Endocrine JC041: I Keep On Bumping Into People On My Side: Pituitary Tumours, Hypopituitarism Flashcards
Presentations of Pituitary tumours
- Local symptoms
- ***Visual loss
- Non-specific headache - S/S of Pituitary hormone **hyper-secretion / **hypo-secretion
- Incidental findings on skull X-ray / CT / MRI
- Skull X-ray: destroyed anterior / posterior clinoid process, ***double floor sign (asymmetric enlargement of pituitary tumour)
Effects of pituitary tumours
Craniopharyngioma:
- ***Panhypopituitarism: delayed puberty, short stature
Acromegaly
- ↑ + non-suppressible serum **GH, ↑ serum **IGF1
- coarse facial features, large feet, ↑ heel pad, large spade-like hands
- ***OSA
Types of Pituitary tumours
- Pituitary adenoma (most common in adults)
- Craniopharyngioma (most common in children)
- Pituitary carcinoma (primary / secondary (lung / breast), ***very rare esp. primary)
Craniopharyngioma
- 50% calcification present
- 50% symptoms in childhood
- 25% symptoms in young adult (20-40)
Clinical features:
1. Hypopituitarism e.g. growth retardation
2. Stalk compression —> Diabetes insipidus (ADH (Vasopressin) deficiency)
3. **Chiasmal compression (common)
4. **Obstruction to 3rd ventricle may occur —> Obstructive hydrocephalus —> ↑ headache
***Pituitary adenoma
- 6-18% of all brain tumours
- unselected autopsy series: prevalence 12-22%, most common being ***Prolactinomas
- asymptomatic tumour tend to be picked up incidentally by CT / MRI for other reasons, others functional
Functioning adenomas (70-80%)
1. ***Prolactinoma (inhibit GnRH)
- Galactorrhoea-amenorrhoea (Female)
- Impotence (Male)
- ***Growth hormone producing tumour
- Acromegaly / Gigantism (before puberty) - ***ACTH producing tumours
- Cushing’s syndrome (Pituitary-dependent Cushing’s / Cushing’s disease) - Glycoprotein secreting tumours (TSH, FSH, LH, α / β subunits)
- Secondary hyperthyroidism (rare)
- Hypopituitarism / Pituitary mass / Visual loss
Non-functioning adenomas (20-30%)
- ***Hypopituitarism / Pituitary mass / Visual loss
***Other causes of Hyperprolactinaemia
Non-stressed prolactin usually <3x normal
Physiological cause:
1. **Pregnancy (Estrogen)
2. **Lactation
Pathological cause:
1. ***Lesions (e.g. Tumours) involving Hypothalamus / Pituitary stalk
- ***Estrogen-containing medications (e.g. Oral contraceptives) (∵ Estrogen —> priming effect on Lactotrophs)
-
**Drugs affecting central **dopaminergic regulation (causing ↓ Dopamine)
- Anti-psychotic drugs (e.g. Phenothiazine)
- Anti-emetics (e.g. Metoclopramide)
- α-methyldopa
- H2 antagonists - Idiopathic
Other cause:
1. ***Hypothyroidism
- ↓ T4 / TSH —> ↑ TRH (a Prolactin-releasing hormone)
- Renal failure
- ***impaired dopamine action
- ↓ prolactin clearance - Chest injury
- irritation of ***intercostal nerve —> carry afferent impulse for suckling reflex
Diagnosis of Pituitary tumours
GH producing tumours:
1. Screening
- ***Serum IGF-1 (produced by liver, integrated index of GH secretion) —> above normal for age / gender
- NOT Serum GH (∵ when taken randomly can be high in normal individuals depending on stress level)
- Confirmation
- **Non-suppressible serum GH during **OGTT —> Nadir >0.4 / 1 ng/ml
(Factors that stimulate GH secretion: - α-Adrenergic signals
- Amino acids
- Hypoglycaemia)
Prolactinoma:
1. ↑ Prolactin (usually ***>10x normal)
- Tumour shrinkage by >50% in 90% patients when treated with ***dopamine agonists (i.e. tumour carries dopamine receptors)
Radiological diagnosis
- ***MRI (modality of choice): provide better brain tissue differentiation
Treatment of Pituitary tumours
- Surgery
- Radiation therapy
- Medical treatment
- Surgery
Indications:
1. **All tumours causing pituitary hyper-function
2. **All macroadenomas
3. Prolactinoma (medical treatment may be preferred if patient ***responds to dopamine agonist)
Route:
1. Transphenoidal: route of choice
- Approach: Transnasal endoscopic / Sub-labial
- Transfrontal: very large ***suprasellar extension, severe chiasmal compression
Advantages:
- Rapid ↓ in secretion + tumour size
Disadvantages:
- Residual tumour / **Recurrence esp. if **large (i.e. macroadenoma)
- **Hypopituitarism
- **Diabetes insipidus (transient if edema / haematoma compression, permanent if severe injury —> monitor recovery)
- Acute complications:
—> Post-op bleeding
—> ***CSF rhinorrhoea (dura mater opening fails to close, open repair may be required, risk of meningitis)
- Radiation therapy
Types:
1. Conventional external irradiation
- >20 sessions in >5-6 weeks
- Radiosurgery / “Gamma knife” / “X-knife”
- not used if suprasellar extension to within ***5mm of optic chiasm (risk of optic nerve damage)
- much more focus on tumour, less damage to intervening brain tissue —> less risk of secondary tumours e.g. Meningioma, Gliomas
Advantage:
- Restrains tumour growth —> ***prevent recurrence of tumour
Disadvantage:
- **Delayed effect on secretion
- **Higher incidence of hypopituitarism (vs surgery)
Use:
- Useful **adjunct to surgery
- Primary therapy for **Macroprolactinomas (in patients who responded well to medical therapy but do not want to have lifelong medication —> radiation therapy then continue medication until secretion normalised)
- Medical treatment
- Effects usually reversible on drug withdrawal
- Adjunct to surgery / RT except for ***Prolactinomas (medical is the sole treatment (Dopamine agonists))
Dopamine agonists: Bromocriptine, Cabergoline
- Bromocriptine
- bd / tds - Cabergoline
- less SE
- less frequency dosing (longer acting: once / twice per week)
- more convenient
- may be more effective
- higher cost
SE:
- **Postural hypotension (∵ Dopamine cause vasodilation)
- **N+V (∵ stimulate Dopamine receptor in CTZ —> induce vomiting)
- ***Constipation (∵ stimulate Dopamine receptor in GI tract —> ↓ peristalsis)
Indications:
1. Prolactinoma
- >90% achieve normal Prolactin + ***↓ in tumour size
- Acromegaly
- IGF-1 normalised in **only 10%
- **no size reduction
- normal situation: D2 agonists stimulate GH secretion
- Acromegaly: D2 agonist cause ***paradoxical ↓ GH secretion (unknown mechanism)
- more effective in patients with pituitary tumours that secrete both Prolactin + GH - FSH-producing tumours
- lower FSH but ***no effect on tumour size (i.e. not very good)
Somatostatin analogs: Octreotide LAR, Lanreotide
- Synthetic ***Somatostatin Receptors (SSTR) Agonist
- Somatostatin: short acting (quickly metabolised by body), inhibit insulin
-
**Octreotide LAR
- longer acting analogue of Somatostatin with **less hyperglycaemic effect (cannot use Somatostatin ∵ quickly metabolised)
- also ↓ tumour size in Pituitary adenoma
- oral BD - ***Lanreotide
- even longer acting analogue of Somatostatin
- also ↓ tumour size in Pituitary adenoma
MOA:
- **Somatostatin analogue: **Inhibit GH release from Anterior pituitary
- Predominantly act on SSTR-2 (more expressed on **GH + **TSH-producing tumours)
—> effective in ↓ secretion of GH + TSH
—> ↓ size in 50% of patient
Use:
- Long acting analogs IM every 4-6 weeks
- **GH + **TSH-producing tumours
- Acromegaly: 60% achieve normal GH / IGF1
- Useful adjunct to surgery + RT
SE:
- GI disturbance: N+V, abdominal cramps, flatulence, steatorrhea (∵ Octreotide/Lanreotide inhibit secretion of GI peptide e.g. gastrin, secretin, motilin etc. —> important for digestion + GI movement)
- **Gallstones (∵ inhibition of gall bladder motility through inhibition of CCK —> precipitation of bile salt)
- **Impaired glucose tolerance (∵ ***Somatostatin inhibit insulin secretion from pancreas)
New drug:
- **Pasireotide LAR
—> higher affinity for SSTR-5
—> effective for **ACTH-producing tumours (more SSTR-5 expression)
—> more effective for some GH-producing tumours (more SSTR-5 expression)
—> ***hyperglycaemia common
GH receptor antagonist: Pegvisomant
***Pegvisomant
- Block GH receptor at Liver level —> normalised IGF1 level
- Daily injections
- Compliance problem
- Available only in some countries (not in HK), high cost
Effect:
- Normalise IGF1 in 90% in 12 months, 76% in long-term study
- No ↓ tumour size (Monitor for ↑ ∵ decreased -ve feedback from IGF1)
SE:
- ↑ Liver transaminase (5%)
Hypopituitarism: Causes
- Structural damage of Hypothalamus / Pituitary / Pituitary stalk
- Tumours (large pituitary / hypothalamic tumours)
- Trauma (surgery, RT, head injury (fracture of basal skull in midline))
- Infarction (post partum necrosis (Sheehan’s syndrome), **pituitary apoplexy)
- Infiltration (haemosiderosis / haemochromatosis, histiocytosis, **sarcoidosis)
- Infection (TB, syphilis, mycosis, toxoplasmosis (AIDS))
- Immunologic (lymphocytic hypophysitis (may be SE of immune check-point inhibitors (CTLA-4, PD-1), lymphocytic infiltration of pituitary stalk), isolated ACTH deficiency) - Functional disorders (Isolated / Multiple)
- Genetic (mutation of genes coding for transcription factors regulating development of pituitary)
—> Panhypopituitarism
—> **Isolated GH deficiency
—> Isolated LH / FSH deficiency (*Kallmann syndrome: may have anosmia)
- Reversible
—> Emotional deprivation (GH deficiency)
—> Anorexia nervosa (excessive weight loss —> LH / FSH +/- TSH deficiency)
Sheehan’s syndrome
Pathogenesis:
- All pregnant women’s pituitary ↑ size + vascularity
—> ***Acute BP ↓ (e.g. severe postpartum haemorrhage, septicaemia, amniotic fluid embolism)
—> Acute necrosis of pituitary
Symptoms:
- Failure of **Lactation
- Failure of **return of menses
- Anterior / Posterior pituitary hormone deficiency (e.g. ***Diabetes insipidus)
Pituitary apoplexy
**Acute necrosis of pituitary
- e.g. due to large pituitary tumour **outgrown blood supply
—> Ischaemia, Necrosis, Bleeding of pituitary
—> Acute pituitary failure (↓ ADH, **Cortisol, **T4)
Symptoms:
- Acute severe headache
- **CN palsies (cavernous sinus)
- If Lateral / Suprasellar extension —> **Acute shock —> ∵ Acute ACTH deficiency unmasked by severe headache
—> Cortisol insufficiency requiring replacement (which can predispose DI ∵ Cortisol ↑ renal perfusion —> further ↓ ADH release —> DI (may need Desmopressin))
—> ***Give Cortisol (most important) before T4 (may predispose Addisonian crisis if hypocortisolaemia not dealt with first ∵ T4 enhance hepatic metabolism of cortisol)
Haemosiderosis
- Fe from Thalassaemia major
-
**Predilection for **gonadotropin producing cells —> Hypogonadotrophic Hypogonadism
—> **Secondary amenorrhoea (Low FSH, LH)
—> **DM (Haemosiderosis affecting ***pancreas)
Practical considerations of Hypopituitarism
- Usually no Hypopituitarism if ***Microadenoma (<1 cm) (Macroadenoma: >1 cm (web))
- Often a ***complication of RT for H+N tumours such as NPC (up to 50%)
- May be hypothalamic in origin —> ↑ Prolactin (∵ **↓ Dopamine) + Diabetes insipidus often present (∵ **↓ ADH)
- ACTH deficiency
- Often **asymptomatic
- **Unmasked by stress (e.g. infection, surgery)
—> Addisonian crisis
—> ∴ GH deficiency / Gonadotrophin deficiency —> must also screen for ACTH deficiency
Hypogonadism
Causes:
1. Hypopituitarism
- Low Estrogen / Testosterone
- ***Normal/↓ FSH / LH
- Gonadal failure
- Low Estrogen / Testosterone
- ***↑ FSH / LH
- e.g. Turner’s syndrome (45XO), Klinefelter’s syndrome (47XXY)
Onset before puberty:
Female:
- ***Primary amenorrhoea
- Impaired breast development
Male:
- **Small testes, scrotum, penis
- ↓ Hair (facial, pubic, axillary, body)
- High-pitched voice
- ↓ Muscle mass and strength
- **Eunuchoidism proportion if no growth impairment (span > height, lower > upper segment ∵ delayed epiphyseal closure)
Onset after puberty:
Female: **Secondary amenorrhoea
Male:
- **↓ Libido
- Impotence
- ↓ Morning erection
- **Infertility
- ↓ Hair (e.g. ↓ shaving)
- Failure of scalp hair to recede
- **Testes soft, size normal / mild ↓
- ***External genitalia normal
GH / ACTH deficiency: Tests of Anterior Pituitary Function
-
**Insulin tolerance test (Gold standard)
- Hypoglycaemia —> Impaired **GH + ***Cortisol response
- CI if epilepsy / CAD (∵ hypoglycaemia can precipitate epileptic attack, MI, arrhythmia) - Alternative tests for Adult GH deficiency
- **Glucagon test
- **Macimorelin test (Oral non-peptide agonist of GH secretagogue receptor (Ghrelin receptor) —> stimulate GH secretion)
ACTH deficiency: Tests of Anterior Pituitary Function
**Short Synacthen test:
- **↓ Cortisol response to 1ug Synacthen + Normal/↓ basal ACTH level
Impaired adrenal response to acute Synacthen stimulation —> ∵ prolonged deprivation of tonic adrenal stimulation by ACTH
Synacthen: Synthetic ACTH
TSH deficiency: Tests of Anterior Pituitary Function
↓ Serum T4 + Normal/↓ TSH
***TRH test: rarely indicated in daily clinical practice
LH / FSH deficiency: Tests of Anterior Pituitary Function
- ↓ Serum Sex hormones + Normal/↓ FSH / LH
***LHRH test: if diagnosis uncertain / fertility induction being considered
Hyperprolactinaemia: Tests of Anterior Pituitary Function
↑ Basal ***Non-stressed prolactin level
Non-stressed:
- Blood obtained after needle inserted for 15-30 mins (after pain by venupuncture subsided ∵ pain can ↑ prolactin)
Treatment of Hypopituitarism
- GH deficiency
- ***GH replacement
- children +/- adults (timely GH replacement in children can result in normal adult height)
- daily SC
- weekly sustained release GH: phase 3 clinical trial, non-inferior to daily injections - Gonadotrophin deficiency
- **Testosterone replacement
- **Estrogen +/- Progestogen replacement (to protect uterus against unopposed estrogen action —> Endometrial hyperplasia / cancer)
- **Fertility induction: **Gonadotrophins
—> HMG / HCG (Human menopausal gonadotrophin: FSH + LH / Human chorionic gonadotrophin: LH)
—> Recombinant FSH / LH - TSH deficiency
- ***Thyroxine replacement - ACTH deficiency
- ***Cortisol replacement
Diabetes insipidus
Causes:
1. ADH / Vasopressin deficiency (Central)
2. Insensitivity to ADH (Nephrogenic)
Effect:
- Impaired ability to produce concentrated urine in respond to **↑ serum osmolality / **volume depletion (不能保存水分係身體)
Clinical presentation:
- **Polyuria (Copious quantity of dilute urine)
- **Polydipsia
- ***HyperNa (if inadequate fluid replacement)
Diagnosis:
- Inadequate ↑ in urine osmolality despite high serum osmolality basally / during ***Water deprivation test
Cranial DI:
- Lesions of hypothalamus / pituitary stalk / posterior pituitary
- Respond to ***DDAVP: Urine osmolality ↑ with Vasopressin
Nephrogenic DI:
- NO response to Vasopressin / DDAVP
- genetic / acquired (e.g. drug-induced by **Lithium carbonate)
—> **HyperCa, ***HypoK
Case:
- 40 yo F
- Oligomenorrhoea 1 year (interval changed from 28 days to 70-90 days)
Investigations:
- Serum PRL ↑↑ 1923 mU/L (<500)
- Estrogen ↓
- LH / FSH not ↑ (i.e. NOT gonadal failure)
- Normal fT4, TSH, 1ug Short Synacthen test
- Visual field normal
- No acromegaly / Cushingoid features
MRI pituitary:
- tumour 2.1 cm height
- left suprasellar extension encroaching on optic chiasm
Treatment:
- Bromocriptine: normalisation of PRL
- menstruation returned suggesting Gonadotrophin deficiency is resulted from **Hyperprolactinaemia —> defect in **GnRH secretion —> normal FSH / LH —> ↓ Estrogen
MRI pituitary 4 months after Bromocriptine:
- no tumour shrinkage
Diagnosis:
- Hyperprolactinaemia due to stalk compression by non-functioning pituitary macroadenoma (instead of Prolactinoma ∵ no shrinkage in size)
Transphenoidal surgery:
- tumour stained negative for all pituitary hormones
Post-op:
- Diabetes insipidus
- Insulin tolerance test: subnormal peak Cortisol + GH —> ACTH + GH deficiency
Treatment:
- Oral DDAVP + Cortisol 10mg om replacement
