ERS13 The Treatment Of Pituitary Disorder Flashcards
Hypothalamic control on Pituitary
- Releasing / Inhibiting factors
2. Tuberoinfundibular dopaminergic pathway
Hypothalamic hormone use
- Diagnostic tests
2. Stimulate pituitary secretion (if hypopituitarism is due to Hypothalamic defect)
Long + Short negative feedback pathway
Long: Hormones from peripheral gland —> Hypothalamus / Anterior pituitary
Short: Anterior pituitary —> Hypothalamus
Hypopituitarism
Causes:
- Ischemia
- Radiation
- Inflammation
- Non-functioning neoplasm of pituitary gland (unable to produce hormone but compressive —> ↓ blood flow to pituitary)
One / more hormones affected
More common:
- ↓ GH
- ↓ Gonadotropin
- ↓ ACTH
Very rare:
- ↓ Thyrotropin
- ↓ Prolactin
Effects of growth hormone
GH (act on hepatocytes):
- ↑ Somatomedin (IGF-1) production by liver
Somatomedins (from liver):
- ↑ SO4 uptake into cartilage (chondroitin sulphate)
- ↑ Bone growth by ↑ Thymidine incorporation into DNA + ↑ Uridine incorporation into RNA
GH + Somatomedins (both act on peripheral tissue):
- ***↑ Protein synthesis + uptake of a.a. into cells
- Initially: Insulin-like effect —> ↑ glucose uptake + ↓ lipolysis
- ***After a few hours: Insulin antagonistic effect —> ↓ glucose uptake + ↑ lipolysis
Growth hormone deficiency (Hypopituitarism)
Pituitary dwarfism
Treatment: ***Somatropin (replacement therapy: synthetic growth hormone)
SE:
1. **Hypothyroidism (GH ↑ conversion of T4 to T3)
2. **Impaired glucose tolerance (∵ antagonise Insulin effect)
3. ***Edema
—> Peripheral edema (activation of Na channel in collecting duct —> Na retention)
—> Papilloedema —> Visual changes
—> Intracranial hypertension —> Headache
Effects of Gonadotropins
Female:
FSH:
- **Development of Graffian follicles into Ovum
- Stimulate Graffian follicles to secrete **Estrogen
—> **Proliferative phase of endometrium
—> **Secondary sexual characteristics
LH:
- **Ovulation
- Remaining follicle: Corpus luteum —> secrete **Progesterone
—> ***Secretory phase of endometrium (wall develop blood vessels, glands) for implantation
Male:
FSH:
- ↑ Spermatogenesis
LH:
- Stimulate testes to secrete **Testosterone
—> **Secondary sexual characteristics
Gonadotropin deficiency (Hypopituitarism)
Women:
- Amenorrhea
- Regression of secondary sexual characteristics
- Infertility
Men:
- Impotence
- Testicular atrophy
- Regression of secondary sexual characteristics
- ↓ Spermatogenesis —> Infertility
Treatment of Gonadotropin deficiency
Replacement therapy
FSH:
- ***Follitropin α/β (recombinant FSH)
- Human menopausal gonadotropin (HMG) (contain both LH and FSH, from urine of postmenopausal women)
LH:
- ***Lutropin α (recombinant LH)
- Human chorionic gonadotropin (HCG) (structurally different from LH but same action, secreted by placenta, obtained from urine of pregnant women)
- Choriogonadotropin α (recombinant HCG)
FSH (Follitropin α/β, HMG) must be used with LH (Lutropin α, HCG, Choriogonadotropin α)
—> permit ovulation + implantation in women
—> permit testosterone production in men
SE:
FSH:
1. **Ovarian hyperstimulation syndrome
- Ovarian enlargement —> burst in blood vessels —> 2. **Hemoperitoneum
- Ascites (water leak out in blood vessels)
- Hydrothorax —> difficult to breathe
- Hypovolemia —> electrolyte imbalance + platelet closer together —> 3. **Arterial thromboembolism
4. **Gynaecomastia (FSH, LH stimulate Aromatase (skin, fat, muscle) —> convert Testosterone to Estrogen —> breast enlargement)
5. Multiple birth (~20%, ∵ >1 mature ovum released)
6. Fever
LH:
- Headache
- Depression
- Edema
- Gynaecomastia
- ***Precocious puberty (∵ ↑ Testosterone)
***Effects of ACTH
- Stimulates adrenal cortex
- ↑ Corticosteroids (Cortisol + Aldosterone (minor)) synthesis and release
(Majority of Aldosterone secreted by RAAS system)
**Cortisol (Glucocorticoid)
- ↓ **Glucose uptake and utilisation
- ↑ Gluconeogenesis in liver
—> ↑ blood glucose level —> Insulin secretion
- ↑ Liver glycogen stores (insulin effect ∵ triggered by ↑ blood glucose)
- ↑ **Protein catabolism
- ↑ **Lipolysis
- Maintenance of CVS function by ***potentiation of E + NE effects
Aldosterone (Mineralocorticoid)
- ↑ Na reabsorption + ↑ K / H secretion in Distal tubule
ACTH deficiency (Hypopituitarism)
Hypoadrenalism (low Cortisol):
- Hypoglycaemia
- Hypotension (∵ ↓ effects of E/NE —> ↓ CO)
- Tiredness, Dizziness (∵ ↓ effects of E/NE —> ↓ CO)
- Intolerance to stress / infection (∵ ↓ effects of E/NE —> ↓ CO —> ↓ energy to overcome stress)
Treatment of ACTH deficiency
ACTH deficiency (Hypopituitarism):
- patient can still produce Aldosterone (via RAAS system)
- only Cortisol is affected
—> Use Corticosteroid with ONLY Glucocorticoid effect is good enough
Addison’s disease (Adrenal insufficiency):
- BOTH Aldosterone + Cortisol affected
—> Use Corticosteroid with BOTH Glucocorticoid + Mineralocorticoid effect
—> e.g. Hydrocortisone + Fludrocortisone (high mineralocorticoid activity)
Choice of Corticosteroid
ALL Corticosteroid have 3 effects:
- Glucocorticoid effect
- Mineralocorticoid effect (no need to consider for ACTH replacement therapy)
- Anti-inflammatory / Immunosuppressive effect
ACTH replacement:
- Hydrocortisone (synthetic Cortisol)
- adequate Glucocorticoid effect with minimal Anti-inflammatory / Immunosuppressive effects - Cortisone
- weak Glucocorticoid effect initially —> converted to Hydrocortisone in body
Prednisolone, Methylprednisolone, Triamcinolone, Dexamethasone, Betamethasone, Fludrocortisone (also high Mineralocorticoid activity):
- high Glucocorticoid effect BUT also high Anti-inflammatory / Immunosuppressive effects
—> unwanted side effects (↑ infection risk)
MOA:
Steroid cross cell membrane
—> bind to Intracellular receptor
—> Steroid-receptor complexes in nucleus then bind to Chromatin
—> Steroid-receptor-chromatin complex stimulate mRNA + protein production
—> produce characteristics action of hormone (effects see Effects of ACTH)
SE: ***Iatrogenic Cushing’s syndrome 1. Muscle wasting 2. Redistribution of fat —> Moon face —> Buffalo hump —> ↑ Abdominal fat —> Thin arm and legs —> Thinning of skin 3. Hyperglycaemia 4. Hypertension (potentiate E, NE effects) 5. Growth suppression in children (inhibit effects of GH) 6. Osteoporosis (↓ Ca absorption + ↑ Ca excretion + inhibition of vitamin D activity in osteoblasts) 7. Susceptibility to infection (high dose) 8. Peptic ulcer (∵ infection) 9. Psychological disturbances 10. Cataracts
Hyperpituitarism
Causes:
- Pituitary adenoma (actively producing hormone)
- Drugs (e.g. Haloperidol —> D2 blocker —> ↓ inhibitory effect on pituitary)
One / more hormones affected
More common:
- ↑ GH
- ↑ Prolactin
- ↑ ACTH
Very rare:
- ↑ Thyrotropin
- ↑ Gonadotropin
Effects of Prolactin
- Lactation
- Inhibitory effects on Hypothalamus (↓ GnRH secretion)
—> ↓ Gonadotropin
—> lack of ovulation
—> protect premature pregnancy in lactating women
Treatment of Prolactin deficiency
No available preparation
Hypersecretion of Prolactin (Hyperpituitarism)
Hyperprolactinaemia
- Galactorrhoea
- Hypogonadism (∵ ↓ GnRH)
- Amenorrhea (∵ ↓ GnRH)
Treatment:
Dopamine agonists (cannot give Dopamine ∵ cannot pass through BBB) (also used in Acromegaly, Parkinson’s)
- **Bromocriptine
- **Cabergoline (long t1/2 + higher selectivity for dopamine receptor)
MOA:
1. Stimulate D2 receptors on Anterior pituitary
—> Inhibit Anterior pituitary
—> ↓ Prolactin
2. Cause significant reduction in size of Prolactin-secreting adenomas
SE:
- ***Postural hypotension (∵ Dopamine cause vasodilation)
- ***N+V (∵ stimulate Dopamine receptor in CTZ —> induce vomiting)
- ***Constipation (∵ stimulate Dopamine receptor in GI tract —> ↓ peristalsis)
- Dizziness
Hypersecretion of Growth Hormone (Hyperpituitarism)
- Acromegaly (adult after puberty)
- enlargement of facial structure, hands, feet
- osteoarthritic vertebral changes (swollen joints) - Gigantism (childhood / puberty before closure of epiphyses)
- very tall
- exaggerated skeletal growth
- enlargement of facial structure, hands, feet
Treatment of Acromegaly / Gigantism
- Octreotide
- longer acting analogue of Somatostatin with less hyperglycaemic effect (cannot used Somatostatin ∵ quickly metabolised)
- also ↓ tumour size in Pituitary adenoma - Lanreotide
- even longer acting analogue of Somatostatin
- also ↓ tumour size in Pituitary adenoma
MOA:
- ***Somatostatin analogue: Inhibit GH release from Anterior pituitary
- Reduce tumour size in minority of patients
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 —> precipitation of bile salt)
- **Impaired glucose tolerance (∵ **Somatostatin inhibit insulin secretion from pancreas)
- Pegvisomant
- GH receptor antagonists
MOA:
Block GH receptor
—> Interfere with GH signal transduction + Somatomedins production from liver
SE:
- ↑ liver enzymes (AST, ALT) —> Hepatotoxicity? Hepatitis? (unknown long term effect)
- nausea + diarrhoea
- Dopamine agonists
- Bromocriptine, Cabergoline
- 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
Hypersecretion of ACTH (Hyperpituitarism)
Cushing’s disease (Too much Cortisol + Aldosterone)
Treatment:
- Metyrapone
- inhibit 11-β-hydroxylase (required for synthesis of Corticosteroid) - Trilostane
- Inhibit 3-β-dehydrogenase (required for synthesis of Corticosteroid)
SE:
- Hypotension (∵ ↓ Cortisol —> ↓ effects of E/NE —> ↓ CO)
- N+V
- Headache, dizziness
- Rash
Effects of ADH
↑ Plasma osmolarity (e.g. dehydration) / ↓ Circulating blood volume (e.g. haemorrhage) / ↓ BP (e.g. heart failure)
—> Stimulate Posterior pituitary
—> secrete ADH
—> act on Distal tubule + Collecting duct
—> V2R (+ V1R —> vascular smooth muscle —> **Vasoconstriction)
—> ↑ cAMP
—> **AQP2 trafficking + insertion on **apical membrane (AQP3, 4 constitutively expressed)
—> **↑ water reabsorption
Impaired secretion of ADH
Diabetes insipidus (tasteless urine) - continuous production of large amount of hypotonic urine
Treatment:
Replacement therapy:
1. Vasopressin (synthetic, identical to ADH)
2. **Desmopressin
- analog of vasopressin
- longer acting
- less vasopressor effect (∵ more **V2 selective)
SE:
1. **Fluid retention
2. **Dilutional hyponatraemia
3. Headache
4. Nausea
5. Allergy
6. ***Spasm of coronary artery —> Angina (Vasopressin: stimulate V1R —> vasoconstriction)
7. Abdominal + Uterine cramps (Vasopressin: stimulate V1R)
—> Desmopressin less selective for V1R —> less side effects
Summary
Treatment of hypopituitarism
- Pituitary dwarfism: Somatropin
- Gonadotropin deficiency: Gonadotropin
- FSH: Follitropin α/β, HMG
- LH: Lutropin α, HCG, Choriogonadotropin α - ACTH deficiency: Corticosteroid (Hydrocortisone, Cortisone)
Treatment of hyperpituitarism
- Hyperprolactinaemia: Dopamine agonists (Bromocriptine, Cabergoline)
- Acromegaly, Gigantism: Octreotide, Lanreotide, Pegvisomant, Dopamine agonists
- Cushing’s disease: Trilostane, Metyrapone
Treatment of posterior pituitary disorder
1. Diabetes insipidus: ADH (Vasopressin, Desmopressin)
