Central Endocrine Glands

What other name does pituitary gland have?

- 'Master gland'

What does the hypothalamus consist of and what is its importance?

- Collection of brain 'nuclei' or centres which have important control

- Important for homeostasis and primitive functionss

What does the hypothalamus control?

- controls autonomic function via brainstem autonomic centres

- controls endocrine function via the pituitary gland

What does the hypothalamus respond to?

- Environmental factors

- Neural signals

- Hormones

What are examples of environmental factors?

- Light (circadian rhythm) - involves interactions with the retina, and the pineal gland (melatonin)

- Stress e.g noise, fear

What are examples of neural signals?

- Visceral afferents from the intestines, heart, liver, stomach - mediated by glutamate, serotonin, AcCh, histamine, GABA, dopamine etc

What is an example of a hypothalamic response to hormones?

- Negative feedback

What are examples of hypothalamic hormones and their corresponding pituitary hormone(s)?

- TRH --> TSH, PRL, FSH

- GnRH --> LH, FSH

- GHRH --> GH

- Somatostatin --> GH

- CRH --> ACTH

- Dopamine --> PRL

What are the lobes of the pituitary gland?

- Anterior (adenohypophysis)

- Posterior (neurohypophysis)

What is the difference between the lobes of the pituitary gland?

- Different embryological origin

What are anterior pituitary hormones regulated by?

- Secreted hypothalamic factors

Where are posterior pituitary hormones synthesised and what are they transported by?

- Synthesised in hypothalamus

- Transported via neuronal projections

How is the pituitary gland connected to the hypothalamus?

- Structurally continuous with the hypothalamus of the brain and attached to hypothalamus by the hypophyseal (or pituitary) stalk

What are examples of cell types and hormones of anterior pituitary hormones?

Cell type : Hormone : Function

- Thyrotroph - TSH (glycoprotein) - thyroid hormone regulation

- Corticotroph - ACTH (protein/polypeptide) - regulation of adrenal cortex

- Gonadotroph - LH/FSH (glycoproteins) - reproductive control

- Somatotroph - GH (protein/polypeptide) - growth

- Lactotroph - PRL (protein/polypeptide) - milk production

* all hormones here (EXCEPT prolactin) are tropic hormones

What do tropic hormones do?

- Target/stimulate other endocrine glands

What are examples of hormones in the posterior pituitary hormones?

Hormone/protein : Function

- ADH (vasopressin) - water regulation

- Neurophysins (carrier protein) - important in ADH synthesis

- Oxytocin - birth, breast milk expression

What are features of protein hormones of the anterior pituitary?

1) Single chain

- Prolactin

- Growth hormone

2) Two chain glycoproteins

- TSH (common α subunit)

- LH

- FSH (unique β subunit)

What does TSH do?

- Stimulates the thyroid to release T3 and T4

Where is TSH made?

- Thryotrophs of anterior pituitary (~5% of the cells) in response to pulsatile TRH release from the hypothalamus

- Hypothalamic --> Pituitary --> Thyroid Axis

How is metabolic rate increased?

1) Hypothalamus releases TRH (positively stimulates anterior pituitary to release TSH)

2) Anterior pituitary releases TSH (positively stimulates Thyroid gland to release T3 and T4)

3) Thyroid gland produces and releases more T4 (prohormone form) than T3 (active thyroid hormone)

4) T3 mainly made by removal of iodine group from T4 production and affects metabolism

5) High T3 and T4 levels decreased by negative feedback:

- High T3/T4 levels - inhibit TRH release from hypothalamus

- High T3/T4 levels - inhibit TSH release from the anterior pituitary

What are thyrotroph problems?

- Pituitary failure - secondary hypothyroidism (underactive thyroid)

- Pituitary tumour (rare) - secondary hyperthyroidism (overactive thyroid

What hormones do Gonadotrophins produce?

- Luteinising hormone (LH)

- Follicle Stimulating Hormone (FSH)

--> made by ~5-10% cells

--> 60% of these secrete both, 18% secrete only LH, 22% only FSH

What are Gonadotrophin hormones (LH and FSH) made in response to?

- GnRH

What are the effects and mechanism of action of LH and FSH?

- Regulate testosterone biosynthesis and spermatogenesis in the tests

- Regulate the menstrual cycle and fertility in the ovary

- Both act through cell membrane receptors coupled to G proteins, resulting in elevation of cAMP and activation of protein kinase A

- Pulsatile secretion essential for actions

What are features of ACTH?

- Polypeptide of 39 amino acids

- Residues 1-24 (mol wt 4500) conserved and used as synthetic analogue

- Synthesised in corticotrophs of the anterior pituitary ~ 10% of cells

How is ACTH synthesised?

- Synthesised from POMC

- POMC --> POMC products in the corticotroph cell (anterior pituitary) --> POMC products in the brain

What is the Hypothalamic-Pituitary-Adrenal (HPA) axis?

- The body's main stress-response system

How does the HPA axis work?

1) Stress signal activates the hypothalamus (positively stimulates the hypothalamus to release CRH)

2) Hypothalamus releases corticotropin-releasing hormone (CRH) which binds to specific receptors in anterior pituitary

- This activates cAMP secondary messenger which activates PKA (protein kinase A)

- PKA positively stimulates the anterior pituitary to release ACTH

3) Anterior Pituitary releases ACTH (ACTH positively stimulates the adrenal cortex by binding to receptors and triggers the release of cortisol - cAMP again acts as a second messenger to help signal cortisol production

4) Adrenal cortex releases cortisol which:

- Increases blood glucose (more energy)

- Enhances fat and protein metabolism

- Suppresses inflammation and immune responses

- Helps the body maintain blood pressure and alertness

5) High cortisol levels reduced by negative feedback:

- Inhibition of Hypothalamus (reduces CRH release)

- Inhibition of Anterior Pituitary (reduces ACTH release)

What are the effects of ACTH?

- Stimulates G-protein receptor coupled to cAMP

- This stimulates the enzymes that convert cholesterol to cortisol or sex steroid precursors

- Like PRL and GH, ACTH rises with stress e.g hypoglycaemia - this is used clinically to test corticotroph function following insulin challenge

Where is prolactin made?

- Lactotroph cells in anterior pituitary which comprise 15-20% of cells

- This percentage increases dramatically during pregnancy due to oestrogen

How is prolactin regulated?

1) Hypothalamus releases dopamine which inhibits prolactin

- Dopamine travels to anterior pituitary

- Dopamine binds to D2 receptors on lactotrophs in the anterior pituitary - inhibiting prolactin secretion

- In normal/resting condiitons, dopamine keeps prolactin low

- Somatostatin also has a negative effect on prolactin secretion (minor)

- TRH + Vasoactive Intestinal Peptide (VIP) stimulate prolactin release

2) Certain stimuli stop the inhibition of prolactin

- Suckling (breastfeeding) --> inhibits dopamine release --> prolactin secretion increases

- High oestrogen levels (e.g during pregnancy) --> increase prolactin gene expression and release

- TRH and oxytocin can mildly stimulate prolactin release

3) Feedback regulation

- High prolactin levels increase dopamine release from the hypothalamus

- This restores inhibition and prevents excessive prolactin secretion

- Forms short negative feedback loop

What are the effects of prolactin?

1) Stimulates mammary gland development

- DNA synthesis

- Epithelial cell proliferation

- Synthesis of casein and lactalbumin

- Synthesis of lactose

- Synthesis of free fatty acids

2) Maintains lactation

- Synergised by glucocorticoids

- Inhibited by oestrogen and progesterone

3) Other effects

- Lymphocytes - regulation e.g Nb2 cells

- Kidney - osmoregulation

- Amnion, choroid plexus - osmoregulation

- Ovary - maintenance or regression of corpus luteum

- Testis - steroid production

- Ovary - steroid production

- Liver - RNA synthesis

What are prolactinomas?

- Most common of the pituitary tumours

- Interferes with HPG (Hypothalamus-Pituitary-Gonadal axis)

How are prolactinomas treated?

- Dopamine agonists e.g bromocriptine, cabergoline

What can hypothyroidism lead to (in relation to prolactin)?

- Hyperprolactinaemia due to elevations in TRH

What cell type is growth hormone released by?

- Somatotrophs - 50% of cell type in anterior pituitary

How is growth hormone released?

- Released throughout life

- Pulsatile release

- Stimulated by low glucose, exercise, sleep

- Effects mediated by GH and IGF1

What factors stimulate growth hormone release?

- GHRH

- Dopamine

- Catecholamines

- Excitatory amino acids

- Thyroid hormone

What factors inhibit growth hormone release?

- Somatostatin

- IGF-1

- Glucose

- FFA

What are the effects of GH deficiency?

- GH receptor mutations - Laron syndrome dwarfism - treated with IGF-1

- GH deficiency - treated with recombinant hGH

- levels fall with age

What are the causes of hypopituitarism?

- Pituitary tumour

- Brain surgery

- Trauma (road accidents)

- Radiotherapy

- Blockedblood supply, bleeding, inflammation

- Autoimmunity

- Infection

What does each hormone in the anterior pituitary do?

- TSH - stimulates growth of gland and secretion of thyroid hormone

- FSH

-> ovaries - stimulates development of eggs and follicles

-> testes - stimulates production of sperm

- LH

-> females - stimulates ovulation and corpus luteum to secrete progesterone and oestrogen

-> males - stimulates interstitial cells of testes to screte testosterone

- ACTH - regulates response to stress, stimulates adrenal cortex to secrete corticosteroids

- GH - main effect is to stimulate liver to produce IGF-1

- Prolactin

-> female - milk synthesis after delivery

-> male - increase LH sensitivity -> increase tesosterone secretion - less clear

What is the structure of ADH and where is it released from?

- It is a nonapeptide (made up of 9 amino acids)

- Secreted from posterior pituitary

Where and how is ADH prepared for release?

- Vasopressin is synthesised and packaged with a carier protein called neurophysin

- Packaged in secretory granules in the magnocellular neurones of the paraventricular and supraoptic nuclei

- Granules move down to the ends of the fibres

- Both are released upon stimulation of the nerves

When is ADH secreted?

- Increased secretion to retain water when dehydrated

Where does ADH act?

- Collecting ducts of the kidney

- Collecting ducts intrinsically impermeable to water

What does ADH stimulate?

- Stimulates the production of water channels and their incorporation into the walls of the collecting ducts

- Allows the reabsorption of 'free' water from tubular fluid

- Can convert a very dilute urine to a very concentrated urine

What causes excess ADH?

- Variety of conditions e.g damage to the heart, secreting tumours

What condition is excess ADH?

- Syndrome of Inappropriate ADH Secretion (SIADH)

What happens if someone has excess ADH?

- (Hyper) water rentention (low serum sodium conc) leads to highly concentrated urine

What happens if someone has ADH deficiency?

- (Hypo water retention) - Excess water secretion

How does ADH work?

- ADH controls serum osmolarity - during water deprivation, ADH levels rise to allow water reabsorption - increase in urine conc and decrease in urine volume

What is diabetes insipidus?

- ADH deficiency

- ADH needed for water absorption in renal collecting ducts

- If posterior pituitary damaged, ADH may be reduced and urine cannot be concentrated

- Can be secondary along other pituitary problems or isolated (only ADH affected)/idiopathic (no known cause)

What diabetes insipidus result in?

- Polyuria (excess urine production) e.g >3L per day

- Polydipsia (excess drinking) as a result

- Also results in Hypertraemia and increased serum osmolarity result

- Diagnosed by having a dilute urine in the context of concentrated plasma

What does oxytocin stimulate?

- Stimulates contraction of smooth muscle (myoepithelial cells) of breast and uterus

- Can be given to induce labour

- Positive feedback

What does oxytocin have roles in?

- Milk ejection reflex

- Parturition (birth)

- Neuro-endocrine reflexes - neuro-endocrine cells secrete hormones from the neural axon terminals into the blood in response to some neural signals

What are the hypothalamus and pituitary central to?

- Many hormonal axes