PBL 4: Pituitary Diseases by

manarmech — 2022-05-02 19:02:10 UTC

manarmech — 2022-05-02 19:26:52 UTC

H & P control periphery hormone system
Anatomy

Hypothalamus (H) sited at the base of the brain around the third ventricle and above the pituitary stalk, which leads down to the pituitary itself\
pituitary (P): anterior pituitary (upgrowth of rathe's punch) + posterior pituitary (outpouching of third ventricle floor)
- above optic chasm (suprasellar extension)
- lateral vascular and nervous structures (lateral extension)

Physiology
Hypothalamus (H)

appetite, thirst, thermal regulation and sleeping/waking, circadian rhythm, menstrual cyclicity, and responses to stress, exercise and mood.
integrator of many neural and endocrine inputs to control the release of pituitary hormone-releasing factors
- H neurones secrete P hormone- releasing/inhibiting factors and hormones into the portal system which run down the stalk to P

Anterior Pituitary (AP)

AP hormones are under control by the H releasing hormones (except prolactin)
Pathological conditions interrupt the flow of hormones between H and P (--> deficiency hormones, oversecretion prolactin)
five major AP axes: the gonadotrophin axis, the growth axis, prolactin, the thyroid axis and the adrenal axis.

Posterior Pituitary (PP)

neuro-anatomically connected to specific H nuclei, and acts as a storage organ
Antidiuretic hormone (ADH, vasopressin) and oxytocin are synthesized in the supraoptic and paraventricular nuclei in the anterior H --> transported along the axon and stored in the PP

Hormones

gonadotropin releasing hormone -GnRH (H) --> follicle stimulating hormone-FSH + Luteinizing hormone- LH (AP) --> gonades
corticotropin-releasing hormone-CRH --> adrenocorticotrophic hormone-ACTH--> adrenal glands
thyroid releasing hormone-TRH (H)--> thyroid stimulating hormone-TSH (AP) --> thyroid (thyroxine-T4 + triiodothyronine-T3)
growth hormone releasing hormone-GHRH (H) --> growth hormone-GH (AP) --> long bones/muscles growth
prolactin inhibitory factors-PIF (H) --> continuously released, when release stops--> prolactin --> milk production
H and PP communicate through nerves pituitary stalk (signal to PP to release hormones)
- Antidiuretic hormone-ADH (PP)--> collecting duct kidney retain water
- oxytocin (PP) --> uterine contractions

H: GnRH, CRH, TRH, GRHR, PIF
AP: FSH/LH, ACTH, TSH, GH, Prolactin
PP: ADH, Oxytocin

tropic hormones: hormones that stimulate other endocrine glands (FLAT)
direct hormones: stimulate part of the body directly (PEG) (E: endorphins)

manarmech — 2022-05-02 19:27:23 UTC

manarmech — 2022-05-02 19:28:23 UTC

Pituitary Tumours

manarmech — 2022-05-02 19:56:05 UTC

= most common cause of pituitary disease,
majority are benign pituitary adenomas (monoclonal)
problems caused by:

local effects of a tumour
excess hormone secretion
the result of inadequate production of hormone by the remaining normal pituitary, i.e. hypopituitarism

manarmech — 2022-05-02 19:56:27 UTC

Investigation(TABLE 19.4^)

manarmech — 2022-05-02 20:12:12 UTC

Is there a tumour? check size + local anatomical effects

pressure/infiltration of:

visual pathways--> field defects, visual loss
cavernous sinus --> III, IV and VI cranial nerve lesions
bony structures and meninges around fossa --> headach
H centres--> altered appetite, obesity, thirst, somnolence/wakefulness or precocious puberty
ventricles --> interruption of cerebrospinal fluid (CSF) flow leading to hydrocephalus
sphenoid sinus with invasion--> CSF rhinorrhoea

Investigations

MRI (P)
- small lesions within the pituitary fossa consistent with small pituitary microadenomas. Such small lesions are sometimes detected during MRI of the head ‘pituitary incidentalomas’.
Visual fields
- plotted formally by automated computer perimetry or Goldmann perimetry, but clinical assessment by confrontation using a small red pin as target is also sensitive and valuable. Common defects are upper temporal quadrantanopia and bitemporal hemianopia

Hormonal excess
3 conditions caused by secretion from P adenomas that show positive immunostaining for the relevant hormone:

Prolactin excess (prolactinoma or hyperprolactinaemia):
GH excess (acromegaly or gigantism): somatotroph adenomas, usually ‘acidophil’, and sometimes due to specific G-protein mutations
excess ACTH secretion (Cushing’s disease and Nelson’s syndrome): corticotroph adenomas, usually ‘basophil’

Is there a deficiency of any hormone?

short stature in a child with a PT is likely to be due to GH deficiency
slow, lethargic adult with pale skin is likely to be deficient in TSH and/or ACTH.
Milder deficiencies may not be obvious, and require specific testing

Treatment

manarmech — 2022-05-02 20:13:50 UTC

Treatment depends on the type and size of tumour

Removal/control of tumour

Surgery
- trans-sphenoidal route
- Very large tumours are removed via the open transcranial route.
Radiotherapy
- when surgery is impracticable or incomplete, as it controls but rarely abolishes tumour mass.
Medical therapy
- somatostatin analogues and/or dopamine agonists sometimes causes shrinkage of specific types of tumour and if successful can be used as primary therapy

Reduction of excess hormone secretion

surgical removal/ medical treatment
- dopamine agonists for prolactinomas or somatostatin analogues for acromegaly, but ACTH secretion usually cannot be controlled by medical means. Growth hormone antagonists are also available for acromegaly

Replacement of hormone deficiencies

Differential Diagnosis

manarmech — 2022-05-02 20:14:28 UTC

pituitary adenomas most common mass of lesion of the pituitary (90%)
Other tumours

Craniopharyngioma
- cystic hypothalamic tumour, often calcified, arising from Rathke’s pouch
- often mimics an intrinsic pituitary lesion.
- most common pituitary tumour in children but may present at any age.
Uncommon tumours include meningiomas, gliomas, chondromas, germinomas and pinealomas.
- Primary pituitary carcinomas are very rare, but prolactin/ ACTH secreting tumours can present in an aggressive manner --> chemotherapy
Hypophysitis and other inflammatory masses
- pituitary-specific conditions
  - e.g. autoimmune hypophysitis, giant cell hypophysitis, postpartum hypophysitis)
- pituitary manifestations of more generalized disease processes (sarcoidosis, Langerhans’ cell histiocytosis, Wegener’s granulomatosis).
- These lesions may be associated with diabetes insipidus and/or an unusual pattern of hypopituitarism.
Other lesions
- Carotid artery aneurysms may masquerade as pituitary tumours and must be diagnosed before surgery.
- Cystic lesions may also present as a pituitary mass, including arach- noid and Rathke cleft cysts.

Pathophysiology

manarmech — 2022-05-03 23:00:50 UTC

Deficiency of H releasing hormones/ P trophic hormones can be selective or multiple
Multiple deficiencies: tumour growth/destructive lesions.
- progressive loss of AP function.
- GH and gonadotrophins are usually first affected.
- Hyperprolactinaemia, rather than prolactin deficiency, early because of loss of tonic inhibitory control by dopamine.
- TSH and ACTH are usually last to be affected.
Panhypopituitarism: deficiency of all AP hormones
- caused by P tumours, surgery or radiotherapy
- ADH and oxytocin affected only if H is involved by a H tumour or major suprasellar extension of a P lesion, or if there is an infiltrative/inflammatory process.
- PP deficiency is rare

manarmech — 2022-05-04 05:14:24 UTC

Clinical Features

manarmech — 2022-05-04 05:24:32 UTC

depend upon the extent H/P deficiencies
Secondary hypothyroidism and adrenal failure

tiredness and general malaise.

Hypothyroidism

weight gain, slowness of thought and action, dry skin and cold intolerance.

Hypoadrenalism

mild hypotension, hyponatraemia and ultimately cardiovascular collapse during severe intercurrent stressful illness

Gonadotrophin/ gonadal deficiencies

loss of libido, loss of secondary sexual hair, amenorrhoea and erectile dysfunction.

Hyperprolactinaemia

galactorrhoea and hypogonadism

GH deficiency

growth failure in children and impaired wellbeing in some adults

panhypopituitarism

pallor with hairlessness (‘alabaster skin’).

hypopituitarism syndromes:
Kallmann’s syndrome.

isolated gonado- trophin (GnRH) deficiency
mutations in the KAL1 gene
anosmia

Septo-optic dysplasia

rare congenital syndrome
mutations in the HESX1 gene
triad of midline forebrain abnormalities, optic nerve hypoplasia and hypopituitarism.

Sheehan’s syndrome

pituitary infarction following postpartum haemorrhage
rare in developed countries.

Pituitary apoplexy

enlarged pituitary tumour owing to infarction or haemorrhage
severe headache, double vision and sudden severe visual loss, sometimes acute lifethreatening hypopituitarism.
replacement of hormones and close monitoring of vision, although if there is a rapid deterioration in visual acuity and fields, surgical decompression of the optic chiasm may be necessary.

The ‘empty sella’ syndrome.

defect in the diaphragma and extension of the subarachnoid space (cisternal herniation)
may follow spontaneous infarction or regression of a pituitary tumour.
sella turcica is devoid of apparent pituitary tissue but pituitary function is usually normal

Investigation

manarmech — 2022-05-04 05:29:49 UTC

Each axis requires separate investigation

simple basal levels (e.g. free T4 for the thyroid axis)
stimulatory tests for the pituitary
tests of feedback for the hypothalamus

Assessment

basal 09:00 hours cortisol levels above 400 nmol/L= adequate reserve
levels below 100 nmol/L = inadequate stress response. In many cases basal levels are equivocal and a dynamic test is essential
the insulin tolerance test = ‘gold standard’
short ACTH stimulation test= routine test of hypothalamic-pituitary-adrenal status.

manarmech — 2022-05-04 05:30:39 UTC

Treatment

manarmech — 2022-05-04 05:35:00 UTC

Treatment

Steroid and thyroid hormones are essential for life

given as oral replacement drugs and levels are monitored by routine hormone assays.

Acromegaly and gigantism (GH excess)

manarmech — 2022-05-04 05:36:00 UTC

Acromegaly (adults) gigantism (children)
prognathism: protrusion jaw

Investigations
GH levels

exclude acromegaly if undetectable but a detectable value is non-diagnostic alone.
Normal adult levels are <0.5 μg/L except during stress or a ‘GH pulse’.

A glucose tolerance test

diagnostic if no suppression of GH
Acromegalics fail to suppress GH below 0.3 μg/L and some show a paradoxical rise (25% positive)

IGF-1 levels

almost always raised in acromegaly
<1 μg/L to exclude acromegaly if the diagnosis is clinically unlikely.

Visual field examination:

defects are common, e.g. bitemporal hemianopia.

MRI scan of pituitary

if above tests abnormal. reveal the pituitary adenoma.

Pituitary function:

partial or complete anterior hypopituitarism

Prolactin:

mild to moderate hyperprolactinaemia (30%)
the adenoma secretes both GH and prolactin

Management and treatment

manarmech — 2022-05-04 05:53:39 UTC

!hard to treat, constant monitoring of IGF-1!

Untreated acromegaly= reduced survival (CVD).
achieve a mean growth hormone level below 2.5 μg/L + normal IGF-1

Surgery.

Trans-sphenoidal surgery is the appropriate first-line therapy. It will result in clinical remission in a majority of cases (60–90%) with pituitary microadenoma, but in only 50% of those with macroadenoma.
high preoperative GH and IGF-1 levels = poor prognostic markers of surgical cure.

Pituitary radiotherapy.

External radiotherapy after pituitary surgery fails to normalize GH levels.
combined medical therapy
may take 10 years or more and is often associated with hypopituitarism

Medical therapy

three receptor targets for the treatment of acromegaly
- pituitary somatostatin receptors antag.
- dopamine (D2) receptors antag.
- growth hormone receptors antag.

Somatostatin receptor agonists.

Octreotide and lanreotide are synthetic analogues of somatostatin act on somatostatin receptor subtypes (SST2 and SST5), which are highly expressed in growth-hormone-secreting tumours.
short-term treatment, monthly depot injections
increased incidence of gallstones and expensive

Dopamine agonists.

act on D2 receptors given to shrink tumours prior to definitive therapy or to control symptoms/ GH secretion
most effective in mixed growth-hormone-producing (somatotroph) and prolactin-producing (mammotroph) tumours.
bromocriptine 10–60 mg daily or cabergoline 0.5 mg daily

Growth hormone antagonists

Pegvisomant (genetically modified analogue of GH) is a GH receptor antagonist binding to and preventing dimerization of the GH receptor.
does not lower growth hormone levels/reduce tumour size but normalize IGF-1 levels.
daily injection

Hyperprolactinaemia

manarmech — 2022-05-04 06:15:13 UTC

Prolactin

a large peptide secreted in the pituitary
inhibition: dopamine, increase: TRH
stimulates milk secretion
inhibits gonadal activity
- decreases GnRH pulsatility, blocks the action of LH on the ovary or testis, producing hypogonadism
Physiological hyperprolactinaemia occurs in pregnancy, lactation and severe stress, as well as during sleep and coitus.
>400 mU/L (400-600 mild can be normal)
Levels above 5000 mU/L = prolactin-secreting pituitary tumour

Causes

prolactinoma
cosecretion of prolactin in tumours causing acromegaly
stalk compression due to pituitary adenomas and other pituitary masses
polycystic ovary syndrome
primary hypothyroidism
‘idiopathic’ hyperprolactinaemia
(oestrogen therapy, renal/liver failure, postictal state and chest wall injury, dopamine antagonist drugs, opiates).

Clinical features

Galactorrhoea
Oligomenorrhoea or amenorrhoea
Decreased libido
Decreased potency in men
Subfertility
Symptoms or signs of oestrogen or androgen deficiency – in the long term osteoporosis may result, especially in women
Delayed or arrested puberty
Mild gynaecomastia is often seen in men due to the associated hypogonadism
headaches and/or visual field defects occur if there is a pituitary tumour

Investigations

Visual fields should be checked.
Primary hypothyroidism cause of hyperprolactinaemia.
Anterior pituitary function hypopituitarism or radiological evidence of a pituitary tumour
MRI of the pituitary suggestive pituitary tumour, prolactin is significantly elevated (> 1000 mU/L).
prolactin levels mass is a prolactinoma or a non-functioning pituitary tumour causing stalk-disconnection hyperprolactinaemia: > 5000 mU/Lmacroadenoma, > 2000 mU/L microadenoma

Treatment
avoid the long-term effects of oestrogen/testosterone deficiency

Medical treatment : dopamine agonist.

Cabergoline (500 μg once or twice a week is the best tolerated and longest-acting drug and is the first drug of choice.
Bromocriptine preferred if pregnancy is planned: initial doses should be small (e.g. 1 mg), taken with food and gradually increased to 2.5 mg two or three times daily. Side-effects include nausea and vomiting, dizziness and syncope, constipation and cold peripheries.
Quinagolide (75–150 μg once daily)

Macroadenomas any pituitary mass effects commonly resolve Microprolactinomas : hyperprolactinaemia will recur if treatment is stopped.

Trans-sphenoidal surgery

Radiotherapy

manarmech — 2022-05-04 06:15:29 UTC

physiology/control GH

manarmech — 2022-05-04 06:19:36 UTC

GH acts by binding to a specific receptor located mainly in the liver --> intracellular phosphorylation cascade (JAK/STAT pathway)
--> STAT proteins are translocated from the cytoplasm into the cell nucleus and cause GH-specific effects by binding to nuclear DNA.

IGF-1 (insulinelike GF) a somatomedin stimulates growth and its hepatic secretion is stimulated by a tissue-specific effect of GH on the liver. multiple IGF-binding proteins in plasma

can be measured clinically to improve assessment of GH status.
The metabolic actions of the system are:

Increasing collagen and protein synthesis
Promoting retention of calcium, phosphorus and nitrogen, necessary substrates for anabolism
Opposing the action of insulin

manarmech — 2022-05-04 06:20:11 UTC

earommelse — 2022-05-04 07:00:12 UTC

earommelse — 2022-05-04 07:00:30 UTC

mmtzclaros1 — 2022-05-04 10:46:01 UTC

target organs!