Neurohormones (neuro)

Question 1

Patterns of communication in nervous system

Answer 1

A: Point to point communication -Fast, restricted
B: Neurons of secretory hypothalamus -slow but widespread
C: Networks of interconnected neurons
Autonomic Nervous System -fast, widespread influence
D: Diffuse modulatory systems -slower, widespread

Question 2

Endocrine system and nervous system

Answer 2

ENDOCRINE SYSTEM
• Mediators travel within blood vessels 
• Utilises chemical mediators (hormones)
• Slow communication
• Effects can be long-lasting
ENDOCRINE SYSTEM
• Mediators travel within blood vessels 
• Utilises chemical mediators (hormones)
• Slow communication
• Effects can be long-lasting
- Neurohormones are produced by specialised nerve cells called neurosecretory cells and released into the blood 
- Because they are defined as hormones, they are secreted into the blood and have their effect on cells some distance away 
- the same compounds can also act as neurotransmitters or as autocrine (self) or paracrine (local) messengers.

Question 3

Types of hormones

Answer 3

• Protein and peptide hormones
- vary considerably in size
- can be synthesised as a large precursor and processed prior to secretion (eg GH, somatostatin, insulin)
- can be post-transitionally modified (eg glycosylation)
- can have multiple subunits synthesised independently and assembled (eg FSH, LH, TSH)
• Amino acid derivatives
- mostly tyrosine derived
- neurotransmitter that can also act as a hormone
- eg Epinephrine, norepinephrine, dopamine
• Steroid hormones
- steroid is a class of lipids derived from cholesterol
- include cortisol, aldosterone, testosterone, progesterone, oestradiol

Question 4

Neurohormones

Answer 4

• neuropeptides (neurohormones) are functionally important transmitters in the hypothalamo-pituitary axis
• the HPA has 2 components (anterior and posterior pituitary)

Question 5

Anatomy of hypothalamo-hypophyseal system

Answer 5

• the pituitary lies in a bony cavity (sella turcica or pituitary fossa) in the sphenoid bone
• the pituitary is connected to the hypothalamus by a stalk
• the hypothalamic hormones are secreted into the portal vein system at the median eminence
• the delivery of these hormones is dependant on an intact pituitary stalk (infundibulum)
• any damage of the pituitary stalk will result in failure of gonadal, thyroid and adrenal function, as well as misregulation of growth
• A number of these peptides act both as hormones and as neurotransmitters; sometimes the endocrine and neural functions are linked in others they are not.
• The neuroendocrine secretory cells are scattered in the hypothalamus but key nuclei are the medial pre-optic, the arcuate and the paraventricular nuclei

Question 6

Hypothalamic neurohormones that control the anterior pituitary

Answer 6

• Corticotrophin releasing hormone (CRH): 41a.a. peptide that controls the release of adrenocorticotrophin (ACTH)
• Thyrotrophin releasing hormone (TRH): 3a.a. peptide that controls the release of thyroid stimulating hormone (TSH) and prolactin (PRL)
• Gonadotrophin releasing hormone (GnRH): 10a.a. peptide that controls release of luteinising hormone (LH) and follicle-stimulating hormone (FSH)
• Growth hormone releasing hormone (GHRH): 44a.a. peptide that controls the release of growth hormone (GH)
• Growth hormone release inhibiting hormone (somatostatin): 14a.a. peptide that inhibits release of GH, gastrin vasoactive intestinal polypeptide (VIP), glucagon, insulin, TSH and PRL
• Dopamine: a monoamine that inhibits the release of PRL

Question 7

Specialised cells responding to hypothalamic hormones

Answer 7

are contained in the anterior pituitary:

• gonadotroph cells that secrete LH and FSH in response to GnRH
• somatotrophs that control GH secretion in response to GHRH
• corticotrophs that control ACTH secretion in response to CRH
• thryotrophs that regulate TSH secretion in response to TRH
• lactotrophs that control the secretion of prolactin in response to TRH, somatostatin and dopamine

Question 8

Adrenocorticotrophic hormone (ACTH)

Answer 8

• ACTH is a 39a.a. peptide with a molecular weight of 4.5kDa
• belongs to a family of related peptide hormones derived from a large precursor glycoprotein, pro-opiomelanocortin (POMC)
• hypothalamic neurons that release corticotrophin releasing hormone (CRH) to stimulate pituitary corticotrophs to release ACTH into circulation
• ACTH stimulates the production of glucocorticoid (cortisol) and sex hormones from the zona fasciculata of adrenal cortex
• cortisol is a steroid hormone, more specifically a glucocorticoid, hydrocortisone is a name for cortisol used as a medication

Question 9

Glucocorticoid secretion shows rhythms of peaks and troughs

Answer 9

• Following changes in brain activity, plasma cortisol levels are highest first thing in the morning and decline during the day (reflecting the pattern of ACTH secretion by the anterior pituitary).
• This circadian rhythm must be taken into account when
  considering cortisol replacement therapy as a clinical treatment.
• The pattern of cortisol secretion probably reflects the body’s response to low blood glucose after overnight fasting.

Question 10

Endocrine control due to regulation of TSH and thyroid secretion

Answer 10

• A good example of endocrine control is the regulation of TSH and thyroid secretion by negative feedback
• Thyrotrophic releasing hormone (TRH) from the hypothalamus stimulates the anterior pituitary to release thyroid-stimulating hormone (TSH).
• TSH acts on the thyroid to increase T4/T3 secretion.
• T3 is the most potent thyroid hormone and target tissues contain 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

Hypothalamic neurohormones that regulate posterior pituitary

Answer 11

Vasopressin and oxytocin

• synthesised in the supraoptic and paraventricular nuclei in the hypothalamus
• transported to the terminals of the nerve fibres located in the posterior pituitary
• structurally quite similar, yet have very different functions

Question 12

Vasopressin

Answer 12

• aka anti-diuretic hormone (ADH)
• release is stimulated by changes in the activity of the osmoreceptor complex in hypothalamus
• controls plasma osmolality 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 13

Oxytocin

Answer 13

• 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
• may also be involved in responses to stroking, caressing and grooming
• regulates contraction of smooth muscles (eg uterus during labour, myoepithelial cells lining the mammary duct, contraction of reproductive tract during sperm ejaculation)

Question 14

Kidneys and hypothalamus

Answer 14

• two way interaction
• kidneys
• Renin converts Angiotensinogen to Angiotensin I.
• Angiotensin I is converted in Angiotensin II
• Angiotensin II is detected by the subfornical organ
• Subfornical organ projects to vasopressin cells and neurons in the lateral hypothalamus
• Vasopressin affects kidneys

Question 15

Hormones during pregnancy

Answer 15

• Estradiol from ovaries activates oxytocin receptors on uterus
• Oxytocin from foetus and mother’s posterior pituitary stimulates uterus to contract and stimulates placenta to make prostaglandins
• prostaglandins stimulate more contractions of uterus
• contractions of uterus provide positive feedback back to placenta making prostaglandins and release of oxytocin

Question 16

CNS effect of oxytocin

Answer 16

• antidepressant
• antipsychotic
• social cognition
• induces trust
• anti-OCD
• treatment of autism
• anxiolytic
• hypnotic

Question 17

Mechanisms of action at cellular level (1)

Answer 17

• the mechanism of action depends on the classes of the hormones and their receptors
• peptide and protein hormones bind to surface receptors and activate intracellular signalling mechanisms
• results in alteration of target protein and/or enzyme activities
• binding of insulin and growth hormone to its cell surface receptors leads to dimerisation of the receptors, subsquently recruiting tyrosine kinases (eg JAK2 or MAPK)
• these phosphorylate target protein (eg STAT) to induce biological responses
• mutations in the GH receptor gene can result in defective hormone binding or reduced efficiency of receptor dimerisation -> GH resistance (‘Laron syndrome’)

Question 18

Mechanisms of action at cellular level (2)

Answer 18

The G protein/ adenylate cyclase pathway:

• G-protein coupled receptors (GPCRs) are the largest of the cell surface receptor groups with over 140 members
• this receptor has unique 7 transmembrane domains
• binding of hormone to GPCR 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 GPCR receptors 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 TSH receptor -> thyroid adenomas ‘constitutive ON’
• inactivating mutations of TSH receptor -> resistance to TSH

Question 19

Mechanisms of action at cellular level (3)

Answer 19

DAG/IP3 pathway:

• oxytocin and GnRH bind to cell surface GPCRs and stimulate phospholipase C
• it converts phosphatidylinositol biphosphate (PIP2) into inositol triphosphate (IP3) and diacylglycerol (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 -> sex hormone deficiency and delayed puberty (hypogonadotrophic hypogonadism)

Question 20

Mechanisms of action at cellular level (4)

Answer 20

Cytoplasmic/nuclear receptors:

• steroid and thyroid hormones can diffuse across the plasma membrane of target cells and bind to intracellular receptors in the cytoplasm or the nucleus
• these receptors function as hormone-regulated transcription factors, controlling gene expression
• nuclear receptors commonly share a transcriptional activation domain (AF1), a Zn2+ finger binding domain and a ligand (hormone) binding/dimerisation domain
• there are more than 150 members of receptor proteins, majority of which are ‘orphan’ receptors

Question 21

Disorders of neurohormone production

Answer 21

• loss of visual field (pressure on optic nerve)
• too much GH (gigantism and acromegaly)
• hypogonadism and infertility
• hypopituitarism (reduced pituitary function)
• too much PRL (hyperprolactinaemia)
• too much ACTH excess cortisol secretion (cushing syndrome)
• pituitary adenoma (tumor on pituitary)

Question 22

Hypothyroidism

Answer 22

• Hypothyroidism occurs if there is too little thyroid hormone.
  This disease affects 1 in 4000 infants.
• If left untreated, it can cause mental retardation,
  slow growth, cold hands and feet, and lack of energy among other things.
• 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 thyroid disease.
• In older people it may follow radioactive iodine treatment,
  thyroid surgery or pituitary dysfunction; sometimes with
  goitre, heart failure, depression and slowed mental
  functioning, myxedema, birth defects.
• Babies may be stillborn or premature with lower IQ in later in life.
• The brain mechanisms underlying these changes in function are not well understood

Question 23

Graves’ disease

Answer 23

The opposite of hypothyroidism is Hyperthyroidism or Graves’ disease
Cause:
- Graves’ disease is also an autoimmune disease.
- Antibodies attack the thyroid gland and mimic
- TSH so the gland make too much thyroid hormone (hyperthyroidism).
- It often occurs in women (20 – 50; with a family history of thyroid disease).
Signs and Symptoms:
- Goitre (enlarged thyroid gland) ,Difficulty breathing, Anxiety, irritability,difficulty sleeping, fatigue, Rapid or irregular heartbeat, trembling fingers, Excess perspiration, heat
sensitivity, Weight loss, despite normal food intake
Complications:
- heart failure, osteoporosis. Pregnant women with uncontrolled Graves’ disease are at greater risk of miscarriage, premature birth, and babies with low birth weight.
- Graves’ ophthalmopathy (occurs if untreated; bulging eyes, relatively rare)

Question 24

Adrenal insufficiency (Addison’s disease)

Answer 24

Adrenal insufficiency (AI):
- occurs when the adrenals do not secrete enough steroids.
Cause:
- The most common cause of primary AI is autoimmune,
Symptoms:
- Symptoms include fatigue, muscle weakness, decreased
appetite, and weight loss, nausea, vomiting, and diarrhea,
muscle and joint pain, low blood pressure, dizziness, low blood glucose, sweating,
darkened skin on the face, neck, and back of the hands and irregular menstruation.

Question 25

Cushing’s syndrome (excessive secretion)

Answer 25

• Cushing’s syndrome result from having excess
  cortisol secretion
• Exogenous Cushing’s syndrome occurs in Patients Taking cortisol-like medications such as Prednisone for the treatment of inflammatory disorders eg asthma and Rheumatoid arthritis or after organ transplant.
• It can also occur with pituitary tumors produces too
  much ACTH (Cushing’s disease).
  Signs and symptoms:
• 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,.