PHILIPPA FALKNER, FOURTH YEAR MEDICAL STUDENT, ACADEMIC YEAR 2011 / 2012

Jonathan Pinkney MD FRCPProfessor of Medicine

Peninsula College of Medicine and DentistryHonorary Consultant Physician Diabetes and Endocrinology

Plymouth Hospitals NHS Trust

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I acknowledge Professor Pinkney for his support and advice in the preparation of this resource.

Introduction

This endocrinology resource is aimed at third and fourth year medical students in

order to help them prior to an endocrinology SSU (Diversity of Endocrinology) or the

‘non-specific symptoms’ pathway week in year four. It is also an educational booklet

to help with the AMK.

It concentrates on disorders of the anterior pituitary gland. Diabetes and Thyroid are

not covered within this booklet as they are taught in earlier years such as the

adolescent case unit in second year.

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Contents Page

Basic Principles of Endocrinology.....................................4-5

Pituitary gland & Pituitary adenomas....................................6

The main hyperfunctioning pituitary adenomas...................7

Non-functioning/non-secretory pituitary adenomas............8

Acromegaly.........................................................................9-11

Hyperprolactinaemia........................................................12-13

Cushing’s syndrome........................................................14-17

Hypopituitarism/Pituitary insufficiency..........................18-21

References..............................................................................12

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Basic Principles of EndocrinologyThe endocrine system is controlled by positive and negative feedback.

Positive feedback stimulates the release of hormones – generally this occurs when hormone levels are low

Negative feedback inhibits the release of hormones – generally this occurs then hormone levels are high

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Hypothalamic hormone Effect on anterior pituitary gland

Thyrotropin releasing hormone release of Thyroid Stimulating Hormone 5

HypothalamusCR

H

ACTH

Adrenal glands

Cortex:cortisolAldoste

roneDHEA

Medulla:Adrenaline, noradrenaline

GHRH

SS

TRH

DA/PIF

GNRH

Growth Hormone

TSH

Prolactin

FSH & LH

Mammary glandsMammar

y gland development & milk production

F: LH – ovary = ovulation & maintains corpus luteumFSH: -ovary = follicle growth & oestradiol & progesterone production

M: LH –testes= leydig cells – testoterone.FSH: -testes=sertoli cells spermatogenesis

Thyroid gland

T4 →active T3

Anterior pituitary glandLive

r (IGF-1)

Ovary

Testes

Stimulates growth of: Bone/soft tissue/muscle/ adipose tissue

(TRH) (TSH) and Prolactin (PRL)

Gonadotropin releasing hormone (GnRH)

release of Leuteinising Hormone (LH) and Follicle Stimulating Hormone (FSH)

Growth hormone releasing hormone (GHRH)

release of Growth Hormone (GH)

Somatostatin (SS) inhibition of GH

Corticotrophin releasing hormone (CRH)

release of AdrenoCorticotrophic Hormone (ACTH)

Dopamine (DA) / Prolactin Inhibiting Factor (PIF)

inhibition of PRL

Diagnostic TestsDirect measurement of hormone levels (non-dynamic tests) are used for: PRL, LH, FSH (and sex steroids), TSH (and free T4/T3)

Dynamic tests are mainly used for Cortisol and Growth Hormone measurements.

EXCESS HORMONE suspected = use a SUPPRESSION test

Hypersecretion of cortisol = dexamethasone suppression test Hypersecretion of GH = oral glucose tolerance test (OGTT)

DEFICIENCY suspected = use a STIMULATION test

Deficiency of Cortisol = Insulin stress test / short synACTHen test. Deficiency of GH = Insulin stress test / glucagon test.

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Pituitary GlandThe pituitary gland is divided into two lobes: Anterior and Posterior.

Anterior pituitary gland secretes:Posterior pituitary gland

secretes:

Growth Hormone (GH)

Gonadotrophins:Follicle-stimulating hormone (FSH)Luteinizing hormone (LH)

Prolactin (PRL)

Thyroid-stimulating hormone (TSH)

Adrenocorticotrophic hormone (ACTH)

Antidiuretic hormone (ADH)

Oxytocin (OXT

The pituitary gland sits in the sella turcica which is surrounded by bony walls at the sides and on the floor. The roof is made up of dura, above which lie the OPTIC CHIASM, hypothalamus and third ventricle. Laterally on each side are the cavernous sinus, internal carotid artery and cranial nerves III, IV, V1, V2 and VI.

Pituitary adenomasAdenoma = a benign epithelial tumour in which the cells form recognizable glandular structures or in which the cells are derived from glandular epithelium.

Pituitary adenomas have effects on the gland causing symptoms of hypOfunction, hypERfunction or mass/pressure effects (non-functioning/non-secretory). They are always benign.

Pituitary tumours (almost always benign adenomas) account for ~ 10% of intracranial tumours and of these, about:

35% are prolactinomas, and secrete prolactin 20% Growth Hormone (GH) producing 7% Adrenocorticotrophic (ACTH) producing 7% PRL &GH secreting ~1% secrete LH/FSH/TSH 30% secrete no obvious hormone in serum (but may immunostain for non-

secreted hormones).7

The main hypERfunctioning pituitary adenomas

Microadenoma ≤10 mm Macroadenoma >10 mm diameter

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Cushing’s disease

Acromegaly(gigantism in children)

GH ↑↑↑

Prolactinoma

Prolactin ↑↑↑

ACTH ↑↑↑

Non-functioning/Non-secretory pituitary adenomasThe commonest pituitary tumour does not secrete known active hormones and is called a ‘non-secretory’ adenoma. HYPOPITUITARISM and/or MASS EFFECTS are the main consequences, although modest HYPERPROLACTINAEMIA is also a common clue to a non-functioning adenoma.

Effects of non-functioning adenomas:

Mass effects:- Headache- Optic Chiasm compression causing visual field defects – bitemporal hemianopia:- Cranial Nerve palsies (due to pressure or invasion of the cavernous sinus): CN III, IV, V (V1 &V2), and VI (3rd nerve palsy = most common)- CSF rhinorrhoea, due to erosion through the floor of the sella turcica

Neuroendocrine effects:- Hypopituitarism (damage to other anterior pituitary cells or interruption of their control)- Hyperprolactinaemia (pituitary stalk disruption interrupting inhibitory effect of hypothalamic dopamine)- Disturbances of temperature, sleep, appetite.- Hypothalamic and/or posterior pituitary damage: Diabetes Insipidus

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Acromegaly ↑↑↑ Growth Hormone (GH)CAUSES

- Benign pituitary tumour (>99% of cases)- Ectopic GHRH secretion (rare)

CLINICAL PRESENTATION

Signs and symptoms of GH excess = excessive soft tissue growth – these present insidiously and go unnoticed for many years resulting in delayed diagnosis.

Musculoskeletal If condition presents before epiphyseal fusion = Increased stature >2m

gigantism Coarsening of facial features Protruding mandible (‘prognathism’), separation of teeth on lower jaw. Big tongue (‘macroglossia’) Enlarged forehead (‘frontal bossing’) Large hands and feet (carpal tunnel syndrome, ↑ring & shoe size) Osteoarthritis (from abnormal joint loading) Arthralgia Obstructive sleep apnoea

Cardiovascular Dilated cardiomyopathy → cardiomegaly → cardiac failure Hypertension

Metabolic Impaired glucose tolerance or diabetes (GH is a potent insulin antagonist)

Skin Irritating, thickened, greasy (increased sebum production) Excessive sweating (hyperhidrosis)

General Headaches Tiredness, often v.disabling & lowers quality of life/ability to work

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- Local pressure effects: (headache, bilateral temporal hemianopia- optic chiasm

compression, CN 3,4,6 palsy, pressure/invasion of cavernous sinus, Diabetes

Insipidus)

- Hypopituitarism - lack of: LH/FSH, Prolactin, TSH, ACTH

INVESTIGATIONS

- Random GH measurement is usually unhelpful – GH secretion is pulsatile &

increases with stress, exercise & hypoglycaemia. (Grossly elevated GH will confirm

a diagnosis)

- Serum IGF-1 (aka Somatomedin C) = screening test - GH acts through insulin-like

growth factor 1 (IGF-1) from the liver, levels correlate to GH over time therefore ↑

with excessive GH secretion (IGF-1 to GH is like HbA1c to blood glucose)

- OGTT – Oral Glucose Tolerance Test = gold standard – glucose inhibits GH

In normal individuals GH secretion is suppressed to undetectable levels with a rise in

glucose.

In acromegaly there is a failure to suppress GH release.

- MRI- Visual fields- Test the rest of the pituitary function for hypopituitarism (see hypopituitarism).

Ectopic Acromegaly – measure Growth Hormone Releasing Hormone (GHRH) levels

in the blood

In patients with a GH-secreting pituitary adenoma – GHRH levels are

low/undetectable, as negative feedback from excess GH suppresses GHRH release.

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MANAGEMENT

Aims to:

Relieve symptoms

Reduce tumour bulk

Normalise IGF-1 and GH

Prevent tumour re-growth

Medical management:

Somatostatin analogues e.g.octreotide (Sandostatin LAR given monthly IM)

and lanreotide (Somatuline LA) – somatostatin secreted by the hypothalamus

inhibits the release of GH from the pituitary gland

Pegvisomant – a GH receptor antagonist (GHRA). Daily s/c injection

Surgical management:

Trans-sphenoidal surgery – Treatment of choice for microadenomas/tumour

confined to sella. For macroadenomas – tumour debulking

Radiotherapy is usually reserved for those not responding to other treatment

modalities or as an adjunct to surgery and medical treatments for selected patients

Radiosurgery (gamma knife): seems to be superior to conventional radiotherapy but

is lacking appropriate LONG TERM COMPARATIVE studies

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Hyperprolactinaemia PRL>390mu/L

CAUSES

1. Excess production from pituitary – prolactinoma

2. Reduced dopamine levels – pituitary stalk damage (tumour, trauma, surgery)

3. Drugs (most common) - (i) Dopamine antagonists (e.g. antipsychotics, metoclopramide) (ii) other drugs: oestrogens, methyldopa.

4. Physiological: pregnancy, breast feeding, stress

PRL 1000-5000mU/L may result from any cause, but >5000mU/L = prolactinoma (macroadenomas with highest levels 10,000 – 100,000)

CLINICAL FEATURES

F: Irregular menses, infertility, galactorrhoea+↓libido, weight↑, dry vagina,

osteoporosis

M: Impotence, hypogonadism,↓facial hair, ↓libido, galactorrhoea, gynaecomastia

(often don’t report sexual dysfunction until treated)

Men & Post-menopausal women usually present due to pressure effects of the

tumour such as headaches and visual field defects.

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hypothalamusTRH Dopamine GnRH

PRL LH/FSH Pituitary

↑PRL suppresses the hypothalamic-pituitary-gonadal axis (FSH and LH) = 2° hypOgonadism – low testosterone & oestrogen = infertility, osteoporosis, reduced libido etc...

INVESTIGATIONS

The PRL level usually correlates well with the size of the tumour.

Basal PRL - non-stressful venepuncture - stress can cause ↑PRL

Pregnancy test (differential diagnosis of amenorrhoea)

TFTs – Thyrotropin releasing hormone (TRH) stimulates the release of PRL

and TSH from the pituitary (raised PRL may occur in hypothyroidism)

U&E (renal failure – a cause of raised PRL)

MRI pituitary if other causes are excluded

MANAGEMENT

Medical: 1st line = Dopamine agonists Cabergoline/Bromocriptine (dopamine

inhibits prolactin release) - often results in tumour shrinkage

Surgical: Trans-sphenoidal Surgery = if visual symptoms / pressure effects are

present which fail to respond quickly to medical treatment or if pregnancy is

contemplated ( ~25% of macroadenomas will expand during pregnancy).

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Cushing’s syndrome:↑cortisol (glucocorticoid)CAUSES

ACTH dependent (↔/↑ ACTH) ACTH stimulating cortisol secretion: Cushing’s disease (pituitary adenoma secreting ACTH), ectopic ACTH production (small cell lung cancer, carcinoid tumours)

ACTH independent (↓ ACTH due to increased cortisol and –ve feedback) excess cortisol not stimulated by excess ACTH : Exogenous glucocorticoids (steroid treatment = most common cause), adrenal tumours, adrenal nodular hyperplasia.

INVESTIGATIONS

24hr urinary free cortisol (∆ if >3x norm) GOLD STANDARD

Overnight 1mg dexamethasone SUPPRESSION test (measure cortisol before and @ 8am):

In normal individuals, steroid administration causes –ve feedback = ACTH ↓ & cortisol ↓

If Cushing’s syndrome = failure to suppress cortisol secretion, cortisol stays↑)

False +ve’s (‘pseudo-Cushing’s’) – in depression, obesity, alcohol excess, liver enzyme inducers

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SYMPTOMS OF EXCESS CORTISOL (example in tv series - Doc Martin, the new GP)

Central (truncal) obesity, wasting of extremities – ‘lemon on stick’, moon facies, supraclavicular fat pads, buffalo hump

Thinning of skin, facial plethora, easy bruising (ecchymosis), purple wide abdominal striae

Muscle weakness – proximal myopathy (can’t do squats)

Hypertension, atherosclerosis, congestive HF, oedema

Gonadal dysfunction & menstrual irregularities

Psychiatric disturbance (depression, emotional lability, irritability, sleep disturbance)

Osteopenia & Osteoporosis & #’s

Increased rate of infections & poor wound healing

Hirsutism - fine facial lanugo hair & acne, temporal scalp hair loss secondary to increased adrenal androgen secretion.

INVESTIGATIONS

The investigation of the presence and probable cause of Cushing’s syndrome is undertaken using a combination of biochemical and imaging techniques.

THERE ARE TWO STAGES TO INVESTIGATION:

1. DOES THE PATIENT ACTUALLY HAVE CUSHING’S SYNDROME?

This question can be confirmed by demonstrating raised urinary cortisol excretion, usually with three 24-hour collections of urine to measure URINARY FREE CORTISOL (UFC).

And then

Demonstration of failure of negative feedback by a separate LOW DOSE DEXAMETHAZONE SUPPRESSION TEST (protocols are available for 24 hour and overnight versions of the test).

IF THEY DO HAVE CUSHING’S SYNDROME - THEN...

2. WHAT IS THE LOCATION OF THE LESION? A KEY CONSIDERATION IS WHETHER THE CUSHING’S IS ACTH-dependent or independent (NB, 60% have PITUITARY CUSHING'S DISEASE, 10% have ECTOPIC ACTH secretion, and about 30% will have an ADRENAL cause)

THERE ARE TWO COMPONENTS TO THIS EVALUATION:

A) BIOCHEMICAL EVALUATION:

A variety of tests are available to make this distinction, and all have a variety of drawbacks and none are 100% sensitive and specific. It is usual, therefore, for the plan of investigation to be tailored to the individual's clinical circumstances. The main tests available are as follows:

i. Measure plasma ACTH : This is a very helpful initial test in identifying adrenal versus other causes of Cushing's syndrome.If ↓ = Adrenal tumour secreting cortisol is likely (-ve feedback causing ↓ ACTH)If ↔/↑ = dependent ACTH production, but from where? – Pituitary gland (Cushing’s disease) or ectopic production?

ii. Corticotrophin releasing hormone (CRH) test: - Give CRH IV – cortisol rises with Cushing’s disease but not with ectopic

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ACTH production. The test is most sensitive after prior administration of dexamethazone.

iii. CRH test with bilateral Inferior Petrosal Sinus (IPS) Sampling = gold standard to differentiate Cushing’s disease from an ectopic ACTH-producing tumour. Using venous sampling catheters placed under radiological control, the IPS are sampled bilaterally for ACTH release from pituitary basally and after stimulation with CRH. Samples from other venous sites will suggest a concentration gradient of ACTH if secreted from ectopic tumours elsewhere. This is the best test, but it is an invasive and time consuming test, and is therefore often undertaken selectively in patients if other less invasive tests have been inconclusive.

iv. High dose dexamethasone suppression test (high dose of dexamethasone over 48 hours). If partial suppression of cortisol, Cushing’s disease is more likely as pituitary retains some feedback control.If no suppression of cortisol, ectopic cortisol with loss of feedback control is possible. This test suffers from false positives and false negatives.

B) Radiographic localisation

The biochemical tests are used to direct the radiological investigations. An important underlying principle of investigating Cushing's syndrome is that a radiological result should never be used to infer a source of cortisol overproduction in the absence of biochemical confirmation.

If UFC is elevated, if plasma cortisol will not suppress <50nmol/l after dexamethasone, and ACTH is suppressed, the diagnosis is likely to be an adrenocortical tumour. A CT scan of the adrenal glands can then be requested straight away.

On the other hand, if tests suggest a pituitary cause, pituitary MRI with contrast injection is appropriate. If tests (or other clinical information) suggest a possible ectopic source of ACTH, then CT of thorax and abdomen may be the appropriate next steps. There may also be other clues to a pituitary tumour such as mass effects or varying degrees of hypopituitarism, and therefore a pituitary MRI scan may be expedited without needing to subject patients to all of the biochemical evaluative methods.

Other important radiological pitfalls to be noted are:(i) that pituitary adenomas may be too small for resolution by MRI(ii) that incidental non-functioning pituitary microadenomas and minor

radiologic abnormalities may occur in up to 10% of normal subjects, and(iii) incidental (usually non-functioning) adenomas occur in the adrenal glands

in a few percent of healthy people. Failure to obtain concordant biochemical and imaging data may lead to the wrong surgical treatment.

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MANAGEMENT – depends on cause

Iatrogenic cause – stop causative drug if possible.

Pituitary tumour (Cushing’s disease) – trans-sphenoidal surgery.

Radiotherapy may also be used to treat large adenomas that are not

fully resectable. Bilateral Adrenalectomy is a last resort for persisting

inoperable pituitary disease.

Ectopic ACTH production – resect surgically

Medications: Aminoglutethimide / metyrapone / ketoconazole (to ↓cortisol prior to

surgery / while radiation takes effect)

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HypOpituitarism / Pituitary insufficiency

Hypopituitarism = Diminished secretion of one or more of the anterior or posterior pituitary hormones

CAUSES

Causes are from 3 levels:

1. Hypothalamus: e.g. Craniopharyngioma, Kallman’s syndrome (hypogonadotrophic hypogonadism: isolated GnRH deficiency, often with anosmia & colourblindness), tumour, inflammation, infection (e.g. meningitis), ischaemia.

2. Pituitary stalk: Trauma, surgery, mass lesion (e.g. craniopharyngioma – tumour between pituitary and floor of 3rd ventricle), meningioma, carotid artery aneurysm.

3. Pituitary: Tumour (most common cause), irradiation, inflammation, infiltration (metastasis, amyloidosis, haemochromatosis), ischaemia (pituitary apoplexy – endocrine emergency resulting from haemorrhage usually into a pre-exisitng tumour; Sheehan’s syndrome – pituitary necrosis following post-partum haemorrhage)

If hypopituitarism is due to mass effect the hormones are affected in the following order: GH, LH, FSH, TSH, ACTH, PRL.

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CLINICAL FEATURES

Due to LACK OF HORMONE:

↓GH: ↓muscle strength, ↓exercise tolerance, central obesity, cardiovascular disease (most common cause of mortality), ↓BMD (osteoporosis), ↓well being – diminished libido & social isolation, dry wrinkly skin, ↓glucose.

↓Gonadotrophins (LH & FSH) ?secondary to pituitary defect, hypothalamic deficiency of LHRH, or functional abnormality such as hyperprolactinaemia:

F: oligo- / amenorrhoea, ↓fertility, ↓libido, osteoporosis, breast atrophy, dyspareunia

M: impotence, ↓libido, ↓muscle bulk, hypogonadism (↓hair all over, small testes,

↓ejaculate vol. ↓spermatogenesis). Often diagnosed retrospectively.

↓TSH: signs & symptoms as for hypothyroidism:

Symptoms: (activity ↓) tiredness, lethargy, depression, dislike of cold, weight gain, constipation, menorrhagia (↑PRL: if hypothyroid – more TRH secreted to increase thyroid hormones; TRH stimulates PRL), hoarse voice, poor cognition/dementia, myalgia.

Signs: bradycardia, dry skin&hair,slow relaxing reflexes, cerebellar ataxia, peripheral neuropathy, ‘toad-like face’.

↓ACTH – secondary adrenal insufficiency in this case (hypothalamic-pituitary disease): symptoms similar to primary adrenal insufficiency except mineralocorticoid (aldosterone) secretion is preserved in patients with pituitary disorders as its secretion is mainly regulated by the renin-angiotensin-aldosterone system (RAA). Also there is no skin hyperpigmentation as ACTH is decreased in 2° adrenal insufficiency, rather than increased in 1°adrenal insufficiency (where the adrenals are the site of disease).

Symptoms are more chronic: malaise, loss of energy, anorexia.

↓PRL: Rare – failure of lactation.

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INVESTIGATIONS for hypopituitarism

Measure serum levels where appropriate / STIMULATION TEST

Thyroid (TSH & T4), Gonadotrophin (LH & FSH) and Prolactin hormone secretion are adequately assessed by measuring basal serum levels to see if deficient.

Prolactin may be ↑ due to loss of dopamine from the hypothalamus (dopamine inhibits PRL release, so if it doesn’t reach the pituitary, prolactin levels are not inhibited so levels rise).

GH & Adrenal axes – IGF-1 can be used to roughly measure GH axis (screening

test) & Cortisol levels (↓) for adrenal axis.

INSULIN STRESS TEST / insulin tolerance test (ITT) (stimulation test) = More accurate test for GH and adrenal axes. Contraindicated in patients with epilepsy, heart disease and adrenal failure (in these patients do a syACTHen test):

INSULIN STRESS TEST= Give IV insulin to make patient hypoglycaemic (essentially – stressed). Their glucose must ↓ to <2.5mmol/L for test to be valid.

In normal individuals GH & cortisol levels should increase with hypoglycaemia (stress) to >20 mU/L and >550mmol/L respectively.

GH and cortisol do not increase above these levels if the patient is hypocortisolaemic (cortisol deficient) and Growth Hormone deficient.

(in obese patients (BMI >35) subtract 4µg/L from the GH cut off level.The test should be carried out in the morning (water only ingested from 22:00h the night before). Have 50% glucose & hydrocortisone to hand & IV access).

MRI to look for pituitary or hypothalamic lesion.

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MANAGEMENT

Hormone replacement & treatment of underlying cause

Secondary adrenal insufficiency (↓ACTH) – replace steroids = HYDROCORTISONE

↓TSH & therefore ↓T4 = THYROXINE (but TSH is invalid for monitoring, therefore T4 can be used alone for monitoring in this situation).

↓ gonadotrophins (LH & FSH) – hypogonadism (treat symptoms & to prevent osteoporosis) =

M: testosterone (3-monthly depot testosterone (Nebido) = most popular, IM injections every 3 wks, daily topical gels)

F: (premenopausal): Oestrogen: transdermal oestradiol patches, oestradiol implants or oral therapy. The oral contraceptive pill exceeds replacement requirement. NB WOMEN WITH INTACT UTERUS REQUIRE CYCLICAL OESTROGEN AND PROGESTERONE.

Gonadotrophin therapy = required to induce fertility in Males & Females.

↓GH = SOMATROPIN (recombinant human growth hormone). GH previously not replaced. GH deficiency is now recognised as a pathologic state in adults and children. GH deficiency impairs physical fitness, quality of life, promotes insulin resistance and dyslipidaemia.

Nice guidelines state:Treat GH deficiency with SOMATROPIN in adults >25yrs if the following criteria are fulfilled:

1. Severe GH deficiency = peak GH response of <9mU/L during ITT.2. Impaired quality of life (QoL), measured by a score of ≥11 on the QoL-

AGHDA (Quality of Life – Assessment of GH Deficiency in Adults) questionnaire.3. Already receiving treatment for other pituitary hormone deficiencies.

In adults <25 yrs achieving adult bone mass is an indication for treatment with somatropin if they fulfil criteria 1 but not 2.

Somatropin should be stopped after 9 months if QoL-AGHDA score does not improve by ≥7 points (indicates no positive effects).

Maximum GH secretion is during adolescence; then secretion falls by ~14% per decade, therefore replacement needs also decrease with age.

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References:Further reading:

Longmore M, Wilkinson I, Turmezi T, Cheung CK. Oxford handbook of clinical

medicine. Seventh Edition. Oxford University Press.

Camacho PM. Clinical Endocrinology & Metabolism, A colour handbook.

Manson Publishing, London.

McDermott MT. Endocrine Secrets. Fifth edition. Mosby Elsevier.

Holt R, Hanley N. Essential Endocrinology and Diabetes. Fifth edition.

Blackwell Publishing.

NICE guidelines: Growth hormone deficiency (adults) – Human growth

hormone. http://guidance.nice.org.uk/TA64 (accessed March 2012).

Jewels C, Tillett A. Endocrine and Reproductive Systems. One Stop Doc.

Hodder education, London.

Acknowledgements:

Pituitary Fossa image created by e-learning team.

Wikicommons for acromegaly images. Database of freely usable media files,

uncopyrighted. http://commons.wikimedia.org/wiki/Main_Page. (accessed

March 2012).

Anonymised photograph of a patient with Cushing’s syndrome. Obtained from

archived endocrinology lecture material. Permission gained from the lecturer.

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