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Hypothalamus and Pituitary

Disorders of endocrine
physiology

Hormones of the hypothalamus


Hypothalamus Name

Thyrotrophin releasing hormone (TRH)


Function

Stimulates release of TSH and PRL

Gonadotrophin releasing hormone (GnRH) Stimulates release of FSH and LH


• Homeostasis
– Controls somatic function Growth hormone releasing hormone (GHRH) Stimulates release of GH

• Release of hormones from the pituitary Somatostatin (SMS) Inhibits release of GH other hormones

gland Corticotrophin releasing hormone (CRH) Stimulates release of ACTH

• Neurones and glandular tissue Dopamine Inhibits release of PRL

• Less than 1% brain Anti-diuretic hormone (ADH) Stimulates water reabsorption in the renal
tubule,muscle contraction, and increases plasma
osmolality

Oxytocin Stimulates milk let down, initiates contractions in


labour

Thyrotrophin Releasing Hormone


(TRH)
• Controls secretion of thyroid stimulating
hormone (TSH) from anterior pituitary.
• Regulated by plasma T4 concentration
– Also regulates TSH
– Investigated in patients with Secondary
hypogonadism due to pituitary malfunction

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Gonadotrophin releasing
TRH
hormone (GnRH)
• Diagnosis of pituitary disease • Decapeptide
– TRH 200mcg IV • Pulsatile release
– Serum TSH basal, 20 and 60 post TRH • Controls release of LH FSH
• Normal response is increase in TSH after 20 – Regulates oestrogens, progesterones and
mins to over 2mU/L androgens
– Falling to below this value after 60 mins • Investigated in hypogonadism
• No response in pituitary disease

Growth hormone releasing factor


GnRH
(GHRH)
• Analysis
– 50mcg GnRH IV • Regulates release of growth hormone (GH)
– Serum LH and FSH basal, 20 and 60 mins post • GH
GnRH – 21 kDa polypeptide
– Peak LH 10-40 IU/L – Metabolic effect is opposite of insulin
FSH 5-25 IU/L Female
– Regulated by GHRH and somastatin
2-14 IU/L Male
– Increases in response stress/exercise
– Ratio FSH:LH >1 in hypopituitarism
– Subnormal response in Cushing’s syndrome

GH GH
• Analysis • Acromegaly and
gigantism
– Measurement of circulating GH ineffective
– Adenomas of
– Insulin stress test anterior pituitary
• Most widely used test of HP axis integrity – V.high levels of GH
– Basal bloods – Gigantism occurs if
– IV insulin 0.15 u/kg adenoma present
– Bloods at 30, 45, 60 and 90 mins before puberty
– Cortisol and glucose – Acromegaly if occurs
– Response is dependant on HPA after puberty

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Cortisol Releasing Hormone
CRH
(CRH)
• 41 amino acids • Analysis
• Main component in controlling the pituitary – 100mcg synthetic CRH
adrenal axis – Basal bloods, 20 and 60 mins
• Released subject to negative feedback from – Peak cortisol at 60 mins
plasma free cortisol – No response in
• Cushing’s syndrome
• Controls secretion of ACTH from pituitary
• Adrenal tumours

Somatostatin
Dopamine
• Secreted by a broad range of tissues including
pituitary • Also produced in substantia nigra and
adrenal medulla
• Inhibits the release of several pituitary hormones
– Growth hormone
• Suppresses PRL production
– Thyroid stimulating hormone – Dopamine agonists used to treat prolactinomas
• Neurotransmitter
• Somatostatin and its synthetic analogues are used – Movement and emotion
clinically to treat a variety of neoplasms. It is also
used in to treat gigantism and acromegaly, due to – Parkinson'
s disease
its ability to inhibit growth hormone secretion

Disorders of the hypothalamus Disorders of the hypothalamus


• Aneurysms and vascular • Obesity • Non-structural dysfunction
malformations – Neuropeptide Y may – No obvious structural defect
– Compression be abnormally – After OCP
• Trauma synthesized in obesity
– Stress
– Head injuries • Old age • Lack of gonadotrophins
• Infiltration – Loss of hypothalamic
– Anorexia
– TB function
• Low GnRH
– Syphilis • due to degenerative
changes • Low prolactin – due to increased dopamine
– Abscesses
• Can delay menstruation for 2 yrs
– Meningitis

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Disorders of the hypothalamus
• Craniopharyngioma
Effect of hypothalamic disease
• Other tumours
• Cysts derived from developmental
process – Primary intracranial
• Benign but increase in size as a result of neoplasia may infiltrate
• Structural
cholesterol rich fluid accumulation hypothalamus – Expanding lesion may cause dysfunction
• Present during childhood/ adulthood
– Space occupying lesion – metastases – Occlusion of the foramen of Monro will result
– Hypothalamic hormone deficiency • Pituitary tumours in hydrocephalus
• Treatment
– May cause – Large space occupying lesions raise intracranial
– Adult
» Large craniopharyngiomas
hypothalamic pressure
best left untreated. compression
– Child – Lack of pituitary releasing hormones causes
» Surgical aspiration, excision of hypopituitarism
cyst capsule
» Irradiation to prevent
reoccurrence

Effect of hypothalamic disease Effect of hypothalmic disease


• Diabetes insipidus
– ADH deficiency – Diagnosis • Oversecretion of ADH
• Trauma • High plasma osmolality > 295 – Excess water retention – Treatment
• Autoimmunity mOsmol/L
• Tumours – Haemodilution • Fluid restriction
• Low urine osmolality
• Mild- asymptomatic • Hypertonic saline
– Inability to concentrate <300mOsmol/L
• Severe • Frusemide
urine
• Dehydration – Confusion • Induce tubular damage
– Treatment – Fits with demeclocycline
• Thirst
• Polyuria/ Nocturia • ADH analogue – Coma – Diagnosis
– O/N urine >1L – Nasal spray 20-40mcg thrice – Death • Low K low Na
daily
– V.expensive
• Low urea
– Nephrogenic cause • Low plasma osmolality
» chlorpropamide • High urine osmolality

Pituitary hormones TSH


• The Anterior Lobe
– Thyroid Stimulating Hormone (TSH)
• Thyrotrophin
– Follicle Stimulating Hormone (FSH) • 2 sub-units alpha and beta
– Both contain CHO moieties
– Luteinizing Hormone (LH)
– Prolactin (PRL) • Assayed via immunometric methods
– Growth Hormone (GH) • Normal basal level is 0.4- 5 mIU/L
– ACTH • Controlled by HPA via TRH
– Alpha Melanocyte-Stimulating Hormone ( -MSH) • Weak circadian rhythm
• The Posterior Lobe • Annual rhythm
– Antidiuretic Hormone (ADH) • Negative feedback control T3 T4
– Oxytocin

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TSH ACTH
• Activates adenylate cyclase activity in • Adrenocorticotrophic hormone
follicular cells of the thyroid • 39 aa 4.5 kDa
• Found in free plasma, ½ life of a few minutes
– Increases metabolic activity and size of the cell
• Pigmentary hormone
– Increases thyroid hormone release – Increased ACTH leads to brownish pigment of sun
• Thyroxine T3 exposed areas, mucous membranes, nipples and
genitals
• Triiodothyronine T4
• Acts on adrenal cortex
• Lack of TSH leads to hypothyroidism – Stimulates synthesis of cortisol and other
corticosteroids
• Also synthesized in brochal mucosa

ACTH and Cushings syndrome


• Discovered in 1932
• 4 main causes
– Iatrogenic (steroid
drugs)
– Adrenal
adenoma/carcinoma
– ACTH secreting
pituitary tumour
– ACTH secreting non-
pituitary tumour

Cushings disease Cushings disease


• Oversecretion of ACTH leads to • Diagnosis • Treatment
– Adrenal hyperplasia – Clinical features – Bromocriptine
– 24hr urine for cortisol – Drugs to decrease
– Increased plasma levels of cortisol and (normal <330nmol/day) adrenal cortisol
mineralocoticoids production
– Dexamethasone
– Increased pigmentation of the skin and mucous suppression – Surgery
membranes – ITT – Irradiation
– Local spatial effects – Skull x-ray
– Increase in plasma ACTH

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Disorders of the pituitary Thyroid gland
• Oversecretion • Undersecretion • Hypothalamus sets level of thyroid hormone,
• Adenomas – Lack of hypothalamic pituitary acts as a “thermostat” to maintain level
stimulus
– Benign tumours • Dopamine and cortisol may suppress TSH release
– Spatial effects – Trauma
– Irradiation • TSH induces synthesis and release of thyroid
– Erosion through sinus hormones
• CSF leakage
Lack of • Thyroxine T4
• Facial nerve compression
• Triiodothyronine T3
– Symptoms depend on GH = dwarfism in young people
secretory nature of tumour • Bound reversibly to plasma proteins
• GH- gigantism and TSH = hypothyroidism – TBG 70% T4, 80% T3
acromegaly
FSH/LH = loss of libido, – Albumin
• PRL – prolactinoma amenorrhea
• ACTH – Cushings syndrome – Free fraction correlates with thyroid status
ACTH = immunosupression,
malaise

Thyroid hormones
• Analysis
– Plasma TSH
• Immunometric assay
– T3 T4
• Labelled antibody methods
– Thyroid antibodies
• 10-20% population +ve for thyroid antibodies
• Inherited predisposition
• More common in women
• Linked to MHC genes on chromosome 6
• Enviromental trigger
– Virus
– Trauma

Hypothyroidism Hyperthyroidism
• Lack of thyroid hormones • Thyrotoxicosis • Diagnosis
– Primary = disease of thyroid • Diagnosis
itself – Low T3 T4 – Overactivity of the thyroid – Low TSH
– Secondary = lack of pituitary – TSH gland – Raised thyroid hormones
stimulation • Primary high – Increased metabolic rate – OCP can raise TBG
• Presentation • Secondary low
– Decreased metabolic rate – Weight loss • Treatment
– Feel cold • Treatment – Increased appetite
– Weight gain – Suppression of thyroid
– Thyroxine analogue – Anxious, irritable
– Coarse skin hormone synthesis
• levothyroxine
– Slow muscle relaxation – Dosage tailored to patient – Palpitations • carbimazole
– Children- growth failure – Blood levels monitored – Muscle weakness and – Radioactive iodine
– Neonates – irreversible brain monthly wasting
damage • Ablates thyroid tissue
– Surgical removal
• Very risky due to position

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Causes of thyroid disease Grave’s disease

• Autoimmune disorders
– Common cause
– Due to presence of anti-thyroid antibodies
– Can lead to hyper or hypothyroidism
• Hyperthyroidism e.g. Graves disease
– IgG bind and stimulate and stimulate adenylate cyclase
causing hypertrophy of thyroid tissue
• Hypothyroidism e.g. Hashimotos thyroiditis
– Thyroid enlargement
– Antibodies to thyroid hormones present

Causes of thyroid disease Adrenal hormones


• Iodine deficiency • Glucocorticoids
– Causes hypothyroidism • Mineralocorticoids
– Decreased thyroid hormones
– Increased TSH enlargement of the thyroid
• Sex steroids
• Neoplasms
– Adenomas seen in 4-8% PM
– Carcinoma 0.8%
– Present as nodular goitre

Glucocorticoids Glucocorticoid excess


• Function • Cushings syndrome
– High blood glucose
– Protein metabolism
– Salt and water retention
– Peripheral fat metabolism – Lowered immunity
– Suppression of inflammation – Increased fat accumulation in face and trunk
– Suppression of pituitary hormones – Low ACTH
– Depression, psychosis
– Carbohydrate metabolism
• Increase blood glucose by stimulation of glycolysis – Protein loss
and gluconeogenesis • Muscle wasting
• osteoporosis

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Glucocorticoid undersecretion Mineralocorticoid hormones
• Hypoglycaemia • Maintain Na, K and H ion balance
– Decreased gluconeogenesis • Involved in salt and water retention
• Undersecretion
• Peripheral fat and protein build up – Postural hypotension
• Loss of salt and water – Hyperkalemia and acidosis
• Malaise • Excess
– Salt and water retention
– Loss of potassium and hydrogen ions
– Hypertension
– Hypokalemic alkalosis

Addison'
s disease
• Hypocortisolism
• Less common than cushings
• Auto immune destruction
• Hereditary defects in enzymes required for
adrenal steroid production
– High serum testosterone
• Lack of all adrenal steroids