Endocrinology 1b – Adenohypophysial Hormones and Disorders Arising from their Excess Production

Anil Chopra1. Explain why suppression tests are useful in the diagnosis of excessive pituitary

hormone secretion. How do the GH responses to oral glucose differ in acromegalics and normal subjects?

2. List the techniques available to examine the hypothalamo-hypophysial axis for the presence of tumours, identifying the different sites where such a tumour might be present.

3. List the individual pituitary hormone excess states that can develop, and describe the principal consequences of each hypersecretory state.

4. Describe the principal signs and symptoms of growth hormone hypersecretion in the child and the adult.

5. Describe how gigantism and acromegaly are diagnosed.6. List the principal treatments available for the treatment of gigantism and acromegaly.7. State that prolactinoma is the most common tumour of the pituitary gland.8. Describe the principal signs and symptoms of hyperprolactinaemia.9. Describe how hyperprolactinaemia is diagnosed.10. List the principal treatments available for the treatment of hyperprolactinaemia.11. Explain why hyperthyroidism, precocious puberty and Cushing’s syndrome can be

primary, secondary (or even tertiary) disease states depending on the site of the lesion.12. Name two dopamine receptor agonists used in the treatment of

hyperprolactinaemia. Explain the unwanted effects of these drugs and note their main pharmacokinetic features.

13. Name a somatostatin analogue used in the treatment of growth hormone excess and describe its main biological actions and pharmacokinetic features. List the potential unwanted effects of these drugs and identify other conditions in which they may also be useful.

14. State that acromegaly may also be treated with dopamine receptor agonists.

HyperpituitarismHyperpituitarism is a condition caused by excess production of adenohypophysial hormones. They are usually caused by pituitary tumours but can also be ectopic (caused by non-endocrine tissue) in origin. The tumours normally cause visual and cranial nerve defects along with other endocrine symptoms.Excess in: Leads to:Corticotrophin Cushing’s DiseaseThyrotrophin (TSH) Thyrotoxicosis Gonadotrophins Precocious pubertyProlactin HyperprolactinaemiaSomatotrophin (GH) Gigantism, acromegaly

Imaging Tumours causing interference with the Hypothalamo-hypophysial axis may be

present in the hypothalamus, pituitary gland or could be hormone secreting ectopic hormones

Imaging – CT, X-ray, MRI can be used to identify Clinical symptoms such as heterozygous hemianopia may also be a sign of a

tumour in the Hypothalamo-pituitary region GH producing tumour can also produce prolactin as these secretory cells share a

developmental history.

Testing for Hyperpituitarism

Initial diagnosis may be made on the basis of signs and symptoms

A definite diagnosis needs biochemical measurement of the hormone. As hormones are secreted episodically and the normal range is broad a measurement before and after treatment is required so…

If an overactive pituitary is suspected then a suppression test is carried out – the exact opposite of a provocation test

Acromegaly may be diagnosed by measuring plasma GH before and after an oral glucose load. Shown on the right:

As can be seen in acromegaly there is no response to a normal stimulus

NB: tumours in the pituitary region can press on the optic chiasm and interfere with nerve signals. Signals from the inner retina cross here and so signals from the nasal retina are lost causing a block of peripheral vision heteronymous (bitemporal) hemianopia.

Hyperprolactinaemia

Hyperprolactinaemia is excess circulating prolactin without a physiological cause such as pregnancy or breastfeeding and is usually caused by a prolactinoma (or microadenomas less than 10mm in diameter). It is the most common type of pituitary tumour.

Symptoms:IN WOMEN

• galactorrhoea (milk production)• secondary amenorrhoea (or oligomenorrhoea) – absence or irregular periods• loss of libido• infertility

IN MEN• galactorrhoea uncommon although more so in fat men (since appropriate

steroid background usually inadequate)• loss of libido• impotence• infertility

Excess Somatotrophin

In children, excess somatotrophin results in gigantism (excess growth particularly of the bones and tissue), whereas in adults it leads to acromegaly. This is insidious (unnoticeable) in onset and the signs and symptoms take many years to manifest. If it is untreated, then patients have high morbidity and mortality rates due to the cardiovascular and respiratory complications.

Effects:INCREASED GROWTH Periosteal bone Cartilage Fibrous tissue Connective tissue Internal organs (cardiomegaly, splenomegaly, hepatomegaly)METABOLIC EFFECTS Increased plasma insulin response when eating. Increased insulin resistance and hence diabetes in 10% of patients Impaired glucose tolerance in 50% of patients. Abnormal glucose tolerance: diabetes mellitus

Clinical Manifestations:• Enlargement of supraorbital ridges and nose, hands and feet, thickening of lips

and general coarseness of features• Excessive sweating (hyperhidrosis)• Mandible grows, leading to protrusion of lower jaw (prognathism)• Carpal tunnel syndrome; joint pain.• Patients have barrel chest; curvature of spine (kyphosis)• Galactorrhoea (often in women, rare in men)• Menstrual abnormalities, decreased libido and impotence• Hypertension

Acromegaly Treatment

Name - octreotide

Usage Used as short-term treatment before pituitary surgery Used as long-term treatment in those not controlled by other means Used in treatment of other neuroendocrine tumours, e.g. carcinoid tumours

Mode of ActionOctreotide is a somatostatin analogue that works by imitating the action of somatostatin to reduce the production of somatotrophin (GH).

Side effects and Pharmacokinetics Administered subcutaneously, 3 times a day. It is a polypeptide and hence cannot be given orally. The D dimer inhibits

enzymatic breakdown which increases its half-life. The dose is adjusted according to need. It is retained in extracellular fluid when it is distributed around the body. It is metabolised by the liver and kidney and has short half life of between 2-4

hours. Its side effects include

o GI tract disturbanceso Initial reduction in insulin secretion; transient hyperglycaemiao Rarely, gallstones

Hyperprolactinaemia Treatment

Name - Bromocriptine

Usage Reduce prolactin secreting tumour size Suppression of lactation Cyclical benign breast tumours Acromegaly Parkinson’s Disease.

Mode of ActionBromocriptine is a dopamine type 2 receptor (DA2) agonist, used to decrease prolactin secretion and reduce tumour size.

Side effects and Pharmacokinetics Administered orally (1 tablet a day). It is bound to plasma protein Has a half life of 7 hrs. Metabolised by liver. Side effects include

o Nauseao Vomitingo Abdominal crampso Psychomotor excitationo Dyskinesiaso Postural hypotensiono Vasospasm in fingers and toes.

Name - Cabergoline

Usage – pituitary tumours

Mode of actionCabergoline is also a dopamine type 2 receptor (DA2) receptor agonist with the same effects a bromocriptine, but as it also has some DA1 receptor activity, the effects are less pronounced.

Side Effects and Pharmacokinetics Also administered orally 1-2 times per week. It has a long half life of 40 hours. Fewer side effects than bromocriptine