolactin is related in sequence to growth hormone
What are the main physiological effects of prolactin on the mammary gland?
- Promotion of milk synthesis
- Maintenance of milk secretion
- The role in males is unclear
- Hyperprolactinemia in men leads to decreased libido, impotence and infertility
Describe the PRL receptor
- Similar in funciton to the GH receptor
- JAK2 kinase, transcriptional control via STAT proteins
What inhibits prolactin release?
Dopamine
- Dopamine is also known as prolactin inhibitory hormone
How are prolactin levels regulated via an autoregulatory mechanism?
When there is increase prolactin in the portal hypophysial blood, it signals the release of dopamine from dopaminergic neurons in the hypothalamus
Remember dopamin inhibits prolactin release
What are the glycoproteins of the anterior pituitary gland?
- Lutenizing hormone (LH)
- Follicle stimulating hormone (FSH)
- Thyroids stimulating hormone (TSH)
Describe the chemical structure of glycoproteins
- There are both alpha and beta subuinits
- The alpha subunits are identical in each glycoprotein hormone
- The specificity of the hormone comes from the beta subunit
What is the mode of action for all glycoprotein hormones?
- Receptors are all G-protein coupled
- They are Gs type of G protein, meaning they all lead to the activation of PKA
What is the physiological function of LH?
- Ovary – stimulates estrogen/progesterone secretion and gametogenesis
- Testes – stimulates testosterone production
What is the physiological function of FSH?
- Ovary – stimulates estrogen/progesterone secretion and gametogenesis
- Testes – functions in spermatogenesis
What is the physiological function of TSH?
Thyroid gland – stimulates all aspects of thyroid hormone synthesis and release
Describe the control of secretion seen in LH and FSH
- LH and FSH are released from gonadotrophs in response to GnRH
- GnRH receptor is G-protein coupled
- This leads to the activation of phospholipase C
- Ultimately this stimulates the transcription of the specific beta subunits of LH and FSH
- The regulation of GnRH is extremely complex and you don’t need to know it
Describe the control of secretion seen in TSH
- TSH is released from thyrotrophs in response to TRH
- This will be covered in a later lecture
