Hypothalamo-Pituitary Axis, Growth Hormone & Pituitary Disorders

Question 1

The hypothalamus and pituitary axis form a complex, function unit, which is the major link between which 2 systems?

Answer 1

Endocrine and nervous systems.

Question 2

What is the sella tunica?

Answer 2

The pituitary gland sits in the socket of the bone called sella tunica.

Question 3

Together, the hypothalamus and pituitary glands modulate a wide variety of processes, list some. (7)

Answer 3

Body growth, milk secretion, let down, reproduction, adrenal/thyroid gland function, water homeostasis and puberty.

Question 4

What different parts is the pituitary gland made up of and what are their distinct embryonic origins?

Answer 4

There’s the infundibulum (pituitary stalk), then the anterior (adrenohypophysis)and posterior (neurohypophysis) pituitary glands. The anterior pituitary arises from the evagination of oral ectoderm (primitive gut tissue) and the posterior pituitary arises from the neuroectoderm (primitive brain tissue). The hypothalamus drops down through the infundibulum to form the posterior pituitary, so they’re connected.

Question 5

What is the neurocrine function of the posterior pituitary?

Answer 5

Oxytocin and ADH/vasopressin are made by neurosecretory cells in the supraoptic and paraventricular nuclei of the hypothalamus and transported down the nerve cell axons to the posterior pituitary, where they are stored and released into circulation to act on distant targets.

Question 6

What type of chemical secreting function does the anterior pituitary gland have?

Answer 6

To an extent, endocrine, neurocrine, paracrine and autocrine.

Question 7

Explain the neurocrine function of the anterior pituitary.

Answer 7

Hormones synthesised in the hypothalamus are transported down axons and stored in the median eminence before their release into the hypophyseal portal system - they stimulate/inhibit target endocrine cells in the anterior pituitary.

Question 8

Explain the endocrine, autocrine and paracrine function of the anterior pituitary.

Answer 8

It secretes hormones into the bloodstream and as well as distant targets, has effects on neighbouring cells (and its own).

Question 9

Hormones produced by hypothalamic nerve cells, can act via which 2 neurocrine pathways?

Answer 9

Direct effect on target tissues after release from the posterior pituitary OR,
Hormones secreted exclusively into the hypophyseal portal system, which affect endocrine cells in the anterior pituitary.

Question 10

Which 2 hormones are produced in the hypothalamus for posterior pituitary release and what do they do?

Answer 10

OT (oxytocin) for milk let down and uterus contraction in birth.
ADH (anti-diuretic hormone/vasopressin) to regulate body water volume.

Question 11

What are tropic hormones?

Answer 11

Tropic hormones affect the release of other hormones in the target tissues (unlike tropic hormones, which affect growth).

Question 12

Name the 6 trophic hormones of the hypothalamus.

Answer 12

Thyrotropin releasing hormone/TRH (also mini +be prolactin effect), Prolactin-release inhibiting hormone/PIH/dopamine, corticotropin releasing hormone/CRH, Gonadotrophin releasing hormone/GnRH, Growth hormone releasing hormone/GHRH and Growth hormone inhibiting hormone/GHIH/Somatostatin.

TRH, PIH, CRH, GnRH, GHRH, GHIH.

Question 13

Pathways by which hypothalamus and anterior pituitary hormones are released are often regulated by negative feedback. To illustrate the point, explain what happens when there’s raised Cortisol.

Answer 13

Cortisol inhibits the hypothalamus from releasing corticotropin releasing hormone (CRH) and the anterior pituitary from releasing Adrenocorticotropic hormone (ACTH). ACTH also makes efforts to stop the hypothalamus producing CRH.

Question 14

What are the 5 hormones produced by the anterior pituitary and their roles?

Answer 14

TSH - thyroid releasing hormone (secretion from gland).
PRL - prolactin for milk secretion and mammary gland development.
ACTH - Adrenocorticotropic hormone for secretion of hormones from adrenal cortex.
LH - luteinising hormone for ovulation and secretion of sex hormones.
FSH - development of eggs and sperm.

Question 15

Growth is influenced by many factors, name some.

Answer 15

Hormones (GH is the most important endocrine regulator of postnatal growth), genetics, nutrition and the environment.

Question 16

Growth hormone, produced by the anterior pituitary is a _________ hormone, with a signal peptide that must be cleaved for proper __________. It is stimulated by ______ and inhibited by ____________. The growth promoting effects are mainly indirect, via _____/somatomedins - cell of skeletal muscle and the _______ made in response to GH.

Answer 16

Protein
Folding
GHRH
Somatostatin/GHIH   - both from the hypothalamus
IGFs (insulin-like growth factors)
Liver

Question 17

What is the role of GH and IGFs?

Answer 17

GH is essential for normal growth in childhood and teenage years, as it stimulates long bone growth (width and prior to epiphyseal closure, length). IGFs stimulate bone and cartilage growth. In adults they both help maintain muscle and bone mass, promote healing and tissue repair and modulate metabolism and body composition.

Question 18

Principal control of the body is assumed by the hypothalamus, with the CVS regulating via inputs into it. When might GH fluctuation be noticed?

Answer 18

There is a surge in GH secretion after the onset of deep sleep, a decrease with R.E.M. sleep, an increase with stress (trauma, surgery, fever) or exercise, a decrease in glucose or fatty acids may result in a GH increase (and the opposite), fasting increases GH secretion and obesity decreases it.

Question 19

Growth hormone secretion is regulated by a long loop of negative feedback, explain it.

Answer 19

There is IGF mediated inhibition of GHRH from the hypothalamus. It also stimulates the release of somatostatin and inhibits the release of GH from the anterior pituitary. The shorter loop is GH itself stimulating somatostatin release.

Question 20

What does growth hormone deficiency in childhood lead to and how is it treated?

Answer 20

Pituitary dwarfism - proportionate, complete/partial deficiency - both respond to GH therapy. Height is < 3rd percentile on a standard growth chart and the rate of growth is slower than expected for a certain age. In teen years, delayed/no sexual development.

Question 21

What does growth hormone excess in childhood lead to and how is this different in adulthood?

Answer 21

Gigantism is the result in childhood, which is rare and often from a pituitary adenoma.
In adulthood, you get Acromegaly with large extremities (hands, feet and lower jaw).

Question 22

How does growth hormone exert its effects on cells?

Answer 22

GH exerts its effects on cells by binding to receptors (tyrosine kinase receptors) and activating Janus kinases (JAKs), with activation of signalling pathways leading to transcription factor activation and IGF production.

Question 23

There are ___ IGFs in mammals (IGF2 is mainly in ________ growth). Binding proteins modulate their ___________ and actions may be paracrine and autocrine as well as ___________.

Answer 23

2
Foetal
Availability
Endocrine

Question 24

IGFs act through IGF receptors to modulate what?

Answer 24

Hypertrophy, hyperplasia, increased rate of protein synthesis and rate of lipolysis in adipose tissue.

Question 25

Which receptors do IGFs work on?

Answer 25

There is cross activation with insulin receptors (with signalling pathways resulting in metabolic effects), a hybrid receptor, IGF1r (leading to mitogenic effects) and IGF2r with no resultant tyrosine kinase activity (target for lysosomal degradation).

Question 26

Other than GH and IGFs, which hormones can influence growth?

Answer 26

Insulin, thyroid hormones, androgens, oestrogens and glucocorticoids.

Question 27

When assessing a patient with a pituitary disorder, what may the clinical presentation of a pituitary tumour involve?

Answer 27

The mass effect on local structures leading to visual loss, a headache and abnormality in pituitary function leading to hypo/hypersecretion.

Question 28

For each of the following situations, what are the consequences?
Pituitary tumour with superior growth, lateral growth or a Cavernous sinus invasion.

Answer 28

Superior growth impinges (puts pressure on) the optic chiasm - visual loss is bitemporal hemi-anopia (loss of half vision form the lateral sides).
Lateral growth leads to pain and double vision.
Cavernous sinus invasion (left side) leads to cranial nerve palsy (L eye compressive problems).

Question 29

What happens in the case of a pituitary tumour blocks the hypothalamic control of the gland?

Answer 29

Levels of TSH, LH, FSH, GH and ACTH decrease, as they are no longer stimulated, but prolactin, usually under negative control, increases - Hypopituitarism.

Question 30

What are the symptoms of Hypopituitarism?

Answer 30

GH deficiency - short stature in children and reduced QoL in adults.
Gonadotropin deficiency - loss of secondary sexual characteristics in adults and loss of periods is an early sign for women.
TSH and ACTH deficiency is a late feature of pituitary tumours - low thyroid hormones mean cold, weight gain, tiredness, slow pulse (low T4 for unraised TSH) and low cortisol means tired, dizzy, low BP, low Na+. HPA is important - may be life threatening.

Question 31

Hormone excess of which pituitary hormones are common and which are rare?

Answer 31

Hormone excess of prolactin, GH and ACTH are common and the extra release of TSH, LH and FSH are rare.

Question 32

What can biochemical assessment of pituitary disease be used for and what are its limits?

Answer 32

Basal blood tests are sufficient for the thyroid axis, gonal axis (LH, FSH, oest/test) and the prolactin axis (serum prolactin), but dynamic blood tests may be needed for the HPA axis for 0900 cortisol (diurnal rhythm) and GH axis.

Question 33

What is dynamic assessment of pituitary disease used for and how?

Answer 33

Stimulation test if suspected deficiency and suppression test if excess. HPA - direct stimulation of adrenals by synACTHen and response to hypoglycaemic stress (insulin stress test). Or, suppress ACTH axis with steroids (dexamethasone). GH axis - insulin stress test or suppress GH axis with glucose load (glucose tolerance test).

Question 34

Other than biochemical or dynamic tests for pituitary disease, how may it be assessed?

Answer 34

There is radiological assessment of pituitary disease with an MRI.

Question 35

What a prolactinoma and the different types?

Answer 35

A prolactin secreting pituitary tumour. A macro adenoma is > 1cm and a micro adenoma is < 1cm. The larger the tumour, the higher the prolactin.

Question 36

Even if a prolactinoma is so large that it causes vision problems, it is treated in the same way as a microadenoma, how is that?

Answer 36

It is treated with a tablet, not an operation (so check prolactin before they’re sent to theatre - 50-400miU/L. It will shrink with a dopamine agonist, as dopamine suppresses prolactin.

Question 37

What are the consequences of hyperprolactinaemia?

Answer 37

Prolactin directly inhibits LH secretion, so there’s menstrual disturbance and fertility problems and galactorrhea. (For microprolactinomas, the serum prolactin is not that high) Men present later, so usually have macroadenomas and present with non specific symptoms of low testosterone (depression, low libido) and may present with mass symptoms (e.g. Visual loss).

Question 38

How can the cause of high prolactin be determined?

Answer 38

Prolactin is under tonic inhibitory control by dopamine, so anything blocking the stalk, means prolactin disinhibition. If prolactin is <5000, it is may be due to disinhibition (stalk effect), rather than active secretion, but >5000, suggests probably a prolactinoma.

Question 39

Non functioning pituitary adenomas do not secrete biologically active hormones, but may secrete inactive hormones. Symptoms are from mass effect or low pituitary hormones. How are non functioning pituitary tumours treated?

Answer 39

Surgically.

Question 40

How might Hypopituitary bloods with disinhibition Hyperprolactinaemia look?

Answer 40

fT4 = 7.4pmol (10-25), TSH = 1.2miU/L (0.3-5), testosterone 0.3nmol/L (9-34), LH and FSH < 0.5, 0900 cortisol 28nmol/L (<400 is too low), prolactin = 1200miU/L (50-400), GH = 0.2 microg//L, IGF-1 = 37micrograms/L (87-239).

Question 41

How is a prolactinoma treated and what must be checked first?

Answer 41

First check the patient isn’t pregnant. Then, bromocriptine and cabergoline which are very effective dopamine agonists working at D2 receptors. Remember dopamine antagonist (anti-sickness or anti-psychotic drugs) can cause high prolactin.

Question 42

What is Acromegaly?

Answer 42

‘Large extremities’- GH secreting pituitary tumour leading to gradual changes to features over the years - tell tale hands and feet.

Question 43

What are the long terms complications of Acromegaly, if it’s left untreated?

Answer 43

Premature CVS death, increased risk of colonic tumours, increased risk of thyroid cancer, disfiguring body changes may be irreversible, hypertension and diabetes - unpleasant symptoms.

Question 44

How is a diagnosis of Acromegaly confirmed?

Answer 44

Biochemical tests to confirm - oral glucose tolerance test (OGTT) with GH response. Failure to suppress GH<1microgram/L, elevated IGF-1 level, GH day curve has an elevated mean. Better to consider it and be wrong.

Question 45

How is Acromegaly treated?

Answer 45

Surgical removal of the tumour (trans-sphenoidal/through nose hypophysectomy). Tumours in the cavernous sinus need additional treatment. Medical treatment: reduce GH secretion - dopamine agonist and somatostatin analogues (octreotide, lanreotide etc) and block GH receptor - pegviosomant. Radiotherapy - external beam with multiple short bursts over weeks, or gamma knife - high concentration, single time.

Question 46

There are new imaging techniques, like PET scans, which can look for what?

Answer 46

Functional activity.

Question 47

What is Cushing’s disease?

Answer 47

ACTH secreting pituitary tumour, with a classical change in appearance.

Question 48

What s the classical change in appearance that accompanies Cushing’s disease?

Answer 48

Round, pink face, round abdomen, skinny and weak limbs, thin skin and easy bruising, striae on abdomen.

Question 49

Other than features affecting appearance, what symptoms are there of Cushing’s disease?

Answer 49

High BP, diabetes and osteoporosis, 50% 5 year mortality.

Question 50

What’s the difference between Cushing’s disease and Cushing’s syndrome?

Answer 50

Cushing’s syndrome may be caused by other pathologies (not just ACTH secreting pituitary tumour).

Question 51

Describe diabetes insipidus as a pituitary disorder.

Answer 51

Large quantities of pale irons and resulting extreme thirst. The posterior pituitary usually secretes vasopressin (ADH), but water is not reabsorbed at the kidney, because not enough is produced (or rarely, the kidney isn’t responding).

Question 52

What are he 2 types of diabetes insipidus?

Answer 52

Cranial DI is a vasopressin deficiency pituitary disease.

Nephrogenic DI is a vasopressin resistant kidney disease.

Question 53

Diabetes insipidus is not standard in pituitary tumours, as they tend just to affect the anterior pituitary, what is the pathology causing cranial DI?

Answer 53

(Hypophysitis) - inflammation, infiltration, malignancy, infection.

Question 54

What are the consequences of untreated diabetes insipidus?

Answer 54

Severe dehydration, hypernatraemia, reduced consciousness - coma and death.

Question 55

How is cranial DI treated?

Answer 55

It responds very well to synthetic vasopressin - Desmopressin as a nasal spray/tablets/injection.

Question 56

What is pituitary apoplexy?

Answer 56

Sudden vascular event in a pituitary tumour, haemorrhage or infarction (stroke).

Question 57

Describe the clinical presentation of pituitary apoplexy.

Answer 57

Sudden onset headache, double vision, visual field loss, cranial nerve palsy, hypopituitarism - cortisol deficiency is the most dangerous - prompt diagnosis and treatment needed.