Session 8: The HPA Axis and Growth Hormone (NOT DONE) Flashcards
Briefly explain the hypothalamic pituitary axis (HPA).
It’s a major link between the nervous and endocrine systems acting together.
Where can you find the hypothalamus?
Below the thalamus
Where is the pituitary gland?
Beneath the hypothalamus in a socket of bone at the base of the skull.
The pituitary gland is embedded in a socket of bone. What is it called?
Sella turcica
The pituitary consists of two parts. Which?
The anterior lobe also called the anterior pituitary or the adenohypophysis. The posterior lobe also called the posterior pituitary or the neurohypophysis.
What’s the major differences between the anterior pituitary and the posterior pituitary? (Origin)
The AP comes from gut ectoderm from the Rathke’s pouch and grows upward from the roof of the mouth. The PP comes from neuroectoderm and grows downwards from the diencephalon of the developing brain.
How is the hypothalamus connected to the posterior pituitary?
By a structure called the infundibulum or the pituitary stalk. It is a structure with axons going down it connecting the two.
What does the posterior pituitary synthesise?
The posterior pituitary doesn’t synthesise any hormones itself, it stores and secrete oxytocin and antidiuretic hormone (vasopressin) however.
Explain the release of oxytocin and ADH.
They are synthesised by the hypothalamus and then transported to the axon terminals of the posterior pituitary by neurocrine signalling where they are stored until the hypothalamus tells the posterior pituitary to release the hormones into the blood stream. This is done by neuronal inputs into the hypothalamus.
What stimulates the secretion of oxytocin?
The stimulus of suckling in the milk let-down reflex is transmitted via neurons from the breast to the hypothalamus resulting in release of oxytocin from the posterior pituitary. Also during childbirth the stimulus of pressure on the cervix and uterine wall is again transmitted to the hypothalamus via neuronal input and release oxytocin from posterior pituitary.
Explain the mode of travel and action of oxytocin.
It is secreted into the blood stream from posterior pituitary gland and travels to mammary glands to cause milk to be released by activating oxytocin receptors on myoepithelial cells surrounding the mammary alveoli causing them to contract squeezing milk into the duct system. In the case of childbirth it goes into general circulation and imitates powerful uterine contractions by activation of oxytocin receptors on uterine smooth muscle cells.
Why would synthetic oxytocin (pitocin) be used?
Often administered to increase uterine tone and control bleeding just after birth.
Explain how ADH works.
It causes a reduction in urine production. ADH binds to receptors that are present on the distal tubular epithelium of the collecting ducts in kidneys. When they are activated by ADH there is an increase in permeability by inducing translocation of aquaporin water channels in plasma membrane allowing more reabsorption of water back into blood.
What stimulates/inhibits ADH?
ADH is stimulated by the detection of low or high blood osmolality in the blood by osmoreceptors (this also controls thirst). A high blood osmolality stimulates secretion of ADH. A low blood osmolality inhibits secretion of ADH. Also alchohol inhibits release of ADH causing polyuria and polydipsia.
ADH also has an effect on vascular system. What?
It increases peripheral vascular resistance by activating ADH receptors on the smooth muscle cells of blood vessels to cause vasoconstriction and an increase in arterial blood pressure. Particularly important in restoring blood pressure in hypovolaemic shock during haemorrhage.
Apart from synthesising Oxytocin and ADH for release from posterior pituitary, what else does the hypothalamus synthesise?
They synthesise and secrete tropic hormones to work on the anterior pituitary which is a gland!
Define tropic hormone.
A hormone which affect the release of another hormone (stimulating or inhibitory).
What tropic hormones are synthesised and released by the hypothalamus?
TRH (Thyrotropin releasing hormone) PRH (prolactin releasing hormone) PIH (prolactin inhibiting hormone = dopamine) CRH (Corticotropin releasing hormone) GnRH (Gonadotropin releasing hormone) GHRH (Growth hormone releasing hormone) GHIH (Groth hormone inhibiting hormone = somatostatin)
Explain the mode of transport of a tropic hormone.
It is synthesised and released by the hypothalamus down axons and stored in a structure caleld the median eminence which can be found just above the anterior pituitary.
They are then released from the median eminence into a local system of blood vessels called the hypophyseal portal system. The blood vessels running away from the median eminence run directly into the anterior pituitary, this means that the AP is directly exposed to the tropic hormones which will either stimulate or inhibit target endocrine cells withing the anterior pituitary gland by binding to specific GPCRs on their surface.
What are the different types of negative feedback of the hypothalamus and AP?
There are four types:
Short loop
Indirect long loop
Direct long loop
Ultra short loop
Explain the short loop.
The hormone secreted by the AP will inhibit further release of the tropic hormone of the hypothalamus.
Explain direct long loop.
The hormone secreted by the target endocrine gland (can be cortisol e.g.) inhibits the release of the hormone from the AP (ACTH).
Explain the indirect long loop.
The hormone released by the target endocrine gland (cortisol e.g.) inhibits the release of the tropic hormone of the hypothalamus (CRH).
Explain the ultra short loop.
The tropic hormone itself inhibits the release of more tropic hormone by hypothalamus.
What is growth hormone produced by?
Somatropecells in the anterior pituitary gland.
How does growth hormone secretion occur?
In a pulsatile fashion depedning on circadian rhythm.
What is secrete in response to GH?
Cells in liver and skeletal muscle secrete insulin like growth factors (IGFs).
What is the main function of IGFs?
Stimulate body growth and regulate metabolism.
What is the main role of GH in childhood and teenage years?
Growth rate of skeleton and skeletal muscles
What is the main role of GH and IGFs in adults?
Maintenance of muscles and bone mass + promote healing and tissue repair.
What types of negative feedback mechanisms are GH secretion regulated by?
Long loop and short loop.
Long loop:
IGFs inhibit the release of GHRH from hypothalamus
IGFs stimulate the relase of somatostatin from the hypothalamus
IGFs inhibit the action of GHRH in the anterior pituitary
Short loop:
GH itself stimulate the release of somatostatin
How does GH exert its effects on cells?
What type of receptors is the GH receptor?
Acts on cells both directly via its own receptor and indirectly via the induced production of IGFs (IGF-I). This means that only cells expressing GF receptors can respond to GH.
GH receptors is a member of the cytokine receptor superfamily and specifically a tyrosine kinase receptor activating Janus Kinases (JAK). It cross phosphorylates JAK and that will turn on transcription factor that turns on production for IGFs.
There are two forms of IGFs. Where are they mainly produced? Where else?
Mainly produced in liver and skeletal muscles.
Also produced in bone, kidneys, and CNS.
Mode of transport of IGFs.
They circulate in blood bound to specific binding proteins which modulate their availability to activate IGF receptors on target cells.
Can be autocrine, paracrine and endocrine.
The IGFs act on target cells trough their own specific receptor which shows some similarites to insulin receptors (tyrosine kinase).
Action of IGF-1.
Mediation of majority of effects of GH in adults:
Hypertrophy
Hyperplasia
Increase in rate of protein synthesis
Increase in rate of lipolysis in adipose tissue
Decrease in glucose uptake.
Can also inhibit apoptosis
Some tumours express abundant IGF-1 receptors inhibit apoptosis.
Action of IGF-2.
Appears to be more impotant during growth and development before birth.
Consequences of growth hormone deficiency in childhood.
How is it treated?
Proportionate type of dwarfism also called pituitary dwarfism.
Growth rate is slower than expected for their age.
Delayed or no sexual development during teen years.
GH therapy (give GH)
Consequence and cause for GH excess in childhood vs adulthood.
Cause is usually pituitary adenoma.
In childhood this leads to gigantism.
In adulthood it leads to acromegaly (large extremities; hands, feet, lower jaw and protruding head)
Explain how GH exerts its effect on cells.
GH binds to GH receptors which activates JAKs (Janus kinases)
This activates a signalling pathway
This activates transcription factors and IGF (insulin-like growth factors) production.
Explain what insulin-like growth factors do.
There are two IGFs. IGF 1 and IGF 2.
IGF2 is most present in foetal growth and IGF 1 in adults.
The action can be autocrine, paracrine and endocrine.
IGFs act on IGF receptors (not GH receptors)
They stimulate hypertrophy, hyperplasia, increased rate of protein synthesis, increased rate of lipolysis in adipose tissue.
Explain the relationship between insulin and insulin-like growth factors relating to receptors.
There are four important receptors:
Insulin receptor (metabolic effect + mitogenic)
IGF-1 receptor (metabolic effect + mitogenic)
IGF-2 receptor
Hybrid receptor (metabolic effect + mitogenic)
Insulin can act on insulin receptor, hybrid receptor and IGF-1 receptor. Stimulating metabolic effects as well as mitogenic.
IGF-1 can act on all 4.
IGF-2 can act on IGF-2 receptors and IGF-1 receptors.
Give other hormones which influence growth and how.
Insulin - enhances somatic growth by interaction with IGF-1 and hybrid.
Thyroid hormones - promote CNS development and enhances GH secretion
Androgens - Increase muscle mass, accelerate pubertal growth, promote closure of epiphyseal plates
Oestrogen - Decrease somatic growth + promote closure of epiphyseal plates.
Glucocorticoids - inhibition of somatic growth
What are the three main conditions caused by excess pituitary hormone production?
Prolactin excess, growth hormone excess and ACTH excess due to pituitary adenoma.
Normal physiological function of prolactin.
Initiate and maintain lactation.
How is prolactin secretion regulated?
What unusual about the regulation of prolactin?
By prolactin releasing hormone which stimulates secretion and by dopamine which inhibits secretion.
However the secretion of prolactin is mainly governed by the inhibition of dopamine.
What is the most common form of pituitary disorders?
Hyperprolactinaemia due to a prolactinoma.
Symptoms of hyperprolactinaemia.
Galactorrhea
Gynecomastia (hard breast tissue)
Hypogonadism (reduced or no activity of testes or ovaries)
Amenorrhea (no menstruation)
Erectile dysfunction
Why does hypogonadism occur in hyperprolactinaemia?
The higher levels of dopamine in the hypothalamus (which results from negative feedback due to increased plasma prolactin) inhibits GnRH secretion from the hypothalamus.
GnRH stimulates secretion of FSH and LH which is needed for release of ovum.
Physiological causes of hyperprolactinaemia.
Pregnancy
Suckling
Stress
Exercise
Drugs like antipsychotics and antidepressants.
What is prolactin inhibiting hormone?
Dopamine
How do you treat hyperprolactinaemia?
Depending on the underlying cause. Assuming it is a prolactinoma:
First line treatment:
treat with a dopamine receptor agonist such as cabergoline which inhibits release of prolactin.
Second line:
If dopamine receptors agonists are not enough trans-sphenoidal surgery might be required by accessing the pituitary gland through the nose and sphenoid bone.
Radiotherapy
How large are usually growth hormone secreting pituitary adenomas?
>10mm in diameter
Why is the size of the adenoma relevant?
It might cause additional symptoms for example by compressing the optic chiasm leading to visual field defects. Also headaches and other cranial nerve palsies can occur.
Explain the action of an adenoma causing growth hormone excess.
Secretion of growth hormone leads to direct actions of GH itself on growth and also stimulation of local IGF-1 production.
The effects of this can take years to manifest (6 or more years before a diagnosis might be made)
Signs of growth hormone secreting pituitary adenoma.
Broad nose, coarse facial features, thick lips, prominent supraorbital ridge. Englargement of hands and feet. Greasy and sweaty skin.
Deepening of the voice due to hypertrophy of soft tissue of the upper airways.
In children this adenoma can lead to gigantism.
Complications of GH secreting pituitary adenoma in children.
Gigantism but also since GH antagonises the actions insulin several metabolic complications can occur including development of diabetes mellitus and increased serum IGF-1 caused by the adenoma may be associated with some forms of cancer.
Treatment of GH secreting pituitary adenoma.
Surgery to remove adenoma
Radiation therapy
Drug therapy: Dopamine receptor agonist have some efficacy in reducing GH levels. Somatostatin can be used as well but have some limited uses because its very short half-life.
GH receptor antagonist may be used like Pegvisomant and is a new drug which may see more use.
