Introduction

This tutorial is designed to aid your learning of the endocrine system and also as a useful revision tool. It should be an addition to your further reading, and not the only learning you do on this topic.

It should take you approximately 40 minutes to complete.

To navigate through the tutorial, use the arrows in the top or bottom right corners or the contents column on the left. There are questions throughout the tutorial for you to check your learning as you go.

Objectives

1. To help you revise the anatomy and embryology of the hypothalamus and pituitary glands.2. To cover the hormones released from theses glands and their action on other glands or organs in the body. 3. To use case studies and interactive questions to consolidate clinical learning of the different conditions associated with these glands.

Embryology and Anatomy

The hypothalamus and pituitary glands are both very closely related in terms of position and function. The following pages should be revision for you.

Embryology

Embryologically, the hypothalamus is part of the forebrain.

The pituitary is divided into two sections - the anterior pituitary and the posterior pituitary. These develop separately in the embryo.

The anterior pituitary comes from the ectoderm of the primitive mouth (Rathke's Pouch). It moves upwards to join the infundibulum from the hypothalamus. When its original blood supply is lost travels, it develops a new one from the hypothalamus. This blood supply is the only communication between the hypothalamus and the anterior pituitary.

Because the anterior pituitary moves upwards during development, there is a possibility of small clusters of epithelial cells being left behind along the path and these may develop into cysts or ectopic hormone-secreting tumours later in life.

The posterior pituitary develops from neuroectoderm and grows down from the hypothalamus. This allows neurosecretory cells to join the hypothalamus and the posterior pituitary, forming their only means of communication.

Anatomy

The hypothalamus lies underneath the thalamus, at the base of the forebrain. It is a link between the neurological and endocrine systems.

The pituitary gland is made up of two parts, the anterior and posterior pituitary. It sits in an indentation into the sphenoid bone called the sella tursica, covered over by the diaphragma sellae which is a thin piece of fibrous tissue.

The pituitary gland lies directly beneath the optic chiasm which means that any large tumours of the pituitary can press on the chiasm and cause visual disturbances (an important symptom to remember!)

The pituitary stalk (infundibulum) connects the posterior pituitary to the median eminence of the hypothalamus.

The anterior pituitary is divided into 3 parts:

1. Pars distalis (the main part of the gland)2. Pars intermedia (this lies between the anterior and posterior parts of the gland and consists of corticotroph cells)3. Pars tuberalis (this surrounds the infundibulum and contains mostly gonadotroph cells)

The blood supply to the hypothalamus is from the superior hypophyseal artery. The blood then travels via portal veins, through the median eminence, to the anterior pituitary. It drains to the cavernous sinuses.

The blood supply to the posterior pituitary is from the inferior hypophyseal arteries and it also drains to the cavernous sinus.

Connections between the Hypothalamus and Pituitary

The anterior pituitary is made up of secretory epithelial tissue and is attached to the hypothalamus by a portal venous blood supply. The hypothalamus releases hormones into these veins and they then stimulate or inhibit the pituitary tissue. When cells of the anterior pituitary are stimulated, they release their hormones into the systemic circulation.

The posterior pituitary is made of neuroendocrine tissue, so although it also derives a blood supply from the hypothalamus, this is not how it receives its instructions. Instead, neurosecretory cells run from the hypothalamus down to the posterior pituitary. The axon terminals are located next to blood sinusoids and release neurosecretory granules when the cells are stimulated. The cells of the posterior pituitary itself are glial cells that support the axons of cells that originate in the hypothalamus.

Negative Feedback

The endocrine system works on the basis of negative feedback. You should be comfortable understanding and reproducing diagrams like these.

                                                                                                                                

                                                              

                                                                                                                                

                                                              

Hormones of the Hypothalamus

Hormone Cells affected in the anterior pituitary

Effect

Growth hormone releasing hormone (GHRH)

Somatotrophs Increased GH release

Growth hormone inhibiting hormone (GHIH/somatostatin)

Somatotrophs and thryotrophs Decreased GH and TSH release

Corticotrophin releasing hormone (CRH)

Corticotrophs Increased ACTH release

Gonadotrophin releasing hormone (GRH)

Gonadotrophs Increased LH and FSH release

Thyrotrophin releasing hormone (TRH)

Thyrotrophs and lactotrophs Increased TSH and prolactin release

Prolactin releasing factors(PRF)

Lactotrophs Increased prolactin release

Dopamine (prolactin inhibiting hormone)

Lactotrophs Decreased prolactin release

Hormones of the Anterior Pituitary

Hormone Effect Stimulated By

Supressed by Produced By

Growth Hormone (GH)

Stimulates the liver to produce IGF-1 opposes the action of insulin

GHRH GHIH and IGF-1 Somatotrophs

Thyroid Stimulating Hormone (TSH)

Stimulates the thyroid gland to release thyroxine

TRH T3 Thyrotrophs

Adrenocorticotrophic Hormone (ACTH)

Stimulates the adrenal cortex to release glucocorticoids and androgens

CRH Glucocorticoids Corticotrophs

Luteinising Hormone (LH) and Follicle Stimulating Hormone (FSH)

Causes the release of sex steroids from reproductive organs

GnRH and sex steroids

Prolactin and sex steroids

Gonadotrophs

Prolactin Initiates lactation and promotes growth of mammary glands and reproductive organs

PRF and TRH Dopamine Lactotrophs

Melanocyte-Stimulating Hormone (MSH)

Stimulates melanin synthesis in melanocytes in the skin

– – Corticotrophs

Beta-Endorphin Not yet fully understood, but possibly involved in pain control

– – Corticotrophs

The first 6 hormones in the table are the main hormones from the anterior pituitary, so you should make sure you know these for your exams.

This mnemonic might help:

Those Pituitaries Are Fun Little Glands

Hormones of the Posterior Pituitary

Hormone Effect Produced By Stimulated By Suppressed By

Anti-diuretic Hormone (ADH)

Increases the permeability of the collecting ducts in the kidneys, causing greater reabsorption of water

Supraoptic vasopressinergic neurons

Raised osmolarity, low blood volume

Reduced osmolarity

Oxytocin Causes smooth muscle contraction of the uterus (leading to birth) or the mammary glands (leading to milk ejection)

Paraventricular oxytocinergic neurons

Stretch receptors in the nipple or cervix, oestrogen

Stress

Remember that anti-diuretic hormone (ADH) is also known as vasopressin, or sometimes as arginine vasopressin (AVP)

Disorders of the Hypothalamus and Pituitary

Presentation

Disorders relating to these two glands usually present with symptoms of a deficiency or excess of one or more of the hormones that they produce. So, if you know the hormones, where they come from and what effect they have, you should know enough to work out most diagnoses. The other symptoms that patients could present with are neurological, such as headaches and visual disturbances from tumours of these glands affecting surrounding structures. The first stage of working out a diagnosis is to work out which hormones are affected and whether there is an excess or a deficit. The next stage is to work out why the hormone has been affected. As with many conditions, you should think about a list of possibilities.

5 Main Causes

Idiopathic Invasion (i.e. tumours)Infarction (e.g. Sheehan's syndrome)Iatrogenic (surgery, radiotherapy or certain drugs)Injury (i.e. head trauma)

Very Rare Causes

Infection (e.g. tuberculosis)Infiltration (e.g. sarcoidosis)Inherited (e.g. congenital hormone deficiency)Immunological (e.g. lymphocytic hypophysitis)

You should certainly be aware of the 5 main causes in order to come up with a reasonable differential diagnosis.

Investigations

There are 3 types of investigations that can be done in these cases:

1. Basal Blood Tests 2. Dynamic Tests 3. Imaging

Hormones that are relatively constant in the blood, such as TSH, can be measured as a baseline test. This means the blood test can be taken at any time because the results of a healthy individual should always lie in a particular range. Other hormones that fluctuate (e.g. FSH and LH levels vary over a month, GH and ACTH vary over a day and also with stress) can be measured in this way as well, but consideration must be made for the time and situation when they were taken.

In cases where basal test results are unclear, it is better to perform dynamic tests. Dynamic tests are either suppression or stimulation tests. If a hormone is stimulated, but levels do not rise, then there must be a problem with the production of that hormone. If an inhibiting substance is given, but normal negative feedback does not occur, then there is likely to be a hormone-producing tumour causing the symptoms.

If a tumour is suspected, imaging is used to determine the location of the tumour and its suitability for surgical treatment. This is usually MRI imaging (on MRI, a micro adenoma is classified as more than 10mm, and a macro adenoma is less than 10mm).

Treatment

There are 3 main forms of treatment:

1. Replacement hormones For deficiency problems or when other treatments designed to reduce excess hormone output destroy too much glandular tissue

2. Surgery or radiotherapy For tumours

3. Drugs that inhibit hormone production When surgery or radiotherapy is not suitable

Acromegaly

Acromegaly is caused by hypersecretion of GH, usually due to a pituitary tumour.

In children, the condition is called gigantism. It is a rare condition (prevalence = 5 per million). The age of onset is usually between 30 and 50. The most common cause of GH hypersecretion is a functioning somatotroph ademona.The symptoms and signs in an adult are mostly caused by the growth of soft tissues and some bones.

Clinical Symptoms Clinical Signs

Enlarged hands and feetEnlarged skull circumferenceEnlarged liver, kidneys and heart (predisposes to cardiomyopathy)Coarse, thickened skin (leads to prominent nasolabial folds and supraorbital ridge)Large lower jaw, nose and tongueSpacing between the lower teethGreasy sweating and Temperature intoleranceMental disturbance and insomniaLoss of peripheral vision (compression of the optic chiasm by a tumour)Carpal Tunnel Syndrome

1 in 3 have hypertension (predisposes to ischaemic heart disease)1 in 10 are hypercalcaemic1 in 4 are glucose intolerance (increases risk of developing diabetes)Altered bone structure (predisposes to osteoarthritis)1 in 5 have hyperthyroidism

In children, the GH causes an increase in the growth of long bones. This results in the child being tall for their age. They may be of an average height when they reach adulthood because GH also causes the epiphyses to fuse at an earlier age. The main problem with gigantism is the risk of diabetes. The oral glucose tolerance test is the investigation of choice in making the diagnosis of acromegaly:

Glucose and GH are measured at 30 minute intervals for 150 minutes. Insulin is released in response to the glucose. In healthy people, insulin causes suppression of GH. However, if there is no suppression or if levels of GH rise, this is diagnostic of acromegaly.

Adenomas are surgically removed if possible. If not, external radiation or medical treatment are options. The drugs that can be used are somatostatin (GHIH) analogues – ocreotide or lanreotide.Follow ups are very important to monitor:

1. Growth Hormone Levels2. Glucose Tolerance3. Cardiovascular System Function4. Thyroid Hormone Levels5. Prolactin Hormone Levels6. Visual fields

Cushing's syndrome describes a chronic excess of glucocorticoids .This may be due to hypersecretion from the anterior pituitary or adrenal glands, excess steroid medication or ectopic ACTH production.

Cushing’s Syndrome and Cushing’s Disease

Clinical Symptoms Clinical Signs

Truncal obesitySupraclavicular fat padPurple abdominal striaeThin hair/male pattern baldnessDepression, confusion, psychosis, insomniaRound “moon” face (due to facial fat deposition)AcneHirsutism (coarse pigmented hair growth on the face, chest or abdomen)Thin, easily bruised skinWasting/weakness of skeletal muscle (leads to thin arms and legs)Menstrual cycle disturbances

Renal calculiPredisposition to infection (also means wounds heal more slowly)HypertensionPredisposition to congestive cardiac failureOsteoporosis, vertebral collapsePredisposition to glucose intolerance/diabetes

Cushing's disease specifically describes an adenoma of corticotrophic cells of the anterior pituitary. The symptoms are the same as for Cushing's syndrome, except the patient also has pigmented skin because the cells that make excess ACTH also make excess MSH.

The investigations of excess glucocorticoid:

A 24 hour urinary free cortisol test is often performed to determine that the patient’s symptoms are because of increased cortisol levels. Doing the test over 24 hours means that circadian rhythm does not affect the interpretation of the results. Normal levels of cortisol in the urine should be less than 280nmol/24hr.

The other screening test used is the Overnight Dexamethasone Suppression Test;

Plasma cortisol is measured, and then 1mg of oral dexamethasone (a synthetic glucocorticoid) is given at midnight. The plasma cortisol is measured again at 8am. This would suppress cortisol levels to less than 50nmol/L in a healthy subject. In patients with excess cortisol, levels will not be suppressed or suppressed very little.

Once you have determined that the patient has excess cortisol, you need to work out where the problem is. There are three main possibilities when thinking about a patient with Cushing’s syndrome.

1. Pituitary adenoma (Cushing’s Disease) producing excess ACTH2. Ectopic ACTH production from a tumour (often small cell lung cancer or carcinoid tumour)3. Adrenal adenoma or carcinoma producing excess cortisol

The first test necessary to distinguish between these causes is a plasma ACTH test;

Plasma ACTH – if the problem is with hypersecretion from the adrenal glands, the ACTH levels will be suppressed to undetectable amounts (because of negative feedback).

If the ACTH is normal or high, you need to distinguish between pituitary and ectopic ACTH. The first line test is a high-dose dexamethasone suppression test;

High-dose dexamethasone suppression test (2mg, 6 hourly for 48 hours) – if the patient has Cushing’s disease, this will cause at least partial depression of cortisol levels. This is because the exogenous cortisol will still have some negative feedback effect if the problem is pituitary-based. If there is no suppression at all at high levels, then the source must be ectopic, such as a small cell lung cancer because these will not have feedback receptors.

Having done these tests to determine the cause of excess cortisol or ACTH, imaging may be required to further investigate the adrenals or pituitary, or to look for a hormone-producing tumour.

These diseases have a mortality rate of 50% at 5 years, so effective treatment is very important.

Treatment options:

1. Pituitary adenomas can be treated with surgery.2. Iatrogenic causes are treated by removing the source if possible.3. Drug therapy using agents such as metyropone or aminoglutethimide to reduce levels of cortisol in the plasma. 4. Adrenal adenomas/carcinomas are treated with surgical resection, after preparatory treatment with metyropone to reduce the risks of surgery.

Medical therapy is also used as palliative treatment in cases where a malignancy is not resectable.

Hyperprolactinaemia

Hyperprolactinaemia is the most common hormone dysfunction of the pituitary. 50% of pituitary adenomas are prolactinomas.

Other causes of increased prolactin secretion are disinhibition by reducing local dopamine levels (e.g. from pituitary stalk compression) or by administration of a dopamine antagonist.

Clinical Symptoms Clinical Signs

Female Decreased libidoWeight gainAmenorrhoea (cessation of menstrual cycle)Galactorrhoea (inappropriate production of breast milk)Infertility

OsteoporosisNeurological signs (from pressure of pituitary tumour)

Male Reduced facial hairImpotenceGalactorrhoea

OsteoporosisNeurological signs (from pressure of pituitary tumour)

The investigations for hyperprolactinaemia are very simple:

A basal test is done between 9am and 4pm. If the levels are significantly raised, the pituitary fossa will be imaged, since the higher the level of prolactin, the more likely it is that the problem is a functioning adenoma.

Treatment is surgery if possible, but radiotherapy or drug treatment if not. The dopamine agonists given may be teratogenic so should not be given to a pregnant woman or a woman who is trying to get pregnant.

Hypopituitarism

Hypopituitarism has several causes:

1. Non-functioning pituitary adenomas2. Other tumours in surrounding tissues compressing the pituitary gland3. Infarction of the pituitary gland -e.g. Sheehan's Syndrome 4. Compression of the pituitary gland -i.e. Empty Sella Syndrome 5. Trauma6. Hypophysectomy (surgical removal of the pituitary) or radiotherapy

Sheehan’s SyndromeInfarction of the pituitary gland occurs if there is a large amount of blood loss during labour. The drop in blood pressure leads to infarction of the pituitary which is very sensitive to hypoxia in pregnancy.

Empty Sella Syndrome A condition in which cerebrospinal fluid gets into the sella turcica and compresses the pituitary gland. Approximately 50% of people have this condition without it becoming pathological. It may be due to a congenital defect in the diaphragma sella, pituitary surgery or radiation, pituitary infarction or a pituitary tumour.

Deficient Hormone Clinical Symptoms Clinical Signs

Corticotrophin DizzinessNauseaPostural hypotensionBreast atrophyWeight loss

Hyponatraemia

Gonadotrophin Oligomenorrhoea/amenorrhoeaDecreased libido

InfertilityOsteoporosis

Androgen Hair lossDecreased libidoErectile dysfunction

Hypogonadism

Growth Hormone Truncal obesityWeakness

AtherosclerosisDecreased cardiac outputOsteoporosis

Thyroid Hormones Weight gainDry skinConstipationLow mood

Investigations

Basal level tests are done for the following hormones:

Prolactin TSH (and TSH) LH FSH

The following hormones are tested with dynamic tests:

GH (insulin tolerance test) ACTH (insulin tolerance test or short synacthen test)

Insulin Tolerance Test:Insulin is giving intravenously to induce hypoglycaemia. GH (and cortisol) should rise in a normal person.

Short Synacthen Test:Synacthen is an ACTH analogue and as such, should induce a rise in cortisol levels in a healthy individual.

Treatment

The treatment is to remove any tumour if possible. If not, then the pituitary hormones must be replaced.

Hormone Replaced With

GH Subcutaneous replacement with human recombinant GH

ACTH Oral cortisol replacement

TSH Oral thyroxine

Oestrogen and Progesterone/Testosterone

Oral oestrogen and progesterone is given cyclically to females, oral or intramuscular testosterone is given to males

LH and FSH If male or female fertility is required, intramuscular human chorionic gonadotrophin, LH and FSH are given

This is a lifelong treatment.

Diabetes Insipidus

There are 2 types of diabetes insipidus;

1. Cranial DI (ADH release from the pituitary is deficient)2. Nephrogenic DI (ADH receptors in the kidney do not function properly)

Both result in the following symptoms: Clinical Symptoms

PolyuriaDilute urinePolydipsiaDehydration (if not drinking sufficient water)

Causes of Cranial DI Causes of Nephrogenic DI

Head InjuryHypophysectomyMetastasesPituitary TumourMeningitisVascular LesionSarcoidosisInheritedIdiopathic (usually self-limiting)

Low Potassium High CalciumDrugs (e.g. lithium)PyelonephritisHydronephritisInheritedPregnancy (rare as a primary cause)

Investigations

The first investigation needed is to determine whether there is a problem with ADH. This is done using a Water Deprivation Test;

The patient is deprived of food and water for a night and then for 8 hours the following day. Plasma and urine osmolality is monitored regularly. The patient's weight is also monitored (and the test is abandoned if more than 3% body weight is lost). If the urine osmolality remains low then the patient can be diagnosed with diabetes insipidus (this shows that the body cannot concentrate the urine in response to dehydration).

The second part of the test is to find out whether the problem is a lack of ADH (cranial DI) or insensitivity of the ADH receptors in the kidneys (nephrogenic DI). This is a suppression test called the Desmopressin Test;

This is done immediately after the water deprivation test so that the patient is still fasted and dehydrated. Desmopressin, an ADH analogue is given and the patient is given water to drink. The urine and plasma osmolality is measured 2 hours later. If the problem was cranial DI, then giving an analogue should return the osmolalities to normal. If it is a nephrogenic DI then the desmopressin will have no effect.

Treatment

The treatment for cranial diabetes insipidus is life-long treatment with desmopressin which is a long-acting ADH analogue. This is given intranasally.

An excess of ADH is called syndrome of inappropriate ADH secretion (SIADH). This is an important cause of hyponatraemia.

Clinical Symptoms Clinical Signs

ConfusionSymptomsNauseaMuscle Weakness

HypertensionCardiac FailureLow Serum Sodium

SIADH can be distinguished from other causes of hyponatraemia by the 4 following features:1. The patient is not dehydrated/no hypovolaemia2. No oedema3. Concentrated urine 4. No diuretic useTreatment is by treating the cause and restricting fluids.

Conclusion

The important points to take away from this tutorial:

1. Know what negative feedback is and be able to describe it. 2. Know the hormones released from the hypothalamus and pituitary.3. Understand the roles of these hormones.4. Know about the major diseases caused by deficiency and excess of these hormones.