Neuro: Neurohormones

Question 1

List some principle endocrine organs of the body.

Answer 1

• Testes. Release testosterone which is very important for spermatogenesis.
• Oestrogen and progesterone are released from the ovaries - involved in oogenesis.
• The pancreas release insulin, glucagon (important for glucose regulation), somatostatin
• The adrenal glands contain a cortex and medulla. The adrenal cortex releases steroid hormones such as aldosterone, cortisol as well as sex hormones. The
  adrenal medulla releases adrenaline and noradrenaline.
• Parathyroid glands release parathyroid hormone
• Thyroid gland releases thyroxine
• The hypothalamus and the pituitary. Packed with neurohormones - neurotransmitters which are released from neurones directly into the blood circulation.

Question 2

Describe the two main control systems of the body (compare and contrast).

Answer 2

The body has two main control system: the endocrine system and the nervous system.

ENDOCRINE SYSTEM:

• mediators travel within blood vessels
• utilises chemical mediators (hormones)
• slow communication
• effects can be long-lasting

NERVOUS SYSTEM:

• signalling along the nerve fibres
• transmission of electrical impulses
• fast communication
• effects are generally short-acting

Question 3

Describe the different types of hormones.

Answer 3

Proteins & Peptide hormones:

• Vary considerably in size
• Can be synthesised as a large precursor and processed prior to secretion (e.g. HG, somatostatin, insulin)
• Can be post-translationally modified (e.g. glycosylation) and then released into blood circulation
• Can have multiple subunits synthesised independently and assembled (e.g. FSH, LH, TSH)
• These peptides come from genes which are responsible for the production of big proteins, the big proteins become cleaved via enzymes

Amino acid derivates

• Mostly tyrosine derived
• There are neurotransmitters (e.g. monoamines) that can also act as a neurohormone (so can also be released in the blood circulation)
• E.g. adrenaline, noradrenaline, dopamine

Steroid hormones

• Steroid is a class of lipids derived from cholesterol
• Includes cortisol (stress hormone), aldosterone, testosterone, progesterone, oestrogen
• Steroid hormones can act on the brain (not released from neurones but from periphery and affect CNS)

Question 4

How are hormone signals sent to both parts of the pituitary

Answer 4

With the anterior pituitary, we have the hypophyseal portal circulation. Hormones are released into these blood vessels, which transport them to the anterior pituitary, where they act.

With the posterior pituitary, we have neurones called magnocellular neurons, which project from the hypothalamus directly into your posterior pituitary. The hormones are released into the PP, where they travel through the capillary network and get released straight into the blood circulation.

Question 5

Where are neurohormones produced?

Answer 5

• Most neurohormones are neuropeptides and are all derived from genes. So they are produced in the cell body.
• From transcription and translation there is production of proteins which are packed into vesicles and undergo post-translational modification e.g. cleavage in the Golgi apparatus. They will then be packed into vesicles.

- The vesicles get transported along the axons to the synaptic terminals. In the synaptic terminals, the neurohormones will get released directly into the
capillary network (blood circulation).

• Calcium entry is usually important in order to drive the release of neurohormones.
• So therefore the neurohormones are synthesised in the hypothalamus, but are released in the posterior pituitary.

Question 6

List the hormones that control the pituitary, and what effect they have.

Answer 6

ANTERIOR PITUITARY:
Corticotrophin releasing hormone (CRH) - a peptide that controls the release of adrenocorticotrophin (ACTH)

Thyrotrophin releasing hormone (TRH) - a peptide that controls the release of thyroid stimulating hormone (TSH) and prolactin (PRL)

Gonadotrophin releasing hormone (GnRH) - a peptide that controls the release of luteinising hormone (LH) and follicle-stimulating hormone (FSH)

Growth hormone releasing hormone (GHRH) - a peptide that controls the release of growth hormone (GH)

Somatostatin - a peptide that inhibits the release of GH, gastrin vasoactive intestinal polypeptide (VIP), glucagon, insulin, TSH and PRL

Dopamine (DA) - a monoamine that inhibits the release of prolactin

POSTERIOR PITUITARY:
Vasopressin - has an antidiuretic effect

Oxytocin - acts on the uterus to induce uterine contraction, and acts on the mammary glands to induce milk ejection

Question 7

List the specialised cells of the anterior pituitary and what they release.

Answer 7

• Gonadotrophs secrete LH and FSH in response to GnRH.
• Somatotrophs control GH secretion in response to GHRH
• Corticotrophs control ACTH secretion in response to CRH
• Thyrotrophs regulate TSH secretion in response to TRH
• Lactotrophs control prolactin secretion in response to TRH, somatostatin and dopamine

Question 8

As a recap, describe the role of ACTH in the release of cortisol.

Answer 8

Hypothalamic neurones release corticotrophin-releasing hormone (CRH) to stimulate pituitary corticotrophs to release ACTH into the circulation.

ACTH stimulates the production of glucocorticoid (cortisol) and sex hormone from the zona fasciculata of the adrenal cortex.

Cortisol provides negative feedback to the hypothalamus and pituitary, reducing the amount of CRH and ACTH released.

Question 9

What happens to the pattern of cortisol secretion throughout the day?

Answer 9

• Varies along the day as it undergoes circadian rhythm.
• High levels in the blood, saliva, urine detected in the morning.
• Throughout the day levels decrease and become very low in evening.
• This circadian rhythm must be taken into account when considering cortisol replacement therapy as a clinical treatment.

Question 10

As a recap, describe the regulation of TSH and thyroid secretion by negative feedback.

Answer 10

• Thyrotropic releasing hormone (TRH) from the hypothalamus stimulates the anterior pituitary to release thyroid-stimulating hormone (TSH).
• TSH acts on the thyroid to increase T3/T4 secretion
• T3 is the most potent thyroid hormone, and targets the tissues containing a deiodinase enzyme (DI) to convert T4 to T3.
• The pituitary also expresses deiodinase to convert T4 to T3 to facilitate negative feedback.

Question 11

As a recap, what happens when you have too much or too little thyroxine?

Answer 11

If you have too much thyroxine, it can lead to hyperthyroidism, tachycardia, anxiety, increased metabolic rate, etc.

If you have too little thyroxine, it can lead to weight gain, low energy, cognitive impairment, depression, etc.

Question 12

Describe the synthesis and transport of the neurohormones of the posterior pituitary.

Answer 12

• The neurohormones of the posterior pituitary are vasopressin and oxytocin.
• Synthesised in the supraoptic and paraventricular nuclei in the hypothalamus. They’re transported to the terminals of the nerve fibres located in the posterior pituitary.
• Structurally, they’re quite similar (only a 2 amino acid difference in a 9 amino acid structure), yet they have very different functions.

Question 13

Describe vasopressin.

Answer 13

• Also called anti-diuretic hormone (ADH). It increases water retention and blood pressure (vasoconstrictive effect). Its release is stimulated by changes in the activity of the osmoreceptor complex in the hypothalamus.
• Controls plasma osmolarity by regulating water excretion and drinking behaviour
• Stimulates vascular smooth muscle contraction in the distal tubules of the kidney to reduce loss of water and raise blood pressure

Question 14

Describe oxytocin.

Answer 14

• Normally undetectable, but elevated during parturition, lactation and mating
• Released in response to peripheral stimuli of the cervical stretch receptors and suckling at the breast. It may also be involved in responses to stroking, caressing, grooming.
• Regulates contraction of smooth muscles (e.g. uterus during labour, myoepithelial cells lining the mammary duct, contraction of reproductive tract during sperm ejaculation)

Question 15

Describe the two-way interaction between the kidneys and the hypothalamus.

Answer 15

The kidneys secrete renin (in response to low BP, etc.). The renin converts angiotensinogen to angiotensin I. Angiotensin I is converted to angiotensin II.

Angiotensin II is detected by the subfornical organ in the brain. Activation of the subfornical organ will give the signal to stimulate magnocellular neurones found in the hypothalamus to release ADH (vasopressin) directly into the blood circulation in the posterior pituitary. This will induce thirst and also ADH will act on the kidney to induce water retention.

Question 16

What happens when oxytocin acts on the receptors?

Answer 16

• Oxytocin receptors are found in mammary glands. Activation of oxytocin receptors in mammary glands will induce milk ejection in lactating females.
• Oxytocin receptors are also found in the uterus. The release of oxytocin will activate the receptors to induce uterine contractions - this is very important for labour.
• Oxytocin also acts in the brain can formed monogamous bonding in some animal species.

Question 17

How is oxytocin involved in child birth?

Answer 17

When it is ready for birth, the foetus pushes on the walls of the uterus, causing the release of oxytocin.

This stimulates uterine contractions. It also stimulates the release of more oxytocin (positive feedback) and only stops when the baby have been delivered.

Question 18

List some CNS effects of oxytocin.

Answer 18

• antidepressant
• anitpsychotic
• social cognition
• induces trust
• anti-OCD
• treatment of autism
• anxiolytic (reduces anxiety)
• hypnotic

Question 19

The mechanism of action of the neurohormones at the cellular level depends on the classes of the hormones and their receptors.

Describe the mechanism of action of peptide/protein hormones (eg. GH).

Answer 19

• Peptide and protein hormones bind to surface receptors and activate intracellular signalling mechanisms that result in alteration of target protein and/or enzyme activities.
• Binding of insulin and growth hormone to its cell surface receptors leads to the dimerisation of the receptors, subsequently recruiting tyrosine kinases (e.g. JAK2 or MAPK) which phosphorylate a target protein (e.g. STAT) to induce a biological response.

Mutations in the GH receptor gene can result in defective hormone binding or reduced efficiency of receptor dimerisation (e.g. GH resistance = “Laron Syndrome”).

Question 20

The mechanism of action of the neurohormones at the cellular level depends on the classes of the hormones and their receptors.

Describe the mechanism of action of TSH and ACTH.

Answer 20

• Binding of hormones to GPCRs results in conformational changes in the receptor, leading to GTP exchange for GDP and catalytic activation of adenylate cyclase.
• TSH and ACTH bind to cell surface GPCRs and activate G-proteins that stimulate or inhibit adenylate cyclase. Stimulation of adenylate cyclase increases intracellular cAMP levels that activate protein kinase A. This phosphorylates target proteins (eg. CREB) to initiate specific gene expressions and biological responses.
• Activating mutations of the TSH receptor can lead to thyroid adenomas (constitutively on). Inactivating mutations of the TSH receptor can lead to resistance to TSH.

Question 21

The mechanism of action of the neurohormones at the cellular level depends on the classes of the hormones and their receptors.

Describe the mechanism of action of oxytocin and GnRH.

Answer 21

• Oxytocin and GnRH bind to cell surface GPCRs and stimulate phospholipase C. It converts PIP2 into IP3 and DAG.
• IP3 stimulates Ca2+ release from intracellular stores, particularly the endoplasmic reticulum. DAG activates PKC. These stimulate the phosphorylation of proteins and alter enzyme activities to initiate a biological response.
• Loss-of-function mutations in GnRHR can lead to sex hormone deficiencies and delayed puberty (hypogonadotrophic hypogonadism).

Question 22

The mechanism of action of the neurohormones at the cellular level depends on the classes of the hormones and their receptors.

Describe the mechanism of action of cytoplasmic/nuclear receptors.

Answer 22

• Steroid and thyroid hormones can diffuse across the plasma membrane of target cells and bind to intracellular receptors in the cytoplasm or the nucleus.
• They then enter the nucleus and can bind to specific motifs of DNA e.g. zinc finger.
• This can increase or decrease transcription which results in an up regulation or down regulation of genes

Question 23

What can happen as a result of pituitary adenoma?

Answer 23

• loss of visual field (pressure on the optic nerve)
• too much GH (gigantism and acromegaly)
• hypogonadism and infertility
• hypopituitarism (reduced pituitary function)
• too much PRL (hyperprolactinaemia)
• too much ACTH causing excess cortisol secretion (Cushing Syndrome)

Question 24

What happens when you have too little secretion of thyroxine from your thyroid glands?

Answer 24

• Hypothyroidism
• Decreased basal metabolic rate and metabolism. This results in weight gain.
• The most common cause is Hashimoto’s Disease, an autoimmune disease in which the immune system makes antibodies to the thyroid. It is seen more often in women and those with a family history of the disease.
• In older people it may follow radioactive iodine treatment, thyroid surgery or pituitary dysfunction. Sometimes, it’s accompanied with goitre, heart failure, depression, lethargy, myxedema, birth defects, etc. Babies may be stillborn or premature with a lower IQ in later life.

Question 25

What happens when you have too much secretion of thyroxine from your thyroid glands?

Answer 25

• Hyperthyroidism/Grave’s Disease.
• Autoimmune disease. Antibodies attack the thyroid gland and mimic TSH so the gland makes too much thyroid hormone. It often occurs in women (20-50; with a family history of the disease).
• Can cause goitre, difficulty breathing, anxiety, irritability, difficulty sleeping, fatigue, rapid or irregular heartbeat, trembling fingers, excess perspiration, heat sensitivity, weight loss despite normal food intake.
• There are complications such as heart failure, osteoporosis, miscarriage, premature birth, babies with low birth weight, ophthalmopathy (bulging eyes).

Question 26

What happens when there is a deficiency in adrenal hormones?

Answer 26

• Addison’s disease - deficiency of cortisol, aldosterone etc
• Most commonly occurs as an autoimmune disease
• Can cause fatigue, muscle weakness, decreased appetite and weight loss, nausea and vomiting and diarrhoea, muscle and joint pain, low BP, dizziness, low blood glucose, sweating, darkened skin on the face, neck, and back of hands, irregular menstruation

Question 27

What happens when there is the hypersecretion in adrenal hormones?

Answer 27

• Cushing’s Syndrome - excess cortisol secretion etc.
• Exogenous Cushing’s syndrome occurs in patients taking cortisol-like medications such as Prednisone for the treatment of inflammatory disorders e.g. asthma and Rheumatoid arthritis or after organ transplant (because cortisol has an immunosuppressant effect and reduces inflammation)
• Can also occur with pituitary tumours that produce too much ACTH (Cushing’s Disease).
• Can cause weight gain, rounded face and extra fat on the upper back and above the clavicles, diabetes, hypertension, osteoporosis, muscle loss and weakness, thin fragile skin that bruises easily, purple-red stretch marks, facial hair in women, irregular menstruation.