Hypothalamic-Pituitary- Adrenal Axis

Question 1

What are the six Anterior Pituitary hormones?

Answer 1

• ACTH: Adrenocorticotropic Hormone
• FSH: Follicle Stimulating Hormone
• TSH: Thyroid Stimulating Hormone
• PRL: Prolactin
• GH: Growth Hormone
• LH: Luteinizing hormone

Question 2

What are the two Posterior Pituitary Hormones?

• production
• transport
• store

Answer 2

• ADH: Antidiuretic Hormone
• Oxytocin
• these are synthesised in neurones of the hypothalamus then converted to their active form in the posterior pituitary gland
  
  • supraoptic nuclei
  • periventricular nucleus
• inactive forms are transported from the nuclei along the hypothalamico-neurohypophyseal tract
• then stored in the posterior pituitary

Question 3

Give an overview of Growth Hormone (GH)

• production
• control
• action/effect

Answer 3

• synthesised in the somatotroph cells of the anterior pituitary gland
• secretion is controlled by the hypothalamus
  
  • GHRH (somatotropin) stimulates its secretion
    
    • Growth hormone-releasing hormone
    • has a greater role than GHRIH
    • stimulated by decreased COH and fatty acids and increased amino acids
  • GHRIH (somatostatin) inhibits is release
    
    • Growth hormone-releasing Inhibiting hormone
• acts via 2nd messenger produced in the liver in some tissues
  
  • ​Insulin-like growth factor 1 and 2
• Primary effects: promote growth in adolescence by increasing protein synthesis and collagen deposition
  
  • ​foetal growth is also dependent

Question 4

Give an overview of Oxytocin

• production
• control
• action/effect

Answer 4

• works via IP3 to cause contraction of the smooth muscle of the genital tract and breast
• production increases during pregnancy
  
  • a parallel increase in oxytocin activity is also seen
• secretion of oxytocin is achieved by stimulation of the genitals and nipples
  
  • most important at parturition and lactation
  • there is a delay between the start of suckling and milk let down
• Oxytocin is not necessary for the initiation of normal labour
  
  • it can be administered to induce labour

Question 5

Describe the cycle that leads to oxytocin release

• nipple stimulation
• stimulation of the cervix and vagina

Answer 5

Question 6

Give an overview of prolactin

• release/ secretion
• control
• action

Answer 6

• secreted by lactotroph (mammotroph) cells in the anterior pituitary gland
  
  • these cells increase during pregnancy and
  • prolactin conc. increases during parturition initiating lactation
  • secreted in both males and females
• secretion is controlled by
  
  • Prolactin Inhibiting factor = DA
  • TRH stimulates prolactin release
• secretion is stimulated by
  
  • mild stress
  • nipple stimulation
  • coitus
• Action
  
  • contain milk production in females
  • maintenance of lactation depends on suckling
  • prolactin with other hormones causes proliferation and differentiation of mammary tissue during pregnancy
  • inhibits gonadotrophin release and/or response of the hormones to these trophic hormone (ovulation doesn’t occur during breastfeeding)

Question 7

What are the actions of Prolactin?

(4)

Answer 7

1. increase during pregnancy under the influence of oestrogen and progesterone to facilitate lobluloalveolar development of the breast
2. causing milk secretion from the breast after oestrogen and progesterone priming
3. inhibits GnRH secretion and antagonizes the action of gonadotropins in the ovaries, inhibiting ovulation
4. hyperprolactinaemia in men is associated with impotence and hupogonadism

Question 8

Give an overview of ADH

• release
• stimulation
• action/ receptors

Answer 8

• The hypothalamic nuclei that control fluid balance lie close to the nuclei that synthesise and secrete ADH.
• Stimuli for ADH release
  
  • increased in plasma osmolarity (sensation of thirst)
  • hypovolaemia - through stretch receptors in the CVS or angiotensin release
• ADH (vasopressin) receptors are all GPCRs
  
  • V1A and V1B
    
    • coupled to phospholipase C/ inositol triphosphate system
    • oxytocin receptors also have GPCRs that are similar to ADH, therefore, ADH acts as a mild agonist at oxytocin receptors
  • V2
    
    • these stimulate AC which mediates the main response of ADH in the kidney on the basolateral membrane of the distal tubule and collecting duct
    • increases the rate of insertion of aquaporins in the collecting duct in the kidneys

Question 9

Give an overview of the control of ADH

Answer 9

• NSAIDs and carbamazepine increase vasopressin effects (Na+ retention)
  
  • Aldosterone (mineralocorticoid) also causes water to be reabsorbed along with sodium.
• Lithium, colchicine and vinca alkaloids decrease vasopressin effects (Na+ excretion).

Question 10

What clinical investigations are carried out?

Answer 10

• Presentation - Primary Or Secondary?
• Stimulate secretion? (ACTH) or Suppress secretion? (Dexamethasone)
  
  • TSH & T4
  • Cortisol
  • LH & FSH
  • A prolactin (PRL) test
  • Testosterone / “Periods”
• After Biochemical Tests: Imaging (e.g. MRI)
• After Imaging: Visual Field Tests
• Bilateral hemianopsia (due to compression of optic chiasm)

Question 11

Give an overview of the hypothalamus

• location
• inputs/outputs
• action/effect

Answer 11

• lies on either side of the third ventricle, below the thalamus, between the optic chiasm and the midbrain
• receives inputs from the limbic system and the retina
• contains neurons that are sensitive to changes in hormone levels, electrolytes and temperature
• efferent output to the autonomic nervous system
  
  • has greater homeostasis of physiological systems:
    
    • thirst, hunger, sodium and water balance, temp. regulation
    • control of circadian and endocrine function
    • formation of anterograde memories (with the limbic system)
    • translation of response to emotional stimuli into endocrinological and autonomic responses

Question 12

What are Sellar masses and how do they present?

Answer 12

• a mass found in the sellar region in the brain this is composed of the
  
  • bony sellaturcica
  • pituitary gland
  • adjacent structures
• present with neurological symptoms
  
  • visual impairment: the most common is bitemporal hemianopsia
    
    • _​_one or both eyes may be affected to varying degrees
    • onset of the visual deficit is usually very gradual –> delayed ophthalmologic consultation
  • diplopia
  • headache: due to the expansion of the sella
  • pituitary apoplexy: sudden haemorrhage into an adenoma –> sudden headaches and diplopia
  • Cerebrospinal fluid rhinorrhea - inferior extension of the mass
  • Parainaud syndrome: a constellation of neuro-ophthalmologic findings (most often paralysis of upward conjugate gaze),
• discovered incidentally through MRI, usually with hormonal abnormalities
  
  • hormone deficiencies are of gonadotropins –> hypogonadism

Question 13

Go over the causes and prevalence of Sellar Masses

• types of adenomas
• differential

Answer 13

• 90% of cellar asses are pituitary adenomas
  
  • these are benign tumours of the anterior pituitary that are neoplastic
• Prevalence of type of adenomas per 100,000
  
  • All adenomas – 77.6
  • Lactotroph adenomas – 44.4
    
    • cause hyperprolactinemia –> hypogonadism in men and women
  • Nonfunctioning adenomas – 22.2
    
    • gonadotroph adenomas
    • thyrotroph adenomas - may cause hyperthyroidism due to increased TSH
  • Somatotroph adenomas – 8.6
    
    • cause acromegaly due in increased GH secretion - the majority are clinically silent
  • Corticotroph adenomas – 1.2
    
    • cause Cushings disease, but majority remain clinically silent
• Pituitary hyperplasia may present as a sellar masses and be misdiagnosed as pituitary adenoma

Question 14

Types of Pituitary hyperplasia

Answer 14

• Lactotroph hyperplasia during pregnancy.
• Thyrotroph and gonadotroph hyperplasia due to longstanding primary hypothyroidism and primary hypogonadism, respectively.
• Somatotroph hyperplasia due to ectopic secretion of growth hormone-releasing hormone, a rare condition.

Question 15

How are Hypothalamic-pituitary hormones transported?

Answer 15

• Neurosecretory cells release peptidergic hormones (median eminence, hypothalamus) – transported in blood via the pituitary portal system.
  
  • hormones also transport via axons from the Parvicellular neurosecretory cells
• Pituitary stalk & pituitary portal vessels pass down through the dura mater which roofs the pituitary fossa.

Question 16

Review the Hypothalamic-pituitary-adrenal axis controls

(draw it out)

Answer 16

Question 17

What type of imaging is this, label key features of the HP axis

• plane and weighting

Answer 17

• MRI scan, coronal plane, T1 weighted

Question 18

What are the Hormones, Receptors & Enzymes of the Adrenal Cortex

Answer 18

• Adrenal cortex hormone production
  
  • GLUCOCORTICOID
    
    • CORTISOL
  • MINERALOCORTICOID
    
    • ALDOSTERONE (renin-angiotensin-aldosterone system)
  • SEX STEROIDS
    
    • ANDROGENS
• Binding proteins:
  
  • 90% cortisol bound to cortisol binding globulin (CBG)
• Receptors:
  
  • Intracellular glucocorticoid and mineralocorticoid receptors (GR and MR)
• Enzymes:
  
  • 11-b-hydroxysteroid dehydrogenase (11- b-HSD)

Question 19

What are the effects of Glucocorticoids?

Answer 19

• Maintenance of homeostasis during stress
  
  • e.g. haemorrhage, infection, anxiety
• Anti-inflammatory
• Energy balance/metabolism
  
  • ­ increase/ maintain normal [glucose]
• Formation of bone and cartilage
• Regulation of blood pressure
• Cognitive function, memory, conditioning

Question 20

What are cortisol levels like across a day

• effect on the circadian rhythms

Answer 20

• rise during the early morning
• peak just prior to awakening
• fall during the day
• are low in the evening
  
  • in preparation of sleep

Question 21

Explain Ultradian Rhythms

Answer 21

• this is spontaneous pulsatile release of glucocorticoids during the day
  
  • varying amplitudes
• amplitude decreases in the circadian trough
• associated with
  
  • noise
  • anticipatory stress
  • response to an unintended stressor

Question 22

What are the circulating androgens?

Answer 22

• DHEAS from the adrenal glands
• Androstenedione
• Testosterone
  
  • converted to oestrogen by Aromatase
• Dihydrostesterone converted from testosterone by 5-alpha reductase

Question 23

Explain the function of the 11-ß-HSD-1/2 enzyme

Answer 23

11-ß-HSD-2

• inactivates cortisol in the kidney, colon, sweat glands
  
  • converts it to cortisone
• this allows aldosterone to bind to the mineralocorticoid receptor as they both have the same affinity

11-ß-HSD-1

• converts cortisone back to cortisol in the
  
  • liver, adipose, CNS
• tissue specificity allows gating of GC access to nuclear receptors and amplification of GC signal in target cells

Question 24

What is the impact of excess cortisol?

Answer 24

• Cushings syndrome
  
  • weight gain
  • central obesity
  • hypertension
  • Insulin resistance
  • Neuropsychiatric problems
  • Osteoporosis

Question 25

What is the pathogenesis of Cushing's syndrome?

Answer 25

* Excess cortisol due to * **Pituitary adenoma:** ACTH-secreting cells * **Adrenal tumour:** adenoma or carcinoma, neoplastic cells also secret cortisol * **'Ectopic ACTH':** carcinoid, paraneoplastic * other non-adrenal cells producing cortisol * **Iatrogenic:** steroid treatment

Question 26

Clinical features of Cushing's syndrome

Answer 26

* Central obesity with thin arms & legs * Fat deposition over the upper back (‘buffalo hump’) * Rounded ‘moon’ face * Thin skin with easy bruising, pigmented striae * Hirsutism * Unwanted, excessive hair growth in women either on face, chest or back. Causing * Hypertension * Diabetes * Psychiatric manifestations * Osteoporosis

Question 27

What is the impact of insufficient Cortisol?

Answer 27

* Addison's disease * gradually falls off in general health at length they gradually sink and expires * becomes languid & weak * indisposed to either bodily or mental exertion * the body wastes * slight pain is referred to the stomach * there is occasionally actual vomiting * discolouration of the skin

Question 28

What is the pathogenesis of Addison's disease?

Answer 28

* Primary adrenal insufficiency ‘Addison’s disease’ * Usually autoimmune in UK * Rare causes include metastases or TB * decreased Production of all adrenocortical hormones * Other causes of hypoadrenalism * Secondary to pituitary disease (rare) * ‘Iatrogenic’ * _patients on high dose, long term steroid Rx, which is suddenly stopped at a time of stress_

Question 29

What are the clinical features of Addison's disease?

Answer 29

* Malaise, weakness, anorexia, weight loss * Increased skin pigmentation: * knuckles, palmar creases, around / inside the mouth, * pressure areas, scars * Hypotension / postural hypotension * Hypoglycaemia

Question 30

What is Autoimmune Polyendocrine Syndrome? - Types

Answer 30

- having multiple autoimmune endocrine dysfunctions * **Type 1** * rare, onset in infancy * AIRE gene (Ar) * common phenotype: * Addison's disease * Hypoparathyroidism * Candidiasis * **Type 2** * **​**more common- infancy to adulthood * polygenic cause * common phenotype * Addison's disease * Type 1 diabetes * Autoimmune thyroid disease

Question 31

What autoimmune conditions might occur together in APS?

Answer 31

* Type 1 diabetes * Autoimmune thyroid disease (hypo- or hyper-) * Also gestational / post-partum thyroiditis * Coeliac disease * Addison’s disease * Pernicious anaemia * Alopecia * Vitiligo * Hepatitis * Premature ovarian failure * Myasthenia gravis

Question 32

What are the clinical implications of those with Autoimmune Polyendocrine Syndromes? - actions to take

Answer 32

* High index of suspicion for additional autoimmune endocrine disorders * T1 DM with fatigue, weight loss & hypos: * ? Addisons disease * T1 DM with non-specific GI symptoms / diarrhoea: * ? Coeliac disease * Consider screening in patients with T1 DM and/or Addison’s disease * Coeliac screen * Thyroid function tests (esp in pregnancy / post-partum)

Question 33

How is the HPAA assessed?

Answer 33

* Basal function tests through * Blood * cortisol * ACTH * timing * Urine * cortisol * 24 hr collection * Saliva * cortisol * timing * Dynamic Tests * stimulated * ACTH * CRH * stress - hypoglycaemia * suppressed * Dexamethasone: synthetic glucocorticoid

Question 34

How would too much cortisol be recognised through HPAA assessments?

Answer 34

* 24 hour urinary free cortisol * ‘AREA UNDER THE CURVE’ * Midnight cortisol (blood / saliva) * ‘TROUGH’ * 9 a.m. ACTH (with paired cortisol) * PITUITARY / ADRENAL / ECTOPIC? * NEGATIVE FEEDBACK AT PITUITARY * DEXAMETHASONE SUPPRESSION * Sensitivity to GC negative feedback at pituitary

Question 35

How would too little cortisol be recognised through HPAA assessments?

Answer 35

* 9 a.m. cortisol * ‘PEAK’ * SynACTHen test * Adrenal response to ACTH * Trophic effect ACTH on adrenals * Insulin tolerance test * Response to hypoglycaemic stress * Can be dangerous! * U & E (¯Na, ­K) in Addison’s disease * Due to mineralocorticoid deficiency * Can measure renin & aldosterone concentrations * decreased blood glucose

Question 36

What golden rules should be followed when assessing the HPAA?

Answer 36

1. Never start investigating a patient for an endocrine condition unless their symptoms & signs suggest they may have it! * Risk of false-positive results 2. Never image any endocrine gland until you have established the diagnosis biochemically! * Risk of discovering ‘incidentalomas’

Question 37

What imaging should be carried out when assessing the HPAA?

Answer 37

* after confirming Cushing's syndrome, consider * CXR * MRI pituitary * CT adrenal * Rarely image Addison's disease patients unless concerned about TB/ metastatic cancer

Question 38

What is the medical management for Cushing's syndrome?

Answer 38

* Surgical (depending on the cause) * Transsphenoidal adenectomy * Adrenalectomy * Pituitary radiatherapy * ¹³¹I

Question 39

What is the medical management of Addison's disease?

Answer 39

* Glucocorticoid replacement therapy * usually, *hydrocortisone* (sometimes *prednisolone*) * needs to be increased to cover 'stresses' (intercurrent illnesses like flu) * recommendations may vary for operations and post-op period * Mineralocorticoid replacement therapy for those with primary adrenal insufficiency * *fludrocortisone* * additional hormone replacement therapy for those with secondary adrenal insufficiency * patients need IV/IM steroid if unable to do so orally * vomiting/ NBM

Question 40

What is the effect of long-term high dose steroid treatment on patients?

Answer 40

* endongenous suppression of adrenal function * They may not mount an adequate ‘stress response’. * Their steroid treatment should not be stopped suddenly. * If they need a major procedure / an operation, they require increased steroid cover as described. * They should be given a ‘Steroid Treatment Card’ to remind them (& their doctors) about this.